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Heart Effects of Fingolimod May Resolve Within Six Hours
ORLANDO—The first-dose cardiovascular effects of fingolimod 0.5 mg may be transient in most patients with multiple sclerosis (MS). The effects begin to resolve within six hours after administration, according to analyses of two phase III trials and interim results of a phase IV study.
The analyses, which were presented at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS, confirmed that the initiation of treatment with fingolimod is associated with a decrease in heart rate and a slowing of atrioventricular conduction, especially in the first four to six hours. Previously reported cases of bradycardia and atrioventricular block have been mostly transient and self-limited, said the investigators.
All patients who receive fingolimod “should be observed and receive hourly pulse and blood pressure measurement for at least six hours after first dose and undergo ECG predose and after the six-hour observation,” according to the drug’s current prescribing information. The label for fingolimod was revised in May 2012 following reports of sudden or unexplained deaths in the United States and Europe after the drug’s 2010 approval for relapsing forms of MS.
Fingolimod Reduced Heart Rate at Five Hours
In the phase IV EPOC (Evaluate Patient Outcomes, Safety, and Tolerability of Fingolimod) study, 783 patients in the United States and Canada were randomized 3:1 to open-label treatment with once-daily fingolimod 0.5 mg or standard-of-care disease-modifying therapy (DMT) for six months. No patients had taken fingolimod previously, and all received at least one dose of the therapy. Subjects had received continuous treatment with a single standard-of-care DMT for six months or more. Patients’ mean age was 46, and most were white (82%) and female (76%). The mean duration of their MS symptoms was 12 years.
Patients’ mean sitting heart rate decreased from 74.1 bpm at baseline to 65.6 bpm at five hours after administration of fingolimod, said Bruce L. Hughes, MD, Director of Ruan MS Center in Des Moines, Iowa, and his colleagues. Heart rate began to recover by the sixth hour.
Most patients (98.6%) were discharged at six hours after treatment. Ten subjects required extended observations after the sixth hour, and three required a second day of observation and were subsequently discharged.
Twelve patients (1.5%) had bradycardia during the first-dose observation period. Of these patients, eight were symptomatic, four were asymptomatic, and none required treatment, according to the researchers. The mean heart rate in this group decreased to 56.3 ± 8.53 bpm and ranged from 38 to 64 bpm during bradycardia events. The patients recovered to 62.6 ± 9.46 bpm, ranging from 52 to 80 bpm, after the symptoms resolved.
Nearly 18% of the patients (137 of 783) underwent ECG at six hours postdose. In 28 subjects, the second ECG differed from the baseline ECG, and the most common new findings were first-degree atrioventricular block (11 patients) and sinus bradycardia (10 patients). There were no second-degree atrioventricular blocks. Other findings included late anterior hemiblock (one patient), atrial premature complex (two patients), and biphasic T waves (one patient).
Heart-Rate Decrease Was Greater for Patients Without Cardiac Factors
The two other studies reported at the meeting also analyzed the first-dose cardiovascular effects of fingolimod 0.5 mg. The FIRST trial was a four-month, open-label, phase IIIb study of 2,417 patients with relapsing MS, and the FREEDOMS II trial was a two-year, double-blind, placebo-controlled, phase III study of 1,083 patients.
In the FIRST trial, the lowest heart rate occurred at four to five hours postdose. The mean decrease was 7.4 bpm in patients without cardiac factors and 6.5 bpm in those with cardiac factors, said the researchers. The cardiac factors included beta-blocker or calcium channel blocker use (120 patients), resting heart rate of 45 to 54 bpm, Mobitz type I second-degree atrioventricular block, positive tilt test, and recurrent symptomatic bradycardia.
Simrat Randhawa, MD, from Novartis Pharmaceuticals, and her colleagues reported that the mean decrease in heart rate was 7.2 and 7.3 bpm in patients without and with concomitant beta-blocker or calcium channel blocker use, respectively. One patient had a greater than three-second pause in screening and postdose ECG results. One patient discontinued the study drug because of second-degree atrioventricular block, the authors reported.
In the FREEDOMS II trial, the clinician-observed mean maximal decrease in heart rate was 8.5 bpm among patients who received fingolimod. The incidence of Mobitz I second-degree atrioventricular block with fingolimod was 3.7%, compared with 2.0% for placebo. In addition, 2:1 atrioventricular block occurred in 2% of patients taking fingolimod and in no control patients.
Most first-occurrence, second-degree atrioventricular blocks were observed less than six hours after the first dose, according to the researchers. No Mobitz II or third-degree atrioventricular blocks were reported in FIRST or FREEDOMS II.
It is difficult to identify which patients should receive fingolimod, but less difficult to identify patients who should not receive it, said Robert P. Lisak, MD, Professor of Neurology at Wayne State University in Detroit and President-Elect of CMSC. “But once they’re on it, and if they don’t have other contraindications, they should be OK.”
—Naseem S. Miller
IMNG Medical News
Suggested Reading
Cohen JA, Chun J. Mechanisms of fingolimod’s efficacy and adverse effects in multiple sclerosis. Ann Neurol. 2011;69(5):759-777.
Espinosa PS, Berger JR. Delayed fingolimod-associated asystole. Mult Scler. 2011;17(11):1387-1389.
Schmouder R, Hariry S, David OJ. Placebo-controlled study of the effects of fingolimod on cardiac rate and rhythm and pulmonary function in healthy volunteers. Eur J Clin Pharmacol. 2012;68(4):355-362.
ORLANDO—The first-dose cardiovascular effects of fingolimod 0.5 mg may be transient in most patients with multiple sclerosis (MS). The effects begin to resolve within six hours after administration, according to analyses of two phase III trials and interim results of a phase IV study.
The analyses, which were presented at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS, confirmed that the initiation of treatment with fingolimod is associated with a decrease in heart rate and a slowing of atrioventricular conduction, especially in the first four to six hours. Previously reported cases of bradycardia and atrioventricular block have been mostly transient and self-limited, said the investigators.
All patients who receive fingolimod “should be observed and receive hourly pulse and blood pressure measurement for at least six hours after first dose and undergo ECG predose and after the six-hour observation,” according to the drug’s current prescribing information. The label for fingolimod was revised in May 2012 following reports of sudden or unexplained deaths in the United States and Europe after the drug’s 2010 approval for relapsing forms of MS.
Fingolimod Reduced Heart Rate at Five Hours
In the phase IV EPOC (Evaluate Patient Outcomes, Safety, and Tolerability of Fingolimod) study, 783 patients in the United States and Canada were randomized 3:1 to open-label treatment with once-daily fingolimod 0.5 mg or standard-of-care disease-modifying therapy (DMT) for six months. No patients had taken fingolimod previously, and all received at least one dose of the therapy. Subjects had received continuous treatment with a single standard-of-care DMT for six months or more. Patients’ mean age was 46, and most were white (82%) and female (76%). The mean duration of their MS symptoms was 12 years.
Patients’ mean sitting heart rate decreased from 74.1 bpm at baseline to 65.6 bpm at five hours after administration of fingolimod, said Bruce L. Hughes, MD, Director of Ruan MS Center in Des Moines, Iowa, and his colleagues. Heart rate began to recover by the sixth hour.
Most patients (98.6%) were discharged at six hours after treatment. Ten subjects required extended observations after the sixth hour, and three required a second day of observation and were subsequently discharged.
Twelve patients (1.5%) had bradycardia during the first-dose observation period. Of these patients, eight were symptomatic, four were asymptomatic, and none required treatment, according to the researchers. The mean heart rate in this group decreased to 56.3 ± 8.53 bpm and ranged from 38 to 64 bpm during bradycardia events. The patients recovered to 62.6 ± 9.46 bpm, ranging from 52 to 80 bpm, after the symptoms resolved.
Nearly 18% of the patients (137 of 783) underwent ECG at six hours postdose. In 28 subjects, the second ECG differed from the baseline ECG, and the most common new findings were first-degree atrioventricular block (11 patients) and sinus bradycardia (10 patients). There were no second-degree atrioventricular blocks. Other findings included late anterior hemiblock (one patient), atrial premature complex (two patients), and biphasic T waves (one patient).
Heart-Rate Decrease Was Greater for Patients Without Cardiac Factors
The two other studies reported at the meeting also analyzed the first-dose cardiovascular effects of fingolimod 0.5 mg. The FIRST trial was a four-month, open-label, phase IIIb study of 2,417 patients with relapsing MS, and the FREEDOMS II trial was a two-year, double-blind, placebo-controlled, phase III study of 1,083 patients.
In the FIRST trial, the lowest heart rate occurred at four to five hours postdose. The mean decrease was 7.4 bpm in patients without cardiac factors and 6.5 bpm in those with cardiac factors, said the researchers. The cardiac factors included beta-blocker or calcium channel blocker use (120 patients), resting heart rate of 45 to 54 bpm, Mobitz type I second-degree atrioventricular block, positive tilt test, and recurrent symptomatic bradycardia.
Simrat Randhawa, MD, from Novartis Pharmaceuticals, and her colleagues reported that the mean decrease in heart rate was 7.2 and 7.3 bpm in patients without and with concomitant beta-blocker or calcium channel blocker use, respectively. One patient had a greater than three-second pause in screening and postdose ECG results. One patient discontinued the study drug because of second-degree atrioventricular block, the authors reported.
In the FREEDOMS II trial, the clinician-observed mean maximal decrease in heart rate was 8.5 bpm among patients who received fingolimod. The incidence of Mobitz I second-degree atrioventricular block with fingolimod was 3.7%, compared with 2.0% for placebo. In addition, 2:1 atrioventricular block occurred in 2% of patients taking fingolimod and in no control patients.
Most first-occurrence, second-degree atrioventricular blocks were observed less than six hours after the first dose, according to the researchers. No Mobitz II or third-degree atrioventricular blocks were reported in FIRST or FREEDOMS II.
It is difficult to identify which patients should receive fingolimod, but less difficult to identify patients who should not receive it, said Robert P. Lisak, MD, Professor of Neurology at Wayne State University in Detroit and President-Elect of CMSC. “But once they’re on it, and if they don’t have other contraindications, they should be OK.”
—Naseem S. Miller
IMNG Medical News
ORLANDO—The first-dose cardiovascular effects of fingolimod 0.5 mg may be transient in most patients with multiple sclerosis (MS). The effects begin to resolve within six hours after administration, according to analyses of two phase III trials and interim results of a phase IV study.
The analyses, which were presented at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS, confirmed that the initiation of treatment with fingolimod is associated with a decrease in heart rate and a slowing of atrioventricular conduction, especially in the first four to six hours. Previously reported cases of bradycardia and atrioventricular block have been mostly transient and self-limited, said the investigators.
All patients who receive fingolimod “should be observed and receive hourly pulse and blood pressure measurement for at least six hours after first dose and undergo ECG predose and after the six-hour observation,” according to the drug’s current prescribing information. The label for fingolimod was revised in May 2012 following reports of sudden or unexplained deaths in the United States and Europe after the drug’s 2010 approval for relapsing forms of MS.
Fingolimod Reduced Heart Rate at Five Hours
In the phase IV EPOC (Evaluate Patient Outcomes, Safety, and Tolerability of Fingolimod) study, 783 patients in the United States and Canada were randomized 3:1 to open-label treatment with once-daily fingolimod 0.5 mg or standard-of-care disease-modifying therapy (DMT) for six months. No patients had taken fingolimod previously, and all received at least one dose of the therapy. Subjects had received continuous treatment with a single standard-of-care DMT for six months or more. Patients’ mean age was 46, and most were white (82%) and female (76%). The mean duration of their MS symptoms was 12 years.
Patients’ mean sitting heart rate decreased from 74.1 bpm at baseline to 65.6 bpm at five hours after administration of fingolimod, said Bruce L. Hughes, MD, Director of Ruan MS Center in Des Moines, Iowa, and his colleagues. Heart rate began to recover by the sixth hour.
Most patients (98.6%) were discharged at six hours after treatment. Ten subjects required extended observations after the sixth hour, and three required a second day of observation and were subsequently discharged.
Twelve patients (1.5%) had bradycardia during the first-dose observation period. Of these patients, eight were symptomatic, four were asymptomatic, and none required treatment, according to the researchers. The mean heart rate in this group decreased to 56.3 ± 8.53 bpm and ranged from 38 to 64 bpm during bradycardia events. The patients recovered to 62.6 ± 9.46 bpm, ranging from 52 to 80 bpm, after the symptoms resolved.
Nearly 18% of the patients (137 of 783) underwent ECG at six hours postdose. In 28 subjects, the second ECG differed from the baseline ECG, and the most common new findings were first-degree atrioventricular block (11 patients) and sinus bradycardia (10 patients). There were no second-degree atrioventricular blocks. Other findings included late anterior hemiblock (one patient), atrial premature complex (two patients), and biphasic T waves (one patient).
Heart-Rate Decrease Was Greater for Patients Without Cardiac Factors
The two other studies reported at the meeting also analyzed the first-dose cardiovascular effects of fingolimod 0.5 mg. The FIRST trial was a four-month, open-label, phase IIIb study of 2,417 patients with relapsing MS, and the FREEDOMS II trial was a two-year, double-blind, placebo-controlled, phase III study of 1,083 patients.
In the FIRST trial, the lowest heart rate occurred at four to five hours postdose. The mean decrease was 7.4 bpm in patients without cardiac factors and 6.5 bpm in those with cardiac factors, said the researchers. The cardiac factors included beta-blocker or calcium channel blocker use (120 patients), resting heart rate of 45 to 54 bpm, Mobitz type I second-degree atrioventricular block, positive tilt test, and recurrent symptomatic bradycardia.
Simrat Randhawa, MD, from Novartis Pharmaceuticals, and her colleagues reported that the mean decrease in heart rate was 7.2 and 7.3 bpm in patients without and with concomitant beta-blocker or calcium channel blocker use, respectively. One patient had a greater than three-second pause in screening and postdose ECG results. One patient discontinued the study drug because of second-degree atrioventricular block, the authors reported.
In the FREEDOMS II trial, the clinician-observed mean maximal decrease in heart rate was 8.5 bpm among patients who received fingolimod. The incidence of Mobitz I second-degree atrioventricular block with fingolimod was 3.7%, compared with 2.0% for placebo. In addition, 2:1 atrioventricular block occurred in 2% of patients taking fingolimod and in no control patients.
Most first-occurrence, second-degree atrioventricular blocks were observed less than six hours after the first dose, according to the researchers. No Mobitz II or third-degree atrioventricular blocks were reported in FIRST or FREEDOMS II.
It is difficult to identify which patients should receive fingolimod, but less difficult to identify patients who should not receive it, said Robert P. Lisak, MD, Professor of Neurology at Wayne State University in Detroit and President-Elect of CMSC. “But once they’re on it, and if they don’t have other contraindications, they should be OK.”
—Naseem S. Miller
IMNG Medical News
Suggested Reading
Cohen JA, Chun J. Mechanisms of fingolimod’s efficacy and adverse effects in multiple sclerosis. Ann Neurol. 2011;69(5):759-777.
Espinosa PS, Berger JR. Delayed fingolimod-associated asystole. Mult Scler. 2011;17(11):1387-1389.
Schmouder R, Hariry S, David OJ. Placebo-controlled study of the effects of fingolimod on cardiac rate and rhythm and pulmonary function in healthy volunteers. Eur J Clin Pharmacol. 2012;68(4):355-362.
Suggested Reading
Cohen JA, Chun J. Mechanisms of fingolimod’s efficacy and adverse effects in multiple sclerosis. Ann Neurol. 2011;69(5):759-777.
Espinosa PS, Berger JR. Delayed fingolimod-associated asystole. Mult Scler. 2011;17(11):1387-1389.
Schmouder R, Hariry S, David OJ. Placebo-controlled study of the effects of fingolimod on cardiac rate and rhythm and pulmonary function in healthy volunteers. Eur J Clin Pharmacol. 2012;68(4):355-362.
Fingolimod heart effects usually resolve within 6 hours
ORLANDO – The first-dose cardiovascular effects of fingolimod 0.5 mg were transient in most patients with multiple sclerosis and began to resolve within 6 hours after administration, according to analyses of two phase III trials and interim results of a phase IV study sponsored by the drug maker.
The analyses, which were presented in two posters at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the Americas Committee for Treatment and Research in Multiple Sclerosis, confirm that the initiation of treatment with fingolimod (Gilenya) is associated with a drop in heart rate (HR) and slowing of atrioventricular conduction, especially in the first 4-6 hours. Previously reported cases of bradycardia and atrioventricular blockhave been mostly transient and self-limited, the authors noted.
Fingolimod’s current prescribing information says that "All patients should be observed and receive hourly pulse and blood pressure measurement for at least 6 hours after first dose and undergo ECG predose and after the 6-hour observation." Its label was revised in May of last year following reports of sudden or unexplained deaths in the United States and Europe after the drug’s 2010 approval for relapsing forms of MS.
In the phase IV EPOC (Evaluate Patient Outcomes, Safety, and Tolerability of Fingolimod) study, 783 patients in the United States and Canada were randomized 3:1 to open-label treatment with once-daily fingolimod 0.5 mg or standard-of-care disease-modifying therapy (DMT) for 6 months.
All patients were fingolimod naive and received at least one dose of the therapy. They had received continual treatment of a single standard-of-care DMT for 6 months or more. The patients’ mean age was 46 years, and most were white (82%) and female (76%). The mean duration of their MS symptoms was 12 years.
Lead investigator Dr. Bruce L. Hughes of Ruan Multiple Sclerosis Center, Des Moines, Iowa, and his colleagues reported that the patients’ mean sitting HR at predose assessment dropped from a mean of 74.1 beats per minute at baseline to a nadir of 65.6 bpm, 5 hours after the therapy’s administration. HR began to recover by the 6th hour.
Most patients (98.6%) were discharged at 6 hours after treatment. Ten required extended observations after the 6th hour; three required a second day of observation and were discharged.
A total of 12 patients (1.5%) had bradycardia during the first-dose observation period. Eight were symptomatic, and four were asymptomatic. None required treatment, the researchers reported. The mean HR in this group decreased to 56.3 plus or minus 8.53 bpm, ranging from 38 to 64 bpm during bradycardia events. The patients recovered to 62.6 plus or minus 9.46 bpm, ranging from 52 to 80 bpm after the symptoms resolved.
Nearly 18% of the patients (137 of 783) had electrocardiography (ECG) performed at 6 hours post dose. In 28, the ECG differed from baseline, and the most common new findings were first-degree atrioventricular block (n = 11), and sinus bradycardia (n = 10). There were no second-degree AV blocks. Other findings included late anterior hemiblock (n = 1), atrial premature complex (n = 2), and biphasic T waves (n = 1).
