In the wake of controversy in the cholesterol field, Esperion Therapeutics Inc. is trying to refocus on getting its oral cholesterol drug ETC-1002 approved for patients who can’t tolerate statins ahead of outcomes data – but the firm's strategy may not cut it with FDA.

The agency has publicly voiced concerns about defining this particular population in recent months, and it confirmed in a statement to "The Pink Sheet" that it wants to see cardiovascular outcomes data prior to approval.

ETC-1002 (bempedoic acid) inhibits ATP citrate lyase, an enzyme on the cholesterol biosynthesis pathway. It works similarly to statins in that it up-regulates LDL receptors, so it has a trusted mechanism of action, but unlike statins it achieves the LDL-C lowering without the muscle pain side effects, according to the company.

After the patent expiration of blockbuster statins with proven outcomes benefits and ahead of the patent loss of Merck & Co. Inc.’s cholesterol absorption inhibitor Zetia (ezetimibe), cholesterol drug development has been inherently challenging.

Sanofi, Regeneron Pharmaceuticals Inc. and Amgen Inc. have launched PCSK9 inhibitors – Praluent (alirocumab) and Repatha (evolocumab), respectively – with initial approvals as add-ons in patients with genetic disorders or CV disease and still-high LDL. The firms would like to expand outside the limited familial hypercholesterolemia markets once their outcomes trials report, expected over the next couple years. At about $14,000 a year, the antibodies are expensive for the traditionally oral and now heavily genericized cholesterol market.

Esperion declined to comment specifically on its plans for pricing, but the company said that as an oral, once-daily, small molecule, bempedoic acid “has the potential to be a cost-effective solution for patients with elevated LDL-cholesterol who are unable to tolerate a statin or require additional cholesterol lowering despite already taking statin therapy.”

Regulatory Limbo

Development has become more precarious with the negative FDA advisory committee review of a CV outcomes claim for Zetia in December, despite a modestly positive result in the IMPROVE-IT study (see related story, Also see "PCSK9 Inhibitors May Feel Effects Of FDA Judgment On IMPROVE-IT" - Pink Sheet, 25 January, 2016.). The LDL hypothesis – the assumption that drugs that lower LDL have the same benefits as statins – or "statin umbrella" is now in doubt.

Esperion, trying to adjust to the shifting regulatory terrain, sees opportunity in the large numbers of people with statin intolerance. The plan is to initially pursue approval for LDL-C reduction in statin-intolerant patients and then expand the label to include a CV risk reduction claim based on data from an outcomes trial.

However, when the PCSK9 sponsors attempted to get statin-intolerance claims, FDA voiced objections about how to define that population ([A#14150605001]).

The “pragmatic diagnostic approach” for intolerance is that if a patient won’t take a statin, by definition they are intolerant, CEO Tim Mayleben said during a Jan. 13 presentation at the J.P. Morgan Healthcare Conference. Patients can’t benefit from an LDL therapy if they can’t or won’t take it, he maintained. Esperion estimates about 10% of the US population, or 3.5m people, are statin-intolerant. There is also upside in the market for those who can’t tolerate an adequate dose of statins to reach targets, about another 10% of the US population, the firm maintains.

The statin-intolerant segment has always been a target population for sponsors of new cholesterol drugs, and off-label use of Zetia in that group was said to be a big driver of sales Also see "Branded Life After Lipitor: Pharma Targets Unmet Needs In Dyslipidemia" - In Vivo, 23 April, 2012..

Statin intolerance could be due to a variety of conditions, including muscle pain or cognitive fuzziness, but the actual incidence has always been difficult to pin down and experience is mostly anecdotal.

Nevertheless, Esperion played up the potential in those with statin intolerance during its presentation at the J.P. Morgan meeting. The company said it is working to develop a regulatory path for the statin-intolerant population, with plans to unveil its Phase III CLEAR development program in the second quarter.

Mayleben stressed that the company has $300m on its balance sheet, which would enable funding of the Phase III program.

The company noted there has been safety and robust efficacy in the clinical trials of 1,000 patients to date. As a monotherapy, ETC-1002 offers 30% LDL reduction and a 50% total reduction when added to ezetimibe.

The company is still in discussions with FDA, so it could not be conclusive about the strategy for the Phase III program. However, it envisions that after initial approval in statin-intolerant patients, it will work with partners to develop the drug in heterozygous familial hypercholesterolemia (HeFH) and arteriosclerotic cardiovascular disease (ASCVD) (see table).

Esperion’s Target Patient Populations: Unmet Needs in LDL-C Lowering
Esperion Focus	Partnership Opportunities
Statin Intolerant: 3.5m patients in US, with high LDL-C levels comparable to pre-statin era, typically 165-190 mg/dL	HeFH: 600,000 patients in US, well-defined population but undiagnosed, with need for “significant effort” to improve awareness	ASCVD: 10m in US with prior CV event, large and diverse, significant overlap with diabetes
Source: Esperion J.P. Morgan presentation, Jan. 13, 2016

On Jan. 13, Esperion announced the start of a Phase III long-term safety study that will test the drug as an add-on to statins. The company also recently started a Phase II combination study testing ETC-1002 as an add-on to the maximum tolerated dose of statin therapy, with results expected in mid-2016.

New Regulatory Terrain, New Roadmap

Historically, there was an assumption that drugs that worked like statins would also have the same CV outcomes benefits.

FDA has not required outcomes data for initial approval, but wants outcomes trials to be under way by the time of regulatory submission.

