RespireRx Pharmaceuticals Inc. is focused on developing drug candidates to treat very large respiration related markets that are unserved or poorly served. RespireRx is also developing drugs for niche respiratory markets where premium pricing is probable. All of the Company’s current efforts are involved with sleep apnea/hypopnea, respiratory depression and respiratory distress.
Obstructive Sleep Apnea (OSA), the most common form of sleep apnea, affects 29.4 million Americans according to Frost & Sullivan, but only 5.9 million adults are diagnosed (23.5 million are undiagnosed). OSA, besides causing next day sleepiness which is a major cause of motor vehicle and industrial accidents, and is co-morbid with cardiovascular disease, type 2 diabetes and other conditions. Treatment options are limited and the most effective treatment, the CPAP device has an extremely high non-compliance rate. Frost & Sullivan estimates that the overall cost to the U.S. economy of the diagnosed and undiagnosed portions of the OSA market were $12.4 billion and $149.6 billion respectively for a total cost of $162.0 billion in 2015. There is no drug therapy approved for OSA (there is a drug approved for next day sleepiness in certain OSA patients, but does not treat OSA itself). RespireRx also believes that if better treatment options were available, more of the currently undiagnosed patient population would get diagnosed.
RespireRx is developing dronabinol, a capsule that is already approved by the U.S. FDA for other indications, for the treatment of OSA. RespireRx believes that patients prescribed a capsule will be more compliant than patients prescribed a CPAP device, a device that the patient must wear while sleeping, that forces air (continuous positive airway pressure) into the patient’s airway and is both uncomfortable and noisy. Dronabinol is D9-THC (delta 9-tetrahydrocannabinol), a synthetic cannabinoid that is a synthetic version of an active cannabinoid found naturally in marijuana. It is considered a Schedule III drug by the U.S. government and prescriptions are monitored. On December 23, 2016, RespireRx announced positive results of the PACE (Pharmacotherapy of Apnea by Cannabimimetic Enhancement) trial conducted by Dr. David Carley and colleagues at the University of Illinois at Chicago and Northwestern University. The PACE trial, a Phase 2B study of dronabinol for the treatment of obstructive sleep apnea (“OSA”), clearly demonstrates that dronabinol significantly improves the primary outcome measures of Apnea Hypopnea Index (“AHI”), daytime sleepiness as measured by the Epworth Sleepiness Scale (“ESS”) and overall patient satisfaction as measured by the Treatment Satisfaction Questionnaire for Medications (“TSQM”).
In a dose dependent fashion, treatment with 2.5 mg and 10 mg dronabinol once a day at night significantly reduced the Apnea Hypopnea Index (“AHI”), a measure of breathing abnormalities during sleep, in 56 patients with moderate to severe OSA who completed the study. Of those, 17 received placebo, 19 received the 2.5 mg dose and 20 received the 10 mg dose. Compared to average baseline AHI values of 26 + 12, six weeks of dronabinol administration to moderate to severe OSA patients reduced AHI values, compared to placebo, by 9.7 + 4 for the 2.5 mg dose and 13.2 + 4 for the 10 mg dose (p=.02 and p=.001, respectively, compared to control). Furthermore, treatment with 10 mg dronabinol significantly improved daytime sleepiness as measured by the ESS (p = 0.0001, compared to placebo) and achieved the greatest overall patient satisfaction with treatment (p=.02) as measured by the TSQM. This study was financed with a $5 million grant from the National Institutes of Health (“NIH”).
In respect to the same study, RespireRx submitted a Form 8-K on November 1, 2016. An exhibit to that Form 8-K was the final project report submitted by the principal investigators to the NIH. At that time the data was reported on a blinded basis. The December 23, 2016 data was unblinded. The November 1, 2016 Form 8-K and the exhibit may be obtained at https://www.sec.gov/Archives/edgar/data/849636/000149315216014392/0001493152-16-014392-index.htm and then follow the separate links for the Form 8-K itself and Exhibit 99.1.
The Phase 2B study was conducted after a successful smaller Phase 2A study. The Company has licensed the rights to commercialize the University’s patents related to the use of cannabinoids for the treatment of sleep related breathing disorders and has developed additional patent strategies to enhance the intellectual property position in this area.
RespireRx is developing another class of compounds called ampakines and today, issued a press release reporting the data from a Phase2A study of its compound, CX1739, in two models of opioid induced respiratory depression.
Ampakines are positive allosteric modulators of the AMPA glutamate receptor. What that means is that they act in the brain stem, specifically in the pre-Bötzinger Complex which is the brain stem’s center that controls respiratory drive, to enhance the excitatory action of the neurotransmitter, glutamate. Simply ampakines drive you to breath.
Morphine, Oxycotin, Fentanyl and all opioids, while providing analgesia and relieving pain, are limited in that they cause respiratory depression and opioid overdoses are a leading cause of death caused by respiratory depression. The Company’s ampakines are being developed to prevent respiratory depression from the use of opioids while preserving the analgesic pain killing effects.
On December 15, 2016, RespireRx filed a Form 8-K and issued a press release that reported summary data from its Phase 2A, CX1739 study conducted at the Duke Clinical Research Unit of the Duke Clinical Research Institute in which CX1739 was studied in the context of respiratory depression caused by remifentanil, a potent opioid. The study was conducted in two parts referred to as REMI-INFUSION and REMI-BOLUS. The REMI-INFUSION component was designed to measure the prevention or respiratory depression in a model of relatively stable blood levels of the opioid, a model of chronic use. The REMI-BOLUS component was designed to determine if CX1739 prevented respiratory depression after a large rapid dose, a model of overdose or sedation.
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. 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.
Safer opioid use and abuse resistant opioids are a key focus area of the FDA and the NIH. See http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm484765.htm
CX1739 has also shown some preliminary efficacy in central and mixed sleep apnea. Central Sleep Apnea (CSA) is a major form of apnea (and is different from Obstructive Sleep Apnea) that is experienced by opioid users and others and is co-morbid with a number of cardiovascular diseases. The presence of CSA in congestive heart failure patients increases the risk of death. The NIH has reported that 37% of patients with heart failure and left ventricular ejection fraction < 45% had CSA.
RespireRx also has a second oral compound, CX717 that has been in several human studies of opioid induced respiratory depression.
CX1942 is an injectable ampakine that is in preclinical development.
Pending funding, the Company plans to conduct human clinical studies in central sleep apnea, additional studies in opioid induced respiratory depression, respiratory distress in spinal cord injury patients and respiratory distress in Pompe Disease patients (an orphan disease and a niche market).