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Concert Pharmaceuticals Presents Positive 48-Week Results from Phase 2 Clinical Trial of CTP-499

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CTP-499 observed to protect against large increases in serum creatinine –

– CTP-499 reduced biomarkers of fibrosis –

– Data presented at late-breaking session at the National Kidney Foundation Spring Clinical Meeting –

Concert Pharmaceuticals, Inc. (NASDAQ: CNCE) today announced 48-week results of its Phase 2 clinical trial of CTP-499 in patients with diabetic kidney disease. CTP-499, when used in addition to the standard of care, is being developed to delay the progression of these patients to end-stage renal failure, which requires dialysis or kidney transplantation. The results suggest that CTP-499 has protective effects on kidney function in patients with type 2 diabetic kidney disease, a condition in which kidney function is progressively lost. In addition, an observed, statistically significant reduction of certain fibrotic biomarkers suggests that CTP-499 may act as an anti-fibrotic agent. The results were presented today during a Late-Breaking session at the National Kidney Foundation 2014 Spring Clinical Meeting by Dr. Bhupinder Singh, a clinical investigator and Medical Director of Apex Research of Riverside.

“The results of this Phase 2 trial after 48 weeks were highly encouraging and, I believe, support the progression of CTP-499 into larger clinical trials. Overall, these data suggest that CTP-499 may protect patients from suffering loss of kidney function by reducing the progression of fibrosis,” said Dr. Singh. “Fibrosis is believed to be a final common pathway for kidney failure due to diabetic kidney disease, a gradual process that occurs over the course of years. Importantly, the biomarker data suggesting predominately anti-fibrotic activity may explain why CTP-499 treatment required a 48 week treatment period to demonstrate a clinical effect.”

Dr. Singh added, “There is an enormous need for new mechanisms, such as inhibition of fibrosis, to treat chronic kidney disease. A new treatment that is well-tolerated and slows the progression of disease could potentially have a major impact on patients' lives.”

The Phase 2 trial was a placebo-controlled, multi-center trial involving three parts:

Part 1—a double-blind, randomized, parallel, two-arm, placebo-controlled study evaluating the safety and efficacy, as measured by urinary albumin to creatinine ratio (UACR), of 600 mg CTP-499 twice daily for 24 weeks. 151 of 182 patients enrolled completed Part 1. Part 2—an optional blinded extension study in which all patients who completed Part 1 were eligible to continue receiving 600 mg of CTP-499 or placebo twice daily for an additional 24 weeks. 123 of 143 patients enrolled completed Part 2. Part 3—all patients who completed Part 2 were eligible to continue with up to 48 weeks of open-label treatment and receive 600 mg of CTP-499 twice daily. This open-label study is ongoing. At 48 weeks, a measurable impact on serum creatinine, a key secondary endpoint, was observed. Increased serum creatinine is a marker of impaired kidney function. These data may indicate a slower decline of kidney function in patients treated with CTP-499 compared to those who received placebo.

The mean serum creatinine level in the 65 patients receiving CTP-499 increased by 0.13 mg/dL compared to an increase of 0.21 mg/dL in the 58 patients receiving placebo through the 48 weeks of treatment (p = 0.057), reflecting a 38% improvement. Six out of the 58 patients receiving placebo, or 10.3%, experienced a 50% or greater increase in serum creatinine levels after 48 weeks compared with one out of the 65 patients receiving CTP-499, or 1.5% (p = 0.026). The primary endpoint of the trial was the change after 24 weeks in UACR, a marker of kidney tissue damage. While the trial did not meet this endpoint, at 48 weeks the longer-term treatment duration suggests a favorable trend in UACR for patients receiving CTP-499 as compared to placebo. At 48 weeks, UACR in patients receiving CTP-499 increased 24 mg/g from baseline compared to 223 mg/g increase in patients receiving placebo (p = 0.097). These data may indicate a stabilization of UACR in patients treated with CTP-499 compared to those who received placebo.

The treatment effects observed at 48 weeks were accompanied by statistically significant changes in urinary fibronectin and plasma collagen IV, two fibrotic biomarkers evaluated in the Phase 2 trial. Treatment with CTP-499 resulted in 52% less urinary fibronectin (p = 0.0081) and 18% less plasma collagen IV (p = 0.022) after 48 weeks compared to placebo. As with other endpoints in the Phase 2 trial, no significant changes in fibronectin and collagen IV were observed after 24 weeks of treatment, whereas significant effects in these biomarkers were seen after 48 weeks of treatment.

Treatment with CTP-499 was generally well tolerated. Gastrointestinal events were reported more frequently in the CTP-499 arm, with mild to moderate nausea being the most commonly reported event. There were a total of 33 patients with at least one serious adverse event reported in the trial; none of these serious adverse events were judged by the investigators to be possibly related to study drug. These events occurred in 20% of patients receiving CTP-499 and 17% of patients receiving placebo. Fewer patients dropped out of the CTP-499 arm than the placebo arm throughout the course of the trial.

“We are encouraged by our 48-week CTP-499 data and have submitted an end of Phase 2 meeting request to the FDA to discuss our development pathway and potential Phase 3 endpoints,” said Roger Tung, Ph.D., President and Chief Executive Officer of Concert Pharmaceuticals. “Diabetic kidney disease is now the nation's leading cause of dialysis, kidney transplant and death from kidney failure. We believe that CTP-499 has a novel mechanism of action for diabetic kidney disease and has the potential to provide a new treatment option for patients with this debilitating and life-threatening condition.”

About Diabetic Kidney Disease

Diabetic kidney disease, a condition in which kidney function is progressively lost, can result in the need for dialysis or kidney transplantation. It is associated with increased morbidity and mortality, and is the leading cause of end-stage renal disease. The current standard of care for chronic kidney disease is treatment with ACEis and/or ARBs, which are blood pressure lowering agents that affect the renin-angiotensin system. Despite the availability of these treatments, many patients progress to end stage renal failure and require dialysis or kidney transplants. Approximately 40% of patients with a history of type 2 diabetes are believed to have diabetic kidney disease.

About CTP-499

CTP-499 is a novel, deuterium-containing, oral multi-subtype selective PDE inhibitor that is being developed to slow the progression of type 2 diabetic kidney disease in patients with macroalbuminuria. In preclinical testing, CTP-499 suppressed fibrotic, inflammatory and oxidative processes associated with the pathophysiology of diabetic kidney disease. CTP-499 is a deuterated analog of 1-(S)-5-hydroxyhexyl-3,7-dimethylxanthine, or HDX, an active metabolite of pentoxifylline. It is being developed as an additive treatment to angiotensin modulation with an ACEi or ARB, which is the current standard of care for type 2 diabetic kidney disease.

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