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Seeds of phase III Catabasis win in DMD sown – or maybe

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By Randy Osborne
Staff Writer

As Catabasis Pharmaceuticals Inc. geared up for an FDA-blessed phase III trial, Wall Street already went to work handicapping the chances for later-stage success with the oral Duchenne muscular dystrophy (DMD) therapy edasalonexent.

The devil might lie in the details, but CEO Jill Milne told BioWorld that, although the study was not powered for statistical significance on the functional endpoints, a “highly consistent response” across all measures provides cause for optimism. MoveDMD, as the study is known, did what it was designed for. “The key elements in the phase II are being transitioned to the phase III,” she said, which ought to bolster hopes.

Chief Medical Officer Joanne Donovan said that “one of the real strengths of the design of our clinical trial [is that] we were not comparing to natural-history data. We were comparing the boys during a control period to an active-treatment period.” That, along with the unwavering response, “gives us great confidence moving into the next stage of clinical study,” she said.

Cambridge, Mass.-based Catabasis’ shares (NASDAQ:CATB), fueled by positive phase II data, did well Wednesday, closing at $3.03, up 20 cents, after trading as high as $3.78.

The NF-kB inhibitor edasalonexent sustained disease-modifying effects in the phase II MoveDMD trial open-label extension after 24 and 36 weeks of treatment, Catabasis said. Across all key assessments of muscle function, improvements turned up in the rate of decline in patients given 100 mg/kg per day compared to the rate of change in the control period for boys prior to getting the drug. The phase III experiment in patients with DMD regardless of mutation type is slated to start in the first half of 2018, with top-line results expected in 2020.

Catabasis reported that supportive changes in measures of muscle health made themselves known in the study, consistent with positive edasalonexent treatment effects. Muscle enzymes significantly decreased compared to baseline at 12 weeks and later time points (p<0.05), and the lower leg muscle magnetic resonance imaging (MRI) T2 rate of change was significantly improved in comparison to progression during the control period (p≤0.05). The drug continued to be well-tolerated, with no safety signals observed.

Specifically, through 36 weeks, the 100 mg/kg per day group showed clinically meaningful numerical improvements in rates of decline compared to rates of change during the control period across all three timed function tests (the 10-meter walk/run, four-stair climb, and time to stand), as well as the North Star Ambulatory Assessment (NSAA), an integrated global assessment of muscle function.

Control-period changes were measured prior to boys receiving edasalonexent, either before phase II or in the placebo group, for time periods averaging 39 weeks. Sixteen boys started taking the drug either at the beginning of phase II or at the beginning of the open-label extension, and at the time of the open-label extension data analysis, all 14 boys continuing to participate had been on 100 mg/kg per day for 24 weeks and 11 had completed 36 weeks. Results are detailed for the 100-mg/kg per day group as all of the boys are currently taking the dose in the open-label extension, Catabasis said.

Four muscle enzymes (creatine kinase, alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase) were significantly decreased compared to baseline following edasalonexent treatment at 12 weeks and later time points (p<0.05), consistent with the ability to slow muscle degeneration and improve muscle integrity. Rate of change in lower leg MRI T2 significantly improved at 12 weeks and at last observation on treatment, compared to the control period (p≤0.05), was consistent with a reduction of inflammation in the muscle.

Pivotal study design ‘rigorous and meaningful’

Edasalonexent continued to be well-tolerated, with no safety signals observed to date in MoveDMD. The majority of adverse events (AEs) have been mild in nature with no serious ones, with no dose reductions and no drug-related discontinuations. The most common AEs were gastrointestinal: primarily mild and transient diarrhea. Height, weight and body mass index growth patterns were similar to standard growth curves for unaffected boys in the age range of the trial subjects. DMD patients of such ages typically show resting tachycardia, but the heart rate of the boys treated with edasalonexent decreased toward age-normative values during treatment.

Catabasis called the heart-rate findings “intriguing.” CEO Milne said the firm “will absolutely be following this up clinically. We’re also planning another trial in the non-ambulatory boys, where the cardiac effects become even more important because we know ultimately that’s what these boys die from.”

Meanwhile, the planned design of the randomized, double-blind, placebo-controlled phase III study is expected to enroll about 125 patients, ages 4 to 7, who have not been on steroids for at least six months. The primary efficacy endpoint will be change in the NSAA after 12 months on drug compared to placebo. Key secondary endpoints likely will include age-appropriate, timed function tests.

If there’s any cause for fretting over the phase III bid, it might be that the phase II found no statistically significant improvement compared to placebo during the double-blind period. The upside in function was seen when patients’ rate of decline was compared while they were on drug to their rate of decline during their period before they got treatment. Earlier, U.S. regulators sifting through data on Cambridge, Mass.-based Sarepta Therapeutics Inc.’s Exondys 51 (eteplirsen) for DMD pointed out that open-label results on effort-based endpoints are tough to weigh, given the possibility for bias – and Catabasis’ analysis included only 16 patients, noted Cowen and Co. analyst Phil Nadeau.

Just the same, the FDA granted Exondys 51 accelerated approval in September 2016, which brought Sarepta a rare pediatric disease priority review voucher. Exondys 51 is indicated to treat patients with a confirmed mutation of the DMD gene amenable to exon 51 skipping, or about 13 percent of the population with DMD, based on the surrogate endpoint of increased dystrophin in skeletal muscle observed in some patients treated.

Regarding Catabasis’ candidate, “lack of progression during the ages studied by [the company] is particularly difficult to interpret, as boys can naturally become stronger and gain function between the ages of 4 and 7,” analyst Nadeau wrote in his report. “For example, a poster recently presented by Ricotti et al. from the University College London found that boys treated with standard of care (typically steroids) on average gained 1.5 units per year in the NSAA until age 7, after which they started declining and lost an average of four units per year. The poster notes a large amount of variability in motor function.”

Also, not forgotten by investors is the February disclosure of top-line proof-of-concept data from part B of MoveDMD, showing that 12 weeks of treatment failed to significantly impact a biomarker indicative of benefits in lower leg muscle composition and inflammation. (See BioWorld Today, Sept. 20, 2016, and Feb. 2, 2017.)

Still, Catabasis seems to have “designed a rigorous and meaningful pivotal trial,” in the view of Nadeau, so that a phase III win, if it happens, “would be a definitive proof of edasalonexent’s efficacy and would establish a place for it in the treatment paradigm.”

CEO Milne said that since, based on its mechanism, edasalonexent should be effective in all patients with DMD, the drug could become “foundational” in the disease. “While we’re developing this as a monotherapy, we also see great potential as a combination therapy with agents like [Exondys 51].”