ICYMI Multiple Sclerosis

Patients with multiple sclerosis (MS) who receive natalizumab may have as much as a 10-fold greater risk of seroconversion to John Cunningham virus (JCV)-positive status, according to a study published online January 27 in Neurology Neuroimmunology & Neuroinflammation.

“An increase in the levels of anti-JCV antibodies could signify an increased risk of progressive multifocal leukoencephalopathy (PML),” said the study’s senior author, Heinz Wiendl, MD, Professor of Neurology at the University of Münster in Germany.

Dr. Wiendl and colleagues performed a longitudinal analysis of 525 German patients with MS and 711 French patients with MS, all of whom were treated with natalizumab, to assess whether the therapy influenced JCV seroconversion or JCV index value (ie, the level of anti-JCV antibody titers). An independent contractor processed and analyzed sera samples with the second-generation enzyme-linked immunosorbent assay kit STRATIFY JCV DxSelect.

Seroconversion and Increasing Index Value

Of the 525 German patients, 296 (56.4%) were JCV-negative throughout the observation period, and 171 were JCV-positive (32.6%). Forty-three patients changed from being JCV-negative to JCV-positive (8.2%), and 15 patients changed from being JCV-positive to JCV-negative (2.9%). When the authors used JCV serostatus to determine seroconversion, the longitudinal assessment started out with 339 initially JCV-negative patients. The serostatus of 43 of these initially JCV-negative patients changed to JCV-positive, which is a rate of 12.7% in 14.8 months (10.3% per year).

Of the 711 French patients, 243 initially were JCV-negative. The serostatus of 20 (8.2%) of these latter patients changed to JCV-positive in their first year of treatment, and 21 (8.6%) of the patients became JCV-positive in their second year of treatment. In all, the serostatus of 41 of 243 patients (16.9%) changed to JCV-positive in the first two years of natalizumab treatment (8.5% per year).

In addition, JCV index values changed in 525 patients during the observation period. The proportion of patients with an index value less than 0.4 was reduced by 20 patients (ie, from 65.1% to 61.3%), and the group of patients with low risk (ie, values between 0.4 and 0.9) was reduced by one patient to 7.8%. The patient groups with medium (ie, 0.9–1.5) and high risk (ie, greater than 1.5) increased by seven patients from 4.6% to 5.9% and by 14 patients from 22.3% to 25%, respectively.Furthermore, 161 of 201 JCV-positive patients (80%) had stable JCV index values over time. The remaining 40 patients (20%) had fluctuations of more than 30% in 14.8 months. Six of these patients (3%) had decreasing index values, and 34 (17%) had increasing index values (mean, 200.8%). Overall, the index value of all JCV-positive patients increased by an average of 15.9% in 14.8 months (12.9% per year).

Increased Index May Not Indicate Imminent PML

The high rate of seroconversion that the investigators observed “clearly supports the facilitation by treatment with natalizumab,” said Dr. Wiendl. “Our observed seroconversion of 8% to 10% per year and the rise in seroprevalence of 5% to 6% in 15 to 24 months is at least eight to 10 times as much as would be expected by age.” The study results imply that not every patient with MS is susceptible to JCV seroconversion by treatment, but natalizumab might facilitate seroconversion in patients who are susceptible.

No research has examined the influence of other MS treatments on JCV index values, and the investigators thus cannot be certain that natalizumab treatment caused the increase in index values observed in the study. But because there was no correlation between age and index value in JCV-positive patients, it is valid to speculate that natalizumab treatment induces rising JCV index values.

“If the hypothesis that treatment with natalizumab is associated with enhanced JCV seroconversion and higher index values is proven, it would also be important to determine whether cessation of natalizumab therapy (or perhaps prolonged infusion intervals) could lead to lower JCV index values as well,” Dr. Wiendl continued. The association “does not diminish [natalizumab’s] clinical efficacy, but calls for more elaborate strategies for PML risk stratification according to current scientific developments, also regarding patients with prior use of immunosuppressants, where the JCV index is not helpful.

“It is important that people with MS taking natalizumab speak with their doctor before making any changes to their treatment,” Dr. Wiendl added. “Still, this study shows anti-JCV antibodies may serve as a useful biomarker…. The results of this study underscore the need for frequent monitoring of anti-JCV antibodies in people who are being treated with natalizumab for MS.”

JCV serology, however, should not be the only PML risk biomarker to stratify patients treated with natalizumab, said Dr. Wiendl. Neurologists should explore and potentially apply additional biomarkers such as CD62L in peripheral blood or IgM bands in CSF. Together, all of these biomarkers may provide more accurate information about patients’ PML risk and help reduce the incidence of PML.

The investigators’ data extend earlier paired, longitudinal studies in various countries of patients treated with natalizumab who had similarly high rates of conversion and a rise in titers, said Adil Javed, MD, PhD, Associate Professor of Neurology, and Anthony T. Reder, MD, Professor of Neurology, both at the University of Chicago, in an accompanying editorial. Although the JCV index appears to be a valid serum marker of risk for PML, “risk is relative,” they said. “Despite a higher JCV replication state, an increase in JCV-antibody index does not necessarily mean that PML infection is imminent…. Schwab et al extend growing observations that JCV-antibody index values need to be monitored and that seroconversion or rising JCV-antibody titers alter the risk of PML in patients treated with natalizumab.”

—Erik Greb

Patients with multiple sclerosis (MS) who receive natalizumab may have as much as a 10-fold greater risk of seroconversion to John Cunningham virus (JCV)-positive status, according to a study published online January 27 in Neurology Neuroimmunology & Neuroinflammation.

“An increase in the levels of anti-JCV antibodies could signify an increased risk of progressive multifocal leukoencephalopathy (PML),” said the study’s senior author, Heinz Wiendl, MD, Professor of Neurology at the University of Münster in Germany.

Dr. Wiendl and colleagues performed a longitudinal analysis of 525 German patients with MS and 711 French patients with MS, all of whom were treated with natalizumab, to assess whether the therapy influenced JCV seroconversion or JCV index value (ie, the level of anti-JCV antibody titers). An independent contractor processed and analyzed sera samples with the second-generation enzyme-linked immunosorbent assay kit STRATIFY JCV DxSelect.

Seroconversion and Increasing Index Value

Of the 525 German patients, 296 (56.4%) were JCV-negative throughout the observation period, and 171 were JCV-positive (32.6%). Forty-three patients changed from being JCV-negative to JCV-positive (8.2%), and 15 patients changed from being JCV-positive to JCV-negative (2.9%). When the authors used JCV serostatus to determine seroconversion, the longitudinal assessment started out with 339 initially JCV-negative patients. The serostatus of 43 of these initially JCV-negative patients changed to JCV-positive, which is a rate of 12.7% in 14.8 months (10.3% per year).

Of the 711 French patients, 243 initially were JCV-negative. The serostatus of 20 (8.2%) of these latter patients changed to JCV-positive in their first year of treatment, and 21 (8.6%) of the patients became JCV-positive in their second year of treatment. In all, the serostatus of 41 of 243 patients (16.9%) changed to JCV-positive in the first two years of natalizumab treatment (8.5% per year).

In addition, JCV index values changed in 525 patients during the observation period. The proportion of patients with an index value less than 0.4 was reduced by 20 patients (ie, from 65.1% to 61.3%), and the group of patients with low risk (ie, values between 0.4 and 0.9) was reduced by one patient to 7.8%. The patient groups with medium (ie, 0.9–1.5) and high risk (ie, greater than 1.5) increased by seven patients from 4.6% to 5.9% and by 14 patients from 22.3% to 25%, respectively.Furthermore, 161 of 201 JCV-positive patients (80%) had stable JCV index values over time. The remaining 40 patients (20%) had fluctuations of more than 30% in 14.8 months. Six of these patients (3%) had decreasing index values, and 34 (17%) had increasing index values (mean, 200.8%). Overall, the index value of all JCV-positive patients increased by an average of 15.9% in 14.8 months (12.9% per year).

Increased Index May Not Indicate Imminent PML

The high rate of seroconversion that the investigators observed “clearly supports the facilitation by treatment with natalizumab,” said Dr. Wiendl. “Our observed seroconversion of 8% to 10% per year and the rise in seroprevalence of 5% to 6% in 15 to 24 months is at least eight to 10 times as much as would be expected by age.” The study results imply that not every patient with MS is susceptible to JCV seroconversion by treatment, but natalizumab might facilitate seroconversion in patients who are susceptible.

No research has examined the influence of other MS treatments on JCV index values, and the investigators thus cannot be certain that natalizumab treatment caused the increase in index values observed in the study. But because there was no correlation between age and index value in JCV-positive patients, it is valid to speculate that natalizumab treatment induces rising JCV index values.

“If the hypothesis that treatment with natalizumab is associated with enhanced JCV seroconversion and higher index values is proven, it would also be important to determine whether cessation of natalizumab therapy (or perhaps prolonged infusion intervals) could lead to lower JCV index values as well,” Dr. Wiendl continued. The association “does not diminish [natalizumab’s] clinical efficacy, but calls for more elaborate strategies for PML risk stratification according to current scientific developments, also regarding patients with prior use of immunosuppressants, where the JCV index is not helpful.

“It is important that people with MS taking natalizumab speak with their doctor before making any changes to their treatment,” Dr. Wiendl added. “Still, this study shows anti-JCV antibodies may serve as a useful biomarker…. The results of this study underscore the need for frequent monitoring of anti-JCV antibodies in people who are being treated with natalizumab for MS.”

JCV serology, however, should not be the only PML risk biomarker to stratify patients treated with natalizumab, said Dr. Wiendl. Neurologists should explore and potentially apply additional biomarkers such as CD62L in peripheral blood or IgM bands in CSF. Together, all of these biomarkers may provide more accurate information about patients’ PML risk and help reduce the incidence of PML.

The investigators’ data extend earlier paired, longitudinal studies in various countries of patients treated with natalizumab who had similarly high rates of conversion and a rise in titers, said Adil Javed, MD, PhD, Associate Professor of Neurology, and Anthony T. Reder, MD, Professor of Neurology, both at the University of Chicago, in an accompanying editorial. Although the JCV index appears to be a valid serum marker of risk for PML, “risk is relative,” they said. “Despite a higher JCV replication state, an increase in JCV-antibody index does not necessarily mean that PML infection is imminent…. Schwab et al extend growing observations that JCV-antibody index values need to be monitored and that seroconversion or rising JCV-antibody titers alter the risk of PML in patients treated with natalizumab.”

—Erik Greb

Patients with multiple sclerosis (MS) who receive natalizumab may have as much as a 10-fold greater risk of seroconversion to John Cunningham virus (JCV)-positive status, according to a study published online January 27 in Neurology Neuroimmunology & Neuroinflammation.

