Summit Therapeutics reports that a new formulation of ezutromid (called F6), its Duchenne muscular dystrophy (DMD) treatment candidate, achieved a greater than six-fold increase in maximum plasma levels in DMD patients participating in a Phase 1 clinical trial, compared to results achieved with its current formulation (F3), and at a lower doses.
Consequent to this positive data, Summit has outlined a revised development strategy — through to filing applications for marketing approval — of the potential treatment, a utrophin modulator. Utrophin modulation is a potential disease modifying treatment for all patients with the DMD, which is caused by genetic defects in the gene that encodes dystrophin, a protein essential for the healthy function of muscles. Summit says that utrophin protein is functionally and structurally similar to dystrophin, regardless of the particular underlying dystrophin gene mutation.
“The rigorous development of ezutromid has identified this new F6 formulation that achieved higher ezutromid plasma levels in patients in this trial allowing us to further explore the therapeutic effect of this promising treatment,” commented Dr. Ralf Rosskamp, Summit’s Chief Medical Officer in a press release. “Following these encouraging Phase 1 data, we plan to incorporate the F6 formulation of ezutromid into our ongoing Phase 2 trial, PhaseOut DMD. This will allow us to directly compare the safety and efficacy of the F6 and F3 formulations of ezutromid, and help determine which to use in future clinical trials.”
He added: “Utrophin modulation focuses on maintaining expression of utrophin protein to protect muscle health and function, and we believe these two formulations of ezutromid are capable of achieving this.”
The company’s revised ezutromid development strategy now includes:
• Incorporation of ezutromid formulation F6 into the ongoing PhaseOut DMD Phase 2 proof-of-concept trial (subject to regulatory approval). The plan is to evaluate F6 in up to 10 of the 40 patients the trial expects to enroll, and to compare the F6 and F3 formulation variants back-to-back in longer-term dosing. Initial data are expected to be released in mid-2017.
• A randomized, placebo-controlled trial designed to support accelerated, conditional regulatory approvals for ezutromid in the U.S. and EU — expected to commence in 2017 (assuming positive interim data from PhaseOut DMD), with data projected to be available for potential regulatory filings in 2019.
“Building on the clinical progress achieved to date, we are pleased to outline our strategy for the development of ezutromid towards possible commercialisation,” said Glyn Edwards, Summit’s chief executive officer, in the release. “These plans focus on efficient evaluation of the efficacy and safety of this utrophin modulator as we work towards making it available to all patients with DMD. Our plans are designed to support early submissions for accelerated and conditional approvals.”
Results of Phase 1 Trial of Ezutromid F6
Clinical data currently being reported are from the second part of the Phase 1 clinical trial, assessing the pharmacokinetics and safety of the F6 formulation of ezutromid at three fixed doses (250 mg, 500 mg and 1,000 mg twice daily) in DMD patients, ages 5 to 9, who followed a modified diet. Ezutromid was observed to be generally well-tolerated at the doses tested. One patient had changes in liver parameters detected in laboratory testing. While he showed no clinical symptoms, he was withdrawn from the trial, with the finding was marked as a serious adverse event.
At the highest dose (1,000 mg twice daily), the remaining five patients achieved an average maximum plasma concentration of 390 ng/mL on the seventh and final day of dosing. Summit said that utrophin modulation is also expected with the F3 formulation, and patients in an earlier Phase 1 trial ,who followed the same modified diet, achieved an average maximum plasma concentration of 63 ng/mL (2,500 mg dose, twice daily) on the final day of dosing (day 14). More detail regarding Phase 1 trial findings are to be reported at future scientific meetings.
DMD is classified as an orphan disease, and ezutromid has been granted orphan drug status by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Orphan drugs are eligible for accelerated approval, additional regulatory support, and a period of market exclusivity following approval. Summit believes utrophin modulation has potential to slow or even arrest DMD progression, and that it could potentially be complementary to other DMD therapeutic approaches.
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Summit Therapeutics plc