Advicor, Simcor Withdrawals Show There's A Lot Riding On CV Outcomes Studies

Surrogate markers for cardiovascular products may be going the way of AbbVie's cholesterol franchise.

FDA's formal withdrawal of two AbbVie Inc. hyperlipidemia drugs for failure to demonstrate cardiovascular benefit is yet another reminder of the regulatory and commercial importance – and ramifications of potential failure – of ongoing CV outcomes studies for the PCSK9 inhibitors and Amarin Corp. PLC's Vascepa.

In an April 18 Federal Register notice, FDA withdrew approval of the NDAs for Advicor (niacin extended-release/lovastatin) and Simcor (niacin ER/simvastatin).

AbbVie discontinued US sales of Advicor and Simcor in December.

"Based on the collective evidence from several large cardiovascular outcome trials, the agency has concluded that the totality of the scientific evidence no longer supports the conclusion that a drug-induced reduction in triglyceride levels and/or increase in HDL-cholesterol levels in statin-treated patients results in a reduction in the risk of cardiovascular events," FDA said.

"Consistent with this conclusion, FDA has determined that the benefits of Advicor and Simcor no longer outweigh the risks, and approval should be withdrawn."

Since the agency determined the drugs were withdrawn for reasons of safety or effectiveness, FDA will not accept or approve ANDAs that reference the two products.

In a separate Federal Register notice, the agency formally withdrew approval of indications related to co-administration with a statin for AbbVie's Niaspan (niacin ER), Trilipix (fenofibric acid) and their generic equivalents. The statin co-administration indications had been removed from the branded products' labels in April 2015.

For AbbVie's branded drugs and the ANDAs referencing Niaspan and Trilipix, the application holders requested the withdrawals and waived their opportunities for a hearing.

Advicor/Simcor Discontinued In 2015

AbbVie said it initiated a voluntary discontinuation of Advicor and Simcor in the US on Dec. 1.

"The decision was based on discussions with the FDA regarding results of recent clinical trials which overall did not demonstrate an incremental outcome benefit associated with the co-administration of extended-release niacin in combination with statin drugs beyond treatment with statins alone in a patient population with well controlled LDL and non-HDL," the company said.

AbbVie said the products' discontinuation is not related to the safety. "AbbVie took appropriate steps to inform prescribers, health care professionals, pharmacies and patients of the decision to facilitate patient transition to alternative therapies."

Niaspan, Trilipix and their generics remain on the market for indications that do not entail concomitant use with a statin.

"Niaspan remains an important treatment option for appropriate patients with mixed dyslipidemia and primary hyperlipidemia and Trilipix remains an important treatment option for appropriate patients with severe hypertriglyceridemia, primary hypercholesterolemia or mixed dyslipidemia," the company said.

Sales of AbbVie's lipid franchise, which also includes TriCor (fenofibrate), have flagged in recent years, beset by the entry of generic competition. In addition, new hypercholesterolemia treatment guidelines in 2013 emphasized statins as a proven mainstay of treatment and noted the lack of evidence for other lipid-modifying drugs (Also see "New Cholesterol Guidelines Follow Long History Of Failed Outcomes Trials" - Pink Sheet, 2 Dec, 2013.).

US sales of AbbVie's dyslipidemia products were $179m in 2015, down 45% from the prior year period. By comparison, in 2011 the franchise rang up US sales of $2.5bn.

AbbVie said it is no longer actively promoting any of the medicines in its lipid franchise.

Highway Strewn With Outcomes Trial Failures

FDA's withdrawal notices refer to several high-profile, post-approval trials that failed to demonstrate a CV outcomes benefit with niacin and fenofibrate.

These include: the ACCORD Lipid trial that tested TriCor with Merck & Co. Inc.'s Zocor (simvastatin) versus simvastatin alone in patients with type 2 diabetes and CV disease; the AIM-HIGH study that tested Niaspan as add-on to Zocor – with or without Merck's Zetia (ezetimibe) – in patients with a history of CV disease; and the HPS2-THRIVE study of Merck's investigational drug Tredaptive (niacin ER with the anti-flushing agent laropiprant) as add-on therapy to intensive background lipid-lowering.

These are some of the same trials that have led FDA to re-examine the use of LDL-cholesterol reduction and other surrogate endpoints for approval and labeling expansions of other lipid-altering agents.

FDA allowed the first PCSK9 inhibitors – Sanofi and Regeneron Pharmaceuticals Inc.'s Praluent (alirocumab) and Amgen Inc.'s Repatha (evolocumab) – to come to market in 2015 on the strength of robust LDL-C lowering effects.

However, the agency limited the drugs' indications to use with maximally tolerated statin therapy in patients with familial hypercholesterolemia or clinical atherosclerotic disease who require additional LDL-C lowering. The approved indications were considerably narrower than the broad populations requested by both drugs' sponsors, with FDA taking the position that any labeling expansion would have to await the results from large, ongoing outcomes studies (Also see "Broad Enough? Sponsors Pleased With Narrower Praluent Label" - Pink Sheet, 24 Jul, 2015.).

Top-line results from the FOURIER outcomes study of Repatha are expected in the second half of 2016, while the ODYSSEY study of Praluent is expected to complete in 2017.

FDA is not the only party demanding additional studies for the PCSK9 inhibitors; the new drugs have had trouble gaining reimbursement coverage and market traction due to their restricted labels, high cost and lack of outcomes data (Also see "PCSK9 Sponsors, Payers In The Ring At ACC" - Pink Sheet, 11 Apr, 2016.).

As with the PCSK9 inhibitors, the commercial future of Amarin's triglyceride-lowering agent Vascepa (icosapent ethyl) is tied to the ongoing REDUCE-IT outcomes trial, which is expected to complete in 2017.

Amarin sought to expand Vascepa's label based on the successful triglyceride endpoint results in the ANCHOR study in statin-treated patients with persistently high triglyceride levels. However, FDA rescinded the Special Protocol Assessment under which the ANCHOR study was conducted after concluding that reduction in serum triglyceride levels is no longer an acceptable surrogate for CV risk reduction given the failures of the AIM-HIGH, ACCORD and HPS2-THRIVE trials (Also see "FDA Makes It Formal, Rescinds SPA For Amarin’s ANCHOR Study" - Pink Sheet, 30 Oct, 2013.). The agency issued a complete response letter in April 2015.

Amarin won a major First Amendment victory in August when a court said it could make truthful, non-misleading statements about the ANCHOR results (Also see "Off-Label Unleashed? Amarin Win Suggests Firms Still Need Strong Data To Skirt FDA" - Pink Sheet, 7 Aug, 2015.). Nevertheless, the company will need robust data on CV risk reduction from REDUCE-IT for a label expansion.

The fate of another non-statin agent with a successful, though not necessarily impressive, outcomes study remains to be seen.

Merck requested a CV risk reduction claim for Zetia based on results from the 18,000-patient IMPROVE-IT trial, which demonstrated a modest but statistically significant 6% reduction in the risk of a major CV event with ezetimibe plus simvastatin compared to simvastatin alone.

However, FDA issued a complete response letter after a negative advisory committee review, during which panelists questioned the robustness of the results and the clinical meaningfulness of the benefit (Also see "FDA’s Zetia/Vytorin Rejection Leaves Cholesterol Drug Sponsors In Limbo" - Pink Sheet, 16 Feb, 2016.).