Cell Therapy HLCM051 Fails to Improve Stroke Outcomes Despite Safe Profile

Kiyohiro Houkin, PhD

In a recently published phase 2/3 randomized clinical trial (NCT02961504), treatment with HLCM051 (Lonza), a bone marrow-derived, allogenic, multipotent progenitor cell product, did not improve short-term outcomes in patients with acute ischemic stroke (AIS) despite being safe. Investigators concluded that additional research is needed to see whether the therapy has a beneficial effect in patients who meet specific criteria, as indicated by the exploratory analyses in the study.¹

Also known as TREASURE, the multicenter, double-blind, parallel-group trial included 206 patients with AIS who received either intravenous HLCM051 (n = 104) in 1 single unit of 1.2 billion cells or placebo (n = 102) within 18 to 36 hours of ischemic stroke onset. The primary end point, excellent outcome at day 90, was defined by modified Rankin Scale (mRS) scores of 1 or less, National Institutes of Health Stroke Scale (NIHSS) total scores of 1 or less, and Barthel index (BI) score of 95 or greater.

Led by Kiyohiro Houkin, president of Hokkaido University, Japan, the study included a high proportion of older patients, with a median age of 79 (range, 40-55) years in the HLCM051 group and 78 (range, 35-95) years in the placebo group. Results at 90 days showed no significant difference between the HLCM051 and placebo groups on the rate of excellent outcomes (11.5% vs 9.8%; P = .90; adjusted risk difference, 0.5%; 95% CI, –7.3 to 8.3%). Secondary outcomes, which included excellent outcome at day 365, mRS score distribution at days 90 and 365, and mRS score of 0 to 1 and 0 to 2 at day 90, were also similar between the 2 groups.

Prior to entering the trial, patients had confirmed acute infarction involving the cerebral cortex that measured more than 2 cm on the major axis, which was determined with diffusion-weighted MRI. In exploratory subgroup analyses of patients with mRS scores of 2 or less at day 90, data showed that those with an ischemic core volume of 50 mL or less had significantly better outcomes on the cell therapy than placebo (29.6% [8 of 27] vs 8.1% [3 of 27]; P = .04; adjusted risk difference, 20.4%; 95% CI, 1.0-39.9). In addition, those aged less than 64 years appeared to have better outcomes in the HLCM051 and placebo groups, although the difference was not statistically significant (80% [8 of 10] vs 41.7% [5 of 12]; P = .08; adjusted risk difference, 37.2%).

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"Although recent studies have demonstrated the efficacy of endovascular therapy for large infarctions, infarct volume remains a substantial factor in poor outcomes,” Houkin et al wrote. "Therefore, our finding that individuals with cerebral infarction of 50 mL or greater benefit from cell therapy holds crucial clinical implications, as these patients may not benefit from conventional treatments like thrombectomy."

An exploratory post-hoc analysis assessed the proportions of patients in the active treated group with global stroke recovery and a BI score of 95 or greater at day 365 with no correction for multiple comparisons. In this specific analysis, HLCM051 outperformed placebo, as 29 patients (27.9%) on active treatment had demonstrated improvement vs 16 (15.7%) of those in the placebo group (adjusted risk difference, 11.0%; 95% CI, 0.8%-21.3%; P = .04). For BI scores of 95 or greater, 37 patients (35.6%) in the active group and 23 (22.5%) in the placebo group had higher scores (adjusted risk difference, 11.3%; 95% CI, 0.2%-22.4%; P = .05).

The study was mainly limited by the patient heterogeneity, as the inclusion of patients with advanced age and posterior circulation involvement in stroke may have diluted the treatment effects. In addition, statistical multiplicity was not considered for the subgroup and post-hoc analyses of the study. Furthermore, patients treated with both t-PA and mechanical thrombectomy were excluded from the study.

A combined analysis of the TREASURE and ongoing phase 3 MASTERS-2 trials will be conducted to confirm the efficacy and safety of the cell therapy. MASTERS-2, a pivotal, 300-patient trial designed under a Special Protocol Assessment, is a follow-up to the previously completed MASTERS study. Results from that phase 2 study were similar to TREASURE, with the agent demonstrating a safe profile that resulted in no significant improvement in neurological outcomes at 90 days.²

REFERENCES
1. Houkin K, Osanai T, Uchiyama S, et al. Allogenic stem cell therapy for acute ischemic stroke: the phase 2/3 TREASURE randomized clinical trial. JAMA Neurol. Published online January 16, 2024. doi:10.1001/jamaneurol.2023.5200
2. Hess DC, Wechsler LR, Clark WM, et al. Safety and efficacy of multipotent adult progenitor cells in acute ischemic stroke (MASTERS): a randmomized, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol. 2017;16(5):360-368. doi:10.1016/S1474-4422(17)30046-7