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

Prasugrel produced a 19 percent reduction in relative risk (p=0.0004) for the primary 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 at the American Heart Association's Scientific Sessions in Orlando, Fla., Nov. 4.

Lilly added that a reduction in risk for cardiovascular events was observed as early as three days in prasugrel patients (60 mg loading dose/10 mg maintenance dose) compared with those on clopidogrel (300 m LD/75 mg MD).

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 was 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 the overall superiority of its top-selling drug. Plavix has annual sales of $7 billion.

"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" DAILY. "The bleeding rate observed with prasugrel in TRITON raises important questions."

The randomized, double-blind, parallel-group trial included more than 13,600 patients across the full spectrum of acute coronary syndrome undergoing percutaneous coronary intervention. It followed the patients for at least 12 months following PCI.

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 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 vs. 12.5, p<0.001)," lilly="">

Researchers are investigating whether pharmacokinetic data from several prasugrel studies, including TRITON, would support giving a lower dose of prasugrel to those three patient groups, 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.

"Our study provided compelling evidence that the prasugrel regimen tested is superior to standard dose clopidogrel...," TIMI Study Group Senior Investigator Elliott Antman, Harvard Medical School, said in a 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 late-day 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 who the 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.

Morgan Stanley analyst Jami Rubin, asked Lilly to comment on a same-day AHA presentation by Eric J. Topol, Case Western Reserve University School of Medicine. "Prescreening may have skewed the results and in a real-world setting, it's likely that many patients vs. the sub-populations you identified, would actually be at risk for bleeding," she said, citing Topol's presentation.

Ware responded, "That's sort of a generic comment that could be made about any clinical trial. I would like to point out that our trial did less cherry picking of patients than any trial ... that comes to memory."

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 (¹ Also see "Lilly, Daiichi Sankyo Suspend Enrollment In Phase II Trials Of Prasugrel" - Pink Sheet, 25 October, 2007.).

The results of the TRITON trial also were published in a Nov. 4 posting on the New England Journal of Medicine Web site.

-Jonathan M. Block (j.block@elsevier.com)

Lilly’s Prasugrel Superior To Bristol’s Plavix In Reducing CV Events In Pivotal TRITON Trial

More from Archive

More from Pink Sheet