Regeneron’s Cholesterol Drug Aces Phase III, Teeing Up US FIling
Executive Summary
The trial linked ANGPTL3 antibody evinacumab to a steep decline in LDL cholesterol in patients with homozygous familial hypercholesterolemia, setting Regeneron up to file for US FDA approval next year.
A Phase III trial of Regeneron Pharmaceuticals Inc.’s evinacumab in homozygous familial hypercholesterolemia (HoFH) has met its primary endpoint.
The study showed intravenous administration of the angiopoietin-like 3 (ANGPTL3) antibody produced a 49% drop in low-density lipoprotein (LDL) in patients with HoFH, a genetic disease that causes elevated levels of the harmful form of cholesterol. That drop was big enough for the trial to hit its primary endpoint.
Going into the trial, participants had average LDL-cholesterol levels of 255mg/dL, despite treatment with statins, PCSK9 inhibitors and other drugs to lower lipid levels. Almost half of the participants had LDL levels of less than than 100mg/dL following treatment with evinacumab, compared to 23% in the control cohort.
With fewer patients in the treatment arm experiencing adverse events than in the control group, Regeneron thinks it has a dataset capable of supporting US Food and Drug Administration approval. Regeneron plans to submit an application to the FDA next year.
How evinacumab will fare beyond that is less clear. Analysts at Cowen are among the observers to question the commercial opportunity for evinacumab, noting that “several suitable options” already exist for the 1,300 people with HoFH in the US. Those options include Amgen’s PCSK9 inhibitor Repatha (evolocumab).
The Phase III results suggest evinacumab can help HoFH patients who do not respond to Repatha. However, given the low prevalence of HoFH there is scope to question whether enough patients are resistant to PCSK9 inhibitors to make evinacumab a commercially important product for Regeneron.
Analysts at Biomedtracker commented: "While a number of patients may not get to goal with Repatha, cost and burden of an extra injectable may be barriers to further treatment, unless LDL-C levels are still quite high. Given the limited number of HoFH patients and the potential competition from PCSK9 inhibitors in a large segment, the market opportunity in HoFH for evinacumab is somewhat limited, and expansion to other severe hypercholesterolemia indications will be important for the drug."
Whatever the commercial prospects, the Phase III results provide scientific validation of Regeneron’s belief in the potential of population-scale DNA sequencing to uncover new targets and therapies. Regeneron scientists came across the angiopoietin gene family more than 20 years ago but their ability to assess the effects of the vascular growth factors it codes for has been enhanced by the company’s investment in DNA sequencing, notably through its alliance with Geisinger Health System.
In 2016, Regeneron published a paper in the New England Journal of Medicine describing the sequencing of the exons of ANGPTL4 samples taken from almost 43,000 people tracked by its DiscovEHR collaboration with Geisinger.
Sequencing the samples identified people with the missense E40K variant, a genetic trait linked to reduced plasma triglyceride levels. Comparing the exon sequencing data to health records showed levels of triglycerides were 13% lower in E40K variant carriers. Regeneron also linked the presence of the E40K variant to a 7% increase in levels of high-density lipoprotein and a significant reduction in the risk of coronary artery disease.
The work led to preclinical tests of an ANGPTL4-neutralizing monoclonal antibody, REGN1001, but Regeneron shifted its focus to ANGPTL3, an endogenous inhibitor of lipoprotein lipase. Regeneron discussed the target, which is related to ANGPTL3, in a 2017 NEJM paper that described a similar research process to the ANGPTL4 publication from the prior year.
Through exon sequencing of samples in the DiscovEHR repository, Regeneron linked loss-of-function variants in ANGPTL3 to a statistically significant reduction in the rate of coronary artery disease. The finding suggested using a drug to inhibit ANGPTL3 could lead to improved cardiovascular outcomes.
By the time of the 2017 NEJM paper, Regeneron was already on its way to validating that hypothesis. The paper describes preclinical studies that linked evinacumab to reductions in atherosclerotic lesion area and necrotic content, plus Phase I data showing steep dose-dependent reductions in fasting triglyceride levels.
Regeneron has moved quickly since then. Last year, Regeneron began a Phase III trial of evinacumab in HoFH patients. This week, roughly 18 months after initiating the trial, Regeneron shared the data it hopes will secure approval of evinacumab.
There is a handful of similar products in the pipeline, but none so advanced. Akcea Therapeutics Inc.’s IONIS-ANGPTL3-LRx, however, has been tested in Phase II for HoFH and other similar inidcations