October 17 and 18, 2012 saw back-to-back meetings of the FDA Endocrine and Metabolic Drugs Advisory Committee (EMDAC) to review pending new drug applications (NDAs) for two drugs for homozygous familial hypercholesterolemia (HoFH): lomitapide from Aegerion Pharma (NASDAQ: AEGR) and mipomersen/Kynamro from Sanofi/Genzyme and Isis Pharma (NASDAQ: ISIS).

As Chimera predicted, both drugs received positive votes from the panel. The key concern for both drugs is the accumulation of fat in the liver which is a direct consequence of the mechanism of action of these drugs. This condition puts patients at an undeniable risk for future liver damage with continued dosing. In each case however, the extreme severe unmet medical need of HoFH and the fact that these patients are at severe risk for cardiovascular events and/or death led to support for the drugs’ use in this ultra orphan population. Isis received a less enthusiastic 9-6 vote vs. Aegerion’s 13-2 tally due to slightly lower efficacy and additional safety concerns including discontinuations, injection sight reactions, inflammatory reactions, and animal carcinogenesis data. The combination of information presented in the briefing documents, Genzyme presentation, and panel discussion confirmed in our mind that the imbalance in cancers in mipomersen clinical trial patients was a non-issue at this point.

Aegerion will answer questions for the first time post-panel from Wall Street on Tuesday, and the brief conference call that Isis held on Thursday was uninformative due to management’s refusal to comment on certain matters and relatively timid analyst questions. Thus, investors have many questions on their mind:

• Will these drugs be approved? Yes, we believe both lomitapide and mipomersen will receive first-cycle FDA approval with narrow labels and REMS programs meant to prevent less dire patients from receiving the drugs. The committee clearly preferred a more stringent definition of HoFH and a requirement for liver safety monitoring, neither of which appeared to be the FDA’s original intention.
• How large is the market? This is the key question of course. If we go by the strictest genetic definition of the disease, there are only ~300 patients in the United States. If we use the more generous figures (shockingly) floated by Isis and Aegerion, the market could be 5-10x that size. Other key considerations include price (pick your number between $100,000 and $400,000 per year), duration of treatment (both pivotal trials had ~1/3 poor responders, and long-term maintenance on either drug will only be a reality for a rather small number of patients), and competition from other drugs in development, such as the PSCK9 inhibitor AMG145 from Amgen which is entering a phase 3 trial that may compete for patients. For reference, each of the ISIS/AEGR multi-national phase 3 trials involved about 30 HoFH patients, though AMGN’s looks to be larger than this. Additionally, Regeneron/Sanofi are running a vast program of REGN727 in heterozygous familial hypercholesterolemia (HeFH), a market which ISIS seeks to pursue in the future.
• What about Europe? The patient populations are roughly the same in the EU and the US. Aegerion has a pending lomitapide application for HoFH. Isis/Genzyme submitted their MAA seeking approval for both HoFH and a broader severe HeFH population. Decisions for both should be available no later than the end of 1h-2013.
• What about broader patient populations? Aegerion has already given up on seeking broader approvals in severe heterozygous FH due to the risk/benefit problems due to liver safety. As mentioned, Isis/Genzyme are seeking broader EU approval based on the four phase 3 trials they have already completed and are currently enrolling a 12-month duration study in severe HeFH (they disclosed at the panel that <80 of the planned 480 patients have accrued over the past ten months) that the FDA required to consider a broader label. Following release of the briefing documents and the panel discussion, we are significantly more bearish on the prospects for mipomersen ever being approved outside of HoFH, in the US or Europe. The panel (and FDA reviewer) seemed strongly against this, and it does not appear than any outcome from the ongoing FOCUS-FH trial will change their minds. The endpoint is still LDL reduction rather than any sort of cardiovascular endpoint, and the nature of the safety concerns suggest that the potential additional data may not be persuasive enough to shift the risk/benefit balance for these lower risk patients. It will realistically be several years before the trial would conclude, and new treatment options such as the PSCK9 inhibitor class may be viable alternatives by then. Along this line, we see little chance of approval of the European MAA for the desired indication. It is not clear whether CHMP could recommend approval for a narrower HoFH indication, or whether the entire package would receive a negative opinion.
• What about the rest of the Isis antisense pipeline? It appears as though the sell-off in Isis shares goes beyond the recognition that mipomersen will never been an economically meaningful product due to restriction to HoFH. Investors may also be worried that some of the safety concerns and adverse events (carcinogenicity risk, kidney findings, and injection site/immune/inflammation reactions) seen with mipomersen may be platform-specific and therefore threaten other pipeline programs. It is simply too early to know if these fears are warranted.
• What other risks remain? Isis shareholders certainly are hoping there isn’t another shoe to drop. If approved, Kynamro/mipomersen will be marketed by Sanofi’s Genzyme unit, a power play in rare diseases. While the FDA seems pleased with the risk/benefit profile of lomitapide for HoFH, there is always the risk of a “chemistry, manufacturing, and controls” or “CMC” issue delaying approval. Also, AEGR intends to market the drug alone in the US and EU – since the company has no commercial experience, there remains some execution risk until we see how the product launch and potential competitive positioning with mipomersen proceeds.

Disclosures: None.

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