Deaths In Esperion's Long-Term Bempedoic Acid Trial Spur Fears Of Commercial Delay

On top of concerns about safety, which could present regulatory hurdles, bempedoic acid is likely to face a tougher competitive environment after the decline in PCSK9 inhibitor pricing.

A numerical imbalance in deaths in Esperion Therapeutics Inc.'s long-term safety study for the cholesterol-lowering drug bempedoic acid is raising concerns about competitive positioning and ability to file prior to having cardiovascular outcomes data, which could delay the product's launch.

Bempedoic acid is a first-in-class inhibitor of ATP citrate lyase (ACL) that upregulates the LDL-C receptor in order to reduce cholesterol synthesis. Esperion is developing the drug as an oral option that is complementary to Merck & Co. Inc.'s Zetia (ezetimibe), which is now generic. The company is developing a fixed-dose combination pill containing bempedoic acid and Zetia; combined, the drugs provide additional LDL reduction of from 40% to 50% beyond statins. (Also see "Esperion Expects Speedy Regulatory Path For Bempedoic Acid/Zetia Combo" - Pink Sheet, 27 Jun, 2017.)

Esperion plans to file the drug in the US by the end of the first quarter of 2019 and in Europe by the end of the second quarter, which would pave the way for approvals in 2020. This timeline is based on plans to file for approval in high-risk populations, prior to having the results from an outcomes study that began in 2016. (Also see "Esperion Says FDA On Board With Filing Strategy For Bempedoic Acid" - Pink Sheet, 20 Mar, 2017.)

FDA approved PCSK9 inhibitors in high-risk populations prior to outcomes study data and during a May 2 investor call Esperion reaffirmed its plan to follow the same regulatory path.

Risk For Regulatory Delay

However, results outlined on May 2 from the long-term Study 1, also called 1002-040, cast doubt on the company's regulatory strategy and the outlook for bempedoic acid overall. The trial, which was the largest and longest trial in the development program, evaluated bempedoic acid against placebo in 2,230 high-risk patients with atherosclerotic cardiovascular disease (ASCVD) on lipid modifying therapy, including maximally-tolerated statin therapy. Patients in the study were randomized 2:1 to bempedoic acid or placebo.

The drug met the primary objective of safety and tolerability and also the key efficacy endpoint for LDL-lowering, but there was a numerical imbalance in the number of deaths.

"The modest efficacy of bempedoic acid, combined with potential questions about safety, though these may just be due to chance, as well as the drug's novel mechanism of action (though its main action is along the same pathway as the statins) does raise the risk that the FDA may want to see a cardiovascular outcomes trial prior to approval," Informa Pharma Intelligence's Biomedtracker service said on May 2.

That would significantly delay the potential approval to beyond 2022, the Biomedtracker analysis noted.

In addition to the trial data, the commercial landscape is changing rapidly in relationship to injectable PCSK9 inhibitors, which provide robust LDL-lowering – with reductions ranging from 50% to 70% on top of statins.

Sanofi and Regeneron Pharmaceuticals Inc. revealed on May 1 a deal with Express Scripts Holding Co. that will give their PCSK9 inhibitor Praluent (alirocumab) preference over Amgen Inc.'s competing PCSK9 inhibitor Repatha (evolocumab) in return for a big discount. This will bring Praluent's cost down from a list price of $14,600 to the low end of a range outlined by the Institute of Clinical and Economic review – $4,500 to $8,000.

Esperion has suggested a list price of about $3,300 to $3,600 per year for bempedoic acid and its pricing advantage is diminishing with greater discounting of PCSK9 inhibitors.

The company's stock price fell 35% on May 2 to close at $45.75.

What The New Data Show

Esperion  notes that it has completed Phase I, II and III studies in more than 1,600 patients to date and the drug demonstrated LDL-C lowering of up to 30% as a monotherapy and up to 50% when used with Zetia on top of statins.  (Also see "Esperion's Oral Bempedoic Acid Passes First Phase III Cholesterol Test" - Scrip, 7 Mar, 2018.) The drug also has been tested as an add-on to PCSK9 therapy. (Also see "PCSK9 Add-On Study Helps Esperion Cover All The Bases With Bempedoic Acid" - Scrip, 27 Mar, 2018.) Results from three more pivotal trials will be released between now and the end of September. 

In Study 1, about half of the patients were on high-intensity statins. CEO Tim Maylebon noted during the call that this is a much more rigorous setting than where the company and key opinion leaders expect bempedoic acid to be used, that is the real world users will be less tolerant of statins and have higher LDL at baseline. In the latest study, bempedoic acid met the key efficacy endpoint with on-treatment additional LDL-C lowering of 20% at 12 and 24 weeks, and 16% at 52 weeks (p<0.001).  Esperion also reported LDL-lowering of 18% at 12 weeks in an intent-to-treat analysis (p<0.001).

Maylebon said during the May 2 investor call that the efficacy results were "unequivocal" and exactly what the company expected.

