Sanofi and Regeneron achieved a modest victory with the much anticipated ODYSSEY Outcomes trial of its cholesterol lowering drug Praluent (alirocumab). The trial met its primary endpoint and even reported a significant improvement in all-cause mortality. But the mortality finding has an asterisk attached to it and it is far from clear whether the overall trial is positive enough to significantly alter the cost-benefit concerns that have so far been the chief barrier to wider use of alirocumab and its close cousin, Amgen’s PCSK9 inhibitor evolocumab (Repatha).
The ODYSSEY Outcomes trial was presented on Saturday morning in Orlando, Florida at the annual meeting of the American College of Cardiology.
ODYSSEY compared alirocumab (Praluent, Sanofi/Regeneron) with placebo in 18,924 patients with a recent (1-12 months) heart attack (MI) or unstable angina. The trial met its primary endpoint, reducing the primary endpoint (the combination of MI, stroke, death from coronary heart disease, or unstable angina requiring hospitalization) by 15% (HR=0.85, CI: 0.78-0.93, p=0.0003).
Individual components of the primary endpoint:
- CHD death: 2.2% for alirocumab versus 2.3%, p=0.38
- Non-fatal MI: 6.6% versus 7.6%, HR 0.86 (CI 0.77 – 0.96), p = 0.006
- Ischemic stroke: 1.2% versus 1.6%, HR 0.73 (CI 0.57 – 0.93), p = 0.01
- Unstable angina: 0.4% versus 0.6%, HR 0.61 (CI 0.41 – 0.92), p = 0.02
The investigators also reported a significant reduction in overall mortality, from 4.1% in the placebo group to 3.5% in the alirocumab group (HR=0.85; CI: 0.73-0.98, p = 0.026). Because, in accordance with the predetermined statistical analysis plan, the reduction in CHD mortality did not achieve statistical significance, the reduction in overall mortality was considered an observational finding. As a result, this means the company will not be able to make a mortality reduction claim without qualification. Sanjay Kaul (Cedars-Sinai) commented that the mortality finding should not be considered robust.
There will almost certainly be a significant amount of discussion about the subgroup of patients who had high levels of LDL at baseline (100 mg/dl or above). Nearly all the benefit in the trial was observed in this subgroup. MACE was reduced by 24%, from 14.9% in the placebo group to 11.5% in the alirocumab group (HR=0.76, CI 0.65-0.87) and overall mortality by 29% (HR=0.71, CI 0.56-0.90). Regeneron and Sanofi estimate that about 1.3 million people in the US fall into the subgroup of ACS patients with persistent LDL levels above 100 mg/dl despite taking statins.
Another important finding is that no new safety issues emerged in the trial. In particular, there was no excess of either diabetes or neurocognitive side effects in the trial, thereby helping to settle an important lingering question about the PCSK9 inhibitors. However, as expected, patients in the alirocumab group did have more injection site reactions.
FOURIER and ODYSSEY
ODYSSEY will likely be seen as both consistent with FOURIER, the earlier cardiovascular outcomes trial (CVOT) with Amgen’s evolocumab, and an incremental advance on that trial. Despite differences in patient populations and trial design, both trials resulted in a significant but modest 15% reduction in the primary endpoint. But the ODYSSEY mortality results and the subgroup results in patients with baseline LDL levels over 100 mg/dl appear to confer a decided advantage for ODYSSEY. The results will likely be seen as confirming the view that Amgen may have shot itself in the foot with FOURIER. In an attempt to gain a competitive advantage over Sanofi/Regeneron, Amgen increased the size of FOURIER to accumulate more endpoint events in as short a period of time as possible. As a result FOURIER was able to report results one year before ODYSSEY. But the downside is that FOURIER may have been unable to reflect the full benefit of evolocumab, since many events in the trial occurred before the beneficial effects of the drug had time to emerge.
It is not at all clear whether the modest incremental benefit of ODYSSEY will lead to significantly increased uptake of the drug. Insurance companies have raised nearly insuperable barriers to reimbursement. (The drugs now have a list price of more than $14,000 per year but are usually discounted to about $9,000.) Many cardiologists have tried and failed to get these drugs approved for their high risk patients with persistently high cholesterol levels even after taking or failing to tolerate statins. ODYSSEY does not appear likely to substantially alter the cost benefit equation.
Some experts speculate that Regeneron and Sanofi will use the results of ODYSSEY to capture market share from Amgen. Regeneron and Sanofi reported worldwide alirocumab sales in 2017 of only $194 million, $131 million of which was in the US. Amgen’s evolocumab had worldwide sales in 2017 of $319 million, $225 million of which was in the US. Regeneron and Sanofi could also use the trial to try to expand the overall marketplace for PCSK9 inhibitors.
Gregory Schwartz (University of Colorado), the principal investigator of ODYSSEY, said he didn’t know if the results would be strong enough to alter concerns about cost. “It will be our peers that will decide this,” he said. The mortality finding is “fundamentally different,” because it matters to both physicians and patients. “With all the caveats of the nominal p value this is plausible and fits with decades of our understanding of the biology,” said Schwartz.
Milton Packer (Baylor Health) pointed out that the results will make it more difficult for companies to study new lipid lowering drugs, since the findings diminish the urgency to lower LDL cholesterol in patients with LDL levels below 100 mg/dl. ODYSSEY, he said, may represent the end of the campaign to consistently drive LDL levels ever lower.
Sanjay Kaul said that in his opinion, “the trial results do not move the needle for PCSK9 inhibitors! I don’t see how the trial results will encourage the payers to be more favorably disposed to this drug unless of course they are convinced/persuaded of the mortality benefit!!”
James Stein said that it “makes sense with everything we know from pathophysiology and other clinical trials” that “people with higher LDL may have benefited more.” He said that PCSK9 inhibitors are safe and effective but that “the challenge will be figuring out the subgroups of who benefits the most and convincing payers to cover this medication at its current price.”In the meantime,” said Stein, “I will continue to add ezetimbe to high dose statin and maximize lifestyle changes, reserving these wonderful new medications for those with the highest LDL values or highest risk. If their price were lower, however, it would be a no-brainer to use them much more. We have proven efficacy and safety in the medium term now, so cost is the major barrier.”