Clinical Trials

Therapeutic area: Cardiovascular diseases - Genetic diseases - Rare diseases

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• • On November 10, 2015, Regeneron Pharmaceuticals and Sanofi announced a new post-hoc analysis of six Phase 3 clinical trials showing that approximately three quarters (74 percent) of patients reached their pre-specified LDL cholesterol targets within 8 weeks of adding Praluent® (alirocumab) Injection 75 mg to their standard-of-care, which included statins. In the 26 percent of patients whose dose was increased to 150 mg, most were able to achieve their pre-specified LDL cholesterol target, with an average additional 14 percent reduction in LDL cholesterol. The results from this and other analyses, which evaluated Praluent every two weeks, were presented at the American Heart Association (AHA) Scientific Sessions in Orlando, FL. These results are based on a pooled post-hoc analysis of 1,291 patients with high cardiovascular (CV) risk or an inherited form of high cholesterol (heterozygous familial hypercholesterolemia, or HeFH) which found 74 percent of patients who added Praluent® 75 mg achieved their LDL cholesterol-lowering goals at week 8, and the remaining 26 percent had their dose adjusted to 150 mg at week 12. In other results: By week 24, 61 percent of patients who switched to 150 mg achieved their goal, with a mean additional LDL cholesterol reduction of 14 percent. Comparable adverse event (AE) rates were observed in patients whose Praluent dose was increased, versus those whose dose was not (66 percent in both arms in placebo-controlled trials; and 55 percent versus 56 percent respectively in ezetimibe-controlled trials). The pooled analysis included results from six Phase 3 ODYSSEY trials where patients added Praluent 75 mg to standard-of-care, and had their dose adjusted at week 12 to 150 mg if they did not reach their LDL cholesterol goals by week 8. Cholesterol goals were either less than 70 mg/dL or less than 100 mg/dL, dependent on CV risk. All patients across the six trials received background statin therapy. In three trials Praluent was compared to placebo (ODYSSEY FH I, FH II, COMBO I), and in three it was compared to ezetimibe (ODYSSEY COMBO II, OPTIONS I, OPTIONS II). In a separate pooled post-hoc analysis of 3,499 patients, individuals with diabetes (n=1,051) who initially received Praluent 75 mg or 150 mg every two weeks had a mean percent difference in LDL cholesterol of 44 percent and 58 percent, respectively, versus placebo at week 24 (p less than 0.0001). In other results: Praluent was generally well tolerated, with the most common adverse events among people with diabetes being nasopharyngitis (11 percent Praluent, 10 percent placebo) and upper respiratory tract infection (8 percent Praluent, 9 percent placebo). • On November 19, 2014, Regeneron Pharmaceutical and Sanofi announced new detailed positive results from six Phase 3 ODYSSEY trials that showed alirocumab significantly reduced low-density lipoprotein cholesterol. Al 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. 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.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. 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. Table 1: Summary of Primary Efficacy Endpoint and Most Common Adverse Events (AEs)