The two other studies reported at the meeting also analyzed the first-dose cardiovascular effects of fingolimod 0.5 mg. The FIRST trial was a 4-month, open-label, phase IIIb study of 2,417 patients with relapsing MS, and the FREEDOMS II trial was a 2-year, double-blind, placebo-controlled, phase III study of 1,083 patients.
In the FIRST trial, the nadir HR occurred 4-5 hours post dose, and the mean decrease was 7.4 in patients without cardiac factors and 6.5 bpm in those with cardiac factors, the authors reported. The cardiac factors included beta-blocker and/or calcium channel blocker use (n = 120), resting HR of 45-54 bpm, Mobitz type I second-degree atrioventricular block, positive tilt test, or recurrent symptomatic bradycardia.
Dr. Simrat Randhawa and her colleagues at Novartis Pharmaceuticals reported that the mean decrease in HR was 7.2 and 7.3 bpm in patients without and with concomitant beta-blocker and/or calcium channel blocker use, respectively. One patient had a greater than 3-second pause in both screening and post dose ECG results. One patient discontinued the study drug because of second-degree AV block, the authors reported.
In the FREEDOMS II trial, the clinician-observed mean maximal decrease in HR was 8.5 bpm in the fingolimod group. The incidence of Mobitz I second-degree AV block with fingolimod was 3.7%, compared with 2.0% in placebo, while 2:1 AV block occurred in 2% of patients taking fingolimod patients and 0% taking placebo.
Most first-occurrence second-degree AV blocks were observed less than 6 hours after the first dose, the authors reported.
There were no Mobitz II or third-degree AV blocks reported in FIRST and FREEDOMS II.
"This is a good example of ‘I can’t predict who should get fingolimod, but I can say who I should be very careful with and maybe not give [them] fingolimod and give [them] something else,’ " said Dr. Robert P. Lisak, professor of neurology at Wayne State University, Detroit, and president-elect of the CMSC. "But once they’re on it, and if they don’t have other contraindications, they should be OK." Dr. Lisak was not involved in the study.
All the studies were supported by Novartis, which markets fingolimod. Dr. Hughes and another EPOC investigator have served as a speaker and/or advisory board member or received research support from Novartis and other companies involved in MS pharmaceutical research and development. Other investigators involved in the EPOC study are employees of Novartis. Dr. Lisak has received research grants from and has been an adviser for several companies, including, Avanir, Bayer, Novartis, Questcor, and Teva.
On Twitter @NaseemSMiller
ORLANDO – The first-dose cardiovascular effects of fingolimod 0.5 mg were transient in most patients with multiple sclerosis and began to resolve within 6 hours after administration, according to analyses of two phase III trials and interim results of a phase IV study sponsored by the drug maker.
The analyses, which were presented in two posters at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the Americas Committee for Treatment and Research in Multiple Sclerosis, confirm that the initiation of treatment with fingolimod (Gilenya) is associated with a drop in heart rate (HR) and slowing of atrioventricular conduction, especially in the first 4-6 hours. Previously reported cases of bradycardia and atrioventricular blockhave been mostly transient and self-limited, the authors noted.
Fingolimod’s current prescribing information says that "All patients should be observed and receive hourly pulse and blood pressure measurement for at least 6 hours after first dose and undergo ECG predose and after the 6-hour observation." Its label was revised in May of last year following reports of sudden or unexplained deaths in the United States and Europe after the drug’s 2010 approval for relapsing forms of MS.
In the phase IV EPOC (Evaluate Patient Outcomes, Safety, and Tolerability of Fingolimod) study, 783 patients in the United States and Canada were randomized 3:1 to open-label treatment with once-daily fingolimod 0.5 mg or standard-of-care disease-modifying therapy (DMT) for 6 months.
All patients were fingolimod naive and received at least one dose of the therapy. They had received continual treatment of a single standard-of-care DMT for 6 months or more. The patients’ mean age was 46 years, and most were white (82%) and female (76%). The mean duration of their MS symptoms was 12 years.
Lead investigator Dr. Bruce L. Hughes of Ruan Multiple Sclerosis Center, Des Moines, Iowa, and his colleagues reported that the patients’ mean sitting HR at predose assessment dropped from a mean of 74.1 beats per minute at baseline to a nadir of 65.6 bpm, 5 hours after the therapy’s administration. HR began to recover by the 6th hour.
Most patients (98.6%) were discharged at 6 hours after treatment. Ten required extended observations after the 6th hour; three required a second day of observation and were discharged.
A total of 12 patients (1.5%) had bradycardia during the first-dose observation period. Eight were symptomatic, and four were asymptomatic. None required treatment, the researchers reported. The mean HR in this group decreased to 56.3 plus or minus 8.53 bpm, ranging from 38 to 64 bpm during bradycardia events. The patients recovered to 62.6 plus or minus 9.46 bpm, ranging from 52 to 80 bpm after the symptoms resolved.
Nearly 18% of the patients (137 of 783) had electrocardiography (ECG) performed at 6 hours post dose. In 28, the ECG differed from baseline, and the most common new findings were first-degree atrioventricular block (n = 11), and sinus bradycardia (n = 10). There were no second-degree AV blocks. Other findings included late anterior hemiblock (n = 1), atrial premature complex (n = 2), and biphasic T waves (n = 1).
The two other studies reported at the meeting also analyzed the first-dose cardiovascular effects of fingolimod 0.5 mg. The FIRST trial was a 4-month, open-label, phase IIIb study of 2,417 patients with relapsing MS, and the FREEDOMS II trial was a 2-year, double-blind, placebo-controlled, phase III study of 1,083 patients.
In the FIRST trial, the nadir HR occurred 4-5 hours post dose, and the mean decrease was 7.4 in patients without cardiac factors and 6.5 bpm in those with cardiac factors, the authors reported. The cardiac factors included beta-blocker and/or calcium channel blocker use (n = 120), resting HR of 45-54 bpm, Mobitz type I second-degree atrioventricular block, positive tilt test, or recurrent symptomatic bradycardia.
Dr. Simrat Randhawa and her colleagues at Novartis Pharmaceuticals reported that the mean decrease in HR was 7.2 and 7.3 bpm in patients without and with concomitant beta-blocker and/or calcium channel blocker use, respectively. One patient had a greater than 3-second pause in both screening and post dose ECG results. One patient discontinued the study drug because of second-degree AV block, the authors reported.
In the FREEDOMS II trial, the clinician-observed mean maximal decrease in HR was 8.5 bpm in the fingolimod group. The incidence of Mobitz I second-degree AV block with fingolimod was 3.7%, compared with 2.0% in placebo, while 2:1 AV block occurred in 2% of patients taking fingolimod patients and 0% taking placebo.
Most first-occurrence second-degree AV blocks were observed less than 6 hours after the first dose, the authors reported.
There were no Mobitz II or third-degree AV blocks reported in FIRST and FREEDOMS II.
"This is a good example of ‘I can’t predict who should get fingolimod, but I can say who I should be very careful with and maybe not give [them] fingolimod and give [them] something else,’ " said Dr. Robert P. Lisak, professor of neurology at Wayne State University, Detroit, and president-elect of the CMSC. "But once they’re on it, and if they don’t have other contraindications, they should be OK." Dr. Lisak was not involved in the study.
All the studies were supported by Novartis, which markets fingolimod. Dr. Hughes and another EPOC investigator have served as a speaker and/or advisory board member or received research support from Novartis and other companies involved in MS pharmaceutical research and development. Other investigators involved in the EPOC study are employees of Novartis. Dr. Lisak has received research grants from and has been an adviser for several companies, including, Avanir, Bayer, Novartis, Questcor, and Teva.
On Twitter @NaseemSMiller
ORLANDO – The first-dose cardiovascular effects of fingolimod 0.5 mg were transient in most patients with multiple sclerosis and began to resolve within 6 hours after administration, according to analyses of two phase III trials and interim results of a phase IV study sponsored by the drug maker.
The analyses, which were presented in two posters at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the Americas Committee for Treatment and Research in Multiple Sclerosis, confirm that the initiation of treatment with fingolimod (Gilenya) is associated with a drop in heart rate (HR) and slowing of atrioventricular conduction, especially in the first 4-6 hours. Previously reported cases of bradycardia and atrioventricular blockhave been mostly transient and self-limited, the authors noted.
Fingolimod’s current prescribing information says that "All patients should be observed and receive hourly pulse and blood pressure measurement for at least 6 hours after first dose and undergo ECG predose and after the 6-hour observation." Its label was revised in May of last year following reports of sudden or unexplained deaths in the United States and Europe after the drug’s 2010 approval for relapsing forms of MS.
In the phase IV EPOC (Evaluate Patient Outcomes, Safety, and Tolerability of Fingolimod) study, 783 patients in the United States and Canada were randomized 3:1 to open-label treatment with once-daily fingolimod 0.5 mg or standard-of-care disease-modifying therapy (DMT) for 6 months.
All patients were fingolimod naive and received at least one dose of the therapy. They had received continual treatment of a single standard-of-care DMT for 6 months or more. The patients’ mean age was 46 years, and most were white (82%) and female (76%). The mean duration of their MS symptoms was 12 years.
Lead investigator Dr. Bruce L. Hughes of Ruan Multiple Sclerosis Center, Des Moines, Iowa, and his colleagues reported that the patients’ mean sitting HR at predose assessment dropped from a mean of 74.1 beats per minute at baseline to a nadir of 65.6 bpm, 5 hours after the therapy’s administration. HR began to recover by the 6th hour.
Most patients (98.6%) were discharged at 6 hours after treatment. Ten required extended observations after the 6th hour; three required a second day of observation and were discharged.
A total of 12 patients (1.5%) had bradycardia during the first-dose observation period. Eight were symptomatic, and four were asymptomatic. None required treatment, the researchers reported. The mean HR in this group decreased to 56.3 plus or minus 8.53 bpm, ranging from 38 to 64 bpm during bradycardia events. The patients recovered to 62.6 plus or minus 9.46 bpm, ranging from 52 to 80 bpm after the symptoms resolved.
Nearly 18% of the patients (137 of 783) had electrocardiography (ECG) performed at 6 hours post dose. In 28, the ECG differed from baseline, and the most common new findings were first-degree atrioventricular block (n = 11), and sinus bradycardia (n = 10). There were no second-degree AV blocks. Other findings included late anterior hemiblock (n = 1), atrial premature complex (n = 2), and biphasic T waves (n = 1).
The two other studies reported at the meeting also analyzed the first-dose cardiovascular effects of fingolimod 0.5 mg. The FIRST trial was a 4-month, open-label, phase IIIb study of 2,417 patients with relapsing MS, and the FREEDOMS II trial was a 2-year, double-blind, placebo-controlled, phase III study of 1,083 patients.
In the FIRST trial, the nadir HR occurred 4-5 hours post dose, and the mean decrease was 7.4 in patients without cardiac factors and 6.5 bpm in those with cardiac factors, the authors reported. The cardiac factors included beta-blocker and/or calcium channel blocker use (n = 120), resting HR of 45-54 bpm, Mobitz type I second-degree atrioventricular block, positive tilt test, or recurrent symptomatic bradycardia.
Dr. Simrat Randhawa and her colleagues at Novartis Pharmaceuticals reported that the mean decrease in HR was 7.2 and 7.3 bpm in patients without and with concomitant beta-blocker and/or calcium channel blocker use, respectively. One patient had a greater than 3-second pause in both screening and post dose ECG results. One patient discontinued the study drug because of second-degree AV block, the authors reported.
In the FREEDOMS II trial, the clinician-observed mean maximal decrease in HR was 8.5 bpm in the fingolimod group. The incidence of Mobitz I second-degree AV block with fingolimod was 3.7%, compared with 2.0% in placebo, while 2:1 AV block occurred in 2% of patients taking fingolimod patients and 0% taking placebo.
Most first-occurrence second-degree AV blocks were observed less than 6 hours after the first dose, the authors reported.
There were no Mobitz II or third-degree AV blocks reported in FIRST and FREEDOMS II.
"This is a good example of ‘I can’t predict who should get fingolimod, but I can say who I should be very careful with and maybe not give [them] fingolimod and give [them] something else,’ " said Dr. Robert P. Lisak, professor of neurology at Wayne State University, Detroit, and president-elect of the CMSC. "But once they’re on it, and if they don’t have other contraindications, they should be OK." Dr. Lisak was not involved in the study.
All the studies were supported by Novartis, which markets fingolimod. Dr. Hughes and another EPOC investigator have served as a speaker and/or advisory board member or received research support from Novartis and other companies involved in MS pharmaceutical research and development. Other investigators involved in the EPOC study are employees of Novartis. Dr. Lisak has received research grants from and has been an adviser for several companies, including, Avanir, Bayer, Novartis, Questcor, and Teva.
On Twitter @NaseemSMiller
AT THE CMSC/ACTRMS ANNUAL MEETING
Major finding: Patients’ mean sitting heart rate at predose assessment dropped from a mean of 74.1 bpm at baseline to a nadir of 65.6 bpm 5 hours after the therapy’s administration. HR began to recover by the 6th hour.
Data source: Analysis of two phase III trials, FIRST and FREEDOMS II, and the interim results of a phase IV study, EPOC.
Disclosures: All the studies were supported by Novartis, which markets fingolimod. Dr. Hughes and another EPOC investigator have served as a speaker and/or advisory board member or received research support from Novartis and other companies involved in MS pharmaceuticals research and development. Other investigators involved in the EPOC study report are employees of Novartis. Dr. Lisak has received research grants from and has been an adviser for several companies, including, Avanir, Bayer, Novartis, Questcor, and Teva.
Recommendations Outline How to Improve Dimethyl Fumarate Tolerability in MS
ORLANDO—The flushing frequently reported in conjunction with oral dimethyl fumarate therapy for relapsing forms of multiple sclerosis (MS) is greatly reduced by aspirin pretreatment, J. Theodore Phillips, MD, PhD, reported at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS.
In contrast, slowed titration of dimethyl fumarate does not diminish the gastrointestinal adverse effects, which are common during the first two months of therapy, noted Dr. Phillips, Research Investigator at the MS Research Program, Baylor Institute for Immunology Research in Dallas.
Dr. Phillips was part of a consensus panel that presented recommendations for maximizing the tolerability of dimethyl fumarate, which was approved earlier this year as the third oral agent for the treatment of MS.
In an interview, Dr. Phillips said that the recommendations are largely based on expert opinion rather than on rigorous, evidence-based guidelines. After the pivotal phase III DEFINE and CONFIRM clinical trials were completed, he and four other study leaders decided to ask the investigators who had enrolled at least 10 patients in the trials how they had managed flushing and gastrointestinal upset problems. The flushing and gastrointestinal side effects were reported by 36% and 42%, respectively, of study patients randomized to the drug. The incidence decreased after the first month. These side effects were generally rated by investigators as mild to moderate in nature. Flushing resulted in study dropout of 2.5% of patients, and 4.3% discontinued because of gastrointestinal adverse events.
Thirty of the 84 invited clinical investigators completed the questionnaire. Investigators at Biogen Idec conducted their own randomized, double-blind, phase IIIb study in 172 healthy volunteers, the results of which have been incorporated into the panel’s recommendations. Participants in the eight-week trial were randomized to one of four treatment arms: dimethyl fumarate titrated in standard fashion for one week plus 325 mg of non–enteric-coated aspirin taken 30 minutes beforehand during weeks 1 to 4, replaced by aspirin placebo in weeks 5 to 8; dimethyl fumarate plus aspirin placebo during weeks 1 to 4; dimethyl fumarate slow-titrated during the course of three weeks; and double placebo.
Roughly 80% of subjects who received dimethyl fumarate without aspirin experienced flushing events self-assessed as mild to moderate. Although participants were taking both dimethyl fumarate and aspirin, their flushing frequency and severity were similar to those of participants receiving double placebo. Slow titration of dimethyl fumarate had no impact on gastrointestinal symptoms or flushing frequency or severity.
The panel’s recommendations for managing nausea or vomiting or abdominal pain were to advise taking the drug with food and consider prescribing a proton pump inhibitor or H2 receptor antagonist. Metoclopramide or domperidone is another recommended option for those with nausea or vomiting. For patients who experience medication-related diarrhea, the panel advised loperamide or other standard antidiarrheal agents.
“Vasocutaneous flushing and gastrointestinal upset in association with dosing of [dimethyl fumarate] could for obvious reasons affect a person’s enthusiasm for going on,” Dr. Phillips commented. “The main thing is for the physician to set expectations by acknowledging up front these issues as part of the risk–benefit discussion prior to initiating the drug. Tell the patient that if those side effects were to happen, we’ve got game plans to deal with them.”
—Bruce Jancin
IMNG Medical News
Suggested Reading
Oh J, O’Connor PW. Safety, tolerability, and efficacy of oral therapies for relapsing-remitting multiple sclerosis. CNS Drugs. 2013;27(8):591-609.
ORLANDO—The flushing frequently reported in conjunction with oral dimethyl fumarate therapy for relapsing forms of multiple sclerosis (MS) is greatly reduced by aspirin pretreatment, J. Theodore Phillips, MD, PhD, reported at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS.
In contrast, slowed titration of dimethyl fumarate does not diminish the gastrointestinal adverse effects, which are common during the first two months of therapy, noted Dr. Phillips, Research Investigator at the MS Research Program, Baylor Institute for Immunology Research in Dallas.
Dr. Phillips was part of a consensus panel that presented recommendations for maximizing the tolerability of dimethyl fumarate, which was approved earlier this year as the third oral agent for the treatment of MS.
In an interview, Dr. Phillips said that the recommendations are largely based on expert opinion rather than on rigorous, evidence-based guidelines. After the pivotal phase III DEFINE and CONFIRM clinical trials were completed, he and four other study leaders decided to ask the investigators who had enrolled at least 10 patients in the trials how they had managed flushing and gastrointestinal upset problems. The flushing and gastrointestinal side effects were reported by 36% and 42%, respectively, of study patients randomized to the drug. The incidence decreased after the first month. These side effects were generally rated by investigators as mild to moderate in nature. Flushing resulted in study dropout of 2.5% of patients, and 4.3% discontinued because of gastrointestinal adverse events.
