Self-Assessment: Novel Therapeutic Approaches for ALS: From Bench to Bedside | Selected Topics on MG-Dr. Shefner Presentation

Dr. Shefner Presentation

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The document by Dr. Jeremy Shefner from Barrow Neurological Institute highlights revolutionary developments in ALS (Amyotrophic Lateral Sclerosis) care and outlines lessons learned from recent clinical trials, both successful and otherwise.<br /><br />**Key Developments in ALS Treatment (2016-2023):**<br />1. **Edaravone (2016):** Approved by the US FDA based on two small clinical trials.<br />2. **TUDCA/URSO (2022):** Approved in the US and Canada following one small trial.<br />3. **Tofersen (2023):** Received accelerated FDA approval based on a Phase 1-2a and a Phase 3 trial which didn’t meet efficacy targets but showed promise via CSF NfL biomarkers.<br />4. **Reldesemtiv (2023):** Its Phase 3 trial was halted due to futility despite a robust 15-year research program.<br /><br />**Clinical Trial Insights:**<br />- **Small Trials:** Can be effective with stringent participant criteria, though their predictive value remains uncertain.<br />- **Disease Progression:** Influenced by trial inclusion criteria (e.g., ALSFRS-R scores and vital capacity).<br />- **ALSFRS-R:** A reliable and sensitive outcome measure that correlates well with other functional scales but highlighted the need for integrating disease-related biomarkers.<br /><br />**Neurofilament (NfL):**<br />- A biomarker for neurodegeneration in both spinal fluid and blood, higher in ALS patients. While associated with treatment efficacy in some cases, not all effective treatments impact NfL levels.<br /><br />**Reldesemtiv Trials:**<br />- Despite initial positive signals in multiple outcome measures, the Phase 3 COURAGE ALS trial was stopped early. This illustrated the critical importance of selecting appropriate endpoints and understanding the mechanisms of action in drug trials.<br /><br />**Remote/Digital Measures:** <br />- Advocated for their ability to reduce site and participant burden and allow more frequent sampling. The COVID-19 pandemic underscored the need for remote measures, especially for assessing speech and functional status in ALS.<br /><br />**Future Trial Design:**<br />- Emphasis on using stringent inclusion criteria and understanding mechanisms of action to determine trial duration. Measures like ALSFRS-R and biomarkers such as NfL will remain pivotal, with the potential inclusion of more sensitive, remote functional measures to enhance trial design.<br /><br />This summary underscores the evolving nature of ALS research, highlighting both the achievements and challenges in improving ALS care through innovative clinical trials and methodologies.

Keywords

ALS

amyotrophic lateral sclerosis

clinical trials

Edaravone

TUDCA

Tofersen

Reldesemtiv

Neurofilament

biomarkers

ALSFRS-R

amyotrophic lateral sclerosis

ALS