Welcome to your weekly digest of approaching regulatory and clinical readouts. Phase II data for Summit’s Duchenne treatment ezutromid are due in the first quarter. The agent works by modulating utrophin, a protein involved in muscle development, and could in theory be used to treat all patients rather than just a genetic subtype.
Meanwhile, after the failure of Cytokinetics’ lead amyotrophic lateral sclerosis drug tirasemtiv at the end of last year, the company quickly pivoted to its next-generation product CK-2127107. Indications of whether this works will come with phase II data in spinal muscular atrophy, also due in the first quarter.
Targeting all patients
Utrophin is a protein similar to dystrophin: both play a role in muscle development but dystrophin usually takes over this function from utrophin as muscles mature. Duchenne patients carry a mutation meaning dystrophin is not produced. The aim of Summit’s ezutromid is to maintain the production of utrophin to compensate for the absence of dystrophin and so protect muscle function.
One advantage of the product is that utrophin modulation is independent of the underlying genetic fault so could in theory treat all patients. It could also potentially be used in combination with other treatment approaches. It is the most advanced utrophin modulator in development.
In October 2016 Summit granted Sarepta Therapeutics European rights to its utrophin modulator pipeline for $40m upfront. Summit, which was formed in 2003 as a spin-out from the University of Oxford, nearly doubled in value on the deal. As of January this year Sarepta also pays 45% of research costs.
Ezutromid is in an open-label phase II study, PhaseOut DMD, which has enrolled 40 male patients aged 5-10, who were ambulatory and not on ventilation at the time of enrolment. Two formulations were tested: 2.5g suspension (30 patients) and 1g powder (10 patients), both given twice daily. There was a screening phase of 28 days, and then a 48-week open-label treatment phase and a 30-day safety follow up, followed by an ongoing extension phase.
The primary endpoints look at the change in leg muscle parameters, as measured by MRI, and ezutromid plasma concentrations. Secondary outcomes measure the change in utrophin membrane staining, change in muscle regenerating fibres and adverse events. All patients will have two muscle biopsies. Exploratory functional endpoints include the six-minute walk test, North Star Ambulatory Assessment (a range of physical function tests) and patient reported outcomes.
24-week data will be reported in the first quarter, with 48-week data due in the third. It is thought unlikely that the former time point will be long enough to show significant functional changes, but mechanistic changes could be evident.
A placebo-controlled pivotal trial is expected to be the next step, should PhaseOut DMD succeed.
With the controversial approval of Sarepta’s own exon-skipping product Exondys 51 in 2016, which was based on limited clinical data, but came after significant pressure from patients and carers, there is a chance that Summit could look for an accelerated approval on the phase II data.
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Take two for Cytokinetics
Last November Cytokinetics’ tirasemtiv failed in its phase III trial in ALS, despite a change to the study’s primary outcome to slow vital capacity – a measure that had showed improvement in a phase II trial. Shares crashed 26% on the news.
The company then turned its attention to its next-generation troponin activator CK-2127107, which it says is potentially more effective than tirasemtiv and will be better tolerated as it does not cross the blood/brain barrier. This theory will be put to the test when a phase II trial, this time in spinal muscular atrophy (SMA), reports in the first quarter.
This trial enrolled 72 patients with type II-IV SMA aged 12 and older. The two dose cohorts were stratified by ambulatory versus non-ambulatory status and patients were randomised to receive 150mg or 450mg CK-2127107 or placebo twice-daily for eight weeks.
Primary measures included multiple assessments of skeletal muscle function and fatigability, including respiratory assessments, upper limb strength and functionality for non-ambulatory patients, as well as the six-minute walk test and timed-up-and-go for ambulatory patients. Secondary measures included safety, tolerability and pharmacokinetics.
The trials are being funded by Astellas, which holds the worldwide license to develop and commercialise the product, with Cytokinetics eligible for milestone payments and royalties. The original deal took place in 2013 with Cytokinetics receiving $40m up front. CK-2127107 is also in phase II trials in ALS and COPD.
In the wake of the tirasemtiv disappointment, efficacy signals for CK-2127107 need to impress.
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