Thirty of the 84 invited clinical investigators completed the questionnaire. Investigators at Biogen Idec conducted their own randomized, double-blind, phase IIIb study in 172 healthy volunteers, the results of which have been incorporated into the panel’s recommendations. Participants in the eight-week trial were randomized to one of four treatment arms: dimethyl fumarate titrated in standard fashion for one week plus 325 mg of non–enteric-coated aspirin taken 30 minutes beforehand during weeks 1 to 4, replaced by aspirin placebo in weeks 5 to 8; dimethyl fumarate plus aspirin placebo during weeks 1 to 4; dimethyl fumarate slow-titrated during the course of three weeks; and double placebo.
Roughly 80% of subjects who received dimethyl fumarate without aspirin experienced flushing events self-assessed as mild to moderate. Although participants were taking both dimethyl fumarate and aspirin, their flushing frequency and severity were similar to those of participants receiving double placebo. Slow titration of dimethyl fumarate had no impact on gastrointestinal symptoms or flushing frequency or severity.
The panel’s recommendations for managing nausea or vomiting or abdominal pain were to advise taking the drug with food and consider prescribing a proton pump inhibitor or H2 receptor antagonist. Metoclopramide or domperidone is another recommended option for those with nausea or vomiting. For patients who experience medication-related diarrhea, the panel advised loperamide or other standard antidiarrheal agents.
“Vasocutaneous flushing and gastrointestinal upset in association with dosing of [dimethyl fumarate] could for obvious reasons affect a person’s enthusiasm for going on,” Dr. Phillips commented. “The main thing is for the physician to set expectations by acknowledging up front these issues as part of the risk–benefit discussion prior to initiating the drug. Tell the patient that if those side effects were to happen, we’ve got game plans to deal with them.”
—Bruce Jancin
IMNG Medical News
ORLANDO—The flushing frequently reported in conjunction with oral dimethyl fumarate therapy for relapsing forms of multiple sclerosis (MS) is greatly reduced by aspirin pretreatment, J. Theodore Phillips, MD, PhD, reported at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS.
In contrast, slowed titration of dimethyl fumarate does not diminish the gastrointestinal adverse effects, which are common during the first two months of therapy, noted Dr. Phillips, Research Investigator at the MS Research Program, Baylor Institute for Immunology Research in Dallas.
Dr. Phillips was part of a consensus panel that presented recommendations for maximizing the tolerability of dimethyl fumarate, which was approved earlier this year as the third oral agent for the treatment of MS.
In an interview, Dr. Phillips said that the recommendations are largely based on expert opinion rather than on rigorous, evidence-based guidelines. After the pivotal phase III DEFINE and CONFIRM clinical trials were completed, he and four other study leaders decided to ask the investigators who had enrolled at least 10 patients in the trials how they had managed flushing and gastrointestinal upset problems. The flushing and gastrointestinal side effects were reported by 36% and 42%, respectively, of study patients randomized to the drug. The incidence decreased after the first month. These side effects were generally rated by investigators as mild to moderate in nature. Flushing resulted in study dropout of 2.5% of patients, and 4.3% discontinued because of gastrointestinal adverse events.
Thirty of the 84 invited clinical investigators completed the questionnaire. Investigators at Biogen Idec conducted their own randomized, double-blind, phase IIIb study in 172 healthy volunteers, the results of which have been incorporated into the panel’s recommendations. Participants in the eight-week trial were randomized to one of four treatment arms: dimethyl fumarate titrated in standard fashion for one week plus 325 mg of non–enteric-coated aspirin taken 30 minutes beforehand during weeks 1 to 4, replaced by aspirin placebo in weeks 5 to 8; dimethyl fumarate plus aspirin placebo during weeks 1 to 4; dimethyl fumarate slow-titrated during the course of three weeks; and double placebo.
Roughly 80% of subjects who received dimethyl fumarate without aspirin experienced flushing events self-assessed as mild to moderate. Although participants were taking both dimethyl fumarate and aspirin, their flushing frequency and severity were similar to those of participants receiving double placebo. Slow titration of dimethyl fumarate had no impact on gastrointestinal symptoms or flushing frequency or severity.
The panel’s recommendations for managing nausea or vomiting or abdominal pain were to advise taking the drug with food and consider prescribing a proton pump inhibitor or H2 receptor antagonist. Metoclopramide or domperidone is another recommended option for those with nausea or vomiting. For patients who experience medication-related diarrhea, the panel advised loperamide or other standard antidiarrheal agents.
“Vasocutaneous flushing and gastrointestinal upset in association with dosing of [dimethyl fumarate] could for obvious reasons affect a person’s enthusiasm for going on,” Dr. Phillips commented. “The main thing is for the physician to set expectations by acknowledging up front these issues as part of the risk–benefit discussion prior to initiating the drug. Tell the patient that if those side effects were to happen, we’ve got game plans to deal with them.”
—Bruce Jancin
IMNG Medical News
Suggested Reading
Oh J, O’Connor PW. Safety, tolerability, and efficacy of oral therapies for relapsing-remitting multiple sclerosis. CNS Drugs. 2013;27(8):591-609.
Suggested Reading
Oh J, O’Connor PW. Safety, tolerability, and efficacy of oral therapies for relapsing-remitting multiple sclerosis. CNS Drugs. 2013;27(8):591-609.
New and Noteworthy Information—August 2013
Patients with Alzheimer’s disease are less likely to have cancer, and patients with cancer are less likely to have Alzheimer’s disease, according to data published online ahead of print July 10 in Neurology. Researchers conducted a cohort study of more than one million people in northern Italy. They derived cancer incidence using the local health authority’s tumor registry and calculated the incidence of Alzheimer’s dementia from registries of drug prescriptions, hospitalizations, and payment exemptions. The risk of cancer in patients with Alzheimer’s dementia was reduced by 50%, and the risk of Alzheimer’s dementia in patients with cancer was reduced by 35%. The investigators observed this relationship in almost all subgroup analyses, suggesting that anticipated potential confounding factors did not significantly influence the results.
Children exposed to antiepileptic drugs in utero may have an increased risk of adverse development within their first three years of life, according to research published online ahead of print July 19 in Epilepsia. From mid-1999 through December 2008, researchers followed children born to mothers who had been recruited at 13 to 17 weeks of pregnancy. Mothers reported their children’s motor development, language, social skills, and autistic traits at 18 months and 36 months. A total of 333 children were exposed to antiepileptic drugs in utero. At 18 months, exposed children had an increased risk of abnormal scores for gross motor skills and autistic traits, compared with nonexposed children. At 36 months, exposed children had an increased risk of abnormal scores for gross motor skills, sentence skills, and autistic traits.
The spatial pattern of amyloid deposition may be related to cognitive performance, according to a study published online ahead of print July 15 in Neurobiology of Aging. Researchers examined the spatial patterns of amyloid deposition throughout the brain using Pittsburgh Compound Blue PET data from the Baltimore Longitudinal Study of Aging. The group approximated spatial patterns of the temporal progression of amyloid plaque deposition from cross-sectional data. Results were consistent with patterns of progression known from autopsy studies. When the investigators categorized participants into subgroups based on longitudinal change in memory performance, they found significantly different spatial patterns of the estimated progression of amyloid deposition between these subgroups. This finding may affect the use of amyloid imaging as a biomarker in research and clinical applications, said the researchers.
A low frequency of physical activity may be associated with an increased risk of stroke, according to data published online ahead of print July 18 in Stroke. Researchers analyzed data for 27,348 participants in the Reasons for Geographic And Racial Differences in Stroke study who had no prior diagnosis of stroke. Participants reported their frequency of moderate-to-vigorous physical activity at baseline according to three categories. Physical inactivity was reported by 33% of participants and was associated with a 20% higher risk of stroke. Adjustment for demographics and socioeconomic factors did not affect the risk, but further adjustment for traditional stroke risk factors completely attenuated the risk. Effects of physical activity are likely to be mediated through the reduction of traditional risk factors, said the researchers.
FTY-720, an immunomodulator for treating multiple sclerosis, may alleviate existing cardiac hypertrophy, according to research published in the July 1 issue of Circulation: Heart Failure. Investigators subjected male C57/Bl6 mice to transverse aortic constriction (TAC) for one week. The researchers treated the mice with FTY-720 for two subsequent weeks while continuing to subject them to TAC. Mice treated with FTY-720 had significantly reduced ventricular mass, ameliorated fibrosis, and improved cardiac performance, compared with mice that received vehicle. Mechanistic studies suggested that FTY-720 appreciably inhibited nuclear factor of activated T-cells activity. In addition, pertussis toxin (Gi-coupled receptor inhibitor) substantially blocked the antihypertrophic effect of FTY-720 in primary rat and human cardiomyocytes. FTY-720 or its analogs could be a promising approach for treating hypertrophic heart disease, said the investigators.
For patients with cardiac arrest who require vasopressors, a combination of vasopressin, epinephrine, and methylprednisolone during cardiopulmonary resuscitation (CPR) and stress-dose hydrocortisone in postresuscitation shock may improve survival to hospital discharge and result in favorable neurologic status, according to data published in the July 17 JAMA. Researchers studied 268 consecutive patients with cardiac arrest requiring epinephrine. Patients received vasopressin plus epinephrine or saline placebo plus epinephrine for the first five CPR cycles after randomization, followed by additional epinephrine if needed. During the first CPR cycle after randomization, patients in the intervention group received methylprednisolone, and patients in the control group received saline placebo. Patients in the treatment arm had higher probability for return of spontaneous circulation of 20 minutes or longer and survival to hospital discharge with cerebral performance category score of 1 or 2.
Chinese people may have a higher risk of stroke than Caucasians, according to research published in the July 16 Neurology. Investigators analyzed studies conducted since 1990 in Chinese populations of first-ever stroke incidence and pathologic types and subtypes of stroke. The team examined hospital- and community-based studies. They also examined community-based stroke studies in Caucasian populations. Age-standardized, annual, first-ever stroke incidence in community-based studies was higher among Chinese than among Caucasian populations. Intracerebral hemorrhage accounted for a larger, more variable proportion of strokes in China than in Taiwan, in Chinese community-based than in hospital-based studies, and in community-based Chinese than in Caucasian studies. The overall proportion of lacunar ischemic stroke was higher in Chinese than in Caucasian populations, but variable study methodologies precluded reliable comparisons.
Narcolepsy in humans may be triggered partly by a proliferation of cells containing histamine, according to data published online ahead of print July 2 in Annals of Neurology. Investigators used immunohistochemistry for histidine decarboxylase (HDC) and quantitative microscopy to detect histamine cells in patients with narcolepsy, Hcrt receptor-2 mutant dogs, and three mouse narcolepsy models. The researchers found an average 64% increase in the number of histamine neurons in human narcolepsy with cataplexy, with no overlap between patients with narcolepsy and controls. The investigators did not observe altered numbers of HDC cells in any of the animal models of narcolepsy, however. The increased histamine cell numbers observed in human narcolepsy may be related to the process causing the human disorder, said the study authors.
Epilepsy may be associated with an early onset of cognitive decline, according to data published online ahead of print on July 8 in JAMA Neurology. Investigators conducted a retrospective observational study of patients at a memory and aging center from 2007 to 2012. Twelve participants had amnestic mild cognitive impairment (aMCI) plus epilepsy, 35 had Alzheimer’s disease plus epilepsy, and seven had Alzheimer’s disease plus subclinical epileptiform activity. Patients with aMCI and epilepsy presented with symptoms of cognitive decline 6.8 years earlier than patients with aMCI who did not have epilepsy. Patients with Alzheimer’s disease who had epilepsy presented with cognitive decline 5.5 years earlier than patients with Alzheimer’s disease who did not have epilepsy. Patients with Alzheimer’s disease and subclinical epileptiform activity also had an early onset of cognitive decline.
Globus pallidus interna (GPi) deep brain stimulation (DBS) may be an effective therapy for DYT1-associated torsion dystonia, according to a study published in the July issue of Neurosurgery. Researchers conducted a retrospective chart review of 47 consecutive patients with DYT1 who were treated by a single surgical team during a 10-year period and followed for up to 96 months. Symptom severity was quantified with the Burke–Fahn–Marsden Dystonia Rating Scale. Motor symptom severity was reduced to less than 20% of baseline after two years of DBS therapy. Disability scores were reduced to less than 30% of baseline. Symptomatic improvement was sustained throughout follow-up. Sixty-one percent of patients had discontinued all dystonia-related medications at their last follow-up. Ninety-one percent had discontinued at least one class of medication.
Concurrent cerebrovascular disease is a common neuropathologic finding in older individuals with dementia, according to an article published online ahead of print July 10 in Brain. Cerebrovascular disease, vascular pathology, and vascular risk factors were studied in 5,715 cases from the National Alzheimer’s Coordinating Centre database who had a single neurodegenerative disease diagnosis based on a neuropathologic examination with or without cerebrovascular disease. After controlling for age and gender, the researchers found a lower prevalence of coincident cerebrovascular disease among patients with α-synucleinopathies, frontotemporal lobar degeneration due to tau and TAR DNA-binding protein 43, and prion disease than among patients with Alzheimer’s disease. This result was more significant in younger patients. Data suggest that these disorders should be targeted by treatments for cerebrovascular disease, according to the researchers.
Athletes who do not get enough sleep the night before undergoing baseline concussion testing may not perform as well as they expect, according to research presented at the 2013 Annual Meeting of the American Orthopaedic Society for Sports Medicine in Chicago. Researchers reviewed 3,686 nonconcussed athletes (1,315 female) with baseline symptom and ImPACT neurocognitive scores. Individuals reported their previous night’s sleep duration as fewer than seven hours, seven to nine hours, or more than nine hours. The study authors observed significant differences in reaction time, verbal memory, and visual memory in the group that had slept less than seven hours. Visual-motor speed scores did not seem to be affected. Significant differences in the total number of reported symptoms were associated with sleeping fewer than seven hours.
Continuation of lipophilic statin therapy may be associated with a decreased risk of Parkinson’s disease, compared with discontinuation, according to research published online ahead of print July 24 in Neurology. Between 2001 and 2008, investigators recruited participants without Parkinson’s disease who had initiated statin therapy. Among 43,810 subjects, the incidence rate for Parkinson’s disease was 1.68 and 3.52 per 1,000,000 person-days for lipophilic and hydrophilic statins, respectively. Continuation of lipophilic statins was associated with a decreased risk of Parkinson’s disease, compared with statin discontinuation. No association between hydrophilic statins and occurrence of Parkinson’s disease was observed. Among lipophilic statins, a significant association was observed for simvastatin and atorvastatin, especially in females. Long-term use of lipophilic or hydrophilic statins was not significantly associated with Parkinson’s disease.
—Erik Greb
Senior Associate Editor
Patients with Alzheimer’s disease are less likely to have cancer, and patients with cancer are less likely to have Alzheimer’s disease, according to data published online ahead of print July 10 in Neurology. Researchers conducted a cohort study of more than one million people in northern Italy. They derived cancer incidence using the local health authority’s tumor registry and calculated the incidence of Alzheimer’s dementia from registries of drug prescriptions, hospitalizations, and payment exemptions. The risk of cancer in patients with Alzheimer’s dementia was reduced by 50%, and the risk of Alzheimer’s dementia in patients with cancer was reduced by 35%. The investigators observed this relationship in almost all subgroup analyses, suggesting that anticipated potential confounding factors did not significantly influence the results.
Children exposed to antiepileptic drugs in utero may have an increased risk of adverse development within their first three years of life, according to research published online ahead of print July 19 in Epilepsia. From mid-1999 through December 2008, researchers followed children born to mothers who had been recruited at 13 to 17 weeks of pregnancy. Mothers reported their children’s motor development, language, social skills, and autistic traits at 18 months and 36 months. A total of 333 children were exposed to antiepileptic drugs in utero. At 18 months, exposed children had an increased risk of abnormal scores for gross motor skills and autistic traits, compared with nonexposed children. At 36 months, exposed children had an increased risk of abnormal scores for gross motor skills, sentence skills, and autistic traits.
The spatial pattern of amyloid deposition may be related to cognitive performance, according to a study published online ahead of print July 15 in Neurobiology of Aging. Researchers examined the spatial patterns of amyloid deposition throughout the brain using Pittsburgh Compound Blue PET data from the Baltimore Longitudinal Study of Aging. The group approximated spatial patterns of the temporal progression of amyloid plaque deposition from cross-sectional data. Results were consistent with patterns of progression known from autopsy studies. When the investigators categorized participants into subgroups based on longitudinal change in memory performance, they found significantly different spatial patterns of the estimated progression of amyloid deposition between these subgroups. This finding may affect the use of amyloid imaging as a biomarker in research and clinical applications, said the researchers.
A low frequency of physical activity may be associated with an increased risk of stroke, according to data published online ahead of print July 18 in Stroke. Researchers analyzed data for 27,348 participants in the Reasons for Geographic And Racial Differences in Stroke study who had no prior diagnosis of stroke. Participants reported their frequency of moderate-to-vigorous physical activity at baseline according to three categories. Physical inactivity was reported by 33% of participants and was associated with a 20% higher risk of stroke. Adjustment for demographics and socioeconomic factors did not affect the risk, but further adjustment for traditional stroke risk factors completely attenuated the risk. Effects of physical activity are likely to be mediated through the reduction of traditional risk factors, said the researchers.
FTY-720, an immunomodulator for treating multiple sclerosis, may alleviate existing cardiac hypertrophy, according to research published in the July 1 issue of Circulation: Heart Failure. Investigators subjected male C57/Bl6 mice to transverse aortic constriction (TAC) for one week. The researchers treated the mice with FTY-720 for two subsequent weeks while continuing to subject them to TAC. Mice treated with FTY-720 had significantly reduced ventricular mass, ameliorated fibrosis, and improved cardiac performance, compared with mice that received vehicle. Mechanistic studies suggested that FTY-720 appreciably inhibited nuclear factor of activated T-cells activity. In addition, pertussis toxin (Gi-coupled receptor inhibitor) substantially blocked the antihypertrophic effect of FTY-720 in primary rat and human cardiomyocytes. FTY-720 or its analogs could be a promising approach for treating hypertrophic heart disease, said the investigators.
For patients with cardiac arrest who require vasopressors, a combination of vasopressin, epinephrine, and methylprednisolone during cardiopulmonary resuscitation (CPR) and stress-dose hydrocortisone in postresuscitation shock may improve survival to hospital discharge and result in favorable neurologic status, according to data published in the July 17 JAMA. Researchers studied 268 consecutive patients with cardiac arrest requiring epinephrine. Patients received vasopressin plus epinephrine or saline placebo plus epinephrine for the first five CPR cycles after randomization, followed by additional epinephrine if needed. During the first CPR cycle after randomization, patients in the intervention group received methylprednisolone, and patients in the control group received saline placebo. Patients in the treatment arm had higher probability for return of spontaneous circulation of 20 minutes or longer and survival to hospital discharge with cerebral performance category score of 1 or 2.
