Kate Hilyard , Managing Director, BioFocus01.29.15
Integrated drug discovery pretty much looks the same whether the work is done at a large pharmaceutical company, a small biotech or outsourced to a contract research organization (CRO). Identifying that rare compound that stands out among thousands of suboptimal candidates requires the integration of biology, chemistry, in vivo pharmacology and the pharmacokinetics of ADME (absorption, distribution, metabolism and excretion).
But while the process of drug discovery remains constant, the groups driving the scientific innovation now include those typically associated with fund-raising, lobbying and patient advocacy. Along with biopharmaceutical companies, which have been at the helm of drug discovery for years and continue to be the dominant player, one finds an increasing number of not-for-profit disease foundations angling for a seat at the lab bench. Examples include the Cystic Fibrosis Foundation, which developed the breakthrough therapy Kalydeco and recently sold the royalty rights for $3.3 billion. Foundations are working with a diverse array of research players—including CROs—to advance their scientific goals. In the process, they are helping to accelerate the often glacial pace of translational research.
How important are CROs in helping charitable organizations advance their science? The Alzheimer’s Drug Discovery Foundation recently created a platform called ACCESS to help foundations work with CROs. The program gives academic and small biotech communities online access to a marketplace of CROs and the industry-standard drug discovery and development services they provide.
A 2013 report from the Milken Institute’s Faster Cures points to the growing influence of disease foundations. The report found that patient advocacy and disease foundations initiated 10% of the 250 research consortia created to accelerate biomedical research. Nearly half the foundations are on single-minded missions to discover disease-specific drugs, devices or vaccines, but some of the consortia have much broader missions—to create broadly used tools applicable across many diseases, or to unlock the research gates and make certain biomarker research data publicly available.
How CROs engage with foundations can vary depending upon the business model, funding and mission of the nonprofit. Much smaller disease foundations may rely on consultants to determine how discovery work should be outsourced. Under this arrangement, CROs may be granted more strategic input into a project, but the work is much more focused.
In contrast, large foundations tend to have their own internal teams of scientists, who manage the projects and contract with outside scientists to conduct the experiments. Imagine a wheel of a bicycle, with the foundation as the scientific hub and the academic labs or CROs as spokes that keep the science moving. Contract scientists may have a certain amount of input into the scientific process and can even propose their own ideas for future projects, but at the end of the day, it is the foundation that will ultimately decide the direction of the project.
No matter what the business model, CROs generally have more input into projects funded by disease foundations compared to those funded by biopharmaceutical companies.
Huntington’s Disease
CHDI Foundation, a nonprofit devoted to Huntington’s disease (HD), offers a good example of a large and sophisticated disease foundation that works closely with CROs. CHDI’s mission is to develop drugs that can slow the progression of the deadly, neurodegenerative disorder, and it has built relationships with the academic and industrial sectors to make that happen. CHDI’s team of scientific experts provide direction and management to more than 600 scientists from academic and commercial labs (including CROs like ours) pursuing novel therapies worldwide. The virtual model encourages scientific collaboration to more directly connect academic research, drug discovery and clinical development. Our scientists and many others attend regular meetings hosted by CHDI to discuss the progress of projects, and we are encouraged to share our own ideas on future projects.
CHDI’s portfolio extends from exploratory biology to the identification and validation of therapeutic targets, and from drug discovery and development to clinical trials. While CHDI mostly conducts discovery and development research, one recent study offers a good illustration of how disease foundations have tried to improve the pace of translational research by working with CROs to validate previously published data. Predicting how a drug will behave in clinical trials can be an exhaustive process. As researchers are aware, reproducing results from preclinical studies is difficult. Novel drugs that look promising in preclinical testing often end up demonstrating much weaker or no efficacy in clinical trials. A review last year in PLoS Medicine referenced the fact that only 11% of investigational drugs that enter clinical testing get licensed.1
CHDI wanted to assess how well certain monoclonal antibodies (mAb) and small molecule drugs mimic or partially activate the tropomyosin-receptor kinase B (TrkB) receptor.2 This protein is the receptor for a family of proteins that induce the survival, development and function of neurons and reduced expression of these receptors is thought to be important in HD progression.
Scientists at BioFocus, now part of Charles River, used recombinant and native assay formats to evaluate two TrkB antibodies and a panel of reported small molecule TrkB agonists. The biomarkers in the in vitro studies helped show that the mAbs were reaching and activating their intended target—suggesting that they might be good tools for vital proof of concept target validation studies in in vivo models or even potential therapeutics in the future. However, equally important were findings that contradicted previous reports suggesting the utility of specific small molecules as TrKB agonists. In contrast to the mAbs, none of the small molecules tested appeared able to activate this pathway in the systems tested. The data underscored how important it is to independently replicate discoveries and to publish such negative findings. Following disclosure of this work, several other labs confirmed that they had similar results, but that they had not wanted or been able to publish negative data. This knowledge can save time and resources by enabling other researchers to focus work on the most robust findings in the search for future therapeutics in HD.
