Age at onset in genetic prion disease and the design of preventive clinical trials

Abstract

ObjectiveTo determine whether preventive trials in genetic prion disease could be designed to follow presymptomatic mutation carriers to onset of disease.MethodsWe assembled age at onset or death data from 1,094 individuals with high penetrance mutations in the prion protein gene (PRNP) in order to generate survival and hazard curves and test for genetic modifiers of age at onset. We used formulae and simulations to estimate statistical power for clinical trials.ResultsGenetic prion disease age at onset varies over several decades for the most common mutations and neither sex, parent's age at onset, nor PRNP codon 129 genotype provided additional explanatory power to stratify trials. Randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials.ConclusionThe characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a postmarketing study could provide opportunities for subsequent determination of clinical benefit.

Prion protein lowering is a disease-modifying therapy across prion disease stages, strains, and endpoints

“…Our findings provide basis for optimism that PrP lowering may be a promising therapeutic strategy, both for prophylaxis against prion disease onset in at-risk individuals with no evidence of disease process underway 43,44 , and for treatment of active prion disease, during either prodromal or manifest disease. The effectiveness of a given PrP-lowering dosing regimen may vary depending on the stage of the disease, suggesting that dose regimens and trial endpoints may need to be adjusted depending on the clinical profile of the trial population.…”

“…Clinically, most prion disease patients die within half a year of first symptoms 36 , and this rapid decline is mirrored by high levels of biofluid neuronal injury and prion seeding biomarkers in the symptomatic phase of disease [37][38][39][40][41][42] . Meanwhile, individuals at risk for genetic prion disease, caused by protein-altering variants in the prion protein gene (PRNP), can be identified through predictive genetic testing when disease onset is on expectation years or decades away 43 , ahead of molecular markers of pathology 44 . This spectrum motivates investigation of a range of treatment timepoints relative to prion inoculation, development of molecular pathology, and presentation of frank symptoms to explore the potential of PrP-lowering treatment.…”

Domain-specific quantification of prion protein in cerebrospinal fluid by targeted mass spectrometry

“…This marker may, however, have even greater importance. Predictive testing of pre-symptomatic individuals harboring highly penetrant genetic mutations 4 that cause prion disease provides an opportunity for early therapeutic intervention to preserve healthy life, but randomization to a clinical endpoint in this population appears infeasible 5 . The U.S. Food and Drug Administration has indicated its willingness to consider lowered CSF PrP in this population as a potential surrogate endpoint for Accelerated Approval 2,6 .…”

Prion protein quantification in cerebrospinal fluid as a tool for prion disease drug development

“…In the context of prevention trials in healthy carriers, it is possible that CSF PrP will be critical not just as a marker of target engagement, but as a surrogate endpoint. Because following pre-symptomatic individuals to a clinical endpoint appears infeasible 53 , lowering CSF PrP has been proposed as a surrogate endpoint meriting Accelerated Approval 54 .…”