It will be the moment of truth for the expensive new cholesterol drugs known as PCSK9 inhibitors.
Next month we will learn much more about the PCSK9 inhibitor class of cholesterol drugs. A lot of the remaining uncertainty about the efficacy— or lack of efficacy— of these drugs will be resolved when a large cardiovascular outcomes trial (CVOT), the ODYSSEY Outcomes trial, is presented in Orlando, Florida at the annual meeting of the American College of Cardiology on March 10.
The bottom line is that most observers believe that the trial may well move the needle at least slightly in favor of the new drugs, but there is only modest expectations that the results will be convincing enough to justify the expense of putting large numbers of new patients on the drugs.
Background
The PCSK9 inhibitor class of cholesterol lowering drugs had been the subject of enormous hype and expectations— until they actually came on the market and fizzled. One reason for their poor performance is that insurance companies, terrified by the high cost of the drugs, raised nearly insuperable barriers to reimbursement. (The drugs carry a list price of more than $14,000 per year but are often discounted to around $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.
Sales figures tell the story. Regeneron and Sanofi, who make the drug used in ODYSSEY, alirocumab (Praluent), reported worldwide sales in 2017 of only $194 million, $131 million of which was in the U.S. Amgen's evolocumab (Repatha) did slightly better, recording worldwide sales in 2017 of $319 million, $225 million of which was in the U.S.
There has been a very broad consensus that widespread use of these drugs won't happen without very convincing evidence that the drugs can deliver a statistically and clinically significant improvement in outcomes. We already know the drugs lower LDL cholesterol in a big way. Now we need to know how this translates in the real world. That is why everyone in the field has been intensely focused on the big CVOT studies.
The first CVOT, FOURIER, published and presented last year, compared evolocumab (Repatha, Amgen) with placebo. Although FOURIER was a successful trial in that it reached its primary endpoint the results were not strong enough to give a significant boost to sales. (The primary end point was reduced by 15%, from 11.3% (1,563 patients) to 9.8% (1,344 patients) (hazard ratio 0.85, CI 0.79-0.92, p <0.001)).
ODYSSEY Outcomes will be the second PCSK9 inhibitor CVOT. The trial will compare alirocumab (Praluent, Sanofi/Regeneron) with placebo in 18,000 patients with a recent (1-12 months) heart attack (acute MI) or unstable angina. The primary endpoint is the time to first occurrence of coronary heart disease death, acute myocardial infarction, hospitalization for unstable angina, or ischemic stroke.
ODYSSEY versus FOURIER
The two trials are broadly similar but there are important differences in the details that may mean that ODYSSEY will have a slightly better chance of delivering a more convincingly positive result than FOURIER. Much of the following analysis derives from comments received from Sanjay Kaul (Cedars-Sinai) and comments on Twitter from Sek Kathiresan (Broad Institute).
"For ODYSSEY to move the needle for PCSK9 inhibitors, it must show a clear-cut mortality benefit or clinically important reduction in clinically relevant nonfatal MI (spontaneous MIs defined by large biomarker elevation and/or ECG changes) or stroke (large disabling stroke) events," said Kaul.
If ODYSSEY does turn out to be more positive than FOURIER it will demonstrate the somewhat counter-intuitive principle that bigger trials are not always better trials. Some observers believe 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 27,000 patients (compared with ODYSSEY's 18,000). The idea here was to accumulate more endpoint events in as short a period of time as possible. As a result Amgen was able to report results one year before the competition. The downside is that the larger number of events may have occurred before the beneficial effects of the drug had time to emerge. (On average it takes about 2 years for the clinical benefits of cholesterol lowering drugs to emerge.) In other words, although it was originally intended to highlight the effects of the drug FOURIER may possibly have hidden or obscured these benefits.
We don't know yet how long the followup time will be in ODYSSEY, but it will almost certainly be longer than the 26 month median followup in FOURIER. Kathiresan expects that ODYSSEY followup will be 3 years. The 10 months longer followup could be an important difference. "Treatment benefits related to LDL-lowering appear to be greater with longer follow-up," said Kaul.
Both Kaul and Kathiresan say that LDL levels will be more tightly controlled in ODYSSEY than in FOURIER. "ODYSSEY is a true treat-to-target trial with achieved LDL targets of <50 mg/dL," said Kaul. He noted that a quarter of the patients in FOURIER had LDL levels over 46 mg/dl. Kathiresan anticipates that the median LDL level of 90 mg/dl will be cut in half in the active treatment group in ODYSSEY.
"If lower LDL levels are associated with greater treatment benefit, then ODYSSEY is likely to show a greater risk reduction," said Kaul. However, he noted, "more subjects in ODYSSEY will be on high-intensity statin background therapy (90% vs 70%), which might dilute between-group LDL differences, and possibly attenuate risk reduction." On the other hand, the patient population in ODYSSEY is higher risk than the FOURIER patient population.
There is a potentially important difference in the primary endpoints of the studies. The ODYSSEY primary endpoint is CHD death, nonfatal MI, fatal or nonfatal ischemic stroke or hospitalization for unstable angina. In FOURIER the primary endpoint was CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina or coronary revascularization." Kaul notes that the treatment benefit in FOURIER was driven by an absolute reduction in revascularization of 1.5%, in nonfatal MI of 1.2%, and in nonfatal stroke of 0.4%, with no benefit in CV death or hospitalization for unstable angina. The ODYSSEY endpoint excludes revascularization, so "the bar is set a little higher," said Kaul. But it should also be noted that revascularization is often considered a soft endpoint, which means that a significant result in ODYSSEY might carry a little extra weight.
Kaul said that the "bottom line" is that if there is no mortality benefit or "substantial benefit on clinically important nonfatal events" then there will be no traction for alirocumab. Kathiresan applied combined data from the statin trials (the CTT analysis) to calculate that there would a significant 20% reduction in the primary endpoint and a significant reduction in CHD mortality but no reduction in all-cause mortality.
Finally, it should be noted that the trial was not stopped early and there has been no early announcement of top line results, either negative or positive. During a February 8 conference call the CEO of Regeneron said that the trial had not yet been unblinded, so it is still possible that a press release announcing a materially significant result one way or another could come out before the March 10 presentation.