Chinese people may have a higher risk of stroke than Caucasians, according to research published in the July 16 Neurology. Investigators analyzed studies conducted since 1990 in Chinese populations of first-ever stroke incidence and pathologic types and subtypes of stroke. The team examined hospital- and community-based studies. They also examined community-based stroke studies in Caucasian populations. Age-standardized, annual, first-ever stroke incidence in community-based studies was higher among Chinese than among Caucasian populations. Intracerebral hemorrhage accounted for a larger, more variable proportion of strokes in China than in Taiwan, in Chinese community-based than in hospital-based studies, and in community-based Chinese than in Caucasian studies. The overall proportion of lacunar ischemic stroke was higher in Chinese than in Caucasian populations, but variable study methodologies precluded reliable comparisons.
Narcolepsy in humans may be triggered partly by a proliferation of cells containing histamine, according to data published online ahead of print July 2 in Annals of Neurology. Investigators used immunohistochemistry for histidine decarboxylase (HDC) and quantitative microscopy to detect histamine cells in patients with narcolepsy, Hcrt receptor-2 mutant dogs, and three mouse narcolepsy models. The researchers found an average 64% increase in the number of histamine neurons in human narcolepsy with cataplexy, with no overlap between patients with narcolepsy and controls. The investigators did not observe altered numbers of HDC cells in any of the animal models of narcolepsy, however. The increased histamine cell numbers observed in human narcolepsy may be related to the process causing the human disorder, said the study authors.
Epilepsy may be associated with an early onset of cognitive decline, according to data published online ahead of print on July 8 in JAMA Neurology. Investigators conducted a retrospective observational study of patients at a memory and aging center from 2007 to 2012. Twelve participants had amnestic mild cognitive impairment (aMCI) plus epilepsy, 35 had Alzheimer’s disease plus epilepsy, and seven had Alzheimer’s disease plus subclinical epileptiform activity. Patients with aMCI and epilepsy presented with symptoms of cognitive decline 6.8 years earlier than patients with aMCI who did not have epilepsy. Patients with Alzheimer’s disease who had epilepsy presented with cognitive decline 5.5 years earlier than patients with Alzheimer’s disease who did not have epilepsy. Patients with Alzheimer’s disease and subclinical epileptiform activity also had an early onset of cognitive decline.
Globus pallidus interna (GPi) deep brain stimulation (DBS) may be an effective therapy for DYT1-associated torsion dystonia, according to a study published in the July issue of Neurosurgery. Researchers conducted a retrospective chart review of 47 consecutive patients with DYT1 who were treated by a single surgical team during a 10-year period and followed for up to 96 months. Symptom severity was quantified with the Burke–Fahn–Marsden Dystonia Rating Scale. Motor symptom severity was reduced to less than 20% of baseline after two years of DBS therapy. Disability scores were reduced to less than 30% of baseline. Symptomatic improvement was sustained throughout follow-up. Sixty-one percent of patients had discontinued all dystonia-related medications at their last follow-up. Ninety-one percent had discontinued at least one class of medication.
Concurrent cerebrovascular disease is a common neuropathologic finding in older individuals with dementia, according to an article published online ahead of print July 10 in Brain. Cerebrovascular disease, vascular pathology, and vascular risk factors were studied in 5,715 cases from the National Alzheimer’s Coordinating Centre database who had a single neurodegenerative disease diagnosis based on a neuropathologic examination with or without cerebrovascular disease. After controlling for age and gender, the researchers found a lower prevalence of coincident cerebrovascular disease among patients with α-synucleinopathies, frontotemporal lobar degeneration due to tau and TAR DNA-binding protein 43, and prion disease than among patients with Alzheimer’s disease. This result was more significant in younger patients. Data suggest that these disorders should be targeted by treatments for cerebrovascular disease, according to the researchers.
Athletes who do not get enough sleep the night before undergoing baseline concussion testing may not perform as well as they expect, according to research presented at the 2013 Annual Meeting of the American Orthopaedic Society for Sports Medicine in Chicago. Researchers reviewed 3,686 nonconcussed athletes (1,315 female) with baseline symptom and ImPACT neurocognitive scores. Individuals reported their previous night’s sleep duration as fewer than seven hours, seven to nine hours, or more than nine hours. The study authors observed significant differences in reaction time, verbal memory, and visual memory in the group that had slept less than seven hours. Visual-motor speed scores did not seem to be affected. Significant differences in the total number of reported symptoms were associated with sleeping fewer than seven hours.
Continuation of lipophilic statin therapy may be associated with a decreased risk of Parkinson’s disease, compared with discontinuation, according to research published online ahead of print July 24 in Neurology. Between 2001 and 2008, investigators recruited participants without Parkinson’s disease who had initiated statin therapy. Among 43,810 subjects, the incidence rate for Parkinson’s disease was 1.68 and 3.52 per 1,000,000 person-days for lipophilic and hydrophilic statins, respectively. Continuation of lipophilic statins was associated with a decreased risk of Parkinson’s disease, compared with statin discontinuation. No association between hydrophilic statins and occurrence of Parkinson’s disease was observed. Among lipophilic statins, a significant association was observed for simvastatin and atorvastatin, especially in females. Long-term use of lipophilic or hydrophilic statins was not significantly associated with Parkinson’s disease.
—Erik Greb
Senior Associate Editor
Patients with Alzheimer’s disease are less likely to have cancer, and patients with cancer are less likely to have Alzheimer’s disease, according to data published online ahead of print July 10 in Neurology. Researchers conducted a cohort study of more than one million people in northern Italy. They derived cancer incidence using the local health authority’s tumor registry and calculated the incidence of Alzheimer’s dementia from registries of drug prescriptions, hospitalizations, and payment exemptions. The risk of cancer in patients with Alzheimer’s dementia was reduced by 50%, and the risk of Alzheimer’s dementia in patients with cancer was reduced by 35%. The investigators observed this relationship in almost all subgroup analyses, suggesting that anticipated potential confounding factors did not significantly influence the results.
Children exposed to antiepileptic drugs in utero may have an increased risk of adverse development within their first three years of life, according to research published online ahead of print July 19 in Epilepsia. From mid-1999 through December 2008, researchers followed children born to mothers who had been recruited at 13 to 17 weeks of pregnancy. Mothers reported their children’s motor development, language, social skills, and autistic traits at 18 months and 36 months. A total of 333 children were exposed to antiepileptic drugs in utero. At 18 months, exposed children had an increased risk of abnormal scores for gross motor skills and autistic traits, compared with nonexposed children. At 36 months, exposed children had an increased risk of abnormal scores for gross motor skills, sentence skills, and autistic traits.
The spatial pattern of amyloid deposition may be related to cognitive performance, according to a study published online ahead of print July 15 in Neurobiology of Aging. Researchers examined the spatial patterns of amyloid deposition throughout the brain using Pittsburgh Compound Blue PET data from the Baltimore Longitudinal Study of Aging. The group approximated spatial patterns of the temporal progression of amyloid plaque deposition from cross-sectional data. Results were consistent with patterns of progression known from autopsy studies. When the investigators categorized participants into subgroups based on longitudinal change in memory performance, they found significantly different spatial patterns of the estimated progression of amyloid deposition between these subgroups. This finding may affect the use of amyloid imaging as a biomarker in research and clinical applications, said the researchers.
A low frequency of physical activity may be associated with an increased risk of stroke, according to data published online ahead of print July 18 in Stroke. Researchers analyzed data for 27,348 participants in the Reasons for Geographic And Racial Differences in Stroke study who had no prior diagnosis of stroke. Participants reported their frequency of moderate-to-vigorous physical activity at baseline according to three categories. Physical inactivity was reported by 33% of participants and was associated with a 20% higher risk of stroke. Adjustment for demographics and socioeconomic factors did not affect the risk, but further adjustment for traditional stroke risk factors completely attenuated the risk. Effects of physical activity are likely to be mediated through the reduction of traditional risk factors, said the researchers.
FTY-720, an immunomodulator for treating multiple sclerosis, may alleviate existing cardiac hypertrophy, according to research published in the July 1 issue of Circulation: Heart Failure. Investigators subjected male C57/Bl6 mice to transverse aortic constriction (TAC) for one week. The researchers treated the mice with FTY-720 for two subsequent weeks while continuing to subject them to TAC. Mice treated with FTY-720 had significantly reduced ventricular mass, ameliorated fibrosis, and improved cardiac performance, compared with mice that received vehicle. Mechanistic studies suggested that FTY-720 appreciably inhibited nuclear factor of activated T-cells activity. In addition, pertussis toxin (Gi-coupled receptor inhibitor) substantially blocked the antihypertrophic effect of FTY-720 in primary rat and human cardiomyocytes. FTY-720 or its analogs could be a promising approach for treating hypertrophic heart disease, said the investigators.
For patients with cardiac arrest who require vasopressors, a combination of vasopressin, epinephrine, and methylprednisolone during cardiopulmonary resuscitation (CPR) and stress-dose hydrocortisone in postresuscitation shock may improve survival to hospital discharge and result in favorable neurologic status, according to data published in the July 17 JAMA. Researchers studied 268 consecutive patients with cardiac arrest requiring epinephrine. Patients received vasopressin plus epinephrine or saline placebo plus epinephrine for the first five CPR cycles after randomization, followed by additional epinephrine if needed. During the first CPR cycle after randomization, patients in the intervention group received methylprednisolone, and patients in the control group received saline placebo. Patients in the treatment arm had higher probability for return of spontaneous circulation of 20 minutes or longer and survival to hospital discharge with cerebral performance category score of 1 or 2.
Chinese people may have a higher risk of stroke than Caucasians, according to research published in the July 16 Neurology. Investigators analyzed studies conducted since 1990 in Chinese populations of first-ever stroke incidence and pathologic types and subtypes of stroke. The team examined hospital- and community-based studies. They also examined community-based stroke studies in Caucasian populations. Age-standardized, annual, first-ever stroke incidence in community-based studies was higher among Chinese than among Caucasian populations. Intracerebral hemorrhage accounted for a larger, more variable proportion of strokes in China than in Taiwan, in Chinese community-based than in hospital-based studies, and in community-based Chinese than in Caucasian studies. The overall proportion of lacunar ischemic stroke was higher in Chinese than in Caucasian populations, but variable study methodologies precluded reliable comparisons.
Narcolepsy in humans may be triggered partly by a proliferation of cells containing histamine, according to data published online ahead of print July 2 in Annals of Neurology. Investigators used immunohistochemistry for histidine decarboxylase (HDC) and quantitative microscopy to detect histamine cells in patients with narcolepsy, Hcrt receptor-2 mutant dogs, and three mouse narcolepsy models. The researchers found an average 64% increase in the number of histamine neurons in human narcolepsy with cataplexy, with no overlap between patients with narcolepsy and controls. The investigators did not observe altered numbers of HDC cells in any of the animal models of narcolepsy, however. The increased histamine cell numbers observed in human narcolepsy may be related to the process causing the human disorder, said the study authors.
Epilepsy may be associated with an early onset of cognitive decline, according to data published online ahead of print on July 8 in JAMA Neurology. Investigators conducted a retrospective observational study of patients at a memory and aging center from 2007 to 2012. Twelve participants had amnestic mild cognitive impairment (aMCI) plus epilepsy, 35 had Alzheimer’s disease plus epilepsy, and seven had Alzheimer’s disease plus subclinical epileptiform activity. Patients with aMCI and epilepsy presented with symptoms of cognitive decline 6.8 years earlier than patients with aMCI who did not have epilepsy. Patients with Alzheimer’s disease who had epilepsy presented with cognitive decline 5.5 years earlier than patients with Alzheimer’s disease who did not have epilepsy. Patients with Alzheimer’s disease and subclinical epileptiform activity also had an early onset of cognitive decline.
Globus pallidus interna (GPi) deep brain stimulation (DBS) may be an effective therapy for DYT1-associated torsion dystonia, according to a study published in the July issue of Neurosurgery. Researchers conducted a retrospective chart review of 47 consecutive patients with DYT1 who were treated by a single surgical team during a 10-year period and followed for up to 96 months. Symptom severity was quantified with the Burke–Fahn–Marsden Dystonia Rating Scale. Motor symptom severity was reduced to less than 20% of baseline after two years of DBS therapy. Disability scores were reduced to less than 30% of baseline. Symptomatic improvement was sustained throughout follow-up. Sixty-one percent of patients had discontinued all dystonia-related medications at their last follow-up. Ninety-one percent had discontinued at least one class of medication.
Concurrent cerebrovascular disease is a common neuropathologic finding in older individuals with dementia, according to an article published online ahead of print July 10 in Brain. Cerebrovascular disease, vascular pathology, and vascular risk factors were studied in 5,715 cases from the National Alzheimer’s Coordinating Centre database who had a single neurodegenerative disease diagnosis based on a neuropathologic examination with or without cerebrovascular disease. After controlling for age and gender, the researchers found a lower prevalence of coincident cerebrovascular disease among patients with α-synucleinopathies, frontotemporal lobar degeneration due to tau and TAR DNA-binding protein 43, and prion disease than among patients with Alzheimer’s disease. This result was more significant in younger patients. Data suggest that these disorders should be targeted by treatments for cerebrovascular disease, according to the researchers.
Athletes who do not get enough sleep the night before undergoing baseline concussion testing may not perform as well as they expect, according to research presented at the 2013 Annual Meeting of the American Orthopaedic Society for Sports Medicine in Chicago. Researchers reviewed 3,686 nonconcussed athletes (1,315 female) with baseline symptom and ImPACT neurocognitive scores. Individuals reported their previous night’s sleep duration as fewer than seven hours, seven to nine hours, or more than nine hours. The study authors observed significant differences in reaction time, verbal memory, and visual memory in the group that had slept less than seven hours. Visual-motor speed scores did not seem to be affected. Significant differences in the total number of reported symptoms were associated with sleeping fewer than seven hours.
Continuation of lipophilic statin therapy may be associated with a decreased risk of Parkinson’s disease, compared with discontinuation, according to research published online ahead of print July 24 in Neurology. Between 2001 and 2008, investigators recruited participants without Parkinson’s disease who had initiated statin therapy. Among 43,810 subjects, the incidence rate for Parkinson’s disease was 1.68 and 3.52 per 1,000,000 person-days for lipophilic and hydrophilic statins, respectively. Continuation of lipophilic statins was associated with a decreased risk of Parkinson’s disease, compared with statin discontinuation. No association between hydrophilic statins and occurrence of Parkinson’s disease was observed. Among lipophilic statins, a significant association was observed for simvastatin and atorvastatin, especially in females. Long-term use of lipophilic or hydrophilic statins was not significantly associated with Parkinson’s disease.
—Erik Greb
Senior Associate Editor
Monoclonal Antibodies Could Become Popular Treatments for MS
ORLANDO—In the expanding array of disease-modifying therapies for multiple sclerosis (MS), some “old companions” among the parenteral agents likely will fall by the wayside, said Patricia K. Coyle, MD, at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS). Dr. Coyle discussed parenteral agents now in development and described the likely future of the current parenteral drugs.
Interferon Beta and Glatiramer Acetate
Since receiving approval from the FDA for relapsing forms of MS and clinically isolated syndrome, interferon beta and glatiramer acetate have become old standbys. The drugs are fairly well tolerated, and their safety profiles have been thoroughly established during the past two decades. These agents’ big disadvantage, however, is that they must be injected with a needle, said Dr. Coyle, Professor of Clinical Neurology at Stony Brook Medical Center in New York.
“I don’t think the market for interferon beta and glatiramer acetate is going to disappear, but I think it’s going to slowly shrink because now we have oral options,” predicted Dr. Coyle. “The biggest impact is going to be on treatment-naïve, newly diagnosed patients. People are going to opt for an oral agent rather than an injectable. “It’s beginning to become a crowded market among the interferon betas. It’s likely you’re going to see one interferon beta emerge as the dominant option in a shrinking market,” she added.
Natalizumab
Although it is highly effective, natalizumab is associated with a risk of progressive multifocal leukoencephalopathy (PML). Nonetheless, natalizumab use could increase during the coming years because of emerging risk-stratification methods that identify a subset of MS patients at low risk of PML. But once the novel anti-CD20 monoclonal antibodies reach the marketplace, natalizumab use will decline, predicted Dr. Coyle.
Mitoxantrone
A true induction agent with sustained efficacy that lasts after the cessation of treatment, mitoxantrone has FDA approval for all forms of MS except primary progressive MS. The drug’s associated risks of cardiotoxicity and leukemia require lifetime monitoring for the patient, however, and the therapy can only be administered 10 or 11 times. “As far as I can tell, mitoxantrone is not being used for MS at all in the United States any longer,” according to Dr. Coyle.
Rituximab
Rituximab, an IgG1-anti-CD20 chimeric monoclonal antibody, rapidly depletes B cells for four to 12 months. Eventually, naïve B cells return pre-ferentially over memory B cells. Rituximab is marketed for non-Hodgkin’s lymphoma and refractory rheumatoid arthritis. Its manufacturer does not intend to seek an indication for MS, but highly promising phase II studies have spurred intensive development of novel anti-CD20 monoclonal antibodies targeting MS.
Some neurologists use rituximab off label for MS. A common regimen includes 1,000 mg of IV rituximab followed 15 days later by 500 mg, with dosing repeated every six months, said Dr. Coyle.
Parenteral Agents in Development
Of the parenteral agents in development, alemtuzumab is likely to be the first to be marketed, said Dr. Coyle. This agent, which knocks out T cells, is now under FDA review for possible marketing approval based on impressive phase III results. Alemtuzumab, a true induction agent, is administered on eight days over the course of two years. The effects appear to last for several years after the last dose, but the drug does not cure MS, Dr. Coyle emphasized.
Pegylated interferon beta-1a is being evaluated in an ongoing, two-year, phase III trial. The first-year results indicated that self-administered subcutaneous dosing every two weeks may be more effective than dosing every four weeks. It is too early to tell whether pegylated interferon beta-1a will become the dominant interferon-beta in the marketplace, said Dr. Coyle. Generic interferon-beta may become available in the US. A 40-mg dose of glatiramer acetate can be administered subcutaneously three times per week, rather than daily, as with the familiar 20-mg formulation. In the Glatiramer Acetate Low Frequency Administration Study, a 40-mg dose of glatiramer acetate was associated with an annualized relapse rate 34% lower than that of placebo and a 34% reduction in new or relapsing T2 lesions on brain MRI.
