The evolution of PCSK9 as a therapeutic target for lowering cholesterol is an elegant example of basic science translating to significant improvements in disease management. Identification of individuals with genetic defects rendering them unable to produce the PCSK9 protein led to the discovery of this potential drug target. Based on these findings, high-profile pharmaceutical companies including Amgen, Regeneron, and Sanofi started to develop monoclonal antibodies (mAbs) that targeted the PCSK9 protein, aiming to mimic the biological effect seen in these few individuals.
Currently there are two PCSK9-targeting mAbs on the market, Amgen’s Repatha and Sanofi and Regeneron’s Praluent. Both therapies were granted orphan drug status by the FDA and EMA, and were approved in a relatively broad patient population. Despite this, uptake has been extremely modest, this has been driven by the high price of these biologics, both demanding an annual cost of approximately $15,000. In order to curtail health care spending on these products, access has been restricted to patients deemed “high risk,” typically those suffering from homozygous familial hypercholesterolemia (HoFH), which has significantly dampened sales of the therapies.
Regeneron and Sanofi have faced several hurdles bringing Praluent to market. It was clear the companies expected higher sales, particularly given the large patient group for which the drug was approved. Price has played a strong influential role, but competition from Amgen’s Repatha has also been a barrier to uptake. Moreover, the continued development of an oligonucleotide-based therapy targeting PCSK9 by Ionis Pharmaceuticals has potential to diminish future sales of Praluent further, as this new therapy boasts an infrequent biannual dosing schedule and promises to undercut the price of the PCSK9 mAbs.
These difficulties haven’t deterred Regeneron from the dyslipidemia market; instead, the company is continuing development of evinacumab, a mAb that targets the angiopoietin-like 3 (ANGPTL3) protein; the therapy has already been granted orphan drug designation from the FDA for HoFH. The identification and subsequent targeting of ANGPTL3 as a therapeutic target in the dyslipidemia space mirrors that of PCSK9: genetic defects in healthy individuals were associated with reduced triglyceride and LDL-C levels. Unfortunately for Regeneron, and as with the PCSK9 story, an oligonucleotide-based therapy targeting the ANGPTL3 gene is also in development by Ionis Pharmaceuticals, which will most likely present a more cost-effective and less burdensome treatment option for patients than evinacumab.
It seems Regeneron has not yet learned from the difficulties they faced alongside Sanofi with the development and launch of Praluent. A common mistake that is emerging in this disease space is to seek market exclusivity by gaining orphan drug status through targeting rare conditions, such as HoFH. But as the most valuable and unique clinical benefit of evinacumab is the significant lowering of triglyceride levels, it would be more advantageous for Regeneron to target patients with high and very high triglyceride levels, as these patient populations have limited effective treatment options.
The current standard of care for these patients, fish oils, is relatively costly, with a burdensome dosing schedule and a questionable mechanism of action. Targeting patients with high triglycerides would distinguish evinacumab, and the drug would not have to compete directly with the PCSK9 mAbs, though it would still face the threat of a future oligonucleotide-based treatment option. Current studies of evinacumab are focusing on HoFH patients, however there is still time for Regeneron to assess the future potential of their drug as a triglyceride-lowering therapy and address this through clinical trial design.