PCSK9 Inhibitors May Feel Effects Of FDA Judgment On IMPROVE-IT

Agency's decision on cardiovascular risk reduction claims for Merck's Zetia and Vytorin may serve as a regulatory barometer for the magnitude and robustness of effect that will be expected in outcomes studies for other LDL-C-lowering agents.

FDA's looming decision on efficacy labeling supplements for Merck & Co. Inc.'s Zetia (ezetimibe) and Vytorin (ezetimibe/simvastatin) could foreshadow the challenges that sponsors of PCSK9 inhibitors and other lipid-altering treatments will face in securing cardiovascular risk reduction claims based on large outcomes studies.

Merck is seeking claims based on the results of the 18,000-patient IMPROVE-IT trial, which demonstrated a modest but statistically significant 6% reduction in the risk of a major CV event with ezetimibe plus simvastatin compared to simvastatin alone.

Although the study results have been lauded by some experts as confirming the so-called LDL hypothesis – that lowering LDL-cholesterol by any means is clinically beneficial – the results were met with generally lackluster enthusiasm by an FDA advisory committee in December, which recommended against approval.

FDA action on the labeling supplements is expected in early 2016; Merck submitted the supplements in early April, which would put the user fee goal date in early February under a 10-month review timeline.

Looking beyond Zetia and Vytorin, the agency's decision may serve as a regulatory barometer for the magnitude and robustness of effect that will be expected in outcomes studies for other LDL-C-lowering agents.

FDA action on Merck's labeling supplements is anticipated in early February.

An FDA conclusion that the IMPROVE-IT data support risk reduction claims would mark the regulator's first affirmation of the LDL hypothesis for a non-statin agent and seemingly set a relatively modest threshold in terms of magnitude of benefit that must be demonstrated for other drugs.

If FDA does not believe the trial's results support a new claim, then it seems likely that sponsors conducting or planning outcomes studies of PCSK9 inhibitors and other lipid-altering agents will need to show far more robust data, both statistically and in magnitude of benefit, to support broad labeling claims and, perhaps, to ensure broad acceptance by payers as well.

In that case, the ongoing PCSK9 outcomes studies, one of which is expected to complete in 2016, would seem the next best chance for affirming the utility of LDL-C lowering as a surrogate endpoint to support approval.

"If the FDA does reject the application, in line with the advisory committee vote, it does confirm that they are being fairly firm about wanting a rigorous, meaningful benefit," said Peter Chang, principal scientific analyst at BioMedTracker.

FDA's regulatory decision on Zetia/Vytorin could also have commercial implications for the currently available PCSK9 inhibitors, Sanofi and Regeneron Pharmaceuticals Inc.'s Praluent (alirocumab) and Amgen Inc.'s Repatha (evolocumab).

If Merck's labeling claim is granted, payers would be more emboldened to require individuals to try ezetimibe first before moving to the more expensive, injectable PCSK9 therapies. In contrast, explicit rejection of a labeling claim could undercut payers' ability to require ezetimibe first, which could increase access to the new class of LDL-C-lowering medicines.

Swimming Against A Tide Of Negative Trials

IMPROVE-IT joins a long history of outcomes trials that have explored the connection between lipid parameters and CV risk.

While the CV benefit that comes with lowering LDL-C through statins has been demonstrated, the clinical benefit of affecting other lipid levels has not been confirmed.

Niacin and fenofibrate fell victim to outcomes trial failures after they were already on the market. In contrast, the high-profile flameout of several cholesteryl ester transfer protein (CETP) inhibitors, which act primarily by raising HDL-C but also exhibit LDL-C-lowering effects, has meant that all candidates in the class must prove themselves in outcomes trials ahead of approval (Also see "New Cholesterol Guidelines Follow Long History Of Failed Outcomes Trials" - Pink Sheet, 2 Dec, 2013.).

Ezetimibe, a cholesterol absorption inhibitor, also has been the subject of two unsuccessful studies: ENHANCE, which measured atherosclerosis progression, and SEAS, which looked at CV events in aortic stenosis patients.

Cumulatively, these trial failures have chipped away at confidence in the use of lipid changes as a surrogate for clinical benefit and have called into question whether lowering LDL-C through a mechanism other than a statin results in any added benefit.

American College of Cardiology/American Heart Association guidelines issued in 2013 strongly emphasize statins as a mainstay treatment and note the lack of evidence for use of other lipid-modifying drugs (Also see "Cholesterol Guidelines Look High And Low: Statin Market Extended At Both Ends" - Pink Sheet, 13 Nov, 2013.).

Is The LDL Hypothesis Now The LDL Principle?

With a slew of negative trials as a backdrop, there has been great interest in what light IMPROVE-IT would shine on the utility of LDL-C lowering as a surrogate for clinical benefit with non-statins.

This anticipation was acknowledged by FDA during the Endocrinologic and Metabolic Drugs Advisory Committee's Dec. 14 review of the landmark 10-year study.

