by Ayisha Sharma in London

Catabasis’ Phase III edasalonexent for Duchene muscular dystrophy (DMD) has experts cautious about its potential to replace steroids as the new standard of care (SOC) due to concerns over its mechanism of action.

DMD is a genetic disorder characterized by progressive muscle degeneration and weakness due to the alterations of a protein called dystrophin.

Although edasalonexent is technically classified as a disease modifier, the NF-kB inhibitor has a relatively downstream mechanism and does not target the root cause of DMD, which is a lack of dystrophin production. It may be better suited to supplementary use as part of a treatment cocktail, versus a stand-alone steroid replacement option, as one analyst report suggested.

Despite the long-term safety concerns associated with steroids, the drugs have a multipronged mechanism. This mechanism significantly prolongs lifespan, so it is unlikely to be replaced in the near future. The currently available Phase I/II data are too premature to say edasalonexent will become SOC.

While edasalonexent is tolerable, according to the aforementioned analyst report, the lack of data on length of diarrhea events observed in the Phase I/II trial raises concerns about whether rehydration treatment was needed or patients who had to abort treatment. However, since the events are described as mild and transient, they likely lasted under one week. Nonetheless, depending on the length of diarrhea, compliance issues could appear in the ongoing Phase POLARIS III trial, reducing its efficacy and posing a problem for its approval prospects.

Top-line data from the Phase III POLARIS trial (NCT03703882) are expected in 4Q20, according to the most recent company earnings report.

Catabasis has a market cap of $127.08m. Edasalonexent is expected to attain worldwide peak sales of $1.1m in 2027, according to the aforementioned analyst report. Catabasis did not respond to a comment request.

Edasalonexent’s targeted mechanism better suited to supplemental use

Despite the aforementioned report highlighting the strong potential for edasalonexent to replace steroids and become the SOC, edasalonexent’s mechanism of action does not address the root cause of DMD, which is lack of dystrophin production, said Dr Alper Dai, professor, Department of Paediatrics, Gaziantep University, Turkey. The treatment is therefore better suited to be used as a supplement to steroids as opposed to being a core SOC, he added.

Although technically classified as a disease-modifying agent, edasalonexent has a relatively downstream target within the disease cascade, which is why it does not compete directly with exxon-skipping agents, agreed Angela Russell, PhD, associate professor of medicinal chemistry, Oxford University, UK. As such, it is well-suited to being an additive treatment to the latter, Russell said. Furthermore, the way steroids tackle disease is multipronged, so they have a broad spectrum of positive downstream efficacy effects, said Dr Matthew Wood, professor of neuroscience, Department of Physiology, Anatomy and Genetics, Oxford University, UK. In contrast, edasalonexent’s niche mechanism of action only inhibits one specific biochemical process, he explained.

While steroids have unpleasant long-term side effects such as stunted growth and weight gain, they also have clear benefits such as significantly prolonging life span, Wood said. As such, steroids are unlikely to be fully replaced in the near future, Russell said, adding the future of DMD treatment could instead see cocktails of multiple treatments targeting different aspects of the disease.

It is premature to claim edasalonexent could become the SOC when other agents in development are also being touted as potential steroid replacements, said Wood. Santhera Pharmaceuticals (SWX:SANN) has made this claim about its dissociative steroidal compound vamorolone. Even if edasalonexent’s efficacy supersedes the efficacy of steroids, it must show improvement over these competitor pipeline treatments for market traction, Wood explained.

Phase I/II efficacy data promising, but fall short of being significant

The currently available edasalonexent data is too premature to claim future SOC status, said Dr Sheffali Gulati, professor, Department of Paediatrics, All India Institute of Medical Sciences, New Delhi. The effects of edasalonexent’s long-term efficacy on increasing the number of ambulatory years over steroids is yet to be seen, she said, but added the Phase I/II data show a clear stabilization of ambulation in the given timeframe. Despite promising functional test data, larger patient numbers up are needed to confirm clinical meaning, Russell said.

