Facing an uncharted regulatory environment post-ENHANCE, Genzyme and Isis Pharmaceuticals announced a delay in filing an NDA for the cholesterol lowering drug mipomersen, spurred by FDA's regulatory requirements.

The companies' development plan for mipomersen now calls for filing in 2010, not 2009, for an initial indication in homozygous familial hypercholesterolemia - a rare, orphan drug indication.

It is the planned filing for a broader indication in patients with high cholesterol at high risk of cardiovascular events, including heterozygous FH, that faces a more significant delay, until 2012 or potentially beyond. The firms originally targeted a 2011 filing.

Genzyme and Isis announced the development setback April 25 following discussions with FDA in which the agency provided guidance on a regulatory path for mipomersen.

While FDA indicated reduction of LDL-cholesterol is an acceptable surrogate endpoint for accelerated approval for patients with hoFH, the agency is requesting two carcinogenicity studies to be included in the filing, rather than the one the firms had been planning to have completed in time for the submission. For the broader indication, FDA is requesting a cardiovascular outcomes trial, a costly and potentially time-consuming prospect.

Despite the setback, management for both companies said they remain confident in the opportunity for mipomersen, a drug targeting apolipoprotein B-100 that has been shown to reduce cholesterol and other atherogenic lipids by more than 40 percent beyond reductions achieved with current standard lipid-lowering drugs.

"FDA has taken an important step in clarifying its position with regard to the evaluation of mipomersen, and as a consequence, we have a much more direct and straightforward plan in mind for developing mipomersen," Isis CEO Stan Crooke said in a same-day conference call.

Genzyme announced it was partnering with Isis on the drug in January in a deal valued at up to $1.9 billion, including upfront payments of $325 million (¹ Also see "Genzyme, Isis Partner On Lipid Lowering Treatment Based On Antisense Technology" - Pink Sheet, 7 January, 2008.).

News of the deal emerged just days ahead of Merck/Schering-Plough's release of top-line data from the ENHANCE trial, which shook up the lipid lowering drug category. Data from that study revealed a considerable quandary - while Vytorin (ezetimibe/simvastatin) lowered LDL levels in patients with FH over simvastatin alone, it did not result in better cardiovascular outcomes (² Also see "Vytorin Fails To Show ENHANCEd Benefit Over Simvastatin In Plaque Reduction" - Pink Sheet, 14 January, 2008.).

The ENHANCE findings have led to much confusion over what the fallout could be for lipid lowering drugs.

"It's very clear that in this space the confusion is significant," Genzyme CEO Henri Termeer said, pointing to Vytorin and Zetia (ezetimibe). "It is a very unfortunate set of circumstances, and they all play in this moment here."

Door hasn't officially closed on the deal

One catch with mipomersen is that Isis and Genzyme have not yet closed the deal, which suggests a window may be open for Genzyme to re-negotiate. Under the original agreement, Genzyme is responsible for paying for all but $75 million of the development costs, meaning it would bear the brunt of the outcomes trial.

The deal is expected to close this quarter, Termeer said during the conference call. Questioned by analysts, the chief exec hedged when asked about re-negotiating, but acknowledged that certain assumptions made in the development plan will change, which could result in changes in the payment schedule.

"What has not changed is the overall economic assumption - certainly from our part," he said. "The ultimate economic payment is to have something that really works for which you can get reimbursement support both here and throughout Europe and the rest of the world that supports a very strong product."

Genzyme/Isis talk up opportunity for small outcomes trial

The firms had planned an outcomes trial as part of the program for mipomersen and said FDA's guidance only hastens the timeline for completing that trial.

In the case of Vytorin, Merck/Schering are currently conducting an outcomes trial, IMPROVE-IT, that is enrolling 18,000 patients, after the companies recently announced they were increasing the patient sampling. Results from the study are expected in 2012.

But Isis and Genzyme said they expect to be able to run a significantly smaller outcomes study.

"We don't think that this is necessarily going to be a 10,000-patient, six- or seven-year trial, not at all," Crooke said.

That is because the drug is being studied in a higher-risk patient than the general patient population, Termeer said, one that as a consequence, has a higher event rate: a 20 percent chance of a cardiac event over 10 years.

JPMorgan analyst Geoff Meacham was skeptical, however, in an April 25 research note. "Outcomes studies for cholesterol-lowering drugs are large (>5,000 patients) and long-term (4 to 5+ years)," he said, citing recent examples.

"Hence, a mipomersen outcomes trial would be lengthy, costly and carries clinical/regulatory risk in light of the recent ENHANCE trial," he added. The growing risk and cost of development does not justify the price Genzyme is paying for the program, he asserted.

Mipomersen highlights the risks to big pharmas and biotechs as they put up consistently higher upfront payments and take on development costs for early- to mid-stage drugs. The latest to raise eyebrows was GlaxoSmithKline's buyout of Sirtris Pharmaceuticals - with a lone compound in early Phase II for diabetes and a more promising preclinical pipeline - for $720 million (³ [A#14080422011]).

-Jessica Merrill (j.merrill@elsevier.com)

Genzyme/Isis’ Mipomersen Development Outlook Pricier And Riskier After FDA Weighs In

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