"Many of us have awaited this trial for a long time," Division of Metabolism and Endocrinology Products Deputy Director James Smith said.

Merck said ezetimibe's benefit was consistent with that observed in the 2010 Cholesterol Treatment Trialists' meta-analysis of statin trials.

In IMPROVE-IT, treatment with the ezetimibe/simvastatin combination resulted in a 6.4% relative risk reduction of the primary composite endpoint for major CV events (HR 0.94; 95% CI: 0.89-0.99, p=0.016), and a 1.8% absolute risk reduction. The results were driven by a reduction in non-fatal myocardial infarctions and non-fatal strokes with ezetimibe compared to the simvastatin arm.

Merck said ezetimibe's CV benefit was consistent with that observed in the 2010 Cholesterol Treatment Trialists' meta-analysis of statin trials and extends the assessment of the relationship between LDL-C lowering and CV outcomes benefit to the lower ranges of LDL-C.

A New England Journal of Medicine editorial that accompanied publication of the IMPROVE-IT results in June said the data "help emphasize the primacy of LDL-cholesterol lowering as a strategy to prevent coronary disease. Perhaps the LDL hypothesis should now be considered the 'LDL principle.'"

Yet, the advisory committee's discussion showed that IMPROVE-IT may not provide the concrete proof for which everyone was searching.

At the meeting's outset, Smith sought to head off debate about the LDL hypothesis and instead focus the panel's attention on whether the IMPROVE-IT data support Merck's request for CV risk reduction claims. However, this did not stop some panelists from debating the merits of the hypothesis and the study's impact (see sidebar).

Ultimately, 10 of 15 committee members opposed approval of CV risk reduction claims for Zetia and Vytorin, with panelists generally questioning the clinical meaningfulness and statistical robustness of the IMPROVE-IT results (Also see "IMPROVE-IT Study: Negative Panel Review Leaves FDA With Tough Choice" - Pink Sheet, 21 Dec, 2015.).

However, committee members left the door open for a narrower indication or other language reflecting the efficacy data (Also see "Zetia, Vytorin CV Risk Reduction Claim Fails To Win FDA Panel Backing" - Pink Sheet, 14 Dec, 2015.).

Although IMPROVE-IT's LDL-C entry-level criteria were set relatively low to be consistent with treatment guidelines in effect at the time the study was designed, some panelists said ezetimibe likely would have demonstrated a more pronounced treatment effect had patients with higher baseline LDL-C levels been enrolled.

This takeaway from the panel review is expected to have design implications for future outcomes studies, as Esperion Therapeutics Inc. highlighted at the J.P. Morgan Healthcare Conference in January (Also see "Does Esperion's Plan For A Statin-Intolerant Claim Have A Shot?" - Pink Sheet, 25 Jan, 2016.).

Implications For PCSK9s

As FDA's Smith noted, strictly speaking the IMPROVE IT results are limited to ezetimibe, a drug that is slated to go generic in 2016. Even if FDA grants the CV claims, the outcomes data are expected to be too little, too late to restore the branded agent's commercial prospects, which were damaged by the unsuccessful ENHANCE and SEAS trials.

However, other sponsors have a lot on the line with how FDA views the IMPROVE-IT data (Also see "Merck's IMPROVE-IT: FDA Panel Review Has Implications Beyond Zetia, Vytorin" - Pink Sheet, 10 Nov, 2015.).

These include the sponsors of Praluent and Repatha, PCSK9 inhibitors that came to market in 2015 on the strength of their LDL-C-lowering effects but with CV outcomes trials ongoing.

IMPROVE-IT was identified as a regulatory risk factor for these companies during the products' development.

During an end-of-Phase II meeting in February 2012, FDA told Sanofi and Regeneron that the IMPROVE-IT results could make the agency reconsider the approval of novel non-statin LDL-C-lowering agents such as alirocumab without pre-approval outcomes data, according to review documents.

Although FDA approved Praluent and Repatha ahead of the outcomes data, it followed the advice of its endocrinologic and metabolic drugs panel and limited the initial indications to patients with familial hypercholesterolemia or atherosclerotic CV disease who require further LDL-C lowering despite maximally tolerated statin therapy.

Approval for broader populations, including those at lower CV risk, would have to await outcomes trial results, FDA concluded (Also see "Praluent Sponsors Set Tone For PCSK9 Labeling, Post-Marketing Negotiations" - Pink Sheet, 18 Jan, 2016.).

PCSK9 inhibitor developers have pointed to the similarity in mechanism between statins and the new class of drugs in proclaiming their confidence that outcomes trials will be successful (Also see "PCSK9 Mechanism Lends Confidence Ahead Of Outcomes Data" - Pink Sheet, 23 Mar, 2015.).

When Will We See PCSK9 Outcomes Data?

