Title of proposed idea: Venture Fund for Research and Development of New Medications to Treat Chronic Pain (see “NIH Award Strategies” in Innovation Brainstorm ideas)

Nominator: NIH Institutes/Centers

 Major obstacle/challenge to overcome: Chronic pain, which affects 116 million Americans and is a significant public health burden, is not adequately managed by current therapies.  Although opiates are the most commonly prescribed medications to treat chronic pain conditions (e.g. cancer pain), their use pose important clinical risks such as abuse liability, diversion, and overdose.  Other types of chronic pain (e.g., neuropathic pain caused by diabetes) are not well managed by either opiates or other approved agents (e.g., antidepressants).   Currently, a significant amount of dollars is being invested in testing medications to treat chronic pain but the results of the studies have not yielded any significant progress in the treatment of this condition. There is an urgent need to conduct research that helps to understand the neurobiological mechanisms of chronic pain, which in turn will help to identify new targets and thus new compounds to treat this condition.

Unfortunately, it has been challenging to develop collaborations and much more to share resources among industry, academia, and government investigators to advance the study of chronic pain. A concerted and synergistic approach among those three groups will greatly advance the understanding and management of chronic pain. It is expected that the development of a venture fund for research and development will facilitate the collaboration among industry, academia, and government which will result in the discovery of new targets and the development of new medications to treat this condition. 

The purpose of this program is to support eligible institutions that enter into a joint venture or collaboration with other entities which concomitantly provides support in the form of funds or resources to conduct research to advance the development of medications to treat chronic pain.

Research may focus on the discovery of new potential therapeutic targets, new molecules with action on those targets, as well as Phase I safety/tolerability studies, single or multisite Phase II or III studies, or translational projects.

Emerging scientific opportunity ripe for Common Fund investment:  Currently, there are multiple individual efforts from industry, academia and government to advance the knowledge of the mechanisms of pain as well as the discovery and development of new pharmacotherapies; however, most of those efforts are not coming to fruition because of the lack of a coordinated and synergistic approach. This initiative is very timely because it aims at channeling all those efforts and making them more synergistic in achieving an ultimate goal of having safer and more effective medications to treat chronic pain

Common Fund investment that could accelerate scientific progress in this field:

It is expected that the identification and validation of novel targets associated with chronic pain can lead to novel and effective therapies.   A pilot phase is proposed that if successful would go on to a therapeutics development phase to be done in collaboration with private sector partners.

Pilot Phase:

            Identification and validation of new therapeutic targets

Therapeutics Development Phase:

            Identification of bioactive compounds for the new targets identified during the pilot phase

            Pre-clinical studies

            Early stage clinical trials

Potential impact of Common Fund investment:

The ability to effectively treat chronic pain conditions will impact more than 116 million Americans. In addition, identifying and validating chronic pain targets – may also lead to diagnostic tests that may prevent or delay the onset of chronic pain conditions. 

Title of proposed idea: Translating Findings on Human Disease Risk Variants into New Interventions: Coordinated Studies for Therapeutic Target Identification (see “Beyond Genome-Wide Association Studies (GWAS)” in Innovation Brainstorm ideas)

Nominator: NIH Institutes/Centers

 Major obstacle/challenge to overcome: The potential to develop new therapies based on the expanding number of findings on human genetic variants’ relationships to disease risk is a well-recognized aspect of the potential for clinical progress stemming from advances in genomics (e.g., Green ED et al. [2011], Charting a course for genomic medicine from base pairs to bedside; Nature 470; 204). A key early rate-limiting step in this pathway is identification of promising therapeutic targets based on epidemiologic findings on risk variants.

The Challenge:  In a few cases (e.g., Crohn’s Disease), substantial progress has occurred from identification of risk variants to identification of therapeutic targets, providing proof-of-principle for this approach.  However, to date, the number of new targets identified by this approach is limited. A major challenge to expanding and accelerating such efforts is the fact that, after an association between a variant and disease risk is established, a critical mass of additional information is needed to determine whether there is a sufficiently promising therapeutic target to justify proceeding with subsequent, generally costly, steps in therapeutics development, e.g., screening small molecules, identifying lead compounds, and pre-clinical studies. The studies needed to identify and evaluate potential targets span a wide range of research areas, including:

• Deep sequencing in the region of the identified risk variant, to examine more closely which sequence variants are related to disease risk and identify additional variants with similar or opposing effects
• Intensive clinical and physiologic phenotyping of individuals with and without the variant to ascertain potential pathways to target
• Determination of the effects of the sequence variant (either in a gene or in an intergenic region) on gene products, levels of expression, and/or differential responses to factors regulating expression
• Identification of tissues in which the gene is expressed and differences among tissues in the degree to which the variant affects gene expression and tissue function
• Development and use of in vitro assays or tests in animal models to study variants’ functional effects and effects on responses to drugs
• Assessing how the variant may differ in susceptibility to epigenetic modifications and the effects of these differences

