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Novo Nordisk's New Hemophilia-B Drug Will Have A Hard Time Getting Through FDA Panel
Apr.24.17 | About: Novo Nordisk (NVO)

Summary

Novo Nordisk has a new hemophilia drug scheduled for an FDA panel review in May.

A briefing document published by the FDA views efficacy positively, but brings up safety issues.

Despite the fact that pegylated clotting factors for hemophilia are already on the market, the tone of the document suggests a decent possibility of rejection on the basis of safety.

A new factor IX coagulation factor is scheduled for review by an FDA panel on May 16. Trademarked Refixia and known clinically as N9-GP, it is a Novo Nordisk (NYSE:NVO) drug for the treatment of hemophilia B. At first glance, FDA approval for Refixia may seem likely, but looking at the recent briefing document issued by the FDA in review of the preclinical and clinical data tells a bit of a different story.

Novo Nordisk is most well-known for its line of diabetes products, but its hemophilia line is also quite significant for its portfolio of drugs. In fact, Novo's blood clotting factor VII NovoSeven is its third bestseller by revenue at $1.37 billion in 2016. Refixia is a F-IX drug (hence ReFIXia) for hemophilia B, so it would not cannibalize revenue from NovoSeven if approved. The first question is will it be approved, and the second is will it sell well even if it is?

As for the first question, Refixia is factor IX fused with polyethylene glycol (PEG) to increase its half-life, or the time it circulates without degradation in the blood. This is for the purpose of less frequent dosing. On Refixia's side is that pegylated clotting factors already exist in the market. Adynovate, for example, is a pegylated version of Shire's (NASDAQ:SHPG) Advate, so on that basis alone one could assume that Refixia will be approved. However, the tone of the FDA's briefing material suggests that rejection on the basis of safety and particularly the risk/benefit analysis is very possible.

Preclinical data analysis

The briefing document does have a positive safety tone in its analysis of animal studies. The FDA first notes that animals did show potentially worrisome side effects including buildup of PEG in the choroid plexus (the part of the brain that produces cerebro-spinal fluid), immune reactions that neutralized the drug. However, these animals were given doses almost 100-fold higher than the proposed prophylactic dose that would prevent bleeding in humans. Specifically, the FDA notes that "Therefore, the likelihood of development of CNS tremors, cellulitis, and meningeal hemorrhage following chronic administration of N9-GP in humans may be low." The side effects listed did occur in animals during preclinical testing.

However, from there more issues arise. The FDA continues by noting that (emphasis mine):

Accumulation of PEG in the connective tissue and cytoplasm of epithelial cells in the choroid plexus, and in blood within brain blood vessels was one of the most consistent observations in the histology. This observation was observed irrespective of the dose level of N9-GP.

Clearly, we can see that the FDA is concerned about the possible safety implications of PEG accumulating in the choroid plexus. Note again that in the previous quote, the document only said that the likelihood of damaging side effects from chronic administration of N9-GP may be low. The paragraph above seems to inject some doubt in that possibility.

The document then speculates that this buildup of PEG in the choroid plexus may be responsible for meningeal hemorrhaging in the highest-dose animals. Since the choroid plexus produces cerebro-spinal fluid (CSF) the agency seems concerned that infection of the CSF with PEG may lead to swelling in the brain and the resulting hemorrhaging. And while yes, the highest dose animals are the only group that had this problem, chronic administration at low doses may still eventually lead to these types of complications though gradual buildup. At least, this is what that FDA seems to be alluding to.

Clinical data analysis

From there, analysis is made of Novo Nordisk's clinical program, which is generally positive in terms of determination of efficacy. However, safety here is brought up as well.

A total of 4 studies were performed on 183 patients, separate studies for each age group. The FDA notes early on in its analysis of the clinical data that "it is unclear whether the size of the safety database (i.e., number of adult and/or pediatric subjects exposed to the product; duration of follow-up of those subjects) is sufficient to assess the safety of the product."

Further, there is this worrisome line:

"The neurological monitoring during the clinical trials may have been insufficient to detect early signs of dysfunction…"

It then specifically says that pediatric patients may be at the greatest risk because they would be taking Refixia for the longest period of time, presumably allowing for the longest building and eventual problems later in life.

Conclusion

With this kind of tone, the FDA panel will definitely be asking plenty of safety questions to the Novo Nordisk staff at the meeting, and it is unclear if the company will be able to assuage the safety concerns. I would guess that even if Refixia is approved, the panel may recommend long-term monitoring of patients, something which may obviate the convenience of less dosing due to the longer half-life of the product. So even if approved, marketing precautions taken may make Refixia less attractive than, say, Biogen's (NASDAQ:BIIB) Alprolix.

Alprolix is a longer-acting factor IX already on the market without any PEG. Instead, it uses the Fc fusion protein to prolong the half-life, a naturally-occurring protein in humans. The fact that there is already a long-acting factor IX on the market is actually an added negative for the approval of Refixia because it lowers the benefit of putting Refixia on the market, given there is already something like it available to patients with a lower risk profile.

I would venture to guess that the chances of an unambiguous vote for approval by the panel in May is less than 40%, and even if a positive vote squeaks through, it could be filled with caveats that may make its chances of success in the market dubious at best.
https://seekingalpha.com/article/4064547-novo-nordisks-new-hemophilia-b-drug-will-hard-time-getting-fda-panel