Concert Pharmaceuticals, Inc. announced the advancement of two programmes from its DCE Platform (Deuterated Chemical Entity Platform). CTP-499 is progressing into phase II clinical trials for diabetic nephropathy and C-21191 has been selected as a lead candidate for spasticity.

CTP-499 is a novel anti-inflammatory, anti-oxidant and anti-fibrotic agent that Concert is developing for the potential treatment of diabetic nephropathy associated with Chronic Kidney Disease (CKD). The company has successfully completed two phase 1 clinical trials and expects to report results at a future scientific meeting. Concert intends to advance the CTP-499 clinical programme into an approximately 170 patient phase II proof-of-concept clinical study by year-end.

Concert also announced that C-21191 has been selected as a lead candidate. C-21191 is a non-sedating subtype-selective GABAA modulator that represents a new therapeutic modality for the potential treatment of spasticity, neuropathic pain and anxiety. Recently, the US Patent and Trademark Office issued a notice of allowance for Concert’s patent application claiming C-21191 and other deuterium-containing GABAA modulators as novel compositions of matter. Concert expects to complete preclinical dose ranging studies during 2011 to support the potential advancement of C-21191 into human clinical testing.

“The efficiency of Concert’s DCE Platform is underscored by the advancement of these two programmes to the next stage of development,” said Roger Tung, PhD, president and chief executive officer of Concert Pharmaceuticals. “We look forward to the continued progress of our chronic kidney disease and CNS programmes as well as applying our technology in other areas where deuterium modification has the potential to provide superior medicines.”

CTP-499 is an analogue of 1-((S)-5-hydroxyhexyl)-3,7-dimethylxanthine (HDX), an active metabolite (M1) of pentoxifylline (PTX), that selectively incorporates deuterium in place of hydrogen at a number of positions. Pentoxifylline is approved for intermittent claudication but has not been formally developed or approved for the treatment of chronic kidney disease.

CTP-499 possesses a pleiotropic mechanism of action with anti-inflammatory, anti-oxidant and anti-fibrotic properties that are different from the current standard of care for CKD. CTP-499 is initially being developed for the treatment of type 2 diabetic nephropathy. In several small, academically sponsored clinical studies, pentoxifylline showed evidence of potential benefit in diabetic nephropathy. Concert leveraged these earlier studies by utilizing its DCE Platform to develop CTP-499, a new chemical entity with a unique pharmacokinetic profile.

Concert has completed two healthy volunteer studies, specifically an assessment of CTP-499 controlled release formulations and a single ascending dose study. Based on its effectiveness in preclinical cellular and in vivo models of renal injury, including a diabetic nephropathy model, Concert expects to evaluate the potential of CTP-499 to protect kidney function and slow disease progression when added to existing standard of care therapy.

Diabetic nephropathy is a common consequence of diabetes and is the leading cause of CKD and need for dialysis in the US. Current standard of care for CKD is treatment with blood pressure lowering agents that affect the renin-angiotensin system, including Angiotensin Converting Enzyme inhibitors (ACEi) and Angiotensin Receptor Blockers (ARBs). Despite the availability of these treatments, many patients progress to renal failure. According to the US Renal Data System, the number of end-stage renal failure patients in the US doubled between 1994 and 2008. There is a critical need for a new agent with a novel mechanism that delays or prevents the decline of kidney function and eventual need for dialysis.

C-21191 is a deuterium-modified subtype-selective GABAA modulator that represents a potential new therapeutic modality for the treatment of spasticity, chronic neuropathic pain. These conditions are associated with multiple neurological disorders including multiple sclerosis, stroke, spinal cord injury and cerebral palsy. Subtype-selective GABAA modulators have the potential to retain the known beneficial actions of the benzodiazepines—including spasmolytic and anxiolytic activities – while minimizing sedative effects and dependency potential. Additionally, C-21191 has demonstrated strong efficacy in a preclinical model of neuropathic pain.

Spasticity is a debilitating aspect of multiple neurological disorders, including multiple sclerosis, spinal cord injury, stroke and cerebral palsy. The most commonly prescribed therapies for spasticity are limited in efficacy and are associated with significant dose-limiting side effects including drowsiness, fatigue and cognitive impairment and result in high rates of therapy discontinuations. According to We Move, less than 50% of patients with spasticity are adequately managed with current treatments.

Deuterium is a safe, non-radioactive relative of hydrogen that can be isolated from sea water and has been used extensively in human metabolic and clinical studies. Since deuterium is an isotope of hydrogen, deuterium-containing compounds are expected to have similar pharmacological activity as their hydrogen analogues. However, because deuterium is heavier than hydrogen, it forms a stronger chemical bond to carbon. The stronger chemical bond obtained by selective deuterium modification may, in certain cases, substantially improve the drug’s metabolic properties, potentially resulting in better safety, tolerability and/or efficacy.

Concert Pharmaceuticals is a clinical stage biotechnology company focused on applying the company’s DCE Platform (Deuterated Chemical Entity Platform) to create novel and differentiated small molecule drugs.