In DMD, Summit Falls Well Short Of Peak It Hoped For

Summit’s utrophin modulator, ezutromid, posted intriguing interim data in January, but failed to meet the primary and all secondary endpoints in a Phase II study. The UK firm discontinued development of ezutromid and will now focus on novel antibiotic candidates.

The promise of interim data reported in January didn’t hold up, as Summit Therapeutics PLC revealed June 27 that its Phase II Duchenne muscular dystrophy candidate ezutromid failed to meet the primary endpoint and all secondary endpoints in the 40-patient PhaseOut DMD study. The Oxford, UK-based firm said it has discontinued all development of the utrophin modulator and is undertaking cost-reduction measures as it switches focus to novel-mechanism antibiotic development.

Summit CEO Glyn Edwards described the study results as disappointing, but also definitive, in a same-day conference call. The company hopes to provide the information gathered in PhaseOut DMD to support others’ DMD research efforts; Edwards noted that this trial failure does not necessarily mean that utrophin modulation won’t have a future role in DMD therapy.

“The trial was designed to assess the effect of ezutromid on a variety of endpoints, which could provide proof-of-concept for ezutromid,” he told the call. “The endpoints related to ezutromid’s mechanism, muscle health and muscle function. While we did observe statistically significant results after 24 weeks of treatment in muscle damage and inflammation, those changes in muscle damage and inflammation were not sustained over 48 weeks of treatment.”

The CEO noted, however, that ezutromid was well-tolerated.

“PhaseOut DMD was designed to provide us with a clear-cut answer on ezutromid safety and efficacy,” Edwards continued. And although it didn’t have the desired outcome, the analytic methods were robust enough and there was enough natural history data to give confidence in the interpretation of the data. “The clarity of the data has allowed us to make the difficult, but responsible, decision to discontinue the development of ezutromid," he said.

Summit reported in January that 24-week data from the study showed a significant and meaningful reduction in muscle damage, with a 23% reduction in mean developmental myosin compared with baseline. (Also see "Summit DMD Data Intrigue But Longer-Term Results Awaited" - Scrip, 26 Jan, 2018.) Developmental myosin is a biomarker of muscle damage found in repairing tissue fibers. The company conceded at the time that a truer measure of the drug’s potential benefit would come from 48-week data, however.

Unclear Why Signal Seen At 24 Weeks Didn’t Carry Through

For 38 of the 40 boys enrolled in PhaseOut DMD, Summit found that the primary endpoint of change from baseline in magnetic resonance measuring of leg muscle was not met at 48 weeks. The company did not break out specific data for this or the secondary endpoints, saying only on the investor call that none of the endpoints were met at 48 weeks, including those that had shown promising trends in the 24-week look.

Asked to compare the data seen at 24 weeks and 48 weeks, Chief Medical Officer David Roblin painted a stark and unexplained picture. “We had a signal on developmental myosin, which is a marker of muscle regeneration, and that was statistically significant at 24 weeks, and we lost that signal entirely for the different set of patients that had their biopsies at 48 weeks,” he said. “And why that occurred, we don't know, but it was a clear-cut set of both primary and secondary outcome measures at 48 weeks, which led us to this conclusion.”

The company said it was too early to make a determination about discontinuing its preclinical work on follow-on utrophin modulators, and that further analysis of the Phase II trial data was needed.

Summit is partnered with Sarepta Therapeutics Inc. – which had the first DMD therapeutic approval for Exondys 51 (eteplirsen) – under an October 2016 collaboration that brought it $40m up front and up to $852m in potential earn-outs. (Also see "Sarepta’s $852m Summit Collaboration Could Enable DMD Drug Combinations" - Scrip, 5 Oct, 2016.) 

As to the status of the partnership, Edwards said Sarepta is “hugely disappointed.” Summit had earned some milestone fees under the agreement, he added, but won’t receive any additional payments; the partnership included language covering what would happen if the drug failed.

With Exondys 51 approved only to treat a small portion of DMD patients with a specific exon-skipping mutation, Sarepta said at the time its deal with Summit was announced that it hoped to find other mechanisms for DMD treatment that might allow its drug to be applied to a wider portion of the disease population under combination regimens.

While the plan for combination therapy with ezutromid has now faded, Sarepta has follow-on exon skipping candidates advancing and reported promising early results for its gene therapy candidate AAVrh74.MHCK7.micro-Dystrophin on June 19. (Also see "Sarepta Outlines A Fast Path Forward For Its DMD Gene Therapy" - Scrip, 19 Jun, 2018.) As with the interim data reported for ezutromid, however, the ultimate promise of this candidate will depend on data in a greater number of patients.

Analysts See Some Promise In Summit’s Antibiotic Program

The market responded harshly, as Summit tumbled nearly 80% to $2.55 per share at the close of trading on June 27. When Summit presented its hopeful interim data on Jan. 26, its share price increased 13% to $13.78.

Ezutromid was a long shot anyway, JMP Securities analyst Liisa Bayko commented. All is not lost for Summit, Bayko said, however, as she believes its lead antibiotic candidate, ridinilazole – slated to begin a Phase III program in first quarter 2019 – “looks competitive.”

Summit previously guided that its current cash should be enough to get it through April 2019. It had about $38m at the end of the first quarter of 2018. Details of Summit’s cash-saving plans are not yet available, Bayko noted, but she projected that with the end of the ezutromid development program, the firm’s cash could see it through to Phase III data for ridinilazole, expected in 2022.

Biomedtracker had given ezutromid a 27% likelihood of approval, three percentage points above average for a Phase II DMD candidate, prior to the data release on June 27 – that projection now is reduced to zero, of course.

BTIG Equity Research analyst Timothy Chiang maintained a “buy” rating of Summit shares in a June 27 note, but reduced his target price sharply, from $33 to $5, noting that the market has ascribed little value to the company’s antibiotic pipeline.

“Clearly, we come away not only surprised but also disappointed as we had viewed the utrophin modulation pathway as a way to treating DMD patients,” Chiang said.