Acasti Announces Definitive Agreement to Acquire Grace Therapeutics, Inc.

CaPre

Image

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.

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 a neutral to potentially positive effect on lowering 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.

In four clinical trials conducted, Acasti saw the following beneficial effects with CaPre:

  • Significant reduction of triglyceride and non-high density lipoprotein cholesterol (non-HDL-C) cholesterol levels in the blood of patients with mild to severe hypertriglyceridemia;
  • No deleterious effect on low-density lipoprotein cholesterol, or "bad" cholesterol (LDL-C), and potential to reduce LDL-C;
  • Potential to increase high-density lipoprotein cholesterol, or "good" cholesterol (HDL-C);
  • Potential to reduce HbA1c, an important marker of glucose control in diabetes
  • Good bioavailability, even under fasting conditions;
  • No significant food effect (low fat vs. high fat meal); and
  • An overall safety profile similar to that demonstrated by currently marketed omega-3s, with added potential for beneficial LDL-C reduction as listed above.

Acasti conducted two Phase 3 trials: the TRILOGY trials. In TRILOGY 1, CaPre® achieved a 30.5% reduction in triglyceride levels at 12 weeks and 36.7% reduction in triglyceride levels at 26 weeks, as well as 42.2% reduction in triglyceride levels among patients receiving CaPre while on background statin therapy at 12 weeks. Despite positive results in the CaPre arm, the TRILOGY 1 study did not reach statistical significance. In TRILOGY 2, CaPre achieved 30.4% median reduction in triglycerides at 12 weeks and 38.4% at 26 weeks, but did not achieve statistical significance for the primary endpoint.

1Sources: Kwantes and Grundmann, Journal of Dietary Supplements, 2014.

2Source: Ulven and Holven, Vascular health and risk management, 2015.

ABOUT HYPERTRIGLYCERIDEMIA (HTG)

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.

TRIAL RESULTS

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.

PHASE 3 STUDIES

Acasti conducted two Phase 3 clinical trials: the TRILOGY trials. In TRILOGY 1, CaPre® achieved a 30.5% reduction in triglyceride levels at 12 weeks and 36.7% reduction in triglyceride levels at 26 weeks, as well as 42.2% reduction in triglyceride levels among patients receiving CaPre while on background statin therapy at 12 weeks. Despite positive results in the CaPre arm, the TRILOGY 1 study did not reach statistical significance. In TRILOGY 2, CaPre achieved 30.4% median reduction in triglycerides at 12 weeks and 38.4% at 26 weeks, but did not achieve statistical significance for the primary endpoint.

TRILOGY 1:

The Company reported a 30.5% median reduction in triglyceride levels among all patients receiving CaPre, compared to a 27.5% median reduction in triglyceride levels among patients receiving placebo at 12 weeks. The Company also reported a 42.2% median reduction in triglycerides among patients receiving CaPre while on background statin therapy at 12 weeks, compared to a 31.5% median reduction in triglyceride levels among patients receiving placebo and on background statin therapy. In addition, the Company reported a 36.7% median reduction in triglyceride levels among patients receiving CaPre at 26 weeks (end of the study), compared to a 28.0% median reduction in triglyceride levels among patients receiving placebo. Both the placebo and CaPre study groups experienced significant reductions in triglycerides within the first four weeks from baseline, and even though the difference at 12 and 26 weeks was in favor of CaPre, due to the unexpectedly large placebo response, TRILOGY 1 did not reach statistical significance. The safety profile of CaPre in TRILOGY 1 was similar to placebo, as there were no significant difference in treatment-related serious adverse events in the trial.

The observed reductions in triglyceride levels in the placebo group were far greater than that seen in any previous triglyceride lowering trial with a prescription omega-3. The placebo used in the TRILOGY trials is simple cornstarch, which is a complex carbohydrate with a low glycemic index, and consequently would be expected to have a neutral effect on key biomarkers of patients in the placebo group. In similar previously conducted triglyceride lowering trials involving prescription omega-3 preparations, the placebo responses (using corn oil, olive oil, or vegetable oil) ranged from a change of +16% to -17% across 18 interventions arms, with 14 of 18 arms ranging between +10% to -10%.

TRILOGY 2:

The Company reported a 30.4% median reduction in triglyceride levels among all patients receiving CaPre, as compared to 30.5% in TRILOGY 1, and a 17.9% median reduction in triglyceride levels among patients receiving placebo at 12 weeks (the Primary Endpoint), as compared to 27.5% in TRILOGY 1. The unadjusted, placebo corrected triglyceride reduction of 12.4% achieved a “p” value of 0.19, which was not statistically significant, and therefore the TRILOGY 2 study did not meet its primary endpoint. CaPre was well tolerated in TRILOGY 2, with a safety profile similar to placebo, and consistent with the Company’s previously conducted Phase 2 and 3 studies.

As a result, the company will not file a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) for patients with severe hypertriglyceridemia, and does not plan to conduct additional clinical trials for CaPre.

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.

Partnering

Acasti is pursuing development and/or distribution partnerships related to CaPre in the United States and in other major global markets.

To learn more, contact us at collaborate@acastipharma.com.