Summit Therapeutics plc has announced encouraging interim results from its phase 2 PhaseOut DMD clinical trial that suggest the experimental treatment ezutromid (formerly SMT C1100) potentially may be effective as a treatment for Duchenne muscular dystrophy (DMD).
The results showed that treatment with the drug was associated with reduced levels of a protein called developmental myosin, a biomarker that signals the presence of muscle damage.
Ezutromid is designed to modulate utrophin protein production
Ezutromid is designed to increase and maintain the production of utrophin, a muscle protein that has been shown in animal studies to partially substitute for dystrophin in muscle fibers. Dystrophin is the muscle protein that is missing or deficient in DMD.
Utrophin is highly expressed in fetal and regenerating muscle but its levels decrease as the muscle fibers mature. In healthy cells it eventually is replaced by dystrophin, which works to maintain the integrity and healthy function of muscle cells.
The inability of individuals with DMD to make dystrophin results in muscle fiber degeneration. However, studies have shown that if utrophin is continually expressed in the mature fiber, it can functionally replace dystrophin and may be able to partially compensate for the deficit in people with DMD.
Summit has demonstrated in nonclinical (animal) efficacy studies that Ezutromid is capable of increasing levels of utrophin protein to restore and maintain the healthy function of muscles, including the heart and diaphragm.
Utrophin may substitute for dystrophin
Since utrophin is naturally produced by people with DMD, raising levels of this protein is expected to be well-tolerated by the body’s immune system. Dystrophin, on the other hand, can sometimes elicit an unwanted immune response in DMD patients.
In addition, utrophin upregulation potentially could be of benefit in DMD regardless of the underlying genetic mutation that causes the disease. By contrast, strategies that focus on upregulating production of functional dystrophin are necessarily targeted at specific DMD mutations.
Results hint that muscle damage may be reduced
The focus of the 24-week interim results from PhaseOut DMD was on biopsy measures that show:
- Treatment with ezutromid resulted in a statistically significant and meaningful reduction in levels of a protein called developmental myosin in muscle biopsies taken after 24 weeks of treatment (a 23 percent decrease compared to baseline measurements). Developmental myosin is a biomarker of muscle damage and is found in muscle fibers that are undergoing repair, so these data suggest that the drug may protect muscles from damage.
- Out of 22 trial participants, 14 showed a decrease in developmental myosin; five of those showed a reduction greater than 40 percent.
- There was a trend toward increased utrophin production measured in biopsies taken at 24 weeks compared to measurements taken prior to beginning treatment with ezutromid.
The combined data suggest that treatment with ezutromid may increase production of the utrophin protein and, in turn, protect muscle from damage. Additional clinical studies will be needed to confirm these results and to determine whether the approach potentially could be a treatment for DMD.
In studies to date, ezutromid has been safe and well tolerated.
MDA has supported development and testing of SMT C1100 (now ezutromid)
MDA has supported the development of utrophin-increasing strategies for many years, including the early development and testing of ezutromid.
In May 2011, MDA-supported geneticist Kay Davies at Oxford University in the U.K., announced key findings showing that daily treatment with SMT C1100 reduced muscle abnormalities, increased overall strength and improved the ability to resist fatigue after exercise in mice with a DMD-like disorder. The study was published in the journal PLoS One. MDA has provided Davies with $1.8 million since 1997 for utrophin-related research.
MDA Venture Philanthropy (MVP) then awarded a $750,000 grant to Summit PLC in December 2011 to test SMT C1100 in humans. MVP is MDA’s drug development program, exclusively focused on funding the discovery and clinical application of treatments and cures for neuromuscular disorders.
At that time, Summit had produced a new formulation of SMT C1100 that it believed would result in high enough blood levels of the drug to increase utrophin production; an earlier formulation had proved inadequate in this respect.
In May 2012, the company announced that the first group of volunteers had begun receiving the drug in a phase 1, dose-escalating trial.
The PhaseOut DMD trial is ongoing, with topline results expected to be reported later in 2018.
After completing 48 weeks of treatment, all trial participants have the option to enroll into an extension phase of the trial. To date, 18 of 19 eligible individuals have enrolled into the extension phase, through which investigators are collecting long-term MRS, functional and safety data on ezutromid.
Summit plans to conduct a randomized, placebo-controlled trial that could potentially support the accelerated and conditional approval of ezutromid in the United States and Europe respectively.
Additional details of the 24-week interim data are expected to be presented at medical and scientific conferences.