Detailed positive results from four ongoing Phase III Odyssey trials of alirocumab (SAR236553/REGN727), which is being developed by Regeneron Pharmaceuticalsin collaboration with Sanofiwere released today at a Hot Line session at the ESC Congress 2014, being held in Barcelona, Spain, August 30 – September 3, 2014.[1]
Alirocumab is an investigational, fully human, monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9 or PCSK9. The trial drug is being evaluated to manage low-density lipoprotein orLDL cholesterol (LDL-C), including in people who do not get to their target LDL levels using statin medicines alone. Researchers have shown that the drug plays an important role in determining circulating levels of LDL-C by regulating the number of LDL receptors on a liver cell?s surface. [1]. They found that inhibiting PCSK9 increases the availability of LDL receptors on liver cells, thereby lowering LDL-C. [2]
These trials showed significant and sustained reductions in LDL-C over a one year period on top of standard-of-care statin therapy across different patient types…
Recent discovery
Researchers discovered the gene that expresses the PCSK9 protein in 2003. Cohen, Boerwinkle, Mosley and Hobbs described a genetic link between PCSK9 and LDL cholesterol in a study published in the March 2006in theNew England Journal of Medicine[3]. In their study, sub normal levels of PCSK9 production due to mutations in the PCSK9 gene were associated with a 28% reduction in mean LDL cholesterol and an 88% reduction in the risk of a cardiac event in African-Americans and with a 15% reduction in LDL cholesterol and a 47% reduction in the risk of a cardiac event in white Americans[2]. These data suggest a strong association between PCSK9, LDL cholesterol, and cardiac risk and open the possibility that a pharmaceutical agent that inhibits PCSK9 may offer clinical utility. Based on this discovery researchers started a development program leading to the trial drug alirocumab.
Sustained reductions
“Across these four trials, alirocumab showed significant and sustained reductions in LDL-C over one year on top of standard-of-care statin therapy across different patient types,” 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.
“We are also encouraged by the consistent safety profile across the trials, including in odyssey long term, the largest Phase III trial of a PCSK9 inhibitor, with the longest follow-up period reported to date,” she continued.
Odyssey trials
The ongoing 2,341-patient, double-blind odyssey long termtrial is designed to evaluate the long-term safety and efficacy of 150 milligrams (mg) alirocumab every two weeks versus placebo in patients with hypercholesterolemia who are at high or very-high cardiovascular (CV) risk, including patients with an inherited form of high cholesterol known as heterozygous familial hypercholesterolemia (HeFH).
Both study groups are treated with statins at a maximally-tolerated dose and some patients also receive additional lipid-lowering therapies. A pre-specified interim analysis was performed when all patients reached one year and approximately 25 percent of patients reached 18 months of treatment. Key data to be presented today include:
- On the primary efficacy endpoint of the trial, at 24 weeks, there was a 61% reduction from baseline in LDL-C levels in the alirocumab group as compared to a 1% increase in the placebo group (62% reduction in alirocumab group compared to placebo), p less than 0.0001.
- At 52 weeks, there was a 57% reduction from baseline in LDL-C levels in the alirocumab group as compared to a 4% increase in the placebo group (61% reduction in alirocumab group compared to placebo), p less than 0.0001.
- 81% of alirocumab patients achieved their pre-specified LDL-C goal (either 70 milligrams/deciliter [mg/dL] or 100 mg/dL depending on patients’ baseline CV risk) compared to 9 percent for placebo (p less than 0.0001).
- The most common adverse events (greater than or equal to 5 percent of patients) were nasopharyngitis (13 percent alirocumab; 13% placebo), upper respiratory tract infection (7% alirocumab; 8% placebo), and injection site reactions (6% alirocumab; 4% placebo). In a post hoc safety analysis, there was a lower rate of adjudicated major CV events (cardiac death, myocardial infarction, stroke, and unstable angina requiring hospitalization) in the alirocumab group compared to placebo (1.4% compared to 3.0%, nominal p-value less than 0.01). These CV events comprise the composite primary endpoint of the ongoing 18,000-patient ODYSSEY OUTCOMES trial, which is prospectively evaluating the potential of alirocumab to demonstrate CV benefit.