The Michael J. Fox Foundation and many others
The consortia created by the Michael J. Fox Foundation for Parkinson’s Research (MJFF) provides another example of how disease foundations are trying to accelerate the pace of research. The long-term goal of the MJFF is to find better treatments for Parkinson’s disease. Identifying an imaging tool that can track how the disease is progressing could potentially overcome one of the major hurdles neuroscientists now face in validating therapeutic agents.
An MJFF group consisting of BioFocus, two academic groups and a radiopharmaceutical company set out to develop a positron emission tomography (PET) radiotracer that could visualize the distribution of alpha-synuclein aggregates, found in pathological conditions characterized by Lewy bodies, such as Parkinson’s disease. The project began three years ago by identifying 10 structurally diverse compounds that bind selectively and with high affinity to alpha-synuclein, but less avidly to other key brain proteins such as tau or amyloid-beta. Optimized compounds are now being radiolabeled and tracked to see how they perform as potential tracers in the brain.
The Myelin Repair Foundation, which describes itself as the only research organization addressing every phase in the drug discovery process—from research all the way to licensing by commercial drug developers—also partners with CROs for critical validation and drug discovery studies for multiple sclerosis.
One can also find examples of CROs screening compounds for foundations that are the only viable funders of research for neglected diseases. The Institute for OneWorld Health (iOWH), now part of the Seattle-based non-profit PATH, advanced a drug to Phase II trial that alleviates severe rehydration related to diarrheal diseases, which kills two million children under the age of five every year in the developing world. BioFocus—one of a number of collaborators on this project—performed medicinal chemistry, biology screening and ADME studies in a partnership that would identify the eventual candidate. The work was funded by the Bill & Melinda Gates Foundation, the largest grant-making institute in the world.
Will any of these foundations put their stamp on a cure or disease modifying treatment? That’s certainly the goal. For now, they are pushing the pace of research in interesting and innovative directions, and making critical progress in discovering treatments for patients hungry for results.
References
Kate Hilyard is Managing Director of UK-based BioFocus, part of Charles River Discovery Services.
But while the process of drug discovery remains constant, the groups driving the scientific innovation now include those typically associated with fund-raising, lobbying and patient advocacy. Along with biopharmaceutical companies, which have been at the helm of drug discovery for years and continue to be the dominant player, one finds an increasing number of not-for-profit disease foundations angling for a seat at the lab bench. Examples include the Cystic Fibrosis Foundation, which developed the breakthrough therapy Kalydeco and recently sold the royalty rights for $3.3 billion. Foundations are working with a diverse array of research players—including CROs—to advance their scientific goals. In the process, they are helping to accelerate the often glacial pace of translational research.
How important are CROs in helping charitable organizations advance their science? The Alzheimer’s Drug Discovery Foundation recently created a platform called ACCESS to help foundations work with CROs. The program gives academic and small biotech communities online access to a marketplace of CROs and the industry-standard drug discovery and development services they provide.
A 2013 report from the Milken Institute’s Faster Cures points to the growing influence of disease foundations. The report found that patient advocacy and disease foundations initiated 10% of the 250 research consortia created to accelerate biomedical research. Nearly half the foundations are on single-minded missions to discover disease-specific drugs, devices or vaccines, but some of the consortia have much broader missions—to create broadly used tools applicable across many diseases, or to unlock the research gates and make certain biomarker research data publicly available.
How CROs engage with foundations can vary depending upon the business model, funding and mission of the nonprofit. Much smaller disease foundations may rely on consultants to determine how discovery work should be outsourced. Under this arrangement, CROs may be granted more strategic input into a project, but the work is much more focused.
In contrast, large foundations tend to have their own internal teams of scientists, who manage the projects and contract with outside scientists to conduct the experiments. Imagine a wheel of a bicycle, with the foundation as the scientific hub and the academic labs or CROs as spokes that keep the science moving. Contract scientists may have a certain amount of input into the scientific process and can even propose their own ideas for future projects, but at the end of the day, it is the foundation that will ultimately decide the direction of the project.
No matter what the business model, CROs generally have more input into projects funded by disease foundations compared to those funded by biopharmaceutical companies.
