Sanofi has stuck a nose out front in the race to get the first of a new generation of lipid-lowering drugs to market. Alirocumab scored impressive results in the first trial to report from its massive phase III programme, showing it was significantly better than Zetia in reducing low-density cholesterol.
Scoring a win over Zetia in monotherapy is admittedly a low bar, so whether it can meet the billion-dollar expectations of investors will only become clear during 2014 as the French group reports trials covering thousands of patients in a variety of settings – including as an add-on to potent statins. Still, it is the best indication of the potential of Sanofi’s most valuable pipeline drug, and as such should lend some confidence that the company has reversed some of its R&D woes.
The PCSK9 inhibitor class to which alirocumab (REGN727/SAR236553) belongs assists in the metabolism of low-density lipoprotein (LDL), or “bad” cholesterol, in the liver. PCSK9, or anti-proprotein convertase subtilisin-like kexin type 9, is an enzyme that binds with LDL-C receptors; blocking its activity with an antibody should be a mechanism toward reducing LDL levels in circulating blood and consequently reduce the formation of atherosclerotic lesions. Hopes are especially high for the class as an add-on to statin therapy as they are known to stimulate PCSK9 production (AHA – PCSK9 inhibitors continue to impress, November 7, 2012).
The Odyssey Mono trial detailed today found that alirocumab reduced LDL levels by 47.2%, compared with 15.6% for Zetia, a finding that was highly significant at a p value of less than 0.0001. That finding for Zetia was in line with earlier clinical trials of the Merck & Co cholesterol absorption inhibitor; as a monotherapy, the clinical trials submitted to regulators achieved LDL reductions of 18%.
As Zetia monotherapy is not viewed as a first-choice cholesterol lowering strategy in most cases – reserved mostly for patients intolerant to or contraindicated for statins – the commercial potential of this population is limited. But as the first trickle of what will be a revealing data flow, Odyssey Mono should have many enthusiastic to see more from alirocumab.
Shares in Sanofi were largely unchanged today. Partner Regeneron Pharmaceuticals, which outlicensed the antibody to Sanofi in 2007, rose 4% to $301.30 in mid-morning trading.
For one, the likely sweet spot for the PCSK9-inhibitor class will, as with Zetia, be as an add-on to statin therapy, particularly for those who do not achieve optimal LDL levels on statins alone. For another, the 47.2% reduction compares favourably to statin monotherapy – the once-a-month subcutaneous injection is in the range of a 10mg daily dose of Crestor.
As a 106-patient trial, no firm conclusions should be drawn from Odyssey Mono, of course. Sanofi is not in a hurry to release more data as it stated it would present details at a medical meeting in 2014. This rules out the American Heart Association meeting next month in Dallas, Texas.
The remainder of the 25,000-patient programme will reveal alirocumab’s real worth – including the Odyssey Combo I and II trials, comprising nearly 1,000 patients altogether, which will compare it as an add-on to statin therapy against placebo and Zetia, respectively, in high cardiovascular risk patients. Those two trials should read out in the middle of 2014.
Also being targeted are patients with heterozygous familial hypercholesterolaemia, as well as evaluations of where alirocumab fits into various medication switching strategies when initial statin therapy fails to achieve LDL control. And of course, there are the long-term safety and outcomes trials. The biggest of these, the 18,000-patient Odyssey Outcomes trial in acute coronary syndrome, will not read out until 2018.
At any rate, getting initial phase III data on the books puts Sanofi in the driving seat ahead of Amgen, Pfizer and Roche. Amgen’s AMG145 (evolocumab) has an equally impressive phase III programme – indeed, even bigger than alirocumab – but the other companies have yet to even initiate pivotal trials. Among the more eagerly awaited pieces of data is Pfizer’s efforts to turn its intravenous formulation of RN316 into a commercially viable subcutaneous product (Upcoming events: Pfizer’s anti-PCSK9 needs a subcutaneous win, July 4, 2013).
Its position is certainly reflected in consensus forecasts. EvaluatePharma puts sales at $617m in 2018, giving it a net present value of $2.15bn, or a not-insignificant 2% of Sanofi’s market capitalisation. AMG145 figures in a less-weighty player at $252m in sales and $1.07bn in NPV, 1% of Amgen’s market cap. Analysts have yet to put any forecast of consequence on the remaining pipeline products.
Odyssey Mono confirms the lead that alirocumab had been assumed to have, but as an alternative to Zetia monotherapy it would not justify the millions of R&D dollars that is being poured into the project. Sanofi really needs it prove its worth as a more widely used cholesterol-lowering agent.
|Odyssey Mono||Alirocumab vs Zetia in patients with hypercholesteroleamia||NCT01644474|
|Odyssey Combo I||Alirocumab vs placebo as add-on to statins in patients with hypercholesterolaemia||NCT01644175|
|Odyssey Combo II||Alirocumab vs Zetia as add-on to statins in patients with hypercholesterolamia||NCT01644188|
|Odyssey FH I||Alirocumab vs placebo as add-on to lipid-modifying therapy in patients with heterozygous familial hypercholesterolaemia||NCT01623115|
|Odyssey FH II||Alirocumab vs placebo as add-on to lipid-modifying therapy in patients with heterozygous familial hypercholesterolaemia||NCT01709500|
|Odyssey Alternative||Alirocumab vs lipid-modifying therapies in patients with primary hypercholesterolaemia and moderate, high, or very high cardiovascular risk who are intolerant to statins||NCT01709513|
|Odyssey Outcomes||Cardiovascular outcomes after acute coronary syndrome during treatment with alirocumab||NCT01663402|