Long‐term Phase 1/2 intraspinal stem cell transplantation outcomes in ALS

Abstract

ObjectiveIntraspinal human spinal cord‐derived neural stem cell (HSSC) transplantation is a potential therapy for amyotrophic lateral sclerosis (ALS); however, previous trials lack controls. This post hoc analysis compared ambulatory limb‐onset ALS participants in Phase 1 and 2 (Ph1/2) open‐label intraspinal HSSC transplantation studies up to 3 years after transplant to matched participants in Pooled Resource Open‐Access ALS Clinical Trials (PRO‐ACT) and ceftriaxone datasets to provide required analyses to inform future clinical trial designs.MethodsSurvival, ALSFRS‐R, and a composite statistic (ALS/SURV) combining survival and ALS Functional Rating Scale revised (ALSFRS‐R) functional status were assessed for matched participant subsets: PRO‐ACT n = 1108, Ph1/2 n = 21 and ceftriaxone n = 177, Ph1/2 n = 20.ResultsSurvival did not differ significantly between cohorts: Ph1/2 median survival 4.7 years, 95% CI (1.2, ∞) versus PRO‐ACT 2.3 years (1.9, 2.5), P = 1.0; Ph1/2 3.0 years (1.2, 5.6) versus ceftriaxone 2.3 years (1.8, 2.8), P = 0.88. Mean ALSFRS‐R at 24 months significantly differed between Ph1/2 and both comparison cohorts (Ph1/2 30.1 ± 8.6 vs. PRO‐ACT 24.0 ± 10.2, P = 0.048; Ph1/2 30.7 ± 8.8 vs. ceftriaxone 19.2 ± 9.5, P = 0.0023). Using ALS/SURV, median PRO‐ACT and ceftriaxone participants died by 24 months, whereas median Ph1/2 participant ALSFRS‐Rs were 23 (P = 0.0038) and 19 (P = 0.14) in PRO‐ACT and ceftriaxone comparisons at 24 months, respectively, supporting improved functional outcomes in the Ph1/2 study.InterpretationComparison of Ph1/2 studies to historical datasets revealed significantly improved survival and function using ALS/SURV versus PRO‐ACT controls. While results are encouraging, comparison against historical populations demonstrate limitations in noncontrolled studies. These findings support continued evaluation of HSSC transplantation in ALS, support the benefit of control populations, and enable necessary power calculations to design a randomized, sham surgery‐controlled efficacy study.

Results from Phase I Clinical Trial with Intraspinal Injection of Neural Stem Cells in Amyotrophic Lateral Sclerosis: A Long-Term Outcome

“…Whether these improvements were the consequence of the cell implantation or were elicited by other factors (such as engagement in the trial assessments and increased generic medical input) remains to be determined, but the latter possibility is unlikely, particularly because the transitory improvement in patients with ALS is generally not believed to be accomplished through these factors. Our findings are also consistent with the report for the NCT 01348451 trial that a transient functional improvement was also observed within 6 months after transplantation, with similar effects emerging when cells are reinjected in the same subject 15 months later . Although the transient improvement of function is not an important functional outcome for the overall course of the disease, it is nevertheless relevant for the design of future efficacy trials.…”

Stable Intracerebral Transplantation of Neural Stem Cells for the Treatment of Paralysis Due to Ischemic Stroke

“…Three clinical studies have been conducted with NSI‐566 allotransplantation: two ALS studies ( n = 30) and one chronic SCI study ( n = 4), amounting to a total of 34 participants, and 2–6 years of human safety/efficacy monitoring so far. These studies' results provide evidence that NSI‐566 can survive in the host parenchyma for at least 2.5 years, even with transient immunosuppression, is safe, and can provide clinical benefits in patients with neurological damage . Phases I and II ALS subjects who received NSI‐566 showed significant functional stabilization as well as significantly better composite functional/survival score at 24 months compared with historical controls .…”

“…These studies' results provide evidence that NSI‐566 can survive in the host parenchyma for at least 2.5 years, even with transient immunosuppression, is safe, and can provide clinical benefits in patients with neurological damage . Phases I and II ALS subjects who received NSI‐566 showed significant functional stabilization as well as significantly better composite functional/survival score at 24 months compared with historical controls . Furthermore, in a phase I study, three out of four complete paraplegic SCI patients with thoracic cord injuries who received NSI‐566 transplantation exhibited new acquisition of voluntary muscle units and two of them showed neurological improvement below the level of injury .…”

“…In this study, the facts that, long after cessation of immunosuppressant (first 4 weeks), new tissues appeared and continued to survive in the stroke lesion where NSI‐566 had been injected and that the clinical effects persisted throughout 24 months suggest that the mode of action by NSI‐566 is regeneration rather than anti‐inflammation, although immunomodulatory effects cannot be ruled out and could explain some of the changes seen in imaging. Long‐term survival of NSI‐566 in ALS patients with only transient immunosuppression has been observed by autopsy as well as by clinical effects . A recent study in SCI primates has also demonstrated a regenerative pathway in which synaptic integration of NSI‐566 neurons with host circuitry resulted in motor recovery .…”

Preconditioning and Cellular Engineering to Increase the Survival of Transplanted Neural Stem Cells for Motor Neuron Disease Therapy

“…The results showed that intraspinal stem cell transplantation can be safely performed at high doses and does not accelerate disease progression. Outcome analysis of the phase 1/2 studies demonstrated significantly improved survival and function in comparison to that in historical datasets [42]. However, despite the encouraging results, the potential biases connected with historical controls underline the limitations of non-controlled studies and post hoc analyses, thereby stating the need for efficacy studies and sufficiently powered and randomized clinical trials.…”