CaPre is a krill oil derived mixture containing polyunsaturated fatty acids (PUFAs), primarily composed of omega-3 fatty acids, principally eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA and DHA are well known to be beneficial for human health, and may promote healthy heart, brain and visual function¹, and may contribute to reducing inflammation, and blood triglycerides.² Krill is a natural source of phospholipids and omega-3 fatty acids. The EPA and DHA contained in CaPre are delivered as free fatty acids or bound to phospholipid esters, allowing these PUFAs to reach the small intestine where they undergo rapid absorption and transformation into complex fat molecules that are required for transport in the bloodstream. Acasti believes that EPA and DHA are more efficiently transported by phospholipids sourced from krill oil than the EPA and DHA contained in fish oil that are transported either by triglycerides (as in dietary supplements) or as ethyl esters in other prescription omega-3 drugs, which must then undergo additional digestion before they are ready for transport in the bloodstream.
Clinically, the phospholipids may not only improve the absorption, distribution, and metabolism of omega-3s, but they may also decrease the synthesis of LDL cholesterol in the liver, impede or block cholesterol absorption, and stimulate lipid secretion from bile. In two Phase 2 studies, CaPre achieved a statistically significant reduction of triglycerides and non-HDL cholesterol levels in patients across the dyslipidemia spectrum from patients with mild to moderate hypertriglyceridemia (patients with TG blood levels between 200mg/dl and 500mg/dl) to patients with severe hypertrigyceridemia (those with TG levels above 500mg/dl). Furthermore, in the Phase 2 studies, CaPre demonstrated the potential to actually reduce LDL, or "bad cholesterol", as well as the potential to increase HDL, or "good cholesterol", especially at the therapeutic dose of 4 grams/day. The Phase 2 data also showed a significant reduction of HbA1c at a 4 gram dose, suggesting that due to its unique omega-3/phospholipid composition, CaPre may actually improve long-term glucose metabolism. Acasti's TRILOGY Phase 3 program is currently underway.
1Sources: Kwantes and Grundmann, Journal of Dietary Supplements, 2014.
2Source: Ulven and Holven, Vascular health and risk management, 2015.
CaPre is intended to be used as a therapy in conjunction with positive lifestyle changes including diet, and is to be administered either alone or with other drug treatment regimens such as statins (a class of drug used to reduce cholesterol levels). CaPre is intended to be taken orally once per day in capsule form.
In four clinical trials conducted to date, Acasti saw the following beneficial effects with CaPre, and is seeking to demonstrate similar safety and efficacy in Phase 3 clinical studies:
In 2016, Acasti completed a bioavailability bridging study comparing CaPre to the market leading omega-3 prescription drug LOVAZA as a means of establishing a scientific bridge between the two. The study successfully met its primary objective, supporting Acasti's strategy to pursue the U.S. Food and Drug Administration's 505(b)(2) regulatory pathway for approval. This regulatory pathway allows Acasti to streamline the overall development program required to support a new drug application (NDA) by relying on the safety data of another approved drug, in this case LOVAZA, in addition to data from all of Acasti's clinical studies of CaPre.
Acasti's TRILOGY Phase 3 program is currently underway, and will evaluate the safety and efficacy of CaPre for the treatment of patients with severe hypertriglyceridemia. TRILOGY, an acronym derived from "Phase 3 Studies of CaPre in Lowering Very High Triglycerides," is a double-blind, placebo-controlled, 26-week, two-trial Phase 3 clinical program. TRILOGY 1 and TRILOGY 2 are running in parallel and will randomize a total of approximately 500 patients. The program is being conducted at approximately 150 sites across the U.S., Canada and Mexico, and the Company expects to report topline results by the end of 2019.
According to The American Heart Association Scientific Statement on Triglycerides and Cardiovascular Disease (2011), triglyceride levels provide important information as a marker associated with the risk for heart disease and stroke, especially when an individual also has low levels of HDL-C, and elevated levels of LDL-C. Hypertriglyceridemia can be caused by both genetic and environmental factors, including obesity, sedentary lifestyle and high-calorie diets. Hypertriglyceridemia is also associated with comorbid conditions such as chronic renal failure, pancreatitis, nephrotic syndrome and diabetes. Multiple genetic studies suggest that patients with elevated triglyceride levels (greater than or equal to 200 mg/dL) have an increased risk of coronary artery disease (CAD) and pancreatitis, a life-threatening condition, as compared to those with normal triglyceride levels. Other studies suggest that lowering and managing triglyceride levels may reduce such risks. In addition, the Japan EPA Lipid Intervention Study (JELIS) demonstrated the long term benefit of an omega-3 (EPA) in the prevention of major coronary events in high risk cardiovascular (CV) patients.3
3Source: Yokoyama et al, Lancet 2007 and Saito et al, Atherosclerosis 2008.
Acasti may seek to identify new potential indications that may be appropriate for future CaPre studies and pipeline expansion. Evidence suggests potential for omega-3s in other cardiometabolic indications.
PHASE 2 STUDIES
In two Phase 2 clinical trials conducted by Acasti in Canada (the COLT and TRIFECTA trials), CaPre was found to be safe and well-tolerated at all doses tested, with no serious adverse events that were considered treatment-related. Among the reported adverse events with an occurrence of greater than 2% of subjects and greater than placebo, only diarrhea had an incidence of 2.3%.
In both Phase 2 clinical trials, CaPre significantly lowered TGs in patients with mild to severe HTG. Importantly, in these studies, CaPre also demonstrated potentially beneficial effects on LDL-C, non-HDL-C, and HDL-C.
CAPRE BRIDGING STUDY
Acasti’s open-label, randomized, four-way, cross-over, bioavailability study (the Bridging Study) compared omega-3 (EPA and DHA) blood levels achieved after taking CaPre as a single dose of 4 grams in fasting and fed (high fat meal) states, with those after taking a single dose of the approved hypertriglyceridemia drug LOVAZA (omega-3-acid ethyl esters) in 56 healthy volunteers. The study met its primary objective by demonstrating that the levels of omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) following administration of CaPre did not exceed the levels following administration of LOVAZA in subjects who were fed a high-fat meal. These results are expected to support the basis for claiming a comparable safety profile of the two products.
Among subjects in the fasting state, CaPre demonstrated better bioavailability than LOVAZA, as measured by significantly higher blood levels of EPA and DHA. In addition, based on the results obtained in another pharmacokinetic study (CAP13-101), the bioavailability of CaPre is not meaningfully affected by the fat content of a meal consumed prior to drug administration.
Acasti believes this could represent a significant clinical and marketing advantage over LOVAZA and feature of CaPre since the administration with a low-fat meal represents a more appropriate regimen for patients with hypertriglyceridemia who follow a physician-recommended, restricted diet.
Acasti is pursuing development and/or distribution partnerships to support the commercialization of CaPre in the United States and in other major global markets.
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