Compound A

Development of a hematopoetic prostaglandin D synthase inhibitor for the treatment of Duchenne muscular dystrophy

Patrick Eidam, GlaxoSmithKline

1st April 2016

Compound A is an orally bioavailable drug candidate anticipated to be complementary to other drugs in development for DMD and with the potential to treat all patients regardless of their specific mutation.

This was a pre-clinical application for TACT expert opinion where GSK proposes to develop Compound A a potent, reversible and selective small molecule inhibitor of hematopoetic prostaglandin D2 synthase (H-PGDS). H-PGDS is the key regulator of synthesis of prostaglandin D2 by mast cells and antigen presenting cells.  There is a  biologic rationale for targeting the prostaglandin pathway:  prostaglandins are involved in myoblast proliferation and differentiation, and mice with elevated H-PGDS have an impaired recovery while H-PGDS null mice show enhanced recovery from injury.

TACT felt that an advantage of the H-PGDS inhibition by Compound A compared to many of the current mechanisms associated with development compounds was its potential to have relevance for all DMD patients regardless of their mutation. The panel believe that the pre-clinical data presented, which demonstrates that Compound A reduces eccentric contraction-induced damage in normal and mdx muscle, was promising. They also suggested that additional data be generated and offered specific guidance on what the further steps should be.

TACT suggested a shorter clinical proof of concept (POC) study followed by an open-label extension phase to make the programme more acceptable to patients and families.

Advice was given on the clinical POC endpoints to be selected and TACT made recommendations to be used instead of or alongside the 6MWT including performance of upper limb (PUL), forced vital capacity (FVC), 10m run and 4 stair climb. In addition, it is suggested by TACT that GSK might consider stratifying patients by functional ability rather than by age.

In addition, the panel suggested that GSK consider conducting juvenile toxicology studies early during the preclinical development stage.

12 Apr 2017