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CIRM MAJOR FACILITIES GRANT APPLICATION #FA1-00605-1

Recommendation: Not recommended for further consideration
Element X Score: N/A
Element Y Score: —
Element Z Score: N/A
Use & Contribution Score:—

Public Abstract (provided by applicant)

Human stem cells have the demonstrated ability to differentiate into a variety of specific cell types. This has generated widespread hope that these cells may be a resource for replacing damaged or deteriorating tissues in patients. However the process of directing stem cell fate toward a beneficial cell type is inefficient. Therefore considerable research is needed to identify and develop compounds, representing new drug candidates, that reliably direct stem cells to desired cell types with regenerative capabilities. Initial ‘hit’ compounds identified through various research approaches typically are not very ‘drug-like’. It’s expected that large numbers of compounds closely related to the initial ‘hit’ must be synthesized and evaluated for improved efficacy and safety before testing in humans is possible. These drug candidates, identified by their ability to positively direct stem cell fate, will require a thorough characterization with regard to their structure, metabolism, and safety. Coordinating the many steps in the process of drug development, from stem cells to testing compounds in animals, would be optimized by housing these activities in one facility.

To address the challenge of translating stem cell research into novel therapeutics, we will establish a new facility for medicinal chemistry and preclinical safety evaluation of drug candidates. We will make available to other CIRM investigators its expertise in the areas of stem cell biology, chemical synthesis and analysis, metabolic studies, and safety evaluation of compounds in animals. The new facility housing these activities will be created through renovation of existing space adjacent to our current Institute, to be divided between new laboratory and administrative areas. The proposed Drug Development Center will support an expanded research and technical staff, contributing to the stem cell initiative through both internal projects as well as ongoing and new collaborations. Six administrative units will be established for managing the research programs. These units will be complementary, and will provide competencies in all steps of the drug development process. The new facility will support our current CIRM funded efforts using stem cells to develop novel therapeutics for heart disease, a leading cause of mortality and decline in quality of life in the developed world.

Similarly, through collaborations with other CIRM investigators the new facility will support drug development efforts in many other disease areas. Our institute has extensive experience with investigational new drug (IND) preparation and new drug applications (NDAs), and today many of those drug candidates are new drugs on the market. The new Drug Development Center will benefit greatly from this experience. By bringing new investigators and a collaborative approach to the stem cell field, this facility responds directly to the CIRM initiative to deliver new therapeutics based on stem cell research.

Statement of Benefit to California (provided by applicant)

Millions of people currently suffer from devastating diseases or injuries that are currently incurable, including cancer, heart disease, Alzheimer’s, spinal cord injuries, and many others. Long-term health care places a heavy burden on patients, their families, and the state health care system. The ability of human stem cells to differentiate into specific cell types has generated enthusiasm that these cells may be a resource for replacing damaged or deteriorating tissues in patients. However the process of directing stem cell determination is inefficient, largely due to an incomplete understanding of the inducing signals and pathways involved. Various technical approaches lead to identification of ‘hit’ compounds with the potential to direct stem cells toward desired cell types, but which frequently have limited efficacy or stability. The drug development process typically requires subsequent chemical synthesis of large numbers of drug-like analogs, and thorough characterization with regard to their metabolism, selectivity, and safety. The California stem cell and regenerative medicine initiative will require a comprehensive program of research, analytical, and preclinical safety evaluation before drug candidates can be tested in a clinical setting.

To address the challenge of translating basic stem cell research into effective therapies, we will establish a new facility for medicinal chemistry and preclinical analysis of lead compounds and optimized drug candidates. The proposed Drug Development Center will support our current CIRM funded efforts to develop potent and selective drug-like molecules to direct stem cell cardiomyogenesis for treatment of heart disease. Coordinating the various steps in preclinical drug development in one facility will offer advantages in efficiency, time, and cost. Through collaborations, other CIRM investigators will similarly benefit by access to our preclinical services in the areas of stem cell biology, chemical synthesis and analysis, ADMET screening, and safety evaluation of lead compounds in vitro and in animals. These collaborations will enhance opportunities for developing effective new therapeutics in many other areas of disease research.