• Top-line results from Amgen's 27,500-patient FOURIER outcomes study of Repatha are anticipated in the second half of 2016.
• Final results from the 18,600-patient ODYSSEY Outcomes study of Sanofi/Regeneron's Praluent are not expected until the second half of 2017, although interim analyses for futility and overwhelming efficacy are expected in 2016.
• Pfizer Inc. is conducting pre-approval outcomes trials for its PCSK9 inhibitor bococizumab; the 17,000-patient SPIRE-1 and 9,000-patient SPIRE-2 trials are expected to report by mid-2018 (Also see "A Closer Look At Pfizer’s Pivotal Program For PCSK9 Bococizumab" - Pink Sheet, 8 Dec, 2014.).

Given the large degree of LDL-C lowering seen with PCSK9 inhibitors and advisory committee questions about the clinical meaningfulness of ezetimibe's CV risk reduction benefit in IMPROVE-IT, it would seem that a much more robust CV benefit, with little divergence among subgroups and primary endpoint components, will be expected from the PCSK9 trials.

Regeneron President and CEO Leonard Schleifer acknowledged as much during the recent J.P. Morgan conference.

During the company's breakout session, Schleifer was asked what would be the minimum acceptable benefit in the outcomes trial. The CEO said it's hard to know what the range should be, although 15% might be appropriate. However, he noted the importance of looking beyond the top-line number on the primary composite endpoint.

"It's not only that range, it's also the consistency of the data, the robustness of the data," he said. "Is it, as somebody I heard say with the ezetimibe, did you sneeze and miss it? Or … is it there strongly, and there's no doubt about it. … I don't think it's the headline number necessarily."

Similarly, Regeneron and Sanofi would have to be satisfied with the consistency and strength of the data at the interim analysis before making a determination to stop the trial due to overwhelming efficacy after 75% of events have accrued.

"Overwhelming efficacy is not just a statistical overwhelming efficacy. There has to be consistency of the data, trends in … the subparts of the score," Schleifer said. "Are there trends in mortality? Is it making sense across the country? If it's all looking really good and there is just no point to go on any further, then there is the possibility to stop … and declare it a success."

The emphasis on consistency across endpoints and subgroups is important. In IMPROVE-IT, a higher incidence of hemorrhagic strokes in the ezetimibe arm proved troubling for some committee members (Also see "Zetia, Vytorin CV Risk Reduction Claim Fails To Win FDA Panel Backing" - Pink Sheet, 14 Dec, 2015.).

And although panelists generally said that disparate subgroup results for diabetics and non-diabetics, and patients under and over 75 years old, were interesting and hypothesis-generating, they were generally reluctant to gauge ezetimibe's efficacy on the basis of these findings.

Data for these subgroups in the PCSK9 inhibitor outcomes trials will be closely scrutinized given the results seen in IMPROVE-IT.

BioMedTracker's Chang noted that although the advisory committee did not place much confidence in the subgroup analyses by age and diabetes status, "if the same pattern is seen in the PCSK9 trials, it could raise some issues about which patients such non-statins are best for."

Will Missing Data Haunt Others?

The PCSK9 sponsors also will have to hope that robustness of the results from their massive studies are not undermined by missing data.

The large amount of missing data in IMPROVE-IT raised questions for FDA review staff and advisory committee members about the reliability of the primary endpoint results. Overall, 11% of subjects discontinued follow-up for the primary endpoint early, and discontinuations were highest in the first year after randomization, which was also when the hazard rate was highest (Also see "Merck's IMPROVE-IT Study: Will Missing Data, Subgroups Hinder Zetia CV Claim?" - Pink Sheet, 10 Dec, 2015.).

The extent of lost follow-up and missing data in large CV trials has been a growing concern for FDA. Johnson & Johnson and Bayer AG's Factor Xa inhibitor Xarelto (rivaroxaban) may be a poster child for this issue, as FDA has repeatedly rejected a claim for use in acute coronary syndrome patients due to shortcomings, including a large amount of missing follow-up, in the pivotal ATLAS trial (Also see "J&J Mulls Xarelto’s Next Steps After Another “Complete Response” In Acute Coronary Syndrome" - Pink Sheet, 14 Feb, 2014.).

The duration of the PCSK9 outcomes trials, which are expected to run about half as long as IMPROVE-IT, may help minimize the problem.

In an interview at the J.P. Morgan conference, Sanofi's Global R&D President Elias Zerhouni suggested the amount of missing data in IMPROVE-IT raised doubts about the trial's ability to confirm the LDL-C hypothesis.

"Doing a long-term study for 10-12 years, people drop out and so on. That’s why I wanted to do our CVOT in four years," Zerhouni said. "We are fully enrolled. We will find out."

Chang noted the PCSK9 inhibitors are expected to show LDL-C reductions and CV benefits that are substantially larger than those seen with ezetimibe "which helps to mitigate the risk that other trial issues would interfere with interpretation."

Jessica Merrill ([email protected]) contributed to this report.