Sanofi, Regeneron say PCSK9 inhibitor alirocumab meets main goal of nine late-stage studies

Sanofi and Regeneron Pharmaceuticals said Wednesday that nine Phase III studies of the experimental PCSK9 inhibitor alirocumab in people with hypercholesterolaemia met their primary endpoint of significantly reducing LDL cholesterol versus placebo or active comparator. Elias Zerhouni, president of global R&D at Sanofi, said "the robust data from these studies in more than 5000 patients is the basis of our global regulatory submissions, which we expect in the US and EU by year end."

The ongoing ODYSSEY clinical programme, which includes studies comparing alirocumab to Merck & Co.'s Zetia (ezetimibe) or Pfizer's Lipitor (atorvastatin), enrolled patients with heterozygous familial hypercholesterolaemia, those with high or very high cardiovascular risk and patients with a history of statin intolerance. The companies noted that nearly all patients received alirocumab in addition to standard-of-care lipid-lowering therapy. Sanofi and Regeneron said the mean percent reduction in LDL cholesterol from baseline at 24 weeks among alirocumab-treated patients in all nine studies "was consistent with results seen in previous alirocumab trials," such as the Phase III ODYSSEY MONO study reported last October, while the therapy was "generally well tolerated" and serious adverse events and deaths were "generally balanced" across the treatment groups.

Specifically, the ODYSSEY LONG TERM trial assessed the efficacy and safety of alirocumab compared to placebo in 2341 patients treated with statins, with some receiving additional lipid-lowering therapies. The companies stated that besides meeting the primary efficacy endpoint, a post-hoc analysis found alirocumab was associated with a lower rate of adjudicated major cardiovascular events versus placebo. Sanofi and Regeneron specified that the ongoing 18 000-patient ODYSSEY OUTCOMES trial is evaluating alirocumab's potential to demonstrate cardiovascular benefit.

In addition, the ODYSSEY ALTERNATIVE study randomised patients with a history of intolerance to at least two statins to receive alirocumab, Zetia or Lipitor. The companies said alirocumab met the study's primary endpoint of a greater percent reduction in LDL cholesterol levels compared to Zetia, with no significant difference in discontinuation rates due to adverse events observed among the three treatment arms. More detailed data will be presented at upcoming medical congresses.

In March, the FDA requested that Sanofi and Regeneron determine whether any neurocognitive adverse events occurred in the development programme for alirocumab, particularly in longer-term studies. At the time, the drugmakers indicated that they did not know of any neurocognitive safety signals associated with alirocumab. The companies also could not say how the agency became aware of such potential issues with PCSK9 inhibitors or whether the events are associated with PCSK9 inhibitors as monotherapy or when combined with statins or other cholesterol-lowering therapies.

Commenting on the ODYSSEY development programme, analysts including Deutsche Bank's Robyn Karnauskas suggested the results are a "major positive" that could give Sanofi and Regeneron an advantage over Amgen. Earlier this year, Amgen revealed that it plans to submit its investigational PCSK9 inhibitor evolocumab for US regulatory approval by the end of 2014 after reporting that the therapy significantly reduced LDL cholesterol levels in patients with statin intolerance.

According to analysts, PCSK9 inhibitors may eventually generate annual sales of $3 billion or more, if approved, with some industry observers estimating alirocumab could amass revenue of 773 million euros ($1 billion) by 2019. For related analysis, see ViewPoints: Standing out from the crowd – as positive data flow continues, can any of the leading PCSK-9 inhibitors differentiate themselves?

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