  Study	Patient group	Primary efficacy endpoint (percent change from baseline in LDL-C at 24 weeks)		Most common AEsa
  		Alirocumab	Comparator
  LONG TERM Alirocumab (n=1,553)  vs. placebo (n=788) 150 mg	All patients (high CV risk)b (total n=2,341)	61 % reduction	1 % increase (placebo)c	Nasopharyngitis, upper respiratory tract infection, injection site reactions, influenza, diarrhea, urinary tract infection, bronchitis, myalgia, headache, back pain, arthralgia
  	HeFH subgroup (n= 416)	56 % reduction	7 % increase (placebo)d
  	Non-HeFH subgroup (n= 1,894)	62 % reduction	0.5 % reduction (placebo)e
  COMBO I Alirocumab  (n=209)  vs. placebo (n=107) 75 mg/150 mg	High CV risk	48 % reduction	2 % reduction (placebo)c	Upper respiratory tract infection, nasopharyngitis, urinary tract infection, dizziness, sinusitis, injection-site reaction
  OPTIONS I [Baseline statin = atorvastatin 20/40 mg] Alirocumab (n=104)  vs. ezetimibe (n=102) or double atorvastatin (n=104)  or switch to rosuvastatinf (n=45) 75 mg / 150 mg dose	High CV risk	44-54 % reduction	- 20.5-23 % reduction (ezetimibe)g  - 5 % reduction (double statin dose)c - 21 % reduction (statin switch)c	Nasopharyngitis, upper respiratory tract infection, hypertension, back pain
  OPTIONS II [Baseline statin = rosuvastatin 10/20 mg] Alirocumab (n=103) vs. ezetimibe (n=101) or double rosuvastatin (n=101) 75 mg / 150 mg dose	High CV risk	36-51 % reduction	- 11-14 % reduction (ezetimibe)h - 16 % reduction (double statin dose)h	Nasopharyngitis, upper respiratory tract infection, hypertension, back pain
  ALTERNATIVE Alirocumab (n=126) vs. ezetimibe (n=125) [Validation arm = atorvastatin 20 mg (n=63)] 75 mg / 150 mg dose	High CV risk and history of intolerance to two or more statins	45 % reduction	15 % reduction (ezetimibe)c	Myalgia, nasopharyngitis, arthralgia, upper respiratory tract infection, headache, fatigue
  HIGH FH Alirocumab (n=72) vs. placebo (n=35) 150 mg dose	HeFH	46 % reduction	7 % reduction (placebo)c	Nasopharyngitis, injection-site reaction, diarrhea, sinusitis, bronchitis, headache, fatigue

  a.Occurred in at least 5 percent of alirocumab-treated patients

  b.Previously reported in August 2014

  c.P less than 0.0001

  d.95 percent confidence interval of the LS mean difference vs. placebo: 57.5-69 percent reduction

  e.95 percent confidence interval of the LS mean difference vs. placebo: 59-64 percent reduction

  f. 45 patients on atorvastatin 40 mg starting dose switched to rosuvastatin 40 mg

  g.For patients on atorvastatin 20 mg starting dose p=0.0004; for patients on atorvastatin 40 mg starting dose p less than 0.0001

  h.For patients on rosuvastatin 10 mg starting dose p less than 0.0001; patients on rosuvastatin 20 mg starting dose did not reach statistical significance

  • On July 30, 2014, Sanofi and Regeneron Pharmaceuticals 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.
• 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.
• 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. 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. More detailed data will be presented at upcoming medical congresses. The 9 ODYSSEY trials reported today, along with the previously announced MONO trial, encompass over 5,000 patients studied in double-blind trials for 24-104 weeks. EY 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.
• • On October 16, 2013, Sanofi and Regeneron Pharmaceuticals have announced that the Phase 3 ODYSSEY MONO trial with alirocumab, an investigational monoclonal antibody targeting PCSK9 (proprotein convertase subtilisin/kexin type 9), met its primary efficacy endpoint.  The mean low-density lipoprotein-cholesterol (LDL-C, or "bad" cholesterol) reduction from baseline to week 24, the primary efficacy endpoint of the study, was significantly greater in patients randomized to alirocumab, as compared to patients randomized to ezetimibe (47.2% vs. 15.6%, p < 0.0001).  In the trial, which employed a dose increase (up-titration) for patients who did not achieve an LDL-C level of 70 milligrams/deciliter (mg/dL), the majority of patients remained on the initial low dose of alirocumab of 75 milligrams (mg).
• The percentage of patients who reported treatment emergent adverse events was 78.4% in the ezetimibe group and 69.2% in the alirocumab group. The most common class of adverse events was infections (39.2% with ezetimibe vs. 42.3% with alirocumab), which included nasopharyngitis, influenza, and upper respiratory tract infection.  Injection-site reactions occurred in less than 2% of patients in both groups.  Muscle-related adverse events occurred in 3.9% of patients treated with ezetimibe and 3.8% of patients treated with alirocumab.
• ODYSSEY MONO is the first study to report data from the 12 Phase 3 trials that have been initiated so far as part of the more than 23,000 patient ODYSSEY clinical trial program.
• Detailed results from the ODYSSEY MONO study will be presented at an upcoming medical conference in 2014.

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