Predicting success: Optimizing phase II ALS trials for the transition to phase III

Abstract

Amyotrophic lateral sclerosis (ALS) research is advancing quickly, but the transition from phase II to phase III trials remains particularly challenging. In part, this is because of the paradox of phase II ALS trials – they are expected to inform researchers about safety, tolerability, dosage selection, and efficacy using a small number of patients, and relying on essentially the same outcome measures used in phase III trials. We examined pharmacokinetics in the cerebrospinal fluid and pharmacodynamic markers to demonstrate target engagement. In addition, primary outcome measures are often not specified or do not reach pre-specified goals for significance. We conclude that future trials should include pharmacokinetic (preferably in CSF) and pharmacodynamic markers of target engagement when possible. Primary endpoints should be pre-specified. Inclusion criteria should be used to reduce heterogeneity and target a relevant subpopulation of people with ALS when possible. Multiple phase II trials might be required before moving to a large phase III trial.

Key words::

• Clinical trials
• phase II
• RCT
• biomarkers

Acknowledgements

We wish to thank the people with ALS and their caregivers who have taken part in these clinical trials, the numerous site investigators and study teams conducting the trials, and the funding agencies who have made the studies possible.

Disclosure of interest: J. D. Berry has served as a consultant to Biogen Idec and Neuraltus Pharmaceuticals, and as a paid speaker for Oakstone Publishing. He receives research support from Cytokinetics and GlaxoSmithKlein.

J. M. Shefner has served as a consultant to Biogen Idec, Cytokinetics, Trophos, ISIS, Glaxo SmithKline, and receives research support from Cytokinetics, Biogen Idec, Sanofi Aventis, and Neuraltus. M. E. Cudkowicz served on DSMB for Synapse and Trophos and was a consultant for TEVA, Cytokinetics, Millenium, GlaxoSmithKline and Biogen. Dr. Cudkowicz has also served as a consultant to Neuraltus Pharmaceuticals.

The authors alone are responsible for the content and writing of the paper.