The breadth of types of studies required to obtain the needed critical mass of information and the need to integrate information from them poses a substantial challenge. The range of expertise required includes genetics, cell biology, physiology, epidemiology, and clinical expertise in specific diseases.  Although it is likely that there will be many individual studies that explore one or a few such effects of various genetic variants, it is presently very uncertain that individual investigator-initiated NIH grant applications alone will frequently provide and integrate the critical mass and range of data regarding a specific genetic variant to justify a subsequent drug development effort. Assembling coalitions of investigators spanning the above disciplines and providing the needed infrastructure for data sharing and collaborative analyses is very challenging. Without an NIH initiative, these challenges, coupled with high uncertainty of funding, are likely to deter even experienced investigators from the considerable effort needed to develop applications for such projects.

This challenge also affects steps in therapeutics development downstream from target identification.  There has been increased NIH support for structured programs to provide the infrastructure and coordination needed for small molecule screening and other steps focused on targets that have previously been identified. However, the steps from finding genetic risk variants through target identification have not been supported nearly as much by structured NIH programs, but rather have been left to investigator-initiated projects that generally address only isolated steps in the process.  While investigator-initiated research has reflected enormous creativity and will continue to make important contributions, the efficiency of identifying targets for intervention might well be enhanced by support for a more integrated path of discovery. This proposal therefore calls for the testing of a complementary paradigm that supports continuity of research from genetic variant through target identification. 

How to overcome this challenge: This challenge could be addressed by an initiative to support multidisciplinary projects, which would each obtain comprehensive information spanning the types of studies noted above, in regard to one or more variants associated with altered disease risk, and analyze this information to identify potential therapeutic targets and evaluate their potential for further development. This initiative would markedly enhance therapeutics development capabilities by these unique contributions in a crucial and currently unfilled niche. 

Such studies could be supported through one or more Common Fund RFAs, with individual awards supported by the most appropriate IC, or multiple ICs if appropriate. Peer review considerations regarding selection of variants for these studies could include the strength of their relationship to health risk, the public health importance of the condition(s) they affect, and the potential for finding new therapeutic targets, based on current knowledge about functions of the gene in which the variant is found. If more active NIH planning is desired regarding the range of conditions and/or selection of genes on which such projects could be focused, one or more pre-RFA advisory workshops could be convened by a trans-NIH committee to identify particularly important foci. Such a workshop could also recommend criteria by which to evaluate the results of individual projects in regard to decisions about proceeding with subsequent therapeutics development steps after target identification.

Coordination among projects could be facilitated by annual meetings and a coordinating center. An independent panel could review progress of the projects with regard to established benchmarks and advise on the rationale for their continuation. Based on these reviews, the efficiency of the set of projects could be enhanced by withdrawing resources from studies showing less promise for finding good targets and increasing resources for those with greater promise.

How the proposed initiative would address this challenge and fill a gap in current efforts: The focused coordinated target identification activities described above would help to increase the rate of discovery of promising therapeutic targets above the current less-than-ideal level, by providing the incentives and organization for their efficient identification and evaluation and a mechanism for focusing on the most promising ones. The initiative would also address the challenge of fulfilling the therapeutic potential of findings on genetic risk variants by promoting substantial progress on the crucial early therapeutic development stage of target identification.

Further, this structured approach would enhance the potential of current structured programs focused on steps after target identification by increasing the number of targets for consideration at the beginning of their therapeutic developmental “pipelines.” By increasing the number of promising targets, it could also provide synergy with NCATS, by enhancing opportunities for NCATS activities focused on subsequent stages of therapeutics development.

Emerging scientific opportunity ripe for Common Fund investment:  The increasing number of genetic risk variants identified by epidemiologic studies provides a well-recognized opportunity for the proposed activities to contribute to therapeutics development. Further, the many large population studies with extensive phenotype data, whose participants have already been genotyped, provide a cost-efficient platform for more detailed studies of specific genetic variants’ relationships to phenotypic differences. The expertise to conduct the proposed types of studies for target identification is available and improving rapidly. The potential contribution of such genetic findings and research expertise to target identification could be greatly enhanced by the proposed coordinated efforts to obtain a critical mass of information about selected variants and their effects.