“An increase in the levels of anti-JCV antibodies could signify an increased risk of progressive multifocal leukoencephalopathy (PML),” said the study’s senior author, Heinz Wiendl, MD, Professor of Neurology at the University of Münster in Germany.

Dr. Wiendl and colleagues performed a longitudinal analysis of 525 German patients with MS and 711 French patients with MS, all of whom were treated with natalizumab, to assess whether the therapy influenced JCV seroconversion or JCV index value (ie, the level of anti-JCV antibody titers). An independent contractor processed and analyzed sera samples with the second-generation enzyme-linked immunosorbent assay kit STRATIFY JCV DxSelect.

Seroconversion and Increasing Index Value

Of the 525 German patients, 296 (56.4%) were JCV-negative throughout the observation period, and 171 were JCV-positive (32.6%). Forty-three patients changed from being JCV-negative to JCV-positive (8.2%), and 15 patients changed from being JCV-positive to JCV-negative (2.9%). When the authors used JCV serostatus to determine seroconversion, the longitudinal assessment started out with 339 initially JCV-negative patients. The serostatus of 43 of these initially JCV-negative patients changed to JCV-positive, which is a rate of 12.7% in 14.8 months (10.3% per year).

Of the 711 French patients, 243 initially were JCV-negative. The serostatus of 20 (8.2%) of these latter patients changed to JCV-positive in their first year of treatment, and 21 (8.6%) of the patients became JCV-positive in their second year of treatment. In all, the serostatus of 41 of 243 patients (16.9%) changed to JCV-positive in the first two years of natalizumab treatment (8.5% per year).

In addition, JCV index values changed in 525 patients during the observation period. The proportion of patients with an index value less than 0.4 was reduced by 20 patients (ie, from 65.1% to 61.3%), and the group of patients with low risk (ie, values between 0.4 and 0.9) was reduced by one patient to 7.8%. The patient groups with medium (ie, 0.9–1.5) and high risk (ie, greater than 1.5) increased by seven patients from 4.6% to 5.9% and by 14 patients from 22.3% to 25%, respectively.Furthermore, 161 of 201 JCV-positive patients (80%) had stable JCV index values over time. The remaining 40 patients (20%) had fluctuations of more than 30% in 14.8 months. Six of these patients (3%) had decreasing index values, and 34 (17%) had increasing index values (mean, 200.8%). Overall, the index value of all JCV-positive patients increased by an average of 15.9% in 14.8 months (12.9% per year).

Increased Index May Not Indicate Imminent PML

The high rate of seroconversion that the investigators observed “clearly supports the facilitation by treatment with natalizumab,” said Dr. Wiendl. “Our observed seroconversion of 8% to 10% per year and the rise in seroprevalence of 5% to 6% in 15 to 24 months is at least eight to 10 times as much as would be expected by age.” The study results imply that not every patient with MS is susceptible to JCV seroconversion by treatment, but natalizumab might facilitate seroconversion in patients who are susceptible.

No research has examined the influence of other MS treatments on JCV index values, and the investigators thus cannot be certain that natalizumab treatment caused the increase in index values observed in the study. But because there was no correlation between age and index value in JCV-positive patients, it is valid to speculate that natalizumab treatment induces rising JCV index values.

“If the hypothesis that treatment with natalizumab is associated with enhanced JCV seroconversion and higher index values is proven, it would also be important to determine whether cessation of natalizumab therapy (or perhaps prolonged infusion intervals) could lead to lower JCV index values as well,” Dr. Wiendl continued. The association “does not diminish [natalizumab’s] clinical efficacy, but calls for more elaborate strategies for PML risk stratification according to current scientific developments, also regarding patients with prior use of immunosuppressants, where the JCV index is not helpful.

“It is important that people with MS taking natalizumab speak with their doctor before making any changes to their treatment,” Dr. Wiendl added. “Still, this study shows anti-JCV antibodies may serve as a useful biomarker…. The results of this study underscore the need for frequent monitoring of anti-JCV antibodies in people who are being treated with natalizumab for MS.”

JCV serology, however, should not be the only PML risk biomarker to stratify patients treated with natalizumab, said Dr. Wiendl. Neurologists should explore and potentially apply additional biomarkers such as CD62L in peripheral blood or IgM bands in CSF. Together, all of these biomarkers may provide more accurate information about patients’ PML risk and help reduce the incidence of PML.

The investigators’ data extend earlier paired, longitudinal studies in various countries of patients treated with natalizumab who had similarly high rates of conversion and a rise in titers, said Adil Javed, MD, PhD, Associate Professor of Neurology, and Anthony T. Reder, MD, Professor of Neurology, both at the University of Chicago, in an accompanying editorial. Although the JCV index appears to be a valid serum marker of risk for PML, “risk is relative,” they said. “Despite a higher JCV replication state, an increase in JCV-antibody index does not necessarily mean that PML infection is imminent…. Schwab et al extend growing observations that JCV-antibody index values need to be monitored and that seroconversion or rising JCV-antibody titers alter the risk of PML in patients treated with natalizumab.”

—Erik Greb

NEW ORLEANS – Stem cell-mediated functional regeneration continues to attract interest in the treatment of multiple sclerosis (MS). The reality, however, is daunting.

“Several types of cell-based therapeutic strategies are under investigation, with different risks, benefits, and goals. Some of these strategies show promise but significant methodological questions need to be answered,” Dr. Andrew D. Goodman said at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

The present reality is that stem cell transplantation is not yet ready for general use to treat MS. Yet, the possible benefits of the approach demand further exploration, including clinical trials, according to Dr. Goodman, professor of neurology, chief of the neuroimmunology unit, and director of the multiple sclerosis center at the University of Rochester (N.Y.).

MS stem cell therapy hinges on the pluripotent nature of stem cells, particularly mesenchymal stem cells (MSCs) and hematopoietic stem cells. MS therapy would involve regeneration of nerve cell myelin in the brain and/or spinal cord and possibly suppression of inflammation.

Autologous HSC transplantation

Immunoablation followed by the autologous HSC transplantation (HSCT) has been explored in the ASTIMS phase II randomized trials (Neurology. Mar 10;84[10]:981-8 and HALT-MS, JAMA Neurol. 2015 Feb;72[2]:159-69), and in a Northwestern University case series (JAMA. 2015 Jan 20;313[3]:275-84).

ASTIMS compared high-dose chemotherapy followed by autologous HSCT with mitoxantrone (which is no longer used). Only 22% percent of patients had relapsing-remitting MS (RRMS; the one where HSCT generally works) and 78% had primary progressive MS (where HSCT generally does not work well or is not optimal). Yet, HSCT worked, with new T2 lesions reduced by 79%. No difference in disability progression was evident. Interim (3-year) results of HALT-MS were encouraging, with sustained remission of active RRMS and improved neurologic function. The Northwestern case series also documented improvements in neurologic disability and other clinical outcomes.

“The available data suggest that immunoablation and HSCT is highly effective in active RRMS. Patients most likely to benefit are young and still ambulatory with a relatively recent disease onset featuring highly active MS with MRI lesion activity and continued activity despite first- and second-line agents,” Dr. Goodman said.

While encouraging, the small patient numbers of the two trials and uncontrolled nature of the case series prevent conclusions concerning the therapeutic use of autologous HSCT in RRMS. Furthermore, risks of the approach include MS relapse, treatment-related adverse effects, adverse effects due to myelosuppression and immunoablation, and secondary autoimmune disorders that may arise at a later time.

Mesenchymal stem cell transplantation

MSCs offer the advantages of a variety of sources in adult tissue, established methods of culture, and either local or peripheral administration. Their finite capacity for proliferation is a drawback. Studies to date of MSC transplantation in MS have involved about 100 patients, so it is much too early to consider MSC use. Even if therapy is contemplated, whether it should be directed at quelling inflammation or to promote repair is undecided. As well, cell production and delivery issues need to be addressed, Dr. Goodman said.

Human oligodendrocyte progenitor cell transplantation

The implantation of CD 140a+ cell populations containing human oligodendrocyte progenitor cells (hOPCs) into the cerebral hemispheres of patients with non-relapsing secondary progressive MS as a means of stabilizing or improving neurological function is being planned. The NYSTEM project, with Dr. Goodman as a lead investigator, will first seek to identify the maximum tolerated dose of hOPCs.

The study is planned with the knowledge of safety issues that include cancer tumorigenesis. Yet exploration of the possible benefits will be evident only by testing in humans. “I don’t know of any way to find out except by trying,” Dr. Goodman said.

Dr. Goodman disclosed receiving research support and/or serving as a consultant to Avanir, Teva, Genzyme/Sanofi, Sun Pharma, Ono, Roche, AbbVie, Biogen, Novartis, Acorda, Purdue, and EMD Serono.

NEW ORLEANS – Stem cell-mediated functional regeneration continues to attract interest in the treatment of multiple sclerosis (MS). The reality, however, is daunting.

“Several types of cell-based therapeutic strategies are under investigation, with different risks, benefits, and goals. Some of these strategies show promise but significant methodological questions need to be answered,” Dr. Andrew D. Goodman said at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

The present reality is that stem cell transplantation is not yet ready for general use to treat MS. Yet, the possible benefits of the approach demand further exploration, including clinical trials, according to Dr. Goodman, professor of neurology, chief of the neuroimmunology unit, and director of the multiple sclerosis center at the University of Rochester (N.Y.).

MS stem cell therapy hinges on the pluripotent nature of stem cells, particularly mesenchymal stem cells (MSCs) and hematopoietic stem cells. MS therapy would involve regeneration of nerve cell myelin in the brain and/or spinal cord and possibly suppression of inflammation.

Autologous HSC transplantation

Immunoablation followed by the autologous HSC transplantation (HSCT) has been explored in the ASTIMS phase II randomized trials (Neurology. Mar 10;84[10]:981-8 and HALT-MS, JAMA Neurol. 2015 Feb;72[2]:159-69), and in a Northwestern University case series (JAMA. 2015 Jan 20;313[3]:275-84).

ASTIMS compared high-dose chemotherapy followed by autologous HSCT with mitoxantrone (which is no longer used). Only 22% percent of patients had relapsing-remitting MS (RRMS; the one where HSCT generally works) and 78% had primary progressive MS (where HSCT generally does not work well or is not optimal). Yet, HSCT worked, with new T2 lesions reduced by 79%. No difference in disability progression was evident. Interim (3-year) results of HALT-MS were encouraging, with sustained remission of active RRMS and improved neurologic function. The Northwestern case series also documented improvements in neurologic disability and other clinical outcomes.

“The available data suggest that immunoablation and HSCT is highly effective in active RRMS. Patients most likely to benefit are young and still ambulatory with a relatively recent disease onset featuring highly active MS with MRI lesion activity and continued activity despite first- and second-line agents,” Dr. Goodman said.

