Involving service providers in early stage evaluation

By Andrew Conrad Ph.D, Global Head of Esoterix Clinical Trials

Early development capabilities are becoming increasingly important to pharmaceutical and biotech companies seeking to reach go/no go decisions earlier in the drug development process. Industry experts believe that the significant increase in the number of therapeutic targets will expand the opportunities for service providers that can participate in early stage drug discovery processes. In order to meet the challenges involved in early evaluation of new therapeutics it is essential that providers are strong in assay development/validation and possess dedicated preclinical and Phase I services. A service provider’s ability to assist in the development of a new test and then implement it into early stage therapeutic evaluation is becoming critical to the pharma/biotech industry in its efforts to expedite the identification of new drugs with therapeutic efficacy.

Because of our extensive scientific and clinical expertise across multiple disease corridors, Esoterix Clinical Trial Services makes a considerable effort to establish strong partnerships and collaborations with sponsors in each of their individual therapeutic areas. Through these partnerships we have participated in protocol design as well as in the review of specific clinical trial protocols where we have initiated logistical, technical, scientific and clinical discussions with sponsor’s scientific/clinical management teams.

Our collaborative efforts with sponsors to define clinical biomarkers continues to have a significant impact on major drug discovery programs in the following ways:

1. We have recommended and developed alternative, advanced analysis systems that are relevant to drug specific activities;
2. We have evaluated testing platforms based upon their scientific and biological significance early in the drug development process;
3. We have modified test portfolios to cost-effectively deliver results with biologically defined endpoints;
4. We have created surrogate testing systems that can measure drug bioactivity directly or indirectly;
5. We have invested in new technologies such as high throughput screening, combinatorial chemistry, mass spec and genomics and will continue to focus on advanced methodologies that have potential for pharmaceutical companies to increase the rate at which they currently discover new compounds and halve drug discovery timelines.

Among the top areas of research, the search for effective anti-cancer drugs continues to be among the highest priority for pharmaceutical companies. New cancer drugs and new indications exist in various stages of development including preclinical discovery, Phase I through Phase III clinical trials and awaiting approval. Other major areas of new drug discovery include efforts to develop novel anti-infective and cardiovascular compounds. In each of these therapeutic disciplines, we have validated specific testing and testing profiles for evaluation of candidate drug activity in the early preclinical stage of the drug development process. These testing services are based on our scientific expertise and are designed to provide relevant information related to drug specific effects and/or biology of the disease indication that could transfer to clinical trials.

Several examples for anti-cancer drugs can be sited: 1) We have designed and validated numerous cell-based receptor occupancy analysis systems for a variety of therapeutic monoclonal antibodies, small peptides and a fusion protein. With our high level of expertise in cytometry and fluorescent quantitation, we have been able to specifically define therapeutic efficacy based upon saturation of cellular receptors (PD) and bioavailability of biologically active unbound drug (PK); 2) We developed a new surrogate cell-based testing system for an oncology specific drug that was capable of tracking inhibition of cyclin-dependent kinase activity throughout the course of therapeutic intervention for a solid tumor.

This analysis system not only defined drug activity by measuring accumulation of upstream p27 protein but also defined drug efficacy by identifying the apoptotic mechanism. Due to the limited availability of patient material to evaluate drug responsiveness, this PK-like system provided the most direct approach, as compared to other laboratory tests, to determine the bio-availability of the drug in patients; and 3) In a gene therapy based clinical trial program we developed the analysis system that defined the mechanism related to drug efficacy. This cell-based assay tracked the successful transfection of an Ad-p53 therapeutic by measuring upregulation of the expression of the intracellular biomarkers p53 and upstream protein MDM2. More importantly, subsequent development demonstrated that successful transfection also lead to upregulation of the apoptotic pathway regulated by BAX expression and that this activity correlated with clinical outcome.

In all three of these examples the analysis systems from early assay development were easily implemented in clinical trials to provide relevant biomarker information that was a true indication of drug activity and clinical efficacy. In addition, results obtained from these analysis procedures eliminated or minimized the need for more expensive invasive procedures on the patient.

As a service provider it is our intention to stay committed to scientific excellence and early development and validation of “cutting edge” analysis systems that are unique to specific therapeutics (or their targets). These systems will be designed to provide direct biological information related to therapeutic drug effects that will successfully reduce the amount of overall testing and allow sponsors to evaluate drug efficacy in an expeditious manner. In addition to our interest in bringing powerful new analysis systems to the drug discovery process, we strongly believe that this approach will result in a more rational selection of drug candidates for clinical trials.

Andrew Conrad: “It is our intention to stay committed to scientific excellence.”