By bringing new investigators and collaborative approaches to the stem cell field, the proposed new facility will respond directly to the CIRM initiative by accelerating development of new therapies for potentially millions of Californians suffering from chronic illnesses and injuries. Patients and their families will benefit, in terms of improved quality of life and reduced financial burden, from treatments that will derive from the proposed stem cell and drug development efforts. Also, benefits to the California health care system will ultimately be realized by switching focus from the maintenance of chronic conditions to prevention and cures.

Review Report

Executive Summary

This application requests support for a CIRM Special Program focused on the creation of a drug discovery and development facility (Element Y) that will perfom large-scale screening of diverse chemicals on human stem cells and the subsequent characterization of selected compounds. Those compounds that display the ability to direct stem cell development and differentiation, for example, will then be taken through a series of steps to make them more “drugable”. Such characterization will lead to investigational new drug (IND) filings for successful candidates and potentially to new drug applications (NDA). Thus, this institute’s program aims to provide complete drug development research in a private academic setting. The proposed facility is composed of six units: (1) chemistry, (2) bioanalytical chemistry, (3) ADMET/pharmacology, (4) cell biology, (5) animal (preclinical) studies, and (6) administration. The facility will conduct it’s own stem cell research as well as provide services to other CIRM investigators in the areas of stem cell biology, chemical synthesis and analysis, metabolic studies, and safety evaluation for compounds in animals. Services will be provided to investigators through a process of charge backs to grants.

Reviewers agreed that after a drug candidate “hit” is found, a lot of work still needs to be done in order to optimize the treatment and demonstrate the safety of the treatment. The facility proposed would, in many ways, do what a typical pharmaceutical company does. One reviewer felt that this work might best be done by pharmaceutical companies as they are more focused on a specific therapeutic aim and have much more substantial resources in terms of synthesis, analysis, and preclinical studies of drugs. Other reviewers, however, felt that there is or will be a need for this type of center for advancing projects that have been developed in academic labs that need small-scale medicinal chemistry, ADME-Tox work, and preclinical work in order to garner the interest of pharmaceutical companies and move therapies forward.

The applicants justify this facility through its proposed collaborations with other CIRM investigators to aid them in delivering “validated therapeutics derived from stem cell research.” However, reviewers felt that the center is not well justified and has little collaboration with others. In addition, there is not much discovery science going on at the organization and it is unclear what studies the internal investigators will undertake. The application emphasizes organizational aspects of the facility and the need for communication but it is not clear that the components of such a facility need to be housed in the same building. The research team will be directed by a scientist who has substantial experience with academic drug development. Other members of the team include a medicinal chemist, an expert bioanalytical chemist, and an expert of cell and molecular biology and biochemistry. The space for the center will be acquired in an adjacent building and 8500 square feet will be renovated for laboratory, office, and administrative space. They suggest oversight by a steering committee and a series of core meetings but not enough detail was provided on how the new projects will be selected, where they will come from, and criteria for progression.

Detailed Summary

Element Y

Score: —

SCIENTIFIC PROGRAM: The institute will provide core facilities for 1) medicinal chemistry with synthesis and purification of compounds using high throughput approaches; 2) bioanalytical chemistry such as NMR and LCMS to support drug discovery applications; 3) molecular and cell biology and protein expression supporting large scale production and purification of proteins; 4) ADMET screening using biochemical and cell based assays 5) in silico screening and computational modeling 6) vivarium resources to test preclinical drug candidates. An experienced investigator will lead each of these activities but it is not clear how many people are in each core.