While encouraging, the small patient numbers of the two trials and uncontrolled nature of the case series prevent conclusions concerning the therapeutic use of autologous HSCT in RRMS. Furthermore, risks of the approach include MS relapse, treatment-related adverse effects, adverse effects due to myelosuppression and immunoablation, and secondary autoimmune disorders that may arise at a later time.

Mesenchymal stem cell transplantation

MSCs offer the advantages of a variety of sources in adult tissue, established methods of culture, and either local or peripheral administration. Their finite capacity for proliferation is a drawback. Studies to date of MSC transplantation in MS have involved about 100 patients, so it is much too early to consider MSC use. Even if therapy is contemplated, whether it should be directed at quelling inflammation or to promote repair is undecided. As well, cell production and delivery issues need to be addressed, Dr. Goodman said.

Human oligodendrocyte progenitor cell transplantation

The implantation of CD 140a+ cell populations containing human oligodendrocyte progenitor cells (hOPCs) into the cerebral hemispheres of patients with non-relapsing secondary progressive MS as a means of stabilizing or improving neurological function is being planned. The NYSTEM project, with Dr. Goodman as a lead investigator, will first seek to identify the maximum tolerated dose of hOPCs.

The study is planned with the knowledge of safety issues that include cancer tumorigenesis. Yet exploration of the possible benefits will be evident only by testing in humans. “I don’t know of any way to find out except by trying,” Dr. Goodman said.

Dr. Goodman disclosed receiving research support and/or serving as a consultant to Avanir, Teva, Genzyme/Sanofi, Sun Pharma, Ono, Roche, AbbVie, Biogen, Novartis, Acorda, Purdue, and EMD Serono.

NEW ORLEANS – Stem cell-mediated functional regeneration continues to attract interest in the treatment of multiple sclerosis (MS). The reality, however, is daunting.

“Several types of cell-based therapeutic strategies are under investigation, with different risks, benefits, and goals. Some of these strategies show promise but significant methodological questions need to be answered,” Dr. Andrew D. Goodman said at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

The present reality is that stem cell transplantation is not yet ready for general use to treat MS. Yet, the possible benefits of the approach demand further exploration, including clinical trials, according to Dr. Goodman, professor of neurology, chief of the neuroimmunology unit, and director of the multiple sclerosis center at the University of Rochester (N.Y.).

MS stem cell therapy hinges on the pluripotent nature of stem cells, particularly mesenchymal stem cells (MSCs) and hematopoietic stem cells. MS therapy would involve regeneration of nerve cell myelin in the brain and/or spinal cord and possibly suppression of inflammation.

Autologous HSC transplantation

Immunoablation followed by the autologous HSC transplantation (HSCT) has been explored in the ASTIMS phase II randomized trials (Neurology. Mar 10;84[10]:981-8 and HALT-MS, JAMA Neurol. 2015 Feb;72[2]:159-69), and in a Northwestern University case series (JAMA. 2015 Jan 20;313[3]:275-84).

ASTIMS compared high-dose chemotherapy followed by autologous HSCT with mitoxantrone (which is no longer used). Only 22% percent of patients had relapsing-remitting MS (RRMS; the one where HSCT generally works) and 78% had primary progressive MS (where HSCT generally does not work well or is not optimal). Yet, HSCT worked, with new T2 lesions reduced by 79%. No difference in disability progression was evident. Interim (3-year) results of HALT-MS were encouraging, with sustained remission of active RRMS and improved neurologic function. The Northwestern case series also documented improvements in neurologic disability and other clinical outcomes.

“The available data suggest that immunoablation and HSCT is highly effective in active RRMS. Patients most likely to benefit are young and still ambulatory with a relatively recent disease onset featuring highly active MS with MRI lesion activity and continued activity despite first- and second-line agents,” Dr. Goodman said.

While encouraging, the small patient numbers of the two trials and uncontrolled nature of the case series prevent conclusions concerning the therapeutic use of autologous HSCT in RRMS. Furthermore, risks of the approach include MS relapse, treatment-related adverse effects, adverse effects due to myelosuppression and immunoablation, and secondary autoimmune disorders that may arise at a later time.

Mesenchymal stem cell transplantation

MSCs offer the advantages of a variety of sources in adult tissue, established methods of culture, and either local or peripheral administration. Their finite capacity for proliferation is a drawback. Studies to date of MSC transplantation in MS have involved about 100 patients, so it is much too early to consider MSC use. Even if therapy is contemplated, whether it should be directed at quelling inflammation or to promote repair is undecided. As well, cell production and delivery issues need to be addressed, Dr. Goodman said.

Human oligodendrocyte progenitor cell transplantation

The implantation of CD 140a+ cell populations containing human oligodendrocyte progenitor cells (hOPCs) into the cerebral hemispheres of patients with non-relapsing secondary progressive MS as a means of stabilizing or improving neurological function is being planned. The NYSTEM project, with Dr. Goodman as a lead investigator, will first seek to identify the maximum tolerated dose of hOPCs.

The study is planned with the knowledge of safety issues that include cancer tumorigenesis. Yet exploration of the possible benefits will be evident only by testing in humans. “I don’t know of any way to find out except by trying,” Dr. Goodman said.

Dr. Goodman disclosed receiving research support and/or serving as a consultant to Avanir, Teva, Genzyme/Sanofi, Sun Pharma, Ono, Roche, AbbVie, Biogen, Novartis, Acorda, Purdue, and EMD Serono.

NEW ORLEANS – The recently published results of the INFORMS multicenter, double-blind, placebo-controlled parallel-group study (NCT00731692) that compared the efficacy of fingolimod in slowing disease progression in primary progressive multiple sclerosis (PPMS) with placebo proved disappointing. However, further scrutiny of the data has provided valuable insights, such as supportive evidence for brain atrophy as a clinically relevant measure in PPMS patients.

“The degree of clinical worsening was directly associated with patient’s extent of brain volume loss. Patients in the extreme category of disability progression had more brain volume loss than patients with only one progression or those who remained clinically stable,” wrote Dr. Jerry Wolinsky of the University of Texas Health Science Center at Houston and his colleagues in a poster presented Feb. 19 at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

Brian Hoyle/Frontline Medical News

In INFORMS, 970 patients with PPMS were randomly allocated (1:1) to receive oral fingolimod 0.5 mg or placebo for at least 36 months and for up to 5 years. The anti-inflammatory effects of fingolimod did not slow disease progression in PPMS.

While INFORMS did not pan out in terms of the primary endpoint, the long duration of the study, use of various progression measures, and rigorous patient selection offered the unique opportunity to assess the associations of magnetic resonance imaging of the brain over at least 3 years of the clinical progression occurring in patients with PPMS.

All patients had being clinically diagnosed with PPMS, with disease duration of 2-10 years and objective evidence of progression in disability in the prior 2 years. The composite endpoint of INFORMS based on the change in Expanded Disability Status Scale (EDSS), 25-Foot Timed Walk Test, or 9-Hole Peg Test was used to gauge 3-month confirmed disease progression (3CDP). The patients were classified according to EDSS-determined disease progression as extreme (more than one occurrence of 3CDP; n = 162), moderate (one occurrence of 3CDP; n = 309), and stable (no 3CDP; n = 499).

Mean age, % male, and baseline EDSS scores were similar across the three categories (whole population: 48.4 ± 8.4 years; 51.6%; and 4.7 ± 1.0, respectively). Mean number of gadolinium-positive lesions in the extreme and stable category was 0.39 ± 1.1 and 0.25 ± 1.0, respectively. Baseline T2 lesion volume was 10,160.8 ± 12,743.3 mm³ in extreme patients and 9,585.8 ± 12,421.6 mm³ in stable patients.

Patients in the extreme category displayed greater changes in the three endpoint measures than did the moderate and stable categories. At month 36, the mean change in brain volume, compared with baseline, was –1.76 ± 1.4 in the extreme group and –1.26 ± 0.9 in stable group. Corresponding values for mean number of gadolinium-positive lesions were 0.40 ± 1.4 and 0.10 ± 0.5. Corresponding numbers of new/newly enlarging T2 lesions from baseline to month 36 were 1.7 ± 4.6 and 0.9 ± 2.9.

Patients in the extreme category exceeded the recently proposed cut-off for pathologically increased brain volume loss by about 60%, compared with only about 14% for patients in the stable category.

The higher change in brain volume from baseline in patients who progressed to extreme disability “supports brain atrophy as a clinically relevant measure of neuroprotection in PPMS trials,” wrote Dr. Wolinsky and his colleagues.

The study was funded by Novartis Pharma AG. Dr. Wolinsky disclosed consulting fees from Genzyme/Sanofi, Hoffmann-La Roche/Genentech, Forward Pharma, Alkermes, AbbVie, Novartis Pharmaceuticals, Teva, and XenoPort and advisory board participation for Hoffman-La Roche/Genentech, Forward Pharma, EMD Serono, Actelion, Novartis Pharmaceuticals, Teva, and Xenoport. He performed contract research for Genzyme/Sanofi.

NEW ORLEANS – The recently published results of the INFORMS multicenter, double-blind, placebo-controlled parallel-group study (NCT00731692) that compared the efficacy of fingolimod in slowing disease progression in primary progressive multiple sclerosis (PPMS) with placebo proved disappointing. However, further scrutiny of the data has provided valuable insights, such as supportive evidence for brain atrophy as a clinically relevant measure in PPMS patients.

“The degree of clinical worsening was directly associated with patient’s extent of brain volume loss. Patients in the extreme category of disability progression had more brain volume loss than patients with only one progression or those who remained clinically stable,” wrote Dr. Jerry Wolinsky of the University of Texas Health Science Center at Houston and his colleagues in a poster presented Feb. 19 at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

Brian Hoyle/Frontline Medical News

In INFORMS, 970 patients with PPMS were randomly allocated (1:1) to receive oral fingolimod 0.5 mg or placebo for at least 36 months and for up to 5 years. The anti-inflammatory effects of fingolimod did not slow disease progression in PPMS.

While INFORMS did not pan out in terms of the primary endpoint, the long duration of the study, use of various progression measures, and rigorous patient selection offered the unique opportunity to assess the associations of magnetic resonance imaging of the brain over at least 3 years of the clinical progression occurring in patients with PPMS.

All patients had being clinically diagnosed with PPMS, with disease duration of 2-10 years and objective evidence of progression in disability in the prior 2 years. The composite endpoint of INFORMS based on the change in Expanded Disability Status Scale (EDSS), 25-Foot Timed Walk Test, or 9-Hole Peg Test was used to gauge 3-month confirmed disease progression (3CDP). The patients were classified according to EDSS-determined disease progression as extreme (more than one occurrence of 3CDP; n = 162), moderate (one occurrence of 3CDP; n = 309), and stable (no 3CDP; n = 499).

