Sanofi and Regeneron Announce New Results from Six Phase 3 Trials
Showing that Alirocumab Significantly Reduced LDL Cholesterol
- All six trials met primary efficacy endpoint -
- Data presented at AHA Scientific Sessions 2014 -
Paris and Tarrytown, New York - November 19, 2014 - Sanofi and Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today announced new detailed positive results from six Phase 3 ODYSSEY trials that showed alirocumab significantly reduced low-density lipoprotein cholesterol (LDL-C, or "bad" cholesterol). Alirocumab is an investigational fully human monoclonal antibody targeting the protein PCSK9 (proprotein convertase subtilisin/kexin type 9) that is being evaluated for its ability to lower LDL-C.
All six trials, ODYSSEY LONG TERM, COMBO I, ALTERNATIVE, OPTIONS I, OPTIONS II, and HIGH FH, met their primary efficacy endpoint of a greater reduction in LDL-C at 24 weeks, versus either active comparator or placebo, which included standard-of-care therapy. Detailed results from these trials were presented as part of a special session on the ODYSSEY program today, and on November 17 during a late-breaker presentation at the American Heart Association (AHA) Scientific Sessions in Chicago, IL. The companies had announced in July that all six studies met their primary efficacy endpoints.
"In these trials patients treated with alirocumab achieved significant and robust LDL-C reductions compared to baseline," said Jennifer Robinson, M.D., M.P.H., Director of the Prevention Intervention Center, Professor, Departments of Epidemiology & Medicine, College of Public Health at the University of Iowa. "New interim results from ODYSSEY LONG TERM provide further support for alirocumab's consistent safety profile, including in more than 500 patients who achieved LDL-C levels lower than 25 mg/dL."
The trials assessed alirocumab in hypercholesterolemic patients who were at high cardiovascular (CV) risk, had an inherited form of high cholesterol known as heterozygous familial hypercholesterolemia (HeFH), and/or a history of intolerance to two or more statins, including one at the lowest dose. All patients received alirocumab in addition to standard-of-care lipid-lowering therapy, with the exception of some patients in ODYSSEY ALTERNATIVE.
Table 1: Summary of Primary Efficacy Endpoint and Most
Common Adverse Events (AEs)
|Étude||Groupe de patients|| Critère d'efficacité principal |
(changement en pourcentage du taux de LDL-C à 24 semaines par rapport au départ)
|Effets indésirables les plus fréquentsa|
| LONG TERM |
Alirocumab (n=1 553) vs placebo (n=788)
Dose de 150 mg
| Tous les patients (risque cardiovasculaire élevé)b |
(total n=2 341)
|Réduction de 61 %||Augmentation de 1 % (placebo)c||Rhinopharyngite, infection des voies respiratoires supérieures, réaction au point d'injection, grippe, diarrhée, infection des voies urinaires, bronchite, myalgie, maux de tête, dorsalgie, arthralgie|
| Sous-groupe HeFH |
|Réduction de 56 %||Augmentation de 7 % (placebo)d|
| Sous-groupe non-HeFH |
(n= 1 894)
|Réduction de 62 %||Réduction de 0,5 % (placebo)e|
| COMBO I |
Alirocumab (n=209) vs placebo (n=107)
Dose 75 mg/150 mg
|Risque cardiovasculaire élevé||Réduction de 48 %|| ||Infection des voies respiratoires supérieures, rhinopharyngite, infection des voies urinaires, vertiges, sinusite, réaction au point d'injection|
| OPTIONS I |
Statine au départ = atorvastatine 20/40 mg
Alirocumab (n=104) vs ézétimibe (n=102) ou double dose d'atorvastatine (n=104)ou passage à rosuvastatinef (n=45)
Dose 75 mg/150 mg
|Risque cardiovasculaire élevé||Réduction de 44-54 %|| ||Rhinopharyngite, infection des voies respiratoires supérieures, hypertension, dorsalgie|
| OPTIONS II |
Statine au départ = rosuvastatine 10/20 mg
Alirocumab (n=103) vs ézétimibe (n=101) ou double dose de rosuvastatine (n=101)
Dose 75 mg/150 mg
|Risque cardiovasculaire élevé||Réduction de 36-51 %|| ||Rhinopharyngite, infection des voies respiratoires supérieures, hypertension, dorsalgie|
| ALTERNATIVE |
Alirocumab (n=126) vs ézétimibe (n=125)
Groupe validation = atorvastatine 20 mg (n=63)
Dose 75 mg/150 mg
|Risque cardiovasculaire élevé et antécédents d'intolérance à deux statines ou plus||Réduction de 45 %||Réduction de 15 % (ézétimibe)c||Myalgie, rhinopharyngite, arthralgie, infection des voies respiratoires supérieures, maux de tête, fatigue|
| HIGH FH |
Alirocumab (n=72) vs placebo (n=35)
Dose de 150 mg
|Hypercholestéro-lémie familiale hétérozygote||Réduction de 46 %||Réduction de 7 % (placebo)c||Rhinopharyngite, réaction au point d'injection, diarrhée, sinusite, bronchite, maux de tête, fatigue|
- Occurred in at least 5 percent of alirocumab-treated patients
- Previously reported in August 2014
- 95 percent confidence interval of the LS mean difference vs. placebo: 57.5-69 percent reduction
- 95 percent confidence interval of the LS mean difference vs. placebo: 59-64 percent reduction
- 45 patients on atorvastatin 40 mg starting dose switched to rosuvastatin 40 mg
- For patients on atorvastatin 20 mg starting dose p=0.0004; for patients on atorvastatin 40 mg starting dose p<0.0001
- For patients on rosuvastatin 10 mg starting dose p<0.0001; patients on rosuvastatin 20 mg starting dose did not reach statistical significance
In a pre-specified interim analysis of the ongoing, 78-week ODYSSEY LONG TERM safety, tolerability and efficacy trial, a generally comparable rate of AEs was observed among the 37 percent (n=562) of alirocumab-treated patients who achieved two consecutive LDL-C values of less than 25 mg/dL, as compared to the overall alirocumab patient population in this trial.
