Concert Pharmaceuticals commences phase 2 dosing of CTP-499, a novel treatment for chronic kidney disease – April 13, 2012

Executive Highlights

  • Concert Pharmaceuticals has begun dosing for its phase 2 clinical trial of novel agent CTP-499 for diabetic nephropathy and other forms of chronic kidney disease (CKD).

Lexington, MA-based biotech company Concert Pharmaceuticals recently announced the initiation of phase 2 dosing for CTP-499, its novel therapy for diabetic nephropathy and other forms of chronic kidney disease (CKD). CTP-499 is intended to be an adjunct to the current standard CKD therapies, angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB), both antihypertensive therapies. A potential first-in-class drug, CTP-499 is a deuterium-stabilized analog of 1-((S)-5-hydroxyhexyl)-3,7-dimethylxanthine (HDX), which in turn is an active metabolite of the intermittent-claudication therapy pentoxifylline (Sanofi’s Trental). The drug’s multi-modal mechanism is believed to involve inhibition of phosphodiesterases, enzymes that regulate cell-signaling pathways that increase inflammation and promote CKD.

The phase 2 clinical trial will enroll approximately 170 patients with type 2 diabetes and stage 2/3 (mild/moderate) CKD that have been on a stable regimen of ACEi or ARB therapy for at least four weeks ( identifier: NCT01487109). Following a stabilization period, patients are randomized 1:1 to take CTP-499 600 mg twice daily or placebo for 24 weeks. The primary endpoint is change in urine albumin to creatinine ratio (UACR) from baseline to 24 weeks, with interim measurements at weeks 16 and 20. Four phase 1 studies indicated a favorable safety profile with the most common adverse event being mild, transient nausea (percentage of patients not provided). By way of ballpark reference, the label for Trental refers to a 28.8% nausea rate with the immediate-release formulation and 2.2% with the extended-release version.

Phase 2 results are expected in mid-2013, which puts CTP-499 behind Reata’s potentially disease- modifying bardoxolone methyl (in partnership with Abbott; phase 3 results expected in 2H2013) and Abbott’s more modestly effective atrasentan (Abbott-owned; phase 3 to begin in 2013). We note that the target patient population is somewhat different; Concert’s study includes mild/moderate (stage 2/3) where Reata is enrolling more advanced CKD patients. The need for treatments is certainly great: the CDC estimates that over 20 million people in the US have CKD. Available treatments can slow the course of disease but do not reverse it, and over 100,000 patients a year progress from CKD to end-stage renal disease (ESRD), at which point they must receive dialysis or kidney transplants. Effective therapies for diabetic nephropathy are especially valuable since 20%-30% of type 1 and type 2 diabetes patients show evidence of nephropathy, the disease accounts for 40% of new cases of ESRD). The annual cost of treating diabetes patients with ESRD exceeds $15.6 billion (Molitch et al., Diabetes Care 2004).


  • CTP-499 is the most advanced drug in Concert Pharmaceuticals’ pipeline. CTP-499 is an analog of 1-((S)-5-hydroxyhexyl)-3,7-dimethylxanthine (HDX), an active metabolite of pentoxifylline (PTX) that is responsible for much of PTX’s therapeutic action. (What this means is that drugs are are modified through the metabolic process into metabolite forms, which often have similar properties. Active metabolites continue to exhibit the beneficial effects of the parent drug, though usually to a lesser degree. HDX is a rare case in that it is believed to play a major role in the therapeutic action of pentoxifylline.) While PTX is currently indicated for intermittent claudication (pain resulting from impaired circulation in the legs), the compound has been reported in multiple clinical trials to reduce proteinuria (a marker of CKD) in diabetes patients with nephropathy. Concert leveraged these studies and designed CTP-499 to retain the renal- protective properties of PTX and HDX, but show an improved PK/PD profile. Specifically, CTP- 499 exhibits anti-inflammatory, anti-oxidant, and anti-fibrotic properties and is believed to inhibit phosphodiesterases, enzymes that regulate cell-signaling pathways that increase inflammation and promote CKD. This is pretty exciting, since as we understand it, the compound could slow or potentially even reverse CKD although it is early to speculate on this front.
  • CTP-499 was modified from HDX using Concert’s novel DCE platform, which replaces select hydrogens in a molecule with deuterium (D) to create a new chemical entity with an improved PK/PD profile. Deuterium, commonly referred to as “heavy hydrogen,” is a naturally occurring stable isotope of hydrogen that has an extra neutron. While deuterium has the same size and shape as hydrogen, carbon-deuterium bonds are much more stronger than carbon-hydrogen bonds and more resistant to the metabolic process. Thus deuterium substitution can lead to a more stable molecule, or one that breaks down through a different metabolic pathway.
  • Management has not yet divulged whether Concert is seeking a partner to commercialize CTP-499, though we would assume that it would eventually be, depending on phase 2 results. Management has expressed interest in commercializing their products in-house, though R&D represents the company’s current focus. In a partnership with GlaxoSmithKline (established in 2009), Concert took the lead in developing an HIV protease inhibitor that GSK would have the option of licensing. The lead compound, CTP-298, was selected in June 2011. More recently, in February 2012 Avanir Pharmaceuticals acquired exclusive worldwide rights to develop and commercialize Concert’s deuterium-modified dextromethorphan (d-DM) as a possible therapy for neurological and psychiatric disorders.
  • Concert’s preclinical pipeline includes a therapy for spasticity and neuropathic pain, potentially including painful diabetic neuropathy. The drug, called C-21191, is a deuterium-modified analog of L-838417 (which was discovered by Merck, showed early promise for efficacy and tolerability as an antianxiety agent, but was found to have a poor pharmacokinetic profile in preclinical tests). C-21191is a GABA(A) modulator like the benzodiazepines (e.g., Valium and Xanax), but evidently without agonism of the GABA(A) a1 receptor or the associated side effects of ataxia (lack of muscle coordination) and sedation. The drug sounds like it has good potential in diabetic neuropathy, though Concert’s first priority appears to be pain and spasticity related to multiple sclerosis: in March 2012 Concert announced an arrangement with Fast Forward, a branch of the National Multiple Sclerosis Society, to fund C-21191’s preclinical development.

--by Nina Ran, Joseph Shivers, and Kelly Close