Yokohama Japan, 25 May 2023: We are pleased to announce the results of the Phase II clinical trial in Japan (protocol number: RS-01) of our regenerative medicine product Stemchymal® (allogeneic adipose-derived mesenchymal stem cells) for the treatment of spinocerebellar ataxia, as follows.
The clinical trial was conducted as a placebo-controlled, multicenter, randomized, double-blinded, parallel-group study to evaluate the safety and efficacy of the drug. Independently, another Phase II clinical trial with a similar design was also conducted in Taiwan by Steminent Biotherapeutics Inc (Taiwan).
Safety
Safety was evaluated in 31 patients in Stemchymal group (STM group) and 28 patients in the placebo group (PCB group), and the incidence of adverse events (AEs) with a possibly causal relationship was 77.4% (24/31) in the STM group and 35.7% (10/28) in the PCB group, but all AEs in both groups were confirmed to have recovered. No serious adverse events suspected to be related to the study product were observed in either the STM or PCB groups. The External Safety Monitoring Board also confirmed that there was no safety issue.
Efficacy
The primary efficacy endpoint was the change in SARA score (Scale for the Assessment and Rating of Ataxia) from baseline (visit 2, pre-treatment) to week 52 (visit 8) from the first dose of study product, specifically the analysis of covariance of change from visit 2 to visit 8 and the analysis of disease progression of SARA score at visit 8. The results of the analysis were as follows.
Regarding the efficacy evaluation in the overall population analysis of this clinical trial, no statistically significant improvement was observed in the STM group compared with the PCB group in the above primary endpoints.
However, a review of previously published papers and other information shows that a placebo effect is observed in more than 90% (of 22/24) of previous clinical trials in spinocerebellar degeneration and that the placebo effect was higher in less severe patients.1,2,3,4 Therefore, in this clinical trial, we performed a placebo analysis and found that a placebo effect was observed with decreasing SARA score from Visit 2 to Visit 8 in the group with lower baseline PCB, which is consistent with the previously published papers. On the other hand, the placebo effect was reduced in the higher baseline subgroups with baseline SARA scores of 11 or higher, showing a trend closer to the natural history of spinocerebellar degeneration, with SARA scores increasing by approximately 1 point per year (1.14 points for SCA3 and 0.86 points for SCA6).5
Based on the statistical analysis plan and advice from medical experts, we performed a subpopulation analysis based on the pre-dose baseline SARA score. The disease progression analysis of SARA score, the primary endpoint, showed a statistically significant improvement with P-value of 0.042 in baseline 11 or higher. In other words, the effect of Stemchymal was evident in the higher baseline subpopulation, where the placebo effect was less pronounced, and the PCB group was closer to the natural history.
Even in the case of the low base subpopulation in the STM group (baseline SARA score of 9 or higher or 10 or higher), the change in SARA score till 52 weeks was similar to that of the high base subpopulation, suggesting Stemchymal had a consistent effect regardless of baselines. In addition, the effect is also indicated by a suppressive effect on clinical symptoms for at least one year. On the other hand, in the PCB group, the placebo effect varied widely by baselines, with a tendency for the placebo effect to be higher in the lower baseline group.
Based on the advice of medical experts, a subgroup analysis was also performed in the high-base subgroup for the secondary endpoints of CGI (clinical global impression), PGI-I (patient global impression of improvement) and percentage improvement in SARA scores. The results showed that the CGI, PGI-I, and percentage improvement in SARA score were indicative of effective inhibition of disease progression by Stemchymal. Thus, the finding of a common trend among change in SARA score, the primary endpoint, and the views of clinicians (CGI) and subjects themselves (PGI-I) supports the efficacy of Stemchymal in inhibiting disease progression.
Results of the Phase II Clinical Trial in Taiwan
In the Phase II clinical trial in Taiwan, the results of the subgroup analysis of SARA score showed a significant improvement in the STM group compared to the PCB group, in the high-base subgroup, confirming the same trend as in the Japan clinical trial. In addition, in the Taiwan trial no serious safety issues were observed as was also observed in the Japan clinical trial.
Based on the above results, Stemchymal has no safety issues and is suggested to have a certain level of efficacy for spinocerebellar degeneration in a high baseline subpopulation where the placebo effect is expected to be minimal.
Spinocerebellar degeneration is a rare disease of unknown cause in which degeneration of nerve cells in the cerebellum, brainstem and spinal cord progressively causes ataxia, such as gait and swallowing difficulties, and makes it difficult for patients to perform daily activities. Stemchymal is administered intravenously (IV) through a blood vessel in the arm, making it a less invasive treatment.
