CTP-354 (formerly known as C-21191) is a potentially first-in-class, non-sedating and once-daily oral formulation being developed by Concert Pharmaceuticals. It aims to treat conditions like multiple sclerosis (MS), cerebral palsy, amyotrophic lateral sclerosis (ALS), spinal cord injury, and hereditary paraplegia, all of which contribute to spasticity in humans.
Planned Phase 2 studies of this treatment in MS and other patients was postponed in late 2014, and have not been rescheduled since.
As part of the CTP-354 development program, Concert is utilizing its deuterated chemical entity (DCE) platform, which involves the addition and modification of existing and approved drugs, or those previously in clinical studies, that use deuterium — a stable hydrogen isotope — to improve their safety and efficacy as treatments. CTP-354 is a modified version of L-838417, an anti-anxiety agent originally developed by Merck.
How CTP-354 works
Chemically, CTP-354 is a subtype-selective GABAA receptor modulator. GABAA receptors are proteins that are abundant in the nervous system. Their main ligand, gamma-aminobutyric acid (GABA), is a major inhibitory neurotransmitter that is involved in the reduction, or inhibition, of the conduction of nerve impulses. GABA inhibitory neurotransmission is important for the normal functioning of the nervous system and the conduction of nerve impulses.
GABA treatment has previously been shown to lower the production of inflammatory cytokines, a protein that can trigger an immune response, in peripheral macrophages. T-cell-mediated autoimmunity and the development of inflammatory responses are also reduced with GABA treatment.
Antigen-presenting cells (APCs) in the immune system possess these GABAA receptors. CTP-354 binds to the GABAA receptors and, in autoimmune diseases like MS, reduce the inflammatory immune response.
History of CTP-354
Preclinical testing of the safety and efficacy of CTP-354 in both rat and dog models was successful, as the observed pharmacological activity and serum levels of GABA were shown to be similar to previous generations of modulators, such as benzodiazepines. CTP-354 treatment also evidenced fewer side effects compared to benzodiazepines.
Concert Pharmaceuticals received financial support in 2012 from Fast Forward, an organization established by the National Multiple Sclerosis Society to accelerate the research and development of potential MS treatments such as CTP-354.
A Phase 1 clinical trial to assess the safety and tolerability of CTP-354 in healthy volunteers with multiple ascending doses was completed in 2014. Concert reported that there was no sedation or ataxia observed in the volunteers, and that the drug had a healthy pharmacokinetic and pharmacodynamic safety profile in all study participants.
In June 2014, the FDA lifted a partial ban placed on the maximum dosage of CTP-354 that could be administered. Following this, Concert Pharmaceuticals announced it intended to begin two Phase 2 trials by the end of 2014, one of which aimed to assess CTP-354 as a treatment for spasticity in people with MS. But the company announced a delay in the trials’ start in favor of further preclinical studies in November 2014. No further updates have been released, and CTP-354 is not listed on the “product pipeline” of investigative treatments on Concept’s current homepage.
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