FDA advisory committee recommends volanesorsen for rare triglyceride disorder

SILVER SPRING, Md. – A novel drug to treat a rare metabolic disorder was recommended for approval by the Endocrinologic and Metabolic Drugs Advisory Committee in a May 10 meeting.
Advisors voted 12 to 8 to recommend volanesorsen, a novel antisense drug, as an adjunct to diet for the treatment of familial chylomicronemia syndrome (FCS).
“The sponsor provided compelling evidence that the drug lowers triglyceride levels, substantially,” said panelist Jean-Pierre Raufman, MD, of the University of Maryland. I think that there is clearly a group of patients with this disease that can benefit from this agent.”

FCS is an extremely rare genetic disorder characterized by severe hypertriglyceridemia and recurrent pancreatitis caused by a deficiency in lipoprotein lipase. Pancreatitis in the setting of hypertriglyceridemia is particularly severe, often leading to multi-organ failure, pancreatic necrosis, and death.

Volanesorsen targets apolipoprotein C-III (apoC-III), a key regulator of lipoprotein lipase, the essential enzyme involved in chylomicron and triglyceride clearance.
Because of the small number of patients affected, estimated at just 3,000-5,000 patients worldwide, the FDA considers FCS to be an orphan disease.

The application, submitted by Akcea Pharmaceuticals, was based on the results of several phase 3 clinical trials conducted both in FCS patients and, because of the rarity of the disorder, patients with high triglycerides. The APPROACH study looked at patients with FCS. The COMPASS study examined patients with hypertriglyceridemia. Additionally, an ongoing, open-label extension of the APPROACH study examined patients with FCS who had completed APPROACH,  COMPASS, and FCS patients who had not participated in a previous volanesorsen trial.

APPROACH APPROACH was a phase 3, double-blind clinical trial to assess the safety and efficacy of volanesorsen in patients with FCS. Because of the extremely small number of patients affected by FCS, non-FCS patients with hypertriglyceridemia were included in the trial.

All patients who had completed a 6 week diet, lifestyle, and medication stabilization period were enrolled in the study. In total, 67 patients were randomized to receive a weekly, subcutaneous 300 mg dose of volanesorsen or a placebo for 52 weeks. Due to the risk of platelet reduction, the study allowed for dosing schedule interruptions or pauses, if needed. To assess efficacy, the study looked at the percent change in fasting triglycerides at month 3 of the study in all randomized patients who received at least one dose of the study drug and who had baseline fasting plasma trigylcerides recorded.

Volanesorsen proved quite effective in reducing fasting triglyceride levels, with a 94% (P < 0.0001) reduction in plasma concentrations at 3 months, compared with placebo.

The effectiveness of volanesorsen extended beyond month 3, with statistically significant reductions in triglyceride concentrations at both month 6 and month 12 compared with placebo. Patients taking volanesorsen had 53% and 40% reductions at month 6 and 12 compared to baseline. Conversely, patients taking placebo experienced increases of 25% and 9%, respectively. The differences between volanesorsen and placebo patients at month 6 (–78%) and month 12 (–49%) were both statistically significant.

Another important finding from this study was that 77% of patients responded to treatment, evidenced by a reduction of triglyceride levels greater than 750 mg/dL, a much better response than the 10% of placebo patients (P =.0001).

Nine patients (27%) discontinued the study due to adverse events (AE). Five of the discontinuations were related to platelet reductions with the other four related to nonplatelet-related adverse events.