Regarding the quality of the scientific program to be housed in the facility, reviewers indicated that it is not clear what science will be carried out in this facility. Most of the named faculty have experience with pharmaceutical companies and drug development but not stem cells. The PI has not done such research before although he/she has a history of considerable organization skills and participating in drug discovery programs. There is no clear plan for any scientific program to be housed outside of the facility. Except for the interactions between the five units that will be housed in the facility, there is no apparent synergy or collaboration with others. The application mentions providing services to outside groups, but it is not clear who would utilize the services of this group. Stem cells are just an incidental part of the research being proposed.

The scientific director of the applicant organization has served in this capacity since 1997. The director has strong management skills and has been PI on a number of NIH program project grants. The director has thirty years of experience in drug discovery, some of it in industry and has displayed very good productivity. His/her role in this proposal is its biggest strength. A couple of the other directors also have some industry experience which is also a strength of the proposal. Another strength is that the organization has a track record for a successful role in NDA submissions. However, the directors (PIs) listed to head the cores have absolutely no track record in stem cell biology. This is a big weakness. Although they seem to have a strong background in drug development, they will be dependent on collaborators who are well-versed in the stem cell field. Only the scientific director has the strong drug development experience in terms of INDs filed, and only one of the other PIs listed in the summary table have received funding from NIH or CIRM.

FORMAL INSTITUTIONAL COLLABORATIONS: This closely-knit organization has enlisted interest in collaborations from 14 other area investigators currently working on CIRM funded projects. As drug candidates emerge they propose working with contract research organizations to resynthesis candidates under GLP conditions. The collaborators are submitting applications that will require drug development services at some point but it is not clear whether these are projects ready for medicinal chemistry and/or drug development support.

This is an excellent core facility with proposed institutional collaborations that have not, however, yet been formalized. There is one letter from an investigator at a nearby institution indicating enthusiasm to collaborate, but this is minimal.

A potential strength of the proposal is the cited track record of fruitful interaction with several nearby institutions. But, the impact exerted by the applicant organization is not established as well as it might have been in the application. The table of collaborations indicates that a market for these services exists but does not indicate specific relevant successes that have been obtained. A much higher level of illustrative detail is provided in one case; however, even there the exact strategy for analogue testing and structure-activity relationships is undeveloped.

CORE SERVICES: There are six existing cores, as listed above under scientific program. Intellectual property is stated to comply with CIRM guidelines and planned to be “open-sharing”. The workflow per se is routine. The mission-critical technologies are not well described.

PLANS FOR GROWTH: There are plans for growth in the adjacent space. However, the previous scientific contributions of the institute itself are not well described, nor are future activities. Each director will also be expected to lead their own research program and obtain funding support to staff the effort. The application mentions a 10-year plan but it is not well justified.

DISCUSSION: One reviewer commented that it is terrific that the program is in an academic setting, but it is missing the assays to evaluate functionality of candidate drugs. Another problem cited is that the application was presented like a core function, without description of internal or external science and no demonstrable commitment from investigators to use this core. A reviewer indicated that the proposal could be a core within a larger group or consortium, but didn’t think the proposal stands alone. The applicants have clear pharmaceutical experience, but no stem cell experience and there is no plan for outside science. Inside the facility, work is focused only on testing drugs. From the proposal, it was also hard to figure out how it will be used by collaborators; the application contained only one letter from one collaborator who would use it. Another weakness was the lack of clarity on how projects will be selected. A table of projects is presented, but the application does not indicate a stage at which they would be selected. Another concern is how they will finance the development work which is very expensive and roughly estimated at about $4M per compound by one reviewer.

Use & Contribution

Score: —

A new 8500 square foot facility is proposed to be built adjacent to a similar center that has been in existence and functioning in this paradigm for the past 10 years. The facility will be will be physically and administratively independent of the current institute. They do not specify what this building is used for currently. They will renovate the new space to create new laboratory and administrative areas dedicated to stem cell biology and drug development. The center will house 5 PhDs as PIs and each PI will be designated as a unit director.

The following Working Group members had a conflict of interest with this application and were therefore recused from participating in review of, discussion of, and voting on the application:

• Feit, Marcy