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Alnylam Finds Partner for Cholesterol Program in The Medicines Company


Alnylam Pharmaceuticals racked up another partnership this week, announcing that it has inked a global development and commercialization deal for its hypercholesterolemia program with The Medicines Company.

For Alnylam, the arrangement represents an important milestone in moving ahead with the program, which includes the phase I intravenous drug ALN-PCS02 and the preclinical subcutaneous agent ALN-PCSsc, as the company had previously disclosed that it would only advance the drug candidates in collaboration with a partner.

For The Medicines Company, meantime, the deal adds another arrow to its quiver of cardiovascular disease therapeutics, which includes MDCO-216, a naturally occurring variant of the high-density lipoprotein component ApoA-I that is being developed to facilitate reverse cholesterol transport.

“We're rapidly building what we believe is a world-class team for lipid-mediated disease-modification programs,” Clive Meanwell, CEO of The Medicines Company, said during a conference call held to discuss the partnership. “The agreement keeps our short-term priorities on our late-stage assets while Alnylam will continue to perform early-stage development.”

Under the terms of the deal, Alnylam will continue working on the ALN-PCS candidates for an estimated one to two years, moving both through a series of phase I trials funded by a $25 million upfront payment from The Medicines Company.

The Medicines Company will be responsible for all development efforts from phase II studies onward to worldwide commercialization. Alnylam stands to receive up to $180 million in milestones, plus double-digit royalties on product sales.

Specific details of Alnylam's phase I plans for the ALN-PCS program were not disclosed, although CEO John Maraganore said during the conference call that the studies will likely evaluate multiple doses of the drugs, as well as their efficacy in patients being treated with cholesterol-lowering statins — all of which will help position the RNAi compounds as alternatives to the antibody-based agents currently under development by other companies.

ALN-PCS02 and ALN-PCSsc consist of siRNAs designed to inhibit proprotein convertase subtilisn/kexin type 9, which has been shown to regulate low-density lipoprotein receptor levels and play a role in plasma low-density lipoprotein clearance.

Last year, Alnylam reported data from a phase I trial of ALN-PCS02 in 32 healthy volunteers with elevated LDL, showing that a single dose of the drug was able to reduce levels of its target in plasma by up to 84 percent and LDL cholesterol by up to 50 percent (GSN 4/26/2012).

But Alnylam — and now The Medicines Company — are not alone in pursuing PCSK9 as a therapeutic target. A number of firms are currently developing antibodies against the gene as a way to control cholesterol, including Regeneron and Sanofi, which are testing REGN727 in a phase III program expected to enroll more than 22,000 patients; as well as Pfizer and Amgen, which have their own PCSK9 antibodies in phase II testing.

During the call, Maraganore noted that although ALN-PCS02 has not outperformed the antibodies in terms of cutting LDL levels, Alnylam has to date only tested single doses of the drug in the absence of concomitant treatment with other cholesterol-lowering drugs. PCSK9-targeting antibodies, in contrast, have all been tested in multi-dose trials, in some cases in combination with statin therapy.

Maraganore also highlighted the ALN-PCS mechanism of action as a potentially key differentiator from these other drugs.

“As compared to monoclonal antibodies targeting PCSK9, ALN-PCS blocks both intracellular and extracellular levels of PCSK9 … both of which are known to be involved in regulating LDL receptor expression on the hepatocyte surface,” he said. “And so, we believe that we can have a more complete effect on blocking PCSK9 activity.”

Additionally, there is a “very wide variation” in PCSK9 levels in humans, notably in patients being treated with statins, he said.

“It turns out that when an antibody is administered, it's administered at a dose that really is addressing the mean levels of PCSK9 in the population,” he added. As a result, such a treatment is potentially an overdose for some patients and an inadequate dose for others.

“Based on the mechanism of action of an RNAi therapeutic blocking the synthesis of PCSK9, we're essentially getting a consistent pharmacologic effect across the entirety of the variation one sees in baseline PCSK9 levels,” and therefore providing “the right dose to all patients,” Maraganore said.

He stressed, however, that while these two features are “important mechanistically,” their importance clinically will need to be established through additional human trials. Specific details about Alnylam's plans for the ALN-PCS program going forward will be disclosed later in the year.

In the end, Meanwell said, The Medicines Company is not discouraged by the headstart held by Regeneron and others playing in the PCSK9 space.

“There is an enormous amount of effort going on in the industry, which we plan to go to school on, watching our colleagues move other programs forward,” he said. “Being a fast follower is something we are comfortable with and look forward to watching the rapidly emerging data from these other programs.”