Cholesterol Drug Approvals May Hinge On Outcomes Studies; FDA Rejects Diabetes-style Tiered Trials

Decreasing cardiovascular events is the only endpoint that matters for cholesterol-lowering drugs, FDA official says at Amarin’s negative Vascepa panel, leaving little room for drug’s expanded approval based on a surrogate endpoint.

FDA’s Deputy Director of the Division of Metabolism and Endocrinology Eric Colman indicated the agency has little willingness to accept a surrogate for new cholesterol-lowering drugs, because the products have one primary purpose – decreasing cardiovascular risk – which appears to lack another marker.

Endocrinologic and Metabolic Drugs Advisory Committee member William Hiatt asked FDA during an Oct. 16 meeting whether it would be willing to take a “staged approach” as it has with diabetes drugs, when considering whether to approve Amarin Corp. PLC’s Vascepa (icosapent ethyl) for an expanded indication in patients with mixed dyslipidemia and coronary heart disease (CHD) or a CHD risk equivalent. That is, would it accept an unproven surrogate endpoint, assuming the drug is safe (Also see "FDA Diabetes Guidance Encourages Enrollment Of Sicker Patients" - Pink Sheet, 17 Dec, 2008.).

“You really don’t want to deal with any uncertainty when the endpoint is the only endpoint that matters,” FDA’s Colman said of the need for cardiovascular outcomes data for Vascepa.

“If we all conclude today that we really don’t know if it’s beneficial to lower triglycerides substantially or not, what would you do if the point estimate was going in the right direction in the event trial, but the confidence intervals still hadn’t made it statistically significant to formally stop the study, but it had a staged approach?” Hiatt, a Professor of Cardiology at the University of Colorado School of Medicine, asked.

“I mean, from my perspective, that might actually be reassuring to let a drug on the market at an earlier time point than one normally would do until you have the completed study,” he suggested.

But FDA’s Colman nixed this approach.

“We have been willing to do that with obesity drugs as you know and the diabetes drugs,” Colman said of Hiatt’s staged approach idea. “But that is because people take obesity drugs and diabetes drugs for reasons other than lowering risk for cardiovascular disease. The only reason someone would be taking Vascepa in this scenario would be to reduce the risk of cardiovascular disease, so I think that paradigm doesn’t quite fit in this scenario, where you really don’t want to deal with any uncertainty when the endpoint is the only endpoint that matters.”

Vascepa’s Clinical Reviewer Mary Roberts also told the committee that while the language of the expanded indication being sought for the drug “strictly speaks to the reduction in lipoprotein levels and the improvement in numbers,” the indication “certainly implies that one should expect cardiovascular benefit with treatment.”

The company submitted a positive Phase III study, ANCHOR, for the expanded indication, showing Vascepa 4 mg demonstrated statistically significant differences compared to mineral oil placebo after 12 weeks of therapy for the primary endpoint of the percent change in TG levels from baseline and with respect to secondary endpoints such as LDL-C and non-HDL-C.

The presumption has been that improving lipid parameters will translate into reduced cardiovascular risk, and the agency historically has considered granting approval for lipid-altering drugs based on favorable changes in the lipid profile, with the assumption that these changes would translate into a benefit on clinical outcomes.

But since FDA and Amarin entered into a special protocol assessment for what is known as the ANCHOR indication, allowing the company to conduct a Phase III with a surrogate endpoint as long as an outcomes study was well underway at the time of the sNDA submission, a number of cardiovascular outcomes trials for cholesterol-lowering drugs approved as add-ons to statins failed.

This led FDA to ask its advisors whether Vascepa’s effects on lipid/lipoprotein parameters is sufficient to grant approval prior to completion of the company’s REDUCE-IT outcomes trial (Also see "Panel To Weigh Amarin’s Expanded Vascepa Use Given Clinical Outcome Concerns" - Pink Sheet, 11 Oct, 2013.).

The panel ultimately voted 9-2 against recommending approval of the drug without cardiovascular outcomes data, but many of these no-voters expressed concern about requiring the high-bar of a lengthy outcomes trial preapproval, especially given that other lipid-lowering drugs that failed in outcomes trials post-approval remain on the market and weren’t subject to such high standards (Also see "Vascepa Negative Panel Vote Clouds Future For Other Cholesterol Drugs" - Pink Sheet, 17 Oct, 2013.).

FDA’s dissatisfaction with the triglycerides surrogate was picked up on by pharma analysts. Canaccord Genuity analyst Ritu Baral said Oct. 17 that based on the advisory panel “we do not foresee FDA approving any drugs for the improvement of non-LDL lipid parameters in the near future – at least not without a long outcomes study. Non-LDL lipids would need formal validation for expedited clinical development.”

Amarin has a Dec. 20 prescription drug user fee act goal date for Vascepa in combination with a statin to reduce triglycerides (TGs), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (Apo-B), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC) and very-low-density lipoprotein cholesterol (CLDL-C) in this dyslipidemia patient population.

The fish oil product, a purified ethyl ester of eicosapentaenoic acid (EPA), already is approved as a monotherapy for the treatment of severe hypertriglyceridemia, but the supplemental indication would represent a 10-fold expansion in the on-label market, according to the company, or about 40 million U.S. patients (Also see "Amarin Raises $100M Debt Funding As It Preps For Vascepa Launch" - Pink Sheet, 10 Dec, 2012.).

