The comparator in AstraZeneca's PLATO trial for its antiplatelet candidate Brilinta (ticagrelor) was clopidogrel (Bristol-Myers Squibb/Sanofi-Aventis' Plavix ) but the real test for the product, should it reach the market, may be against Eli Lilly/Daiichi Sankyo's recently approved Effient (prasugrel).

AstraZeneca released Phase III data for Brilinta at the European Society of Cardiology congress in Barcelona Aug. 30, confirming that in head-to-head competition it bested clopidogrel at reduction of cardiovascular events in acute coronary syndrome patients without an increase in major bleeding, but the report also gives competitors a few points to bring up with prescribers.

In the 18,624-patient PLATO study (the Study of Platelet Inhibition and Patient Outcomes), ticagrelor was associated with a 16 percent relative risk reduction with regard to the primary end-point - a composite of death from cardiovascular causes, myocardial infarction and stroke (p<0.001). the="" incidence="" of="" major="" bleeding="" was="" 11.6="" percent="" versus="" 11.2="" percent="" (p="">

The event rate reduction was driven by a reduction in cardiovascular deaths (4.0% vs. 5.1%, p=0.001) and myocardial infarction (5.8% vs. 6.9%, p=0.005), with no impact on stroke, a finding that is "old news," for antiplatelet developers, AstraZeneca Executive Director of Clinical Development Jay Horrow said in an interview.

Face-To-Face In The Market Place

But the biggest challenge to either Effient or Brilinta is the impending genericization of Plavix in the U.S. in 2012, "The price disparity between Effient, Brilinta, and generic Plavix could tip those payers/patients/physicians who are 'on the fence' about which drug to use to choose the least costly alternative - generic Plavix," Stanford C. Bernstein analyst Timothy Anderson argues in an Aug. 31 note.

Lilly and Sanofi are hoping that pharmacogenomics language in Effient's label will help differentiate it from Plavix, which added a precaution about potential non-responders earlier this year (¹ Also see "Plavix Pharmacogenomic Label Update May Help Lilly With Effient Launch" - Pink Sheet, 3 August, 2009.).

Looking ahead to 2015, Bernstein has Plavix maintaining its dominant position, yet earning only $2.7 billion because of generic competition, with Effient second at $1 billion and Brilinta earning around $600 million, not having much eroded Effient market share. Eli Lilly and Daiichi Sankyo gained approval for Effient in July (² Also see "Effient Labeling Could Give Edge Against Plavix Through Pharmacogenetics" - Pink Sheet, 10 July, 2009.).

However, competition from each other isn't the most important challenge the competitors have. AstraZeneca and Eli Lilly "shifting a few hundred million dollars from one company to the other will not move the profit needles much" in the face of the patent cliffs both companies are approaching, Anderson says.

Leerink Swann wasn't as sure an approved Brilinta along with clopidogril's success wouldn't cut into Effient's sales. Based on feedback from physicians attending the congress, analysts Seamus Fernandez and Kathryn Alexander sent out a note Aug. 31 announcing that "we are reducing our Effient forecasts by $40 million in '09 to $55 million and by $1.025 billion to $900 million in 2015."

The "off-target" side effects seen with Brilinta means Effient will still have a place in treatment, but we expect it to be further "niched" by Brilinta, they say.

Even before the PLATO data, AstraZeneca was talking up Brilinta's reversibility and its fast action compared to Plavix, a prodrug, or Effient, an intermediate metabolite. Ticagrelor is an active compound that is rapidly absorbed in the intestine, without the need for further biotransformation. It is a first-in-class cyclo-pentyl-triazolo-pyrimide, chemically distinct from the thienopyridine class, which includes clopidogrel and prasugrel.

And unlike the others, its action is reversible, a plus for patients likely to need CABG surgery and an advantage AstraZeneca featured when it released top-line data in May (³ Also see "AstraZeneca’s Antiplatelet Agent Brilinta Superior To Plavix In Phase III Trial" - Pink Sheet, 11 May, 2009.).

AstraZeneca is on track to submit the ticagrelor NDA in the fourth quarter, making a launch possible late in 2010.

Avoiding Major Problems - For Brilinta And Patients

"For every 54 patients treated with ticagrelor instead of clopidogrel for about a year," Horrow said, "we'll save one major adverse cardiac event, and these are important events we're talking about: death or heart attack."

Compared with clopidogrel, there were no significant increases in the rate of total major bleeding with ticagrelor. But ticagrelor was associated with a higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P=0.03).

And when minor bleeding was added to the major bleeding results, ticagrelor showed an increase versus clopidogrel (16.1% vs. 14.6%, p=0.008).

The results were published simultaneously in the New England Journal of Medicine.