Mean age, % male, and baseline EDSS scores were similar across the three categories (whole population: 48.4 ± 8.4 years; 51.6%; and 4.7 ± 1.0, respectively). Mean number of gadolinium-positive lesions in the extreme and stable category was 0.39 ± 1.1 and 0.25 ± 1.0, respectively. Baseline T2 lesion volume was 10,160.8 ± 12,743.3 mm³ in extreme patients and 9,585.8 ± 12,421.6 mm³ in stable patients.

Patients in the extreme category displayed greater changes in the three endpoint measures than did the moderate and stable categories. At month 36, the mean change in brain volume, compared with baseline, was –1.76 ± 1.4 in the extreme group and –1.26 ± 0.9 in stable group. Corresponding values for mean number of gadolinium-positive lesions were 0.40 ± 1.4 and 0.10 ± 0.5. Corresponding numbers of new/newly enlarging T2 lesions from baseline to month 36 were 1.7 ± 4.6 and 0.9 ± 2.9.

Patients in the extreme category exceeded the recently proposed cut-off for pathologically increased brain volume loss by about 60%, compared with only about 14% for patients in the stable category.

The higher change in brain volume from baseline in patients who progressed to extreme disability “supports brain atrophy as a clinically relevant measure of neuroprotection in PPMS trials,” wrote Dr. Wolinsky and his colleagues.

The study was funded by Novartis Pharma AG. Dr. Wolinsky disclosed consulting fees from Genzyme/Sanofi, Hoffmann-La Roche/Genentech, Forward Pharma, Alkermes, AbbVie, Novartis Pharmaceuticals, Teva, and XenoPort and advisory board participation for Hoffman-La Roche/Genentech, Forward Pharma, EMD Serono, Actelion, Novartis Pharmaceuticals, Teva, and Xenoport. He performed contract research for Genzyme/Sanofi.

NEW ORLEANS – The recently published results of the INFORMS multicenter, double-blind, placebo-controlled parallel-group study (NCT00731692) that compared the efficacy of fingolimod in slowing disease progression in primary progressive multiple sclerosis (PPMS) with placebo proved disappointing. However, further scrutiny of the data has provided valuable insights, such as supportive evidence for brain atrophy as a clinically relevant measure in PPMS patients.

“The degree of clinical worsening was directly associated with patient’s extent of brain volume loss. Patients in the extreme category of disability progression had more brain volume loss than patients with only one progression or those who remained clinically stable,” wrote Dr. Jerry Wolinsky of the University of Texas Health Science Center at Houston and his colleagues in a poster presented Feb. 19 at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

Brian Hoyle/Frontline Medical News

In INFORMS, 970 patients with PPMS were randomly allocated (1:1) to receive oral fingolimod 0.5 mg or placebo for at least 36 months and for up to 5 years. The anti-inflammatory effects of fingolimod did not slow disease progression in PPMS.

While INFORMS did not pan out in terms of the primary endpoint, the long duration of the study, use of various progression measures, and rigorous patient selection offered the unique opportunity to assess the associations of magnetic resonance imaging of the brain over at least 3 years of the clinical progression occurring in patients with PPMS.

All patients had being clinically diagnosed with PPMS, with disease duration of 2-10 years and objective evidence of progression in disability in the prior 2 years. The composite endpoint of INFORMS based on the change in Expanded Disability Status Scale (EDSS), 25-Foot Timed Walk Test, or 9-Hole Peg Test was used to gauge 3-month confirmed disease progression (3CDP). The patients were classified according to EDSS-determined disease progression as extreme (more than one occurrence of 3CDP; n = 162), moderate (one occurrence of 3CDP; n = 309), and stable (no 3CDP; n = 499).

Mean age, % male, and baseline EDSS scores were similar across the three categories (whole population: 48.4 ± 8.4 years; 51.6%; and 4.7 ± 1.0, respectively). Mean number of gadolinium-positive lesions in the extreme and stable category was 0.39 ± 1.1 and 0.25 ± 1.0, respectively. Baseline T2 lesion volume was 10,160.8 ± 12,743.3 mm³ in extreme patients and 9,585.8 ± 12,421.6 mm³ in stable patients.

Patients in the extreme category displayed greater changes in the three endpoint measures than did the moderate and stable categories. At month 36, the mean change in brain volume, compared with baseline, was –1.76 ± 1.4 in the extreme group and –1.26 ± 0.9 in stable group. Corresponding values for mean number of gadolinium-positive lesions were 0.40 ± 1.4 and 0.10 ± 0.5. Corresponding numbers of new/newly enlarging T2 lesions from baseline to month 36 were 1.7 ± 4.6 and 0.9 ± 2.9.

Patients in the extreme category exceeded the recently proposed cut-off for pathologically increased brain volume loss by about 60%, compared with only about 14% for patients in the stable category.

The higher change in brain volume from baseline in patients who progressed to extreme disability “supports brain atrophy as a clinically relevant measure of neuroprotection in PPMS trials,” wrote Dr. Wolinsky and his colleagues.

The study was funded by Novartis Pharma AG. Dr. Wolinsky disclosed consulting fees from Genzyme/Sanofi, Hoffmann-La Roche/Genentech, Forward Pharma, Alkermes, AbbVie, Novartis Pharmaceuticals, Teva, and XenoPort and advisory board participation for Hoffman-La Roche/Genentech, Forward Pharma, EMD Serono, Actelion, Novartis Pharmaceuticals, Teva, and Xenoport. He performed contract research for Genzyme/Sanofi.

NEW ORLEANS – The majority of multiple sclerosis–related emergency department visits in a recent chart review were related to pseudoflares or MS-related complications, rather than to true MS relapse.

The findings suggest that many diagnostic tests, treatments, and hospital admissions are unnecessary, Dr. Hesham Abboud of the Cleveland Clinic and his colleagues reported in a poster at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

©EyeMark/thinkstockphotos.com

Of 97 MS-related visits among 75 patients, 33 were for new neurologic symptoms, 29 were for worsening of preexisting symptoms, and 36 were for MS-related complications. New relapse was diagnosed in only 27 visits (27.8%), and urinary tract infections were found in about one-third of patients presenting with either urinary or neurologic symptoms, the investigators said.

New MRIs were ordered in 37 patients (38.1%); 89 emergency department visits (91.7%) resulted in hospital admissions and 40.4% were related to neurology; and steroid treatment was used in 24 visits (24.7%), 7 of which were for worsening of preexisting symptoms, the investigators said.

Of the visits involving new neurologic symptoms, one-third were not from relapse; 59% of the MRIs done in those situations were positive for enhancing or new lesions. Of the visits with worsening preexisting symptoms, only 16.6% were associated with a new relapse, and 28.5% of MRIs done in those situations were positive, the investigators said.

Although many ED visits among MS patients are driven by neurologic complaints, true relapse is rarely present, and not all those with true relapse require hospital admission and steroid treatment, they noted, concluding that developing a care path and triaging system for MS patients in the ED could prevent unnecessary MRIs, steroid treatment, and hospital admissions.

The investigators reported having no disclosures.

sworcester@frontlinemedcom.com

NEW ORLEANS – The majority of multiple sclerosis–related emergency department visits in a recent chart review were related to pseudoflares or MS-related complications, rather than to true MS relapse.

The findings suggest that many diagnostic tests, treatments, and hospital admissions are unnecessary, Dr. Hesham Abboud of the Cleveland Clinic and his colleagues reported in a poster at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

©EyeMark/thinkstockphotos.com

Of 97 MS-related visits among 75 patients, 33 were for new neurologic symptoms, 29 were for worsening of preexisting symptoms, and 36 were for MS-related complications. New relapse was diagnosed in only 27 visits (27.8%), and urinary tract infections were found in about one-third of patients presenting with either urinary or neurologic symptoms, the investigators said.

New MRIs were ordered in 37 patients (38.1%); 89 emergency department visits (91.7%) resulted in hospital admissions and 40.4% were related to neurology; and steroid treatment was used in 24 visits (24.7%), 7 of which were for worsening of preexisting symptoms, the investigators said.

Of the visits involving new neurologic symptoms, one-third were not from relapse; 59% of the MRIs done in those situations were positive for enhancing or new lesions. Of the visits with worsening preexisting symptoms, only 16.6% were associated with a new relapse, and 28.5% of MRIs done in those situations were positive, the investigators said.

Although many ED visits among MS patients are driven by neurologic complaints, true relapse is rarely present, and not all those with true relapse require hospital admission and steroid treatment, they noted, concluding that developing a care path and triaging system for MS patients in the ED could prevent unnecessary MRIs, steroid treatment, and hospital admissions.

The investigators reported having no disclosures.

sworcester@frontlinemedcom.com

NEW ORLEANS – The majority of multiple sclerosis–related emergency department visits in a recent chart review were related to pseudoflares or MS-related complications, rather than to true MS relapse.

The findings suggest that many diagnostic tests, treatments, and hospital admissions are unnecessary, Dr. Hesham Abboud of the Cleveland Clinic and his colleagues reported in a poster at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

©EyeMark/thinkstockphotos.com

Of 97 MS-related visits among 75 patients, 33 were for new neurologic symptoms, 29 were for worsening of preexisting symptoms, and 36 were for MS-related complications. New relapse was diagnosed in only 27 visits (27.8%), and urinary tract infections were found in about one-third of patients presenting with either urinary or neurologic symptoms, the investigators said.

New MRIs were ordered in 37 patients (38.1%); 89 emergency department visits (91.7%) resulted in hospital admissions and 40.4% were related to neurology; and steroid treatment was used in 24 visits (24.7%), 7 of which were for worsening of preexisting symptoms, the investigators said.

Of the visits involving new neurologic symptoms, one-third were not from relapse; 59% of the MRIs done in those situations were positive for enhancing or new lesions. Of the visits with worsening preexisting symptoms, only 16.6% were associated with a new relapse, and 28.5% of MRIs done in those situations were positive, the investigators said.

Although many ED visits among MS patients are driven by neurologic complaints, true relapse is rarely present, and not all those with true relapse require hospital admission and steroid treatment, they noted, concluding that developing a care path and triaging system for MS patients in the ED could prevent unnecessary MRIs, steroid treatment, and hospital admissions.

The investigators reported having no disclosures.

sworcester@frontlinemedcom.com

NEW ORLEANS – Treatment with fingolimod improved gait impairment in treatment-naive multiple sclerosis (MS) patients and those on a previous first-line therapy in a small, single-center study.

“Fingolimod [Gilenya] is the first disease-modifying treatment shown to improve gait impairment in MS,” commented Dr. Soledad Pérez-Sánchez of Virgen Macarena University Hospital, Seville, Spain, who presented the study as a poster at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

©solitude72/iStockphoto

The investigators also found that patients who were unsuccessfully treated with natalizumab (Tysabri) prior to fingolimod did not improve their gait during the course of the 6-month study. Natalizumab is a second-line drug in Spain, and fingolimod is a second-line therapy there as well, except in cases of aggressive onset of disease, according to the investigators.

