Abstract 26: First-in-human Phase 1/2a Study of Intracerebral Transplantation using Embryonic-derived Neural Stem Cells (NR1) for Chronic Ischemic Stroke (NCT04631406): 12 Months Outcomes

Introduction: Except for vagal nerve stimulation, no treatment exists to restore function in chronic stroke patients. Several prior intracerebral stem cell trials were promising, but are not being further developed. Objective: NR1 is a human embryonic derived neural stem cell that improved motor-sensory function in rodent stroke models, and was expanded to produce GMP cryopreserved cell lots. The safety&efficacy of NR1 intracerebral transplantation in chronic stroke patients was assessed over 12 months. Methods: Inclusion Criteria: 18-75 yo; 6-60 mos post-ischemic subcortical MCA stroke; mRS 3-4. Subjects were transplanted with 2.5M, 5M, 10M or 20M. Primary Outcomes: Adverse events 0-12 mos; Change in total Fugl-Meyer motor score (FMMS, max 100) compared to baseline at 12 months (≥10 points improvement considered “clinically meaningful”). Other outcomes: UE FMMS, LE FMMS, Gait Speed test, Barthel Index (BI), NIHSS, MR FLAIR, Resting State fMRI and [18F]FDG PET. Results: 18 patients were transplanted. Adverse events included headache, worsened baseline expressive aphasia and asymptomatic chronic subdural hygroma, all resolving spontaneously. All 17 pts with f/u ≥3 mos demonstrated improved total FMMS and 11 of these 17 subjects showed clinically meaningful recovery in total FMMS. At 12 mos subjects increased 12.1 (+/- 1.8) points for total FMMS (p=0.00002), 7.4 (+/-1.6) points for UE FMMS (p=0.00057), 4.7 (+/-0.5) points for LE FMMS (p =0.0000009), 7.7 (+/-2.5) points for BI, while NIHSS improved by 1.77 (+/-0.47) and gait speed improved substantially. 14/18 pts demonstrated new transient FLAIR signal in premotor cortex at d7, that resolved by 2 mos, which was highly correlated with sustained neurologic recovery. Resting state fMRI showed improved functional brain connectivity in sensorimotor network, both ipsilesionally&contralesionally. FDG PET showed increased activity in the ipsilesional motor cortex&contralesional cerebellum. Conclusions: Intraparenchymal transplantation of NR1 cells in chronic stroke patients appears safe and well tolerated. Results suggest improved motor function starting at 1 mos and increasing to clinically meaningful recovery in most patients at 12 mos post-implant. UE FMMS improvement surpassed vagal nerve stimulation outcomes.