Concert Pharmaceuticals (NASDAQ:CNCE), which is modifying known drugs with its deuterium technology, last week initiated a multiple ascending dose Phase 1 trial with healthy volunteers of its next generation drug for cystic fibrosis (CF), CTP-656, as a stepping stone to a small Phase 2 efficacy trial in the second half of 2016.
“We hope to showcase how deuterium, a heavier form of hydrogen, can create new medicines from existing drugs to potentially enhance safety and efficacy as well as treat new indications,” Roger Tung, president and CEO, says in an interview with BioTuesdays.com.
The current trial will include three different doses of CTP-656 as well as a single dose crossover comparison of CTP-656 with Kalydeco, or ivacaftor, which is the first drug that treats the underlying cause rather than the symptoms of CF in patients with certain mutations of the disease.
Those mutations account for 4% to 5% of CF cases. Treatment with Kalydeco runs about $300,000 per patient per year. CF affects approximately 70,000 patients worldwide.
Jim Cassella, chief development officer, says top-line results of the multiple ascending dose trial will be reported in the first half next year.
CTP-656 potentiates the cystic fibrosis transmembrane conductance regulator (CFTR) and was developed by Concert using its Deuterated Chemical Entity (DCE) Platform. As a deuterated analog of ivacaftor, CTP-656 has the potential to improve CFTR activity and treat the basis of CF, Dr. Tung contends.
He explains that the company applies its DCE Platform to design drug compounds that selectively incorporate deuterium to potentially improve the effectiveness, safety and tolerability of known drugs, without materially changing a compound’s biochemical potency or selectivity.
He says substituting hydrogen with deuterium in biologically active molecules has the effect of increasing a molecule’s chemical bond stability and potentially providing it with unique properties.
“We have implemented this approach to develop a robust pipeline of new medicines that offer improved ways to target a broad range of disease areas, including CNS disorders, renal disease, inflammation and cancer,” he adds.
Dr. Cassella says that in an earlier Phase 1 single ascending dose trial of its cystic fibrosis drug candidate, CTP-656 demonstrated a superior pharmacokinetic profile, compared with Kalydeco, and the trial results support once-daily dosing. CTP-656 was well tolerated and its safety profile was comparable to Kalydeco, he adds.
He says the company’s international Phase 2 study next year will enroll fewer than 40 patients, with treatment over four weeks, to evaluate two doses coming out of the current multiple ascending dose trial. The Phase 2 clinical endpoints will include a sweat chloride marker and FEV1, or the forced expiratory volume of air from the lungs in the first second.
Beyond cystic fibrosis, Concert has partnered its AVP-786 CNS drug candidate with Avanir Pharmaceuticals, which was acquired by Otsuka Pharmaceutical Co. for $3.5-billion earlier this year. AVP-786 is a combination of deuterium-substituted dextromethorphan and an ultra-low dose of quinidine.
In September, Avanir began recruiting patients in a Phase 2 trial to evaluate AVP-786 as an adjunctive treatment for patients with residual schizophrenia. Avanir also is evaluating AVP-786 in resistant major depressive disorder.
Avanir yesterday initiated dosing patients in a Phase 3 clinical trial with AVP-786 for the treatment of agitation in Alzheimer’s disease.
The Phase 3 program is expected to enroll about 700 patients to compare AVP-786 against a twice-daily placebo in two studies over 12 weeks. The primary endpoint is expected to be an analysis of the Neuropsychiatric Inventory of agitation and aggression. Patients who complete the program will be eligible to enter a long-term safety and efficacy extension study, with completion slated for the third quarter of 2018.
In addition, Concert has ongoing collaborations with Jazz Pharmaceuticals to evaluate JZP-386 for the treatment of narcolepsy and with Celgene to evaluate CTP-730 in inflammatory diseases. Proof-of-concept Phase 1 studies have been completed in both programs.
JZP-386 is a product candidate containing deuterated sodium oxybate, which is the active ingredient in the marketed drug, Xyrem. CTP-730 is a deuterated apremilast analog for the potential treatment of inflammatory disease, which is in development under a multi-product collaboration with Celgene.
Dr. Tung says Concert also has obtained a special protocol assessment from the FDA for a Phase 3 clinical trial of its CTP-499 drug candidate for the treatment of diabetic nephropathy and is seeking one or more collaborators for its future development.
Concert’s existing collaborations with Avanir, Jazz and Celgene have a combined potential of $1.6-billion in milestone payments plus mid-single to low-double digit royalties on sales of each product. The company’s milestone tally is expected to reach some $53-million by the end of 2015.
“Because we’ve established that deuterated-modified compounds can share many of the properties, including safety and tolerability, of the preexisting drugs, we believe there is the potential for accelerated development of certain deuterated compounds by referencing data established for non-deuterated drugs,” Dr. Tung contends.