Upcoming events – Translarna and tremelimumab target underserved diseases

Welcome to your weekly digest of approaching regulatory and clinical readouts. Amid questions over what constitutes an approvable dataset for Duchenne muscular dystrophy PTC Therapeutics plans to file its contender Translarna with the FDA before the year end.

It will hope that mixed phase III results will be enough – but this looks in doubt after an advisory committee was unconvinced by BioMarin’s drisapersen this week. Meanwhile, AstraZeneca’s anti-CTLA4 MAb tremelimumab is due to report interim phase II data in mesothelioma by the end of the year that, if positive, might be enough for approval for this unmet need.

Translarna touts subgroup data

PTC reported in October that the phase III ACT DMD trial of Translarna had not shown a significant improvement in its primary endpoint, the six-minute walk test, in the intent-to-treat population.

However, there was a significant benefit in a prespecified group of patients with a six-minute walk distance of 300-400m at baseline, the moderately affected population. In addition, a meta analysis combining all patients in ACT DMD and the phase IIb Study 007 found a significant improvement in six-minute walk distance.

Will this be enough for the FDA? Recent experience with drisapersen, now known as Kyndrisa, suggests not. The agency questioned both the efficacy and safety of BioMarin’s project in its briefing documents, and an advisory panel, while not asked to provide a straight yes-or-no vote, did not exactly give it the thumbs up (FDA parks BioMarin while Sarepta readies for its big day, November 25, 2015). 

PTC’s stock closed down 7% on Wednesday, the day after Kyndrisa’s panel review, with investors perhaps worried about the implications of the FDA’s strict stance in DMD.

A glimmer of hope remains for Translarna and Kyndrisa, as well as other agents in development including Sarepta’s eteplirsen, due to face an adcom on January 22, and Santhera’s Raxone (idebenone), expected to be filed in the first quarter. DMD is a highly debilitating and politically sensitive disease – the lack of alternative therapies, and strong patient lobbying, could work in the companies’ favour.

Translarna has a different mechanism from Kyndrisa and eteplirsen, targeting a nonsense DNA mutation that leads to DMD, so it might not be linked with the same safety concerns.

PTC can also take heart from Translarna’s path in Europe – originally given a negative opinion by the CHMP, it was conditionally approved a few months later after some success was seen in certain patients, including those who could walk 350 metres or less at baseline (As Duchenne winds change, PTC and Santhera score surprise wins, May 23, 2014). 

The company is also studying Translarna in other inherited diseases including cystic fibrosis and mucopolysaccharidosis I, or Hurler’s syndrome.

But approval in these other indications probably hinges on a result in DMD, according to Citi analysts, who point out that the drug is thought to work via the same mechanism across various diseases. If the FDA is as hard on Translarna as it was on drisapersen, PTC, which is reliant on the project for all of its forecast revenues, could be all but finished.

Tremelimumab takes aim at mesothelioma

Astra is targeting another underserved disease, mesothelioma, which carries a grim prognosis. Current treatment options are limited to surgery, chemo and radiation therapy.

The 564-patient phase IIb study is comparing tremelimumab versus placebo with a primary endpoint of overall survival. Secondary endpoints include progression-free survival and response rate. If it is positive, Astra will file the project for mesothelioma in the US – where it has orphan drug designation – in the first half of next year, and in the EU in second half.

Convincing results could also give Astra a march on its rivals – other drugs in late-stage development for mesothelioma include MolMed’s vascular targeting agent NGR-hTNF, which reported mixed phase III results at Asco in June and seems to have stalled while the company looks for a partner; Eisai’s anti-mesothelin MAb amatuximab is in the phase II Artemis study.

If tremelimumab is approved it would become the second CTLA4-targeting MAb to make to to the market, after Bristol-Myers Squibb's Yervoy, though this is not indicated for mesothelioma. Given Yervoy's notorious adverse events profile the safety of tremelimumab will be closely watched, though toxicity will be counterbalanced by the intractable nature of mesothelioma.

Astra is also combining tremelimumab with other agents including the anti-PD-L1 MAb durvalumab in lung cancer (Asco – Check mate for combination promise and shortcomings, May 31, 2015). 

Success in this and other bigger indications would likely boost tremelimumab’s consensus sales forecast, which EvaluatePharma consensus puts at just $222m in 2020. But getting a positive outcome in mesothelioma is the first hurdle that Astra needs to clear.

To contact the writer of this story email Madeleine Armstrong in London at [email protected] or follow  @medtech_ma on Twitter