National Institutes of Health Blueprint Neurotherapeutics Network: Results to Date and Path Forward
The BPN’s initial target was to start up to 20 milestone-driven projects and advance those projects with the most promise of obtaining Food and Drug Administration approval to enter and execute phase I clinical trials with BPN resources. Another explicit goal of the BPN was to de-risk the development of new, impactful therapies that could attract commercial interest enabling a hand-off to industry for late-stage development and additional clinical trials. Therefore, careful consideration was given in the program to ensure that intellectual property of the contributing academic institution or small business was protected and unencumbered by the NIH in order to simplify licensing discussions with pharma and venture capital investors.
Portfolio of Blueprint Neurotherapeutics Network projects starting 2011–13
Columbia University Health Sciences
Small-molecule drugs for treatment of dry age-related macular degeneration
Targeting cytokine-mediated pathologies for neuroprotection in treatment of AMD
University of Miami School of Medicine
Triazine-based compounds to promote regeneration in optic neuropathies
Axerion Therapeutics, Inc.
Small-molecule development of PrPc antagonists for the treatment of Alzheimer’s disease
Tetra Discovery Partners, Inc.
PDE4D allosteric modulators for treating cognitive impairment
University of California San Diego
Optimization of soluble gamma-secretase modulators for the treatment of Alzheimer’s disease
Sage Therapeutics, Inc.
Neuroactive steroid GABAA receptor positive modulators for fragile X syndrome
Scripps Florida/Eolas Therapeutics, Inc.
Orexin receptor antagonists for drug addiction and panic disorder
University of Washington
Drug discovery for the prevention of hearing loss
A novel delta opioid receptor-biased agonist for major depressive disorder
Brigham and Women’s Hospital
Small-molecule modulators of the glutamate transporter for treatment of ALS
EP2 allosteric Potentiators for subarachnoid hemorrhage
Massachusetts General Hospital
Optimization of compounds to improve mRNA splicing in familial dysautonomia
Northwestern University at Chicago
A novel calcium channel antagonist for neuroprotection in Parkinson’s disease
Reset Therapeutics, Inc.
Orexin receptor agonists for the treatment of excessive daytime sleepiness and cataplexy
However, the BPN did encourage the principal investigators (Table 1) to continue promising avenues and, in the case of the hearing-loss program at the University of Washington, it continued with non-BPN NIH funding, and the team was able build on the BPN results to address the underlying issues, garner outside funding, and launch a new company for further development . A second project from Reset Therapeutics targeting excessive daytime sleepiness and cataplexy recently established a research collaboration with Alkermes . The reasons for not reaching the milestones in the Hit-to-Lead/Lead Optimization phase varied from inability to optimize both activity and metabolic stability into the same molecule to the need to develop a more robust animal model, which was out of the scope and budget of the BPN resources. To date, two projects have graduated from the program successfully. The Familial Dysautonomia project at Massachusetts General Hospital was licensed and internalized in the preclinical phase [7, 8]. The second project, from Tetra Discovery Partners, successfully completed all milestones including successful completion of the phase I Single Ascending Dose study as part of the BPN program and is advancing further via additional NIH and external funding resources [9, 10, 11, 12]. The remaining 3 active programs from the original 15 are advancing through preclinical activities in preparation for filing Investigational New Drug applications to enable phase I trial in 2017. Consistent with the goal to move from NIH-funded, to industry-funded development, the Eolas project started with Scripps Florida, then transferred from the academic institution to Eolas, a company founded by the principal investigators, and successfully entered a worldwide license and partnership agreement with AstraZeneca [13, 14]. Additionally, the Columbia Dry Age-Related Macular Degeneration project became the most recent project to announce a licensing agreement as it prepares to enter the clinic .
In conclusion, during the first 5 years, the BPN exceeded the goals for the program, and overall advancement of projects is in-line with industry average attrition . These milestone-driven cooperative agreements allowed for timely decisions while focusing valuable NIH resources and grant funding on the most promising projects. Importantly, projects starting in the academic setting were well represented at every stage of the BPN program. From the original 15 projects, 1 project completed its phase I trial and progressed to additional clinical trials, and 4 licensing agreements were announced to date. Additional projects are poised to enter the clinic in the near future. In light of the BPN pilot program’s success, it was decided to continue the project for an additional 5 years. Several Funding Opportunity Announcements were generated by the National Institute of Neurological Disorders and Stroke in conjunction with other NIH Blueprint for Neuroscience Research ICs with the goal of helping to ensure project preparedness in the early stages of the neuroscience translational research and to ensure the resources to discover, develop, and advance promising small molecules from academic laboratories and small businesses to phase I clinical trials. (See IGNITE and BPN Funding Opportunity Announcements http://www.ninds.nih.gov/funding/areas/translational_research/funding_programs_researchers.htm). This suite of grant mechanisms, supported by experienced program managers at NIH and contract resources, are available to the neuroscientific community. Investigators are encouraged to make use of these resources to translate their discoveries to therapies that will advance health.