ODYSSEY ALTERNATIVE is the first trial of a PCSK9 inhibitor to reassess statin intolerance, as measured by skeletal muscle AEs, by including a validation arm (atorvastatin 20 mg). In clinical practice, 10 to 25 percent of patients report intolerance to statins, and many have poorly-controlled LDL-C, which puts them at greater risk of CV events.1,2 In this trial, there were fewer skeletal muscle AEs in the alirocumab group compared to patients treated with atorvastatin (32.5 percent versus 46 percent, hazard ratio = 0.61; nominal p value = 0.042), and there was no significant difference when compared to the ezetimibe group (41 percent). In addition, there were numerically fewer discontinuations for skeletal muscle AEs in the alirocumab group, but this did not reach statistical significance (alirocumab 16 percent, ezetimibe 20 percent, atorvastatin 22 percent). In comparison, the overall rate of discontinuations for skeletal muscle AEs across the Phase 2 and 3 alirocumab placebo-controlled studies, where the majority of patients were also on statins, was 0.4 percent for alirocumab (n=2,476) and 0.5 percent for placebo (n=1,276).
Patients in all six randomized, double-blind, Phase 3 ODYSSEY trials received alirocumab via a single, self-administered 1-mililter (mL) subcutaneous injection, every two weeks. Alirocumab-treated patients received the 150 milligram (mg) dose in ODYSSEY LONG TERM and HIGH FH, and the 75 mg dose (increasing to 150 mg if needed to reach pre-specified LDL-C levels) in ODYSSEY ALTERNATIVE, OPTIONS I, OPTIONS II, and COMBO I. 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 the 75 mg dose. Average baseline LDL-C levels in all six trials were between approximately 100-120 mg/dL, with the exception of ODYSSEY ALTERNATIVE and HIGH FH where baseline LDL-C levels were greater than 190 mg/dL.
The six ODYSSEY trials reported at AHA Scientific Sessions 2014, along with results from four other Phase 3 studies, encompass more than 5,000 patients studied in double-blind trials for 24-104 weeks. Regulatory submissions are planned in the U.S. and EU before the end of this year.
The ODYSSEY clinical trial program is ongoing. Click here for more information on alirocumab, LDL-C, and the ODYSSEY studies presented at the AHA Scientific Sessions 2014. Alirocumab is currently under clinical development and its safety and efficacy have not been evaluated by any regulatory authority.
Sanofi, an integrated global healthcare leader, discovers, develops and distributes therapeutic solutions focused on patients' needs. Sanofi has core strengths in the field of healthcare with seven growth platforms: diabetes solutions, human vaccines, innovative drugs, consumer healthcare, emerging markets, animal health and the new Genzyme. Sanofi is listed in Paris (EURONEXT: SAN) and in New York (NYSE: SNY).
About Regeneron Pharmaceuticals, Inc.
Regeneron is a leading science-based biopharmaceutical company based in Tarrytown, New York that discovers, invents, develops, manufactures, and commercializes medicines for the treatment of serious medical conditions. Regeneron commercializes medicines for eye diseases, colorectal cancer, and a rare inflammatory condition and has product candidates in development in other areas of high unmet medical need, including hypercholesterolemia, oncology, rheumatoid arthritis, asthma, and atopic dermatitis. Several Regeneron programs are based on human genetics findings. For additional information about the company, please visit www.regeneron.com.
- Bruckert E, Hayem G, Dejager S, et al. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients -the PRIMO study. Cardiovasc Drugs Ther. 2005;19:403-414.
- Cohen JD, Brinton EA, Ito MK, Jacobson TA. Understanding statin use in America and gaps in patient education (USAGE): an internet-based survey of 10,138 current and former statin users. J Clin Lipidol. 2012 May-Jun;6(3):208-15.
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