24 January 2019 - - US-based Ironwood Pharmaceuticals, Inc. (NASDAQ: IRWD) has initiated a Phase 1 study evaluating IW-6463 in healthy volunteers. IW-6463 is an orally administered central nervous system -penetrant soluble guanylate cyclase stimulator that is being developed for the treatment of serious and orphan CNS disorders, the company said.

Data from the Phase 1 study are expected in the second half of 2019.

The randomised, placebo-controlled Phase 1 clinical study is designed to assess the safety, tolerability, and pharmacokinetics of oral IW-6463 in healthy volunteers. The study will evaluate both single-ascending and multiple-ascending doses of IW-6463 in healthy subjects using a randomised, placebo-controlled, double-blind, sequential-group design.

IW-6463 is one of five differentiated sGC stimulator programs expected to be advanced by Cyclerion, a clinical-stage biopharmaceutical company focused on breakthrough treatments for serious and orphan diseases. The separation of Ironwood and Cyclerion is on track to be completed in the first half of 2019.

sGC stimulators are small molecules that act synergistically with nitric oxide on sGC to boost production of cyclic guanosine monophosphate. cGMP is a key second messenger that, when produced by sGC, regulates diverse and critical biological functions throughout the body including blood flow and vascular dynamics, inflammation and fibrosis, metabolism and neuronal function.

Cyclerion expects to advance a portfolio of five sGC stimulators, each designed to target tissues most relevant to the diseases they are intended to treat.

As an orally administered sGC stimulator that has been shown pre-clinically to readily cross the blood-brain barrier, IW-6463 presents the opportunity to expand the utility of sGC pharmacology to serious neurodegenerative diseases.

Clinical and nonclinical research suggests that nitric oxide signaling plays a critical role in the CNS in memory formation and retention, control of cerebral blood flow and modulation of neuroinflammation.

Nitric oxide is a potent neurotransmitter, and impaired nitric oxide-sGC-cGMP signaling is believed to play an important role in the pathogenesis of several neurodegenerative diseases.

In preclinical models, IW-6463 has been associated with an increase in cerebral blood flow, improved neuronal health and function, reduced markers of neuroinflammation and enhanced cognition.

CNS pharmacological activity of IW-6463 has been observed preclinically using multiple non-invasive techniques that can be employed in clinical studies.

Cyclerion Therapeutics is a clinical-stage biopharmaceutical company harnessing the power of sGC pharmacology to discover, develop and commercialize breakthrough treatments for serious and orphan diseases.

The company plans to advance its portfolio of five differentiated sGC stimulator programs with distinct pharmacologic and biodistribution properties that are uniquely designed to target tissues of greatest relevance to the diseases they are intended to treat.

These programmes, each of which have important milestones in 2019, include olinciguat in Phase 2 development for sickle cell disease, praliciguat in Phase 2 trials for heart failure with preserved ejection fraction (HFpEF) and for diabetic nephropathy, IW-6463 in Phase 1 development for serious and orphan central nervous system diseases, and two late-stage discovery programs targeting serious liver and lung diseases, respectively.