Novel Anti-CD20 Agents
Ocrelizumab is the furthest along in development of the novel anti-CD20 agents. The humanized monoclonal antibody is in three phase III clinical trials: two for relapsing MS and one for primary progressive MS. In a phase II study, various doses of ocrelizumab reduced relapses by 73% to 80% and suppressed MRI contrast lesions by 89% to 96%. “The data with ocrelizumab look great. I think it could potentially replace natalizumab, depending on the safety,” said Dr. Coyle. Development of ocrelizumab as a treatment for rheumatoid arthritis and lupus was discontinued because of concerns about an increase in opportunistic infections. “We’ve not really seen that [effect] in the MS cohort. So far, ocrelizumab seems pretty safe,” said Dr. Coyle.
Daclizumab, a humanized IgG1 monoclonal antibody against CD25, is a subcutaneously administered agent on the market for the prevention of transplanted organ rejection. Investigators are comparing the drug with intramuscular interferon beta-1a as a treatment for MS in an ongoing phase III clinical trial. Previous studies raised concerns regarding daclizumab’s safety and tolerability.
Neurologists have long sought biomarkers of efficacy for MS therapies. Daclizumab appears to provide such a biomarker in the form of an increase in CD56 bright natural killer cells.
Other anti-CD20 monoclonal antibodies in development include ofatumumab, which is now marketed for the treatment of refractory chronic lymphocytic leukemia. A second, secukinumab, is an anti-interleukin-17 monoclonal antibody that showed efficacy in terms of MRI lesions in a small study. In addition, an anti-LINGO-1 monoclonal antibody in development is intended to stimulate myelin repair.
Dr. Coyle predicted that more efficacy biomarkers will emerge and that neuroprotection and CNS restoration will be fertile areas for drug development. “A high-efficacy monoclonal antibody, if it’s safe and convenient, could seize the market. The safety will be the critical issue,” she concluded.
—Bruce Jancin
IMNG Medical News
Suggested Reading
Deiß A, Brecht I, Haarmann A, Buttmann M. Treating multiple sclerosis with monoclonal antibodies: a 2013 update. Expert Rev Neurother. 2013;13(3):313-335.
Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358(7):676-688.
Hawker K, O’Connor P, Freedman MS, et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol. 2009;66(4):460-471.
Kieseier BC, Calabresi PA. PEGylation of interferon-b-1a: a promising strategy in multiple sclerosis. CNS Drugs. 2012;26(3):205-214.
ORLANDO—In the expanding array of disease-modifying therapies for multiple sclerosis (MS), some “old companions” among the parenteral agents likely will fall by the wayside, said Patricia K. Coyle, MD, at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS). Dr. Coyle discussed parenteral agents now in development and described the likely future of the current parenteral drugs.
Interferon Beta and Glatiramer Acetate
Since receiving approval from the FDA for relapsing forms of MS and clinically isolated syndrome, interferon beta and glatiramer acetate have become old standbys. The drugs are fairly well tolerated, and their safety profiles have been thoroughly established during the past two decades. These agents’ big disadvantage, however, is that they must be injected with a needle, said Dr. Coyle, Professor of Clinical Neurology at Stony Brook Medical Center in New York.
“I don’t think the market for interferon beta and glatiramer acetate is going to disappear, but I think it’s going to slowly shrink because now we have oral options,” predicted Dr. Coyle. “The biggest impact is going to be on treatment-naïve, newly diagnosed patients. People are going to opt for an oral agent rather than an injectable. “It’s beginning to become a crowded market among the interferon betas. It’s likely you’re going to see one interferon beta emerge as the dominant option in a shrinking market,” she added.
Natalizumab
Although it is highly effective, natalizumab is associated with a risk of progressive multifocal leukoencephalopathy (PML). Nonetheless, natalizumab use could increase during the coming years because of emerging risk-stratification methods that identify a subset of MS patients at low risk of PML. But once the novel anti-CD20 monoclonal antibodies reach the marketplace, natalizumab use will decline, predicted Dr. Coyle.
Mitoxantrone
A true induction agent with sustained efficacy that lasts after the cessation of treatment, mitoxantrone has FDA approval for all forms of MS except primary progressive MS. The drug’s associated risks of cardiotoxicity and leukemia require lifetime monitoring for the patient, however, and the therapy can only be administered 10 or 11 times. “As far as I can tell, mitoxantrone is not being used for MS at all in the United States any longer,” according to Dr. Coyle.
Rituximab
Rituximab, an IgG1-anti-CD20 chimeric monoclonal antibody, rapidly depletes B cells for four to 12 months. Eventually, naïve B cells return pre-ferentially over memory B cells. Rituximab is marketed for non-Hodgkin’s lymphoma and refractory rheumatoid arthritis. Its manufacturer does not intend to seek an indication for MS, but highly promising phase II studies have spurred intensive development of novel anti-CD20 monoclonal antibodies targeting MS.
Some neurologists use rituximab off label for MS. A common regimen includes 1,000 mg of IV rituximab followed 15 days later by 500 mg, with dosing repeated every six months, said Dr. Coyle.
Parenteral Agents in Development
Of the parenteral agents in development, alemtuzumab is likely to be the first to be marketed, said Dr. Coyle. This agent, which knocks out T cells, is now under FDA review for possible marketing approval based on impressive phase III results. Alemtuzumab, a true induction agent, is administered on eight days over the course of two years. The effects appear to last for several years after the last dose, but the drug does not cure MS, Dr. Coyle emphasized.
Pegylated interferon beta-1a is being evaluated in an ongoing, two-year, phase III trial. The first-year results indicated that self-administered subcutaneous dosing every two weeks may be more effective than dosing every four weeks. It is too early to tell whether pegylated interferon beta-1a will become the dominant interferon-beta in the marketplace, said Dr. Coyle. Generic interferon-beta may become available in the US. A 40-mg dose of glatiramer acetate can be administered subcutaneously three times per week, rather than daily, as with the familiar 20-mg formulation. In the Glatiramer Acetate Low Frequency Administration Study, a 40-mg dose of glatiramer acetate was associated with an annualized relapse rate 34% lower than that of placebo and a 34% reduction in new or relapsing T2 lesions on brain MRI.
Novel Anti-CD20 Agents
Ocrelizumab is the furthest along in development of the novel anti-CD20 agents. The humanized monoclonal antibody is in three phase III clinical trials: two for relapsing MS and one for primary progressive MS. In a phase II study, various doses of ocrelizumab reduced relapses by 73% to 80% and suppressed MRI contrast lesions by 89% to 96%. “The data with ocrelizumab look great. I think it could potentially replace natalizumab, depending on the safety,” said Dr. Coyle. Development of ocrelizumab as a treatment for rheumatoid arthritis and lupus was discontinued because of concerns about an increase in opportunistic infections. “We’ve not really seen that [effect] in the MS cohort. So far, ocrelizumab seems pretty safe,” said Dr. Coyle.
Daclizumab, a humanized IgG1 monoclonal antibody against CD25, is a subcutaneously administered agent on the market for the prevention of transplanted organ rejection. Investigators are comparing the drug with intramuscular interferon beta-1a as a treatment for MS in an ongoing phase III clinical trial. Previous studies raised concerns regarding daclizumab’s safety and tolerability.
Neurologists have long sought biomarkers of efficacy for MS therapies. Daclizumab appears to provide such a biomarker in the form of an increase in CD56 bright natural killer cells.
Other anti-CD20 monoclonal antibodies in development include ofatumumab, which is now marketed for the treatment of refractory chronic lymphocytic leukemia. A second, secukinumab, is an anti-interleukin-17 monoclonal antibody that showed efficacy in terms of MRI lesions in a small study. In addition, an anti-LINGO-1 monoclonal antibody in development is intended to stimulate myelin repair.
Dr. Coyle predicted that more efficacy biomarkers will emerge and that neuroprotection and CNS restoration will be fertile areas for drug development. “A high-efficacy monoclonal antibody, if it’s safe and convenient, could seize the market. The safety will be the critical issue,” she concluded.
—Bruce Jancin
IMNG Medical News
ORLANDO—In the expanding array of disease-modifying therapies for multiple sclerosis (MS), some “old companions” among the parenteral agents likely will fall by the wayside, said Patricia K. Coyle, MD, at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS). Dr. Coyle discussed parenteral agents now in development and described the likely future of the current parenteral drugs.
Interferon Beta and Glatiramer Acetate
Since receiving approval from the FDA for relapsing forms of MS and clinically isolated syndrome, interferon beta and glatiramer acetate have become old standbys. The drugs are fairly well tolerated, and their safety profiles have been thoroughly established during the past two decades. These agents’ big disadvantage, however, is that they must be injected with a needle, said Dr. Coyle, Professor of Clinical Neurology at Stony Brook Medical Center in New York.
“I don’t think the market for interferon beta and glatiramer acetate is going to disappear, but I think it’s going to slowly shrink because now we have oral options,” predicted Dr. Coyle. “The biggest impact is going to be on treatment-naïve, newly diagnosed patients. People are going to opt for an oral agent rather than an injectable. “It’s beginning to become a crowded market among the interferon betas. It’s likely you’re going to see one interferon beta emerge as the dominant option in a shrinking market,” she added.
Natalizumab
Although it is highly effective, natalizumab is associated with a risk of progressive multifocal leukoencephalopathy (PML). Nonetheless, natalizumab use could increase during the coming years because of emerging risk-stratification methods that identify a subset of MS patients at low risk of PML. But once the novel anti-CD20 monoclonal antibodies reach the marketplace, natalizumab use will decline, predicted Dr. Coyle.
Mitoxantrone
A true induction agent with sustained efficacy that lasts after the cessation of treatment, mitoxantrone has FDA approval for all forms of MS except primary progressive MS. The drug’s associated risks of cardiotoxicity and leukemia require lifetime monitoring for the patient, however, and the therapy can only be administered 10 or 11 times. “As far as I can tell, mitoxantrone is not being used for MS at all in the United States any longer,” according to Dr. Coyle.
Rituximab
Rituximab, an IgG1-anti-CD20 chimeric monoclonal antibody, rapidly depletes B cells for four to 12 months. Eventually, naïve B cells return pre-ferentially over memory B cells. Rituximab is marketed for non-Hodgkin’s lymphoma and refractory rheumatoid arthritis. Its manufacturer does not intend to seek an indication for MS, but highly promising phase II studies have spurred intensive development of novel anti-CD20 monoclonal antibodies targeting MS.
Some neurologists use rituximab off label for MS. A common regimen includes 1,000 mg of IV rituximab followed 15 days later by 500 mg, with dosing repeated every six months, said Dr. Coyle.
Parenteral Agents in Development
Of the parenteral agents in development, alemtuzumab is likely to be the first to be marketed, said Dr. Coyle. This agent, which knocks out T cells, is now under FDA review for possible marketing approval based on impressive phase III results. Alemtuzumab, a true induction agent, is administered on eight days over the course of two years. The effects appear to last for several years after the last dose, but the drug does not cure MS, Dr. Coyle emphasized.
Pegylated interferon beta-1a is being evaluated in an ongoing, two-year, phase III trial. The first-year results indicated that self-administered subcutaneous dosing every two weeks may be more effective than dosing every four weeks. It is too early to tell whether pegylated interferon beta-1a will become the dominant interferon-beta in the marketplace, said Dr. Coyle. Generic interferon-beta may become available in the US. A 40-mg dose of glatiramer acetate can be administered subcutaneously three times per week, rather than daily, as with the familiar 20-mg formulation. In the Glatiramer Acetate Low Frequency Administration Study, a 40-mg dose of glatiramer acetate was associated with an annualized relapse rate 34% lower than that of placebo and a 34% reduction in new or relapsing T2 lesions on brain MRI.
Novel Anti-CD20 Agents
Ocrelizumab is the furthest along in development of the novel anti-CD20 agents. The humanized monoclonal antibody is in three phase III clinical trials: two for relapsing MS and one for primary progressive MS. In a phase II study, various doses of ocrelizumab reduced relapses by 73% to 80% and suppressed MRI contrast lesions by 89% to 96%. “The data with ocrelizumab look great. I think it could potentially replace natalizumab, depending on the safety,” said Dr. Coyle. Development of ocrelizumab as a treatment for rheumatoid arthritis and lupus was discontinued because of concerns about an increase in opportunistic infections. “We’ve not really seen that [effect] in the MS cohort. So far, ocrelizumab seems pretty safe,” said Dr. Coyle.
Daclizumab, a humanized IgG1 monoclonal antibody against CD25, is a subcutaneously administered agent on the market for the prevention of transplanted organ rejection. Investigators are comparing the drug with intramuscular interferon beta-1a as a treatment for MS in an ongoing phase III clinical trial. Previous studies raised concerns regarding daclizumab’s safety and tolerability.
Neurologists have long sought biomarkers of efficacy for MS therapies. Daclizumab appears to provide such a biomarker in the form of an increase in CD56 bright natural killer cells.
Other anti-CD20 monoclonal antibodies in development include ofatumumab, which is now marketed for the treatment of refractory chronic lymphocytic leukemia. A second, secukinumab, is an anti-interleukin-17 monoclonal antibody that showed efficacy in terms of MRI lesions in a small study. In addition, an anti-LINGO-1 monoclonal antibody in development is intended to stimulate myelin repair.
Dr. Coyle predicted that more efficacy biomarkers will emerge and that neuroprotection and CNS restoration will be fertile areas for drug development. “A high-efficacy monoclonal antibody, if it’s safe and convenient, could seize the market. The safety will be the critical issue,” she concluded.
—Bruce Jancin
IMNG Medical News
Suggested Reading
Deiß A, Brecht I, Haarmann A, Buttmann M. Treating multiple sclerosis with monoclonal antibodies: a 2013 update. Expert Rev Neurother. 2013;13(3):313-335.
Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358(7):676-688.
Hawker K, O’Connor P, Freedman MS, et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol. 2009;66(4):460-471.
Kieseier BC, Calabresi PA. PEGylation of interferon-b-1a: a promising strategy in multiple sclerosis. CNS Drugs. 2012;26(3):205-214.
Suggested Reading
Deiß A, Brecht I, Haarmann A, Buttmann M. Treating multiple sclerosis with monoclonal antibodies: a 2013 update. Expert Rev Neurother. 2013;13(3):313-335.
Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358(7):676-688.
Hawker K, O’Connor P, Freedman MS, et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol. 2009;66(4):460-471.
Kieseier BC, Calabresi PA. PEGylation of interferon-b-1a: a promising strategy in multiple sclerosis. CNS Drugs. 2012;26(3):205-214.
Analysis: Healthy babies born after accelerated elimination of teriflunomide
ORLANDO – When individuals with multiple sclerosis who were treated with teriflunomide and were using contraception, but became pregnant and followed the clinical program by stopping treatment and flushing the drug out of their systems, they had healthy babies, according to the drug maker’s analysis of several phase II and III trials.
The authors, who presented their findings as a poster at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis, said that there’s need for more prospective data on pregnancy outcomes, and a registry is planned.
The Food and Drug Administration approved teriflunomide, a once-daily oral medication for treating relapsing forms of multiple sclerosis, last year. The drug is currently classified as "X" and is contraindicated in pregnant women and women of childbearing age. Animal studies have shown that teriflunomide is teratogenic and embryo lethal, the authors wrote, although there has been no evidence that it affected the genes or fertility.
For those who worry about using the drug in women, "This is reassuring that if you follow the guidelines, it’s not going be an issue for mommies and daddies for teratogenicity," said Dr. Robert P. Lisak, professor of neurology at Wayne State University, Detroit, and president-elect of the Consortium of Multiple Sclerosis Centers (CMSC).
Dr. Lisak, who was not involved in the analysis, but has been a part of one of the trials used in the analysis, said that his concern, as a practicing physician, is that women outside of clinical trials are not monitored as closely.
Women who are using the drug are advised to use contraception. Those who want to become pregnant are advised to discontinue treatment and undergo an elimination procedure with cholestyramine or activated charcoal until the drug’s plasma concentrations are less than 0.02 mcg/mL. Men should also stop treatment and undergo accelerated elimination.
Researchers summarized the results of nine phase II and III clinical trials in the MS clinical development program, which included pregnancy outcomes in female patients and partners of men who were exposed to teriflunomide.
The patients had received 7 mg or 14 mg teriflunomide, interferon-beta, placebo, or a combination of treatments. In all trials, reliable contraception was required, but pregnancies were reported.
From a total of more than 4,000 patients, there were 81 pregnancies, 63 of which occurred in women taking teriflunomide, and 18 in women who were on placebo or interferon-beta.
Of those 63, 20 were live births, 26 were induced abortions, 12 were miscarriages, and 5 pregnancies were ongoing when the data collection stopped on April 2013.
The live births in patients treated with teriflunomide resulted in healthy babies. Most of the women had discontinued the drug a few days to 11 weeks after becoming pregnant and underwent an accelerated elimination procedure after discontinuing treatment. Two refused to undergo the procedure. Seven became pregnant after completing the elimination procedure.
The rate of miscarriage in the teriflunomide group was 19%, which is within the range reported in the non–MS population (Eur. J. Obstet. Gynecol. Reprod. Biol. 2002;102:111-9), the authors wrote.
There were 20 pregnancies in partners of 17 men in the teriflunomide clinical trials. In 16, the father was exposed to the drug. There were 12 live births of healthy babies, 1 induced abortion, 1 miscarriage, and 2 ongoing pregnancies when data collection stopped.
Researchers said that planned teriflunomide pregnancy registries will provide more information, but data so far haven’t shown the teratogenic signal seen in the leflunomide registry.
Teriflunomide is the main active metabolite in rheumatoid arthritis drug leflunomide. Animal studies for leflunomide have shown embryo lethality and teratogenicity. But in small human studies, there was no significant difference in teratogenicity and spontaneous abortion rates, compared with the general population (Arthritis Rheum. 2010;62:1494-503; Arthritis Rheum. 2012;64:2085-94), the authors noted.
Teriflunomide also has been detected in human semen. Although there have been no animal studies, researchers said that the estimated female exposure via semen of men treated with the drug is expected to be 100 times lower than in those who actually take the drug with 14-mg dosing.
"Pregnancy outcomes among women who received teriflunomide, including rates of spontaneous abortion, and gestational age and weight at birth, are consistent with those for non–MS populations," the authors wrote. The treatment "is a therapeutic option for women of childbearing potential and for male patients with female partners of childbearing potential, when using reliable contraception."
Some of the authors were employees of Sanofi or had received research support from the company. The study was supported by Genzyme, a Sanofi company, which is marketed as teriflunomide (Aubagio).
