Event – Sanofi hopes its JAK will not be a dull boy
Pivotal results for Sanofi’s myelofibrosis candidate SAR302503 are due within weeks, and it needs to show disease-modifying effects if it is to be anything more than an also-ran to Incyte’s Jakafi. With gastrointestinal tolerability problems threatening to limit its appeal to patients, outperformance on symptomatic relief and perhaps even survival measures could help the French company take on the world’s first JAK inhibitor.
After a trying period, Sanofi’s pipeline has begun to sputter into life, with three regulatory approvals already in 2013 and a fourth due within weeks. But with a big patent expiry due for Lantus in 2015, R&D needs to continue to deliver, and good news from the Jakarta trial in myelofibrosis would help improve sentiment.
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Also-ran or best in class?
Jakafi was launched on FDA approval in 2011 and is on track to become a blockbuster in 2016 when ex-US sales of partner Novartis, which sells it as Jakavi, are taken into account. It was the first inhibitor of janus kinase 1 and 2 (JAK1/2) and also the first drug treatment for myelofibrosis (Incyte hoping JAK be nimble and quick, November 17, 2011).
The JAK 1 pathway plays a role in inflammatory response and JAK 2 in blood cell production. Both are dysfunctional in myelofibrosis patients.
The Incyte pill was approved on the basis of symptomatic control – reduction in spleen volume and other indicators such as night sweats and abdominal pain. The spleens of myelofibrosis patients swell because that organ is called upon to produce red blood cells as bone marrow becomes scarred during disease progression.
Post-hoc analyses showed improvements over placebo, but because they were not included in the trial protocol there is some scepticism over the accuracy of the finding. In addition, there is some concern over whether Jakafi's effect on spleen volume are more the result of its control of the cytokine response regulated by JAK 1 than because of its effects on JAK 2, which affects erythropoiesis.
If spleen shrinkage is mostly due to Jakafi's anti-inflammatory powers the implication would be that the drug treats the symptoms rather than influencing the actual course of the disease.
In phase II, Sanofi’s contender SAR302503 was able to achieve impressive spleen shrinkage. At the maximum tolerated dose, 680mg, 45%-50% achieved a sustained 50% reduction in spleen size. In phase III, Jakafi used a lower 35% reduction in spleen size endpoint.
In the phase III trial, that 35% hurdle will be the primary endpoint, with the 50% shrinkage standard a secondary outcome measure along with progression-free and overall survival. To measure the action of JAK 2 inhibition, Sanofi will be looking for signs of disease modification including changes to bone marrow.
Given the action of JAK 2 inhibition of blood cell production, anaemia will likely be a side effect, something that is already difficult to manage in myelofibrosis patients. The gastrointestinal side effects, meanwhile, are believed to be the result of off-target effects on another tyrosine kinase.
Thus, while proving itself the equal of Jakafi on symptomatic control would likely be enough to win approval, the side effects will probably require SAR302503 to outperform the Incyte drug to compete in the market.
Hoping for better
Forecasts for the Sanofi pill are modest for now – $170m in 2018, a sum Jakafi nearly achieved in 2012 in its first full year on the market. Successful readout of Jakarta will likely see that number rise, and markedly so should SAR302503 decisively outperform Jakafi.
SAR302503 is one of three rather high-risk phase III readouts due by mid-year for Sanofi, the others being the blood thinner otamixaban and cancer project inaparib. All three are projected as 2014 launches, but only otamixaban has a better than 50-50 shot at success, according to Deutsche Bank analyst Richard Parkes.
Failure for all three would be a clear blow to investor sentiment. As such, a positive readout would be good news, but even better would be SAR302503 decisively beating Jakafi.