Huntington’s Disease
CHDI Foundation, a nonprofit devoted to Huntington’s disease (HD), offers a good example of a large and sophisticated disease foundation that works closely with CROs. CHDI’s mission is to develop drugs that can slow the progression of the deadly, neurodegenerative disorder, and it has built relationships with the academic and industrial sectors to make that happen. CHDI’s team of scientific experts provide direction and management to more than 600 scientists from academic and commercial labs (including CROs like ours) pursuing novel therapies worldwide. The virtual model encourages scientific collaboration to more directly connect academic research, drug discovery and clinical development. Our scientists and many others attend regular meetings hosted by CHDI to discuss the progress of projects, and we are encouraged to share our own ideas on future projects.
CHDI’s portfolio extends from exploratory biology to the identification and validation of therapeutic targets, and from drug discovery and development to clinical trials. While CHDI mostly conducts discovery and development research, one recent study offers a good illustration of how disease foundations have tried to improve the pace of translational research by working with CROs to validate previously published data. Predicting how a drug will behave in clinical trials can be an exhaustive process. As researchers are aware, reproducing results from preclinical studies is difficult. Novel drugs that look promising in preclinical testing often end up demonstrating much weaker or no efficacy in clinical trials. A review last year in PLoS Medicine referenced the fact that only 11% of investigational drugs that enter clinical testing get licensed.1
CHDI wanted to assess how well certain monoclonal antibodies (mAb) and small molecule drugs mimic or partially activate the tropomyosin-receptor kinase B (TrkB) receptor.2 This protein is the receptor for a family of proteins that induce the survival, development and function of neurons and reduced expression of these receptors is thought to be important in HD progression.
Scientists at BioFocus, now part of Charles River, used recombinant and native assay formats to evaluate two TrkB antibodies and a panel of reported small molecule TrkB agonists. The biomarkers in the in vitro studies helped show that the mAbs were reaching and activating their intended target—suggesting that they might be good tools for vital proof of concept target validation studies in in vivo models or even potential therapeutics in the future. However, equally important were findings that contradicted previous reports suggesting the utility of specific small molecules as TrKB agonists. In contrast to the mAbs, none of the small molecules tested appeared able to activate this pathway in the systems tested. The data underscored how important it is to independently replicate discoveries and to publish such negative findings. Following disclosure of this work, several other labs confirmed that they had similar results, but that they had not wanted or been able to publish negative data. This knowledge can save time and resources by enabling other researchers to focus work on the most robust findings in the search for future therapeutics in HD.
The Michael J. Fox Foundation and many others
The consortia created by the Michael J. Fox Foundation for Parkinson’s Research (MJFF) provides another example of how disease foundations are trying to accelerate the pace of research. The long-term goal of the MJFF is to find better treatments for Parkinson’s disease. Identifying an imaging tool that can track how the disease is progressing could potentially overcome one of the major hurdles neuroscientists now face in validating therapeutic agents.
An MJFF group consisting of BioFocus, two academic groups and a radiopharmaceutical company set out to develop a positron emission tomography (PET) radiotracer that could visualize the distribution of alpha-synuclein aggregates, found in pathological conditions characterized by Lewy bodies, such as Parkinson’s disease. The project began three years ago by identifying 10 structurally diverse compounds that bind selectively and with high affinity to alpha-synuclein, but less avidly to other key brain proteins such as tau or amyloid-beta. Optimized compounds are now being radiolabeled and tracked to see how they perform as potential tracers in the brain.
The Myelin Repair Foundation, which describes itself as the only research organization addressing every phase in the drug discovery process—from research all the way to licensing by commercial drug developers—also partners with CROs for critical validation and drug discovery studies for multiple sclerosis.
One can also find examples of CROs screening compounds for foundations that are the only viable funders of research for neglected diseases. The Institute for OneWorld Health (iOWH), now part of the Seattle-based non-profit PATH, advanced a drug to Phase II trial that alleviates severe rehydration related to diarrheal diseases, which kills two million children under the age of five every year in the developing world. BioFocus—one of a number of collaborators on this project—performed medicinal chemistry, biology screening and ADME studies in a partnership that would identify the eventual candidate. The work was funded by the Bill & Melinda Gates Foundation, the largest grant-making institute in the world.
Will any of these foundations put their stamp on a cure or disease modifying treatment? That’s certainly the goal. For now, they are pushing the pace of research in interesting and innovative directions, and making critical progress in discovering treatments for patients hungry for results.
References
- PLoS Medicine, 10(7), e1001489, 2013
- PLoS One, 9(2), e87923, 2014
Kate Hilyard is Managing Director of UK-based BioFocus, part of Charles River Discovery Services.