With a label broadened by the FDA in December and two aspiring competitors apparently picked off via late-stage trial blowups, Amarin Corp. plc finds itself in strong position with fish oil therapy Vascepa (icosapent ethyl) – at least pending the outcome of court proceedings that involve challengers to patents for the cardiovascular (CV) drug.
As CEO John Thero put the matter during a conference call last month, “the value of the [Vascepa] opportunity continues to increase with the passage of time,” and time’s most recent passage saw Cambridge, U.K.-based Astrazeneca plc concede that, based on advice from an independent data monitoring committee, the firm is closing the phase III Strength experiment with Epanova (omega-3 carboxylic acids) due to its low likelihood of demonstrating a benefit to patients with mixed dyslipidemia who are at increased risk of CV disease. The effort is a global outcomes study testing the safety and efficacy of Epanova compared to placebo when both are used with standard-of-care statin medicines. Shares (NYSE:AZN) closed at $49.67, down 18 cents.
Failing more dramatically was Acasti Pharma Inc., of Laval, Quebec, which said an unexpectedly large placebo effect foiled statistical significance in top-line results from the phase III Trilogy 1 trial with its lead candidate, Capre (omega-3 phospholipid). The compound is meant to treat hypertriglyceridemia (triglyceride levels from 500 mg/dL to 1,500 mg/dL), and the primary endpoint is triglyceride knockdown at 12 weeks and 26 weeks. Acasti continues to sift the data, but meanwhile shares of the company (NASDAQ:ACST) closed at 76 cents, down $1.42, or 65%.
Jefferies analyst Michael Yee noted in a report that Amarin’s stock has been the subject of “a few key investor debates including competition and to a related degree, patent clarity (generics).” The news from Astrazeneca and Acasti “essentially cleared up and resolved uncertainty on potential branded competition, and this should increase investor confidence in the ability for Amarin to hit $3-4 billion peak sales or more,” he said. Vascepa gained its first FDA clearance to trim triglycerides in adults with severe hypertriglyceridemia. The label was expanded in late 2019 so that the drug can be prescribed to reduce CV risk. The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee said by a vote of 16-0 in November that Amarin provided sufficient evidence of efficacy and safety to support approval of Vascepa to reduce the chance of CV events in adults with triglyceride levels ≥135 mg/dL and other factors that can lead to CV disease.
Matinas omega-3 ‘compelling’
SVB Leerink analyst Ami Fadia opined in a report that Astrazeneca’s CV player is “all but eliminated” as a problem for Dublin-based Amarin’s prescription omega-3 market edge. With a nod to what she called the “perplexing” Acasti results, she said that “the near-term focus has been and will remain squarely on the patent litigation,” the trial for which got underway just as the Astrazeneca and Acasti news broke. Dr. Reddy’s Laboratories Ltd., of Hyderabad, India, and London-based Hikma Pharmaceuticals plc are facing off against Amarin, which in May 2018 settled a patent skirmish with Teva Pharmaceuticals Co. Ltd., of Jerusalem. Fadia said in a December report that, “heading into the trial, our analysis suggests that it is in both parties’ interests to settle the case for a generic entry in the late 2020s.” She pointed to two key issues in the case, saying Amarin needs to prevail on both. The company must prove that its patents are valid but also that generics infringe its patents on inducement, a form of secondary liability. “We believe Amarin has a strong upper hand on patent validity but on patent infringement through inducement, while we believe it has a lead, we cannot say that it is by an overwhelming margin,” she said.
As lawyers duke the matter out, Wall Street ransacked the Acasti and Astrazeneca disclosures for indicators of what might happen next. The Astrazeneca development was straightforward enough but Acasti’s report set off a round of speculation. Capre, an EPA plus DHA combo omega-3 drug therapy derived from krill oil instead of fish oil, yielded findings from the 26-week Trilogy 1 trial characterized as “mixed” by Roth analyst Yasmeen Rahimi. Capre showed 30.5% and 36.7% triglyceride drops from baseline at 12 and 26 weeks, respectively, but the placebo group turned up a whopping 27.5% and 28% reduction at the same time points, which meant statistical significance wasn’t reached. “In our view, despite Capre’s trailing position in clinical development vs. Vascepa, these new results for Capre continue to add more validation to the differentiation of the EPA-only omega-3 mechanism of action in CV risk reduction,” though Amarin’s commercial prospects are “firmly entrench[ed],” she said.
Aegis Capital’s Nathan Weinstein was incredulous. “We never imagined a situation where an omega-3 [therapy] could show this degree of triglyceride lowering and yet still not reach statistical significance,” he said in a report. “We await further insights from Acasti to better understand the large placebo effect and regulatory path, while noting that the company said there could potentially still be an NDA on the table.” Acasti “has not yet identified the root cause of the placebo effect (which was higher than that seen in any other omega-3 study), but did note that a high placebo response in five out of the 54 enrolling sites contributed disproportionately to the overall placebo response rate,” and the company is conducting a full audit. Results from Trilogy 2, the second phase III experiment with Capre, are expected in mid-February. That study enrolled patients in the U.S., Canada and Mexico (instead of just the U.S., as was the case with Trilogy 1). Weinstein said Trilogy 2 likely has “limited, though not zero, site overlap with Trilogy 1.”
Another prospect in the space is held by Bedminster, N.J.-based Matinas Biopharma Holdings Inc., which said in November that it had commenced prescreening of patients for a head-to-head comparative study of MAT-9001 and Vascepa, and was on track to initiate enrollment in the first quarter of this year. The study will evaluate pharmacodynamic (PD) markers for MAT-9001 and Vascepa in a 28-day crossover study in patients with elevated triglycerides. A previous trial showed that, compared to Vascepa, MAT-9001 provided significantly greater reductions in PD markers known to be associated with increased risk of CV disease. Aegis’ Weinstein started covering Matinas earlier this month with a buy rating and a $3.50 price target. “We think Matinas has a compelling omega-3 candidate with MAT-9001,” which consists mainly of EPA and DPA, he said. Given the good showing already in the head-to-head Vascepa study, the compound “could have the makings of a future best-in-class drug,” in his view. Shares of Matinas (NYSE:MTNB) closed at $1.30, down 16 cents.
Amarin’s stock (NASDAQ:AMRN) ended the day at $19.75, up 80 cents.