Discovery-stage Drug Development

Discovery-stage Drug Development 2017-11-01T14:09:52-04:00

Alzheimer’s Disease Risk Biomarker

In collaboration with scientists at Duke University Medical Center, a Cabernet Pharmaceuticals team described a genetics-based risk algorithm as a simple prognostic tool for assessing age-of-onset of Alzheimer’s disease in cognitively normal, elderly subjects (Roses et al, 2010, Roses et al, 2014, Lutz et al, 2016, Roses et al, 2016).  The algorithm comprised APOE (apolipoprotein E) and TOMM40 (translocase of outer mitochondrial membrane) genes associated with Alzheimer’s. Cabernet assisted with filing a patent for a risk algorithm and sought a partner for a drug/device co-development program to validate the biomarker. Cabernet also presented to the Food and Drug Administration, through a Voluntary Exploratory Data Submission, a clinical-development strategy to qualify a biomarker and test a potential therapeutic to delay the onset of mild cognitive impairment due to Alzheimer’s in cognitively normal but high-risk individuals. A pre-study, “enabling” phase was then initiated in collaboration with clinical-site teams from the Joseph and Kathleen Bryan Alzheimer’s Disease Research Center at Duke and from Imperial College London. This step focused on preparing pivotal research sites for accelerated recruitment by identifying “research-ready” subject populations within site-specific registries before enrollment commenced. (Romero et al, 2014, Hayden et al, 2014, Larsen et al, 2015).

The resulting Phase III clinical trial, called the TOMMORROW study and sponsored by the Zinfandel-Takeda alliance, is under way and fully enrolled.

Predicting the onset of cognitive decline: An algorithm combining APOE and TOMM40 genotypes serves to stratify study subjects in the TOMMORROW trial by age-related disease risk. The trial is evaluating the use of the drug pioglitazone to delay the onset of mild cognitive impairment due to Alzheimer’s disease. Among APOE alleles, APOE4 is understood to impart the greatest disease risk and APOE2, except when paired with APOE4, the least. Risk associated with genotypes incorporating APOE3, however, varies considerably with the length of a specific tract within an intron of the TOMM40 gene, which lies next to APOE. Stratifying disease risk is crucial to age-of-onset studies, which seek to find ways to delay or prevent the clinical symptoms Alzheimer’s rather than treat the disease when it is well-established and perhaps intractable to any current therapy.