Additional trial results presented
During theESC Congress 2014 congress in Barcelona, three additional trials (ODYSSEY COMBO II, FH I and FH II) will also be presented. In these three trials, alirocumab-treated patients receive an initial dose of alirocumab 75 mg every two weeks, increasing to 150 mg if needed to reach pre-specified LDL-C levels. The 75 mg and 150 mg alirocumab doses were delivered as a single, self-administered 1 milliliter (mL) injection.
“As physicians, we often start patients on a lower dose of a medication and only increase it if needed. In these trials, the majority of patients who were started at a 75 mg dose of alirocumab, were able to achieve their target LDL-C goals while remaining on their initial dose,” said Christopher Cannon M.D., Professor of Medicine, Harvard Medical School.
ODYSSEY COMBO II trial
The ODYSSEY COMBO II is a double-blind, 720-patient trial designed to evaluate the safety and efficacy of alirocumab compared to ezetimibe in patients with hypercholesterolemia who are at high CV risk and had inadequate LDL-C reduction at baseline despite stable maximally-tolerated statin therapy. Key data to be presented today include:
- On the primary endpoint of the trial, at 24 weeks, there was a 51% reduction from baseline in LDL-C levels in the alirocumab group compared to a 21% reduction in the ezetimibe group (30% reduction in alirocumab group compared to ezetimibe group), p less than 0.0001.
- At 52 weeks, there was a 50% reduction from baseline in LDL-C levels in the alirocumab group compared to an 18% reduction in the ezetimibe group (32% reduction in alirocumab group compared to ezetimibe group), p less than 0.0001.
- 77% of patients in the alirocumab group achieved an LDL-C level of 70 mg/dL at 24 weeks.
- Approximately 80% of patients in the alirocumab group remained on the initial 75 mg alirocumab dose.
- The most common adverse events (greater than or equal to 5% of patients) were upper respiratory tract infection (6.5% alirocumab; 6% ezetimibe), accidental overdose (6% alirocumab; 7% ezetimibe), dizziness (5% alirocumab; 5% ezetimibe), and myalgia (4% alirocumab; 5% ezetimibe).
ODYSSEY FH I and FH II trials
The ODYSSEY FH I and FH II trials enrolled a total of 738 HeFH patients and compare alirocumab to placebo. All patients are on maximally-tolerated daily statin therapy and the majority of patients also receive ezetimibe. Despite receiving this high level of background therapy, patients in these studies had mean baseline LDL-C levels of 145 mg/dL (FH I) and 134 mg/dL (FH II). Key data to be presented today for FH I and FH II include:
- On the primary endpoint of the trials, at 24 weeks, there was a 49% reduction from baseline in LDL-C levels in both FH I and FH II alirocumab gr
oups compared to an increase of 9% in FH I and 3% in FH II in the placebo groups (58 and 51% reduction compared to placebo), p less than 0.0001. - At 52 weeks, in FH I, there was a 47% reduction from baseline and, in FH II, a 50% reduction from baseline in LDL-C levels in the alirocumab groups compared to an increase of 9 and 8% in the placebo groups, respectively (56 and 58% reduction compared to placebo), p less than 0.0001.
- 72% of alirocumab-treated patients in FH I, and 81% of alirocumab-treated patients in FH II, achieved their pre-specified LDL-C goal (either 70 mg/dL or 100 mg/dL) at 24 weeks compared to 2 and 11% in the placebo groups, respectively (p less than 0.0001).
- Approximately 50% of patients in the alirocumab groups remained on the 75 mg dose. In pooled data from both trials, the most common adverse events (greater than or equal to 5% of patients) were injection site reactions (11.5% alirocumab; 9% placebo), nasopharyngitis (10% alirocumab; 11% placebo), influenza (9% alirocumab; 6 percent placebo), and headache (5.5% alirocumab; 7% placebo).
