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Portola in the News

BioWorld Insight
September 6, 2010
By Trista Morrison

The days of the mega-blockbuster are not over. Big pharma’s biggest sellers may be tumbling off the patent cliff, and replacements in the pipeline may be increasingly aimed at niche indications, but the drug industry is about to hit it big with a new class of anti-clotting drugs.

How big? On the antiplatelet side, where drugs seek to prevent platelets in the arteries from attaching to plaques and forming clots, market leader Plavix (clopidogrel bisulfate, Sanofi -Aventis SA and Bristol-Myers Squibb Co.) generated $6.1 billion last year. On the anticoagulant side, where drugs like Lovenox (enoxaparin, Sanofi -Aventis SA) and warfarin interfere with the coagulation cascade to prevent clots in the veins, analysts say the opportunity could be worth upwards of $10 billion.

And in both categories, new drugs emerging from Phase III trials offer opportunities to expand the market.

Slow Climb to the Top
Plavix, Lovenox and warfarin are not particularly new drugs. Warfarin has been around since the 1950s, while Lovenox came on the scene in 1993 and Plavix followed in 1997.

That means it has been more than a decade since any newcomers challenged these standards in the lucrative anticlotting market. That seems like an awfully long time, given that each has significant drawbacks. Plavix is relatively slow to act, irreversible once it starts, and ineffective in an estimated 30 percent to 40 percent of patients. Lovenox is mainly limited to acute, hospital settings. Warfarin is plagued by drug interactions and bleeding risk, requiring careful monitoring, and about 40 percent to 50 percent of patients can’t tolerate it.

William Lis, CEO of Portola Pharmaceuticals Inc., said the lack of progress in the anti-clotting field is “not for lack of trying.”

Lis said the current standards, when used at the right dose in the right patients, are quite effective. Initially, drug makers were unsure if they’d be able to find new targets and produce new drugs that were superior to what was already available. If the new drugs were just noninferior with perhaps some added convenience, would they be worth the risk?

And the risk is significant. Back when Lovenox was first approved, the average cardiovascular clinical trial had some 500 to 1,000 patients. Now each Phase III trial might have 10,000 to 25,000 patients, and each drug might be undergoing several Phase III trials simultaneously. The clinical program supporting Johnson & Johnson and Bayer AG’s anticoagulant rivaroxaban is expected to enroll more than 65,000 patients. “That’s the magnitude of what it takes to get drugs approved in these indications,” Lis said. “These are big bets.”

All the bigger because it’s difficult to translate Phase II success into Phase III. While Phase II trials might show an impact on biomarkers, they aren’t big enough to measure clinical outcomes. And so there have been setbacks, with some drug makers shifting their focus away from cardiology in favor of oncology or other indications.

All of which has kept most biotechs out of the space. “There’s either nobody foolish enough to try or no one as skilled as we are,” Lis quipped.

Portola’s history traces back to COR Therapeutics Inc., which was acquired by Millennium Pharmaceuticals Inc. (now part of Takeda Pharmaceutical Co. Ltd.) in 2001 . The original COR team spun out as Portola a few years later. “Our founders were told this was too big of a challenge to take on,” Lis said. And indeed, the massive cost of cardiovascular drug development forced privately-held Portola to find partners for both of its lead programs: antiplatelet drug elinogrel is partnered with Novartis AG in a $575 million deal, while anticoagulant betrixaban is partnered with Merck & Co. Inc. under a $470 million deal.

Summit in Sight
But after a decade of work, the pieces are starting to come together not just for Portola and its partners, but for several players on both the antiplatelet and anticoagulant sides of the equation. The antiplatelet space is slightly more advanced. Eli Lilly and Co.’s Effient (prasurgrel), a P2Y12ADP antagonist, gained approval last year for percutaneous coronary intervention. The drug’s black-box warning for bleeding risk has hampered its ability to compete with Plavix; it sold only about $32 million in the first half of this year. But Lis said the drug proved you could improve cardiovascular outcomes by pushing the efficacy of a platelet inhibitor.

