Merck Calls It Quits On Anacetrapib

Despite the success in the REVEAL outcomes trial for the cholesteryl ester transfer protein (CETP) inhibitor, Merck will not submit the cholesterol therapy for regulatory approval.

Merck & Co. Inc. is making the prudent choice in opting not to pursue regulatory approval for the CETP inhibitor anacetrapib, avoiding the commercial quagmire of the cholesterol market that has hindered uptake of the PCSK9 inhibitor class.

"The decision follows a thorough review of the clinical profile of anacetrapib, including discussions with external experts," the firm said in its Oct. 11 announcement.

“Unfortunately, after comprehensive evaluation, we have concluded that the clinical profile for anacetrapib does not support regulatory filings,” Merck Research Laboratories President Roger Perlmutter said in the statement.

The company has been signaling this may be the fate for anacetrapib ever since the surprise success of its massive cardiovascular outcomes study, REVEAL.

Merck announced in June that anacetrapib met the primary endpoint in REVEAL, with a significant reduction in a composite of major coronary events compared with placebo, and with a safety profile in line with previously released studies. (Also see "Big REVEAL: Merck's Anacetrapib Surprises With Success, But What Next?" - Scrip, 27 Jun, 2017.) At the time, however, the company's lack of guidance on filing plans raised questions about whether the drug would ever see the light of day.

The firm followed up in August with a full presentation of results at the European Society of Cardiology meeting, with simultaneous publication in the New England Journal of Medicine, but signaled that it was consulting with experts about next steps, including whether to file for regulatory approval.

REVEAL tested the drug against placebo in 30,449 patients at high risk of a cardiovascular event and already well-managed on intensive standard of care lipid-lowering therapy with Pfizer Inc.'s Lipitor (atorvastatin). Anacetrapib significantly improved the primary endpoint, reducing the risk of a composite of major coronary events (coronary death, myocardial infarction or coronary revascularization) by 9% over placebo. The baseline LDL in the trial was very low at 61 mg/dL, which is below the traditional 70 mg/dL target for high-risk patients, and baseline HDL was 40 mg/dL. Patients in the test arm got an additional 17 mg/dL of LDL lowering (18%) while HDL was up by 43 mg/dL (104%).

Researchers also reported that there was no significant improvement for anacetrapib on the secondary composite outcome of major atherosclerotic events, which included myocardial infarction, coronary death or ischemic stroke.

The benefit seen in the study was consistent with LDL-lowering effects but not HDL-raising benefits, REVEAL investigators reported. While statistically significant, 9% was a lower reduction than desired and raised questions with analysts about whether it was robust enough to spur prescriptions of the drug.

Rough Road

Seeking approval would have been a tough regulatory road, given the prior history of failure in the class – starting with Pfizer Inc.'s torcetrapib in 2006, with Roche's dalcetrapib following in 2012 and Eli Lilly & Co. ending evacetrapib development in 2015. (Also see "Big REVEAL: Merck's Anacetrapib Surprises With Success, But What Next?" - Pink Sheet, 27 Jun, 2017.)

CETP History

Once upon a time, hopes were very high for anacetrapib and other CETP inhibitors as a new class of oral drugs to augment the effects of generic standard-of-care therapies in high-risk patients. (Also see "Branded Life After Lipitor: Pharma Targets Unmet Needs In Dyslipidemia" - In Vivo, 23 Apr, 2012.) The reality played out as a string of failures, however.

