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Portola in the News

BioCentury
November 7, 2011
By Michael Flanagan

In its first significant deal since naming new heads of BD and R&D, Biogen Idec Inc. licensed a SYK inhibitor from Portola Pharmaceuticals Inc. that it hopes will overtake the first movers among oral rheumatoid arthritis products by offering better tolerability and more convenient dosing. PRT062607 will begin Phase IIa testing for RA in 2H12.

Steven Holtzman and Douglas Williams joined in January as EVPs of corporate strategy and R&D, respectively, to revamp Biogen Idec’s pipeline. Part of the plan is to fill a gap in Phase I and Phase II programs in neurology, immunology and hematology via licensing or acquisition (see BioCentury, Aug. 29).

According to Holtzman, PRT062607 ticked all the right boxes. Biogen Idec began looking at the program during his first week on the job, “and the more we learned about the compound, the better we liked it,” he said. In late October, Portola granted Biogen Idec exclusive, worldwide rights to PRT062607 to treat autoimmune and inflammatory disorders.

The SYK (spleen tyrosine kinase) inhibitor is in Phase I testing for RA. Williams was particularly keen on partnering with Portola because he believes oral small molecules will soon shift the treatment paradigm for RA by providing similar efficacy to tumor necrosis factor (TNF) alpha inhibitors but with much better convenience for patients.

SYK is a non-receptor protein activated in immune conditions by autoantibodies. It triggers the release of inflammatory mediators such as cytokines, TNF alpha and IL-1. Thus, blocking SYK may help address both the inflammation and tissue damage components of RA (see BioCentury, July 19, 2010).

The only other SYK inhibitor in the clinic is Rigel Pharmaceuticals Inc.’s fostamatinib, which began Phase III testing for RA last month. The program is partnered with AstraZeneca plc.

According to Williams, PRT062607 is far more selective for SYK than fostamatinib, which should translate into more potent inhibition at lower doses and better toler- ability. In addition to SYK, the Rigel compound hits vascular endothelial growth factor (VEGF) receptor 2 (KDR/Flk-1; VEGFR-2), as well as other undisclosed kinases.

PRT062607 is 80-fold more potent for SYK than the next closest kinase, according to John Curnutte, EVP of R&D at Portola.

“Rigel deserves credit for paving the road for SYK inhibitors, but one of the lessons we have learned from oncology is that there is a price to be paid” for hitting multiple kinases, he said.

Adverse events in fostamatinib’s Phase II program included diarrhea, upper respiratory infection, neutropenia and hypertension. In response, AstraZeneca spokesperson Sameena Conning said “there is no evidence to date that a more selective SYK inhibitor would have an improved risk/ benefit profile over that of fostamatinib. Furthermore, there is no evidence to date that exquisite selectivity against SYK would result in a superior safety, efficacy and tolerability profile.”

According to Portola, no safety issues for PRT062607 emerged at high exposures in animal models, and no signals have been seen in single- and multiple ascending dose Phase I trials. “We have dosed for up to 10 days in humans and have yet to see any serious side effects either clinically or in laboratory analyses of blood counts, liver function and renal function,” said Curnutte.

Portola CEO William Lis said PRT062607’s half-life offers once-daily dosing, which should differentiate it from other oral RA agents in the clinic. “These are all either twice-daily drugs or aregiven once daily but are pushing the bounds of their PK profile,” he said.

Gilead Sciences Inc. obtained a preclinical SYK inhibitor program via its 2010 acquisition of CGI Pharmaceuticals Inc. The company declined to comment on the status of its program.

Biogen Idec will lead global development and commercialization of PRT062607 in major indications, including RA, systemic lupus erythematosus (SLE) and allergic asthma.

Portola has an option to co-promote the compound in the major indications and will lead U.S. development and commercialization for some smaller indications, such as idiopathic thrombocytopenic purpura (ITP), hemolytic anemia and neutropenia.

It also will lead discovery for follow-on SYK inhibitors. Costs and profits from the program will be split 75/25 between Biogen Idec and Portola.

Portola will receive a $9 million equity investment plus $36 million in upfront money, and is eligible for $508.5 million in milestones.

Lis said the deal provides Portola with the resources to advance its lead compound, betrixaban, to a regulatory submission in a niche indication. The company plans to start a Phase III trial of the Factor Xa inhibitor In 1H12 to treat or prevent life-threatening blood clots in patients undergoing high-risk surgery.

Merck & Co. Inc. returned the rights for betrixaban in March (see BioCentury, April 25).

COMPANIES AND INSTITUTIONS MENTIONED
AstraZeneca plc (LSE:AZN; NYSE:AZN), London, U.K.
Biogen Idec Inc. (NASDAQ:BIIB), Weston, Mass.
Gilead Sciences Inc. (NASDAQ:GILD), Foster City, Calif.
Merck & Co. Inc. (NYSE:MRK), Whitehouse Station, N.J.
Portola Pharmaceuticals Inc., South San Francisco, Calif.
Rigel Pharmaceuticals Inc. (NASDAQ: RIGL), South San Francisco, Calif.