Now it is alirocumab’s turn. Sanofi and Regeneron Pharmaceuticals released details on four key trials from the pivotal Odyssey programme for the phase III drug, showing it to be a strong competitor to Amgen’s evolocumab.
Eager to prove its worth in ever broader populations of heart disease patients, investigators of the 2,000-patient Odyssey Long Term trial released a retrospective analysis indicating that alirocumab showed a long-term benefit in preventing cardiovascular deaths and complications. Sanofi and Regeneron will need to show such positive outcomes data to stimulate broad adoption of the antibody, although regulators and physicians no doubt will give more weight to the results from the prospectively designed Odyssey Outcomes trial.
Pulling the curtain back
Alirocumab and its counterparts that act on the proprotein convertase subtilisin-like kexin type 9 (PCSK9) pathway are known as potent cholesterol-lowering agents. However, because statins have shown themselves as effective first-line pills for reducing low-density lipoprotein (LDL), the so-called “bad” cholesterol, the patients for which the PCSK9 drugs will be approved has been a big unknown. Cardiologists and investors alike have been trying to come to grips with the size of this population, an effort complicated by a neurocognitive signal revealed earlier this year.
The ESC meeting in Barcelona was the first chance for alirocumab’s sponsors to offer a broad look at phase III data for the antibody, which prevents PCSK9’s natural inhibition of LDL metabolism. Data were detailed from four trials: Odyssey Combo, in which alirocumab and Zetia were used as a dual therapy in patients unable to control LDL on a maximum statin dose; Odyssey FH I and II, two separate trials in patients with heterozygous familial hypercholesterolaemia; and the most important one commercially, Odyssey Long Term, a test in more than 2,300 patients as an add-on to statins and other lipid-lowering thearapies over more than a year of treatment.
Given the known potency of PCSK9s, the fact that alirocumab achieved LDL reductions over baseline of as much as 61% - the mark hit in Odyssey Long Term – is not a big surprise. Should their safety be confirmed, they likely are headed for approval sometime next year in limited groups of patients who have not managed to control their LDL levels using statins like Pfizer’s Lipitor, at a minimum.
The question that has hung over the PCSK9 drugs – a class that includes evolocumab and Pfizer’s bococizumab – will be in which population they are used outside of patients with genetically elevated LDL and patients unable to tolerate statins. This is the reason all the PCSK9 agents that have reached phase III are in the midst of recruiting massive outcomes trials that will not read out for several years, driven by ever-tightening clinical guidelines and regulatory requirements.
Thus, the release today of a retrospective outcomes analysis from Odyssey Long Term is a very intriguing hint as to their potential preventive benefit. Over a mean treatment duration of 65 weeks, patients taking alirocumab plus a maximum tolerated dose of statin and other lipid-lowering therapies were 54% less likely to have suffered from cardiovascular death, a non-fatal myocardial infarction or other heart-related complications.
Investigators shied away from calling that finding a categorical win – regulators most likely will want more robust data from a prospective analysis before allowing Sanofi and Regeneron to make such a claim on alirocumab’s label – but did say it was a good start.
“What this data tells us is that we’re on the right track,” said Jennifer Robinson, an internal medicine professor at the University of Iowa who presented the Odyssey Long Term results. “It’s not the definitive answer. We need the outcomes trials to validate this data and also to establish the long-term safety of these drugs.
“We can’t approve it and give it routinely to everybody after a cardiovascular event,” Dr Robinson said. “That’s not what this data tells us.”
Coming soon to a doctor’s office near you
The safety, of course, remains a question mark. There was a numerical difference in neurocognitive events between the two arms – 18 of 1,550 in the alirocumab arm vs four of 788 in the placebo arm. This may be a finding that will not please investors thrown by this disclosure earlier this year (Second time around, something else for PCSK9 class to worry about, March 10, 2014).
The event rate was fairly low – 1.2% vs 0.5% – leading Dr Robinson to argue that there was “no imbalance,” but given it is a new drug class to be used on a long-term basis, regulators are likely to give it a long look.
Alirocumab has given the sector an exciting preview of its potential in a broad population of patients unable to control their cholesterol. The immediate outlook of this class should firm up in coming months as regulatory filings proceed – Amgen’s submission of evolocumab to the FDA last week is a sign of how imminent their launch may be.