Portola strengthens on hopes for cardiovascular franchise

Date October 21, 2013

For all the touted benefits of factor Xa inhibitors like Xarelto and Eliquis, their long half-lives come with a disadvantage that is hard to ignore: patients in need of emergency surgery are put at increased risk of dangerous bleeding incidents if they are taking these anticoagulants (Vantage Point – As Eliquis limps on Xarelto dominates oral blood thinners, October 9, 2013).

So as Portola Pharmaceuticals’ PRT4445 continues to demonstrate efficacy in reversing the effects of this new class of cardiovascular drugs, it appears as though there may be more value yet to be unlocked from this new arrival to the public markets. Collaborations with the owners of both of the marketed Xa inhibitors suggest a healthy commercial potential for Portola’s drug; its biggest question may be whether to outlicense or launch solo.


The latest drop of positive news was new interim data from the phase II trial of PRT4445, also known as andexanet alfa, in reversing the effects of Bristol-Myers Squibb and Pfizer’s Eliquis. The antidote reversed 92% of the anticoagulant activity of Eliquis two minutes after completion of a 420mg bolus dose, and maintained 91% reversal following a two-hour infusion.

Finding a viable antidote is as important commercially to the makers of factor Xa inhibitors as it is to Portola. Eliquis, along with Bayer and Johnson & Johnson’s Xarelto, is aimed at unseating warfarin as the preferred drug in stroke prevention, but does not have a quick antidote as warfarin does in prothrombin complex concentrates and intravenous vitamin K. Quick reversal of the effect of factor Xa inhibitors can be achieved with prothombin complexes like Octaplex, but tends to be used for life-threatenting bleeds. Fresh frozen plasma can be used with warfarin and factor Xa inhibitors alike to maintain haemostasis.

Still, warfarin’s persistence and the failure of Xarelto and especially Eliquis to match bullish forecasts could be partly explained by specialists’ familiarity with the venerable drug’s safety (Warfarin proves resilient against oral blood thinners, August 21, 2012). Warfarin is not as easy to dose as the factor Xa inhibitors and has numerous drug interactions, but when haemorrhagic events occur or emergency surgery is necessary, the knowledge that prothombin complex concentrates and IV vitamin K can achieve complete reversal in 10-15 minutes should be comforting to physicians.

The owners of Eliquis and Xarelto seem to agree. All have chipped in to support trials of ‘4445 in combination with their drugs; data from the Eliquis phase II study was the first to emerge (Portola chalks up two big pharma names in factor Xa antidote tie-up, November 5, 2012). The similarity in mechanism of action bodes well for the Xarelto trial.

Sales are forecast to hit $162m in 2018, according to EvaluatePharma’s consensus data.

Through the IPO window

Portola floated on the Nasdaq in May and has enjoyed a decent run – shares are up 64% on its offering price of $14.50 through Friday’s market close. But in these days of an inflating biotech bubble, Portola may represent a less-than-common case of the valuation of a development stage company not becoming unhinged from its expectations.

The combined net present value of its two products – ‘4445 and the phase III factor Xa inhibitor betrixaban – stand at $1.05bn, slightly above its market capitalisation of $941m. However, Portola has a disadvantage in that its lead two projects are not in the red-hot oncology space – Pharmacyclics, for example, is now worth 64% more than the NPV of its one major product, haematological cancer drug ibrutinib.

As Credit Suisse analyst Jason Kantor noted when initiating coverage in June, late stage cardiovascular companies are scarce, if only because the necessity of a large sales and marketing force push most late-stage assets into the hands of big pharma. In the case of Portola, however, some wise moves set up the possibility that its two cardiovascular assets could be marketed with a small sales force, allowing it to launch independently.

For one, the South San Francisco-based group has chosen to focus its efforts with betrixaban on preventing thrombotic events in the acutely medically ill immobilised during a hospital stay, an indication in which both Eliquis and Xarelto have failed. For another, the drugs are direct counterpoints, which will allow its sales representatives to pitch the two products to the same physicians. That target audience would be hospital-based physicians rather than those in offices, an effort that Credit Suisse estimates would require 140 people.

Given the previous failures of factor Xa inhbitors in the medically ill population, betrixaban appears to be a bigger risk – although as a phase II product ‘4445 has much to prove. Mr Kantor adds that Portola has learned from the Xarelto and Eliquis stumbles and has improved the design of its phase III study by enrolling sicker and older patients and has taken steps to improve compliance with ultrasounds to identify thromboembolic events.

Portola remains as high-risk as any other mid- to late-stage drug developer, but if it produces positive data and biotech valuations keep climbing, it has the potential to join the ranks of the multi-billion-dollar market cap club in coming months.

To contact the writer of this story email Jonathan Gardner in London at jonathang@epvantage.com or follow @JonEPVantage on Twitter

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