Surprising Overall Mortality Effect

But while Brilinta's advantage over Plavix in major bleeding appears not without cost, the novel antiplatelet drug had some interesting surprises in its readout.

One positive surprise, Harrow said, is the reduction in cardiac mortality. "Other drugs have not shown a difference in cardiovascular death, so ... that's new and exciting, and it's really gaining the attention of the physicians" at the congress.

Another exciting discovery: The benefit grows with time. "In previous trials the benefit occurs early on, and then it remains. ...With ours not only does the initial benefit remain, it actually grows with time, and this has not been seen before."

Finally, Brilinta appears to have a positive effect on overall mortality that warrants further inquiry. When AstraZeneca did its all-cause mortality check to be sure the drug wasn't adversely affecting health in some other part of the body, researchers found that "we had at least as good a savings in all-cause mortality as we had in cardiovascular mortality, Horrow said. The rate of death from any cause was 4.5 percent versus 5.9 percent with clopidogrel (p=0.001).

"We think there's something special going on here." AstraZeneca plans to continue development efforts to examine what other properties ticagrelor might have, he said.

And then there's the "North American oddity." Inexplicably, a subgroup analysis of data from PLATO patients in North American showed no treatment advantage for ticagrelor. While analysts coped with how FDA might perceive the finding, AstraZeneca said it is investigating the inconsistency, but it won't impede the firm's submission plans (see ⁴ Also see "Brilinta's North America Anomaly Stymies AstraZeneca, Worries Analysts" - Pink Sheet, 7 September, 2009.).

PLATO Bleeding Vs. TIMI Bleeding

Different studies define bleeding in different ways, and it's important to understand the definitions used in the PLATO trial when comparing the data with other trials, said Horrow.

PLATO bleeding definitions are different from TIMI (thrombosis in myocardial infarction) definitions, which are "very appropriate for the acute care setting, focused on cath lab and angioplasty and clot-busting drugs," but not for both acute and chronic settings, Horrow said. PLATO is actually more inclusive than TIMI.

The PLATO definition of "major bleed" correlates very closely with what would be called a TIMI Major plus Minor bleed, so "when we say PLATO major bleeding, we're talking about all bleeds that are more than the kind of thing that would just send somebody to a doctor for intervention," Horrow explained.

"What we really want to get across here is people have different views of bleeding, and it's really important to evaluate it using different scales [but] you can slice this several different ways and you get the same results in PLATO - namely no increase in bleeding," he stressed.

In any event, AstraZeneca analyzed the PLATO study data by TIMI methods as well as its own, "and there was no difference on the TIMI major scale, there was no difference on the PLATO major scale, and there was no difference on the TIMI Major plus Minor scale, because it is very similar to PLATO, he said.

But, while the announcement that Brilinta bested Plavix on major bleeding may be technically correct, there is still the question of the bleeding in patients who did not undergo bypass surgery, Bernstein's Anderson said. Using TIMI criteria, they account for approximately one-third of major bleeds in the study, a "substantial proportion," he said. Measuring by TIMI, the result for non-CABG-related major bleeding was 2.8 percent versus 2.2-percent, according to the NEJM report.

That said, the fact Brilinta showed no increased bleeding in CABG patients "is no small feat," and a strong indication of the antiplatelet drug's potential usefulness in the peri-procedural setting or general acute coronary syndrome setting, where it is not known whether patients will progress to CABG, said Anderson.

Brilinta's treatment benefit was apparent in the first 30 days and persisted through the treatment period, Arnold points out in her Aug. 31 note. That finding supports the use of Brilinta as a chronic-use drug, she asserts.

Adverse Events Unusual But Not Remarkable?

Ticagrelor has some new off-target side effects not seen with clopidogrel or prasugrel, and though they don't seem to add risk, they "may certainly have an effect on the quality of life," Albert Schömig, Deutsches Herzzentrum/First Medizinische Klinik rechts der Isar, Muchich, said in a commentary accompanying the NEJM article.

Because of those effects - dyspnea (shortness of breath), bradyarrhythmias (ventricular pauses) and increased uric acid and creatinine serum levels -ticagrelor probably shouldn't be used in patients with chronic obstructive pulmonary disease, hyperuricemia, any degree of renal failure, bradyarrhythmias not protected by pacemakers, syncope, or a need for treatment with an ADP-receptor antagonist for more than a year, says Schömig.

Patients on the drug should be carefully observed in the long term to establish the overall impact of these effects, he says.

Marketers of Effient and Plavix will be able to point to those side effects, however, regardless whether they have real implications for safety.

- Shirley Haley ( ⁵ s.haley@elsevier.com )

AstraZeneca's Ticagrelor Brilliant At ECS Congress; Will It Outshine Effient?

More from Archive

More from Pink Sheet