Portola/Novartis Plan Phase III Trial For Elinogrel, With Eyes For Plavix Market

Portola's anti-thrombotic vision: Execs discuss possibilities for two partnered, Phase III ready drugs - elinogrel and betrixaban.

After airing data for two Phase III-ready and successfully partnered drugs - elinogrel and betrixaban - execs for the privately-held Portola said they are well-positioned to take advantage of enthusiasm for a new and improved generation of anti-thrombotics.

The European Society of Cardiology meeting in Stockholm was the platform for releasing the first Phase II data for the anti-platelet drug elinogrel, partnered with Novartis, as well as additional Phase II efficacy results for the oral Factor Xa inhibitor betrixaban, which is partnered with Merck.

Portola execs said that the most important data set for the company at the ESC meeting were the Phase II results for elinogrel in the INNOVATE-PCI trial, which compared elinogrel to Sanofi/Bristol's blockbuster Plavix (clopidogrel).

With elinogrel, the companies are aiming for a drug that has enhanced anti-platelet activity with lower risk of bleeding compared to Plavix. Elinogrel is being positioned as a direct-acting, reversible P2Y12 ADP receptor antagonist. One key advantage, developers say, will be its availability in oral and intravenous forms, which should prove convenient in the hospital setting, where patients make the transition from I.V. to oral delivery.

"It's the only drug available orally and intravenously. It's ideally suited for acute situations," said Chief Medical Officer Dan Gretler.

Portola Chief Executive Officer Bill Lis noted that there is considerable excitement at the ESC meeting for novel anti-thrombotics, with the release of Phase III data for a number of late-stage drugs such as Bayer/J&J's Xarelto (rivaroxaban) and Bristol's apixaban.

Portola acknowledges that at the Phase II stage, its data are not definitive - but they are nevertheless encouraging and bode well for gaining a place in a growing market for that some analysts estimate could be worth $10 billion to $20 billion.

Novartis and Portola are aiming to establish elinogrel for use in patients with stable coronary disease and acute coronary syndrome. Following the Phase II results, the firms are set to launch a trial in the first quarter of 2011 testing two doses of the drug along with aspirin in 24,000 patients with a prior myocardial infarction. This could serve as a pivotal Phase III trial to allow for a regulatory filing, Lis said.

Writing in an Aug. 30 note, Leerink Swann analyst Seamus Fernandez noted that the planned trial for elinogrel would address a broad population of patients with prior MIs and" appears to target the successful aspects of the CHARISMA (Plavix vs. aspirin in high risk and stable CAD patients) study."

Timing of a second trial in ACS has not been determined nor have plans been firmed up for other indications.

Per a partnership deal in February 2009, Novartis owns worldwide rights and will foot the entire Phase III bill for the drug (Also see "Coulda, Shoulda? Sanofi's Skip On Portola Proves Clot-Buster Gain For Novartis" - Pink Sheet, 12 Feb, 2009.).

Meanwhile, the Phase III strategy for betrixaban is being mapped out, but Merck has not yet released details and timing. As with the Novartis partnership, Merck is set to finance the whole Phase III program for betrixaban.

INNOVATE-PCI Results

Results from the randomized, double-blind INNOVATE-PCI dose-ranging study of 650 patients undergoing non-urgent percutaneous coronary interventions were released at ESC on Aug. 30. The study evaluated anti-platelet activity of I.V. elinogrel followed by oral elinogrel based on several endpoints over a treatment period of 60 to 120 days in comparison with standard-of-care Plavix.

Patients taking elinogrel had more "rapid and greater" antiplatelet activity than Plavix. This was achieved without increasing the risk for major bleeding and elinogrel was well-tolerated.

There were no TIMI major bleeding events in the acute 24 hour phase in either the clopidogrel arm or in patients treated with 100 or 150 mg doses of elinogrel. One TIMI minor bleeding event occurred in each of the elinogrel 150 mg and 100 mg arms, Portola noted.

In the chronic phase of treatment between 24 hours and 120 days, bleeding events were low with no TIMI major and one TIMI minor bleeding event in the clopidogrel-treated patients and two TIMI major and no TIMI minor events in both the elinogrel 150 mg and 100 mg arms, the company reported. There was a dose-dependent trend in the rate of lesser bleeds (bleeding requiring medical attention) with elinogrel during the peri-PCI period (3.9 percent for the clopidogrel arm vs. 6.6 percent and 9 percent for each of the pooled intravenous doses).

Researchers noted that liver enzymes were elevated with elinogrel, though they resolved spontaneously within 60 days of treatment. Rates of shortness of breath were also higher for the elinogrel patients but tended to be mild and not to result in discontinuation. Discontinuation rates overall were similar for the two drugs.

Further Betrixaban Data Hones In On Phase III Design

Also at the ESC meeting, Portola aired some additional pharmacodynamic data for its novel oral direct Factor Xa inhibitor betrixaban. Initial results from the Phase II dose-ranging EXPLORE-Xa study had been released at the American College of Cardiology meeting in March (Also see "Momentum Grows For Novel Oral Anticoagulants Out To Replace Warfarin" - Pink Sheet, 29 Mar, 2010.). The trial tested three doses -40 mg, 60 mg and 80 mg - against warfarin in 500 patients with non-valvular atrial fibrillation or atrial flutter and at least one risk factor for stroke. The study met its primary endpoint of time to occurrence of major or clinically relevant non-major bleed.

Further analysis presented at the ESC showed that betrixaban was effective at reducing incidence of bleeds at all three doses based on three pharmacodynamic factors - anti-Factor Xa units, thrombin generation and D-dimer results. These suggest that the company could include the lowest dose in a Phase III trial to suit a different population at higher risk of bleeding. However, dosing in Phase III has not been decided. The companies have also not decided whether they need to advance a smaller-size pill. Gastrointestinal side effects had been an issue in the trial and were possibly related to pill size.

With Phase III expenses for two "potential mega-blockbusters" covered, Portola execs said they are free to develop their proprietary compounds. Since 2003, the company has raised $218 million.

Portola has an antidote in development in conjunction with the betrixaban program that would work for all Factor Xa inhibitors; the ability to reverse an anti-coagulant effect can be an asset for patient management. The firm also has developed a thromboxane receptor antagonist targeted at patients who cannot tolerate aspirin. Furthermore, its pipeline includes PRT062607, a Syk-specific kinase inhibitor for rheumatoid arthritis and other chronic inflammatory diseases.

The partnerships with Merck and Novartis for betrixaban and elinogrel restrict possibilities for a merger or acquisition exit for investors, but the company signaled at the ESC conference and confirmed in an interview with "The Pink Sheet" DAILY that it's open to an IPO in 2011.

- Emily Hayes ([email protected])