NEW YORK--(BUSINESS WIRE)--Remedy Pharmaceuticals announced today that preliminary results from GAMES-RP, an exploratory Phase 2 randomized double blind, placebo-controlled, multi-center trial in severe stroke patients administered CIRARA®, a revolutionary intravenous drug for acute central nervous system conditions, were presented in an exclusive 75-minute session at the Neurocritical Care Society Annual Meeting in Scottsdale, AZ on October 9, 2015.
Key initial findings from the 90-day follow up include:
- Mortality in the CIRARA group was reduced by 53% vs. placebo.
- There were no deaths in patients treated with CIRARA less than 8 hours from onset of stroke. In contrast, half the placebo subjects treated in less than 8 hours died.
- 29% more CIRARA-treated subjects had 0-4 modified Rankin Scale (mRS) — a standard measure of functional outcome — vs. placebo patients.
- In subjects dosed <8 hours, 75% of CIRARA patients had 90-day mRS of 0-4 and 63% had a 90-day mRS of 0-3 vs. 25% for both mRS of 0-3 and 0-4 in the placebo group.
- Midline shift, a key indicator of brain swelling, was halved in the CIRARA group vs. placebo.
- There were no safety issues.
“The evidence in favor of CIRARA’s safety and efficacy in treating cases of severe stroke is overwhelming,” states Sven Jacobson, CEO of Remedy Pharmaceuticals. “All three recognized indicators of outcome, namely mortality, modified Rankin Scale and midline shift were dramatically improved, demonstrating CIRARA’s potential in treating these critically-ill patients.”
MORTALITY VERY DRAMATICALLY REDUCED
Of the 77 patients in the primary analysis, there were 19 deaths within the first 30-day period, 6 of 41 in the CIRARA group (14%), versus 13 of 36 (36%) in the placebo group (p=0.03), corresponding to a reduction in mortality of 62%. Within the 90-day follow up period, there were a total of 20 deaths, 7 of 41 subjects in the CIRARA group (17%), versus 13 of 36 (36%) in the placebo group (p=0.06), a reduction in mortality of 53%.
NO DEATHS AND BETTER OUTCOMES IN <8 HOUR CIRARA TREATMENT GROUP
While the average time to treatment was over 9 hours, a post hoc analysis showed there were 16 patients dosed within 8 hours of onset of stroke, equally divided 8 patients each between the CIRARA and placebo groups. Four of the 16 subjects died, all in the placebo group. There were no deaths in this CIRARA dosed subgroup.
GREATER PROPORTION OF 0-4 mRS PATIENTS
The modified Rankin Scale (mRS) is a common outcome measure to determine the degree of disability or dependence in the daily activities of people who have suffered a stroke. The scale runs from 0 to 6, 0 being perfect health, to 6 indicating death. 61% of CIRARA group had a 90-day mRS of 0-4, versus 47% for the placebo group (p=0.23), or 29% more subjects in the CIRARA group. The median mRS in the CIRARA group was 4 versus 5 in the placebo arm (p=0.18). In subjects dosed within 8 hours, 63% (5/8) had a 90-day mRS of 0-3, versus 25% (2/8) of <8 hour placebo subjects.
MIDLINE SHIFT CUT IN HALF
Brain edema (swelling) formation is a serious and deadly complication in large strokes. As the affected hemisphere of the brain swells, its space-occupying effect can lead to midline-shift, where, as the name implies, the brain shifts past the midline, pushing into and compressing the other hemisphere of the brain. This shift directly results in altered consciousness and when severe, coma. Consistent with CIRARA’s mechanism of action, there was a 50% reduction in edema measured by midline shift at 72-96 hours of 4.4mm for CIRARA-treated patients, versus 8.8mm in the placebo group (p=0.0006).
THE EFFECTS OF DECOMPRESSIVE SURGERY
An unexpected observation from the study was the apparent randomness of decompressive craniotomy (DC), a neurosurgical procedure in which a large part of the skull is removed (and later re-attached) to allow the swollen brain room to expand outward, to prevent compressing normal brain and to lower the intracranial pressure.
Thirteen subjects, or 32% of CIRARA subjects received a DC, versus 8, or 22% of placebo subjects (p=0.35). There was no correlation with either growth in Diffusion Weighted Image (DWI) lesion volume or midline shift, two key selection criteria commonly used for determining whether a patient should undergo DC. Variability in the use of DC appeared to be predominantly site related. Some centers performed no DCs, and at others, up to 75% of subjects had a DC. Nevertheless, based on post hoc analysis CIRARA patients had improved outcomes regardless of whether they had a DC or not. As a result of this inconsistent practice of DC, the study missed statistical significance in its primary composite endpoint of improved 90-day modified Rankin Score (mRS) of 0-4 AND no DC, which was 42% for CIRARA subjects versus 39% for placebo subjects (p=0.77).
The three secondary endpoints were also affected by DC. All trended positive, but due to small study size and the impact of DC, they did not achieve statistical significance. Death by day 14 or DC improved by 16%, more specifically 37% in the CIRARA group versus 44% for placebo subjects (p=0.48). A 26% favorable change in lesional swelling from 0-72 hours was observed, 58 cm3 in the CIRARA subjects versus 78 cm3 for the placebo subjects (p=0.41). There was also a 13% improvement in the change in hemispheric volume from 0-72 hours of 68 cm3 for the CIRARA group versus 78 cm3 for placebo subjects (p=0.28). In a post-hoc analysis of hemispheric swelling in non-DC patients only, the 36% improvement of CIRARA over placebo was statistically significant, with a mean of 49 cm3 in the CIRARA group versus 77 cm3 for placebo subjects (p=0.03). Lesional swelling in non-DC patients was reduced by 45% with a mean of 41 cm3 in the CIRARA group and 75 cm3 in placebo (p=0.15).
