RespireRx Pharmaceuticals Inc, which develops medicines for respiratory disorders, including sleep apneas and drug-induced respiratory depression, announces data for its CX1739 clinical study in opioid-induced respiratory depression.
Arnold Lippa, PhD, executive chairman and chief scientific officer says in a release: “We are pleased with the positive results of our recent Phase 2A study, which encourages us to take CX1739 forward in additional studies. We look forward to conducting additional studies investigating the effects of CX1739 on opioid-induced respiratory depression in post-surgical patients self-administering opioids in a hospital setting as well as on central sleep apnea in out-patients taking oral opioids chronically for pain management.”
Opioid analgesics are now the most commonly prescribed class of medicines in the United States, where chronic pain is estimated to affect around 68 million people each year. Opioids are useful and effective analgesics but produce several unwanted side effects, including episodes of potentially life-threatening respiratory depression, which resulted in over 30,000 deaths in 2014. While some of these deaths are from abuse of opioids, a large number are accidental deaths by patients who require opioids for pain management, in both an acute and chronic setting.
The respiratory depression produced by opioids is most sensitively detected during sleep and is manifested as apnea/hypopnea or central sleep apnea (CSA). Opioid-induced sleep apneas are observed with intravenous opioid infusions in a post-surgical hospital setting. Furthermore, patients chronically taking oral opioids for pain relief also present with CSA. Overall, sleep apnea is the major risk factor for mortality and morbidity in opioid overdose. Clearly, preventing or reducing the respiratory depressive effects of opioids will save lives.
In short, there is very substantial unmet medical need and very large market potential in treating respiratory depression/sleep apnea in patients who require short-term or long-term treatment with opioids to manage their pain. CX1739 belongs to a class of drugs called ampakines that the company is developing to be taken in conjunction with opioids in order to reduce respiratory depression without altering analgesia.
Summary of Clinical Trial Results
In order to understand the relevance of the data in this study, it is important to understand the conditions under which opioids are used. The preponderance of opioid use is for the treatment of pain. Regardless of whether the opioid is taken orally or intravenously, either acutely or chronically, the treatment of pain requires stable opioid blood levels that also can produce respiratory depression/sleep apnea. Alternatively, some opioid users consume a large acute dose of opioid, whether orally or intravenously, intentionally, or accidentally, that also can produce potentially fatal respiratory depression. While opioid antagonists, such as Narcan, are the gold-standard for the treatment of acute opioid overdose, their use is inappropriate for patients taking the opioids for pain relief because they antagonize the analgesic effects of the opioids at the same time that they antagonize respiratory depression.
The recently completed Phase IIa clinical trial evaluated the ability of CX1739 to overcome the respiratory depression induced by the powerful, yet short-acting opioid, remifentanil, in two models of opioid use: During REMI-INFUSION, respiration, pain, and other parameters were measured during a 30-minute intravenous infusion of remifentanil in order to produce stable blood levels resulting in approximately 50% declines in respiratory rate over this period. During REMI-BOLUS, a model of acute opioid overdose, a single, intravenous bolus injection of remifentanil was administered at a dose calculated to achieve approximately 50% respiratory depression.
During REMI-INFUSION, CX1739 treatment antagonized the respiratory rate depression produced by remifentanil, with statistically significant effects observed at 300mg (p<.005) and 900mg (p<.001). The antagonism produced by the 600mg dose did not achieve statistical significance. This lack of a linear, dose response effect is not unusual in early stage clinical trials. During this period, CX1739 did not significantly alter the analgesic and sedative effects of reminfentanil.
During REMI-BOLUS, CX1739 treatment did not prevent respiratory depression, nor improve time to recovery at any of the doses tested.
Overall, CX1739 was found to be safe and well tolerated, both prior to and during administration of remifentanil. Treatment-related adverse events (AEs) for the various doses of CX1739 were mild, with an incidence comparable to that reported for placebo. The great majority of AEs occurred after remifentanil administration.
Description of the Study Design
The study consisted of two separate stages. Stage 1 was a randomized, double-blind, crossover study comparing 300 mg CX1739 to placebo and Stage 2 was an open-label, ascending dose study to assess 600 and 900 mg of CX1739. Subjects were tested once a week over a 4-week period. Statistical comparisons were performed for Stage 1 alone as well as for Stage 1 and Stage 2 combined.
On each study day, REMI-BOLUS was initiated with an intravenous, bolus injection of remifentanil 3 hours after subjects received either placebo or CX1739. Respiration was measured for 20 minutes and then compared to the baseline respiration recorded 5 minutes prior to the bolus injection. REMI-INFUSION was initiated 3.5 hours after placebo or CX1739, with an intravenous infusion protocol designed to maintain stable remifentanil blood levels and calculated to produce approximately 50% respiratory depression.
The study was conducted at the Duke Clinical Research Unit of the Duke Clinical Research Institute. The ClinicalTrials.gov identifier is NCT02735629.