Common Fund investment that could accelerate scientific progress in this field:  Therapeutic target identification could be accelerated by a Common Fund investment in the types of projects described above. Ideally, these might be supported by a seven-year investment (one year for detailed planning and protocol refinement, five years of data collection, and one year for analyses). An interim evaluation of ongoing projects would be used to inform decisions of subsequent resource allocation, selecting those projects that would continue and those that would be revised or discontinued.  Based on costs of the types of studies that would be included in the projects, it is estimated that studies on the effects of 20 variants could be supported by an investment of approximately $30M (direct costs) over seven years. The average annual direct cost would be approximately $4.3M, though first- and last-year costs would likely be lower, with higher costs in the intervening years.  It is possible that the studies could be organized as a private-public partnership, which could expand resources and the number of targets identified.

Potential impact of Common Fund investment:

Identification of several new, well-validated, therapeutic targets by this program would have transformative, durable impacts that would persist after the Common Fund support ended. The program would have impacts in at least two domains:

• Most obviously, it could advance subsequent therapeutic development and testing (either by private sector or NIH support) on the targets identified by the Common Fund program after this program was completed. (It is also worth noting that this approach could identify targets that might not have been pursued by the private sector for financial or other reasons, but which nonetheless merit further investigation because of their public health importance.)
• More generally, the project would allow acquisition of experience with this coordinated approach to target identification and validation, and the formation of research teams with expertise in these new approaches. Such teams, and others modeled on them, could provide important contributions to the translational missions of various individual ICs, which could be supported by these ICs long after the Common Fund project ended. 

Title of proposed idea: Gene-Based Therapeutics:  Manipulating the Output of the Genome to Treat Disease

Nominator: NIH Institutes/Centers

Major obstacle/challenge to overcome:  Gene-based therapeutics are tools to manipulate the output of the genome to treat disease.  The most well-known gene-based therapeutic is gene therapy, which is most commonly done using viral vectors, although other vehicles (e.g. nanoparticles), can be used as well.   Other gene-based therapies include small interfering RNA (siRNA) and oligonucleotide therapeutics, and zinc-finger nucleases and transposons to modify the genome directly.  

For many gene-based therapies, development and proof of principle preclinical studies are within the budget of a typical RO1 grant award.   The major obstacle is moving from preclinical research into clinical trials.  Major hurdles at the preclinical level include limitations on the size and sequence of nucleic acids used in gene-based therapeutics, as well as tissue and cell-type specific targeting.  Moving to the clinic, hurdles include the practical reality of scaling up production, funding for GMP drug manufacture and toxicology testing, and funding for clinical trials themselves.   

What is needed to overcome this obstacle is a program dedicated to making gene-based therapies a clinical reality.  Our proposal is for the Common Fund to support such mechanism, which would facilitate the translation of current gene-based therapies into clinical trials.

Emerging scientific opportunity ripe for Common Fund investment:  Gene-based therapies are clearly ripe for investment by the Common Fund.   It has now been established that viral vector based gene therapy is effective in humans.  In addition, novel gene targeted therapies are being developed and validated at an accelerating pace.  In 2011 alone, we have  seen the first evidence that zinc-finger nucleases can be effective in a mouse model  of hemophilia , and the use of exosomes to deliver therapeutic siRNA across the blood-brain barrier in mice . 

NIH ICs have provided the majority of funding for the discovery and preclinical developments of multiple gene-based therapies, and will do so in the future.  However, they not positioned to support translation to the clinic at the level that is necessary. 

 Common Fund investment that could accelerate scientific progress in this field:    We envision a program that combines aspects of RAID (Rapid Access to Investigational Drugs) and TRND (Therapeutics for Rare and Neglected Diseases), but is focused exclusively on gene-based therapeutics.  Projects will be chosen for support by streamlined competitive process, and funding provided in a step-wise manner dependent upon continued progress and meeting project targets (similar to RID).  For some viral-vector based therapies, the new program could support investigators to utilize the NHLBI gene therapy resource program.  For other types of therapeutics, the fund could provide support large scale production of GMP grade nucleic acids, or zinc-finger nucleases, as well as CROs for animal toxicology testing.  By funding such a large effort, significant cost savings would be expected based upon economies of scale. 

Another aspect of the program, modeled after the TRND program, would be to carry out Phase 0 and Phase 1 clinical studies to de-risk gene–based therapies, and thereby encourage adoption by industry.  It is possible that industry could be involved with this program at an earlier stage in a public-private partnership.

It should be emphasized that TRND does not work with biologics or gene therapy, so the new program would complement TRND, rather than duplicate effort.  While gene therapy and biologics are a part of RAID, given the rate of development of new technologies in this area, and the potential clinical impact, we believe that a much larger program, exclusively focused on gene-based therapeutics, is needed. 

Potential impact of Common Fund investment: If the proposed Common Fund program were to achieve its objectives, the impact would be that one or more gene-based therapies would become established as a treatment option for patients with genetic disease.  As a benchmark, gene-based therapy would become as common as bone marrow transplantation is currently at major academic medical centers.  Such an outcome could transform the clinical outlook and lives of patients with genetic disease.  This would be especially important for rare diseases where in most cases no other treatment options exist.  

