Jan-9-2017

On a day of big news  (Amgen Wins Ban on Sanofi Sales of Praluent) in the area of PCSK9 inhibitors, Alnylam Pharmaceuticals published the results of its phase 1 trial for inclisiran (ALN-PCSsc) in this week’s NEJM. Inclisiran is an interference RNA that inhibits the synthesis of PCSK9 with the goal of lowering LDL cholesterol (LDL-C) and thus reducing cardiovascular (CV) events.

Healthy volunteers with an LDL-C of ≥ 100 mg/dL were randomized to receive subcutaneous inclisiran or a placebo. Dosing schedule was either a single-dose phase, with ascending doses ranging from 25 mg up to 800 mg, or a multi-dose phase with doses ranging from 125 mg weekly for 4 doses, to 500 mg monthly for 2 doses.

No serious adverse events were reported, and no patients dropped out due to adverse events. Those that did occur were mild to moderate and included upper respiratory symptoms, diarrhea, headache, muscle and back pain.  In the single-dose arm, 100 mg or more of inclisiran lowered LDL-C by a mean of 50.6% from baseline, and all dose regimens in the multi-dose arm lowered LDL-C by a mean of 59.7% from baseline. PCSK9 levels were also measured and were lowered by means of 74.5% and 83.8% for single- and multi-dose regimens, respectively. These results held at 6 months. Amgen is in the midst of a CV outcomes trial, which, if positive, could affect these recommendations.

This publication comes on the same day as Amgen’s win in their PCSK9 inhibitor patent infringement claim against Sanofi and Regeneron Pharmaceuticals. After a jury in March 2016 found in favor of Amgen, the maker of Repatha (evolocumab), confirming 2 of its patents for the development of monoclonal antibodies directed against PCSK9, a U.S. district judge on Thursday issued an injunction against the makers of Praluent (alirocumab), halting sales for 12 years. The injunction will take effect in 30 days from the ruling. Regeneron has joined Sanofi in filing an appeal.  In November Pfizer terminated development of its PCSK9 inhibitor bococizumab after completing several clinical trials. Reasons cited included an “unexpected attenuation” in LDL-C lowering over time.

Barring a reversal, or an unexpected royalty agreement, Amgen will now have a considerable head start in this lucrative market. Still, despite 2 approved agents (for now), adoption of PCSK9 inhibitors has been slower than anticipated. There are several factors involved, including current ACC/AHA guidelines that no longer target specific LDL-C levels, and published guidance by ACC on the use of non-statin LDL-C lowering agents, which calls for maximizing statins first, followed by use of ezetimibe (Zetia, Merck). The guidelines cited lack of long-term CV efficacy data, and safety data, as reasons for recommending that PCSK9 inhibitors not be used as first line agents.

Another factor is cost: an August 2016 study published in JAMA estimated that the annual drug price of these agents would have to decrease from over $14,000 to $4,536 to attain value. However, there is a tailwind for this market in the form of mounting evidence that the lower the cholesterol the better, and to levels that statins alone may not always be able to achieve. Medication adherence, ever an issue, is always a consideration as well. With biweekly or monthly subcutaneous injection as the route of administration, adherence is expected to be better than with daily oral medications. As clinicians become more familiar with this class of LDL-C lowering agents, adoption is likely to increase.

Promising data for inclisiran is significant in that it is not a monoclonal antibody directed against PCSK9, but rather a small interference RNA that decreases the synthesis of PCSK9.  The patents held by Amgen that were used against Sanofi and Regeneron should not be applicable here.  While inclisiran is years away from approval, if eventually approved, it could be entering the market at the right time, as the target population for these agents becomes more clear.