FDA has taken the rare step of formally rescinding Amarin Corp. PLC’s special protocol assessment for the company’s ANCHOR study of its cholesterol-lowering fish oil drug Vascepa (icosapent ethyl).

Amarin is attempting to expand the indication for Vascepa based on the Phase III ANCHOR study, which showed a reduction in triglyceride levels. But the ANCHOR application came in the wake of previous trials that failed to support use of the triglyceride endpoint as a surrogate for cardiovascular risk. At the Oct. 16 advisory committee review of the sNDA, it became clear that context had caught up with Amarin’s application.

Amarin received written notification Oct. 29 that FDA rescinded the SPA because the agency determined a “substantial scientific issue essential to determining the effectiveness of Vascepa in the studied population was identified after testing began,” the company said in a same-day SEC filing.

Specifically, FDA said it no longer considers a change in serum triglyceride levels as sufficient to establish the effectiveness of a drug intended to reduce cardiovascular risk in subjects with serum triglyceride levels below 500 mg/dL.

Vascepa has a Dec. 20 user fee goal date for use in combination with a statin to reduce triglycerides, non-high-density lipoprotein cholesterol, apolipoprotein B, low-density lipoprotein cholesterol, total cholesterol and very-low-density lipoprotein cholesterol in adults with mixed dyslipidemia and coronary heart disease or a CHD risk equivalent.

The company had an agreement with FDA that a Phase III trial with a surrogate endpoint could support the application as long as an outcomes trial was already more than half-way enrolled at the time of submission. Amarin had SPAs for both ANCHOR and their ongoing outcomes study, REDUCE-IT. ANCHOR did show that Vascepa significantly reduced triglyceride levels from baseline compared to placebo after 12 weeks of therapy, but the application landed at FDA’s desk after a number of cardiovascular outcomes trials for cholesterol-lowering drugs approved as add-ons to statins failed Also see "Panel To Weigh Amarin’s Expanded Vascepa Use Given Clinical Outcome Concerns" - Pink Sheet, 11 October, 2013..

FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 9-2 against approval, saying an expanded indication should not be granted prior to the completion of a cardiovascular outcomes trial, citing the failed cardiovascular outcomes trials of drugs approved on a surrogate of improved cholesterol as a major factor ([A#14131016005]). The SPA revocation letter echoed discussion at the advisory committee, Amarin said.

At the meeting FDA said the failure of previous outcomes studies to demonstrate cardiovascular benefit, including Abbott Laboratories Inc.’s (now AbbVie Inc.) AIM-HIGH study of Niaspan (extended-release niacin) and the ACCORD study of TriCor (fenofibrate), along with Merck & Co. Inc.’s HPS2-THRIVE study of Tredaptive (extended-release niacin/laropiprant), were game changers for Amarin’s SPA. The studies were completed after FDA’s agreement on Amarin’s ANCHOR SPA.

These studies “fail to support the hypothesis that triglyceride-lowering drugs significantly reduces the risk for cardiovascular events among statin-treated patients with mixed dyslipidemia and residually high serum triglyceride levels (200-499 mg/dL), FDA’s letter said, according to Amarin.

FDA indicated at the advisory panel that future cholesterol drug approvals may hinge on outcomes studies Also see "Cholesterol Drug Approvals May Hinge On Outcomes Studies; FDA Rejects Diabetes-style Tiered Trials" - Pink Sheet, 21 October, 2013..

The announcement has already changed the expectations for other cholesterol drug programs, with Pfizer Inc. announcing Oct. 29 it is preparing to have cardiovascular outcomes data for its PCSK9 inhibitor bococizumab in the event regulators need it pre-approval ([A#14131029004]). But the sponsors behind the lead PCSK9 programs maintain that based on consultation with FDA, they will be able to file on cholesterol endpoints as long as outcomes trials are underway ([A#14131016001]).

Amarin May Be Gearing Up To Challenge FDA…

A “complete response” letter has been considered a foregone conclusion for the Vascepa sNDA since the advisory committee meeting. The unusual step of officially revoking the SPA could be an indication of how interactions are going with the agency.

On an analyst call following the advisory panel, and before the formal SPA revocation, Amarin Chief Compliance Officer & Senior VP Joseph Kennedy said the company has “a lot of legal options on the table” regarding Vascepa’s sNDA and that it planned to spend a lot of time in Washington reviewing these options, the SPA and the history of the FDA.

CEO Joseph Zakrzewski acknowledged the drug’s approval following the negative advisory panel was “an uphill battle,” but said Amarin would be “spending some significant time with the FDA trying to continue to make our case.”

The company plans to schedule a Type A meeting to discuss the rescinded SPA.

A 2011 update to FDA’s 2002 final guidance on SPA’s allows sponsors to resolve disagreements with FDA action under the SPA program through the formal dispute resolution process, another option Amarin could pursue.

Vascepa was approved in 2012 for use as an adjunct to diet to reduce triglyceride levels in adult patients with severe hypertriglycerdeimia, but the sNDA represents about a 10-fold expansion in the on-label market, according to the company, and the expanded approval may be necessary to keep the company afloat. Following the negative advisory panel the company announced plans Oct. 22 to eliminate about 50% of its staff positions to reduce operating expenses.

Amarin shares closed down 13.6% Oct. 30 at $1.81, a 52-week low. The company had already lost 61% of its value after the advisory committee, dropping from $5.17 on Oct. 15 to $2.01 on Oct. 17.

…But History Suggests It May Not Have Much To Stand On

FDA has long held that SPA agreements are not binding and do not guarantee drug approval, particularly when the science underlying the agreement changes.

For example, both FDA’s 2007 draft and 2010 final guidance on the use of non-inferiority studies to support antibacterial drug approval noted that since the state of the science has changed, prior commitments under an SPA may no longer be valid Also see "Special Protocol Assessments Get Special Focus In Antibiotic Guidance" - Pink Sheet, 1 December, 2010..

In 2009, FDA officials were even pushing for the SPA program, first authorized under PDUFA III in 1997, to move away from the term “agreement” and emphasize the idea that the program was about aligning a clinical trial program with FDA’s current thinking Also see "FDA Says "Agreement" Does Not Have To Be Holy Grail Of SPA Discussions" - Pink Sheet, 6 July, 2009..

And a handful of companies have received “complete responses” despite having an SPA. In November 2009, FDA asked GTx Inc. for an entirely new Phase III trial for toremifene, despite the company meeting the SPA it had agreed upon with the agency Also see "FDA's "Complete Response" On GTx's Toremifene Moves The Goal Posts, CEO Says" - Pink Sheet, 2 November, 2009..

Chelsea Therapeutics International Ltd.’s neurogenic orthostatic hypotension drug Northera (droxidopa), also had an SPA and received a “complete response” in March 2012 with FDA requesting data from an additional trial showing efficacy and durability of effect.

At Northera’s February 2012 advisory committee review, Office of Drug Evaluation I Acting Director Ellis Unger said “a special protocol assessment is for a protocol for a study, it’s not a blessing of a development program” Also see "Northera Review Shows Regulatory Challenges In Difficult Therapeutic Space" - Pink Sheet, 5 March, 2012..

FDA Makes It Formal, Rescinds SPA For Amarin’s ANCHOR Study

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