Of 36 patients in the study, 24 were treatment-naïve/first-line patients (17 females and 7 males; mean age, 38.25 years), with the remaining 12 (9 females, 3 males; mean age, 44.25 years) having been treated with natalizumab. The mean duration of MS was 11.2 years in the naïve/first-line group and 17.9 years in patients on natalizumab prior to fingolimod. The mean Extended Disability Status Scale score in the two groups was similar at 3.79 and 3.38, respectively.

The investigators measured gait profile changes during fingolimod treatment with the Gaitrite Electronic System, which comprises an electronic pathway equipped with sensors designed to measure the timing and position of walking. The measurement parameters included velocity, ambulation time, and functional ambulation profile (FAP), the time to move unassisted through five common environmental terrains.

All patients completed the walking test prior to treatment and 3 months after treatment. At 6 months, 20 naïve/first-line patients and 11 patients previously on natalizumab completed the test. For each group of patients, the results prior to treatment and 3 months after were statistically similar. But significant differences were evident for naïve/first-line patients between the 3- and 6-month measures of velocity (89.10±31.03 to 100.70±23.75 cm/s; P = .01) and FAP (82.81±16.93 to 91.95±9.02 seconds; P = .01). These measurements trended toward significance when the values prior to treatment and 6 months after treatment were compared (P = .096, .077, and .065, in the same respective order).

Patients who had been treated with natalizumab did not display appreciable changes in velocity, ambulation time, and FAP.

“Our study shows that fingolimod improves gait impairment in naïve patients and those switched from first-line therapy. Our data are consistent with other clinical measures published so far which have pointed to better outcomes with fingolimod in naïve/first-line patients than in natalizumab-switched patients,” Dr. Pérez-Sánchez and her colleagues said.

The single-center study design and small number of patients limit any conclusions on the use of fingolimod as a gait-improving therapy in MS until further studies are completed, according to the researchers.

Funding was provided by Novartis. Dr. Pérez-Sánchez had no disclosures.

NEW ORLEANS – Treatment with fingolimod improved gait impairment in treatment-naive multiple sclerosis (MS) patients and those on a previous first-line therapy in a small, single-center study.

“Fingolimod [Gilenya] is the first disease-modifying treatment shown to improve gait impairment in MS,” commented Dr. Soledad Pérez-Sánchez of Virgen Macarena University Hospital, Seville, Spain, who presented the study as a poster at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

©solitude72/iStockphoto

The investigators also found that patients who were unsuccessfully treated with natalizumab (Tysabri) prior to fingolimod did not improve their gait during the course of the 6-month study. Natalizumab is a second-line drug in Spain, and fingolimod is a second-line therapy there as well, except in cases of aggressive onset of disease, according to the investigators.

Of 36 patients in the study, 24 were treatment-naïve/first-line patients (17 females and 7 males; mean age, 38.25 years), with the remaining 12 (9 females, 3 males; mean age, 44.25 years) having been treated with natalizumab. The mean duration of MS was 11.2 years in the naïve/first-line group and 17.9 years in patients on natalizumab prior to fingolimod. The mean Extended Disability Status Scale score in the two groups was similar at 3.79 and 3.38, respectively.

The investigators measured gait profile changes during fingolimod treatment with the Gaitrite Electronic System, which comprises an electronic pathway equipped with sensors designed to measure the timing and position of walking. The measurement parameters included velocity, ambulation time, and functional ambulation profile (FAP), the time to move unassisted through five common environmental terrains.

All patients completed the walking test prior to treatment and 3 months after treatment. At 6 months, 20 naïve/first-line patients and 11 patients previously on natalizumab completed the test. For each group of patients, the results prior to treatment and 3 months after were statistically similar. But significant differences were evident for naïve/first-line patients between the 3- and 6-month measures of velocity (89.10±31.03 to 100.70±23.75 cm/s; P = .01) and FAP (82.81±16.93 to 91.95±9.02 seconds; P = .01). These measurements trended toward significance when the values prior to treatment and 6 months after treatment were compared (P = .096, .077, and .065, in the same respective order).

Patients who had been treated with natalizumab did not display appreciable changes in velocity, ambulation time, and FAP.

“Our study shows that fingolimod improves gait impairment in naïve patients and those switched from first-line therapy. Our data are consistent with other clinical measures published so far which have pointed to better outcomes with fingolimod in naïve/first-line patients than in natalizumab-switched patients,” Dr. Pérez-Sánchez and her colleagues said.

The single-center study design and small number of patients limit any conclusions on the use of fingolimod as a gait-improving therapy in MS until further studies are completed, according to the researchers.

Funding was provided by Novartis. Dr. Pérez-Sánchez had no disclosures.

NEW ORLEANS – Treatment with fingolimod improved gait impairment in treatment-naive multiple sclerosis (MS) patients and those on a previous first-line therapy in a small, single-center study.

“Fingolimod [Gilenya] is the first disease-modifying treatment shown to improve gait impairment in MS,” commented Dr. Soledad Pérez-Sánchez of Virgen Macarena University Hospital, Seville, Spain, who presented the study as a poster at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

©solitude72/iStockphoto

The investigators also found that patients who were unsuccessfully treated with natalizumab (Tysabri) prior to fingolimod did not improve their gait during the course of the 6-month study. Natalizumab is a second-line drug in Spain, and fingolimod is a second-line therapy there as well, except in cases of aggressive onset of disease, according to the investigators.

Of 36 patients in the study, 24 were treatment-naïve/first-line patients (17 females and 7 males; mean age, 38.25 years), with the remaining 12 (9 females, 3 males; mean age, 44.25 years) having been treated with natalizumab. The mean duration of MS was 11.2 years in the naïve/first-line group and 17.9 years in patients on natalizumab prior to fingolimod. The mean Extended Disability Status Scale score in the two groups was similar at 3.79 and 3.38, respectively.

The investigators measured gait profile changes during fingolimod treatment with the Gaitrite Electronic System, which comprises an electronic pathway equipped with sensors designed to measure the timing and position of walking. The measurement parameters included velocity, ambulation time, and functional ambulation profile (FAP), the time to move unassisted through five common environmental terrains.

All patients completed the walking test prior to treatment and 3 months after treatment. At 6 months, 20 naïve/first-line patients and 11 patients previously on natalizumab completed the test. For each group of patients, the results prior to treatment and 3 months after were statistically similar. But significant differences were evident for naïve/first-line patients between the 3- and 6-month measures of velocity (89.10±31.03 to 100.70±23.75 cm/s; P = .01) and FAP (82.81±16.93 to 91.95±9.02 seconds; P = .01). These measurements trended toward significance when the values prior to treatment and 6 months after treatment were compared (P = .096, .077, and .065, in the same respective order).

Patients who had been treated with natalizumab did not display appreciable changes in velocity, ambulation time, and FAP.

“Our study shows that fingolimod improves gait impairment in naïve patients and those switched from first-line therapy. Our data are consistent with other clinical measures published so far which have pointed to better outcomes with fingolimod in naïve/first-line patients than in natalizumab-switched patients,” Dr. Pérez-Sánchez and her colleagues said.

The single-center study design and small number of patients limit any conclusions on the use of fingolimod as a gait-improving therapy in MS until further studies are completed, according to the researchers.

Funding was provided by Novartis. Dr. Pérez-Sánchez had no disclosures.

NEW ORLEANS – The visual system is relevant and accessible for the study of multiple sclerosis and can aid in the measurement of neuronal and axonal injury.

Capturing primary neuronal loss in the afferent visual pathway was among the topics addressed during a session focused on novel methods for measuring disease progression in MS at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

In this video interview at the meeting, session chair Dr. Fiona Costello of the University of Calgary, Alta., discussed the presentation on the visual pathway, as well as presentations on the use of microRNA biomarkers and the use of MRI as an outcome measure in progressive MS.

“The gestalt is that the field is moving in a new direction; the field is looking for not only a better understanding of what causes disability in MS, but also more reliable, objective, accessible means of capturing the same thing that is relevant and meaningful to patients and their caretakers,” she said.

sworcester@frontlinemedcom.com

NEW ORLEANS – The visual system is relevant and accessible for the study of multiple sclerosis and can aid in the measurement of neuronal and axonal injury.

Capturing primary neuronal loss in the afferent visual pathway was among the topics addressed during a session focused on novel methods for measuring disease progression in MS at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

In this video interview at the meeting, session chair Dr. Fiona Costello of the University of Calgary, Alta., discussed the presentation on the visual pathway, as well as presentations on the use of microRNA biomarkers and the use of MRI as an outcome measure in progressive MS.

“The gestalt is that the field is moving in a new direction; the field is looking for not only a better understanding of what causes disability in MS, but also more reliable, objective, accessible means of capturing the same thing that is relevant and meaningful to patients and their caretakers,” she said.

sworcester@frontlinemedcom.com

NEW ORLEANS – The visual system is relevant and accessible for the study of multiple sclerosis and can aid in the measurement of neuronal and axonal injury.

Capturing primary neuronal loss in the afferent visual pathway was among the topics addressed during a session focused on novel methods for measuring disease progression in MS at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

In this video interview at the meeting, session chair Dr. Fiona Costello of the University of Calgary, Alta., discussed the presentation on the visual pathway, as well as presentations on the use of microRNA biomarkers and the use of MRI as an outcome measure in progressive MS.

“The gestalt is that the field is moving in a new direction; the field is looking for not only a better understanding of what causes disability in MS, but also more reliable, objective, accessible means of capturing the same thing that is relevant and meaningful to patients and their caretakers,” she said.

sworcester@frontlinemedcom.com

NEW ORLEANS – On top of the first success with an investigational pharmaceutical agent for primary progressive multiple sclerosis reported last year, the otherwise negative results from recent clinical trials in progressive disease are at least informing the field of which direction to take in future research, Dr. Fred D. Lublin said at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

“The breaking news is that we are making headway. Two years ago we didn’t have a clue. Now we have clues,” said Dr. Lublin, professor of neurology and director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Medical Center, New York.

In the ORATORIO trial, the selective B-cell–targeting monoclonal antibody ocrelizumab (600 mg intravenous infused every 6 months as two 300-mg infusions given 2 weeks apart) was compared with placebo in 732 people with primary progressive MS (PPMS) in a 120-week blinded treatment continued for at least 120 weeks. After 24 weeks of treatment, ocrelizumab lessened the risk of progression in clinical disability by 25%, compared with placebo. Over the 2-year blinded treatment, the volume of hyperintense T2 lesions was reduced by 3.4% in the treatment arm, compared with a 7% increase in the placebo arm. Rate of whole brain volume loss was also reduced. A subgroup analysis presented at the ACTRIMS Forum revealed the influence of gadolinium-enhanced lesions on treatment efficacy.

