PARIS—October and November have been good to Sanofi and Tarrytown, N.Y.-based Regeneron Pharmaceuticals Inc., as two of their partnerships yielded positive Phase III clinical trial news. First came word that the ODYSSEY MONO trial with monoclonal antibody alirocumab met its primary efficacy endpoint and that, as a monotherapy, alirocumab reduced low-density lipoprotein (LDL) cholesterol three times more than ezetimibe. Next up was the SARIL-RA-MOBILITY Phase III clinical trial of monoclonal antibody sarilumab in adult patients with active rheumatoid arthritis who were inadequate responders to methotrexate therapy, which met all three co-primary endpoints.
For Regeneron, this news adds to the momentum of its commercial success with the eye drug Eylea for wet age-related macular degeneration, and for Sanofi, it means good news after recent months brought setbacks in its oncology research and development programs.
Alirocumab targets proprotein convertase subtilisin/kexin type 9 (PCSK9), which is known to be a determinant of circulating LDL levels, binding to LDL receptors and resulting in their degradation so that fewer are available on liver cells to remove excess LDL cholesterol (LDL-C) from the blood. As Sanofi and Regeneron note, traditional LDL-lowering therapies such as statins stimulate the production of PCSK9, an effect that can actually inhibit their ability to lower LDL-C, making blockage of the PCSK9 pathway a potentially novel mechanism for lowering LDL cholesterol.
In the top-line results reported for ODYSSEY MONO in mid-October, alirocumab reportedly reduced LDL-C 47.2 percent by week 24, compared to 15.6 percent for patients randomized to ezetimibe. In the trial, which employed a dose increase for patients who did not achieve an LDL-C level of 70 mg/dL, the majority of patients remained on the initial low dose of alirocumab of 75 mg.
“There are still millions of people around the globe who have poorly controlled LDL-C,” noted Dr. George D. Yancopoulos, chief scientific officer of Regeneron and president of Regeneron Laboratories. “Three years ago, our Phase I trials generated the first clinical evidence that blocking PCSK9 could markedly lower cholesterol levels in humans. Today, it is very gratifying to be able to report the first Phase III data for this promising potential new class of lipid-lowering agents.”
Dr. Jay Edelberg, head of the PCSK9 Development and Launch Unit in the Sanofi Group, is “excited with the findings from the first Phase III trial with alirocumab,” noting that while the majority of his company’s clinical program is investigating alirocumab in combination with lipid-lowering therapies, “these monotherapy results are encouraging.”
Many analysts have been positive about the potential for alirocumab and other PCSK9 inhibitors. For example, Robert W. Baird & Co. analysts have predicted annual revenues of $717 million for alirocumab by 2017, and Alistair Campbell of Berenberg Bank, looking farther forward, thinks that alirocumab could exceed sales of $3 billion by 2025.
On Nov. 22, Sanofi and Regeneron said of the SARIL-RA-MOBILITY study that treatment with sarilumab—reportedly the first fully human anti-interleukin-6 receptor (IL-6R) monoclonal antibody—in combination with methotrexate improved rheumatoid arthritis signs and symptoms as well as physical function, and inhibited progression of joint damage.
According to Sanofi and Regeneron, both sarilumab groups in the study showed clinically relevant and statistically significant improvements compared to the placebo group in all three co-primary endpoints. This included improvement in signs and symptoms of rheumatoid arthritis at 24 weeks, as measured by the American College of Rheumatology score, and the sarilumab 200 mg and sarilumab 150 mg groups combined with methotrexate showed 66-percent and 58-percent improvement, respectively, compared to 33-percent for placebo with methotrexate.
“IL-6 blockade is emerging as an important therapeutic approach for rheumatoid arthritis,” said Dr. Neil Graham, vice president of program direction, immunology and inflammation for Regeneron.
Participants also showed improvement in physical function, as measured by change from baseline in the Health Assessment Question-Disability at week 16, and inhibition of progression of structural damage at week 52, as measured by the change in the modified Van der Heijde total Sharp score.
“Irreversible joint damage can be a consequence for patients suffering from rheumatoid arthritis, and this is accompanied by reduced physical function in these patients,” noted Tanya M. Momtahen, sarilumab global project head for Sanofi. “This remains a major concern for rheumatoid arthritis patients. We are encouraged by these Phase III results and the impact sarilumab demonstrated on inhibition of progression of structural damage assessed radiographically in this study.”
Since 2007, Regeneron has collaborated with French pharma giant Sanofi to discover, develop, manufacture and commercialize fully human monoclonal antibodies utilizing the New York company’s VelociSuite set of technologies. In the first three years of the collaboration, five antibodies have entered clinical development, Regeneron notes on its website. The collaboration was expanded in 2009, setting an ambitious goal of advancing 20 to 30 additional antibodies into clinical development by 2017. Under the terms of the expanded collaboration, Sanofi has agreed to provide $160 million per year in research funding through 2017.
Sanofi has the exclusive option to co-develop each drug candidate in the collaboration portfolio. Development costs are to be shared between the two companies, with Sanofi funding development costs up front and Regeneron reimbursing half of the development costs from its share of future profits. Although Sanofi will take the lead in commercialization activities, Regeneron will have the right to co-promote all collaboration products worldwide. In the United States, profits will be shared equally, while outside the United States, profits will be split on a pre-determined sliding scale.
