Within the next few months the entire pivotal study programme for AstraZeneca’s rheumatoid arthritis project fostamatinib – a key late-stage asset – will read out. Unfortunately for the struggling UK company the omens are not good.
Phase II data were mixed, and analysts have raised questions over safety and changing regulatory requirements. If that were not enough, Pfizer’s recently approved tofacitinib threatens to squeeze what little remains of fostamatinib’s commercial window. As Astra tries to justify the $125m it has paid Rigel Pharmaceuticals so far for rights to the molecule, one of the few things it has going for it is a novel mechanism of action.
|% of market cap||2%||178%|
|Event type||Late-stage trial data|
|Date||Q4 2012/H1 2013|
The trouble for fostamatinib's developers is that it is no longer clear how it might fit into the treatment spectrum for RA, which tends to be targeted first with methotrexate and then with Roche’s Actemra or TNF-alpha inhibitors like Abbott’s Humira.
Tofacitinib, a JAK inhibitor now known as Xeljanz, got the US green light two weeks ago for second-line RA, and although it will likely intially be used third line its oral dosing convenience could subsequently make it a strong competitor against biologicals (US approval makes tofa a potential blockbuster – eventually, November 7, 2012).
Meanwhile, fostamatinib’s three pivotal studies, Oskira-1, 2 and 3, are due to yield data early next year, and focus on combining the agent with methotrexate or other disease-modifying agents, as well as looking at the later setting of patients who have failed a TNF inhibitor.
But first to report will be a phase II monotherapy study, Oskira-4, pitting the agent head-to-head against Humira – a setting in which a miss would be alarming. There is concern that failure to show non-inferiority to Humira, combined with the earlier inability to demonstrate efficacy in the Taski3 phase II trial in patients who had failed on biologicals, could close the second and third-line opportunities, even before factoring in the threat from tofacitinib.
Analysts remain cautious, expecting 2018 revenue of just $468m against tofacitinib’s $1.9bn, according to EvaluatePharma’s consensus estimates.
Results from Taski1 and 2 – phase II trials in patients whose RA was insufficiently controlled with methotrexate – demonstrated good fostamatinib efficacy, and this at least bodes well for the rest of the pivotal programme. But here analysts have raised the issue of blood pressure signals seen in phase II. This will be watched closely as the larger trials read out, especially given the patient population enrolled.
While tofacitinib was tested in a 4,000-patient phase III study, fostamatinib’s pivotal programme enrolment numbers just over 2,000. Although regulators will have rubber-stamped this, the spectre of safety issues has already caused some to doubt whether the patient base is big enough.
Filling a hole
Astra licensed fostamatinib from Rigel in 2010 for $100m up front, and paid a $25m milestone when the agent entered phase III. The deal was one of several aimed at filling a patent expiry-based revenue shortfall, but setbacks followed, as did the departure of the company’s CEO, David Brennan, and broad cost-cutting.
The timing of the Rigel deal could throw another spanner into the works, Morgan Stanley suggests, because the following year the EU regulator changed the guidelines covering RA drug approvals. The analysts recently wrote that they were no longer sure whether fosta’s phase III programme was sufficient to demonstrate head-to-head efficacy against standard treatments.
Accordingly, even before considering the pivotal readouts they expect a delay to European approval. Astra is targeting US and EU regulatory submissions in the second half of 2013.
Not surprisingly, analysts following Rigel are more bullish. Jefferies, for instance, cites fostamatinib’s unique mechanism of action as something that could allow it to show a benefit on bone protection; Pfizer aims to file a label extension for tofacitinib to make a structural damage prevention claim based on recently reported results from the Oral Start study.
It is true that fostamatinib’s mechanism is unique: the molecule is the most advanced of just four clinical-stage inhibitors of Syk, or spleen tyrosine kinase, according to EvaluatePharma. In contrast, numerous other JAK inhibitors are being developed in tofacitinib's wake.
Given the many uncertainties, however, this alone is unlikely to give Astra the boost it so desperately needs.
|Fostamatinib studies, in order of expected data release|
|Oskira-4||NCT01264770||Phase IIb, 284 patients, monotherapy versus Humira (Q4 2012)|
|Oskira-1||NCT01197521||Phase III, 922 patients on methotrexatre but not responding (Q1 2013)|
|Oskira-2||NCT01197534||Phase III, 913 patients on DMARDs but not responding (H1 2013)|
|Oskira-3||NCT01197755||Phase III, 322 patients on methotrexate who failed on TNF-alpha (H1 2013)|
To contact the writer of this story email Jacob Plieth in London at firstname.lastname@example.org