On Twitter @naseemsmiller
ORLANDO – When individuals with multiple sclerosis who were treated with teriflunomide and were using contraception, but became pregnant and followed the clinical program by stopping treatment and flushing the drug out of their systems, they had healthy babies, according to the drug maker’s analysis of several phase II and III trials.
The authors, who presented their findings as a poster at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis, said that there’s need for more prospective data on pregnancy outcomes, and a registry is planned.
The Food and Drug Administration approved teriflunomide, a once-daily oral medication for treating relapsing forms of multiple sclerosis, last year. The drug is currently classified as "X" and is contraindicated in pregnant women and women of childbearing age. Animal studies have shown that teriflunomide is teratogenic and embryo lethal, the authors wrote, although there has been no evidence that it affected the genes or fertility.
For those who worry about using the drug in women, "This is reassuring that if you follow the guidelines, it’s not going be an issue for mommies and daddies for teratogenicity," said Dr. Robert P. Lisak, professor of neurology at Wayne State University, Detroit, and president-elect of the Consortium of Multiple Sclerosis Centers (CMSC).
Dr. Lisak, who was not involved in the analysis, but has been a part of one of the trials used in the analysis, said that his concern, as a practicing physician, is that women outside of clinical trials are not monitored as closely.
Women who are using the drug are advised to use contraception. Those who want to become pregnant are advised to discontinue treatment and undergo an elimination procedure with cholestyramine or activated charcoal until the drug’s plasma concentrations are less than 0.02 mcg/mL. Men should also stop treatment and undergo accelerated elimination.
Researchers summarized the results of nine phase II and III clinical trials in the MS clinical development program, which included pregnancy outcomes in female patients and partners of men who were exposed to teriflunomide.
The patients had received 7 mg or 14 mg teriflunomide, interferon-beta, placebo, or a combination of treatments. In all trials, reliable contraception was required, but pregnancies were reported.
From a total of more than 4,000 patients, there were 81 pregnancies, 63 of which occurred in women taking teriflunomide, and 18 in women who were on placebo or interferon-beta.
Of those 63, 20 were live births, 26 were induced abortions, 12 were miscarriages, and 5 pregnancies were ongoing when the data collection stopped on April 2013.
The live births in patients treated with teriflunomide resulted in healthy babies. Most of the women had discontinued the drug a few days to 11 weeks after becoming pregnant and underwent an accelerated elimination procedure after discontinuing treatment. Two refused to undergo the procedure. Seven became pregnant after completing the elimination procedure.
The rate of miscarriage in the teriflunomide group was 19%, which is within the range reported in the non–MS population (Eur. J. Obstet. Gynecol. Reprod. Biol. 2002;102:111-9), the authors wrote.
There were 20 pregnancies in partners of 17 men in the teriflunomide clinical trials. In 16, the father was exposed to the drug. There were 12 live births of healthy babies, 1 induced abortion, 1 miscarriage, and 2 ongoing pregnancies when data collection stopped.
Researchers said that planned teriflunomide pregnancy registries will provide more information, but data so far haven’t shown the teratogenic signal seen in the leflunomide registry.
Teriflunomide is the main active metabolite in rheumatoid arthritis drug leflunomide. Animal studies for leflunomide have shown embryo lethality and teratogenicity. But in small human studies, there was no significant difference in teratogenicity and spontaneous abortion rates, compared with the general population (Arthritis Rheum. 2010;62:1494-503; Arthritis Rheum. 2012;64:2085-94), the authors noted.
Teriflunomide also has been detected in human semen. Although there have been no animal studies, researchers said that the estimated female exposure via semen of men treated with the drug is expected to be 100 times lower than in those who actually take the drug with 14-mg dosing.
"Pregnancy outcomes among women who received teriflunomide, including rates of spontaneous abortion, and gestational age and weight at birth, are consistent with those for non–MS populations," the authors wrote. The treatment "is a therapeutic option for women of childbearing potential and for male patients with female partners of childbearing potential, when using reliable contraception."
Some of the authors were employees of Sanofi or had received research support from the company. The study was supported by Genzyme, a Sanofi company, which is marketed as teriflunomide (Aubagio).
On Twitter @naseemsmiller
ORLANDO – When individuals with multiple sclerosis who were treated with teriflunomide and were using contraception, but became pregnant and followed the clinical program by stopping treatment and flushing the drug out of their systems, they had healthy babies, according to the drug maker’s analysis of several phase II and III trials.
The authors, who presented their findings as a poster at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis, said that there’s need for more prospective data on pregnancy outcomes, and a registry is planned.
The Food and Drug Administration approved teriflunomide, a once-daily oral medication for treating relapsing forms of multiple sclerosis, last year. The drug is currently classified as "X" and is contraindicated in pregnant women and women of childbearing age. Animal studies have shown that teriflunomide is teratogenic and embryo lethal, the authors wrote, although there has been no evidence that it affected the genes or fertility.
For those who worry about using the drug in women, "This is reassuring that if you follow the guidelines, it’s not going be an issue for mommies and daddies for teratogenicity," said Dr. Robert P. Lisak, professor of neurology at Wayne State University, Detroit, and president-elect of the Consortium of Multiple Sclerosis Centers (CMSC).
Dr. Lisak, who was not involved in the analysis, but has been a part of one of the trials used in the analysis, said that his concern, as a practicing physician, is that women outside of clinical trials are not monitored as closely.
Women who are using the drug are advised to use contraception. Those who want to become pregnant are advised to discontinue treatment and undergo an elimination procedure with cholestyramine or activated charcoal until the drug’s plasma concentrations are less than 0.02 mcg/mL. Men should also stop treatment and undergo accelerated elimination.
Researchers summarized the results of nine phase II and III clinical trials in the MS clinical development program, which included pregnancy outcomes in female patients and partners of men who were exposed to teriflunomide.
The patients had received 7 mg or 14 mg teriflunomide, interferon-beta, placebo, or a combination of treatments. In all trials, reliable contraception was required, but pregnancies were reported.
From a total of more than 4,000 patients, there were 81 pregnancies, 63 of which occurred in women taking teriflunomide, and 18 in women who were on placebo or interferon-beta.
Of those 63, 20 were live births, 26 were induced abortions, 12 were miscarriages, and 5 pregnancies were ongoing when the data collection stopped on April 2013.
The live births in patients treated with teriflunomide resulted in healthy babies. Most of the women had discontinued the drug a few days to 11 weeks after becoming pregnant and underwent an accelerated elimination procedure after discontinuing treatment. Two refused to undergo the procedure. Seven became pregnant after completing the elimination procedure.
The rate of miscarriage in the teriflunomide group was 19%, which is within the range reported in the non–MS population (Eur. J. Obstet. Gynecol. Reprod. Biol. 2002;102:111-9), the authors wrote.
There were 20 pregnancies in partners of 17 men in the teriflunomide clinical trials. In 16, the father was exposed to the drug. There were 12 live births of healthy babies, 1 induced abortion, 1 miscarriage, and 2 ongoing pregnancies when data collection stopped.
Researchers said that planned teriflunomide pregnancy registries will provide more information, but data so far haven’t shown the teratogenic signal seen in the leflunomide registry.
Teriflunomide is the main active metabolite in rheumatoid arthritis drug leflunomide. Animal studies for leflunomide have shown embryo lethality and teratogenicity. But in small human studies, there was no significant difference in teratogenicity and spontaneous abortion rates, compared with the general population (Arthritis Rheum. 2010;62:1494-503; Arthritis Rheum. 2012;64:2085-94), the authors noted.
Teriflunomide also has been detected in human semen. Although there have been no animal studies, researchers said that the estimated female exposure via semen of men treated with the drug is expected to be 100 times lower than in those who actually take the drug with 14-mg dosing.
"Pregnancy outcomes among women who received teriflunomide, including rates of spontaneous abortion, and gestational age and weight at birth, are consistent with those for non–MS populations," the authors wrote. The treatment "is a therapeutic option for women of childbearing potential and for male patients with female partners of childbearing potential, when using reliable contraception."
Some of the authors were employees of Sanofi or had received research support from the company. The study was supported by Genzyme, a Sanofi company, which is marketed as teriflunomide (Aubagio).
On Twitter @naseemsmiller
AT CMSC/ACTRIMS ANNUAL MEETING
Major finding: Women and partners of men treated with teriflunomide who became pregnant and underwent accelerated elimination procedure had healthy babies.
Data source: Pregnancy outcomes in female patients and partners of men who were exposed to teriflunomide in nine phase II and III clinical trials.
Disclosures: Some of the authors were employees of Sanofi or had received research support from the company. The study was supported by Genzyme, a Sanofi company, which is marketed as teriflunomide (Aubagio).
Selecting the right oral MS drug
ORLANDO – Effective oral therapy has been at the top of the wish list of many multiple sclerosis patients for a long time – and now, seemingly all of a sudden, three approved oral agents are available to choose from.
For patients, the obvious attractions of oral therapy are ease of administration and that it’s less of a reminder that they have a serious chronic illness. But which agent is the right fit for a given patient?
All three oral drugs – fingolimod (Gilenya), teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera) – are "definitely" suitable as first-line therapy in selected newly diagnosed MS patients, Dr. Mariko Kita asserted at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
But the three oral drugs are not interchangeable. Each has a different mechanism of action and its own side effect profile, emphasized Dr. Kita, director of the Virginia Mason MS Center, Seattle, and director of the MS clinical trials unit at Virginia Mason’s Benaroya Research Institute.
Today few neurologists – certainly less than 10% – are using any oral agent as first-line therapy. That’s in part due to cost and reimbursement issues, but to a much greater extent it’s because most physicians don’t yet feel comfortable that the safety profiles of the oral agents are fully known. The drugs are still too new, in the eyes of most practitioners. After all, both natalizumab (Tysabri) – considered the most effective of the injectable agents – and fingolimod – the first oral agent to receive marketing approval, back in October 2010 – had to have revisionary cautions added to their labeling shortly after they were introduced.
But provider experience with the orals is expected to grow quickly. And absent any late bombshells regarding side effects, it’s widely anticipated that the use of oral agents for MS will surge within the next few years, with a corresponding decline in popularity of injectable therapies.
Demand for oral therapy will be high all across the patient spectrum: in newly diagnosed patients, in individuals with a lengthy disease history who have tried all the available disease-modifying therapies with less than satisfactory results and have been awaiting something new, in patients intolerant to or experiencing breakthrough disease on a first-line injectable agent, as well as in patients who are stable on their current injectable disease-modifying therapy but are experiencing injection fatigue or growing more concerned about their parenteral therapy’s long-term risks, Dr. Kita predicted.
Choosing between the oral options appropriately requires a focus on patient-specific factors, including comorbid conditions, reproductive status, and consideration of how the oral drug will fit in to the big picture of a long-term, staged therapy plan, she added.
Here’s her personal clinical rundown on the approved oral drugs:
• Fingolimod: This is a drug best reserved for MS patients who are otherwise relatively healthy, in Dr. Kita’s view. Specifically, it’s a less favorable option for patients with diabetes, smokers, and others with reduced pulmonary function, and in individuals at increased risk of infection, including those with a high Expanded Disability Status Scale score.
Fingolimod is a sphingosine-1-phosphate agonist. It sequesters lymphocytes in the lymph nodes so they can’t participate in autoimmune activity. The required testing prior to starting the drug, the need for careful observation during the first dose, and the necessary ongoing monitoring as long as the patient is on fingolimod make this a labor-intensive drug.
Bearing those caveats in mind, she continued, fingolimod is "reasonable" to use as a first-line agent, or as a second-line agent in the setting of intolerance to or breakthrough disease while on prior therapy.
"But I would caution those who are reserving these oral agents as second-line that we need to think about what we can reasonably expect from them. If we’re moving to them as second-line because of tolerability issues with first-line agents, yes, I think that’s most reasonable. But if we’re moving because of breakthrough disease, our experience with these agents in cases of failure with standard first-line therapies is very, very limited. Sure, the differing mechanism of action offers a reasonable alternative option, but the expectation that the oral will be better than a failed injectable has not yet been proven," Dr. Kita said.
• Teriflunomide: This is the active metabolite of leflunomide, a treatment approved by the Food and Drug Administration for rheumatoid arthritis. It was approved for treating relapsing forms of MS last fall. Teriflunomide nonselectively inhibits rapidly dividing cell populations by curbing pyrimidine synthesis via bonding to the enzyme dihydroorotate dehydrogenase.
Who’s the right fit for teriflunomide? Because the drug is rated category X and has teratogenicity potential in both men and women, it’s a given that the candidate must be on effective contraception. Also, the patient should definitely not have comorbid liver disease. And in Dr. Kita’s view, an appropriate candidate for teriflunomide has mild MS. Otherwise, the physician can get backed into a corner. That’s because the drug is excreted very slowly and is not dialyzable. Indeed, it takes 8-24 months after drug discontinuation for plasma levels to become undetectable.
"Teriflunomide could definitely be used as first-line therapy. It can be used second-line in a patient intolerant to a prior agent. But I think the long half-life complicates its use as second-line therapy in patients who’ve had breakthrough disease on prior agents, because if we need to consider a switch from teriflunomide, that long half-life has to be taken into consideration. You’ll need to consider the elimination protocol," she advised.
Patients find the elimination protocol arduous. It entails swallowing 8 g of oral cholestyramine every 8 hours for 11 days, or 50 g of activated charcoal given orally every 12 hours for 11 days.
• Dimethyl fumarate: This twice-daily oral agent, which was approved last March, activates the nuclear factor transcriptional pathway, thereby defending against oxidative stress–induced neuronal death. Dimethyl fumarate also supports myelin integrity in the central nervous system.
The drug’s side effect profile, consisting mostly of short-term flushing and gastrointestinal complaints, is the most benign of the three oral agents. Thus, it could potentially see broader use both as a first-line drug in newly diagnosed patients and as second-line therapy in patients intolerant to or experiencing disease breakthrough on other agents.
That being said, it’s still unclear whether any of the available oral agents is the best choice after natalizumab discontinuation. A couple of studies of fingolimod showed a high relapse rate in this situation, and there are simply no data as yet on the two newer agents, according to Dr. Kita.
• Upcoming oral agents: The investigational oral agent furthest along in the developmental pipeline is laquinimod, a quinolone-3-carboxamide small molecule that has completed two phase III clinical trials and is now under review by the European Medicines Agency for possible marketing approval. Teva has not yet applied to the Food and Drug Administration for U.S. approval.
Several second-generation sphingosine-1-phosphate agonists are in development. They are believed to act more selectively and thus pose fewer potential immunocompromise issues than fingolimod. These include siponimod, ponesimod, and ONO-4641.
Dr. Kita reported receiving research support from Biogen Idec (which markets Tecfidera), Novartis (which markets Gilenya and is developing siponimod), Serono, and Acorda, as well as personal compensation from Biogen Idec, Bayer, and Genzyme (which markets Aubagio).
ORLANDO – Effective oral therapy has been at the top of the wish list of many multiple sclerosis patients for a long time – and now, seemingly all of a sudden, three approved oral agents are available to choose from.
For patients, the obvious attractions of oral therapy are ease of administration and that it’s less of a reminder that they have a serious chronic illness. But which agent is the right fit for a given patient?
All three oral drugs – fingolimod (Gilenya), teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera) – are "definitely" suitable as first-line therapy in selected newly diagnosed MS patients, Dr. Mariko Kita asserted at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
But the three oral drugs are not interchangeable. Each has a different mechanism of action and its own side effect profile, emphasized Dr. Kita, director of the Virginia Mason MS Center, Seattle, and director of the MS clinical trials unit at Virginia Mason’s Benaroya Research Institute.
Today few neurologists – certainly less than 10% – are using any oral agent as first-line therapy. That’s in part due to cost and reimbursement issues, but to a much greater extent it’s because most physicians don’t yet feel comfortable that the safety profiles of the oral agents are fully known. The drugs are still too new, in the eyes of most practitioners. After all, both natalizumab (Tysabri) – considered the most effective of the injectable agents – and fingolimod – the first oral agent to receive marketing approval, back in October 2010 – had to have revisionary cautions added to their labeling shortly after they were introduced.
But provider experience with the orals is expected to grow quickly. And absent any late bombshells regarding side effects, it’s widely anticipated that the use of oral agents for MS will surge within the next few years, with a corresponding decline in popularity of injectable therapies.
Demand for oral therapy will be high all across the patient spectrum: in newly diagnosed patients, in individuals with a lengthy disease history who have tried all the available disease-modifying therapies with less than satisfactory results and have been awaiting something new, in patients intolerant to or experiencing breakthrough disease on a first-line injectable agent, as well as in patients who are stable on their current injectable disease-modifying therapy but are experiencing injection fatigue or growing more concerned about their parenteral therapy’s long-term risks, Dr. Kita predicted.
Choosing between the oral options appropriately requires a focus on patient-specific factors, including comorbid conditions, reproductive status, and consideration of how the oral drug will fit in to the big picture of a long-term, staged therapy plan, she added.
Here’s her personal clinical rundown on the approved oral drugs:
• Fingolimod: This is a drug best reserved for MS patients who are otherwise relatively healthy, in Dr. Kita’s view. Specifically, it’s a less favorable option for patients with diabetes, smokers, and others with reduced pulmonary function, and in individuals at increased risk of infection, including those with a high Expanded Disability Status Scale score.
Fingolimod is a sphingosine-1-phosphate agonist. It sequesters lymphocytes in the lymph nodes so they can’t participate in autoimmune activity. The required testing prior to starting the drug, the need for careful observation during the first dose, and the necessary ongoing monitoring as long as the patient is on fingolimod make this a labor-intensive drug.
Bearing those caveats in mind, she continued, fingolimod is "reasonable" to use as a first-line agent, or as a second-line agent in the setting of intolerance to or breakthrough disease while on prior therapy.
"But I would caution those who are reserving these oral agents as second-line that we need to think about what we can reasonably expect from them. If we’re moving to them as second-line because of tolerability issues with first-line agents, yes, I think that’s most reasonable. But if we’re moving because of breakthrough disease, our experience with these agents in cases of failure with standard first-line therapies is very, very limited. Sure, the differing mechanism of action offers a reasonable alternative option, but the expectation that the oral will be better than a failed injectable has not yet been proven," Dr. Kita said.
• Teriflunomide: This is the active metabolite of leflunomide, a treatment approved by the Food and Drug Administration for rheumatoid arthritis. It was approved for treating relapsing forms of MS last fall. Teriflunomide nonselectively inhibits rapidly dividing cell populations by curbing pyrimidine synthesis via bonding to the enzyme dihydroorotate dehydrogenase.
