Epanova contains EPA and DHA in their free fatty acid form at a total concentration of 50-60% EPA and 15-25% DHA along with other potentially active omega-3 fatty acids stored in a patent‑protected capsule with a patent‑protected coating designed to maximize bioavailability and tolerability. Free fatty acids are the chemical form in which essential fatty acids, such as EPA and DHA, are absorbed in the digestive tract. The active ingredient of Epanova is a complex mixture of concentrated omega-3 free fatty acids purified from crude marine fish oil and are, therefore, of natural origin. Our strategy is to initially develop and commercialize Epanova in the United States as a prescription monotherapy as an adjunct to low-fat diet in patients for the reduction of triglyceride levels greater than or equal to 500 mg/dL, or severe hypertriglyceridemia.
The present Epanova formulation is the result of the further development of a drug originally intended to serve as treatment of Crohn’s disease, which ultimately proved safe but ineffective for treatment of Crohn’s disease. Before halting internal development and licensing its rights to the drug formulation to us, Tillotts Pharma AG (the predecessor entity to Chrysalis) conducted two large pivotal Phase III trials in 762 randomized patients with Crohn’s disease in both the European Union and North America.
We have completed pharmacokinetic and Phase III clinical studies to investigate the safety and efficacy profile of Epanova. Epanova has demonstrated improved absorption characteristics and bioavailability as compared to Lovaza, an ethyl‑ester formulation of omega-3. Ethyl‑ester forms of omega-3s require enzymatic breakdown prior to absorption, with the extent of absorption dependent upon the stimulation of pancreatic enzyme production, often instigated by the co-ingestion of high-fat meals. Unlike ethyl‑ester forms of omega-3 fatty acids, such as Lovaza and Vascepa, the free fatty acid form can easily cross the intestinal wall without enzymatic breakdown allowing more predictable and consistent absorption at lower doses independent of meal-fat content.
Our pharmacokinetic clinical program ECLIPSE, which consisted of two studies comparing the bioavailability of Epanova and Lovaza, showed that the absorption of the ethyl‑ester form found in other concentrated omega-3 compounds is significantly impacted by the fat content of meals, whereas the absorption of the free fatty acid form of Epanova does not appear to be constrained by this food effect. We expect that this improved bioavailability would yield either similar efficacy with a lower daily dosage (i.e. two 1-gram capsules, once per day) or improved triglyceride lowering efficacy at doses comparable to existing omega-3 products currently on the market or approved for marketing (i.e. twice‑daily doses of two 1‑gram capsules or once‑a‑day dose of four 1‑gram capsules for Lovaza).
Our Phase III program consisted of two clinical studies designed to further investigate the potential safety and efficacy of Epanova in patients with dyslipidemia: our pivotal Phase III EVOLVE trial (EpanoVa fOr Lowering Very high triglyceridEs); and our Phase III ESPRIT trial (Epanova combined with a Statin in Patients with hypertRiglycerIdemia to reduce non-HDL cholesTerol). In April 2012, we announced results from our pivotal Phase III EVOLVE clinical trial. The primary endpoint of the trial, conducted with patients with severe hypertriglyceridemia, was the percentage change in triglycerides from baseline to week 12 and secondary endpoints were the changes in other lipoproteins. The EVOLVE trial demonstrated that the free fatty-acid form of omega-3 fatty acids in the 2-gram dose of Epanova produced significantly improved blood levels of EPA and DHA that, in turn, led to significant decreases in triglyceride levels and non-HDL-C. In November 2012, we announced the results from our Phase III ESPRIT clinical trial, which supported the efficacy of Epanova as an adjunct to a low-fat diet and statin therapy for the further reduction of non-HDL-C and triglyceride levels in patients with high triglycerides and high risk for cardiovascular disease. These results are comparable to the results found in third‑party studies of other FDA-approved ethyl‑ester omega-3 prescription products. We believe our EVOLVE and ESPRIT Phase III trials provide statistically significant evidence that Epanova reduces triglycerides and non-HDL-C and improves other lipid parameters.
We obtained an SPA agreement with the FDA for both our EVOLVE and ESPRIT studies. An SPA is an agreement with the FDA that the proposed trial protocol design, clinical endpoints and statistical analyses are acceptable to support regulatory approval, if the trial demonstrates sufficiently favorable efficacy results, safety profiles and benefit/risk of a treatment. Based on our clinical experience to date, we expect to submit an NDA with the FDA in mid‑2013 pursuant to the provisions of Section 505(b)(1) of the Federal Food, Drug and Cosmetic Act, or FDCA, to commercialize Epanova for severe hypertriglyceridemia. Accordingly, we do not expect that any FDA approval of Epanova will be affected by any regulatory exclusivity granted to currently approved prescription omega-3 products under the Hatch‑Waxman amendments to the FDCA. After commercially launching Epanova in the severe hypertriglyceridemia indication, we will consider pursuing the development and commercialization of Epanova in combination with statins as a therapy for non-HDL-C and triglyceride reduction in high cardiovascular risk patients with levels of triglycerides above 200 mg/dL and less than 500 mg/dL, as well as other indications. Under the SPA for our ESPRIT study, we are able to submit an NDA for an indication for Epanova for the reduction of non-HDL-C and triglycerides in patients with high triglycerides in combination with statin therapy after we obtain approval for Epanova for patients with severe hypertriglyceridemia and are substantially underway with a cardiovascular outcomes study. While we do not intend to immediately pursue such an outcomes study and, therefore, be able to submit a supplemental NDA for this indication, we will review our strategy with respect to this second indication in light of Epanova’s commercial success in severe hypertriglyceridemia and our ability to find a suitable pharmaceutical partner to enter into a development and commercial collaboration.