• Pfizer Inc.'s CETP inhibitor torcetrapib failed spectacularly in 2006 with a negative effect on mortality, although there was hope this was not a class effect but rather specific to the drug, which was associated with an increase in blood pressure. (Also see "Pfizer’s Lipitor Extension Shot Down By Failure Of Torcetrapib Silver Bullet" - Pink Sheet, 11 Dec, 2006.)
• The release of the Phase III DEFINE study of anacetrapib in November 2010 had wowed cardiologists with an LDL decline of 39.8% and a jaw-dropping increase in HDL of 138.1%. (Also see "Merck’s Anacetrapib Debut Many Years Away, Despite Robust Phase III Data" - Pink Sheet, 22 Nov, 2010.)
• In 2012, Roche's dalcetrapib was terminated due to lack of efficacy in the dal-OUTCOMES study, but some industry observers kept faith in the class, reasoning that the lipid effects were better for others in the class and therefore outcomes could also still prove to be superior. (Also see "Dalcetrapib Failure Raises Yet More Questions On Value Of Tinkering With HDL Cholesterol" - Pink Sheet, 14 May, 2012.)
• Merck and Lilly pressed on with outcomes studies of their CETP inhibitors – anacetrapib and evacetrapib, respectively. (Also see "Merck, Lilly Vow To Press On With CETP, Despite Dalcetrapib Disaster" - Pink Sheet, 7 May, 2012.)
• Then, in late 2015, Eli Lilly & Co.'s evacetrapib flamed out in the ACCELERATE outcomes study under mysterious circumstances, putting an end to development. (Also see "Inflammation A Clue Left In ACCELERATE CETP Wreckage" - Pink Sheet, 18 Apr, 2016.)

Even though it has been argued that there are mechanistic differences between the molecules, anacetrapib did show some increase in blood pressure in REVEAL (the issue behind the torcetrapib failure) and had mixed results on secondary endpoints – issues that could have been stumbling blocks with the US FDA.

And the commercial environment is different than it would have been when the CETP class first came onto the scene, more than a decade ago. Now the entire statin class is available as inexpensive generics, and the lack of success for the injectable PCSK9 inhibitors (Amgen Inc.'s Repatha and Sanofi/Regeneron Inc.'s Praluent) shows how challenging it can be to introduce a pricey new therapy in the cholesterol field. (Also see "PCSK9 Sales Still Slow, But May Get Boost From Label, Guideline Changes" - Scrip, 4 Aug, 2017.)

In addition, the theory that raising HDL improves heath has been damaged along the way, with disappointing results from outcomes trials of fenofibrates and niacin. (Also see "More Disheartening News For Abbott Cholesterol Franchise: Niaspan/Statin Study Halted Due To Lack Of Added Benefit" - Pink Sheet, 26 May, 2011.) and (Also see "HPS2-THRIVE Post-Mortem: Lessons Learned For CV Drug Developers" - Pink Sheet, 18 Mar, 2013.) The emphasis on increasing HDL through CETP inhibition had been muted and the class had been repositioned for its broader effects, but at this point PCSK9 inhibitors can achieve very low LDL levels – and that hasn't been enough to capture market share.

Final Nail In The Coffin

Merck's decision not to file anacetrapib may be the final nail in the coffin for the CETP class and could have broader implications for HDL-raising drugs. According to the Biomedtracker database, development of most CETP inhibitors has already been suspended.

Amgen Inc.'s AMG 899 is the only other new CETP inhibitor in clinical development. The company told Scrip it is "currently evaluating its development plan for AMG 899."

Using private financing, DalCor Pharmaceuticals is testing Roche's dalcetrapib in a genetic subgroup of patients with acute coronary syndromes – in the dal-OUTCOMEs study the 20% of patients with an AA polymorphism at the rs1967309 location in the ADCY9 gene had a much lower rate of events compared with placebo, according to the company. (Also see "DalCor To Develop Failed Roche CETP Inhibitor In Genetic Subgroup" - Scrip, 22 Apr, 2016.)

Merck noted that it will continue research in cardiovascular diseases. The company currently has only one other CV program in clinical development, per its August pipeline update. Vericiguat, a stimulator of soluble guanylate cyclase (sGC), is in a Phase IIb trial in patients with heart failure and preserved ejection fraction suffering from worsening chronic heart failure. The company also still markets Zetia (ezetimibe) and Zocor (simvastatin), both of which are available as generics.