Who’s the right fit for teriflunomide? Because the drug is rated category X and has teratogenicity potential in both men and women, it’s a given that the candidate must be on effective contraception. Also, the patient should definitely not have comorbid liver disease. And in Dr. Kita’s view, an appropriate candidate for teriflunomide has mild MS. Otherwise, the physician can get backed into a corner. That’s because the drug is excreted very slowly and is not dialyzable. Indeed, it takes 8-24 months after drug discontinuation for plasma levels to become undetectable.
"Teriflunomide could definitely be used as first-line therapy. It can be used second-line in a patient intolerant to a prior agent. But I think the long half-life complicates its use as second-line therapy in patients who’ve had breakthrough disease on prior agents, because if we need to consider a switch from teriflunomide, that long half-life has to be taken into consideration. You’ll need to consider the elimination protocol," she advised.
Patients find the elimination protocol arduous. It entails swallowing 8 g of oral cholestyramine every 8 hours for 11 days, or 50 g of activated charcoal given orally every 12 hours for 11 days.
• Dimethyl fumarate: This twice-daily oral agent, which was approved last March, activates the nuclear factor transcriptional pathway, thereby defending against oxidative stress–induced neuronal death. Dimethyl fumarate also supports myelin integrity in the central nervous system.
The drug’s side effect profile, consisting mostly of short-term flushing and gastrointestinal complaints, is the most benign of the three oral agents. Thus, it could potentially see broader use both as a first-line drug in newly diagnosed patients and as second-line therapy in patients intolerant to or experiencing disease breakthrough on other agents.
That being said, it’s still unclear whether any of the available oral agents is the best choice after natalizumab discontinuation. A couple of studies of fingolimod showed a high relapse rate in this situation, and there are simply no data as yet on the two newer agents, according to Dr. Kita.
• Upcoming oral agents: The investigational oral agent furthest along in the developmental pipeline is laquinimod, a quinolone-3-carboxamide small molecule that has completed two phase III clinical trials and is now under review by the European Medicines Agency for possible marketing approval. Teva has not yet applied to the Food and Drug Administration for U.S. approval.
Several second-generation sphingosine-1-phosphate agonists are in development. They are believed to act more selectively and thus pose fewer potential immunocompromise issues than fingolimod. These include siponimod, ponesimod, and ONO-4641.
Dr. Kita reported receiving research support from Biogen Idec (which markets Tecfidera), Novartis (which markets Gilenya and is developing siponimod), Serono, and Acorda, as well as personal compensation from Biogen Idec, Bayer, and Genzyme (which markets Aubagio).
ORLANDO – Effective oral therapy has been at the top of the wish list of many multiple sclerosis patients for a long time – and now, seemingly all of a sudden, three approved oral agents are available to choose from.
For patients, the obvious attractions of oral therapy are ease of administration and that it’s less of a reminder that they have a serious chronic illness. But which agent is the right fit for a given patient?
All three oral drugs – fingolimod (Gilenya), teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera) – are "definitely" suitable as first-line therapy in selected newly diagnosed MS patients, Dr. Mariko Kita asserted at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
But the three oral drugs are not interchangeable. Each has a different mechanism of action and its own side effect profile, emphasized Dr. Kita, director of the Virginia Mason MS Center, Seattle, and director of the MS clinical trials unit at Virginia Mason’s Benaroya Research Institute.
Today few neurologists – certainly less than 10% – are using any oral agent as first-line therapy. That’s in part due to cost and reimbursement issues, but to a much greater extent it’s because most physicians don’t yet feel comfortable that the safety profiles of the oral agents are fully known. The drugs are still too new, in the eyes of most practitioners. After all, both natalizumab (Tysabri) – considered the most effective of the injectable agents – and fingolimod – the first oral agent to receive marketing approval, back in October 2010 – had to have revisionary cautions added to their labeling shortly after they were introduced.
But provider experience with the orals is expected to grow quickly. And absent any late bombshells regarding side effects, it’s widely anticipated that the use of oral agents for MS will surge within the next few years, with a corresponding decline in popularity of injectable therapies.
Demand for oral therapy will be high all across the patient spectrum: in newly diagnosed patients, in individuals with a lengthy disease history who have tried all the available disease-modifying therapies with less than satisfactory results and have been awaiting something new, in patients intolerant to or experiencing breakthrough disease on a first-line injectable agent, as well as in patients who are stable on their current injectable disease-modifying therapy but are experiencing injection fatigue or growing more concerned about their parenteral therapy’s long-term risks, Dr. Kita predicted.
Choosing between the oral options appropriately requires a focus on patient-specific factors, including comorbid conditions, reproductive status, and consideration of how the oral drug will fit in to the big picture of a long-term, staged therapy plan, she added.
Here’s her personal clinical rundown on the approved oral drugs:
• Fingolimod: This is a drug best reserved for MS patients who are otherwise relatively healthy, in Dr. Kita’s view. Specifically, it’s a less favorable option for patients with diabetes, smokers, and others with reduced pulmonary function, and in individuals at increased risk of infection, including those with a high Expanded Disability Status Scale score.
Fingolimod is a sphingosine-1-phosphate agonist. It sequesters lymphocytes in the lymph nodes so they can’t participate in autoimmune activity. The required testing prior to starting the drug, the need for careful observation during the first dose, and the necessary ongoing monitoring as long as the patient is on fingolimod make this a labor-intensive drug.
Bearing those caveats in mind, she continued, fingolimod is "reasonable" to use as a first-line agent, or as a second-line agent in the setting of intolerance to or breakthrough disease while on prior therapy.
"But I would caution those who are reserving these oral agents as second-line that we need to think about what we can reasonably expect from them. If we’re moving to them as second-line because of tolerability issues with first-line agents, yes, I think that’s most reasonable. But if we’re moving because of breakthrough disease, our experience with these agents in cases of failure with standard first-line therapies is very, very limited. Sure, the differing mechanism of action offers a reasonable alternative option, but the expectation that the oral will be better than a failed injectable has not yet been proven," Dr. Kita said.
• Teriflunomide: This is the active metabolite of leflunomide, a treatment approved by the Food and Drug Administration for rheumatoid arthritis. It was approved for treating relapsing forms of MS last fall. Teriflunomide nonselectively inhibits rapidly dividing cell populations by curbing pyrimidine synthesis via bonding to the enzyme dihydroorotate dehydrogenase.
Who’s the right fit for teriflunomide? Because the drug is rated category X and has teratogenicity potential in both men and women, it’s a given that the candidate must be on effective contraception. Also, the patient should definitely not have comorbid liver disease. And in Dr. Kita’s view, an appropriate candidate for teriflunomide has mild MS. Otherwise, the physician can get backed into a corner. That’s because the drug is excreted very slowly and is not dialyzable. Indeed, it takes 8-24 months after drug discontinuation for plasma levels to become undetectable.
"Teriflunomide could definitely be used as first-line therapy. It can be used second-line in a patient intolerant to a prior agent. But I think the long half-life complicates its use as second-line therapy in patients who’ve had breakthrough disease on prior agents, because if we need to consider a switch from teriflunomide, that long half-life has to be taken into consideration. You’ll need to consider the elimination protocol," she advised.
Patients find the elimination protocol arduous. It entails swallowing 8 g of oral cholestyramine every 8 hours for 11 days, or 50 g of activated charcoal given orally every 12 hours for 11 days.
• Dimethyl fumarate: This twice-daily oral agent, which was approved last March, activates the nuclear factor transcriptional pathway, thereby defending against oxidative stress–induced neuronal death. Dimethyl fumarate also supports myelin integrity in the central nervous system.
The drug’s side effect profile, consisting mostly of short-term flushing and gastrointestinal complaints, is the most benign of the three oral agents. Thus, it could potentially see broader use both as a first-line drug in newly diagnosed patients and as second-line therapy in patients intolerant to or experiencing disease breakthrough on other agents.
That being said, it’s still unclear whether any of the available oral agents is the best choice after natalizumab discontinuation. A couple of studies of fingolimod showed a high relapse rate in this situation, and there are simply no data as yet on the two newer agents, according to Dr. Kita.
• Upcoming oral agents: The investigational oral agent furthest along in the developmental pipeline is laquinimod, a quinolone-3-carboxamide small molecule that has completed two phase III clinical trials and is now under review by the European Medicines Agency for possible marketing approval. Teva has not yet applied to the Food and Drug Administration for U.S. approval.
Several second-generation sphingosine-1-phosphate agonists are in development. They are believed to act more selectively and thus pose fewer potential immunocompromise issues than fingolimod. These include siponimod, ponesimod, and ONO-4641.
Dr. Kita reported receiving research support from Biogen Idec (which markets Tecfidera), Novartis (which markets Gilenya and is developing siponimod), Serono, and Acorda, as well as personal compensation from Biogen Idec, Bayer, and Genzyme (which markets Aubagio).
EXPERT ANALYSIS FROM THE CMSC/ACTRIMS ANNUAL MEETING
Mark Freedman, MD
Evidence-based medical marijuana for MS symptoms
ORLANDO – The randomized trials evidence supporting a positive clinical effect for medical marijuana in relieving symptoms of multiple sclerosis is strongest for improvement of pain, patient-reported spasticity, and sleep disturbances.
That’s the clear message from an analysis of the 19 published, reasonable-quality randomized trials of cannabis use in patients with MS, Dr. Allen C. Bowling reported at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
"That’s consistent with my personal observation in a state where we’ve had medical marijuana for 12 years and where recreational marijuana was approved in last November’s election. The most consistent effect my patients report is on nocturnal pain and/or spasticity, which is consistent with the results of the clinical trials. The patients typically use a little bit at bedtime," according to Dr. Bowling, medical director of the MS service and director of the complementary and alternative medicine service at the Colorado Neurological Institute, Englewood.
The evidence that medical marijuana is of benefit for the bladder dysfunction associated with MS is weaker: Of 9 clinical trials that included bladder dysfunction as an endpoint, 4 were positive, 5 negative.
Occupying the bottom tier in terms of evidence-based therapy are objectively measured spasticity and tremor. Of 13 clinical trials that incorporated objective, clinician-assessed spasticity as an endpoint, only 2 were positive, with 11 negative. And none of the 5 decent-quality randomized trials that examined medical marijuana for relief of tremor in MS patients was positive.
In contrast, 9 of 11 studies that looked at pain as an endpoint reported a positive effect. Of 13 studies with patient-reported spasticity as an endpoint, 9 were positive, 4 negative. And of 6 randomized trials with sleep quality as an endpoint, 5 were positive, 1 negative, noted Dr. Bowling, who is clinical professor of neurology at the University of Colorado, Denver.
Medical marijuana is now legal in 18 states and the District of Columbia.
The largest and in Dr. Bowling’s view one of the best-conducted randomized trials in the field was the multicenter U.K. CAMS trial. The 15-week study included 630 MS patients who were randomized to oral tetrahydrocannabinol (Marinol); Cannador, an oral capsule containing a standardized amount of whole-plant extract; or placebo. The investigators found no significant difference between the cannabis-based therapies and placebo in improving spasticity as objectively measured using the Ashworth score, which was the primary study endpoint. However, the two active treatment arms did show significant benefit in terms of the secondary endpoints of improvement in pain, self-reported spasticity, and sleep (Lancet 2003;362:1517-26).
Another speaker at the session on prescribing medical marijuana underscored the beneficial effect on sleep disruption.
"In every single population – whether it’s Crohn’s disease, epilepsy, HIV, noncancer pain, cancer pain – improved sleep is always one of the most robust outcomes patients report. This is something that in clinical practice we tend to push to one side. We have some medications for pain management that we sometimes use for sleep, but cannabis use at nighttime seems to be a very powerful agent to improve sleep quality," observed Dr. Mark F. Ware, a family physician and anesthesiologist who is director of clinical research at the Alan Edwards Pain Management Unit of McGill University in Montreal.
Dr. Bowling estimated that roughly 80% of his MS patients have little or no interest in medical marijuana. Those who are using it span a spectrum ranging from patients who were recreational users of pot before their MS diagnosis and who now seek beneficial MS effects or simply a license to use it recreationally, to elderly individuals with no history of marijuana use who have found cannabis is the only thing that effectively relieves some of their symptoms.
The neurologist noted two glaring paradoxes that emerged from his review of the clinical trials literature on medical marijuana for MS. One is that only 2 of the 19 studies utilized smoked marijuana, even though it’s far and away the most readily available form of the agent for U.S. patients. The most widely studied agent nabiximols (Sativex), an extract formulated as an oral spray – is approved as a prescription drug in Canada, the United Kingdom, and other countries, but not in the United States. And while Marinol and oral nabilone (Cesamet) are approved by the Food and Drug Administration, they’re not widely prescribed.
"I find it particularly challenging to apply the medical literature in this area to clinical situations. In our clinical practice, the way it seems to work out best is for patients to experiment on their own with marijuana as a prn add-on to their spasticity and/or pain medications, especially at bedtime or, if symptoms are worse, in the afternoon. But the dose, frequency, formulation, quality control ... it’s a real challenge. It’s like there are parallel universes of care, where we’re prescribing the conventional medications, and then we find out that the patients are also using marijuana," Dr. Bowling said.
The other paradox is the huge disconnect between the generally quite favorable subjective patient self-reports of improvement in spasticity and the largely negative objective results. The explanation may lie in part in the inadequacy of the Ashworth score as an outcome measure. It has come under frequent criticism, since some approved antispasticity medications have shown only modest or no improvement in Ashworth scores. But the limitations of the Ashworth score are probably only part of the story, in Dr. Bowling’s view.
"Patients’ assessments are 24/7; ours is a brief clinical visit at a prespecified time. Also, there is a pain component to spasticity, so for some patients who feel their spasticity is improving with the use of marijuana it may just be the pain aspect of the spasticity, or a euphoric view of the world that’s changing their perception of how severe the spasticity is. But for some patients, maybe it doesn’t matter whether it’s a subjective or objective assessment that’s improving, especially for those who don’t have high physical or cognitive demands during the day," he said.
Dr. Bowling reported having no conflicts of interest. Dr. Ware has received lecture fees from the Canadian Consortium for the Investigation of the Cannabinoids and a research grant and honoraria from Valeant for conducting a randomized trial of nabilone in fibromyalgia patients.
ORLANDO – The randomized trials evidence supporting a positive clinical effect for medical marijuana in relieving symptoms of multiple sclerosis is strongest for improvement of pain, patient-reported spasticity, and sleep disturbances.
That’s the clear message from an analysis of the 19 published, reasonable-quality randomized trials of cannabis use in patients with MS, Dr. Allen C. Bowling reported at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
"That’s consistent with my personal observation in a state where we’ve had medical marijuana for 12 years and where recreational marijuana was approved in last November’s election. The most consistent effect my patients report is on nocturnal pain and/or spasticity, which is consistent with the results of the clinical trials. The patients typically use a little bit at bedtime," according to Dr. Bowling, medical director of the MS service and director of the complementary and alternative medicine service at the Colorado Neurological Institute, Englewood.
The evidence that medical marijuana is of benefit for the bladder dysfunction associated with MS is weaker: Of 9 clinical trials that included bladder dysfunction as an endpoint, 4 were positive, 5 negative.
Occupying the bottom tier in terms of evidence-based therapy are objectively measured spasticity and tremor. Of 13 clinical trials that incorporated objective, clinician-assessed spasticity as an endpoint, only 2 were positive, with 11 negative. And none of the 5 decent-quality randomized trials that examined medical marijuana for relief of tremor in MS patients was positive.
In contrast, 9 of 11 studies that looked at pain as an endpoint reported a positive effect. Of 13 studies with patient-reported spasticity as an endpoint, 9 were positive, 4 negative. And of 6 randomized trials with sleep quality as an endpoint, 5 were positive, 1 negative, noted Dr. Bowling, who is clinical professor of neurology at the University of Colorado, Denver.
Medical marijuana is now legal in 18 states and the District of Columbia.
The largest and in Dr. Bowling’s view one of the best-conducted randomized trials in the field was the multicenter U.K. CAMS trial. The 15-week study included 630 MS patients who were randomized to oral tetrahydrocannabinol (Marinol); Cannador, an oral capsule containing a standardized amount of whole-plant extract; or placebo. The investigators found no significant difference between the cannabis-based therapies and placebo in improving spasticity as objectively measured using the Ashworth score, which was the primary study endpoint. However, the two active treatment arms did show significant benefit in terms of the secondary endpoints of improvement in pain, self-reported spasticity, and sleep (Lancet 2003;362:1517-26).
Another speaker at the session on prescribing medical marijuana underscored the beneficial effect on sleep disruption.
"In every single population – whether it’s Crohn’s disease, epilepsy, HIV, noncancer pain, cancer pain – improved sleep is always one of the most robust outcomes patients report. This is something that in clinical practice we tend to push to one side. We have some medications for pain management that we sometimes use for sleep, but cannabis use at nighttime seems to be a very powerful agent to improve sleep quality," observed Dr. Mark F. Ware, a family physician and anesthesiologist who is director of clinical research at the Alan Edwards Pain Management Unit of McGill University in Montreal.
Dr. Bowling estimated that roughly 80% of his MS patients have little or no interest in medical marijuana. Those who are using it span a spectrum ranging from patients who were recreational users of pot before their MS diagnosis and who now seek beneficial MS effects or simply a license to use it recreationally, to elderly individuals with no history of marijuana use who have found cannabis is the only thing that effectively relieves some of their symptoms.
The neurologist noted two glaring paradoxes that emerged from his review of the clinical trials literature on medical marijuana for MS. One is that only 2 of the 19 studies utilized smoked marijuana, even though it’s far and away the most readily available form of the agent for U.S. patients. The most widely studied agent nabiximols (Sativex), an extract formulated as an oral spray – is approved as a prescription drug in Canada, the United Kingdom, and other countries, but not in the United States. And while Marinol and oral nabilone (Cesamet) are approved by the Food and Drug Administration, they’re not widely prescribed.
"I find it particularly challenging to apply the medical literature in this area to clinical situations. In our clinical practice, the way it seems to work out best is for patients to experiment on their own with marijuana as a prn add-on to their spasticity and/or pain medications, especially at bedtime or, if symptoms are worse, in the afternoon. But the dose, frequency, formulation, quality control ... it’s a real challenge. It’s like there are parallel universes of care, where we’re prescribing the conventional medications, and then we find out that the patients are also using marijuana," Dr. Bowling said.
