CEVA101 is a novel cellular product composed of Autologous Bone Marrow-derived Mononuclear Cells (BMMNCs) which are harvested and undergo isolation and processing. CEVA101 is intravenously infused within 48 hours of injury, by slow IV push at doses to be defined by ongoing Phase 2 clinical trials. CEVA101 is currently being developed for the treatment of severe traumatic brain (closed head) injury in adults and children.
Three previous completed clinical studies in pediatric and adult patients provide evidence that CEVA101 is an attractive clinical development candidate for the treatment of TBI, a serious and life-threatening and debilitating condition. The first Phase 1 in head injured children 5 to 14 years of age was conducted at a single-center, Children’s Memorial Hermann Hospital in Houston, Texas. The primary endpoint of this initial clinical study was to assess safety of an autologous bone marrow harvest and infusion-related toxicity. No adverse events were associated with CEVA101 or temporally related to the stem cell harvest of infusion. There were no subject deaths and no subject withdrawals due to adverse events. Magnetic Resonance Imaging (MRI) comparing grey matter, white matter, and cerebral spinal fluid (CSF) volumes showed no reduction from 1 to 6 months post-injury. Dichotomized Glasgow Outcome Score at 6 months showed 70% with good outcomes and 30% with moderate to severe disability. Study results were published in Neurosurgery. Cox, Baumgartner et al 2011
A second study was conducted to evaluate whether pediatric TBI patients receiving CEVA101 within 48 hours of injury experienced a reduction in therapeutic intensity directed toward managing elevated intracranial pressure relative to matched controls. This retrospective cohort designed study compared pediatric subjects treated with CEVA101 (treatment group) in the initial Phase 1 trial with a control group of age- and severity-matched children. Both groups received treatment for their severe TBI at the Children’s Memorial Hermann Hospital (CMHH) in Houston, Texas. The control group was treated in an identical fashion, per standard of care, guided by the CMHH traumatic brain injury management protocol, derived from American Association of Neurological Surgeons guidelines. The primary measure was the Pediatric Intensity Level of Therapy (PILOT) scale used to quantify treatment of elevated intracranial pressure. Secondary measures included Pediatric Logistic Organ Dysfunction score and days of intracranial pressure (ICP) monitoring as a surrogate for length of neurointensive care. Study results showed that CEVA101 therapy was associated with a reduction in treatment intensity required to manage ICP associated severity of organ injury and duration of ICP monitoring following severe TBI, as compared to the matched control group. Study results were published in Pediatric Critical Care Medicine. Liao, Harting et al 2015
A third study was completed to determine the safety and efficacy of CEVA101 on brain structure and neurocognitive functional outcomes after TBI in adults, 18 to 55 years of age. The study consisted of four cohorts, including three dose groups and a control group. Subjects assigned to CEVA101 treatment received 6 ´ 106, 9 ´ 106, or 12 ´ 106 cells/kg of body weight depending upon their cohort group. Enrollment of 25 subjects was completed. Results support the primary outcome that a bone marrow mononuclear cell harvest and autologous CEVA101 infusion after TBI can be safely completed. There was no difference in GOS (functional outcome measurements) between groups. The study was not powered to detect functional measures of efficacy, but the data was intended to only guide future development. Strong correlations between structural preservation and functional outcomes were demonstrated. Analysis of inflammatory biomarkers demonstrated some significant differences between the treatment and control groups in IL-1b and IL-10 with strong, dose-dependent trends in reduction of TNF-a, INF-g, and IL-6. Analysis of imaging data supports that CEVA1010 infusion post-TBI is neuroprotective. Improved fiber tract integrity was observed in the treatment group with reduction in global white matter volume loss when compared to the control group. Adverse events were reported for all cohort groups, and were as expected for patients with severe TBI. No adverse events were associated with, or temporally related to the stem cell harvest or infusion of CEVA101. There were no subject deaths or withdrawals due to adverse events. Study results were published in Stem Cells (Cox CS and Hetz RA 2017) CS and Hetz RA 2017.
Phase I clinical results to date:
- CEVA101 observed to be safe when administered to children and adults at various dose levels.
- In children, CEVA101 in demonstrated preliminary clinical evidence for both early and late outcomes, indicative of clinical benefit in terms of (a) reduction in therapeutic intensity and intracranial pressure relative to controls, (b) structural preservation of global central nervous system (CNS) volumetric measurements of grey and white matter, which correlates with improved outcomes and (c) continued late improved in functional outcomes (GOS and GOS-E, expanded for children) relative to historical controls.
- In adults, CEVA101 demonstrated early efficacy signals as evidenced by CNS structural preservation, consistent with the pediatric trial results, and dose-dependent downregulation of pro-inflammatory cytokines.
Based on these promising clinical results, Cellvation is currently enrolling two Phase 2 randomized, placebo-controlled, trials (RCT) to confirm the beneficial clinical outcomes and the protective function of CEVA101 in both adult and pediatric) patients with severe TBI.
- (1) Protocol HSC-MS-13-0038 (NCT01851083), “A Phase 2 Multicenter Trial of Pediatric Autologous Bone Marrow Mononuclear Cells (BMMNCs) for Severe Traumatic Brain Injury (TBI)”. This randomized, blinded, placebo controlled, Bayesian adaptive dose escalation design study aims to determine the safety and efficacy of CEVA101 on brain structure and neurocognitive functional outcomes after severe traumatic brain injury in children 5 to 17 years of age. The study consists of 3 cohorts (two dosing groups of CEVA101 and a control group). Enrollment of fifty subjects (randomized 3:2 is planned).
- (2) Protocol HSC-MS-16-0283 (NCT02525432), “Treatment of Adult Severe Traumatic Brain Injury Using Autologous Bone Marrow Mononuclear Cells”. This randomized, blinded, placebo controlled, Bayesian adaptive dose escalation design study aims to determine the safety and efficacy of CEVA101 on brain structure and neurocognitive functional outcomes after severe traumatic brain injury in adults 18 to 55 years of age. The study consists of 3 cohorts (two dosing groups of CEVA101 and a control group). Enrollment of fifty-five subjects (randomized 3:2 is planned)
These ongoing Phase 2 trials are supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS) and US Department of Defense (DoD). Cellvation licensed the exclusive worldwide rights to CEVA101 from The University of Texas at Houston, Health Science Center at Houston, Texas in November 2016.