RespireRx Enters Collaboration With National Institute for Neurological Disorders & Stroke to Advance its Lead GABAkine Toward Clinical Development

RespireRx Pharmaceuticals Inc. recently announced it has been accepted into the NIH HEAL Initiative NINDS Preclinical Screening Platform for Pain (PSPP) program. The company’s lead GABAkine, KRM-II-81, has been shown to be effective in relieving acute, chronic, and neuropathic pain in a number of models without tolerance development or sedation.

The Helping to End Addiction Long-term Initiative, or NIH HEAL Initiative, is an aggressive, trans-agency effort to speed scientific solutions to stem the national opioid public health crisis. Launched in April 2018, the initiative is focused on improving prevention and treatment strategies for opioid misuse and addiction, and enhancing pain management. For more information, visit https://heal.nih.gov.

The PSPP program, part of the NIH HEAL Initiative, evaluates non-opioid assets in a battery of established preclinical models. The PSPP program accepts small molecules, biologics, devices, or natural products for evaluation, from researchers in academia and industry worldwide. For more information, visit https://heal.nih.gov/research/preclinical-translational/screening-platform.

The RespireRx team is led by Dr. Arnold Lippa, RespireRx Executive Chairman and Chief Scientific Officer and Drs. James M. Cook, Jeffrey M. Witkin and Rok Cerne, all of whom are RespireRx Research Fellows in addition to their academic affiliations at University of Wisconsin-Milwaukee, Ascension St. Vincent and Indiana University/Purdue University, respectively. The team has extensive expertise in drug discovery and development including the development of novel analgesic drugs and an extensive publication record with a combined total of over 1,000 scientific publications. The team has already profiled KRM-II-81 activity in a broad range of preclinical studies where it has displayed a high degree of analgesic activity and is excited at the prospect of advancing the companay’s lead GABAkine toward clinical development. In cellular studies, KRM-II-81 preferentially bound to specific subtypes of GABA_A receptors and boosted the ability of GABA to inhibit pain sensory neurons in the spinal dorsal root ganglia. In intact animal models of acute and chronic pain, the analgesic efficacy of KRM-II-81 was comparable to or greater than commonly used analgesics. At the same time, KRM-II-81 did not display side effects such as sedation and motor impairment, but even more importantly, it did not produce tolerance, dependence, respiratory depression, or behavioral changes indicative of abuse liability, which are produced by opioid narcotics and are at the heart of the opioid epidemic.

Unrelated to the NINDS project, KRM-II-81 has also shown promising results in multiple animal models of treatment resistant epilepsy and in human translational studies by reducing epileptiform electrical signaling in brain tissue removed from treatment resistant epileptic patients undergoing surgery.

Dr. Cerne commented “We believe that the expansion of our understanding of GABA_A receptor structure and function has created a new surge in the discovery and development of GABAkines that target such receptors in a unique manner. This opens the promise of improved medicines for pain, epilepsy and other disorders caused by disruption of neuronal signaling.”

Dr. Lippa added, “We are very excited about developing KRM-II-81 and expanding the IND enabling studies so as to begin human studies. Pending clinical validation, we believe that KRM-II-81 has the potential to represent a breakthrough treatment for pain, epilepsy, and other neuropsychiatric disorders.”

RespireRx Pharmaceuticals Inc. is a leader in the discovery and development of medicines for the treatment of psychiatric and neurological disorders, with a focus on treatments that address conditions affecting millions of people, but for which there are few or poor treatment options, including attention deficit hyperactivity disorder (ADHD), epilepsy, pain, recovery from spinal cord injury (SCI), certain neurological orphan diseases and obstructive sleep apnea (OSA). RespireRx is developing a pipeline of new and re-purposed drug products based on our broad patent portfolios for two drug platforms: (i) pharmaceutical cannabinoids, which include dronabinol, a synthetic form of ∆9-tetrahydrocannabinol (Δ9-THC) that acts upon the nervous system’s endogenous cannabinoid receptors and (ii) neuromodulators, which include AMPAkines and GABAkines, proprietary chemical entities that positively modulate (positive allosteric modulators or PAMs) AMPA-type glutamate receptors and GABA_A receptors, respectively.

The company holds exclusive licenses and owns patents and patent applications or rights thereto for certain families of chemical compounds that claim the chemical structures and their uses in the treatment of a variety of disorders, as well as claims for novel uses of known drugs.