The other paradox is the huge disconnect between the generally quite favorable subjective patient self-reports of improvement in spasticity and the largely negative objective results. The explanation may lie in part in the inadequacy of the Ashworth score as an outcome measure. It has come under frequent criticism, since some approved antispasticity medications have shown only modest or no improvement in Ashworth scores. But the limitations of the Ashworth score are probably only part of the story, in Dr. Bowling’s view.
"Patients’ assessments are 24/7; ours is a brief clinical visit at a prespecified time. Also, there is a pain component to spasticity, so for some patients who feel their spasticity is improving with the use of marijuana it may just be the pain aspect of the spasticity, or a euphoric view of the world that’s changing their perception of how severe the spasticity is. But for some patients, maybe it doesn’t matter whether it’s a subjective or objective assessment that’s improving, especially for those who don’t have high physical or cognitive demands during the day," he said.
Dr. Bowling reported having no conflicts of interest. Dr. Ware has received lecture fees from the Canadian Consortium for the Investigation of the Cannabinoids and a research grant and honoraria from Valeant for conducting a randomized trial of nabilone in fibromyalgia patients.
ORLANDO – The randomized trials evidence supporting a positive clinical effect for medical marijuana in relieving symptoms of multiple sclerosis is strongest for improvement of pain, patient-reported spasticity, and sleep disturbances.
That’s the clear message from an analysis of the 19 published, reasonable-quality randomized trials of cannabis use in patients with MS, Dr. Allen C. Bowling reported at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
"That’s consistent with my personal observation in a state where we’ve had medical marijuana for 12 years and where recreational marijuana was approved in last November’s election. The most consistent effect my patients report is on nocturnal pain and/or spasticity, which is consistent with the results of the clinical trials. The patients typically use a little bit at bedtime," according to Dr. Bowling, medical director of the MS service and director of the complementary and alternative medicine service at the Colorado Neurological Institute, Englewood.
The evidence that medical marijuana is of benefit for the bladder dysfunction associated with MS is weaker: Of 9 clinical trials that included bladder dysfunction as an endpoint, 4 were positive, 5 negative.
Occupying the bottom tier in terms of evidence-based therapy are objectively measured spasticity and tremor. Of 13 clinical trials that incorporated objective, clinician-assessed spasticity as an endpoint, only 2 were positive, with 11 negative. And none of the 5 decent-quality randomized trials that examined medical marijuana for relief of tremor in MS patients was positive.
In contrast, 9 of 11 studies that looked at pain as an endpoint reported a positive effect. Of 13 studies with patient-reported spasticity as an endpoint, 9 were positive, 4 negative. And of 6 randomized trials with sleep quality as an endpoint, 5 were positive, 1 negative, noted Dr. Bowling, who is clinical professor of neurology at the University of Colorado, Denver.
Medical marijuana is now legal in 18 states and the District of Columbia.
The largest and in Dr. Bowling’s view one of the best-conducted randomized trials in the field was the multicenter U.K. CAMS trial. The 15-week study included 630 MS patients who were randomized to oral tetrahydrocannabinol (Marinol); Cannador, an oral capsule containing a standardized amount of whole-plant extract; or placebo. The investigators found no significant difference between the cannabis-based therapies and placebo in improving spasticity as objectively measured using the Ashworth score, which was the primary study endpoint. However, the two active treatment arms did show significant benefit in terms of the secondary endpoints of improvement in pain, self-reported spasticity, and sleep (Lancet 2003;362:1517-26).
Another speaker at the session on prescribing medical marijuana underscored the beneficial effect on sleep disruption.
"In every single population – whether it’s Crohn’s disease, epilepsy, HIV, noncancer pain, cancer pain – improved sleep is always one of the most robust outcomes patients report. This is something that in clinical practice we tend to push to one side. We have some medications for pain management that we sometimes use for sleep, but cannabis use at nighttime seems to be a very powerful agent to improve sleep quality," observed Dr. Mark F. Ware, a family physician and anesthesiologist who is director of clinical research at the Alan Edwards Pain Management Unit of McGill University in Montreal.
Dr. Bowling estimated that roughly 80% of his MS patients have little or no interest in medical marijuana. Those who are using it span a spectrum ranging from patients who were recreational users of pot before their MS diagnosis and who now seek beneficial MS effects or simply a license to use it recreationally, to elderly individuals with no history of marijuana use who have found cannabis is the only thing that effectively relieves some of their symptoms.
The neurologist noted two glaring paradoxes that emerged from his review of the clinical trials literature on medical marijuana for MS. One is that only 2 of the 19 studies utilized smoked marijuana, even though it’s far and away the most readily available form of the agent for U.S. patients. The most widely studied agent nabiximols (Sativex), an extract formulated as an oral spray – is approved as a prescription drug in Canada, the United Kingdom, and other countries, but not in the United States. And while Marinol and oral nabilone (Cesamet) are approved by the Food and Drug Administration, they’re not widely prescribed.
"I find it particularly challenging to apply the medical literature in this area to clinical situations. In our clinical practice, the way it seems to work out best is for patients to experiment on their own with marijuana as a prn add-on to their spasticity and/or pain medications, especially at bedtime or, if symptoms are worse, in the afternoon. But the dose, frequency, formulation, quality control ... it’s a real challenge. It’s like there are parallel universes of care, where we’re prescribing the conventional medications, and then we find out that the patients are also using marijuana," Dr. Bowling said.
The other paradox is the huge disconnect between the generally quite favorable subjective patient self-reports of improvement in spasticity and the largely negative objective results. The explanation may lie in part in the inadequacy of the Ashworth score as an outcome measure. It has come under frequent criticism, since some approved antispasticity medications have shown only modest or no improvement in Ashworth scores. But the limitations of the Ashworth score are probably only part of the story, in Dr. Bowling’s view.
"Patients’ assessments are 24/7; ours is a brief clinical visit at a prespecified time. Also, there is a pain component to spasticity, so for some patients who feel their spasticity is improving with the use of marijuana it may just be the pain aspect of the spasticity, or a euphoric view of the world that’s changing their perception of how severe the spasticity is. But for some patients, maybe it doesn’t matter whether it’s a subjective or objective assessment that’s improving, especially for those who don’t have high physical or cognitive demands during the day," he said.
Dr. Bowling reported having no conflicts of interest. Dr. Ware has received lecture fees from the Canadian Consortium for the Investigation of the Cannabinoids and a research grant and honoraria from Valeant for conducting a randomized trial of nabilone in fibromyalgia patients.
EXPERT ANALYSIS FROM THE CMSC/ACTRIMS ANNUAL MEETING
Is MS therapy getting to be too much for general neurologists?
ORLANDO – The burgeoning treatment options for multiple sclerosis are increasingly pushing the disease beyond the comfort zone of general neurologists, according to Dr. Mariko Kita.
"MS has become a very, very active area. We’re diagnosing this condition now earlier than ever before. We are initiating treatments at the earliest sign of this condition. We’re going to be seeing, if we haven’t already, a greater influx of patients into MS centers to try to tease apart which disease-modifying therapy might be best for them. And it’s possible that the general neurologists who aren’t referring patients to us at MS centers are going to limit their discussion. They’re going to stick to their go-to drugs: They’ll say, ‘I’ve got one go-to injectable and one go-to oral, and those are the things I’m going to talk about,’ " predicted Dr. Kita, director of the Virginia Mason MS Center, Seattle, and director of the MS clinical trials unit at Virginia Mason’s Benaroya Research Institute.
There are currently nine Food and Drug Administration–approved disease-modifying therapies for MS, including three recently approved oral agents. Plenty of additional medications are advancing through the developmental pipeline.
"All of these new treatments have definitely had an impact on our clinical practice. They’ve increased our burden in a number of ways," Dr. Kita said at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
For one, patient education regarding treatment options has become quite time consuming.
"The discussion of the educational component of the injectables has already been fairly complicated, and now we’re adding to it agents that have a very wide spectrum of mechanisms of action," the neurologist said. "So the question is, how much detail do you go into? What information do you share? And if you’re not in an MS center, do you have help from a nurse educator or others to do this education?"
And then there is the numbing challenge of securing insurance authorization for treatment. "This is perhaps the single biggest unreimbursed burden on my clinic and clinic staff. This is really a major deal for MS centers," Dr. Kita said.
Requisite patient monitoring is also increasingly elaborate. This may include testing prior to putting a patient on an agent, first-dose monitoring, and ongoing monitoring for treatment adherence and the possible emergence of serious side effects.
Take, for example, fingolimod (Gilenya), approved in September 2010 as the first disease-modifying oral agent for MS, and thus the oral drug with which physicians have the most experience.
"The start-up, let’s face it, is labor intensive," Dr. Kita said.
Her personal practice before placing a patient on fingolimod is to order an electrocardiogram, pulmonary function tests, a retinal optical coherence tomography (OCT) scan, a dermatologic evaluation, and a check of varicella titers, with vaccination if appropriate. Then comes the supervised, 6-hour, first-dose observation period.
"We do that in the clinic. We have the patient bring in a companion. They take up an exam room and are not under continuous surveillance, so if issues should arise, we want a companion on hand to call for help. Plus, a medical assistant goes in every hour. And the prescribing physician checks in before the first dose and at the end of the day," she explained.
If patients are taking a medication that prolongs the QT interval, however, as many do in order to control their chronic pain, they should be hospitalized for the first dose of fingolimod, Dr. Kita added.
Monitoring needs to be done on an ongoing basis, although as yet there are no clear guidelines as to the specifics. She recommended an annual brain MRI, an ECG, pulmonary function tests, a dermatologic evaluation, and an OCT, because cases of macular edema have occurred 2 years into treatment.
"That’s not necessarily everyone’s standard practice, but it’s what we do," she continued.
And then there is the issue of monitoring circulating CD4 cell counts. Fingolimod’s mechanism of action involves sequestration of lymphocytes in lymph nodes so they can’t contribute to autoimmunity. As a result, patients maintained on fingolimod experience abnormally low levels of circulating CD4 cells, the clinical significance of which remains unclear.
"I think the immunocompromise issue hasn’t really been resolved. I know of practitioners who say, ‘I don’t want to check CD4 counts because it makes me nervous,’ and I’m not sure that’s the best practice. Having said that, it’s hard to know what to do with those exceedingly low CD4 counts," Dr. Kita said.
She added that she views the development of shingles in a patient on fingolimod as a potential red flag warranting serious consideration of a switch to another agent.
Dr. Kita reported receiving research support from Biogen Idec, Novartis (which markets Gilenya), Serono, and Acorda, and personal compensation from Biogen Idec, Bayer, and Genzyme.
ORLANDO – The burgeoning treatment options for multiple sclerosis are increasingly pushing the disease beyond the comfort zone of general neurologists, according to Dr. Mariko Kita.
"MS has become a very, very active area. We’re diagnosing this condition now earlier than ever before. We are initiating treatments at the earliest sign of this condition. We’re going to be seeing, if we haven’t already, a greater influx of patients into MS centers to try to tease apart which disease-modifying therapy might be best for them. And it’s possible that the general neurologists who aren’t referring patients to us at MS centers are going to limit their discussion. They’re going to stick to their go-to drugs: They’ll say, ‘I’ve got one go-to injectable and one go-to oral, and those are the things I’m going to talk about,’ " predicted Dr. Kita, director of the Virginia Mason MS Center, Seattle, and director of the MS clinical trials unit at Virginia Mason’s Benaroya Research Institute.
There are currently nine Food and Drug Administration–approved disease-modifying therapies for MS, including three recently approved oral agents. Plenty of additional medications are advancing through the developmental pipeline.
"All of these new treatments have definitely had an impact on our clinical practice. They’ve increased our burden in a number of ways," Dr. Kita said at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
For one, patient education regarding treatment options has become quite time consuming.
"The discussion of the educational component of the injectables has already been fairly complicated, and now we’re adding to it agents that have a very wide spectrum of mechanisms of action," the neurologist said. "So the question is, how much detail do you go into? What information do you share? And if you’re not in an MS center, do you have help from a nurse educator or others to do this education?"
And then there is the numbing challenge of securing insurance authorization for treatment. "This is perhaps the single biggest unreimbursed burden on my clinic and clinic staff. This is really a major deal for MS centers," Dr. Kita said.
Requisite patient monitoring is also increasingly elaborate. This may include testing prior to putting a patient on an agent, first-dose monitoring, and ongoing monitoring for treatment adherence and the possible emergence of serious side effects.
Take, for example, fingolimod (Gilenya), approved in September 2010 as the first disease-modifying oral agent for MS, and thus the oral drug with which physicians have the most experience.
"The start-up, let’s face it, is labor intensive," Dr. Kita said.
Her personal practice before placing a patient on fingolimod is to order an electrocardiogram, pulmonary function tests, a retinal optical coherence tomography (OCT) scan, a dermatologic evaluation, and a check of varicella titers, with vaccination if appropriate. Then comes the supervised, 6-hour, first-dose observation period.
"We do that in the clinic. We have the patient bring in a companion. They take up an exam room and are not under continuous surveillance, so if issues should arise, we want a companion on hand to call for help. Plus, a medical assistant goes in every hour. And the prescribing physician checks in before the first dose and at the end of the day," she explained.
If patients are taking a medication that prolongs the QT interval, however, as many do in order to control their chronic pain, they should be hospitalized for the first dose of fingolimod, Dr. Kita added.
Monitoring needs to be done on an ongoing basis, although as yet there are no clear guidelines as to the specifics. She recommended an annual brain MRI, an ECG, pulmonary function tests, a dermatologic evaluation, and an OCT, because cases of macular edema have occurred 2 years into treatment.
"That’s not necessarily everyone’s standard practice, but it’s what we do," she continued.
And then there is the issue of monitoring circulating CD4 cell counts. Fingolimod’s mechanism of action involves sequestration of lymphocytes in lymph nodes so they can’t contribute to autoimmunity. As a result, patients maintained on fingolimod experience abnormally low levels of circulating CD4 cells, the clinical significance of which remains unclear.
"I think the immunocompromise issue hasn’t really been resolved. I know of practitioners who say, ‘I don’t want to check CD4 counts because it makes me nervous,’ and I’m not sure that’s the best practice. Having said that, it’s hard to know what to do with those exceedingly low CD4 counts," Dr. Kita said.
She added that she views the development of shingles in a patient on fingolimod as a potential red flag warranting serious consideration of a switch to another agent.
Dr. Kita reported receiving research support from Biogen Idec, Novartis (which markets Gilenya), Serono, and Acorda, and personal compensation from Biogen Idec, Bayer, and Genzyme.
ORLANDO – The burgeoning treatment options for multiple sclerosis are increasingly pushing the disease beyond the comfort zone of general neurologists, according to Dr. Mariko Kita.
"MS has become a very, very active area. We’re diagnosing this condition now earlier than ever before. We are initiating treatments at the earliest sign of this condition. We’re going to be seeing, if we haven’t already, a greater influx of patients into MS centers to try to tease apart which disease-modifying therapy might be best for them. And it’s possible that the general neurologists who aren’t referring patients to us at MS centers are going to limit their discussion. They’re going to stick to their go-to drugs: They’ll say, ‘I’ve got one go-to injectable and one go-to oral, and those are the things I’m going to talk about,’ " predicted Dr. Kita, director of the Virginia Mason MS Center, Seattle, and director of the MS clinical trials unit at Virginia Mason’s Benaroya Research Institute.
There are currently nine Food and Drug Administration–approved disease-modifying therapies for MS, including three recently approved oral agents. Plenty of additional medications are advancing through the developmental pipeline.
"All of these new treatments have definitely had an impact on our clinical practice. They’ve increased our burden in a number of ways," Dr. Kita said at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
For one, patient education regarding treatment options has become quite time consuming.
"The discussion of the educational component of the injectables has already been fairly complicated, and now we’re adding to it agents that have a very wide spectrum of mechanisms of action," the neurologist said. "So the question is, how much detail do you go into? What information do you share? And if you’re not in an MS center, do you have help from a nurse educator or others to do this education?"
And then there is the numbing challenge of securing insurance authorization for treatment. "This is perhaps the single biggest unreimbursed burden on my clinic and clinic staff. This is really a major deal for MS centers," Dr. Kita said.
Requisite patient monitoring is also increasingly elaborate. This may include testing prior to putting a patient on an agent, first-dose monitoring, and ongoing monitoring for treatment adherence and the possible emergence of serious side effects.
Take, for example, fingolimod (Gilenya), approved in September 2010 as the first disease-modifying oral agent for MS, and thus the oral drug with which physicians have the most experience.
"The start-up, let’s face it, is labor intensive," Dr. Kita said.
Her personal practice before placing a patient on fingolimod is to order an electrocardiogram, pulmonary function tests, a retinal optical coherence tomography (OCT) scan, a dermatologic evaluation, and a check of varicella titers, with vaccination if appropriate. Then comes the supervised, 6-hour, first-dose observation period.
"We do that in the clinic. We have the patient bring in a companion. They take up an exam room and are not under continuous surveillance, so if issues should arise, we want a companion on hand to call for help. Plus, a medical assistant goes in every hour. And the prescribing physician checks in before the first dose and at the end of the day," she explained.
If patients are taking a medication that prolongs the QT interval, however, as many do in order to control their chronic pain, they should be hospitalized for the first dose of fingolimod, Dr. Kita added.
Monitoring needs to be done on an ongoing basis, although as yet there are no clear guidelines as to the specifics. She recommended an annual brain MRI, an ECG, pulmonary function tests, a dermatologic evaluation, and an OCT, because cases of macular edema have occurred 2 years into treatment.
"That’s not necessarily everyone’s standard practice, but it’s what we do," she continued.
And then there is the issue of monitoring circulating CD4 cell counts. Fingolimod’s mechanism of action involves sequestration of lymphocytes in lymph nodes so they can’t contribute to autoimmunity. As a result, patients maintained on fingolimod experience abnormally low levels of circulating CD4 cells, the clinical significance of which remains unclear.
"I think the immunocompromise issue hasn’t really been resolved. I know of practitioners who say, ‘I don’t want to check CD4 counts because it makes me nervous,’ and I’m not sure that’s the best practice. Having said that, it’s hard to know what to do with those exceedingly low CD4 counts," Dr. Kita said.
She added that she views the development of shingles in a patient on fingolimod as a potential red flag warranting serious consideration of a switch to another agent.
Dr. Kita reported receiving research support from Biogen Idec, Novartis (which markets Gilenya), Serono, and Acorda, and personal compensation from Biogen Idec, Bayer, and Genzyme.
EXPERT ANALYSIS FROM THE CMSC/ACTRIMS ANNUAL MEETING
