Eli Lilly released powerful efficacy results from an eagerly anticipated Phase III head-to-head trial of its experimental antiplatelet agent prasugrel, which has the potential to take market share from Bristol-Myers Squibb's blockbuster Plavix (clopidogrel).

Prasugrel produced a 19 percent reduction in relative risk (p=0.0004) for the primary efficacy endpoint, a composite of cardiovascular death, non-fatal heart attack or non-fatal stroke compared with Plavix, in the TRITON TIMI-38 trial, whose results were released Nov. 4 at the American Heart Association's Scientific Sessions in Orlando, Fla.

Lilly added that a reduction in risk for cardiovascular events was observed as early as three days into therapy for prasugrel patients (60 mg loading dose/10 mg maintenance dose) compared with those on clopidogrel (300 mg LD/75 mg MD). The study included more than 13,600 patients across the full spectrum of acute coronary syndrome undergoing percutaneous coronary intervention.

In light of the superior TRITON results, Lilly and development partner Daiichi Sankyo have decided to launch another Phase III head-to-head trial pitting prasugrel against Plavix -- TRILOGY ACS. That study will enroll about 10,000 patients in 35 countries, the firms said.

Lilly/Daiichi said they plan to file an NDA by year end and submit a marketing application in Europe in 2008.

Despite the efficacy benefit, TRITON results were not entirely rosy for Lilly. Prasugrel patients without coronary artery bypass graft experienced significantly more major bleeding (2.4 percent vs. 1.8 percent, p=0.03) and higher rates of life-threatening bleeding (1.4 percent vs. 0.9 percent, p=0.01) than clopidogrel patients.

Not surprisingly, Bristol is eyeing the increased bleeding results as a way to maintain market-leader status for its top-selling drug. Plavix sales for the third quarter of 2007 were $1.3 billion worldwide, with $1.1 billion of that in the U.S.

"With the wealth of safety and efficacy data on Plavix, this drug is well understood by physicians in a real-world setting," Bristol told "The Pink Sheet." "The bleeding rate observed with prasugrel in TRITON raises important questions."

The randomized, double-blind, parallel-group trial followed the patients for at least 12 months after percutaneous coronary intervention.

Prasugrel significantly reduced the relative risk of cardiovascular death, non-fatal heart attack and non-fatal stroke by 21 percent in patients with high-risk heart attack and 18 percent in patients suffering from unstable angina compared with clopidogrel. Prasugrel-treated patients experienced a 34 percent decline in urgent target vessel revascularization and a 42 percent reduction in heart attack with subsequent death from cardiovascular causes, the study showed.

The data were published in a Nov. 4 article posted on the New England Journal of Medicine Web site. The article says, "Our data support the hypothesis that the greater inhibition of adenosine diphosphate-induced platelet aggregation by means of the tested regimen of prasugrel, a potent oral P2Y12 inhibitor, is more effective at preventing ischemic events than is the inhibition conferred by a standard regimen of clopidogrel."

The increased bleeding rates, however, could hamper efforts by Lilly/Daiichi to convince doctors with patients on Plavix or patients eligible for blood thinning treatments to switch to prasugrel, should the drug be approved.

In announcing the results, Lilly also took proactive steps to identify patient groups most susceptible to increased bleeding.

The firm noted that TRITON identified three distinct patient subpopulations in both treatment arms with the highest risk of major bleeding: patients aged 75 or older, patients weighing less than 132 lbs and those with past history of transient ischemic attack or stroke.

"In the subpopulations defined as being at greater risk of bleeding, the net clinical benefit was not different between prasugrel- and clopidogrel-treated patients (p=0.43). Without the subpopulations defined as being at greater bleeding risk, the net clinical benefit was 20 percent (10.2 percent vs. 12.5 percent, p<0.001)," Lilly said.

The NEJM article expresses concern about the results in patients who had had a cerebrovascular event before enrollment. It says that in addition to more frequent bleeding, those patients had "numerically worse clinical outcomes," as measured by the primary endpoint, than those without such a history. The findings "add to the concerns about the risk of intensive inhibition of platelet aggregation in this population."

Researchers are investigating whether pharmacokinetic data from several prasugrel studies, including TRITON, would support giving a lower dose of prasugrel to the three patient groups that experienced higher rates of bleeding, Lilly said.

The drug maker also maintained that despite the bleeding risk, there is a net clinical benefit for prasugrel compared with Plavix. The prasugrel arm had a 13 percent reduction (12.2 percent vs. 13.9 percent, p=0.004) in overall events.

Elliott Antman, senior investigator for the TIMI Study Group at Harvard Medical School, said in a written statement, "With the data from TRITON and other studies, we expect to define populations at particular bleeding risk to help establish clear guidance for using this promising therapy."

During a Lilly conference call Nov. 4, several Wall Street analysts expressed concern that the bleeding results could discourage doctors from prescribing prasugrel.

Sanford Bernstein analyst Tim Anderson questioned how many physicians would prescribe prasugrel given the bleeding profile.

J. Anthony Ware, Lilly's cardiovascular platform leader for prasugrel, responded, "As a cardiologist, I really think that these data will be very exciting for the cardiologists because of the efficacy. Especially because we're able to provide information as to [which] patients are at risk ... [the efficacy] will be something that they will find appealing."

He added that an additional prasugrel study, TIMI 44, will be published Dec. 18.

Late last month, Lilly and Daiichi announced they were suspending enrollment in two small Phase II pharmacodynamic studies also comparing prasugrel to clopidogrel. Those studies were suspended while the firms work out undisclosed dosing issues, Lilly said.

No safety signals triggered the action, Lilly told "The Pink Sheet."

"This was an analysis of a number of studies and in looking over the statistics and looking over all the information, from [those with acute coronary syndrome] to healthy patients, we decided we might want to take a look at dosing," Lilly said.

"Patient enrollment will resume as soon as additional analyses of pharmacokinetic and clinical data are completed, and the protocols are amended and approved by institutional review boards," Lilly added.

One of the suspended studies, TABM, is a parallel assignment trial designed to observe 150 U.S. patients with acute coronary syndrome taking clopidogrel 75 mg daily following percutaneous coronary intervention with stent placement.

The randomized, double-blind, pharmacodynamic trial is assessing the effects on platelet activity at 24 hours, one week and two weeks after first study dose among three arms: patients on a 10 mg maintenance dose of prasugrel; patients receiving a 60 mg loading dose of prasugrel followed by a 10 mg maintenance dose of prasugrel; or those on a maintenance dose of 75 mg clopidogrel.

Enrollment was also halted in a French trial, TABN, a crossover assignment study designed to establish prasugrel's advantage at a 10 mg maintenance dose compared with 150 mg clopidogrel after a 900 mg loading dose of clopidogrel.

To date, 119 patients had been enrolled in both trials out of an estimated 220, Lilly said.

The FDA-approved loading dose for Plavix is 300 mg.

Phase I results for prasugrel showed faster onset of action and greater clotting activity than the standard dose of Plavix.

Lilly noted that the expected changes in protocol for the suspended Phase II trials "do not provide a basis for inferring overall outcomes of other prasugrel trials."

- Jonathan M. Block (j.block@elsevier.com) and Pamela Taulbee (p.taulbee@elsevier.com)

Lilly Prasugrel Beats Plavix In TRITON, But Bleeding Data Raise Questions

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