FDA panel supports approval of volanesorsen for familial chylomicronemia syndrome

The Endocrinologic and Metabolic Drugs Advisory Committee of the FDA voted 12-8 in favor that Akcea provided sufficient data on the safety and efficacy of volanesorsen to support approval of its application.

Industry and FDA members presented information during the meeting on the safety and efficacy of volanesorsen (Waylivra) when used in conjunction with diet to lower cholesterol in patients with familial chylomicronemia syndrome.

Besides safety and efficacy, draft questions for this meeting included the risk for thrombocytopenia that is associated with volanesorsen, whether familial chylomicronemia syndrome is a sufficient description for the target population for this approval, the potential for future study in the pediatric population and whether a risk evaluation and mitigation strategy is necessary.

Application vote

“Clearly there’s a strong unmet need for a rare genetic condition with great suffering, as we heard, significant physical, emotional and financial burden of the disease,” Elaine H. Morrato, DrPH, MPH, associate dean for public health practice and associate professor in the department of health systems, management and policy at University of Colorado Anschutz Medical Campus Colorado School of Public Health in Aurora, said during the vote. “We were being asked to trade off two potentially life-threatening conditions, the pancreatitis as well as the drug-attributable thrombocytopenia. Unfortunately, we had limited information on both of them, but I think at the end of the day, I felt that for some patients, the tradeoff to avoid the pancreatitis risk made sense given their personal history, but recognizing that for others, that may not be the appropriate benefit-risk for them.”

Some members who voted no said they understood the burdens that these patients face, although the data were not sufficient.

“This was a very difficult decision for me because I know how difficult life is for patients with familial chylomicronemia syndrome, but I looked at the question literally, which asked has the applicant provided sufficient efficacy and safety data to support approval of volanesorsen, and I felt that although there was a significant reduction in triglycerides with the dose used which may not be the dose used in clinical practice, that there was no clinical benefit on either pancreatitis, abdominal pain or on any other symptoms or signs that these patients might have,” Connie B. Newman, MD, FACP, FAHA, FAMWA, adjunct professor of medicine at New York University School of Medicine and attending physician in the department of veteran affairs at New York Harbor Healthcare Center, said during the vote.

Representatives from Akcea and clinicians presented information on the safety and efficacy of volanesorsen. To address various adverse effects of volanesorsen, Akcea proposed a risk management program to support patient safety and compliance.

“Our labeling provides details regarding patient selection, treatment with instructions on dose adjustments and platelet monitoring,” Louis St.L. O’Dea, MB, BCh, BAO, CSPQ, FRCP(C), chief medical officer for Akcea Therapeutics, said during the presentation. “We’re collaborating with the agency to develop a risk evaluation and mitigation strategy, or REMS, with added elements to ensure safe use. It will include mandatory registration of all patients, prescribers and pharmacies.”

The REMS includes updated labeling, enhanced pharmacovigilance, a treatment registry study and elements to assure safe use of volanesorsen. Other steps to be taken include weight-based dosing, a medication guide, an early threshold for dose pause and platelet monitoring every 2 weeks.

Approximately 70% of patients with familial chylomicronemia develop pancreatitis, and nearly half of them have between two and 96 episodes of pancreatitis over their lifetime.

“The suffering of these patients cannot be underestimated, where meals are a frequent trigger of abdominal pain, and patients live in constant fear that one of these bouts will put them in the hospital and likely in the intensive care unit,” Steve Freedman, MD, PhD, professor of medicine at Harvard Medical School and chief of the division of translational research and director of the Pancreas Center at Beth Israel Deaconess Medical Center, said during the presentation. “Unfortunately, this is a typical scenario for these patients. All available data indicate that the risk for pancreatitis increases and decreases as a continuum related to triglyceride levels. Therefore, an effective medication to substantially lower triglycerides will allow patients to achieve triglyceride levels below those associated with an elevated pancreatitis risk.”

Volanesorsen has been shown in several studies to decrease triglyceride levels of up to 94% in patients with familial chylomicronemia syndrome compared with placebo, and the decrease was sustained over time.

