Early-stage Drug Development

Early-stage Drug Development 2017-11-01T14:09:58-04:00

Opioid-receptor antagonist

Endogenous opioid-mediated reward pathways play a role in the development and maintenance of alcohol dependence. Eli Lilly and Company, a Cabernet client, therefore sought to determine whether a brain opioid-receptor antagonist (LY2196044 or LY) would reduce drinking in alcohol-dependent patients. The challenge was that pharmacotherapy of alcohol dependence shows widely divergent responses between patients, and part of this variability can be attributed to the underlying genotype. Response to the opioid-receptor antagonist naltrexone, for example, is predicted by a genetic variant of the mu-opioid receptor gene (OPRM1). Cabernet analyzed the effect of two genetic variants implicated in alcohol dependence, OPRM1 and DRD4 (dopamine-receptor subtype D4) on the efficacy of therapeutic response to LY.  One OPRM1 genetic variant demonstrated an enhanced response to LY treatment when evaluated by changes in heavy drinking days (HDD), days of abstinence, or drinks per day. In addition, LY-treated patients who had a specific DRD4 genotype (DRD4-L) also showed reduced HDD, increased days of abstinence, and reduced drinks per day. Interestingly, 34% of African Americans, but less than 1% of Caucasians possessed the beneficial OPRM1 variant in this study, a finding that suggested ethnicity-specific drug response to LY. In contrast, the DRD4-L carriers comprised nearly 40% of trial participants, and drug response was not ethnicity-specific.  DRD4-L carriers have also demonstrated better response to other treatments for alcohol consumption including olanzapine and naltrexone. The pharmacogenetic results indicate that both OPRM1 and DRD4-L may represent common, robust genetic markers of LY therapeutic response, and form the basis for a potential tailored drug-development program and companion diagnostic for LY.  Wong et al, 2014


In collaboration with Eli Lilly and Company, a Cabernet team evaluated the PGx of response to evacetrapib, an investigational cholesterol-ester-transfer-protein (CETP) inhibitor for hyperlipidemia and cardiovascular disease. The gene that encodes CETP is highly polymorphic, and mutations within the CETP gene can attenuate CETP enzymatic activity.  Patients with reduced activity might therefore be expected to show modulated treatment response to the CETP inhibitor. Particularly in Japan, where most cases of total CETP deficiency have been reported, there was concern over potential complication of efficacy analyses. Cabernet analyzed three CETP variants, two of them rarer Asian-specific variants and one common across all ethnicities. The results reported to Japanese regulators discharged the potential risk of genetic heterogeneity, demonstrating that while patients with different genetic makeup had varying CETP mass and activity, there were no significant changes in treatment response to evacetrapib as monotherapy or in combination with the statin atorvastatin.

CCK-A receptor agonist

While on staff at GlaxoSmithKline, scientists now at Cabernet integrated PGx into a Phase IIa/POC study of a cholecystokinin agonist being evaluated as an obesity drug. Three genetic variants from three putative mechanism-related genes segregated with high weight loss, modest weight loss, and modest weight gain. The segregation pattern identified hypotheses for any subsequent PGx-based efficacy trials with this drug candidate. Roses, 2004, Roses, 2009

Assessing an obesity drug: In a proof-of-concept study, genetic differences appeared to explain why patients responded differently to an investigational obesity drug, thus indicating how patient populations might be better defined in subsequent studies. An analysis of candidate genes related to the mechanism of action of the drug, a cholecystokinin-receptor agonist, identified single-nucleotide polymorphisms (SNPs) that segregated with drug response. Depicted in this graph is the response associated with a specific allele characterized by a single SNP.  The green line represents drug-treated patients and the blue line placebo-treated patients.  A sub- group of patients who were homozygous for the 2-allele showed an especially pronounced response, losing up to nine percent of body weight (Graph area 2-2).  Heterozygous patients clustered in the middle part of the graph (1-2), where the response curve for treated patients begins to shift toward weight loss. Patients lacking the 2-allele altogether (1-1) gained weight.


While on staff at GlaxoSmithKline, scientists now at Cabernet contributed a PGx-study plan within the scope of a Phase IIb study of rosiglitazone in Alzheimer’s disease. The plan provided for analysis according to whether subjects carried the APOE4 allele. As determined by ADAS-cog scores, non-carriers showed a benefit in cognitive response. Agreement was then reached with the Food and Drug Administration on a Phase III program designed to determine drug effect according to APOE genotype. Roses et al, 2007