COMPASS

The COMPASS study primarily looked at patients without FCS, but severe hypertriglyceridemia, to evaluate the safety and efficacy of volanesorsen in a similarly ill, but less severe, population over a 6 month study period. Patients with FCS had baseline fasting plasma triglyceride levels of 2,644 mg/dL and 2,134 mg/dL in the placebo and volanesorsen groups, respectively. This is nearly double what was seen in non-FCS patients in the study, and is 14-17 higher than the upper limit of normal (ULN).
Researchers enrolled 114 patients and randomized them 2:1 to receive volanesorsen or placebo. This led to 75 patients taking volanesorsen and 34 placebo.
The efficacy results were similar to those in the FCS-focused APPROACH trial, with volanesorsen treatment leading to reductions in triglyceride levels after 3 months, with further reductions over the 6-month study treatment.
Weekly treatment with volanesorsen reduced triglycerides by nearly 71%  in the total patient population, compared to placebo, which only achieved a 0.9% decrease in triglycerides. These reductions were conserved at the end of week 26 in patients who had to reduce their dosing to biweekly (62%) and patients who maintained weekly dosing treatments (78%). Overall, a greater than 40% reduction of fasting triglyceride levels after 3 months of treatment was achieved in 87% of volanesorsen-treated patients, compared to 13% of placebo-treated patients (P < 0.0001).
Serious adverse events (SAEs) occurred in nine patients (8%). In the placebo group, two patients (5%) reported acute pancreatitis. Apart from the bouts of pancreatitis, some of the most common AEs were decreased platelet count, thrombocytopenia, and nasopharyngitis.

APPROACH OPEN LABEL

The open label portion of the APPROACH study is ongoing and was designed to assess the safety and efficacy of extended treatment with volanesorsen in patients with FCS who had previously completed APPROACH or COMPASS studies or had never received volanesorsen treatment. Patients received 300 mg of volanesorsen once weekly for 52 weeks. Patients who completed the trial were eligible to continue treatment for an additional 52 weeks or until a product is available. As of August 31, 2017, after the data cutoff, 60 patients were enrolled.
The results of this open label portion of the APPROACH trial were similar to that of the APPROACH trial itself. Patients who transitioned from APPROACH or COMPASS showed decreases in their open label extension (OLE) baseline triglyceride measurements to OLE month 3 of 48.1% and 52.1%, respectively. Treatment-naive patients displayed a nearly 60% decrease in their triglyceride levels 3 months.
Of the 60 patients who started the study, 12 have discontinued the study prematurely. The majority of patients, eight, who discontinued did so because of adverse events and four withdrew voluntarily.
Adverse events were not uncommon, with 56 patients (93%) experiencing an AE during the course of the study. Some of the most common AEs were decreased platelet count, thrombocytopenia, and nasopharyngitis.
Akcea has developed a Risk Evaluation and Mitigation program to mitigate the risk of serious bleeding related to severe thrombocytopenia with volanesorsen use in patients with FCS.
Panelist Susan Z. Yanovksi, MD, of the National Institutes of Health, said she voted no over safety concerns, but felt conflicted.
“There’s no question that volanesorsen is effective in dramatically reducing triglycerides, but I had a lot of concerns whether the data presented by the sponsor actually established favorable risk-benefit ratio.”

The FDA is expected to decide on the application by August 30. The FDA usually follows the recommendations of its advisory panels, which are not binding.

ilacy@mdedge.com

SILVER SPRING, Md. – A novel drug to treat a rare metabolic disorder was recommended for approval by the Endocrinologic and Metabolic Drugs Advisory Committee in a May 10 meeting.
Advisors voted 12 to 8 to recommend volanesorsen, a novel antisense drug, as an adjunct to diet for the treatment of familial chylomicronemia syndrome (FCS).
“The sponsor provided compelling evidence that the drug lowers triglyceride levels, substantially,” said panelist Jean-Pierre Raufman, MD, of the University of Maryland. I think that there is clearly a group of patients with this disease that can benefit from this agent.”

FCS is an extremely rare genetic disorder characterized by severe hypertriglyceridemia and recurrent pancreatitis caused by a deficiency in lipoprotein lipase. Pancreatitis in the setting of hypertriglyceridemia is particularly severe, often leading to multi-organ failure, pancreatic necrosis, and death.

Volanesorsen targets apolipoprotein C-III (apoC-III), a key regulator of lipoprotein lipase, the essential enzyme involved in chylomicron and triglyceride clearance.
Because of the small number of patients affected, estimated at just 3,000-5,000 patients worldwide, the FDA considers FCS to be an orphan disease.

