A Phase 2 Oral Drug Product
RespireRx has completed a Phase I human safety and tolerability study with CX1739 involving approximately 100 subjects, tested at doses up to 1200mg per day. The plasma half-life of CX1739 was around 8 hours, and CX1739 exhibited an excellent clinical safety and good tolerability profile. A very small pilot study of a single dose of CX1739 in twenty otherwise healthy sleep apnea patients has also been conducted. This double-blind, placebo-controlled pilot study was the first step in an assessment of potential efficacy of CX1739 in sleep apnea, and thus was not powered (i.e., not large enough) to provide statistical significance in treating sleep apnea. The study did show that a single dose of CX1739 was able to improve blood oxygenation, and provided a hint that CX1739 may treat central sleep apnea, since a few patient’s central sleep apnea score was noticeably reduced on the night they received CX1739.
RespireRx filed an Investigational New Drug (“IND”) application with the U.S. Food and Drug Administration (“FDA”) to conduct a double-blind, placebo-controlled, dose-ascending Phase 2A clinical trial in approximately 18 subjects to determine the ability of orally administered CX1739, the Company’s lead Ampakine, to prevent the respiratory depression produced by remifentanil, a strong opioid, without altering remifentanil’s analgesic properties. The clinical protocol is designed to evaluate the safety and efficacy of three escalating doses of CX1739 versus placebo when administered prior to remifentanil, with respiration, analgesia and a number of other clinical measures being taken after administration of both drugs. The clinical trial, to be conducted at Duke University was initiated in March 2016.
The commencement of this clinical trial was subject to resolution of two deficiencies (since resolved) raised by the FDA in its clinical hold letter dated November 3, 2015.
- The FDA cited a single incidence of mild necrosis in cardiac tissue from a rat in the highest dose group tested in a 4-week toxicology study. In that study, histopathology analysis was performed on the heart tissue only from rats that received placebo and the highest of three doses of CX1739. In its letter, the FDA requested that cardiac tissue from all animals in all dosage groups be analyzed. This analysis has been completed and, according to two independent, board-certified pathologists, there does not appear to be any drug-related histopathology and the original finding most likely was due to “progressive rodent cardiomyopathy”, a syndrome commonly observed in this strain of rats.
- The FDA requested that the Company perform an additional study in which rats are to be given a single administration of three dosages of CX1739, followed by neuro-histopathology evaluation 1, 5 and 14 days after drug administration. In two previous studies, no neuropathology had been observed after 14 or 28 days of CX1739 administration at very high doses. The agreed upon single dose study has begun and is scheduled to be completed by year end.
We performed the requested analysis, the additional study and, on January 29, 2016 responded to the FDA and provided an amendment to the IND. On February 25, 2016 removed the clinical hold allowing us to commence the clinical trial shortly thereafter.
We previously showed that a predecessor Amapakine compound, CX717, was able to prevent fentanyl-induced respiratory depression without affecting the painkilling, analgesic activity of the opiate. While having an identical mechanism of action, CX1739 is more potent than CX717, and is covered by a recently allowed patent, affording it much longer patent life. As discussed in the Respiratory Disorders section, RespireRx believes that an agent which can prevent drug-induced respiratory depression, without affecting the drug’s intended use as an analgesic or anesthetic, will be welcomed by practitioners who are constantly concerned about the potentially serious, even lethal, respiratory side effects of opioid painkillers, as they try to provide as much comfort for their patients from post-surgical pain.