Effient Approval Shows Mark Of FDA Controls

Postmarketing trials offer opportunity to investigate a possible means to control the bleeding caused by prasugrel, but REMS includes messaging aimed at limited off-label use.

The bleeding risk for Lilly/Daiichi Sankyo's platelet inhibitor Effient (prasugrel) has led FDA to use its full range of safety powers granted under the FDA Amendments Act: mandatory postmarket trials and a Risk Evaluation and Mitigation Strategy.

FDA did go ahead and approve the antiplatelet agent on July 10 for reduction of thrombotic cardiovascular events in acute coronary syndrome patients who will undergo certain forms of percutaneous coronary intervention, based on the strong efficacy for the first-in-class agent. But the newly released FDA approval letter and summary review documents reveal the extent to which the primary safety concerns raised during the review - the increased bleeding events and cancer risk - continue to be a concern.

The approved labeling includes an extensive boxed warning on the increased bleeding risk, with specific directions to minimize the potential risk (Also see "Effient Labeling Could Give Edge Against Plavix Through Pharmacogenetics" - Pink Sheet, 10 Jul, 2009.). FDA, however, is not stopping with labeling.

Having determined that spontaneous adverse event reporting "will not be sufficient to assess a known serious risk of major bleeding and a signal of a serious risk of increased incidence of malignancies" - and because FDA's new pharmacovigilence system required under FDAAA has not yet been established - the agency has determined that "only a clinical trial (rather than a non-clinical or observational study)" will be enough to elucidate the safety issues, and so is mandating two trials.

Mandatory Trial Could Provide Patch To Prasugrel Bleeding Risk

The first required trial aims at better understanding the connection of the platelet inhibition and the bleeding - specifically to study the effects of adding additional platelets to a patient who has received prasugrel and see how long it takes to return to normal clotting. Understanding how the platelet inactivation effect holds up after additional platelets are infused should give FDA - and clinical practitioners - some guide as to how to control any major bleeding events caused by prasugrel administration.

The requirement is for an open-label trial of ex vivo reversal of platelet inhibition by exogenous platelets as a function of time and plasma level of prasugrel active metabolite in 28 normal volunteers given a single 60 mg loading dose of prasugrel plus 325 mg of aspirin. A protocol submission is due in September, and the final report is expected by September 2011.

For Lilly and Daiichi, that's getting off on a serious risk quite easily - given how significant the bleeding risk is, all they need to do is a 28 patient laboratory study. Plus, that study could give them a major advantage, by showing how to control any excess bleeding that occurs with prasugrel use. It could give them the solution to the primary problem that would keep people from using the drug.

The sponsors are also getting somewhat of a pass on the cancer risk. The concerns about malignancy do not appear in the warnings/precautions section of labeling, giving some indication as to how much of an issue FDA has deemed it. The mandatory postmarketing trial to clarify the signal is working with a trial Lilly already has ongoing.

FDA is asking the companies to gather baseline cancer history and cancer adverse event data from the ongoing TRILOGY trial, in 10,300 patients with acute coronary syndrome who are being managed medically (without coronary revascularization). That trial will be completed by December 2012, with the final report due a month later.

A Backdoor To A New Version Of Effient?

On top of the required postmarketing trials, which are aimed at the known serious risks, FDA has asked for a slew of non-mandatory postmarketing commitments that have some intriguing implications.

Two of the four postmarketing commitments are actually a pathway to approval of a different formulation of the prasugrel drug product. Daiichi reports that the alternate formulation will significantly reduce or eliminate the conversion of salt to base; there have been some instability issues. FDA's review documents note that correcting the instability would increase bioavailability in patients using proton pump inhibitors, so there might be greater platelet inhibition.

FDA is asking for the new formulation to be submitted as an sNDA with development, manufacture, control and stability information. A separate postmarketing commitment covers a clinical trial to test the pharmacokinetics of the new formulation versus the marketed version "with respect to concentrations of the prasugrel active metabolite and effects on platelet inhibition." Protocols for those fasting and fed bioequivalence studies have already been submitted, and should be completed in August. The final report is expected at FDA in December.

The other pair of postmarketing commitments should help Lilly and Daiichi build better evidence to put behind the personalized medicine commercial opportunity for Effient.

A bonus element of the final labeling was the inclusion of a separate analysis of the pivotal trial that showed that the prasugrel active metabolite works in patients who do not respond to Plavix due to a genetic variant to the CYP2C19 allele - where both active versions are metabolized. Thirty percent of the population have the decreased function in the CYP2C19 pathway, and thus have a natural lowered response to clopidogrel, and the opportunity gets bigger because that pathway can also be blocked by use of proton pump inhibitors ( (Also see "Lilly, Daiichi Explore Pharmacogenomic Marker For Prasugrel" - Pink Sheet, 11 May, 2009.), p. 18).

The companies have already completed a trial comparing the marketed and reformulated versions of prasugrel in the presence and absence of proton pump inhibitors; FDA has set a December deadline for that report.

FDA is also asking the companies to collect baseline samples in TRILOGY for genotyping CYP450 enzymes, "to allow a comparison of effectiveness and bleeding in prasugrel and clopidogrel subgroups by metabolizer status." That analysis will come in with the full TRILOGY results, in January 2013.

REMS Requires Communication - For Two Years Only

The Effient sponsors are also getting off lightly on the risk management front. There is a REMS for prasugrel - submitted on July 10, the day of the approval - but it stops short of the full complement of controls that might have been put in play, given the recognized bleeding risk.

The REMS consists mainly of a Medication Guide, but there is also a required communication plan that will cover a broad swath of the medical community: interventional cardiologists, clinical cardiologists, emergency medicine physicians, internal medicine physicians and primary care physicians.

FDA stipulates that there will be a Dear Healthcare Provider letter and a prescriber brochure, which will communicate two aims: 1) the serious risk of bleeding associated with Effient, and 2) appropriate patient selection (emphasizing patients in whom Effient should not be used).

But the communication requirement is only temporary. "This element of the REMS is not intended to continue over the lifetime of the product; it will function only to inform prescribers of the serious risk of bleeding associated with Effient therapy for a period of two years," the REMS documents note.

The communication plan, even with the limited timeframe, should be enough to have a controlling effect on off-label use.

Considering that the approved indication is somewhat limited (to only certain forms of PCI) and how fully labeling proscribes use to avoid bleeding problems, that too could discourage broader use of prasugrel. Off-label use in a wider variety of settings, however, is an essential component of the antithrombotic market.

In the end, there's more opportunity - carved out by the greater regulatory flexibility allowed by the FDAAA powers - than there could have been (see (Also see "An 18 Percent Solution? Lilly And Daiichi Bet On A Premium Price For Effient Over Plavix" - Pink Sheet, 15 Jul, 2009.)). That the approval is not as broad as Plavix is a disappointment based on the original development rationale for the drug, but considering the bleeding profile that emerged in late-stage clinical trials, the REMS-balanced approval (and the personalized medicine opportunity) gives Lilly/Daiichi a shot at a blockbuster product, though maybe not the mega-blockbuster envisioned.

- Mary Jo Laffler ([email protected])