Sanofi and Regeneron Pharmaceuticals, Inc., a fully integrated biopharmaceutical company that discovers, invents, develops, manufactures, and commercializes medicines for the treatment of serious medical conditions,  announced that several trials within ODYSSEY, the phase 3 clinical programme of SAR236553/REGN727, have initiated patient enrollment.

SAR236553/REGN727 is a potential first-in-class, subcutaneously administered, fully-human antibody that lowers low-density lipoprotein (LDL) cholesterol by targeting PCSK9 (proprotein convertase subtilisin/kexin type 9), an enzyme which binds LDL receptors, leading to their accelerated degradation and increased LDL-cholesterol (LDL-C) levels.

 “We are delighted to lead the field of PCSK9 late stage development with the broad global 22,000 patient ODYSSEY clinical trial programme, and would like to thank in advance the patients and physicians who will contribute to the first phase 3 programme evaluating a PCSK9-targeted therapy,” said Jay Edelberg M.D., Ph.D., Head of the PCSK9 Development and Launch Unit, Sanofi. “This comprehensive phase 3 programme will test the safety and efficacy of SAR236553/REGN727 administered as one single injection every two weeks in multiple treatment strategies and patient types, such as those who are at elevated cardiovascular risk, are unable to tolerate statin therapy, or have familial hypercholesterolemia.”  

“Lowering LDL-C remains the primary objective for the management of hypercholesterolemia and has been supported by numerous morbidity and mortality trials. Despite the existence of very effective LDL-C lowering therapies, many patients, such as those with heterozygous familial hypercholesterolemia or those with elevated cardiovascular risk who are unable to achieve their LDL-C goals,” said Professor Henry N. Ginsberg, M.D., Columbia University Medical Center, New York and Chair of the ODYSSEY Steering Committee. “Sustained PCSK9 blockade represents a potential new option to further reduce LDL-C on top of standard of care statin therapy and help patients achieve their LDL-C goals.”

The ODYSSEY programme will enrol more than 22,000 patients.  This includes over ten clinical trials evaluating the effect of SAR236553/REGN727 on the lowering of LDL cholesterol and an 18,000 patient cardiovascular outcomes (e.g., heart attacks, stroke) study. LDL-C is expected to be the p efficacy endpoint for regulatory filings.  The studies will be conducted in clinical centres around the world including the United States, Canada, Western and Eastern Europe, South America, Australia and Asia. Studies are currently enrolling patients with familial hypercholesterolemia or elevated cardiovascular risk, as well as patients unable to tolerate statin therapy.

“We believe that Regeneron’s expertise in antibody discovery and development, combined with Sanofi’s experience in clinical development and self-injectable delivery systems, will be an advantage as we work to bring this important new therapy to patients who are unable to reach their LDL-C goals with traditional lipid-modifying therapies as quickly as possible,” said George D. Yancopoulos, M.D., Ph.D., chief scientific officer of Regeneron and president of Regeneron Research Laboratories.

In parallel, Sanofi announced the creation of a dedicated PCSK9 Development & Launch Unit. Jay Edelberg, M.D., Ph.D. has recently been appointed as Head of the Development & Launch Unit, reporting to Elias Zerhouni, president, Global R&D and Hanspeter Spek, president, Global Operations, Sanofi. The creation of a dedicated unit for this new PCSK9 inhibitor underscores Sanofi’s commitment to develop this potential first-in-class therapeutic agent.

PCSK9 is known to contribute to circulating LDL-C levels, as it binds to LDL receptors resulting in their degradation so that fewer are available on liver cells to remove LDL-C from the blood.  Moreover, traditional LDL-lowering therapies such as statins actually stimulate the production of PCSK9, which limits their own ability to lower LDL-C.  Inhibiting the PCSK9 pathway is therefore a potentially novel mechanism for lowering LDL-C.

SAR236553/REGN727, created using Regeneron’s VelocImmune technology, is a fully human monoclonal antibody directed against PCSK9, administered via subcutaneous injection.  By inhibiting PCSK9, a determinant of circulating LDL-C levels in the blood, SAR236553 / REGN727 increases the number of free LDL receptors which can clear circulating LDL-C from the bloodstream.  
SAR236553/REGN727 has been studied in three phase 2 clinical studies: two in patients with primary hypercholesterolemia and one in patients with heterozygous familial hypercholesterolemia (heFH). In the primary hypercholesterolemia trials treatment with different dose regimens of SAR236553/REGN727 on top of statin therapy significantly reduced LDL-C from baseline by 40% to 72% over the 8 or 12-week treatment period.  A third Phase 2 study was in patients with HeFH whose LDL-C levels remained elevated despite statin therapy with or without ezetimibe. Across the four tested doses of SAR236553/REGN727 for up to 12 weeks, patients achieved a mean reduction in LDL-C from baseline of 28% to 68%. In the phase 2 programme, injection site reactions were the most common adverse events with SAR236553/REGN727. Rare cases of hypersensitivity reaction were also reported.   There were five serious adverse events (SAE) in the active treatment arms (1.8%, 5/275) and two SAEs in the placebo groups (2.6%, 2/77).

The phase 3 ODYSSEY programme will include over ten clinical trials designed to test the efficacy and long-term safety of SAR236553/REGN727 both as monotherapy, and in combination with other lipid-lowering agents. ODYSSEY will enrol several patient populations including patients with heFH who are inadequately controlled by current lipid-modifying therapy, and high cardiovascular risk patients with primary hypercholesterolemia.  The primary efficacy parameter will be LDL-C; however, multiple lipid parameters will be evaluated.  The global phase 3 programme will be conducted across more than 2000 study centers across the United States, Canada, Western and Eastern Europe, South America, Australia and Asia.  

The phase 3 ODYSSEY programme will include the following studies:

ODYSSEY FH I, FH2 and HIGH FH: The primary objective of these three studies is to demonstrate the efficacy and safety of SAR236553/REGN727 as add-on therapy in patients with heFH who are not adequately controlled with their lipid-modifying therapy.

ODYSSEY COMBO I and COMBO II: The primary objective of these two studies is to demonstrate the safety and efficacy of SAR236553/REGN727 as an add-on therapy in patients with primary hypercholesterolemia at high cardiovascular risk who are not adequately controlled with their lipid-modifying therapy.

ODYSSEY MONO: The primary objective of this study is to demonstrate the safety and efficacy of SAR236553/REGN727 as monotherapy in comparison with ezetimibe in patients with primary hypercholesterolemia.

ODYSSEY ALTERNATIVE: The primary objective of this study is to demonstrate the safety and efficacy of SAR236553/REGN727 in comparison with ezetimibe in patients with primary hypercholesterolemia who are unable to tolerate statins.

ODYSSEY OPTIONS I and OPTIONS II: The primary objective of these studies is to evaluate the safety and efficacy of SAR236553/REGN727 as an add-on therapy in   patients with primary hypercholesterolemia at high cardiovascular risk or with heFH who are not adequately controlled on statins, in comparison to several second line lipid lowering strategies.

ODYSSEY LONG TERM: The primary objective of this study is to evaluate the long-term safety and tolerability of SAR236553/REGN727 in patients with hypercholesterolemia at high cardiovascular risk or patients with heFH inadequately controlled with their current lipid-modifying therapy.

In addition, the ODYSSEY programme will also include ODYSSEY OUTCOMES, a Phase 3 cardiovascular outcomes trial which will enroll about 18,000 patients and evaluate the effect of SAR236553/REGN727 on the occurrence of cardiovascular events.