Taking the next step is AstraZeneca plc’s Brilinta (ticagrelor), another P2Y12ADP antagonist, but one that is reversible, which is expected to help manage bleeding. In a Phase III trial, the drug bested Plavix in reducing cardiovascular events without increasing major bleeding risk. Brilinta is under FDA review with an approval decision expected by Sept. 16, following a positive advisory panel recommendation last month.

Lis said Portola and Novartis’ elinogrel, also a P2Y12ADP antagonist, is aiming to go even farther in pushing efficacy while minimizing bleeding risk. Phase II data presented at last week’s European Society of Cardiology annual meeting showed elinogrel provided better and faster antiplatelet activity than Plavix, and a 24,000-patient Phase III trial in coronary heart disease is slated to kick off early next year.(See BioWorld Today, Aug. 31, 2010.)

In the anticoagulant space, the most advanced up-and comer is Boehringer Ingelheim GmbH’s Factor IIa inhibitor Pradaxa (dabigatran etexilate). The drug is approved overseas and has completed Phase III studies in the acute deep vein thrombosis space and chronic atrial fibrillation setting. It is under FDA review with a panel meeting coming next month.

At last week’s ESC meeting, the spotlight focused on Phase III data from Factor Xa inhibitors apixaban (Pfizer Inc. and Bristol-Myers Squibb Co.) and rivaroxaban (Johnson & Johnson and Bayer AG). Apixaban proved it was better than aspirin at preventing strokes or systemic embolisms in atrial fibrillation patients who couldn’t tolerate warfarin.

Meanwhile rivaroxaban was noninferior to Lovenox followed by warfarin in preventing recurrent venous thromboembolism in DVT patients. (See BioWorld Today, Sept. 1, 2010.)

Portola and Merck’s Factor Xa inhibitor, betrixaban, is slated to start Phase III in atrial fibrillation next year. Although there are several new players emerging in the antiplatelet and anticoagulant fields, Leerink Swann Research analyst Seamus Fernandez believes they will each find a big niche.

“It’s going to come down to the trials each company conducts,” Fernandez said. For example, on the antiplatelet side, Brilinta appears primed to replace Plavix as the new standard of care in acute coronary syndrome. But Portola and Novartis’ Phase III elinogrel trial will focus on coronary heart disease, a huge indication for which Plavix is used off-label but not approved.

On the anticoagulant side, Fernandez noted that Pfizer and BMS’ apixaban may be the only drug with data comparing it to aspirin, which is signifi cant because 40 percent to 50 percent of patients can’t tolerate warfarin and take aspirin instead.

Meanwhile rivaroxaban offers an opportunity to replace two drugs with one and avoid the Lovenox-to-warfarin transition. “I see the need for warfarin becoming significantly decreased over time,” Fernandez predicted. He added that doctors and patients consider warfarin “a real pain in the butt” and are eager for new options.

The Next Big Thing
With so many new anti-clotting drugs nearing the market, Fernandez said physicians will have a “smorgasbord” of options and will be able to pick which drugs are the best fit for each patient.

And once the initial approvals are granted, Lis expects to see exploration of combinations of antiplatelet and anticoagulant drugs. He estimated that some 10 percent to 15 percent of patients could be candidates for both drugs, such as an atrial fibrillation patient who needs a stent placed, or a DVT patient who develops acute coronary syndrome.

Lis also expects to see a new unmet need develop for Factor Xa inhibitor antidotes. Because although the new Factor Xa inhibitors will be safer than warfarin, they will still have some bleeding issues, and there will still be situations where their activity needs to be reversed. Portola has a Factor Xa antidote in preclinical development, and Lis said this is one segment of the market he believes biotechs will be able to enter.

Lis also expects to see increased biotech competition for another of Portola’s early stage programs: thromboxane receptor antagonism. These drugs are similar to aspirin, but without the gastrointestinal side effects.

Biotechs in the heart failure space may also be positioned to benefit as the anti-clotting market explodes. As Lis explained, if there is one big area of unmet medical need in the cardiovascular space outside of anti-clotting drugs, it is heart failure.