“The degree of triglyceride reduction should reduce the risk of pancreatitis, and point estimates for pancreatitis risk support this potential,” O’Dea said. “In fact, in all exploratory assessments of pancreatitis, volanesorsen consistently showed a numeric benefit. Given the severity of this disease and the absence of effective alternative therapy, these substantial reductions in triglycerides, which drive the symptoms and complications of this disease, are meaningful and medically important to these patients.”

The safety profile of volanesorsen is well-understood, according to the applicant presentation. The primary safety concern is thrombocytopenia, and although platelet reductions occurred, they were reversible and did not result in serious bleeding events.

“I am confident that volanesorsen should be approved,” Seth J. Baum, MD, FACC, FACPM, FAHA, FNLA, FASPC, president of the American Society of Preventive Cardiology and affiliate clinical professor of medicine at Schmidt College of Medicine in Boca Raton, Florida, said during the presentation. “We have seen the data. We know the risks and the benefits. We know that we need to monitor the risks, and we have the support system to do so. Most importantly, this small group of patients needs a therapy to lower their triglycerides. Now we can give them that opportunity by recommending approval to the FDA.”

Seth J. Baum

Patient identification

Even with data showing that volanesorsen decreases triglycerides in patients with familial chylomicronemia syndrome, there still needs to be a way to identify patients with the syndrome in whom the benefits outweigh the risks, according to the FDA.

“How best to identify patient population for whom volanesorsen may have a favorable benefit-risk profile should be kept in mind while considering the efficacy and safety profile of volanesorsen,” Mary D. Roberts, MD, clinical reviewer for the FDA, said during the presentation.

Analyses for abdominal pain, pancreatitis and quality-of-life outcomes did not show any evidence of benefit for treatment with volanesorsen. Other safety concerns include injection-site reactions, influenza-like reactions, renal events, hepatic events and thrombocytopenia that may lead to bleeding.

Predicting extreme cases of type 1 thrombocytopenia through the relationship between body weight, drug exposure and nadir platelet counts may help mitigate these cases, although the body weight cutoff would need to be optimized, according to the FDA presentation.

“At the current stage, an intensive platelet monitoring plan appears clinically critical,” Yunzhao Ren, MD, PhD, clinical pharmacology reviewer in the division of clinical pharmacology II for the FDA, said during the presentation.

The FDA previously proposed a REMS that included prescriber certification and training, pharmacy or dispenser certification, documentation of safety conditions at the time of treatment initiation, documented routine patient monitoring every 90 days and enrollment of all patients in a REMS registry. Akcea proposed an amendment to the strategy in April, which now aligns with what the FDA has suggested to ensure safety, according to the presentation.

“We’ve attempted to strike a balance between safety and burden, knowing that patients should be monitored routinely,” Ingrid N. Chapman, PharmD, BCPS, risk management analyst in the division of risk management of the FDA, said during the presentation. “Our proposed REMS can ensure prescribers are educated and patients are aware of the risk and the need for frequent monitoring. However, there are limitations to the proposal, one being rapid and severe decreases in platelets may not be prevented even with compliance with rigorous monitoring and dose modifications per the prescribing information. The second limitation is that the proposed REMS will not enforce monitoring as described in the prescribing information. It’s uncertain if the burden associated with additional requirements will add a greater degree of safety.”

An open public hearing was also held during the meeting, in which patients with familial chylomicronemia syndrome, organizations and clinicians commented on their desire for the application for volanesorsen to be approved. Some of the patients who commented were treated with volanesorsen during a study.

Although a webcast was not provided, meeting materials were made available on the FDA website, according to the meeting announcement.

“We look forward to working with the FDA to complete the final stages of regulatory review for Waylivra,” Paula Soteropoulos, CEO of Akcea Therapeutics, said in a prepared statement from the company. “We are committed to the [familial chylomicronemia syndrome] community and will continue to focus on bringing Waylivra to people suffering with this devastating disease.” – by Darlene Dobkowski

Reference:

FDA Briefing Document. NDA 210645.