De-Risking PWS Drug Development Through Preclinical Screening


Any drug development process proceeds through several stages in order to produce a drug that is safe, efficacious, and has passed all regulatory requirements. The discovery phase converts what we have learned about the causes and the biology of the disease through basic research into new drug candidates.

Before drug candidates can be tested in humans, they need to show they are safe and efficacious in animal models of the disease. This second phase, called preclinical stage, requires developing animal models that recapitulate at least some of the features or mechanisms of the disease for which the drug has been developed. When successful, drug candidates are typically tested in humans in clinical trials through three phases namely I,II and III before approval. A drug that is shown to be safe and effective in these three phases can be approved and marketed to the public.

The Drug Development Process

Drug development is a long, expensive and risky process. It can take more than 10 years from the time the drug is identified to when it receives approval from the FDA. Developing one single new drug can cost a billion dollars. More worrisome is the fact that less than 1 in10 candidates that make it into phase I clinical trials will be approved by the FDA. The lack of efficacy in patients is one of the main reasons for drug failure.

Shifting Risk to Prevent Failure in Clinical Trials

These unique challenges require a thoughtful strategy to decrease the drug failure rate at the clinical stage. FPWR`s approach is to de-risk the drug development process through the implementation of strategic programs such as the pre-clinical animal network (PCAN) that aims at shifting the risk from the clinical stage to the preclinical stage.

Traditionally, drug failure has been viewed as an issue with clinical trials since clinical failure rate averages approximately 90% and represents ~70% of the total drug development cost due to the high cost of clinical trials. In contrast, the preclinical stage represents approximately 35% of drug failures and account for only 2% of the total cost of drug development due to the relatively inexpensive cost of this stage. Developing more stringent success criteria, thus increasing the failure rate at the pre-clinical stage, could decrease the possible failure rates at the clinical stage, shorten the length and decrease the cost of drug development. This, however, depends on the capacity of preclinical models to predict clinical efficacy of a specific drug candidate.

Several mouse models for PWS have been generated. Although none of them recapitulate all of the PWS characteristics, each model bears some of the features of human PWS, making these models a potential tool for advancing preclinical research for PWS. Their predictive value for assessing treatment efficacy is, however, unknown mainly due to the limited characterization of existing models, the variability of assessment methods, the lack of comprehensive, rigorous and standardized phenotyping and the limited knowledge on the translatability of human phenotypes into animal read-outs. Challenges are also related to silos that exist within and across academic, industry and clinical stakeholders that are often misaligned and impede the transfer of information as projects move from the pre-clinical stage to clinical stage. 

Making PWS Drug Development More Efficient 

In this context, FPWR is developing and directing a preclinical animal network (PCAN) composed of international expert laboratories such as Drs. Wevrick (Canada), Tucci (Italy), Isles (UK), Resnick (USA) Muscatelli (France) and others to develop and validate preclinical mouse animal models of PWS to better predict clinical trial outcomes. The ultimate goal is to create a preclinical screening platform for drug candidates for PWS.

In July 2016, we organized a workshop integrating the views of clinicians, drug development experts from industry and academic researchers to discuss how to bridge the gaps between preclinical animal studies and clinical trials for PWS. The PWS scientific community recognized the importance of developing PCAN to validate preclinical animal models for PWS and create a screening platform for candidate therapeutics. Validating preclinical animal models and assessing their predictive value and ensuring data is robust and reproducible was highlighted during the meeting. Work is underway to determine which animal models to select and which tests to perform. Collaboration with the International Mouse Phenotypic Consortium is under investigation.

PCAN is an innovative initiative that integrates the views and best practices of basic researchers, clinicians and industrial to break silos, decrease inefficiencies along the drug development path and improve validation of drug targets earlier and at substantially reduced costs. We, as patient representatives, are in a unique position to improve preclinical research and cross successfully what has been traditionally called the “Valley of Death” by drug developers due to scarce funding and lack of incentives from academics and industry.

FPWR Highlighted in Biocentury Innovations

Since the publication of this blog, FPWR’s PCAN program (PreClinical Animal Network) was highlighted in Biocentury Innovations, a magazine that provides information, analyses and data for Biotechs and Pharma companies, investors, academia and government about Life Science ventures worldwide. In the article, Nathalie Kayadjanian, Director of Translational Research for FPWR, speaks about how PCAN is addressing some of the key challenges of drug development and speeding therapeutic development.

From Biocentury Innovations: In the wake of the 2015 clinical failure of Zafgen Inc.’s subcutaneous beloranib for obesity in Prader-Willi syndrome patients, the Foundation for Prader-Willi Research (FPWR)  launched a five-year, $26 million strategic research plan that included an initiative to develop better preclinical models for the indication. With the program, FPWR joins a growing group of patient-centric disease organizations playing a pivotal and expanding role in supporting and de-risking potential therapeutics as they move through preclinical stages and into the clinic.

Nathalie Kayadjanian, director of translational research for FPWR, told BioCentury the strategic plan was born out of the foundation's analysis of the gaps and challenges along the therapeutic development path. Within this program, we are developing different initiatives that address challenges at the basic research level, drug discovery and preclinical stage, as well as clinical trials and beyond," said Kayadjanian. The plan was an expansion beyond FPWR’s traditional investigator-initiated grant program. She added that speeding therapeutics through this pathway would take a variety of collaborative means to develop the expertise internally and externally, with stakeholders from industry, academia and patient organizations.

A key piece of the strategic plan is built around improvements to preclinical research. According to Kayadjanian, there are a number of mouse models that were developed for basic researchers to better understand the genetic component of disease. FPWR started a preclinical animal network of 5 expert model labs -- including University of Alberta, Italian Institute of Technology, Cardiff University, University of Florida and Mediterranean Institute of Neurobiology (INMED) at Aix-Marseille University -- to validate the existing and new models, with the goal of ultimately utilizing the network as a preclinical platform for drug screening down the road, said Kayadjanian.

The full article ban be read here.

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Topics: Research

Nathalie Kayadjanian


Nathalie Kayadjanian, Ph.D is an expert in translational biomedical research. A neuroscientist by training, she has extensive R&D experience in academia, biotech, and the pharmaceutical industry in Europe and the USA. Nathalie has occupied top management positions in patient-driven non-profit organizations, developing and implementing strategies to accelerate the development of innovative therapies for rare diseases.

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