Importantly, we anticipate that this program would dramatically impact basic science as well.  A commitment to gene-based therapeutics by the Common Fund, would certainly stimulate even more preclinical studies in this field, which would in term feed into the new program, and also provide new tools for basic science.  As an example, if the program achieved its objectives, tools could be available that would make manipulating the genome of a mouse, in a specific cell population, as routine as transformation of bacteria is today.  If this were to become reality, it would dramatically change the way biomedical science is done.   With support from the Common Fund, these impacts are feasible within the 10 year time frame specified by the Common Fund criteria.

References:

Simonelli F, Maguire AM, Testa F, et al. Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther. Mar 2010;18(3):643-650.

Aiuti A, Roncarolo MG. Ten years of gene therapy for primary immune deficiencies. Hematology Am Soc Hematol Educ Program. 2009:682-689.

Li H, Haurigot V, Doyon Y, et al. In vivo genome editing restores haemostasis in a mouse model of haemophilia. Nature. Jul 14 2011;475(7355):217-221.

Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. Apr 2011;29(4):341-345.

Title of proposed idea Chronic Pain Conditions: A Transformative Classification for Stimulating Research, Improving Diagnosis, and Personalizing Treatment

Nominator: NIH Institutes/Centers

Major obstacle/challenge to overcome: Chronic pain conditions afflict as many as one-third of the US population and incur $560-635 billion per year in incremental healthcare costs and lost productivity (IOM Report June 29, 2011). The long term clinical goal in alleviating chronic pain is to develop targeted therapies and identify patients responsive to these therapies, both of which are supported by etiological- and mechanism-based case definitions and diagnostic criteria of disease. A major challenge in the field is the lack of a mechanism-based case definition and diagnostic criteria for multiple chronic pain conditions. Common Fund investments could facilitate the development of a new objective, biopsychosocial classification system for chronic pain disorders to overcome this major obstacle. This new system will accelerate research by standardizing research diagnoses used across laboratories, enhance clinical diagnoses by developing more objective, mechanism-based measures of disease, and identify subjects responsive to new therapies by developing novel biomarkers of disease and clinical outcomes.

Emerging scientific opportunity ripe for Common Fund investment:    We propose a research program to develop a new, comprehensive, mechanism-based, biopsychosocial classification of chronic pain conditions. Three opportunities are ready for Common fund investment. This proposal endorses the ideas and sharpens the focus of “Molecular Classification of Disease”, a topic that emerged from the Innovation Brainstorm meeting, and takes on sophisticated data management and analysis elements of the topics on “Beyond GWAS” and “Cross-Cutting Issues in Computation and Informatics”.

Common Fund investment that could accelerate scientific progress in this field:   This program would create a centralized data bank/repository containing information from a large chronic pain cohort to include study subjects with Temporomandibular Joint Disorders, Fibromyalgia, Chronic Fatigue Syndrome, Vulvodynia, Endometriosis, Irritable Bowel Syndrome, Interstitial Cystitis, Headache, Low Back Pain, Arthritis, etc., recruited and identified using today’s best diagnostic criteria.  Many of these subjects will have multiple, comorbid chronic pain conditions. This cohort would be genotyped as well as phenotyped extensively using molecular, imaging and psychosocial methodologies.  All data would be agnostically analyzed via pathway analyses and new algorithms for lumping and splitting in order to subtype and re-classify these chronic pain patients.  Results emerging from the Common Fund incubator space would lead to a breakdown in the current “walls” separating these disorders (and researchers) and a transformation of diagnostic criteria based on a completely new classification of chronic pain conditions. After an intense 5 year effort, the data bank/repository and analytical tool set would become self sustaining with support from Pharma, the genotyping industry, and the NIH Pain Consortium.

Potential impact of Common Fund investment: The outcome of this project will be a completely new way of discovery and management of chronic pain conditions: researchers currently housed in different laboratories collaborating in multidisciplinary teams to study pain, rapid discovery of therapeutic targets, development of novel analgesic therapies based on common mechanisms of disease, introduction of individualized medical treatments and identification of those likely to respond to therapy. Ultimately, results from this project will lead to an overall reduction in the burden of chronic pain, currently $560-$635 billion/year in the US in incremental healthcare costs and lost productivity.

Chronic pain should be thought of as a disease unto itself like other chronic conditions such as diabetes and heart disease, and not merely a symptom of disease.  Research approaches to and management of chronic pain conditions must consider that, like other chronic conditions, disease progression and complexity, early identification and intervention, and effective therapies, all influence patient burden and economic costs of disease. A transformative classification of chronic pain conditions will ultimately reduce long-term morbidity and decrease the economic impact of these wide-spread conditions.