The application, submitted by Akcea Pharmaceuticals, was based on the results of several phase 3 clinical trials conducted both in FCS patients and, because of the rarity of the disorder, patients with high triglycerides. The APPROACH study looked at patients with FCS. The COMPASS study examined patients with hypertriglyceridemia. Additionally, an ongoing, open-label extension of the APPROACH study examined patients with FCS who had completed APPROACH,  COMPASS, and FCS patients who had not participated in a previous volanesorsen trial.

APPROACH APPROACH was a phase 3, double-blind clinical trial to assess the safety and efficacy of volanesorsen in patients with FCS. Because of the extremely small number of patients affected by FCS, non-FCS patients with hypertriglyceridemia were included in the trial.

All patients who had completed a 6 week diet, lifestyle, and medication stabilization period were enrolled in the study. In total, 67 patients were randomized to receive a weekly, subcutaneous 300 mg dose of volanesorsen or a placebo for 52 weeks. Due to the risk of platelet reduction, the study allowed for dosing schedule interruptions or pauses, if needed. To assess efficacy, the study looked at the percent change in fasting triglycerides at month 3 of the study in all randomized patients who received at least one dose of the study drug and who had baseline fasting plasma trigylcerides recorded.

Volanesorsen proved quite effective in reducing fasting triglyceride levels, with a 94% (P < 0.0001) reduction in plasma concentrations at 3 months, compared with placebo.

The effectiveness of volanesorsen extended beyond month 3, with statistically significant reductions in triglyceride concentrations at both month 6 and month 12 compared with placebo. Patients taking volanesorsen had 53% and 40% reductions at month 6 and 12 compared to baseline. Conversely, patients taking placebo experienced increases of 25% and 9%, respectively. The differences between volanesorsen and placebo patients at month 6 (–78%) and month 12 (–49%) were both statistically significant.

Another important finding from this study was that 77% of patients responded to treatment, evidenced by a reduction of triglyceride levels greater than 750 mg/dL, a much better response than the 10% of placebo patients (P =.0001).

Nine patients (27%) discontinued the study due to adverse events (AE). Five of the discontinuations were related to platelet reductions with the other four related to nonplatelet-related adverse events.

COMPASS

The COMPASS study primarily looked at patients without FCS, but severe hypertriglyceridemia, to evaluate the safety and efficacy of volanesorsen in a similarly ill, but less severe, population over a 6 month study period. Patients with FCS had baseline fasting plasma triglyceride levels of 2,644 mg/dL and 2,134 mg/dL in the placebo and volanesorsen groups, respectively. This is nearly double what was seen in non-FCS patients in the study, and is 14-17 higher than the upper limit of normal (ULN).
Researchers enrolled 114 patients and randomized them 2:1 to receive volanesorsen or placebo. This led to 75 patients taking volanesorsen and 34 placebo.
The efficacy results were similar to those in the FCS-focused APPROACH trial, with volanesorsen treatment leading to reductions in triglyceride levels after 3 months, with further reductions over the 6-month study treatment.
Weekly treatment with volanesorsen reduced triglycerides by nearly 71%  in the total patient population, compared to placebo, which only achieved a 0.9% decrease in triglycerides. These reductions were conserved at the end of week 26 in patients who had to reduce their dosing to biweekly (62%) and patients who maintained weekly dosing treatments (78%). Overall, a greater than 40% reduction of fasting triglyceride levels after 3 months of treatment was achieved in 87% of volanesorsen-treated patients, compared to 13% of placebo-treated patients (P < 0.0001).
Serious adverse events (SAEs) occurred in nine patients (8%). In the placebo group, two patients (5%) reported acute pancreatitis. Apart from the bouts of pancreatitis, some of the most common AEs were decreased platelet count, thrombocytopenia, and nasopharyngitis.

