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Mixed Results Reported From Phase II Trial of CTP-499 in Diabetic Kidney Disease

PDE inhibitor fails to meet primary endpoint

Mixed results have been reported from a 48-week, phase II study of CTP-499 (Concert Pharmaceuticals) in patients with diabetic kidney disease (DKD). The drug, 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 trial results suggest that CTP-499 may have protective effects on kidney function in patients with type-2 DKD, a disease in which kidney function is progressively lost. In addition, a statistically significant reduction of certain fibrotic biomarkers suggests that CTP-499 may act as an anti-fibrotic agent.

The results were presented April 25 at the National Kidney Foundation 2014 Spring Clinical Meeting, held in Dallas, Texas.

CTP-499 is an oral, deuterium-containing, multi-subtype–selective phosphodiesterase (PDE) inhibitor that is being developed to slow the progression of type-2 DKD in patients with macroalbuminuria. In preclinical testing, CTP-499 suppressed fibrotic, inflammatory, and oxidative processes associated with the pathophysiology of DKD.

The compound is a deuterated analog of 1-(S)-5-hydroxyhexyl-3,7-dimethylxanthine (HDX), an active metabolite of pentoxifylline. It is being developed as an additive treatment to angiotensin modulation with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB), which is the current standard of care for type-2 DKD.

The new phase II, placebo-controlled trial was conducted in three parts:

  • Part 1 was a double-blind, randomized, parallel, two-arm, placebo-controlled study evaluating the safety and efficacy (as measured by the urinary albumin-to-creatinine ratio [UACR]) of CTP-499 600 mg twice daily for 24 weeks. Of the 182 patients enrolled, 151 completed part 1.
  • Part 2 was 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. Of the 143 patients enrolled, 123 completed part 2.
  • In part 3, all patients who completed part 2 were eligible to continue with up to 48 weeks of open-label treatment and to receive 600 mg of CTP-499 twice daily. This open-label study is ongoing.

The trial’s primary endpoint was the change in the UACR, a marker of kidney tissue damage, after 24 weeks of treatment. While the trial did not meet this endpoint, at 48 weeks the longer-term treatment duration suggested a favorable trend in the UACR for patients receiving CTP-499 compared with those given placebo. At 48 weeks, the UACR in patients receiving CTP-499 increased 24 mg/g from baseline compared with a 223-mg/g increase in patients receiving placebo (P = 0.097).

At 48 weeks, a measurable effect on serum creatinine (SCr), a key secondary endpoint, was observed:

  • The mean SCr level in the 65 patients receiving CTP-499 increased by 0.13 mg/dL compared with an increase of 0.21 mg/dL in 58 patients receiving placebo through the 48 weeks of treatment (P = 0.057), reflecting a 38% improvement with the active treatment.
  • Six (10.3%) of the 58 patients receiving placebo experienced a 50% or greater increase in SCr levels after 48 weeks of treatment compared with one (1.5%) of the 65 patients receiving CTP-499 (P = 0.026).

Increased SCr is a marker of impaired kidney function. According to the investigators, the SCr data may indicate a slower decline of kidney function in patients treated with CTP-499 compared with 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 study. Treatment with CTP-499 resulted in 52% less urinary fibronectin (P = 0.008) and 18% less plasma collagen IV (P = 0.022) after 48 weeks of treatment compared with placebo. As with other endpoints in the phase II trial, no significant changes in fibronectin and collagen IV were observed after 24 weeks of treatment, whereas significant effects on these biomarkers were seen after 48 weeks of treatment.

Source: Concert Pharmaceuticals; April 25, 2014.

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