“ORATORIO has opened the door to the problem of solving progressive MS”, said Dr. Lublin. Yet, considerable challenges remain. This was true even in the ORATORIO trial, where the treatment success was tempered by a 2.3% rate of malignancies in patients receiving ocrelizumab, which was more than double the 0.8% rate in the placebo arm.

Impact of trial design

The ORATORIO trial also highlighted another conundrum of trials to date, namely patient selection. The trial was designed to include young people with brain inflammation, a population that can respond well to treatment. But, in real life, patients with progressive MS can be older without signs of inflammation. For them, and for patients with a longer history of progressive MS, treatment might be less effective.

Other aspects of trial design that can bear on the outcome include the target (inflammation or degeneration), who to target, how to measure treatment outcome, and whether the endpoint is a confirmed decline that persists for a defined time or the more rigorous sustained decline, in which the decline is maintained for the course of the study. The disease phenotypes can also be important in trial design when it comes to screening patients. For example, one recognized MS phenotype is an active form that features clinical relapses and/or gadolinium-enhancing lesions on MRI, but which does not progress. Inclusion of this phenotype in a study can dilute the power of the study to detect a treatment effect if the progressive disease is in a nonprogressive phase during the study period.

Subgroup analysis of a trial with a failed primary outcome may reveal some patients who respond better to treatment, as in the OLYMPUS randomized, placebo-controlled trial. While the difference to confirmed disease progression in PPMS between rituximab and placebo was not significant overall, disease progression was significantly delayed in older patients.

Informative negative trials

With a solid trial design, a failed outcome can be informative, as it is likely because of a biological reason rather than a faulty trial design. The randomized, double-blind, phase III INFORMS trial of fingolimod versus placebo in PPMS is an example. While the primary and secondary outcomes involving delay to 3-month confirmed disease progression were not met, fingolimod treatment was associated with significantly fewer T2 and gadolinium-enhanced T1 lesions. Scrutiny of the study results could inform future trials.

A second example is the ASCEND trial of natalizumab in patients with secondary progressive MS. The trial’s failure likely reflected the very rigorous primary endpoint of a delay of confirmed disease progression at 3 months that was sustained up to 6 months or longer.

The MS-SPI randomized, multicenter, double-blind, placebo-controlled study that evaluated oral biotin in patients with PPMS or secondary progressive MS was especially noteworthy for its primary endpoint of improvement in disease at 1 year. The endpoint was met by 13% of those in the treatment arm versus 0% in the placebo arm (P = .0051).

“I wish I had more breaking news to report. But we are making progress with progressive disease. We learn from each study, and we are developing a clearer understanding of how to more effectively approach progression,” Dr. Lublin said.

Dr. Lublin reported receiving research support and/or serving as a consultant for many companies marketing MS drugs, including Biogen, Genentech, and Novartis.

NEW ORLEANS – On top of the first success with an investigational pharmaceutical agent for primary progressive multiple sclerosis reported last year, the otherwise negative results from recent clinical trials in progressive disease are at least informing the field of which direction to take in future research, Dr. Fred D. Lublin said at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

“The breaking news is that we are making headway. Two years ago we didn’t have a clue. Now we have clues,” said Dr. Lublin, professor of neurology and director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Medical Center, New York.

In the ORATORIO trial, the selective B-cell–targeting monoclonal antibody ocrelizumab (600 mg intravenous infused every 6 months as two 300-mg infusions given 2 weeks apart) was compared with placebo in 732 people with primary progressive MS (PPMS) in a 120-week blinded treatment continued for at least 120 weeks. After 24 weeks of treatment, ocrelizumab lessened the risk of progression in clinical disability by 25%, compared with placebo. Over the 2-year blinded treatment, the volume of hyperintense T2 lesions was reduced by 3.4% in the treatment arm, compared with a 7% increase in the placebo arm. Rate of whole brain volume loss was also reduced. A subgroup analysis presented at the ACTRIMS Forum revealed the influence of gadolinium-enhanced lesions on treatment efficacy.

“ORATORIO has opened the door to the problem of solving progressive MS”, said Dr. Lublin. Yet, considerable challenges remain. This was true even in the ORATORIO trial, where the treatment success was tempered by a 2.3% rate of malignancies in patients receiving ocrelizumab, which was more than double the 0.8% rate in the placebo arm.

Impact of trial design

The ORATORIO trial also highlighted another conundrum of trials to date, namely patient selection. The trial was designed to include young people with brain inflammation, a population that can respond well to treatment. But, in real life, patients with progressive MS can be older without signs of inflammation. For them, and for patients with a longer history of progressive MS, treatment might be less effective.

Other aspects of trial design that can bear on the outcome include the target (inflammation or degeneration), who to target, how to measure treatment outcome, and whether the endpoint is a confirmed decline that persists for a defined time or the more rigorous sustained decline, in which the decline is maintained for the course of the study. The disease phenotypes can also be important in trial design when it comes to screening patients. For example, one recognized MS phenotype is an active form that features clinical relapses and/or gadolinium-enhancing lesions on MRI, but which does not progress. Inclusion of this phenotype in a study can dilute the power of the study to detect a treatment effect if the progressive disease is in a nonprogressive phase during the study period.

Subgroup analysis of a trial with a failed primary outcome may reveal some patients who respond better to treatment, as in the OLYMPUS randomized, placebo-controlled trial. While the difference to confirmed disease progression in PPMS between rituximab and placebo was not significant overall, disease progression was significantly delayed in older patients.

Informative negative trials

With a solid trial design, a failed outcome can be informative, as it is likely because of a biological reason rather than a faulty trial design. The randomized, double-blind, phase III INFORMS trial of fingolimod versus placebo in PPMS is an example. While the primary and secondary outcomes involving delay to 3-month confirmed disease progression were not met, fingolimod treatment was associated with significantly fewer T2 and gadolinium-enhanced T1 lesions. Scrutiny of the study results could inform future trials.

A second example is the ASCEND trial of natalizumab in patients with secondary progressive MS. The trial’s failure likely reflected the very rigorous primary endpoint of a delay of confirmed disease progression at 3 months that was sustained up to 6 months or longer.

The MS-SPI randomized, multicenter, double-blind, placebo-controlled study that evaluated oral biotin in patients with PPMS or secondary progressive MS was especially noteworthy for its primary endpoint of improvement in disease at 1 year. The endpoint was met by 13% of those in the treatment arm versus 0% in the placebo arm (P = .0051).

“I wish I had more breaking news to report. But we are making progress with progressive disease. We learn from each study, and we are developing a clearer understanding of how to more effectively approach progression,” Dr. Lublin said.

Dr. Lublin reported receiving research support and/or serving as a consultant for many companies marketing MS drugs, including Biogen, Genentech, and Novartis.

NEW ORLEANS – On top of the first success with an investigational pharmaceutical agent for primary progressive multiple sclerosis reported last year, the otherwise negative results from recent clinical trials in progressive disease are at least informing the field of which direction to take in future research, Dr. Fred D. Lublin said at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

“The breaking news is that we are making headway. Two years ago we didn’t have a clue. Now we have clues,” said Dr. Lublin, professor of neurology and director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Medical Center, New York.

In the ORATORIO trial, the selective B-cell–targeting monoclonal antibody ocrelizumab (600 mg intravenous infused every 6 months as two 300-mg infusions given 2 weeks apart) was compared with placebo in 732 people with primary progressive MS (PPMS) in a 120-week blinded treatment continued for at least 120 weeks. After 24 weeks of treatment, ocrelizumab lessened the risk of progression in clinical disability by 25%, compared with placebo. Over the 2-year blinded treatment, the volume of hyperintense T2 lesions was reduced by 3.4% in the treatment arm, compared with a 7% increase in the placebo arm. Rate of whole brain volume loss was also reduced. A subgroup analysis presented at the ACTRIMS Forum revealed the influence of gadolinium-enhanced lesions on treatment efficacy.

“ORATORIO has opened the door to the problem of solving progressive MS”, said Dr. Lublin. Yet, considerable challenges remain. This was true even in the ORATORIO trial, where the treatment success was tempered by a 2.3% rate of malignancies in patients receiving ocrelizumab, which was more than double the 0.8% rate in the placebo arm.

Impact of trial design

The ORATORIO trial also highlighted another conundrum of trials to date, namely patient selection. The trial was designed to include young people with brain inflammation, a population that can respond well to treatment. But, in real life, patients with progressive MS can be older without signs of inflammation. For them, and for patients with a longer history of progressive MS, treatment might be less effective.

Other aspects of trial design that can bear on the outcome include the target (inflammation or degeneration), who to target, how to measure treatment outcome, and whether the endpoint is a confirmed decline that persists for a defined time or the more rigorous sustained decline, in which the decline is maintained for the course of the study. The disease phenotypes can also be important in trial design when it comes to screening patients. For example, one recognized MS phenotype is an active form that features clinical relapses and/or gadolinium-enhancing lesions on MRI, but which does not progress. Inclusion of this phenotype in a study can dilute the power of the study to detect a treatment effect if the progressive disease is in a nonprogressive phase during the study period.

Subgroup analysis of a trial with a failed primary outcome may reveal some patients who respond better to treatment, as in the OLYMPUS randomized, placebo-controlled trial. While the difference to confirmed disease progression in PPMS between rituximab and placebo was not significant overall, disease progression was significantly delayed in older patients.

Informative negative trials

With a solid trial design, a failed outcome can be informative, as it is likely because of a biological reason rather than a faulty trial design. The randomized, double-blind, phase III INFORMS trial of fingolimod versus placebo in PPMS is an example. While the primary and secondary outcomes involving delay to 3-month confirmed disease progression were not met, fingolimod treatment was associated with significantly fewer T2 and gadolinium-enhanced T1 lesions. Scrutiny of the study results could inform future trials.

A second example is the ASCEND trial of natalizumab in patients with secondary progressive MS. The trial’s failure likely reflected the very rigorous primary endpoint of a delay of confirmed disease progression at 3 months that was sustained up to 6 months or longer.

The MS-SPI randomized, multicenter, double-blind, placebo-controlled study that evaluated oral biotin in patients with PPMS or secondary progressive MS was especially noteworthy for its primary endpoint of improvement in disease at 1 year. The endpoint was met by 13% of those in the treatment arm versus 0% in the placebo arm (P = .0051).

“I wish I had more breaking news to report. But we are making progress with progressive disease. We learn from each study, and we are developing a clearer understanding of how to more effectively approach progression,” Dr. Lublin said.

Dr. Lublin reported receiving research support and/or serving as a consultant for many companies marketing MS drugs, including Biogen, Genentech, and Novartis.

NEW ORLEANS – Stem cell therapy for progressive multiple sclerosis is an intriguing and controversial topic, and the state of the related science was addressed during a session on “the treatment pipeline” at a meeting sponsored by the Americas Committee for Treatment and Research in Multiple Sclerosis.