In August, Esperion assured investors that LDL-C remains an acceptable clinical surrogate endpoint for approval in populations with a high unmet medical need, including those with HeFH or ASCVD who are already taking maximally tolerated statin therapies but require additional LDL-C reduction ([A#14150818002]).

At J.P. Morgan, Mayleben stressed once again, to avoid any misunderstandings, that FDA wants the company to have a CV outcomes trial well under way at the time of an NDA submission, but does not require that data at the time of the filing. “FDA did not say to us – to be clear – complete a CV outcomes trial prior to approval. I want to be clear on that,” he said. An outcomes study is set to start by the end of 2016.

FDA has also guided that LDL-C-lowering drugs will be evaluated based on their own individual risk-benefit profile.

“The regulatory environment has changed, but we now understand that change,” the CEO said. “There is no halo effect associated with statins in the LDL-cholesterol-lowering space any longer. Each drug class will stand on its own.”

The exec asserted that the LDL-C-lowering hypothesis is still valid at FDA when elevated levels are being reduced to normal levels. Hence, he said, the company is focusing more on the statin-intolerant population, which needs reduction to normal levels, for its own development work.

But Esperion's messages to investors have not been as reassuring as hoped. On Jan. 16, Los Angeles-based Goldberg Law PC announced a class action lawsuit against Esperion, charging that the company “had no clear path to approval for ETC-1002.”

“In addition, the FDA had encouraged the company to initiate a cardiovascular outcomes trial ('CVOT') and that completion of a CVOT could be necessary prior to approval of ETC-1002,” the law firm said in a release.

IMPROVE-IT: Lessons Learned

FDA made it clear from the start of the IMPROVE-IT review that the LDL hypothesis was not on trial and that the discussion applied only to ezetimibe, Senior VP-Strategic Marketing and Product Planning Marianne Andreach said during Esperion’s breakout session at the J.P. Morgan meeting Also see "LDL Hypothesis Brings Out Skeptics, Supporters At FDA Panel" - Pink Sheet, 25 January, 2016..

Another big plus coming out of the advisory committee meeting was that five clinicians on the panel favored approval of the new claim and noted the need for new therapies to reduce LDL cholesterol, Andreach said Also see "IMPROVE-IT Study: Negative Panel Review Leaves FDA With Tough Choice" - Pink Sheet, 21 December, 2015..

The advisory committee discussion suggested that one problem with the IMPROVE-IT trial was that baseline LDL was already low in many patients, so there wasn’t as much potential benefit for the participants. This is a factor the company will consider in the design, including eligibility criteria, of its own Phase III program, execs said.

Intolerance Likely A Tough Sell

But while the company thinks it can avoid the complications of IMPROVE-IT and that there is a commercial opportunity for statin intolerance, it will need to convince FDA where other sponsors in the last six months have failed.

During the breakout session at J.P. Morgan, Chief Medical Officer Mary McGowan maintained that “pragmatically, FDA absolutely believes in statin intolerance” and recognizes this as an underserved population.

Esperion is likely to have a tough time getting approval for ETC-1002 in statin-intolerant patients without outcomes data.

Creators of the latest cholesterol guidelines from the American College of Cardiology and American Heart Association were wary about statin intolerance and more generally about new classes of drugs unproven in outcomes studies. During the 2013 AHA annual meeting, experts suggested a careful check of patient history to evaluate whether patients actually are intolerant to statins or alternatively whether there might be a different cause for certain symptoms Also see "Cholesterol Guidelines Look High And Low: Statin Market Extended At Both Ends" - Pink Sheet, 13 November, 2013..

FDA confirmed in an emailed response to questions from “The Pink Sheet” that its current thinking regarding the concept of “statin intolerance” is consistent with the views presented and discussed at the June 9 and 10, 2015 meetings of the Endocrinologic and Metabolic Drugs Advisory Committee on alirocumab and evolocumab.

Specifically, the review division recognizes that there are patients for whom statins are indicated but who cannot take statins for any number of reasons. Double-blind, randomized controlled clinical trials that have included a statin rechallenge arm, however, have shown that it is difficult to reliably identify patients who are intolerant of the pharmacologic class.

In the PCSK9 review documents, FDA said its working definition for statin intolerance is a patient who is not able to tolerate the lowest starting daily dose of a statin, in addition to any dose of another statin, due to prespecified symptoms that began or increased during statin therapy and ended when statins were discontinued. But the agency noted in the briefing documents for the Praluent review that “many patients who are not able to take statins are not truly intolerant of the pharmacological class.”

The agency noted in an email that it has voiced concern that indicating a drug specifically for “statin-intolerant patients” could promote a condition that is not well-understood and perhaps encourage some patients to prematurely abandon statins, a class that has robustly established benefits on CV outcomes, in favor of drugs that may only have evidence of effect on LDL-C levels.

This concern could be mitigated if a drug were to demonstrate a favorable effect on CV morbidity/mortality in an outcomes trial that is applicable to a “statin-intolerant” population, FDA said.

Asked why it might succeed in getting a statin-intolerant claim where the PCSK9 inhibitors failed, Esperion responded by noting that there are “currently no therapeutic options approved specifically for use in patients with statin intolerance."

“Based on Phase I and Phase II data – including the lowering of elevated LDL-cholesterol, hsCRP lowering, safety and tolerability achieved, and reduced potential for muscle-related side effects – bempedoic acid is uniquely positioned for use in this patient population. Following a Phase III program in patients with elevated LDL-cholesterol who are statin intolerant, we expect bempedoic acid will be clearly differentiated from other therapeutic options, a potentially important factor for patients, physicians and payers,” the company said in an email.

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