EndeavourRx: Neuromodulators

GABAkines: Under a License Agreement with the University of Wisconsin-Milwaukee Research Foundation, Inc. (UWMRF) and on behalf of its EndeavourRx business unit, RespireRx has licensed rights to certain selectively acting GABAkines because of their ability to selectively amplify inhibitory neurotransmission at a highly specific, subset of GABA_A receptors, thus producing a unique efficacy profile with reduced side effects. Preclinical studies have documented their efficacy in a broad array of animal models of interrelated neurological and psychiatric disorders including epilepsy, pain, anxiety, and depression in the absence of or with greatly reduced propensity to produce sedation, motor-impairment, tolerance, dependence and abuse. The Company currently is focusing on developing KRM-II-81 for the treatment of epilepsy and pain.

KRM-II-81 has displayed a high degree of anti-convulsant activity in a broad range of preclinical studies, including in treatment resistant and pharmaco-resistant models. Not only was KRM-II-81 highly effective in these models, but pharmaco-resistance or tolerance did not develop to its anti-convulsant properties. These latter results are particularly important because pharmaco-resistance occurs when medications that once controlled seizures lose efficacy as a result of chronic use and it is a principal reason some epileptic patients require brain surgery to control their seizures. In support of its potential clinical efficacy, translational studies have demonstrated the ability of KRM-II-81 to dramatically reduce epileptiform electrical activity when administered in situ to brain slices excised from treatment resistant epileptic patients undergoing surgery.

In addition, KRM-II-81 has displayed a high degree of analgesic activity in a broad range of preclinical studies. In intact animal models of pain, the analgesic efficacy of KRM-II-81 was comparable to or greater than commonly used analgesics. At the same time, KRM-II-81 did not display side effects such as sedation and motor impairment, but even more importantly, it did not produce tolerance, dependence, respiratory depression or behavioral changes indicative of abuse liability, which are produced by opioid narcotics and are at the heart of the opioid epidemic.

AMPAkines: Through an extensive translational research effort from the cellular level through Phase 2 clinical trials, the Company has developed a family of novel, low impact AMPAkines, including CX717, CX1739 and CX1942 that may have clinical application in the treatment of CNS-driven neurobehavioral and cognitive disorders, spinal cord injury, neurological diseases, and certain orphan indications. Our lead clinical compounds, CX717 and CX1739, have successfully completed multiple Phase 1 safety trials. Both compounds have also completed Phase 2 proof of concept trials demonstrating target engagement, by antagonizing the ability of opioids to induce respiratory depression.

AMPAkines have demonstrated positive activity in animal models of ADHD, results that have been extended translationally into statistically significant improvement of symptoms observed in a Phase 2 human clinical trial of CX717 in adult patients with ADHD. Statistically significant therapeutic effects were observed within one week. We believe AMPAkines may represent a novel, non-stimulant treatment for ADHD with a more rapid onset of action than alternative non stimulants, such as Straterra (atomoxetine), and without the drawbacks of amphetamine-type stimulants.

In a series of important studies funded by grants from the National Institutes of Health and published in a number of peer reviewed articles, Dr. David Fuller (University of Florida), a long-time RespireRx collaborator, has demonstrated the ability of CX1739 and CX717, the Company’s lead AMPAkines, to improve motor nerve activity and muscle function in animal models of spinal cord injury (SCI).

ResolutionRx: Pharmaceutical Cannabinoids 

Dronabinol: RespireRx’s ResolutionRx business unit is developing dronabinol, ∆-9-THC, a synthetic version of the naturally occurring substance in the cannabis plant, for the treatment of OSA, a serious respiratory disorder that impacts an estimated 29.4 million people in the US according to the American Academy of Sleep Medicine (AASM), published in August 2016. OSA has been linked to increased risk for hypertension, heart failure, depression, and diabetes, and has an annual economic cost in the US of $162 billion according to the AASM. There are no approved drug treatments for OSA.

Two Phase 2 clinical trials have been completed demonstrating the ability of dronabinol to significantly reduce the symptoms of OSA and, subject to raising sufficient financing (of which no assurance can be provided) and pending the outcome of an intended meeting with the FDA, RespireRx believes that it will be able to commence a pharmacokinetic study for a recently discovered and to-be-developed formulation followed by a Phase 3 clinical study for the treatment of OSA with the new formulation. Because dronabinol is already FDA approved for the treatment of AIDS related anorexia and chemotherapy induced nausea and vomiting, the Company further believes that its re-purposing strategy would only require approval by the FDA of a 505(b)(2) new drug application (“NDA”), an efficient regulatory pathway that allows the use of publicly available data. For more information, visit  www.RespireRx.com.