Patient Segmentation in ALS Studies

Does genotypic vs. phenotypic segmentation make sense in the context of an amyotrophic lateral sclerosis (ALS) study? It’s a provocative question, but one that warrants consideration. Research into the nature of ALS points to genetic mutations, often taking the form of miss aggregated or misfolded proteins. More than 20 genes have been causally linked to ALS. Four genetic mutations are common; the others are relatively rare . Certain genetic mutations appear to run in families but the same mutations can also be found in sporadic (i.e., non-familial) cases. These mutations have formed the basis for past patient segmentation efforts but there is reason to question whether such segmentation efforts have any relevance to the presentation of ALS itself. Do these genetic mutations actually express different phenotypes? Do they play any role in the sign, symptoms, or trajectories of the disease? Conversely, do therapies targeting the identified genes- even if they could effectively correct the physiological consequences of a specific mutation-actually have an effect on ALS in the patient? The recent history of drug development offers mixed answers to these questions. In the world of oncology, targeted, personalized genetic therapies are producing compelling outcomes . Conversely, targeted therapeutic development for ALS has largely been ultimately unsuccessful, despite promising early phase clinical results . It may be that targeted therapies in oncology have been successful because the underlying biology of different cancers is more fully understood. In contrast, much remains unknown about the underlying biology of ALS . Further, treatment of a systemic disease such as ALS may inherently be more difficult than treatment of a disease with a specific target such as a solid tumor with a discreet set of genetic mutations as may be the case in oncology. While many genetic mutations in ALS have been identified and studied, and while the phenotypic presentations of ALS are identifiable and agreed upon, the connections between genotype and phenotype remain incomplete. As efforts to find therapies targeting ALS continue down both paths, it becomes increasingly important for members of the clinical and research communities to develop a better understanding of where and how genotype and phenotype are linked, particularly because the links between phenotype and genotype can affect the design and conduct of ALS clinical trials in critical ways.