Sanofi and Regeneron Pharmaceuticals Inc. has reported additional positive results from a phase II trial of SAR236553/REGN727 (Study 1003, NTC01266876) in patients with heterozygous familial hypercholesterolemia (heFH). SAR236553 / REGN727 is a subcutaneously administered, fully-human antibody targeting PCSK9 (proprotein convertase subtilisin/kexin type 9) in clinical development.

The results from this study were published online in The Lancet and also presented at a late-breaking oral session at the 80th European Atherosclerosis Society Congress (EAS) in Milan, Italy. Positive, top-line results from this study were announced in November 2011.

The trial randomized 77 patients with heFH whose LDL-cholesterol (LDL-C) levels remained uncontrolled on statin therapy with or without ezetimibe. Across the four different dosing regimens tested, patients receiving SAR236553 / REGN727 for 12 weeks achieved a mean LDL-C reduction  from baseline of 28.9 per cent to 67.9 per cent, compared to 10.7 per cent in patients receiving placebo (p<0.05 ). In addition, in the most intense dose regimen tested where the greatest LDL-C reduction was observed (150 milligrams [mg] every two weeks), 93.8 per cent of patients achieved LDL-C levels lower than 100 mg/dL (2.59 mmol/L), compared to 13.3 per cent of patients on placebo, and 81.3 per cent reached LDL-C levels lower than 70 mg/dL (1.81 mmol/L), compared to none on placebo.

There were no serious adverse events (SAE) on active treatment, while a single SAE was recorded for a patient in the placebo group. There were no elevations in liver function tests (LFT) >3 times the upper limit of normal (ULN) and no cases of elevated creatinine kinase (CK) were reported. The most common adverse event reported was injection-site reaction.

“Heterozygous familial hypercholesterolemia is a common, serious, and often undiagnosed cause of early heart disease. There remains a high degree of unmet need in these patients as a large percentage are unable to reach optimal LDL-C goals despite being on maximal lipid-lowering therapy,” said Evan A Stein, MD, PhD, director of the Metabolic and Atherosclerosis Research Centre in Cincinnati, Ohio, and Principal Investigator of the study. “These data suggest that SAR236553 / REGN727 may provide a new option, on top of existing therapies, to lower LDL-cholesterol and finally reach LDL-C goals for these difficult-to-treat patients.”

Sanofi and Regeneron also announced that based on discussions with the US and European regulatory authorities, they intend to initiate a global phase III programme with SAR236553 / REGN727 in June. This will be the first phase III programme of an investigational drug targeting PCSK9.

“These data, along with recently presented data in patients with hypercholesterolemia, further support our belief that blocking PCSK9 with our antibody has the potential to offer a novel mechanism for lowering LDL-cholesterol in a broad range of patients,” said George D Yancopoulos, MD, PhD, chief scientific officer of Regeneron and president of Regeneron Laboratories.

Dr Elias Zerhouni, president, Global Research & Development, Sanofi, added: “Our global phase III programme will include patients with high unmet medical need, such as patients with familial hypercholesterolemia or with elevated cardiovascular risk who cannot reach their LDL-cholesterol goals with current standard therapies. The programme reflects our excitement and commitment to develop this potential therapeutic option for these patients.”

PCSK9 is known to be a determinant of circulating LDL-C levels, as it binds to LDL receptors resulting in their degradation so that fewer are available on liver cells to remove excess 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. Blocking the PCSK9 pathway is therefore a potentially novel mechanism for lowering LDL-C.

SAR236553/REGN727 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 bind to circulating LDL-C and clear it from the bloodstream. SAR236553 / REGN727 was created using Regeneron’s VelocImmune technology.

Study 1003 was a randomized, double-blind, placebo-controlled, dose-finding study in patients with heFH. The primary objective of the trial was to assess the efficacy of various subcutaneous doses and dosing regimens of SAR236553 / REGN727 on LDL-C in patients with heFH.

HeFH is an inherited disease that is characterized by very high LDL-C levels and familial patterns of increased risk of premature coronary artery disease and heart disease-related death due to these elevated LDL-C levels. The majority of these patients have inherited abnormalities in the gene for the LDL receptor. This results in a decreased ability to clear LDL-C from the blood and consequently leads to high levels of LDL-C in the blood that can accelerate the initiation and progression of atherosclerosis. As a result of the severe elevations in LDL-C, many of these patients cannot reach treatment goals with existing therapies.

Sanofi, a global and diversified healthcare leader, discovers, develops and distributes therapeutic solutions focused on patients’ needs. It 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.

Regeneron is a fully integrated biopharmaceutical company that discovers, invents, develops, manufactures, and commercializes medicines for the treatment of serious medical conditions.