In Japan, it has been designated as a regenerative medicine product for rare diseases since December 2018, which entitles us to have the development cost subsidies (up to 50%), preferential tax treatment and support measures such as priority review.
We will continue to prepare for regulatory submission so that the new treatment method can be made available to patients suffering from the diseases as soon as possible.
Dr. Chikafumi Yokoyama, CEO of REPROCELL Inc., comments:
“We are pleased that the Phase II clinical trial has shown that Stemchymal is expected to be effective in inhibiting disease progression and its safety has been confirmed, and that these clinical data in Japan are consistent with the data independently obtained in Taiwan. We will continue to make efforts to bring this new treatment to patients as soon as possible.
Professor Masao Katsuno, Department of Neurology, Nagoya University Graduate School of Medicine, comments:
“This clinical trial demonstrated the safety of Stemchymal in patients with spinocerebellar degeneration. The subpopulation analysis also showed its efficacy data, so further detailed studies are needed.”
Explanation of terms
Placebo Control: A placebo is a "dummy" that resembles the study drug as closely as possible in color, weight, taste, and other physical characteristics, but does not contain the drug's active ingredient. In clinical trials, this is a study design in which subjects are divided into two groups: one that receives the actual study drug and one that receives a placebo, so that the effectiveness of the study drug can be evaluated statistically.
Randomized controlled trial: In a randomized controlled trial, subjects are randomly divided into two groups, one receiving Stemchymal and the other receiving a placebo. Randomization is considered to provide a higher level of evidence than non-randomized controlled trials because the nature of each group is more equal and has less influence on the results.
Double-blind: This is a method of testing in which neither the subjects themselves nor their physicians (double) know which drug (Stemchymal or placebo) is being administered (blinded). If a clinical trial is conducted with the knowledge of which drug is being administered, the evaluation may be mixed with subjectivity and placebo effects, resulting in a loss of objectivity. Double-blind is a method that minimizes the risk of bias in trial results and is known as the most common method used in comparative trials to confirm the therapeutic efficacy of new drugs.
Parallel group study: A study in which a treatment is compared by simultaneously observing and comparing a group receiving Stemchymal with a placebo group being compared.
SARA score (Scale for the Assessment and Rating of Ataxia): A widely used measure of spinocerebellar ataxia symptoms. The score is based on the investigator's observation of walking, standing, speaking, and finger movements to assess symptoms. The worse the symptoms are, the higher the score is. It has eight categories with accumulative scores ranging from 0 (no ataxia) to 40 (most severe ataxia).
CGI (Clinical Global Impression): An index in which the subject's change from the start of treatment is rated by an experienced investigator from seven categories (1. marked improvement to 7. marked deterioration). Scores increase as symptoms worsen.
PGI-I (Patient Global Impression of Improvement): This is an overall index for classifying changes in response to treatment and is a questionnaire in which subjects themselves select the appropriate response from seven categories (1. markedly improved to 7. markedly worsened). The worse the symptoms, the higher the score.
References
- Choi JH, Shin C, Kim HJ, Jeon B. Placebo response in degenerative cerebellar ataxias: a descriptive review of randomized, placebo-controlled trials. J Neurol. 2022;269(1):62-71.
- Nishizawa M, Onodera O, Hirakawa A, Shimizu Y, Yamada M; Rovatirelin Study Group. Effect of rovatirelin in patients with cerebellar ataxia: two randomised double-blind placebo-controlled phase 3 trials. J Neurol Neurosurg Psychiatry. 2020;91(3):254-262.
- Benussi A, Dell'Era V, Cotelli MS, et al. Long term clinical and neurophysiological effects of cerebellar transcranial direct current stimulation in patients with neurodegenerative ataxia. Brain Stimul. 2017;10(2):242-250.
- Maas RPPWM, Teerenstra S, Toni I, Klockgether T, Schutter DJLG, van de Warrenburg BPC. Cerebellar Transcranial Direct Current Stimulation in Spinocerebellar Ataxia Type 3: a Randomized, Double-Blind, Sham-Controlled Trial. Neurotherapeutics. 2022;19(4):1259-1272.
- Ashizawa T, Figueroa KP, Perlman SL, et al. Clinical characteristics of patients with spinocerebellar ataxias 1, 2, 3 and 6 in the US; a prospective observational study. Orphanet J Rare Dis. 2013;8:177
