LONDON – After failing to reach the primary endpoint in a 507-patient phase IIb trial in acute coronary syndrome (ACS), Cerenis Therapeutics SA has found a route forward for its CER-001 recombinant high-density lipoprotein (HDL), securing orphan drug status in two variants of an inherited rare disorder that causes HDL deficiency.
At the beginning of 2014, the company reported CER-001 failed to reach the primary endpoint of reducing atherosclerotic plaque in patients who had previously suffered heart attacks. That was a huge blow for Toulouse, France-based Cerenis, which had raised $70 million for the all-or-nothing phase IIb trial, after showing CER-001 cut cholesterol levels in healthy volunteers.
Now prospects have brightened considerably, with the granting of EMA orphan drug designation for CER-001 in familial primary hypoalphalipoproteinemia (FPHA), a rare disease caused by inherited defects in the apoA-I gene or the ABCA1 gene.
Both variants result in HDL deficiency and mean patients are unable to eliminate cholesterol via reverse lipid transport, the natural mechanism by which cholesterol is removed from the body. As a result, cholesterol accumulates, particularly in blood vessels, leading to accelerated atherosclerosis and premature cardiovascular disease.
Statins have no impact on the reverse lipid transport pathway, and statin therapy is only partially ineffective in treating FPHA.
The orphan designations were granted on the back of proof-of-mechanism data from a phase II academic trial, which showed that CER-001 reconstituted the reverse lipid transport pathway, promoting elimination of cholesterol in FPHA.
After one month of treatment with CER-001 in addition to standard of care, there was a reduction in the vessel wall thickness of the carotid artery, demonstrating that plaque was removed.
Erik Stroes, the principal investigator in the FPHA trial at the Academic Medical Center in Amsterdam, said, "Increased lipid removal was accompanied by marked reductions in the vessel wall dimensions of atherosclerotic arteries in patients [with FPHA]."
The results of the seven-patient study support the use of CER-001 for chronic administration, Stroes said.
Cerenis CEO Jean-Louis Dasseux said securing the orphan drug designations validates the company's approach and will enable it to accelerate development of the product. "CER-001 has the potential to be an important therapy, not only for patients with rare diseases but also for larger patient population, such as post-ACS," Dasseux said.
On Jan. 2, Cerenis reported that although the phase IIb study of CER-001 in post-ACS showed the product reduced cholesterol levels in patients who had suffered heart attacks, the study did not meet the primary endpoint of promoting a significant reduction in coronary atherosclerotic plaque.
However, one of the three doses tested did reach statistical significance vs. placebo. "One dose [level] was active and reduced plaque vs. baseline, and also vs. placebo," Dasseux told BioWorld Today. "So although we didn't meet the primary endpoint, we learned what is the effective dose. It defines the dose in [treating] post-ACS to set up the follow-on trial that needs to be done."
Dasseux is a veteran of recombinant HDL development. Before founding Cerenis in 2005, his research underpinned another HDL specialist, Esperion Therapeutics Inc., of Ann Arbor, Mich. Esperion was acquired by Pfizer Inc., of New York, for $1.3 billion in 2004 but divested in 2008.
Cerenis took a huge bet on the phase IIb trial, which was the largest study to date of an HDL mimetic in cardiovascular disease. "Of course the outcome would have been better if the ACS trial [had] met the primary endpoint. But there are a lot of questions over HDL and for the first time we took a true mimetic and demonstrated in patients that you get elimination of cholesterol, and the lipid-lowering effect occurs in a short period of time," Dasseux said.
CER-001 has been shown to act like endogenous HDL in all preclinical and clinical studies to date, promoting the reverse lipid transport pathway and leading to elimination of cholesterol. The clinical benefit seen in FPHA supports the use of HDL therapy in the broader treatment of atherosclerosis, Dasseux said.