Cerenis Therapeutics acknowledged today that its lead candidate CER-001 has failed a Phase II clinical trial assessing the drug in post-acute coronary syndrome (ACS). CER-001 failed the Phase II CARAT study by missing its primary endpoint of showing statistically significant regression of coronary plaque in ACS, the company said.
CER-001 is a negatively charged lipoprotein particle that contains human recombinant apolipoprotein A-1 (apoA-1), the natural high-density lipoprotein (HDL) protein, and two natural phospholipids—sphingomyelin and dipalmitoyl phosphatidylglycerol.
CER-001 particles were designed to work by increasing transient apoA-I and the number of HDL particles; stimulating the removal of excess cholesterol and other lipids from tissues, including the arterial wall, and becoming mature HDL particles; and supporting esterification of the trapped cholesterol through the apoA-I highly stereospecific activation of the lecithin-cholesterol acyltransferase (LCAT) enzyme.
The particles were designed to be recognized by the liver when transformed in mature HDL, leading to the elimination of the transported lipids and cholesterol through a process called reverse lipid transport. The empty particles were ultimately supposed to be recycled.
While CARAT confirmed the safety profile of CER-001, Cerenis said, it did not produce even the limited positive results shown by the candidate in the earlier Phase II CHI-SQUARE study.
In results reported in 2014, CHI-SQUARE missed its primary endpoint of reducing total atheroma volume (TAV) versus placebo in the complete modified Intention to Treat (mITT) population of 417 patients. While the study showed a statistically significant reduction in TAV versus baseline in a mITT population of 369 patients, that reduction did not reach statistical significance when compared with placebo for the primary clinical endpoint.
However, the study showed nominal statistical significance versus placebo for reductions in both TAV and percent atheroma volume (PAV) in a modified Per Protocol (mPP) population of 295 patients at one dose level.
“Although we were convinced by the analyses of the Phase II CHI-SQUARE study highlighting the efficacy of the optimal 3 mg/kg dose, we are surprised and disappointed by the results of the CARAT study,” Stephen Nicholls, M.D., Ph.D., MBBS, principal investigator and chairman of the steering committee for the Phase II clinical CARAT study, said in a statement.
In the CARAT study, 301 randomized patients were administered 3 mg/kg of CER-001 or placebo on day 1 and weekly thereafter for a total of 10 infusions, followed by 2 weeks of observation. The study was conducted in the U.S., Australia, Hungary, and The Netherlands.
Cerenis presented CARAT trial data at the Annual American College of Cardiology Scientific Sessions in Washington, D.C.
Cerenis continues to study CER-001 in the Phase III TANGO study in patients with genetic HDL deficiencies. The company also plans to begin clinical studies of CER-209, an oral P2Y13 receptor agonist that in December won FDA approval for an IND assessing the candidate in nonalcoholic steatohepatitis and nonalcoholic fatty liver disease.