APPROACH OPEN LABEL

The open label portion of the APPROACH study is ongoing and was designed to assess the safety and efficacy of extended treatment with volanesorsen in patients with FCS who had previously completed APPROACH or COMPASS studies or had never received volanesorsen treatment. Patients received 300 mg of volanesorsen once weekly for 52 weeks. Patients who completed the trial were eligible to continue treatment for an additional 52 weeks or until a product is available. As of August 31, 2017, after the data cutoff, 60 patients were enrolled.
The results of this open label portion of the APPROACH trial were similar to that of the APPROACH trial itself. Patients who transitioned from APPROACH or COMPASS showed decreases in their open label extension (OLE) baseline triglyceride measurements to OLE month 3 of 48.1% and 52.1%, respectively. Treatment-naive patients displayed a nearly 60% decrease in their triglyceride levels 3 months.
Of the 60 patients who started the study, 12 have discontinued the study prematurely. The majority of patients, eight, who discontinued did so because of adverse events and four withdrew voluntarily.
Adverse events were not uncommon, with 56 patients (93%) experiencing an AE during the course of the study. Some of the most common AEs were decreased platelet count, thrombocytopenia, and nasopharyngitis.
Akcea has developed a Risk Evaluation and Mitigation program to mitigate the risk of serious bleeding related to severe thrombocytopenia with volanesorsen use in patients with FCS.
Panelist Susan Z. Yanovksi, MD, of the National Institutes of Health, said she voted no over safety concerns, but felt conflicted.
“There’s no question that volanesorsen is effective in dramatically reducing triglycerides, but I had a lot of concerns whether the data presented by the sponsor actually established favorable risk-benefit ratio.”

The FDA is expected to decide on the application by August 30. The FDA usually follows the recommendations of its advisory panels, which are not binding.

ilacy@mdedge.com

SILVER SPRING, Md. – A novel drug to treat a rare metabolic disorder was recommended for approval by the Endocrinologic and Metabolic Drugs Advisory Committee in a May 10 meeting.
Advisors voted 12 to 8 to recommend volanesorsen, a novel antisense drug, as an adjunct to diet for the treatment of familial chylomicronemia syndrome (FCS).
“The sponsor provided compelling evidence that the drug lowers triglyceride levels, substantially,” said panelist Jean-Pierre Raufman, MD, of the University of Maryland. I think that there is clearly a group of patients with this disease that can benefit from this agent.”

FCS is an extremely rare genetic disorder characterized by severe hypertriglyceridemia and recurrent pancreatitis caused by a deficiency in lipoprotein lipase. Pancreatitis in the setting of hypertriglyceridemia is particularly severe, often leading to multi-organ failure, pancreatic necrosis, and death.

Volanesorsen targets apolipoprotein C-III (apoC-III), a key regulator of lipoprotein lipase, the essential enzyme involved in chylomicron and triglyceride clearance.
Because of the small number of patients affected, estimated at just 3,000-5,000 patients worldwide, the FDA considers FCS to be an orphan disease.

The application, submitted by Akcea Pharmaceuticals, was based on the results of several phase 3 clinical trials conducted both in FCS patients and, because of the rarity of the disorder, patients with high triglycerides. The APPROACH study looked at patients with FCS. The COMPASS study examined patients with hypertriglyceridemia. Additionally, an ongoing, open-label extension of the APPROACH study examined patients with FCS who had completed APPROACH,  COMPASS, and FCS patients who had not participated in a previous volanesorsen trial.

APPROACH APPROACH was a phase 3, double-blind clinical trial to assess the safety and efficacy of volanesorsen in patients with FCS. Because of the extremely small number of patients affected by FCS, non-FCS patients with hypertriglyceridemia were included in the trial.

All patients who had completed a 6 week diet, lifestyle, and medication stabilization period were enrolled in the study. In total, 67 patients were randomized to receive a weekly, subcutaneous 300 mg dose of volanesorsen or a placebo for 52 weeks. Due to the risk of platelet reduction, the study allowed for dosing schedule interruptions or pauses, if needed. To assess efficacy, the study looked at the percent change in fasting triglycerides at month 3 of the study in all randomized patients who received at least one dose of the study drug and who had baseline fasting plasma trigylcerides recorded.

Volanesorsen proved quite effective in reducing fasting triglyceride levels, with a 94% (P < 0.0001) reduction in plasma concentrations at 3 months, compared with placebo.