“Although the indication strictly speaks to the reduction in lipoprotein levels and the improvement in numbers, this indication for this population certainly implies that one should expect cardiovascular benefit with treatment,” Vascepa Clinical Reviewer Mary Roberts said.

Is FDA Being “Unfair” To The Late Comer?

While FDA’s shift in thinking on the need for outcomes studies will have dramatic implications for Vascepa’s supplemental application, it is unclear what the impact will be for the products whose failed trials contributed to the agency’s reassessment.

Abbott Laboratories Inc.’s (now AbbVie Inc.) Niaspan (extended-release niacin) and TriCor (fenofibrate) both failed to demonstrate cardiovascular benefit in their post-market cardiovascular outcomes trials AIM-HIGH and ACCORD, respectively, and those products now both carry a “limitations of use” caveat in their indications sections (Also see "More Disheartening News For Abbott Cholesterol Franchise: Niaspan/Statin Study Halted Due To Lack Of Added Benefit" - Pink Sheet, 26 May, 2011.).

The concept of placing a “limitation of use” in Vascepa’s label was not discussed at the advisory committee.

Hiatt told FDA during the advisory committee meeting, “I see the challenge you’re facing. You’ve sort of set yourself up. Historically, you’ve approved lipid drugs because they improved lipid parameters and diabetes drugs because they dropped blood sugar and A1c, and it’s only later that we really learned whether those decisions were the right or the wrong thing.”

He chided the agency, saying, “It would seem to me unfair to the sponsor if you historically approved lipid drugs because in the population they do something that looks good and you suddenly change that bar at this moment in time.”

FDA’s Colman said that the agency believes the results of ACCORD-LIPID, AIM-HIGH, Merck & Co. Inc.’s HPS2-THRIVE for Tredaptive (extended-release niacin/paropiprant) and perhaps some of the omega-3 fatty acid outcomes trials that have been published in the last two or three years “changes the landscape” for statin add-on therapies (Also see "HPS2-THRIVE Post-Mortem: Lessons Learned For CV Drug Developers" - Pink Sheet, 18 Mar, 2013.).

And Colman said that given the agency’s recent experience with CETP inhibitors, FDA now requires that applications for compounds that primarily raise HDL cholesterol have a completed outcomes trial before submission (Also see "Merck, Lilly Vow To Press On With CETP, Despite Dalcetrapib Disaster" - Pink Sheet, 7 May, 2012.).

Amarin argued at the advisory panel that it would be a challenge for the small company to complete a large, lengthy outcomes trial preapproval and that since the drug has been shown to be safe and tolerable – an assertion to which FDA agreed – the company should be able to complete an outcomes study post-market.

FDA, however, argued that the product does not fit into any of the criteria that the agency has for accelerated approval, and it cannot compel such a post-market outcomes study under its current statutory framework, so it lacks a tidy enforcement mechanism for ensuring the product gets positive results or gets the indication removed.

How Will Current Cholesterol Pipeline Fair?

The current pipeline of dyslipidemia drugs that could be affected by an FDA decision that it wants cardiovascular outcomes data prior to approval of cholesterol-lowering drugs, particularly those that are not targeting LDL-C, is relatively small (Also see "Branded Life After Lipitor: Pharma Targets Unmet Needs In Dyslipidemia" - In Vivo, 23 Apr, 2012.).

AstraZeneca PLC agreed to $260 million plus contingency payments to acquire Omthera Pharmaceuticals Inc., the makers of Epanova, a late-stage fish oil product for dyslipidemia, in May (Also see "The Other Fish In The Sea: AstraZeneca Buys Omthera" - Pink Sheet, 28 May, 2013.).

PCSK9 inhibitors including Sanofi/Regeneron Pharmaceuticals Inc.’s monoclonal antibody alirocumab (SAR236553/REGN727) and Amgen Inc.’s AMG 145, also are being positioned to treat dyslipidemia, including for those who are statin-intolerant, as an add-on to statins for those who can’t reach cholesterol target and as a therapy for patients with genetic disorders predisposing them to unusually high cholesterol levels (Also see "Sanofi/Regeneron’s PSCK9 Inhibitor Alirocumab Passes First Phase III Test" - Pink Sheet, 16 Oct, 2013.).

Amgen, Regeneron and Sanofi have said they will not need outcomes study results for the biologics prior to approval but they plan to have these studies well underway before filing.

PCSK9 inhibitors may not face the same hurdles as Vascepa or other add-ons to statins that target lipid parameters besides LDL-C, because these biologics are geared toward lowering LDL-C, a biomarker that is considered a more valid surrogate for cardiovascular risk.

The only other prescription fish oil product currently on the market is GlaxoSmithKline PLC’s Lovaza, a mixture of EHA and docosahaxaenoic acid (DHA), the other major constituent of fish oils derived from cold-water fish. Vascepa is thought to have an advantage over Lovaza since it does not contain DHA which is believed to negatively impact LDL cholesterol. Lovaza has increased LDL-C in some patients while in Phase III Vascepa lowered LDL-C levels in patients with mixed dyslipidemia (Also see "Amarin’s Vascepa May Give Lovaza A Run For Its Money" - Pink Sheet, 27 Jul, 2012.).