In a video interview at the meeting, session chair Dr. Mark Freedman of the University of Ottawa (Ont.) discussed the status of autologous hematopoietic stem cell transplantation; how mesenchymal stem cells are thought to be a potential source for immune system repair; and the intriguing potential for remyelinating therapy with human oligodendrocyte progenitor cells. Research is in the “very preliminary stage” on human oligodendrocyte progenitor cells, but “enticing news” of a safety trial set to begin in North America was presented during the session, he said.

NEW ORLEANS – Stem cell therapy for progressive multiple sclerosis is an intriguing and controversial topic, and the state of the related science was addressed during a session on “the treatment pipeline” at a meeting sponsored by the Americas Committee for Treatment and Research in Multiple Sclerosis.

In a video interview at the meeting, session chair Dr. Mark Freedman of the University of Ottawa (Ont.) discussed the status of autologous hematopoietic stem cell transplantation; how mesenchymal stem cells are thought to be a potential source for immune system repair; and the intriguing potential for remyelinating therapy with human oligodendrocyte progenitor cells. Research is in the “very preliminary stage” on human oligodendrocyte progenitor cells, but “enticing news” of a safety trial set to begin in North America was presented during the session, he said.

NEW ORLEANS – Stem cell therapy for progressive multiple sclerosis is an intriguing and controversial topic, and the state of the related science was addressed during a session on “the treatment pipeline” at a meeting sponsored by the Americas Committee for Treatment and Research in Multiple Sclerosis.

In a video interview at the meeting, session chair Dr. Mark Freedman of the University of Ottawa (Ont.) discussed the status of autologous hematopoietic stem cell transplantation; how mesenchymal stem cells are thought to be a potential source for immune system repair; and the intriguing potential for remyelinating therapy with human oligodendrocyte progenitor cells. Research is in the “very preliminary stage” on human oligodendrocyte progenitor cells, but “enticing news” of a safety trial set to begin in North America was presented during the session, he said.

NEW ORLEANS – The greatest effect of the investigational, B-cell–targeting humanized monoclonal antibody ocrelizumab in treating primary progressive multiple sclerosis (PPMS) may be in patients with T1 gadolinium-positive (Gd+) lesions at baseline, which are indicative of an ongoing or recent MS relapse, according to a subgroup analysis of the randomized, double-blind, placebo-controlled ORATORIO trial.

The analysis hinted at the possibility that ocrelizumab may reduce the risk of confirmed disability progression (CDP) at 12 weeks or 24 weeks to a slightly higher degree among PPMS patients with T1 Gd+ lesions than in those without such lesions, although the differences did not reach statistical significance. The findings await further study because ORATORIO was not powered to demonstrate efficacy differences between the subgroups, Dr. Jerry Wolinsky of the University of Texas Health Science Center at Houston noted in a presentation at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

Brian Hoyle/Frontline Medical News

In ORATORIO, ocrelizumab (600 mg intravenous infused every 6 months as two 300-mg infusions given 2 weeks apart) was compared with placebo in 732 people with PPMS in a 120-week blinded treatment. The number of patients with T1 Gd+ lesions at baseline was similar in the placebo arm (60/244, 24.7%) and the ocrelizumab arm (133/488, 27.5%). T1 Gd-negative (Gd-) lesions, which are likely older and indicative of the absence of a relapse, were identified in 183 and 350 of the patients in the placebo and ocrelizumab arms, respectively.

Time to onset of 12-week confirmed disability progression (CDP) was delayed in a quarter of the overall population (hazard ratio, 0.76; 95% confidence interval, 0.59-0.98). Risk reduction was greater in the presence of T1 Gd+ lesions at baseline (HR, 0.65; 95% CI, 0.40-1.06), compared with patients harboring T1 Gd- lesions at baseline (HR, 0.84; 95% CI, 0.62-1.13). A similar pattern was evident for time to onset of 24-week CDP.

The changes in timed 25-foot walk from baseline to week 20, and in brain T2 hyperintense lesion volume from baseline to week 120 were significantly reduced overall by treatment. Reductions in walk time and lesion volume were apparent in the T1 Gd+ and Gd- lesion subgroups, with similar percentage change. In the overall study, ocrelizumab significantly slowed decline in brain volume from weeks 24 to 120, and slowed declines were also evident in the T1 Gd+ and Gd- lesion subgroups, compared with placebo.

The findings warrant further studies powered to assess the apparent treatment benefit in patients with Gd+ lesions – who are likely relapsing – at baseline. If the findings hold, stratifying patients prior to treatment based on MRI of T1 Gd+ lesions could help to guide ocrelizumab treatment.

Gadolinium normally cannot pass from the bloodstream into the brain or spinal cord because of the presence of the blood-brain barrier. Active inflammation in the brain or spinal cord during a MS relapse disrupts the barrier. Gadolinium enters the brain or spinal cord and permeates into MS lesions, which appear bright on MRI. 

The study was funded by Hoffmann-La Roche/Genentech. Dr. Wolinsky disclosed receiving consulting fees; compensation for service on steering committees or data monitoring boards; and/or research support from many companies that market MS drugs, including Hoffmann-La Roche/Genentech.

NEW ORLEANS – The greatest effect of the investigational, B-cell–targeting humanized monoclonal antibody ocrelizumab in treating primary progressive multiple sclerosis (PPMS) may be in patients with T1 gadolinium-positive (Gd+) lesions at baseline, which are indicative of an ongoing or recent MS relapse, according to a subgroup analysis of the randomized, double-blind, placebo-controlled ORATORIO trial.

The analysis hinted at the possibility that ocrelizumab may reduce the risk of confirmed disability progression (CDP) at 12 weeks or 24 weeks to a slightly higher degree among PPMS patients with T1 Gd+ lesions than in those without such lesions, although the differences did not reach statistical significance. The findings await further study because ORATORIO was not powered to demonstrate efficacy differences between the subgroups, Dr. Jerry Wolinsky of the University of Texas Health Science Center at Houston noted in a presentation at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

Brian Hoyle/Frontline Medical News

In ORATORIO, ocrelizumab (600 mg intravenous infused every 6 months as two 300-mg infusions given 2 weeks apart) was compared with placebo in 732 people with PPMS in a 120-week blinded treatment. The number of patients with T1 Gd+ lesions at baseline was similar in the placebo arm (60/244, 24.7%) and the ocrelizumab arm (133/488, 27.5%). T1 Gd-negative (Gd-) lesions, which are likely older and indicative of the absence of a relapse, were identified in 183 and 350 of the patients in the placebo and ocrelizumab arms, respectively.

Time to onset of 12-week confirmed disability progression (CDP) was delayed in a quarter of the overall population (hazard ratio, 0.76; 95% confidence interval, 0.59-0.98). Risk reduction was greater in the presence of T1 Gd+ lesions at baseline (HR, 0.65; 95% CI, 0.40-1.06), compared with patients harboring T1 Gd- lesions at baseline (HR, 0.84; 95% CI, 0.62-1.13). A similar pattern was evident for time to onset of 24-week CDP.

The changes in timed 25-foot walk from baseline to week 20, and in brain T2 hyperintense lesion volume from baseline to week 120 were significantly reduced overall by treatment. Reductions in walk time and lesion volume were apparent in the T1 Gd+ and Gd- lesion subgroups, with similar percentage change. In the overall study, ocrelizumab significantly slowed decline in brain volume from weeks 24 to 120, and slowed declines were also evident in the T1 Gd+ and Gd- lesion subgroups, compared with placebo.

The findings warrant further studies powered to assess the apparent treatment benefit in patients with Gd+ lesions – who are likely relapsing – at baseline. If the findings hold, stratifying patients prior to treatment based on MRI of T1 Gd+ lesions could help to guide ocrelizumab treatment.

Gadolinium normally cannot pass from the bloodstream into the brain or spinal cord because of the presence of the blood-brain barrier. Active inflammation in the brain or spinal cord during a MS relapse disrupts the barrier. Gadolinium enters the brain or spinal cord and permeates into MS lesions, which appear bright on MRI. 

The study was funded by Hoffmann-La Roche/Genentech. Dr. Wolinsky disclosed receiving consulting fees; compensation for service on steering committees or data monitoring boards; and/or research support from many companies that market MS drugs, including Hoffmann-La Roche/Genentech.

NEW ORLEANS – The greatest effect of the investigational, B-cell–targeting humanized monoclonal antibody ocrelizumab in treating primary progressive multiple sclerosis (PPMS) may be in patients with T1 gadolinium-positive (Gd+) lesions at baseline, which are indicative of an ongoing or recent MS relapse, according to a subgroup analysis of the randomized, double-blind, placebo-controlled ORATORIO trial.

The analysis hinted at the possibility that ocrelizumab may reduce the risk of confirmed disability progression (CDP) at 12 weeks or 24 weeks to a slightly higher degree among PPMS patients with T1 Gd+ lesions than in those without such lesions, although the differences did not reach statistical significance. The findings await further study because ORATORIO was not powered to demonstrate efficacy differences between the subgroups, Dr. Jerry Wolinsky of the University of Texas Health Science Center at Houston noted in a presentation at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

Brian Hoyle/Frontline Medical News

In ORATORIO, ocrelizumab (600 mg intravenous infused every 6 months as two 300-mg infusions given 2 weeks apart) was compared with placebo in 732 people with PPMS in a 120-week blinded treatment. The number of patients with T1 Gd+ lesions at baseline was similar in the placebo arm (60/244, 24.7%) and the ocrelizumab arm (133/488, 27.5%). T1 Gd-negative (Gd-) lesions, which are likely older and indicative of the absence of a relapse, were identified in 183 and 350 of the patients in the placebo and ocrelizumab arms, respectively.

Time to onset of 12-week confirmed disability progression (CDP) was delayed in a quarter of the overall population (hazard ratio, 0.76; 95% confidence interval, 0.59-0.98). Risk reduction was greater in the presence of T1 Gd+ lesions at baseline (HR, 0.65; 95% CI, 0.40-1.06), compared with patients harboring T1 Gd- lesions at baseline (HR, 0.84; 95% CI, 0.62-1.13). A similar pattern was evident for time to onset of 24-week CDP.

The changes in timed 25-foot walk from baseline to week 20, and in brain T2 hyperintense lesion volume from baseline to week 120 were significantly reduced overall by treatment. Reductions in walk time and lesion volume were apparent in the T1 Gd+ and Gd- lesion subgroups, with similar percentage change. In the overall study, ocrelizumab significantly slowed decline in brain volume from weeks 24 to 120, and slowed declines were also evident in the T1 Gd+ and Gd- lesion subgroups, compared with placebo.

The findings warrant further studies powered to assess the apparent treatment benefit in patients with Gd+ lesions – who are likely relapsing – at baseline. If the findings hold, stratifying patients prior to treatment based on MRI of T1 Gd+ lesions could help to guide ocrelizumab treatment.

