Additional clinical trials of mipomersen announced by Genzyme and Isis Jan. 12 will serve as an interim step that will inform the design of a subsequent outcomes trial FDA has requested for the cholesterol-lowering drug candidate.

FDA told the firms last April that LDL cholesterol reduction is an acceptable surrogate endpoint for accelerated approval of mipomersen in homozygous familial hypercholesterolemia, the first indication to be sought by the development partners. At the same time, the agency said it would require a dyslipidemia outcomes study for full approval and approval of any expanded indications (¹ Also see "Genzyme/Isis’ Mipomersen Development Outlook Pricier And Riskier After FDA Weighs In" - Pink Sheet, 25 April, 2008.).

Although the Jan. 12 announcement unveils three Phase III trials (and one Phase II), none of those is the expected outcomes study. Instead, the new clinical trials will provide additional data on mipomersen use in high-risk patient populations and should support an expanded indication to include patients with elevated cholesterol who are at high risk of cardiovascular events.

Isis/Genzyme recently began recruiting patients for CS-35, a Phase III trial testing the safety and efficacy of mipomersen in patients with severe hypercholesterolemia on a maximally tolerated lipid-lowering regimen but not on LDL cholesterol apheresis.

Another Phase III study, CS-12, has begun enrolling up to 180 patients at high risk for coronary heart disease on maximally tolerated statin doses. In August, the firms began study CS-7, a Phase III trial of mipomersen in 100 heterozygous FH patients. CS-19, a Phase II trial, has begun dosing and will study up to 30 individuals with FH who are intolerant to statins.

The partners expect data from all those trials to be available before the outcomes study begins in mid-2010. They plan to file for U.S. regulatory approval for the initial hoFH indication in the second half of that year.

LDL endpoint may be enough for full approval in EU

In the EU, Isis and Genzyme have "made good progress in understanding the requirements" for marketing approval, Isis CEO Stanley Crooke said Jan. 12 at the annual JPMorgan Healthcare Conference in San Francisco. Importantly, he noted, the partners "have the potential for a broader indication than severe familial hypercholesterolemia using just the LDL reduction endpoint."

Mipomersen is a second-generation antisense drug that reduces the production of apoB-100, a protein critical to the synthesis and transport of LDL cholesterol. Crooke said mipomersen has the potential to be a first-in-class therapy. "ApoB is the most logical target if you want to lower all atherogenic lipids. In a linear, dose-dependent fashion, [mipomersen] works in every single human being who gets it."

Genzyme and Isis announced the development and commercialization agreement at last year's JPMorgan conference, under which Genzyme has exclusive worldwide rights to mipomersen (² Also see "Genzyme, Isis Partner On Lipid Lowering Treatment Based On Antisense Technology" - Pink Sheet, 7 January, 2008.).

The firms later re-jiggered the deal to increase Isis' development costs after FDA asked for the outcomes trial. Isis is responsible for the first $125 million in development costs; after that the two companies split expenses 50/50 (³ Also see "Genzyme, Isis Retool Mipomersen Deal" - Pink Sheet, 24 June, 2008.).

-Pamela Taulbee (p.taulbee@elsevier.com)

Genzyme/Isis Expand Clinical Trial Program For Mipomersen

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