Heart-smart commercialization

Collaboration targets R&D of RNAi compound to treat cholesterol issues

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PARSIPPANY, N.J.—The Medicines Company, which providesmedical solutions to improve health outcomes for patients in acute andintensive-care hospitals worldwide, and Alnylam Pharmaceuticals Inc., a leadingRNAi therapeutics company, have formed an exclusive global alliance for thedevelopment and commercialization of Alnylam's ALN-PCS RNAi therapeutic programfor the treatment of hypercholesterolemia. The collaboration targets elevatedLDL-C as a major modifiable risk factor in cardiovascular disease, the leadingcause of mortality worldwide.
Based on the agreement, the Medicines Company obtains anexclusive global license to advance Alnylam's ALN-PCS RNAi therapeutic program.Alnylam receives $25 million in upfront payments in addition to milestonepayments and royalties on product sales. Alnylam, which may also receivepotential development and commercial milestone payments of up to $180 million,will be eligible to receive scaled double-digit royalties on global productsales of ALN-PCS products.
Alnylam will continue the program while funded by theMedicines Company for an estimated one to two years to complete certainpreclinical and Phase I clinical studies. The Medicines Company is responsiblefor leading and funding development from Phase II forward with the ultimategoal of commercializing the ALN-PCS program if the trial continues to provesafety and efficacy for lowering LDL-C, according to Alnylam PharmaceuticalsCEO Dr. John Maraganore, who adds that the partnership "enables the advancementof ALN-PCS, an important program within our product development andcommercialization strategy focused on RNAi therapeutics directed towardgenetically validated targets." 
According to Dr. Clive Meanwell, chairman and CEO of theMedicines Company, "Alnylam brings the ALN-PCS program, which holds greatpromise for the development of a significant new therapeutic option forpatients with hypercholesterolemia, and that the unique mechanism of action forALN-PCS could provide a differentiated and potentially best-in-class strategyfor PCSK9 antagonism." For the Medicines Company, this collaboration fits "ouracute and intensive care portfolio, as we address the spectrum of acutecoronary syndromes with the potential of two disease-modifying agents—PCSK9antagonism addressing LDL cholesterol disease modification, along with the HDLdisease-modifying properties of our MDCO-216 product candidate."
Maraganore believes the "alliance unites two organizationswith a shared culture and commitment to innovation." He says the MedicinesCompany "has demonstrated industry-wide leadership in the advancement ofcardiovascular medicines to patients and remarkable success in its strategy ofin-licensing, developing and commercializing breakthrough products."
According to Dr. Daniel J. Rader, professor of medicine andchief of the division of translational medicine and human genetics at thePerelman School of Medicine of the University of Pennsylvania, and a member ofAlnylam's scientific advisory board, "as a key regulator of the LDL receptor,liver-expressed PCSK9 is one of the most important and best-validated newtargets in molecular medicine for the treatment of hypercholesterolemia. TheALN-PCS data generated to date are very encouraging, and I look forward tocontinued clinical studies that highlight the unique mechanistic approach ofPCSK9 synthesis inhibitors."
Meanwell adds that PCSK9 "is an excellent target for thepotential development of RNAi therapeutics based on data from human geneticstudies. Literature shows that human mutations in PCSK9 that increase PCSK9activity are linked with an autosomal dominant form of hypercholesterolemiawith a prevalence estimated in less than one in 2,500 people. Research hasdemonstrated that human polymorphisms that lower PCSK9 function are associatedwith an 88-percent risk reduction in coronary heart disease." 
In addition, Meanwell says "the unique mechanism of actionfor ALN-PCS, which inhibits the synthesis of PCSK9 in liver cells therebyreducing both its intracellular and extracellular functions, provides adifferentiated strategy for PCSK9 antagonism. This mechanism of action forALN-PCS results in potent and durable LDL-C reductions and consistent clinicalactivity across a wide range of baseline PCSK9 plasma levels, includingindividuals with very high PCSK9 levels."
Both companies agree that the commercial potential is enormous.In the United States alone, more than 16 million patients in the high-riskcategory are not meeting target LDL-cholesterol of less than 100 mg/dL and arein need of additional therapies to complement current lipid-lowering drugs,including statins, Meanwell says. Within that large market opportunity is theuniverse of 1.4 million patients with acute coronary syndromes (ACS). ACSpatients have vulnerable plaques that can rupture or erode, occluding acoronary artery. 
Severe forms of hypercholesterolemia are estimated to affectmore than 500,000 patients worldwide. As a result, there is a significant needfor novel therapeutics to treat patients with hypercholesterolemia whosedisease is inadequately managed by existing therapies, Maraganore concludes.

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