Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that leads to significant morbidity and mortality, but with substantial variability in the rate of progression [1,2]. A common primary outcome measure used in ALS clinical studies is the ALSFRS-R. Change in this measure may also be used to stratify fast and slow progressors, typically with the assumption of linear decline. Reported limitations of the ALSFRS-R and the assumption of linear slope may hinder novel therapy development. Here we use two distinct populations from a clinical trial database (PRO-ACT) and a natural history registry (ALS TDI) to show that ALSFRS-R fine and gross motor subdomains are more sensitive to disease progression than total score and bulbar and respiratory subdomain scores. We also present a novel non-linear method for defining fast and slow progressors. Together these results may improve demonstration of outcomes in ALS interventional studies using the ALSFRS-R.

Robert Ellis is an employee of and owns stock in Koneksa Health. No other disclosures. John Wagner was an employee of and owns stock and/or stock options in Koneksa Health at the time of the work. No other disclosures. Anthony Scotina was an employee of and owns stock and/or stock options in Koneksa Health at the time of the work. No other disclosures. Danni Tu is an employee of and owns stock in Regeneron. No other disclosures. Shawn Mishra is an employee of and may own stock in Regeneron. No other disclosures. Oren Levy is an employee of and may own stock in Regeneron. No other disclosures. Nikesh Patel is an employee of and may own stock in Regeneron. No other disclosures. Jiangnan Lyu is an employee of and may own stock in Regeneron. No other disclosures. William B. Nowell is an employee of and may own stock in Regeneron. No other disclosures. Matthew Wipperman is an employee of and may own stock in Regeneron. No other disclosures

This work was jointly funded by Koneksa Health and Regeneron. Regeneron licensed the ALS TDI dataset used in this analysis from the ALS TDI ARC Data Commons.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This research uses data available from the The Pooled Resource Open-Access ALS Clinical Trials Consortium (PRO-ACT) and ALS TDI Arc Data Commons

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Contributions Design: R.E., A.S. / Analysis R.E., A.S., M.W., D.T., J.L., S.M., W.N. / Manuscript R.E., W.N., O.L., M.W., J.W.

↵* Data used in the preparation of this article were obtained from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) Database. As such, the following organizations and individuals within the PRO-ACT Consortium contributed to the design and implementation of the PRO-ACT Database and/or provided data, but did not participate in the analysis of the data or the writing of this report:

• Amylyx Pharmaceuticals, Inc.

• ALS Therapy Alliance

• Cytokinetics, Inc.

• Knopp Biosciences

• Neuraltus Pharmaceuticals, Inc.

• Neurological Clinical Research Institute at Massachusetts General Hospital

• Northeast ALS Consortium

• Novartis

• Orion Corporation

• Prize4Life Israel

• Regeneron Pharmaceuticals, Inc.

• Sanofi

• Teva Pharmaceutical Industries, Ltd.

• The ALS Association

The Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital

Funding This work was jointly funded by Koneksa Health and Regeneron. Regeneron licensed the ALS TDI dataset used in this analysis from the ALS TDI ARC Data Commons.

Disclosures Robert Ellis is an employee of and owns stock in Koneksa Health. No other disclosures.

John Wagner was an employee of and owns stock and/or stock options in Koneksa Health at the time of the work. No other disclosures.

Anthony Scotina was an employee of and owns stock and/or stock options in Koneksa Health at the time of the work. No other disclosures.

Danni Tu is an employee of and owns stock in Regeneron. No other disclosures.

Shawn Mishra is an employee of and may own stock in Regeneron. No other disclosures.

Oren Levy is an employee of and may own stock in Regeneron. No other disclosures.

Nikesh Patel is an employee of and may own stock in Regeneron. No other disclosures.

Jiangnan Lyu is an employee of and may own stock in Regeneron. No other disclosures.

William B. Nowell is an employee of and may own stock in Regeneron. No other disclosures.

Matthew Wipperman is an employee of and may own stock in Regeneron. No other disclosures.