Welcome to your weekly digest of approaching regulatory and clinical readouts. Data are expected before the end of the year from Astranzeneca’s Arctic trial in third-line lung cancer, evaluating the combination of Imfinzi and tremelimumab; hopes are low since the Mystic study failed its first analysis in first-line disease.
Meanwhile, Cytokinetics’ phase III data on tirasemtiv in amyotrophic lateral sclerosis (ALS) are due in December. After changing an endpoint because of a failure in phase II, the company will need to show a benefit in respiratory measures, but the real aim for ALS treatments would be evidence of improved survival, a high bar to reach.
Winter is coming
Astra’s phase III Arctic trial has three ongoing experimental arms, all in patients classed as PD-L1 negative, whose tumours express PD-L1 at 25% or below: Imfinzi and tremelimumab monotherapies, and a combination of the two, versus physician’s choice as active control. The primary measures are overall and progression-free survival, and data are due before the end of the year.
Another arm investigating Imfinzi monotherapy in PD-L1-positive patients – defined as those with PD-L1 levels of over 25% – was halted in 2016, and it is not known whether these results will be formally analysed.
Hopes are not high for Arctic since the Mystic trial showed a lack of PFS benefit in first-line PD-L1-positive patients in both the Imfinzi monotherapy and combination arms (Mystic falls at the first hurdle, July 27, 2017). Arctic readout has already been delayed, and indeed Astra itself has said that this trial is not material.
However, one point of interest for investors is how Arctic data read across to the final analysis of Mystic, which is due to yield OS data in the first half of next year. A negative result, for instance, could strengthen the argument that Imfinzi is less effective than other agents targeting PD-(L)1.
And if Arctic does manage to show a benefit, the fact that it is being conducted in third-line lung cancer ultimately means that its commercial value is low, as patients will increasingly get their first exposure to an anti-PD-(L)1 in a first or second-line setting.
Second time’s a charm
Three years ago Cytokinetics’ tirasemtiv failed the phase II Benefit-ALS trial, missing a composite primary endpoint measuring the ALS functional rating scale (ALSFRS-R), causing a 65% share price plunge.
The company did, however, see a benefit on a spirometry measure called slow vital capacity, which is the primary endpoint in the current phase III trial, Vitality-ALS. Data are expected at an oral presentation on December 8 at the International Symposium on ALS/MND in Boston.
As an activator of skeletal muscle troponin, tirasemtiv aims to improve muscle contractility. The hypothesis is that it slows the decline in diaphragm strength and therefore delays respiratory disability in ALS.
Vitality-ALS enrolled 743 patients who initially received two weeks of open-label tirasemtiv at 250mg/day, and were then randomised into a double-blind treatment phase at 250mg/day, 375mg/day or 500mg/day versus placebo for 48 weeks. Afterwards patients stayed on treatment or were randomised to placebo for a four-week withdrawal phase.
Patients who were already receiving Sanofi’s older ALS drug, Rilutek, could stay on this but at a reduced dose of 50mg daily.
The primary slow vital capacity endpoint was measured at 24 weeks. Secondary endpoints included progress to respiratory failure, mechanical breathing assistance or death at 48 weeks. The respiratory components of the ALS functional rating scale were used, but other parts such as handwriting, dressing and feeding were not considered.
With respiratory trends evident in the earlier study tirasemtiv could pass phase III, but it is uncertain whether the endpoint will be enough to convince regulators.
Earlier this year Mitsubishi Tanabe Pharma’s Radicava became the first ALS drug to get FDA approval since Rilutek back in 1995. Radicava, a free-radical scavenger, showed a significant improvement over placebo in the ALSFRS-R and the ALSAQ40 quality of life questionnaire at 24 weeks, and this effect was sustained over 12 months in an extension study (Radicava bags approval without a radical benefit, May 8, 2017).
Rilutek on the other hand modestly extended survival or time to insertion of a breathing tube in trials.