AZ Halts Epanova Study As High Placebo Effect Kills Acasti’s Omega-3 TRILOGY-1 Trial
AZ’s Epanova Hopes Dented, Acasti Focus Turns To Coming TRILOGY-2 Results
Executive Summary
Acasti’s omega-3 candidate drug CaPre missed the primary endpoint in TRILOGY-1 due to an unexplained high placebo effect, as AstraZeneca said its STRENGTH study was unlikely to show a treatment benefit.
AstraZeneca PLC’s hopes of emulating Amarin Corp. PLC’s Vascepa with its omega-3 product Epanova have been hit just as commercial prospects were put on hold for Acasti Pharma Inc.'s similar product CaPre after a late-stage study in severe hypertriglyceridemia failed to meet its primary endpoint.
AstraZeneca said it was closing the Phase III large-scale cardiovascular (CV) outcomes trial STRENGTH of Epanova (omega-3 carboxylic acids) on the recommendation of an independent data monitoring committee due to its low likelihood of demonstrating a benefit to patients with mixed dyslipidemia (MDL) who are at increased risk of CV disease.
STRENGTH Sapped
The disappointment came with a financial hit. AstraZeneca is reviewing its $533m current value of the intangible asset, and is taking a $100m write down on inventory. Any impairment will be treated as a non-Core item in the fourth quarter of 2019, it said.
Epanova is approved in the US and indicated as an adjunct to diet to reduce triglyceride levels in adult patients with severe (≥500 mg/dL) hypertriglyceridaemia, which is not affected by the data from the STRENGTH trial, AstraZeneca noted. The company gained the product via its acquisition of Omthera Pharmaceuticals in 2013, when the product was approaching the approval stage for the initial indication. AstraZeneca had hoped that CV outcomes success would have propelled it to blockbuster status.
STRENGTH was comparing the effect of Epanova 4g daily with corn oil placebo on reducing the risk of major adverse cardiovascular events (MACE) in patients on optimal statin therapy with mixed dyslipidaemia and at high risk for CV disease. A total of 13,086 patients had been enrolled and the full data will be presented at a forthcoming medical meeting, AstraZeneca said.
Placebo ‘Krilller’
On the same day Acasti’s CaPre is a purified omega-3 phospholipid concentrate derived from krill oil. It is being developed to treat high levels of triglycerides in the blood, a metabolic condition that contributes to increased risk of cardiovascular disease and pancreatitis.
But CaPre’s effectiveness was put in doubt after TRILOGY 1 data showed a high placebo effect, cancelling out the drug’s effectiveness in the trial.
Top-line results from TRILOGY-1 were released on 13 January and showed CaPre reduced triglycerides by 30.5% and 36.7% at 12 weeks and 26 weeks in patients, an impressive outcome that was effectively neutralized by triglyceride reductions of 27.5% and 28.0% in patients on placebo.
The study had been seeking a 20% difference in triglyceride reduction versus placebo, an endpoint TRILOGY-1 failed to meet because of the “unprecedented” high placebo effect seen at five testing sites, the company said.
TRILOGY-1 was a randomized, double-blind study that compares 4g of CaPre daily against placebo in 242 patients with severe hypertriglyceridemia at a total of 54 enrolling sites. The placebo used in the trial was simple cornstarch.
"While we are encouraged by the magnitude of reduction in triglyceride levels seen among patients receiving CaPre, the large placebo effect was completely unexpected, and was about double what was seen in all other therapeutic omega-3 hypertriglyceridemia trials," said Jan D’Alvise, president and CEO of Canada-based Acasti.
The topline line trial results also confounded investors, who sought shelter in the confusion by selling Acasti stock, causing its price to plummet.
Analysts reacted by putting the Canadian biotech’s prospects under review. “The high placebo response in TRILOGY-1 came as a surprise to us as cardiovascular trials normally do not usually have this issue," analysts at Mackie Research said in a same day note to investors.
Aegis Capital analysts echoed that view, adding that “Acasti's release today perhaps raises more questions than it answers. We never imagined a situation where an omega-3 could show this degree of triglyceride-lowering and yet still not reach statistical significance.”
Acasti said a full audit of enrolling sites, including review of all raw data and records from patients taking both CaPre and placebo, would now be conducted to identify a possible main cause for the high placebo effect. It said CaPre showed itself to be safe in the trial.
The data audit “is likely to take at least several weeks, with an outcome expected by the end of February 2020,” the company said. Additional avenues of investigation will include further assessment related to specific continuation or discontinuation of other lipid lowering drugs during screening, and changes in the use of other lipid-lowering medications during the trial.
Topline results of the ongoing TRILOGY 2 trial with CaPre are expected in mid-February. These may provide additional important information and insight into the data from TRILOGY-1. The placebo used in that trial is also simple cornstarch.
“It is a shame that the high placebo response in TRILOGY-1 made the difference between CaPre and placebo non-significant. We are expecting Acasti’s full audit of the trial and TRILOGY -2 results to provide better clarity as to what caused such a high placebo effect,” analysts at Aegis Capital said.
Others suggested Acasti should run a third Phase III study of CaPre for clarity.
“There are still reasons to argue the negative TRILOGY-1 results were not due to CaPre per se, as it demonstrated decent efficacy in triglyceride reduction. There is still a chance that CaPre could make it through to a regulatory application if another Phase III trial is run – and provided the TRILOGY 2 trial is successful,” analysts at Mackie Research said.
The field of competitors developing Omega-3 treatments for elevated triglycerides is currently led by Amarin Corp. PLC’s blockbuster-in-waiting cardiovascular treatment Vascepa, a synthetic derivative of the omega-3 fatty acid eicosapentaenoic acid (EPA). (Also see "Vascepa Gains European Filing Nod" - Scrip, 2 Dec, 2019.)
In addition to AstraZeneca's Epanova, other rival omega 3-based candidates include and Matinas BioPharma Holdings Inc.’s lead candidate MAT9001.
Aegis Capital said it maintained its bullish view on the omega-3 category overall despite the TRILOGY-1 wobble. “We remain believers in the omega-3 class, maintaining our buy ratings on Amarin and Matinas. Our estimates, rating, and price target on Acasti remain under review,” they told investors.