When I reported on the initial Galvus approval delay in November, I promised a follow-up story. Yesterday, Novartis (NYSE:NVS) reported that FDA took the action of granting the Galvus NDA approvable status. Novartis had obviously expected this decision for a while, since label negotiations never occurred, but the company chose to make the announcement after the decision was made official by FDA on the 23rd.
The approvable letter wasn’t disclosed by the company, but Novartis shared FDA’s general reasons for the decision in their presentation to investors. Seems that FDA remains concerned about the skin lesions Novartis observed in its 1-year monkey tox study, despite the lack of similar lesions being observed in humans. It’s asked the company to conduct further clinical study or studies to investigate the finding further, specifically requesting a clinical study in patients with renal impairment.
Reading into FDA’s decision, and aided by Novartis’ mostly frank responses to investors on its conference call, it appears that FDA believes there is reason to think that the finding might be dose-administered and metabolite-related and therefore unmasked by studying the drug in a population with higher average steady-state Galvus metabolite concentrations than the population originally studied. Of note, Novartis indicated that about 900 study subjects with mild to moderate renal impairment received at least one dose of Galvus in its Phase two and three of the program, including 600 who received Galvus for at least six months. This is a decent safety exposure, especially given that the parent drug is not renally cleared, but it’s not large enough to rule out a potentially clinically important incidence of a rare adverse drug reaction.
During the conference call, Novartis’ Head of Global Development, James Shannon, stated that the FDA division reviewing the drug, the DMEDP, has been under much criticism and public scrutiny lately. Although he stopped short of suggesting that this criticism influenced the DMEDP decision, it’s unreasonable to expect that such criticism would not influence the division to err on the side of caution. Regrettably, FDA remains as politically and publicly vulnerable as any federal agency, installation of a ‘permanent’ head notwithstanding.
Despite the allure of chalking up FDA’s approvable decision on Galvus to a case of the cautious pneumonia, it’s impossible to understand the logic behind FDA’s decision and to speculate intelligently on what Novartis will have to demonstrate to gain U.S. marketing approval for Galvus without answers to some key questions. What was the incidence and PK-relationship, including the active metabolite, of the monkey skin lesions? Why wasn’t an advisory committee used to debate the importance of this unusual (perhaps unprecedented) preclinical finding before FDA made its decision? Did FDA have an internal immuno- or derm-tox review of the skin findings performed? If so, what were the reviewer’s conclusions?
If FDA believes the skin finding to be a pharmacological effect of DPP-IV inhibition, why hasn’t it alerted prescribers and users of Merck’s (NYSE:MRK) Januvia, the first drug product in this new class? If FDA believes the finding to be specific to Galvus, and possibly specific to its metabolite, what incidence of the finding in renally impaired humans is it willing to accept to allow approval, perhaps with population warnings? Outsiders are unlikely to have any answers to these questions for quite a while.
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