Gadolinium normally cannot pass from the bloodstream into the brain or spinal cord because of the presence of the blood-brain barrier. Active inflammation in the brain or spinal cord during a MS relapse disrupts the barrier. Gadolinium enters the brain or spinal cord and permeates into MS lesions, which appear bright on MRI. 

The study was funded by Hoffmann-La Roche/Genentech. Dr. Wolinsky disclosed receiving consulting fees; compensation for service on steering committees or data monitoring boards; and/or research support from many companies that market MS drugs, including Hoffmann-La Roche/Genentech.

NEW ORLEANS – Three potentially useful blood-based biomarkers of relapse and of the response to glatiramer acetate treatment have been identified in patients with relapsing-remitting multiple sclerosis (RRMS).

The study was small, so much more needs to be done to move the findings to the bedside. Nonetheless, the hope is that the findings will someday help guide treatment decisions and outcomes in MS patients, Adam Kruszewski, a medical student at the University of Maryland, Baltimore, commented in a poster presentation at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

Brian Hoyle/Frontline Medical News

The study had its roots in the researcher’s prior findings that the Response Gene to Complement (RGC)–32 is expressed by CD3+ and CD4+ T cells in peripheral blood mononuclear cells (PBMCs) and in brain tissue from RRMS patients. As well, RGC-32 regulates the expressions of Fas ligand (FasL) and interleukin-21 (IL-21), and the activities of CDC2 and Akt.

In the current study, the investigator explored the potential value of RGC-32, FasL, IL-21, CDC2, and Akt as longitudinal biomarkers of relapse and as a way of gauging the response to the treatment of RRMS patients with glatiramer acetate – one of the most common immunomodulatory approaches used in RRMS therapy.

A cohort of 15 glatiramer acetate–treated RRMS patients was enrolled over a 2-year period. The battery of inclusion criteria included an age of 18-65 years; meeting the McDonald criteria for definite MS; a disease course featuring relapses and remissions; newly diagnosed MS or MS not treated with currently used immunomodulatory drugs for 3 months prior to study entry; no exacerbations in the 4 weeks before the study; no steroid therapy for 4 weeks prior to study enrollment; no treatment with natalizumab (Tysabri), fingolimod (Gilenya), dimethyl fumarate (Tecfidera), mitoxantrone, cyclophosphamide, or investigational drugs during the prior year; and an Extended Disability Status Score (EDSS) of 0-5.5. Exclusion criteria were a history of autoimmune disorders, vascular disease, or active acute or chronic infections; use of antibiotics in the last 30 days; a history of intracranial or intraspinal tumor or metabolic myelopathy; or a history of alcohol or drug abuse.

The 15 patients were clinically monitored and PBMCs were collected at 0, 3, 6, and 12 months. mRNA expression of the five candidate biomarkers in the PBMCs was determined using real-time quantitative polymerase chain reaction testing. Nonresponders to glatiramer acetate treatment were defined as patients who exhibited two or more relapse events following the initiation of the treatment.

Acute relapse was associated with decreased expression of RGC-32 and FasL (both P less than .0001) and increased expression of IL-21 (P = .04). No relapse-associated changes in CDC2 or AKT were evident. Compared with those who did not respond to glatiramer acetate, responders displayed an increased expression of RGC-32 and FasL (both P less than .0001), and a decreased expression of IL-21 (P = .02).

Receiver operating characteristic analysis was done to find the cutoff values that best distinguished treatment responders from nonresponders for each candidate biomarker. The probability of accurately detecting relapse was 90% for RGC-32, 88% for FasL, and 75% for IL-21. The probability of accurately detecting response to glatiramer acetate was 85%, 90%, and 85% in the same respective order.

“Right now, there is no test that can help identify a responder or nonresponder in MS therapy. Often, treatment is started and then a trial and error process with time determines the treatment course,” said Mr. Kruszewski during an interview at the poster.

The aim is to expand these results with RCG-32, FasL, and IL-21 to a randomized, controlled trial with the goal of tailoring treatment at the early stage of MS.

NEW ORLEANS – Three potentially useful blood-based biomarkers of relapse and of the response to glatiramer acetate treatment have been identified in patients with relapsing-remitting multiple sclerosis (RRMS).

The study was small, so much more needs to be done to move the findings to the bedside. Nonetheless, the hope is that the findings will someday help guide treatment decisions and outcomes in MS patients, Adam Kruszewski, a medical student at the University of Maryland, Baltimore, commented in a poster presentation at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

Brian Hoyle/Frontline Medical News

The study had its roots in the researcher’s prior findings that the Response Gene to Complement (RGC)–32 is expressed by CD3+ and CD4+ T cells in peripheral blood mononuclear cells (PBMCs) and in brain tissue from RRMS patients. As well, RGC-32 regulates the expressions of Fas ligand (FasL) and interleukin-21 (IL-21), and the activities of CDC2 and Akt.

In the current study, the investigator explored the potential value of RGC-32, FasL, IL-21, CDC2, and Akt as longitudinal biomarkers of relapse and as a way of gauging the response to the treatment of RRMS patients with glatiramer acetate – one of the most common immunomodulatory approaches used in RRMS therapy.

A cohort of 15 glatiramer acetate–treated RRMS patients was enrolled over a 2-year period. The battery of inclusion criteria included an age of 18-65 years; meeting the McDonald criteria for definite MS; a disease course featuring relapses and remissions; newly diagnosed MS or MS not treated with currently used immunomodulatory drugs for 3 months prior to study entry; no exacerbations in the 4 weeks before the study; no steroid therapy for 4 weeks prior to study enrollment; no treatment with natalizumab (Tysabri), fingolimod (Gilenya), dimethyl fumarate (Tecfidera), mitoxantrone, cyclophosphamide, or investigational drugs during the prior year; and an Extended Disability Status Score (EDSS) of 0-5.5. Exclusion criteria were a history of autoimmune disorders, vascular disease, or active acute or chronic infections; use of antibiotics in the last 30 days; a history of intracranial or intraspinal tumor or metabolic myelopathy; or a history of alcohol or drug abuse.

The 15 patients were clinically monitored and PBMCs were collected at 0, 3, 6, and 12 months. mRNA expression of the five candidate biomarkers in the PBMCs was determined using real-time quantitative polymerase chain reaction testing. Nonresponders to glatiramer acetate treatment were defined as patients who exhibited two or more relapse events following the initiation of the treatment.

Acute relapse was associated with decreased expression of RGC-32 and FasL (both P less than .0001) and increased expression of IL-21 (P = .04). No relapse-associated changes in CDC2 or AKT were evident. Compared with those who did not respond to glatiramer acetate, responders displayed an increased expression of RGC-32 and FasL (both P less than .0001), and a decreased expression of IL-21 (P = .02).

Receiver operating characteristic analysis was done to find the cutoff values that best distinguished treatment responders from nonresponders for each candidate biomarker. The probability of accurately detecting relapse was 90% for RGC-32, 88% for FasL, and 75% for IL-21. The probability of accurately detecting response to glatiramer acetate was 85%, 90%, and 85% in the same respective order.

“Right now, there is no test that can help identify a responder or nonresponder in MS therapy. Often, treatment is started and then a trial and error process with time determines the treatment course,” said Mr. Kruszewski during an interview at the poster.

The aim is to expand these results with RCG-32, FasL, and IL-21 to a randomized, controlled trial with the goal of tailoring treatment at the early stage of MS.

NEW ORLEANS – Three potentially useful blood-based biomarkers of relapse and of the response to glatiramer acetate treatment have been identified in patients with relapsing-remitting multiple sclerosis (RRMS).

The study was small, so much more needs to be done to move the findings to the bedside. Nonetheless, the hope is that the findings will someday help guide treatment decisions and outcomes in MS patients, Adam Kruszewski, a medical student at the University of Maryland, Baltimore, commented in a poster presentation at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

Brian Hoyle/Frontline Medical News

The study had its roots in the researcher’s prior findings that the Response Gene to Complement (RGC)–32 is expressed by CD3+ and CD4+ T cells in peripheral blood mononuclear cells (PBMCs) and in brain tissue from RRMS patients. As well, RGC-32 regulates the expressions of Fas ligand (FasL) and interleukin-21 (IL-21), and the activities of CDC2 and Akt.

In the current study, the investigator explored the potential value of RGC-32, FasL, IL-21, CDC2, and Akt as longitudinal biomarkers of relapse and as a way of gauging the response to the treatment of RRMS patients with glatiramer acetate – one of the most common immunomodulatory approaches used in RRMS therapy.

A cohort of 15 glatiramer acetate–treated RRMS patients was enrolled over a 2-year period. The battery of inclusion criteria included an age of 18-65 years; meeting the McDonald criteria for definite MS; a disease course featuring relapses and remissions; newly diagnosed MS or MS not treated with currently used immunomodulatory drugs for 3 months prior to study entry; no exacerbations in the 4 weeks before the study; no steroid therapy for 4 weeks prior to study enrollment; no treatment with natalizumab (Tysabri), fingolimod (Gilenya), dimethyl fumarate (Tecfidera), mitoxantrone, cyclophosphamide, or investigational drugs during the prior year; and an Extended Disability Status Score (EDSS) of 0-5.5. Exclusion criteria were a history of autoimmune disorders, vascular disease, or active acute or chronic infections; use of antibiotics in the last 30 days; a history of intracranial or intraspinal tumor or metabolic myelopathy; or a history of alcohol or drug abuse.

The 15 patients were clinically monitored and PBMCs were collected at 0, 3, 6, and 12 months. mRNA expression of the five candidate biomarkers in the PBMCs was determined using real-time quantitative polymerase chain reaction testing. Nonresponders to glatiramer acetate treatment were defined as patients who exhibited two or more relapse events following the initiation of the treatment.

Acute relapse was associated with decreased expression of RGC-32 and FasL (both P less than .0001) and increased expression of IL-21 (P = .04). No relapse-associated changes in CDC2 or AKT were evident. Compared with those who did not respond to glatiramer acetate, responders displayed an increased expression of RGC-32 and FasL (both P less than .0001), and a decreased expression of IL-21 (P = .02).

Receiver operating characteristic analysis was done to find the cutoff values that best distinguished treatment responders from nonresponders for each candidate biomarker. The probability of accurately detecting relapse was 90% for RGC-32, 88% for FasL, and 75% for IL-21. The probability of accurately detecting response to glatiramer acetate was 85%, 90%, and 85% in the same respective order.

“Right now, there is no test that can help identify a responder or nonresponder in MS therapy. Often, treatment is started and then a trial and error process with time determines the treatment course,” said Mr. Kruszewski during an interview at the poster.

The aim is to expand these results with RCG-32, FasL, and IL-21 to a randomized, controlled trial with the goal of tailoring treatment at the early stage of MS.