Disease stages and therapeutic hypotheses in two decades of neurodegenerative disease clinical trials

Abstract

Structured AbstractBackgroundNeurodegenerative disease is increasing in prevalence and remains without disease-modifying therapies, and most trials of new drugs fail. Proposed solutions include aiming upstream: targeting molecular root causes of disease and testing therapies earlier, even at pre-symptomatic stages. We sought to understand what disease stages were eligible to enroll in neurodegenerative disease clinical trials in recent years and what molecular targets were tested in these trials.MethodsWe combined automated analysis and manual curation of trial registrations from ClinicalTrials.gov for Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia / amyotrophic lateral sclerosis, and Huntington’s disease.Findings3,241 trials from 2000-2020 were curated. Industry-sponsored drug trials, a minority (34%) of trials but a majority (61%) of patient-years, were more likely to complete, to have specified phase, and to have placebo or standard-of-care control arms. The mean number of inclusion and exclusion criteria more than doubled over this period, and eligible score ranges shrank. Trials have shifted towards less severely impaired participants, but only 2.7% of trials were open to pre-symptomatic individuals and these were depleted for industry sponsors (OR = 0.32) and for drug trials (OR = 0.59), instead being enriched for behavioral interventions (OR = 3.1). 16 novel, genetically supported therapeutic hypotheses have been tested in drug trials, with a mean lag of 13 years from genetic association to first trial. Such trials comprised just 18% of patient-years.InterpretationEligibility criteria for trials have shifted towards earlier, milder disease stages but are still overwhelmingly focused on symptomatic patients, particularly for industry-sponsored drug trials. Drugs targeting disease genes supported by human genetics comprise just a fraction of drug development effort, and their success may be hindered by a focus on symptomatic patients, where the relevance of the target to the rate of disease progression is less clear.

Refining the impact of genetic evidence on clinical success

“…We hypothesized that genetic support might be most pronounced for drug mechanisms with disease-modifying effects, as opposed to those that manage symptoms, and that the proportion of such drugs differ by therapy area 20,21 . We were unable to find data with these descriptions available for a sufficient number of drug mechanisms to analyze, but we reasoned that targets of disease-modifying drugs are more likely to be specific to a disease, whereas targets of symptom-managing drugs are more likely to be applied across many indications.…”

A single-cell map of antisense oligonucleotide activity in the brain

“…Pharmacologic interventions are seldom trialed in pre-symptomatic individuals at risk for neurodegenerative disease 53 . Observing clinical endpoints in such individuals may require lengthy follow-up 54 or may be outright numerically infeasible 55 .…”

Human genetic evidence enriched for side effects of approved drugs

“…Side effect data were obtained from the SIDER database 11 (v4.1). Citeline Pharmaprojects 14 and DrugBank 15 were parsed as described 7,9,16 , and SIDER drug names were mapped to Pharmaprojects indications using text matches to Pharmaprojects drug name synonyms, or, by mapping first to DrugBank using either ATC codes or name matches to obtain CAS numbers, and then looking up CAS numbers in Pharmaprojects; the proportion of drugs mapped by various approaches is provided in Table S2. Pharmaprojects matches were used to tic te s t. at ts n e obtain human gene targets and MeSH terms for approved indications as described 9 .…”