“Heterozygous FH patients often have high LDL-C despite treatment with statins and other options,” said Michel Farnier, M.D., Ph.D., Point Medical, Dijon, France. “Although a large majority of patients in ODYSSEY FH I and FH II had high LDL-C at baseline, at least 70% of alirocumab-treated patients reached their treatment goals.”
The four ODYSSEY trials reported today, along with results from six other Phase III studies, include more than 5,000 patients studied in double-blind trials for 24-104 weeks. Sanofi and Regeneron anticipate alirocumab regulatory submissions in the U.S. and EU by the end of 2014. In the U.S., the companies intend to use a Priority Review Voucher to obtain priority review status for the alirocumab regulatory submission.
The ODYSSEY clinical trial program remains ongoing. The trial drug is currently under clinical development and its safety and efficacy have not been evaluated by any regulatory authority.
For more information:
[1] Raal F, Panz V, Immelman A, Pilcher G. Elevated PCSK9 Levels in Untreated Patients With Heterozygous or Homozygous Familial Hypercholesterolemia and the Response to High?Dose Statin Therapy. J Am Heart Assoc.2013;2:e000028 [Article][PubMed]
[2]. Mayne J, Dewpura T, Raymond A, et al. Novel loss-of-function PCSK9 variant is associated with low plasma LDL cholesterol in a French-Canadian family and with impaired processing and secretion in cell culture. Clin Chem. 2011;57(10):1415-1423.[Article][PubMed]
[3] Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.N Engl J Med. 2006 Mar 23;354(12):1264-72. [Article][PubMed]
Clinical trials:
[a] ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab SAR236553 (REGN727) – NCT01663402 [Study Record Detail]
[b] Open Label Study of Long Term Safety Evaluation of Alirocumab (ODYSSEY OLE) – NCT01954394 [Study Record Detail]
[c] Study of Alirocumab (REGN727/ SAR236553) in Patients With heFH (Heterozygous Familial Hypercholesterolemia) Who Are Not Adequately Controlled With Their LMT (Lipid-Modifying Therapy) (Odyssey FH II) – NCT01709500 [Study Record Detail]
[d] Efficacy and Safety of Alirocumab SAR236553 (REGN727) Versus Placebo on Top of Lipid-Modifying Therapy in Patients With Heterozygous Familial Hypercholesterolemia Not Adequately Controlled With Their Lipid-Modifying Therapy (ODYSSEY FH I)- NCT01623115 [Study Record Detail]
[e] Phase III Study To Evaluate Alirocumab in Patients With Hypercholesterolemia Not Treated With a Statin (ODYSSEY CHOICE II) – NCT02023879 [Study Record Detail]
[f] Efficacy and Safety of Alirocumab SAR236553 (REGN727) Versus Ezetimibe on Top of Statin in High Cardiovascular Risk Patients With Hypercholesterolemia (ODYSSEY Combo II) – NCT01644188 [Study Record Detail]
[g] Efficacy and Safety of Alirocumab SAR236553 (REGN727) Versus Placebo on Top of Lipid-Modifying Therapy in Patients With Heterozygous Familial Hypercholesterolemia (ODYSSEY High FH) – NCT01617655 [Study Record Detail]
[h] Study to Evaluate the Efficacy and Safety of an Every Four Weeks Treatment Regimen of Alirocumab (REGN727/ SAR236553) in Patients With Primary Hypercholesterolemia (ODYSSEY CHOICE 1) – NCT01926782 [Study Record Detail]
[i] Long-term Safety and Tolerability of Alirocumab SAR236553 (REGN727) Versus Placebo on Top of Lipid-Modifying Therapy in High Cardiovascular Risk Patients With Hypercholesterolemia (ODYSSEY Long Term) – NCT01507831 [Study Record Detail]
[j] Study of Alirocumab (REGN727/ SAR236553) in Patients With Primary Hypercholesterolemia and Moderate, High, or Very High Cardiovascular (CV) Risk, Who Are Intolerant to Statins (Odyssey Alternative) – NCT01709513 [Study Record Detail]
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