MiToS and King’s staging as clinical outcome measures in ALS: a retrospective analysis of the FORTITUDE-ALS trial

Abstract

Objective

To evaluate the Milano-Torino staging (MiToS) and King’s staging systems as potential outcome measures for clinical trials in amyotrophic lateral sclerosis (ALS) by assessing these outcomes in FORTITUDE-ALS.

Methods

This was a post hoc analysis of the phase 2b FORTITUDE-ALS trial (NCT03160898), a double-blind, randomized, dose-ranging, placebo-controlled, parallel-group study of reldesemtiv in patients with ALS. The treatment period was 12 weeks, with a follow-up assessment at week 16. Patients were retrospectively classified into MiToS and King’s stages. Outcomes were the mean time maintaining baseline stage and risk of progression from the baseline stage to a later stage.

Results

The full analysis set consisted of 456 patients randomized 3:1 (reldesemtiv n = 342, placebo n = 114) who received at least one dose of double-blind study drug and had at least one post-baseline assessment. At baseline, MiToS and King’s stages were balanced between the reldesemtiv and placebo groups: >99% of patients were in MiToS stage 0 or 1 and King’s stage 1, 2 or 3. Time of maintaining the baseline stage was similar in both groups, for each staging system. The two staging systems exhibited considerably disparate results for risk of progression from baseline to a later stage: hazard ratio (HR) = 0.62 (95% confidence interval [CI] 0.38, 0.99) for MiToS and HR = 0.96 (95% CI 0.63, 1.44) for King’s.

Conclusion

This exploratory analysis showed the feasibility of MiToS and King’s staging as potential outcome measures in ALS. Additional studies of these staging systems are needed to further explore their utility in ALS clinical trials.

Keywords:

• Randomized clinical trial
• amyotrophic lateral sclerosis
• reldesemtiv
• MiToS
• King’s staging

Acknowledgements

We wish to thank the participants of FORTITUDE-ALS and their families for their contributions to this clinical trial, the investigators of FORTITUDE-ALS, FORTITUDE-ALS study group and members of the Data Monitoring Committee and Steering Committee.

Author contributions

PG contributed to concept and study design. PG, JW and LM contributed to the statistical analysis. PG and PS conducted interpretation of data. PG drafted the manuscript, and all authors were involved in critical revision and review of the paper.

Disclosure statement

PG, LM, SAR, JW and AAW own stock in and are employees of Cytokinetics, Incorporated. PS was an employee of Cytokinetics, Incorporated at the time of this study. AC serves on the advisory board for Biogen, Cytokinetics, Incorporated, Denali Pharma, Amylyx and Mitsubishi Tanabe. JAA has received research funding to their institution from Alexion, AZTherapies, Amylyx, Biogen, Cytokinetics, Orion, Novartis, MGH Foundation, Ra Pharma, Biohaven, Clene, and Prilenia and consulting fees from AL-S Pharma, Affinia, Amylyx, Apellis, Biogen, Cytokinetics, Denali, Orphazyme, Neurosense, Novartis, UCB, and Wave Life Sciences. AG served as a consultant for Alexion, AL-S Pharma, Biogen, Calico and Cytokinetics, Incorporated. CEJ has served as a member of data safety monitoring boards for Anelixis Therapeutics, Inc. and Mitsubishi Tanabe Pharma America. NL is a consultant for Cytokinetics, Incorporated. TMM is a consultant for Cytokinetics, Incorporated and Disarm Therapeutics; has licensing agreements with C2N Diagnostics and Ionis Pharmaceuticals; and serves on the advisory board and receives research support from Biogen. JMS received personal compensation from Avexis, Biogen, Brainstorm Cell Therapeutics, Cytokinetics, Incorporated, Mitsubishi Tanabe Pharma America, Neurosense, Orphazyme, Otsuka and Revalesio; and research support from Amylyx, Brainstorm Cell Therapeutics, Cytokinetics, Incorporated, Medicinova and Mitsubishi Tanabe Pharma America.

Data availability statement

Data reported herein are part of a sponsor-led clinical development program that is ongoing, and thus complete datasets for the trial will not be made available with this report.

Additional information

Funding

FORTITUDE-ALS was conducted by Cytokinetics, Incorporated in collaboration with Astellas Pharma Inc. The authors acknowledge Jayna Patel, PhD (Evidence Scientific Solutions, Horsham, UK) and Richard Fay, PhD, CMPP (Evidence Scientific Solutions, Philadelphia, PA, US) for editorial assistance, which was funded by Cytokinetics, Incorporated.