Efficacy of 18% in the intent-to-treat population at 12 weeks and 16% at 52 weeks was lower than the 20% to 30% reduction reported in short Phase II studies, but this latest result was not completely unexpected and could be due to trial fatigue and lower compliance in long-term versus short term trials, Jefferies analyst Michael Yee said in a May 2 note. Such was the case in studies of PCSK9 inhibitors, he noted.

"FDA likely understands those issues and we don't think it impacts approval," Yee said.

Drilling Down On Safety

Esperion reported that the drug was safe and well tolerated in Study 1. The rate of adverse events was 78.5% for bempedoic acid versus 78.7% for placebo and the rates of serious adverse events were 14.5% and 14%, respectively. The discontinuation rate was 10.9% for bempedoic acid versus 7.1% for placebo.

Muscle-related adverse events have been problematic with statins. In Esperion's study, the discontinuation rate due to this type of event was 2.2% for bempedoic acid versus 1.9% for placebo.

However, there were two causes of concern for investors – a numerical increase in deaths and elevations in liver function tests. The percentage of patients with elevations in AST/ALT liver function tests (three times the upper limit of normal) was low overall, but higher in the bempedoic acid arm – 0.54 % versus 0.13% for placebo. Esperion pointed out that these results are in line with expectations for bempedoic acid and also with statins.

"The number of patients now treated with bempedoic acid in Phase II and Phase III clinical trials totals 2,434. Of these, 0.58% had elevations in liver function tests greater than three times the upper limit of normal, repeated and confirmed," the company said in a statement.

As with statins, the liver elevations returned to normal while patients were on therapy or after they dropped treatment, and no cases of increased bilirubin or Hy's Law were reported.

Esperion faced numerous questions about reported deaths during a lengthy May 2 investor call.

There were 15 deaths in the study altogether, 13 in the bempedoic acid arm and two in the placebo arm; all were deemed to not be related to treatment by study investigators. Out of the 13 deaths in the bempedoic acid arm, five were cardiovascular-related, five were related to lung cancer, one was a pancreatic gastrointestinal event, one was neurological and one was not detailed in the call.

In the placebo arm, one death was cardiovascular-related and the other was related to sepsis.

Execs explained during the call that the patients enrolled were very sick, as they had already experienced a cardiovascular event, and about two-thirds were smokers or had a history of smoking, so the lung cancer deaths were not so surprising. Given the high risk nature of the population, the overall death rate was about what you would expect, Bill Sasiella, senior vice president of clinical development, told the call.

The company noted that there had been no issues with two-year preclinical carcinogenicity studies submitted to FDA in 2015. Also, the cancer deaths occurred during the first 60 or 90 days of Study 1 and had not been reported in previously released short-term studies, and Sasiella noted that "it's highly unlikely you are going to see anything cause a neoplasm in the first month or three of treatment."

Biomedracker's analysts commented that "the early onset does suggest the cases were not due to the drug, so it may well not be an issue. We should mention, though, sometimes the FDA or an advisory committee is still cautious, and there can be a concern that a drug accelerates growth of a cancer."

For example, FDA delayed the approval of AstraZeneca PLC's diabetes drug Farxiga (dapagliflozin) due to concerns about an imbalance in the number of cases of bladder cancer, the analysts noted. But in that case there was an imbalance even excluding the cases that occurred within one year. The drug was approved in early 2014 with a subdued warning about bladder cancer noting the absence of evidence for the risk, two years after the agency issued a complete response letter. (Also see "AstraZeneca’s Farxiga Label Includes, But Downplays, Bladder Cancer Risk" - Pink Sheet, 13 Jan, 2014.)

FDA may not be as concerned about the early bempedoic cases, especially if no imbalance is seen in other studies, Biomedtracker analysts said.

Sasiella also noted that looking at nonfatal and fatal cardiovascular events overall, which were adjudicated by an independent committee, the rate was actually slightly numerically lower in the bempedoic acid arm – and though the numbers are small, this provides an additional point of comfort.

That could well be reassuring, though the FDA may still have questions, particularly in the face of modest efficacy, Biomedtracker analysts commented.

A Buying Opportunity?

Some analysts rushed to the defense of the stock.

Jefferies analyst Yee said in his note that the comments in the call made it clear that the deaths were unrelated to the drug and that the safety was "very clean."

The 16% to 20% LDL reduction is solid, considering that patients seek oral alternatives, as evidenced by the $2.5bn brought in by Zetia at its peak and $2.8bn for Merck's Vytorin (ezetimibe/simivastatin), Yee concluded.

"Ultimately we think the drug appears approvable and a clean oral pill that adds 15%-20% LDL reduction and is a good option for statin intolerant [patients] is attractive to a part of a large patient population (1m) who still need options," Yee said.

JMP Securities analyst Jason Butler concluded that the results from Study 1 "reinforce the robust, safe, clinical profile of bempedoic acid" and said that the stock weakness is a "compelling buying opportunity."

Needham and Co's Chad Messer said the LDL reduction of 20% at 12 weeks was within expectations, but "apparently disappointing versus Street expectations" and also advised buying on weakness.