Sanofi and Regeneron Pharmaceuticals, Inc. have announced that nine new Phase 3 ODYSSEY trials of alirocumab in people with hypercholesterolemia met their primary efficacy endpoint of a greater percent reduction from baseline in low-density lipoprotein cholesterol (LDL-C) at 24 weeks compared to placebo or active comparator. Alirocumab is an investigational monoclonal antibody targeting PCSK9 (proprotein convertase subtilisin/kexin type 9).
In the nine ODYSSEY trials, the mean percent reduction in LDL-C from baseline at 24 weeks in alirocumab-treated patients was consistent with results seen in previous alirocumab trials. The nine trials included ODYSSEY LONG TERM, FH I, FH II, HIGH FH, COMBO I, COMBO II, OPTIONS I, OPTIONS II and ALTERNATIVE. All patients received alirocumab in addition to standard-of-care lipid-lowering therapy, with the exception of some patients in ODYSSEY ALTERNATIVE.
The 2,341-patient ongoing ODYSSEY LONG TERM trial evaluated the long-term safety and efficacy of alirocumab compared to placebo. Both treatment groups received statins and some patients also received additional lipid-lowering therapies. The trial met its primary efficacy endpoint at 24 weeks. A pre-specified interim safety analysis was performed when all patients reached one year and approximately 25 percent of patients reached 18 months of treatment. A lower rate of adjudicated major cardiovascular events (cardiac death, myocardial infarction, stroke, and unstable angina requiring hospitalization) was observed in the alirocumab arm compared to placebo in a post-hoc analysis (p-value of less than 0.05). The potential of alirocumab to demonstrate cardiovascular benefit is being prospectively assessed in an ongoing 18,000-patient ODYSSEY OUTCOMES trial.
Alirocumab was generally well tolerated in the 9 ODYSSEY trials. The most common adverse events were nasopharyngitis and upper respiratory tract infections, which were generally balanced between treatment groups. Injection site reactions occurred more often in the alirocumab group compared to placebo. Serious adverse events and deaths were generally balanced between treatment groups as were other key adverse events including musculoskeletal, neurocognitive and liver-related events.
"Clinical data to date show consistent, positive results in LDL-C lowering, with an encouraging safety and tolerability profile across all Phase 3 alirocumab trials that we have reported," said George D. Yancopoulos, M.D., Ph.D., Chief Scientific Officer of Regeneron and President, Regeneron Laboratories. "Importantly, in the trials that used an individualized approach with 75 mg and 150 mg doses, the majority of patients reached their LDL-C goal while remaining on a 75 mg dose. This dosing approach was designed to provide physicians and patients with the flexibility to tailor therapy to patients' lipid-lowering needs."
The ODYSSEY ALTERNATIVE trial evaluated patients with a history of intolerance to two or more statins, who were randomized to receive alirocumab, ezetimibe or atorvastatin 20 mg (a calibrator arm). This trial met its primary efficacy endpoint of a greater percent reduction from baseline in LDL-C at 24 weeks with alirocumab compared to ezetimibe. In the ALTERNATIVE trial, rates of discontinuation due to adverse events were 25 percent for atorvastatin, 25 percent for ezetimibe and 18 percent for alirocumab; these differences between treatment groups were not statistically significant.
"The robust data from these studies in more than 5,000 patients is the basis of our global regulatory submissions, which we expect in the U.S. and EU by year end," said Elias Zerhouni, M.D., President, Global R&D, Sanofi. "We look forward to potentially providing a new treatment option for patients who may need a more aggressive cholesterol-lowering treatment on top of standard of care."
More detailed data will be presented at upcoming medical congresses.
The ODYSSEY trials assessed the potential of subcutaneous alirocumab in one or more patient groups where there is high unmet need:
- Heterozygous Familial hypercholesterolemia (HeFH), an inherited form of high cholesterol: ODYSSEY FH I, FH II and HIGH FH focused solely on patients in this group. HeFH is an inherited disorder of lipid metabolism that predisposes a person to high LDL-C and premature severe cardiovascular disease (CVD).1
- High or very high cardiovascular (CV) risk: ODYSSEY COMBO I, COMBO II, OPTIONS I, OPTIONS II and LONG TERM.
- Patients with a history of statin-intolerance: ODYSSEY ALTERNATIVE included patients who had a history of being intolerant to statins and at moderate- to very-high CV risk.
The 9 ODYSSEY trials reported recently, along with the previously announced MONO trial, encompass over 5,000 patients studied in double-blind trials for 24-104 weeks. ODYSSEY MONO reported positive results in October 2013. All trials included patients with LDL-C not at goal with or without a documented history of CVD. ODYSSEY OPTIONS I, OPTIONS II, COMBO II, MONO and ALTERNATIVE included at least one active comparator (e.g., ezetimibe). The trials evaluated two distinct dosing regimens: 150 milligrams (mg) every two weeks or 75 mg every two weeks increasing to 150 mg if needed to reach protocol-specified LDL-C targets. The 75 mg and the 150 mg dose were delivered with a single, self-administered one-milliliter (mL) injection.
The ODYSSEY clinical trial program remains ongoing. This includes three additional studies, CHOICE I, CHOICE II (both evaluating monthly doses of alirocumab) and OUTCOMES, which are expected to report primary endpoints in 2015 and beyond. Click here for more information on the ODYSSEY program, alirocumab, PCSK9, and LDL-C. Alirocumab is currently under clinical development and its safety and efficacy have not been fully evaluated by any regulatory authority.