Early safety and efficacy data from a Phase 1 trial suggest that Taiho Pharmaceutical’s investigational compound TAS-205 may hold the potential to treat patients with Duchenne’s muscular dystrophy (DMD).
The results were reported in the study, “A phase I study of TAS-205 in patients with Duchenne muscular dystrophy,” published in Annals of Clinical and Translational Neurology.
DMD is a genetic disease characterized by deficient production or activity of the dystrophin protein. Although the role of this protein remains poorly understood, several studies have revealed possible molecules that may contribute to the progression of this rare disease.
Among these is prostaglandin D2 (PGD2), which has been found to be increased in DMD patients, and may play a role in the underlying molecular mechanisms that promote the progression and symptomatic presentations of this disease.
Supported by these findings, Taiho has developed TAS-205, a highly selective inhibitor of the hematopoietic prostaglandin D synthase (HPGDS) enzyme, which is responsible for the production of PGD2.
Preclinical studies with a mouse model of DMD have shown that TAS-205 could reduce muscle damage and help recover locomotor activity in these animals, while it significantly reduced PD2 production.
The company conducted a Phase 1 trial (NCT02246478) to explore the safety, tolerability, and overall body stability and activity of this investigational therapy in children with confirmed DMD.
A total of 21 DMD patients, ages 5-15, were enrolled at a single clinical site in Tokyo, Japan. They were randomly assigned to receive one of three doses — low, middle, and high — of TAS-205, ranging between 1.67 and 13.33 mg/kg, or a placebo. The patients received the treatment orally, either in a single administration or twice daily for seven days.
The treatment was found to be generally safe and well-tolerated. Adverse events were more common in the TAS-205-treated group. Still, no similar events were reported in the single-dose and repeated- dose regimens, which suggests that these events were most likely not related to TAS-205.
Urine analysis showed that TAS-205 treatment — either single or repeated dose — reduced the amount of PGD2, while it had little to no effect in another important similar molecule, prostaglandin E2 (PGE2). The inhibitory effect of TAS-205 was found to be more significant in the group treated with the highest tested dose.
“PGD2 has an inhibitory effect on muscle fiber regeneration, while prostaglandin E2 and major prostaglandin promote muscle fiber regeneration,” researchers wrote. “Therefore, increased muscle fiber regeneration is achieved by selectively inhibiting PGD2.”
Patients who were unable to walk had higher urine values of both PGD2 and PGE2 compared to those who were still ambulatory, further confirming the relevance of PGD2 inhibition.
Collectively, these results demonstrate that TAS-205 is safe and tolerable in patients with DMD, with early evidence of potential therapeutic activity in this population.
Additional studies are still necessary to further evaluate TAS-205’s activity and efficacy.
Taiho has already completed a Phase 2 trial (NCT02752048) in which researchers evaluated the impact of TAS-205 after 24 weeks of repeated oral doses in comparison with a placebo. Results from this trial have not yet been released.