Our Therapeutic Approach: Ion-Channel Modulators

MT-002, a potent and selective Phase 2 ready P2X7 Antagonist licensed from the AstraZeneca Open Innovations portfolio

MyoTherix exclusively licensed MT-002 from AstraZeneca and identified CMT1A and DMD as key indications for clinical development.

In previous Phase I and Phase II clinical studies (in more than 400 patients), MT-002 was generally well tolerated across a wide range of doses and demonstrated high oral bioavailability with pharmacokinetics consistent with once-daily oral dosing, and pharmacodynamics consistent with 100% receptor blockade for 24 hours at a dose of approximately 5 mg/Kg.

There are several publications with compelling preclinical data that demonstrate the therapeutic potential of a P2X7 antagonist in both CMT1A and DMD.

P2X7 and CMT1A

CMT1A is associated with a duplication on part of chromosome 17p11.2 leading to a 1.4MB repetition of ca. 10 genes including the gene for peripheral myelin protein 22 (PMP22). PMP22 is produced primarily by Schwann cells, and it has long been established that overexpression of PMP22 alone is responsible for the demyelinating peripheral neuropathy and to severely reduced nerve conduction velocity. But the mechanisms involved in the demyelinating process have remained elusive.

PMP22 binds directly to the cytoplasmic C-terminal domain of P2X7, and consequently, it has been established that P2X7 expression is also doubled in CMT1A Schwann cells as a direct consequence of increased PMP22 expression. CMT1A is recognized as a disease of aberrant Ca 2+ handling mediated by the P2X7-PMP22 protein complex.

CMT1A Schwann cells display a classical purinergic phenotype; exquisitely sensitive to calcium leading to cell death, and responsive to P2X7 antagonists that can revert CMT1A Schwann cell function back to that seen in normal cells. Down-regulation of the P2X7 receptor in CMT1A Schwann cells (or treatment with a P2X7 receptor antagonist) improves myelination, corrects altered intracellular calcium and restores functional parameters.

These studies establish a pathogenetic link between P2X7 expression, intracellular calcium and impaired Schwann cell function in CMT1A and MT-002 represent an exciting and new first-in-class approach to treatment.

P2X7 and DMD

Over the past decade, the role played by P2X7 in DMD has been assembled by a large group of investigators, most notably with the work of Dr. Darek Gorecki et al. at the University of Portsmouth in the UK. A clearer picture of its involvement in Duchenne came from genetic deletion of P2X7 in the mdx mouse as well as studies utilizing P2X7 small molecule antagonists in this dystrophin null mouse model. P2X7 is markedly upregulated in DMD patients, and activation of the P2X7 channel appears to be a prominent and early event in the dystrophic process, with the ion-channel actively involved in muscle death and fibrosis as well as the osteoporosis and loss of bone mineral density that is a hallmark of the disease in patients.

MT-002 represents a novel, first-in-class approach to treating all DMD patients regardless of their genetic mutation.

NO-Donating Ryanodine Modulator

“Nitric oxide donating ryanodine calcium release channel stabilizers” (aka RyNOs) represent a new therapeutic agent and a novel therapeutic approach to treat neuromuscular disorders. It brings together two distinct validated mechanisms of ryanodine modulation and nitric oxide donation (in one orally bioavailable drug) that when combined have the potential to provide a robust synergistic effect – more pronounced that either mechanism alone.

In the mdx mouse model, RyNOs offer a more robust therapeutic effect than that seen with Rycals® (e.g. ARM210/S48168) or CINOD’s (cyclooxygenase inhibiting nitric oxide donators e.g. naproxinod) and have the potential to treat a range of muscle disorders and muscular dystrophies (DMD, LGMD etc.).

MyoTherix has established a robust patent position covering the use of new and novel ryanodine modulators and RyNO’s and is currently conducting lead optimization studies with a goal of selecting an IND-track candidate.