The effectiveness of volanesorsen extended beyond month 3, with statistically significant reductions in triglyceride concentrations at both month 6 and month 12 compared with placebo. Patients taking volanesorsen had 53% and 40% reductions at month 6 and 12 compared to baseline. Conversely, patients taking placebo experienced increases of 25% and 9%, respectively. The differences between volanesorsen and placebo patients at month 6 (–78%) and month 12 (–49%) were both statistically significant.

Another important finding from this study was that 77% of patients responded to treatment, evidenced by a reduction of triglyceride levels greater than 750 mg/dL, a much better response than the 10% of placebo patients (P =.0001).

Nine patients (27%) discontinued the study due to adverse events (AE). Five of the discontinuations were related to platelet reductions with the other four related to nonplatelet-related adverse events.

COMPASS

The COMPASS study primarily looked at patients without FCS, but severe hypertriglyceridemia, to evaluate the safety and efficacy of volanesorsen in a similarly ill, but less severe, population over a 6 month study period. Patients with FCS had baseline fasting plasma triglyceride levels of 2,644 mg/dL and 2,134 mg/dL in the placebo and volanesorsen groups, respectively. This is nearly double what was seen in non-FCS patients in the study, and is 14-17 higher than the upper limit of normal (ULN).
Researchers enrolled 114 patients and randomized them 2:1 to receive volanesorsen or placebo. This led to 75 patients taking volanesorsen and 34 placebo.
The efficacy results were similar to those in the FCS-focused APPROACH trial, with volanesorsen treatment leading to reductions in triglyceride levels after 3 months, with further reductions over the 6-month study treatment.
Weekly treatment with volanesorsen reduced triglycerides by nearly 71%  in the total patient population, compared to placebo, which only achieved a 0.9% decrease in triglycerides. These reductions were conserved at the end of week 26 in patients who had to reduce their dosing to biweekly (62%) and patients who maintained weekly dosing treatments (78%). Overall, a greater than 40% reduction of fasting triglyceride levels after 3 months of treatment was achieved in 87% of volanesorsen-treated patients, compared to 13% of placebo-treated patients (P < 0.0001).
Serious adverse events (SAEs) occurred in nine patients (8%). In the placebo group, two patients (5%) reported acute pancreatitis. Apart from the bouts of pancreatitis, some of the most common AEs were decreased platelet count, thrombocytopenia, and nasopharyngitis.

APPROACH OPEN LABEL

The open label portion of the APPROACH study is ongoing and was designed to assess the safety and efficacy of extended treatment with volanesorsen in patients with FCS who had previously completed APPROACH or COMPASS studies or had never received volanesorsen treatment. Patients received 300 mg of volanesorsen once weekly for 52 weeks. Patients who completed the trial were eligible to continue treatment for an additional 52 weeks or until a product is available. As of August 31, 2017, after the data cutoff, 60 patients were enrolled.
The results of this open label portion of the APPROACH trial were similar to that of the APPROACH trial itself. Patients who transitioned from APPROACH or COMPASS showed decreases in their open label extension (OLE) baseline triglyceride measurements to OLE month 3 of 48.1% and 52.1%, respectively. Treatment-naive patients displayed a nearly 60% decrease in their triglyceride levels 3 months.
Of the 60 patients who started the study, 12 have discontinued the study prematurely. The majority of patients, eight, who discontinued did so because of adverse events and four withdrew voluntarily.
Adverse events were not uncommon, with 56 patients (93%) experiencing an AE during the course of the study. Some of the most common AEs were decreased platelet count, thrombocytopenia, and nasopharyngitis.
Akcea has developed a Risk Evaluation and Mitigation program to mitigate the risk of serious bleeding related to severe thrombocytopenia with volanesorsen use in patients with FCS.
Panelist Susan Z. Yanovksi, MD, of the National Institutes of Health, said she voted no over safety concerns, but felt conflicted.
“There’s no question that volanesorsen is effective in dramatically reducing triglycerides, but I had a lot of concerns whether the data presented by the sponsor actually established favorable risk-benefit ratio.”

The FDA is expected to decide on the application by August 30. The FDA usually follows the recommendations of its advisory panels, which are not binding.

ilacy@mdedge.com