FDA's Anti-Infective Drugs Advisory Committee will assess Novartis' malaria candidate Coartem (artemether/lumefantrine) Dec. 3 for the treatment of acute, uncomplicated malaria infection due to Plasmodium falciparum or mixed infections including P. falciparum. But some of the larger questions about the review are about FDA's process rather than the product itself.

A positive review could put Novartis in line to be the first to obtain a priority review voucher from FDA, entitling it to a rapid review of another product of its choosing. And while review of the product is relatively straightforward, the implications of the voucher program - which is designed to encourage development of treatments for tropical diseases - are anything but (¹ Also see "Novartis Malaria Combo Set For FDA Committee Review" - Pink Sheet, 10 October, 2008.).

The questions FDA has for the committee are routine for the most part - "Has the proposed six-dose regimen been shown to be effective?" -and FDA's briefing documents appear to contain no significant reasons to vote against the drug. FDA does suggest the committee consider whether there should be post-market studies on neurotoxicity and the development of resistance, though.

The meeting, then, will be an opportunity for observers to consider larger questions about the review process, such as whether FDA's decision to hold a meeting suggests that drugs with the potential to create a voucher will receive greater scrutiny because their approval would trigger more than just availability of the product in question.

FDA's decision to ask for input on what appears to be a conundrum-free review is in keeping with the agency's recent trend of holding more advisory committees, driven in part by a congressional mandate to open more applications up to scrutiny by outside experts (² [A#00700440012], p. 23).

A combination product

One noteworthy aspect of the Coartem application that could have contributed to an advisory committee is that it involves what would be two new molecular entities. The product is an oral fixed-dose tablet containing artemether (20 mg) and lumefantrine (120 mg) in a 1:6 ratio. Neither drug is approved in the U.S., although Coartem is approved in over 80 countries, including 16 in the European Union.

Artemether is rapidly metabolized into an active metabolite dihydroartemisinin, and together they generate free carbon radicals active against malaria. While the exact mechanism of lumefantrine is not well-defined, data suggest it inhibits the formation of B-hematin by forming a complex with hemin. Data from in vitro and in vivo activity studies show the combination is more effective than either used singly, FDA states in its briefing documents.

Novartis' NDA is backed up by eight primary studies and 13 supportive active-controlled studies. FDA identified three studies as being the most important: A023 and ABM02, which compared Coartem to its components, and A025, which compared the 4-dose regimen to the 6-dose regimen. Through these studies, FDA said in the briefing documents, Novartis was able to demonstrate the superiority of Coartem compared to artemether alone and a shorter time to parasite and fever clearance compared to lumefantrine.

In the briefing documents, FDA also acknowledged that Novartis' trials had met all the entry inclusion and exclusion criteria in the draft Guidance for Industry on Malaria.

The panel will also discuss whether the data demonstrate that Coartem is efficacious in treating patients with co-infections due to P. vivax.

In five of the applicant's six-dose studies, patients were enrolled with mixed infections at baseline, including P. vivax. Coartem was shown to clear circulating P. vivax from the blood, but recurrences occurred in about a third of patients, which is not unexpected since Coartem does not have activity against the liver hypnozoites and therefore does not provide a radical cure. WHO Guidelines state that primaquine is needed along with artemisinin combination therapy for radical cure of P. vivax, except in high transmission settings where the risk of reinfection is high.

Priority reviews come to fruition

Novartis met with the agency's Division of Special Pathogen and Transplant Products for a pre-NDA meeting in October 2006 to discuss the adequacy of available data to support an NDA and various regulatory issues, and again in November 2007, when the agency agreed that information from the eight clinical trials could constitute substantial evidence.

Foreseeing the large amount of information included for Coartem's NDA, FDA asked Novartis to consider requesting fast-track designation so it could review material as it came in; the application was completed in June. Novartis was granted orphan designation in January.

-Lauren Smith (lauren.smith@elsevier.com)

Novartis’ Coartem: Will An Unusual Drug Have A Bland Advisory Committee Review?

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