FDA’s rejection of a cardiovascular risk reduction claim for Merck & Co. Inc.’s Zetia and Vytorin leaves more questions than answers about prospects for other sponsors of new cholesterol-lowering drugs, including PCSK9 inhibitors.

Merck announced Feb. 15 that FDA issued a complete response letter for supplemental new drug applications supporting a claim for Zetia (ezetimibe), a cholesterol absorption inhibitor, and Vytorin, which combines the statin simvastatin with Zetia, in reducing cardiovascular events.

Merck said in a statement that it is “reviewing the letter and will determine next steps,” but declined to provide any further details about the content of the letter or its plans.

For the particular products involved, the commercial impact is limited. Together, the drugs yielded $3.8bn in sales for 2015, down from $4.2bn the prior year. But they are likely to face generic competition at the end of 2016 under a deal with Glenmark Pharmaceuticals Inc. allowing entry ahead of patent expiry the following April. Zetia’s patent expires in Europe in October 2017.

However, the verdict has had important implications for new non-statin classes.

A claim for Zetia could have helped lay the groundwork for Merck’s Phase III CETP inhibitor anacetrapib, which raises HDL and also lowers LDL substantially, though hopes for that class have been diminished by failures, most recently by Eli Lilly & Co.’s evacetrapib in October ([A#14151012003]). Merck is expecting outcomes data for anacetrapib in 2017, which it needs pre-approval.

Other classes that could be affected by the regulatory action include the potent injectable PCSK9 inhibitors, which work similarly to statins and therefore have a mechanism that is better understood compared to CETP. Sanofi/Regeneron Pharmaceuticals Inc.’s Praluent (alirocumab) andAmgen Inc.’s Repatha (evolocumab) were both initially approved by FDA for some claims without morbidity/mortality data, but need more proof of outcomes benefit to be cleared for larger patient populations Also see "PCSK9 Inhibitors May Feel Effects Of FDA Judgment On IMPROVE-IT" - Pink Sheet, 25 January, 2016..

The CRL suggests that FDA will hold a high bar for the outcomes studies when they come in, and reinforces the importance of a well-designed outcomes trial for future sponsors. Although FDA generally has accepted cholesterol drugs while an outcomes trial is still ongoing, a series of failures has raised uncertainty in the field Also see "LDL Hypothesis Brings Out Skeptics, Supporters At FDA Panel" - Pink Sheet, 25 January, 2016..

The future of Esperion Therapeutics Inc.’s oral ETC-1002 (bempedoic acid), which inhibits ATP citrate lyase, could also be affected. Esperion has been planning on securing approval prior to having outcomes data, based on LDL-C lowering. The company acknowledged the changing regulatory climate in its presentation 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 January, 2016.. At the meeting, execs said that every class will have to stand on its own risk/benefit profile, rather than riding on the coattails of the statins.

Rejected As Expected

Merck’s sNDAs for expanded labeling on CV risk reduction were supported by the 18,000 patient IMPROVE-IT study. In that trial, adding Zetia to statin therapy resulted in a statistically significant 6% reduction in risk.

But the data did not hold up well to scrutiny. FDA’s Endocrinologic and Metabolic Drugs Advisory Committee had a number of concerns, including about missing data, the modest benefit and differences in effects for various subgroups ([A#00150907013]). While the advisory committee voted against approval of the claims, there was some support for a narrower indication or other language regarding efficacy based on IMPROVE-IT Also see "IMPROVE-IT Study: Negative Panel Review Leaves FDA With Tough Choice" - Pink Sheet, 21 December, 2015..

There also was a suggestion that language about no evidence of an outcomes effect could be removed. The limitations on use section of Zetia’s labeling notes: "The effect of ZETIA on cardiovascular morbidity and mortality has not been determined." Similarly, Vytorin’s labeling notes that “no incremental benefit of Vytorin on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.”

What Does The CRL Mean?

More details about the CRL would shed further light on FDA’s current thinking about LDL cholesterol drugs and determine implications for drugs in the pipeline, but the fact of the letter itself is an affirmation that the agency is willing to wait for high-quality data.

Some advisory committee members thought that the IMPROVE-IT study results were somewhat in line with what might be expected, with limited LDL-C lowering seen in the study, commented Peter Chang, principal scientific analyst at BioMedTracker.

The agency could be taking a hard line that the trial failed to demonstrate any benefit, which would raise questions about whether modest benefits in LDL-C lowering with non-statins in well-controlled patients has any impact, he noted. In that case, FDA may want to see cardiovascular outcomes data prior to approval for drugs that similarly show a modest benefit, like Esperion’s ETC-1002.

On the other hand, if the agency is asking for more information to support the claim that the benefit is somewhat meaningful or is open to changing labeling, implications for other drugs with a modest benefit “may not be as dire,” the analyst suggested.

As for the PCSK9 inhibitors, this class has demonstrated more robust LDL-C lowering than Zetia and ETC-1002, though it’s still unclear how this will translate into cardiovascular outcomes. The first outcomes study results are due in 2016.

Since the PCSK9 inhibitors have stronger LDL-C reductions, the data should be more robust, Chang said. That is, assuming the relationship between LDL-C lowering and outcomes holds up in trials where the baseline LDL is already low.

In Chang’s view, a positive result in outcomes studies of PCSK9 inhibitors could give FDA confidence in approving new oral drugs based on LDL-C lowering, even with more modest LDL-lowering, because use in combination with other drugs like Zetia boosts efficacy.

Prior to Merck’s CRL, some had speculated that a claim for CV risk reduction could be a negative for PCSK9 inhibitors from a reimbursement perspective, in that it might encourage payers to require patients to use Zetia as an add-on drug prior to PCSK9.

The CRL makes that less likely, so it could be an upside for the drugs.

The PCSK9 launches have been somewhat disappointing, in large part because payers have been conservative. Amgen Inc. did not break out sales of its Repatha in its fourth-quarter earnings call ([A#14160129005]). Praluent brought in worldwide sales of only $11m for the fourth quarter ([A#14160209002]).

Regeneron Executive VP-Commercial Bob Terifay explained in an earnings call that it would take time for payers to do formulary reviews, make coverage decisions and process claims. Terifay also noted that with strict utilization-management criteria, it continues to expect a “gradual uptake.”

FDA’s Zetia/Vytorin Rejection Leaves Cholesterol Drug Sponsors In Limbo

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