SUMMARIZING THE TRIAL RESULTS
"This exploratory Phase 2 trial was designed to evaluate the safety and efficacy of intravenous CIRARA administered over a 72-hour period following the occurrence of severe stroke, and it certainly did just that quite convincingly,” notes Remedy’s Jacobson. “What’s amazing is that these were the sickest of the sick stroke patients. The average lesion size was over 150 cm3. That’s the volume of a tennis ball, and add to that average time to start treatment of over 9 hours. The startling reduction in mortality and other robust indicators in the drug treated subjects suggest the potential for CIRARA to dramatically transform severe stroke treatment. That’s very exciting.”
“Each hour in which treatment fails to occur, the brain loses as many neuron as it does in over three-and-a-half years of normal aging,” notes David Geliebter, Executive Chairman of Remedy. “The fact that there were no deaths in patients who received CIRARA treatment early (<8 hours) and that functional outcomes were even better by all standard measures than those treated later (≥8 hours), is astonishing. We saw a similar phenomenon in the early tPA trials, which missed their primary endpoints until later studies focused on minimizing time to treatment. We now have the critical data needed to move to the next phase in this process of bringing a life-saving drug to people in need.”
“Brain swelling is a very common cause of death and disability after stroke and other acute brain disorders,” notes Dr. Kevin Sheth, MD, chief, Division of Neurocritical Care and Emergency Neurology, and chief of clinical research, Department of Neurology, Yale University, New Haven, Connecticut, and co-Principal Investigator of the GAMES-RP study. “The initial results from this Phase 2 blinded study offer compelling evidence to support the effort to provide definitive proof of CIRARA’s effectiveness. Doing so has implications for not just stroke but an entire range of neurological disorders.”
“GAMES-RP is the first trial of its kind that shows strong evidence of effect on key intermediate outcomes directed at CIRARA’s proposed mechanism of action in attenuating brain edema,” states W. Taylor Kimberly, M.D., Ph.D., Associate Director of the Massachusetts General Hospital Neuroscience Intensive Care Unit and an Assistant Professor of Neurology at Harvard Medical School, and co-Principal Investigator of the GAMES-RP study. “The mortality and functional outcome signals are notable and provide clear support for a Phase 3 study. ”
NEXT STEPS
“Ischemic stroke continues to be one of the most challenging diseases in translational neurology,” notes Jacobson. “Edema is one of the strongest mortality risks associated with large stroke. Some 78% of all deaths in the first week of a large ischemic stroke are attributable to edema. This study and other studies and findings suggest that CIRARA plays an important role in preventing malignant cerebral edema. There are currently no therapies for patients with large hemispheric strokes, which are lethal and debilitating. We have an opportunity to change this bleak landscape, to save and improve lives, and now with these data in hand, we intend to move quickly to consultation with FDA in regards the design and implementation of a Phase 3 study.”
ABOUT GAMES-RP
GAMES-RP is a randomized, double blind, placebo controlled, multi-center, Phase 2 study of CIRARA in patients with a severe ischemic stroke. The primary data set comprised 77 patients with centrally read baseline lesion volumes of 82-300 cm3 enrolled and treated with CIRARA or placebo at 18 U.S. Centers. Mean age was 58 years in the CIRARA arm, and 62.5 years in the placebo arm. Median baseline NIH Stroke Score was 20 in the CIRARA arm and 20.5 in placebo, and mean baseline lesion size was 154 cm3 in the CIRARA group and 159 cm3 in the placebo group. Treatment with CIRARA was commenced a median of 9.1 hours after stroke (minimum 5.6 hours, maximum 10.6 hours). 90-day clinical follow up was available for all patients.
Eighteen leading medical centers were involved in the GAMES-RP trial (in alphabetical order): Abington Memorial Hospital, Abington, PA; Cleveland Clinic, Cleveland, OH; Maine Medical Center, Portland, ME; Massachusetts General Hospital, Boston, MA; Medical University of South Carolina, Charleston, SC; Northwestern Memorial Hospital, Chicago, IL; Oregon Health & Science University Hospital, Portland, OR; Ohio State University/Wexner Medical Center, Columbus, OH; Rutgers (Robert Wood Johnson University Hospital), New Brunswick, NJ; Stanford University Medical Center, Stanford, CA; UMASS Memorial Medical Center, Worcester, MA; University of Arizona Medical Center - University Campus, Tucson, AZ; University of Florida, Jacksonville, FL; University of Louisville Hospital, Louisville, KY; University of Maryland Medical Center, Baltimore, MD; University of Utah Healthcare, Salt Lake City, UT; UPMC Presbyterian Hospital, Pittsburgh, PA; and Yale-New Haven Hospital, New Haven, CT.
ABOUT CIRARA
CIRARA is a patented, high affinity inhibitor of Sur1-Trpm4 channels, which were discovered by the University of Maryland neurosurgeon, J. Marc Simard, M.D., Ph.D. to play a crucial role in swelling and hemorrhage following stroke, traumatic brain injury, spinal cord injury and other CNS conditions. CIRARA is suitable for intravenous delivery at the bedside or even in an ambulance. CIRARA uses Remedy’s proprietary, patented MPD™ technology to enable optimal drug delivery to the injured area.
ABOUT REMEDY PHARMACEUTICALS
Remedy Pharmaceuticals, Inc. is a privately-held, clinical stage pharmaceutical company focused on bringing life saving treatment to millions of people affected by acute central nervous system conditions -- including stroke and traumatic brain injury as well as other ischemic injuries and neurological disorders such as subarachnoid hemorrhage and spinal cord injury. For more information, please visit: www.remedypharmaceuticals.com.