Concerns about a possible safety issue with the investigational glycoPEGylated factor IX product nonacog beta pegol (N9-GP) for the treatment of hemophilia B left members of the Blood Products Advisory Committee of the Food and Drug Administration divided during an April 4 committee meeting about whether additional study should take place prior to FDA approval of a Biologics Licensing Application or in the postmarketing setting.

The committee was not asked to vote on a recommendation for approval of N9-GP. Committee members agreed that if N9-GP is approved, standardized postmarketing monitoring would be needed, particularly in very young and very old patients.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

Repetitive dosing of the long-acting product, for which Novo Nordisk has submitted the Biologics Licensing Application, has been associated with polyethylene glycol (PEG) accumulation in the choroid plexus in monkeys and rats. No safety signals clearly linked to PEG accumulation were seen in multiple clinical trials; however, it was unclear whether monitoring of neurologic function during the course of those studies was adequate to detect clinically important neurological signs or symptoms.

As a result, the FDA asked the advisory committee to consider the clinical significance of the preclinical findings, the nature and level of any safety concerns in various populations, the sufficiency of evidence from toxicology and clinical studies for intermittent and chronic use, clinical or laboratory assessments that might help ensure patient safety, and recommendations for additional studies to support the safety of the product.

Novo Nordisk is specifically seeking FDA marketing approval of N9-GP, which is administered weekly, for control and prevention of bleeding episodes, perioperative management, and routine prophylaxis in adults and children. The company submitted evidence for these indications from three phase III trials and a phase III extension study in adults and children.

“The Office of Tissues and Advanced Therapies – OTAT – appreciates that hemophilia B is a serious disease and we need improved therapies to benefit patients. We also appreciate that this is a rare disease, which limits the availability of data to address issues of safety and effectiveness,” Wilson Bryan, MD, director of OTAT, which is part of the FDA’s Center for Biologics Evaluation and Research, told the advisory committee.

The committee then heard from Novo Nordisk representatives who spoke about the unmet public health need for hemophilia B treatments, and N9-GP clinical efficacy, long-term safety, and risk/benefit analyses.

Shawn Hoskin, senior director of regulatory affairs for Novo Nordisk, noted that with weekly dosing of N9-GP, no adverse effects were seen in preclinical studies at doses up to 42 times the human dose. Further, no adverse effects were reported in clinical studies, in which high levels of factor IX were achieved.

“Our trials demonstrated that the higher factor IX levels achieved with N9-GP lead to better outcomes for patients, including reduced annual bleed rate, reduction in the number of spontaneous bleeds, and resolution of target joints,” he said.

Stephanie Seremetis, MD, chief medical officer and corporate vice president for hemophilia at Novo Nordisk, said the company has proposed a postapproval monitoring plan and safety study.

The advisory committee also heard from patients invited by Novo Nordisk to share their experiences, and from Maria Lehtinen, PhD, of Boston Children’s Hospital, who was invited to speak about choroid plexus biology.

The patients agreed that there is an urgent need and desire for effective, long-acting treatments. Ben Shuldiner, for example, said he was part of the clinical trials for N9-GP, has never had as much success sticking to a treatment regimen, and “is in much better shape, much less pain.”

“The [hemophilia] community needs choice,” said Mr. Shuldiner, a professor at Hunter College in New York, and an activist. He stressed that what works for one patient doesn’t necessarily work for another.

Committee members didn’t question the efficacy or value of the long-acting product, but did express concern about the unknown effects of PEG accumulation. One member questioned whether it might be feasible to restrict licensing to children over age 6 years and to adults under age 65 years pending additional study. Other members said that approach would restrict treatment for patients who might benefit the most from N9-GP.

Meera B. Chitlur, MD, noted that most children with hemophilia B are treated prophylactically by age 1, or at least by the time they are walking, and suggested it might be better to allow use of the product in those who need it, while collecting data going forward.

“Only over the last couple years have our patients finally had the opportunity to have something that has substantially changed how they are managed or what they can do. This class of drugs is one that has made it possible for these patients to lead a better life, so I think it is really important for us,” said Dr. Chitlur of Wayne State University and Children’s Hospital of Michigan, Detroit.

“The youngest children will probably benefit the most. Yes, there are concerns ... but at the same time I think I haven’t heard anything today, or read anything, that has made me want to say it is not safe for the patients that I’m going to take care of,” she added, noting that informed consent is possible and important.

Dr. Chitlur said she completely agrees with the need for systematic data collection, and feels there are already mechanisms in place to achieve that goal.

“I feel comfortable taking this to my patients and saying that here is another option for you,” she said.

Laura Manuelidis, MD, of Yale University, New Haven, Conn., a temporary voting member of the committee, said she was “less sanguine,” about immediate approval. Additional studies of the effects of PEG accumulation in animals are feasible, she said, and could be performed rapidly before approving treatment in children under age 2 years.

Michael Dobbs, MD, of the University of Kentucky, Lexington, also a temporary voting member, agreed it would be valuable to test available cerebrospinal fluid of animals from the preclinical studies. He had no recommendation for additional studies, but agreed on the importance of extensive postmarketing surveillance. He added that patients who undergo CSF testing or magnetic resonance imaging for other clinical reasons should be evaluated for the possible effects of PEG accumulation.

“I think we should follow cognitive outcomes in the postmarket data, probably requiring more neurocognitive data in pediatrics with some validated, standardized tests. It would be reasonable to require a full neurological exam pre- and post-[treatment], especially in those at fixed developmental states,” he said.

It would also be reasonable to monitor children for signs and symptoms of hydrocephalus and for papilledema and other visual disturbances, he added.

“But again, most of all ... whatever we really do recommend, we need standardization, validation – to do this the same [way] for all of the patients,” he said.

Dr. Bryan, of OTAT, said the input from members and guests will be considered as the FDA proceeds with its review of the Biologics Licensing Application for N9-GP. The FDA is not bound by the committee’s guidance.

All members of the advisory committee have been screened and found to be in compliance with respect to potential conflicts of interest. No conflict of interest waivers were issued. Patients who spoke in favor of N9-GP received travel and/or other support from Novo Nordisk.

sworcester@frontlinemedcom.com

Safety of N9-GP for hemophilia B needs further study, FDA committee agrees