RespireRx Pharmaceuticals Inc. Announces Preliminary Top-Line Analysis of Data From Duke University Phase 2A Clinical Trial of CX1739
Marketwired September 12, 2016
GLEN ROCK, NJ--(Marketwired - Sep 12, 2016) - RespireRx Pharmaceuticals Inc. ( OTCQB : RSPI ) ("RespireRx" or the "Company") is a leader in the development of medicines for respiratory disorders, including drug-induced respiratory depression (RD) and sleep apneas.
RespireRx is today reporting preliminary top-line data from its Phase 2A clinical trial of CX1739, the Company's proprietary, orally administered ampakine. CX1739 was determined to be safe and well tolerated, and antagonized the respiratory depressive effects of remifentanil (REMI), a potent opioid, in clinical models of acute opioid overdose and chronic opioid use. These results demonstrate target engagement of AMPA glutamate receptors and confirm the Company's translational approach to developing medicines for respiratory disorders.
The Duke University School of Medicine initiated this Company-funded Phase 2A clinical trial in March 2016. The dosing and data accumulation phase of the clinical trial was completed in June 2016 and the clinical trial was formally completed on July 11, 2016. Database unblinding occurred on September 7, 2016.
Study Design
The clinical trial, conducted in two separate stages over a four week period, was designed to assess the safety of CX1739, as well as its ability to antagonize the respiratory depressive effect of REMI without altering its analgesic properties.
Stage 1, a randomized, double-blind, crossover study comparing 300 mg of CX1739 to placebo, was considered a primary outcome study. After an overnight stay at the clinical facility, subjects were administered either placebo or CX1739. For the first visit, subjects were randomly administered either placebo or 300 mg CX1739. On the second visit, subjects were crossed over and administered the other compound.
Three hours after receiving placebo or CX1739, subjects underwent a REMI 1 period in which respiration was measured by impedance plethysmography for 5 minutes, in order to establish a baseline. Subjects then received an intravenous bolus injection of REMI (1 µg/kg) and respiration was measured for an additional 20 minutes after the bolus injections). During REMI 1, the primary measure used to determine antagonism of respiratory depression was the calculated time to recover (recovery time - RT) from the maximal respiratory depressant effects (Emax) of REMI.
Thirty minutes after the bolus injection of REMI, subjects underwent a REMI 2 period in which a continuous infusion protocol for REMI was begun (0.25 µg /kg bolus followed immediately by a constant infusion calculated to achieve blood levels of 2 ng/ml). After allowing 10 minutes for equilibration, respiratory rate, pain and pupilometry measurements were taken.
REMI 1 was designed as a model of acute opioid overdose, while REMI 2 was designed as a model of chronic, opioid consumption in which opioid blood levels remain relatively constant.
The clinical trial also evaluated the safety of CX1739 when taken alone and in conjunction with REMI and investigated the effect of CX1739 on the analgesic and sedative effects of REMI. These latter data have not yet been analyzed and will be reported at a future date.
Stage 2 took place during the second two week period and was designed as an open-label, ascending dose study to assess the ability of 600 and 900 mg of CX1739 to antagonize the respiratory depressive effects of REMI. Otherwise, Stage 2 was conducted in the same manner as Stage 1.
Safety and Study Conduct
Twenty-one subjects initially were enrolled in the study and all were included in the safety analysis. Four subjects terminated early, two because of scheduling problems and two because of adverse events (AEs). Of the 17 subjects who completed the study, two did not display maximal depression of respiration rate (Emax) >25% and were not included in the respiratory data analyses.
In general, CX1739 was safe and well tolerated, and no serious adverse events (SAEs) occurred. By far, the most frequent AEs were nausea, vomiting, headache and dizziness, all of which are common side effects of opioids. Forty-nine AEs were reported by 15 of the 21 subjects. Thirty-nine AEs occurred after the administration of REMI and 8 AEs occurred less than one hour after ampakine or placebo administration, a time period that is too early for significant blood levels of CX1739 to have occurred.
Efficacy Measures
REMI 1. Acute bolus injection of REMI caused a rapid and dramatic decline in respiration, with Emax ranging from 15% - 100% across subjects. When subjects in Stage 1 were pre-treated with 300 mg of CX1739, a statistically significant reduction of RT, the primary outcome measure, was observed. RT was reduced from a mean of 6.8+ 0.98 after placebo pre-treatment to a mean of 4.4+0.77 after 300 mg of CX1739 pre-treatment (p=.01, paired t test). In Stage 2, RT was reduced for both doses, although no significant differences (p>.05) were observed when these doses were compared to either placebo or 300 mg. While this difference between 300 mg and the higher doses might reflect greater efficacy at the 300 mg dose, the Company believes that this lack of significance for the higher doses might also reflect inter-subject variability in what doses produced the optimum decline in RT. Supporting this idea, responder analysis revealed that decreases in RT were observed, in a statistically significant proportion of subjects (13 out of 15, p<.005, z test), after one or more doses of CX1739. Using these data from optimum doses, mean RT was significantly (p<.002, paired t test) reduced from 6.8 +0.98 minutes after placebo to 3.7 +0.70 minutes after CX1739.
REMI 2. The REMI 2 period began 30 minutes after the REMI 1 bolus injection of REMI and in this case was a continuous intravenous infusion. Baseline respiration was recorded during the first 2 minutes. Ten minutes after REMI 2 began, when respiratory rates and presumably blood levels of REMI had stabilized, respiration was monitored continuously for 5 minutes and the average percentage change from baseline for the 5 minute interval was determined. The data from 5 subjects was excluded from analysis because the REMI produced less than 25% depression of respiratory rate when these subjects were pretreated with placebo. CX1739 produced a dose-related diminution in the respiratory depression produced by REMI, with statistically significant differences from placebo observed at 600 mg (p < 0.05, t test) and 900 mg (p = 0.01, t test).
Data regarding CX1739's ability to alter the opioid's analgesic properties have not yet been analyzed. A full statistical analysis is expected to be completed during October 2016 and a clinical study report is expected to be completed by the end of December 2016.
Conclusions
Having demonstrated proof of principle and target engagement, the Company has concluded that further development of CX1739 to determine its potential efficacy in the appropriate clinical indications is warranted, and future studies are being designed and planned.