The drug demonstrated meaningful slowing of disease in the Phase II portion of its 31-patient, randomized, Phase I/II study (NCT02439216) and in the open-label extension period, according to a poster of Phase I/II data at the 2020 Muscular Dystrophy Association Clinical & Scientific Conference in March. Results in the North Star Ambulatory Assessment (NSAA) efficacy measure showed the score decreasing from approximately 22 at 36 weeks prior to trial initiation to approximately 17 at the start of the trial. In contrast, the score was maintained and raised to approximately 18 at 72 weeks of edasalonexent treatment. Change from baseline in NSAA score is the primary endpoint of the Phase III trial.

Data in the Phase I/II primary efficacy endpoint of muscle composition and inflammation, as measured by magnetic resonance imaging (MRI), were also promising, Wood said. During the off-treatment control period, the rate of MRI transverse relaxation time (T2) was nearly 4m/sec/year, but during the treatment period it was less than 1m/sec/year, according to the aforementioned poster. MRI T2 is a direct marker of whether muscle inflammation has been slowed or stopped, Wood explained, adding this is a helpful endpoint to measure as edasalonexent works by preventing inflammation.

The MRI T2 data came from a composite of five lower leg muscles. While leg muscle data has important implications for ambulation, it would also be important to see MRI T2 data from the diaphragm, as this is a key muscle for breathing, Wood said. However, MRI data cannot be correlated directly with functional improvement, Gulati noted. At week 72, the p-value of MRI T2 data was 0.0052. The result was therefore not quite statistically significant, Gulati added.

Safety was the other Phase I/II primary endpoint. MRI is not measured in the Phase III, according to

Diarrhea adverse event raises some safety concerns

While the aforementioned analyst report stated edasalonexent is well-tolerated with mostly mild adverse events, the rate at which the events occur is rather high and could be problematic, Dai said. In the Phase II portion of the Phase I/II study and open-label extension, edasalonexent treatment in 31 patients was most commonly associated with diarrhea (51.6%), upper abdominal pain (22.6%), nausea (9.7%) and vomiting (9.7%), according to the aforementioned poster. The diarrhea, which is not associated with steroids treatment, was described as being mild and transient.

However, it is unclear exactly what this description means, and a median and interquartile range of the length of diarrhea should have been provided to give a clearer picture of safety, Gulati stated. While a specified length would have been preferred, diarrhea is a fairly common and nonspecific adverse event and is usually not problematic enough to result in aborted therapy, said Dr Andre Prochoroff, pediatric neurologist, MetroHealth, Cleveland, Ohio. However, if the diarrhea lasts 5–7 days or longer and is severe enough to mandate the use of rehydration therapy, it could create treatment compliance issues in both future trials and real-world use, Gulati said. Nonetheless, seeing as the events were described as mild and transient, it is likely they lasted for less than one week, Prochoroff stated.

Despite some differences in protocol, similarity in enrolment criteria between the Phase I/II and the 131-patient, randomized, double-blind, Phase III trial (NCT03703882) mean diarrhea events are likely to reappear at the same rate and severity in the latter, said Gulati and Dr Oscar Mayer, director, Pulmonary Function Laboratory, Children’s Hospital of Philadelphia, Pennsylvania. Safety is a secondary Phase III outcome. Criteria for both trials specify children ages 4–7 years with a confirmed diagnosis of DMD, according to The Phase I/II trial randomized patients 1:1 treatment to placebo, while the Phase III trial is randomizing patients 2:1 treatment to placebo. Furthermore, the Phase I/II trial studied both the 67mg/kg and 100mg/kg doses while the Phase III trial will only study the higher dose.

If diarrhea occurs in the Phase III trial and lasts for a week or longer, it should not pose a problem for FDA approval, as the overall safety profile is supposed to supersede the safety profile of steroids, Gulati said. However, if diarrhea becomes persistent and severe enough to be classified as a severe adverse event rather than a target adverse event, this could negatively affect its approval prospects, Wood stated.

If diarrhea resulted in reduced treatment compliance, it could then dampen efficacy, which would be problematic for approval, Prochoroff said. However, this is unlikely given the aforementioned mild and transient description, he added. Diarrhea appears less of a serious safety issue and more of a potential problem for patient quality of life, said Mayer. Young children really struggle with diarrhea, and since there are many DMD drugs in development, if an alternative steroid replacement with fewer or no diarrhea events is approved, it would be preferred, he explained.

Ayisha Sharma is a Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.