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Optimistic news for FCS and FPL patients
CARLSBAD, Calif. & CAMBRIDGE, Mass.—In December, Akcea Therapeutics, a wholly owned subsidiary of Ionis Pharmaceuticals Inc., announced positive results from their Phase 3 COMPASS study, a randomized, double-blind, placebo-controlled, Phase 3 study evaluating volanesorsen in patients with severe hypertriglyceridemia. Patients were given weekly injections of the drug for 26 weeks, making it the largest and longest-running study to date.
The COMPASS study is an important component of the planned regulatory filings for volanesorsen, an antisense drug designed to decrease triglyceride levels by directly targeting apolipoprotein C-III (ApoC-III), being developed for the treatment of patients with the rare diseases familial chylomicronemia syndrome (FCS) and familial partial lipodystrophy (FPL).
The study included 113 patients with an average incoming triglyceride level of 1,261 mg/dl. At the primary endpoint of the study, volanesorsen-treated patients saw a statistically significant mean reduction in triglycerides of 71.2 percent from baseline after 13 weeks of treatment, a mean absolute reduction of 869 mg/dl in treated patients, while patients given a placebo saw a mean reduction of 0.9 percent.
Seven of the participating patients had FCS, a rare, genetic disorder characterized by extremely high levels of triglycerides and the risk of recurrent, potentially fatal pancreatitis. People with FCS experience a deficiency of lipoprotein lipase, an enzyme that helps to break down triglycerides, causing an inability to effectively clear large, triglyceride-rich lipid particles called chylomicrons. The average incoming triglyceride level of this subset was 2,280 mg/dl. From that group, the volanesorsen-treated patients achieved a mean reduction in triglycerides of 73 percent from baseline after 13 weeks of treatment, representing a mean absolute reduction of 1,511 mg/dl, while the placebo-treated patients actually saw a 70 percent mean increase.
FPL is a rare, underdiagnosed metabolic disorder characterized by an inability of the body to store fat in normal locations, causing high levels of triglycerides in the bloodstream, abnormal fat distribution around and within organs, such as the liver and heart, and a range of metabolic abnormalities, including severe insulin resistance. People with FPL are at increased risk of acute pancreatitis in addition to long-term, progressive consequences, such as premature cardiomyopathy, atherosclerosis and liver disease.
Additionally, 82 percent of patients treated with volanesorsen, including three of the FCS patients, achieved triglyceride levels less than 500 mg/dl after 13 weeks of treatment, compared to 14 percent of those given placebos. All of these results remained consistent for the entirety of the 26 week study.
“Current therapies are inadequate for patients with extremely high triglycerides, most specifically those with FCS, leaving them at risk for significant morbidity and mortality, including pancreatitis,” said Dr. Daniel Gaudet, associate professor of medicine and director of the Community Genomic Medicine Center in the Department of Medicine at the Université de Montréal, as well as scientific director and strategic development officer of BioBank, Genome Quebec’s Technological Centers. “People with FCS have particular challenges because in addition to having triglyceride levels that can be 10 to 20 times normal values, the currently available triglyceride-lowering drugs are usually ineffective. The data from studies in patients with FCS treated with volanesorsen, including those from the COMPASS study, show that for the first time these patients can achieve the triglyceride reductions needed to potentially improve their health.”
COMPASS results were consistent with those from the Phase 2 program for volanesorsen, which were published twice in the New England Journal of Medicine. In the three FCS patients profiled in one publication, the incoming average triglyceride number was 1,844 mg/dl, with an average triglyceride reduction after three months of dosing with volanesorsen of 1,298 mg/dl. In the COMPASS study, the average incoming triglyceride level of the five FCS patients treated with volanesorsen was 2,134 mg/dl, with an average triglyceride reduction of 1,511 mg/dl after three months of dosing.
Current therapies include dietary changes, exercise, and omega-3 fatty acids, which are often simply not enough. “We find ourselves in the position to have exhausted every option we have and still have a patient with high triglyceride values and at a high risk for his next pancreatitis for whom we can do nothing more,” said Dr. Ioanna Gouni-Berthold, a professor of medicine at the University of Cologne, in an interview with DDNews. “ Having a therapeutic option that decreases triglycerides so robustly is great news for our patients.”
“The findings in COMPASS reinforce the efficacy and safety of volanesorsen observed in Phase 2 studies across multiple patient populations, including FCS,” said Dr. Louis O’Dea, chief medical officer for Akcea. “No drug available today has demonstrated the magnitude of the triglyceride reductions observed with volanesorsen. These results confirm the potential value of targeting ApoC-III to lower triglycerides in patients who have high unmet need with potentially life-threatening consequences.”
Akcea Therapeutics is also conducting the pivotal APPROACH study in patients with FCS. The company plans to have top-line data available in the first quarter of 2017 and data from the BROADEN study in patients with FPL in 2019. Patients with FCS who have completed or meet the study criteria for the APPROACH and COMPASS studies can enroll in an open-label extension (APPROACH OLE) study, and patients in the BROADEN study are eligible to roll over into an open-label extension study upon completing dosing of the current study.
Akcea’s drug pipeline includes novel antisense drugs designed to address a number of lipid risk factors, including LDL-cholesterol, ApoC-III, triglycerides and Lp(a), its most advanced being the volanesorsen study, but the company has a strong pipeline of development-stage drugs covering multiple targets and diseases using advanced RNA-targeted antisense therapeutics.