We acknowledge the Blueprint Neurotherapeutics Network (BPN) investigators, consultants, and contractors who work collaboratively throughout this program. Additionally, the we acknowledge the Program Managers and Science Officers from National Institutes of Health (NIH) Blueprint Institutes and Centers who made the success of the program possible: Neeraj Agarwal [National Eye Institute (NEI)], Francesca Bosetti [National Institute of Neurological Disorders and Stroke (NINDS)], Roderick Corriveau (NINDS), Jamie Driscoll [National Institute of Mental Health (NIMH)], Thomas Greenwell (NEI), Amelie Gubitz (NINDS), Katrina Gwinn (NINDS), Janet He (NINDS), Nancy Freeman (National Institute on Deafness and Other Communication Disorders), Elena Koustova, [National Institute on Drug Abuse (NIDA)] , Qi-Ying Liu (National Institute on Alcohol Abuse and Alcoholism), Miroslaw Mackiewicz [National Institute on Aging (NIA)] , Laura Mamounas (NINDS), Enrique Michelotti (NIMH), Mary Ann Pelleymounter (NINDS), Lorenzo Refolo (NIA), Zhaoxia Ren (National Institute of Child Health and Human Development), Ming Shih (NIDA), Beth-Ann Sieber (NINDS), Tina Urv (NIMH), and Lois Winsky (NIMH). We especially thank Jill Heemskerk and Rebecca Farkas (founding Program Directors for the BPN) and the past and current NIH Blueprint for Neuroscience Research Institutes and Centers Directors for supporting and guiding this program.
- 2.Stovall, S. R&D cuts curb brain-drug pipeline: development of new medicines for brain disorders could be threatened as major drug makers scale back research. Wall Street Journal; March 27, 2011. Available at: http://www.wsj.com/articles/SB10001424052748704474804576222463927753954 Accessed February 8, 2017.
- 5.Funding was continued via a R01 grant and resulted in funding from outside sources and formation of a new company. Available at: http://www.oricularx.com. Accessed August 7, 2016.
- 6.Reset Therapeutics, Inc. establishes research collaboration with Alkermes for discovery and development of novel orexin modulators. Available at: http://www.businesswire.com/news/home/20160317005378/en/. Accessed March 17, 2016.
- 7.Massachusetts General Hospital. Optimization of compounds to improve mRNA splicing in familial dysautonomia (PI: Susan Slaugenhaupt). Available at: https://projectreporter.nih.gov/project_info_description.cfm?aid=8918034&icde=30204642. Accessed March 28, 2017.
- 8.PTC therapeutics and massachusetts general hospital collaborate on rare disease research. Available at: http://ir.ptcbio.com/releasedetail.cfm?releaseid=946252. Accessed December 9, 2015.
- 9.Tetra Discovery Partners. PDE4D allosteric modulators for treating cognitive impairment (PI: Mark Gurney). Available at: https://projectreporter.nih.gov/project_info_description.cfm?aid=9068253&icde=30204682. Accessed March 28, 2017.
- 10.Tetra Discovery advances Alzheimer's treatment candidate BPN14770 to phase i multiple ascending dose trial. Available at: http://www.prnewswire.com/news-releases/tetra-discovery-advances-alzheimers-treatment-candidate-bpn14770-to-phase-i-multiple-ascending-dose-trial-300244787.html. Accessed April 1, 2016.
- 11.Tetra Discovery Partners raises $10 million through series A financing and two National Institutes of Health grants. Available at: http://www.prnewswire.com/news-releases/tetra-discovery-partners-raises-10-million-through-series-a-financing-and-two-national-institutes-of-health-grants-300369553.html?tc=eml_cleartime. Accessed November 29, 2016.
- 12.Tetra Discovery Partners announces positive results from phase 1 studies of cognition drug candidate, BPN14770. Available at: http://www.prnewswire.com/news-releases/tetra-discovery-partners-announces-positive-results-from-phase-1-studies-of-cognition-drug-candidate-bpn14770-300379985.html. Accessed December 19, 2016.
- 13.Eolas Therapeutics. Orexin receptor antagonists for drug addiction and panic disorder (PI: Paul Kenny). Available at: https://projectreporter.nih.gov/project_info_description.cfm?aid=8856678&icde=30204721. Accessed March 28, 2017.
- 14.Eolas Therapeutics and AstraZeneca partner to develop orexin-1 receptor antagonist for multiple indications. Available at: http://www.prnewswire.com/news-releases/eolas-therapeutics-and-astrazeneca-partner-to-develop-orexin-1-receptor-antagonist-for-multiple-indications-300106505.html. Accessed June 30, 2015.
- 15.Lin Bioscience licenses first-in-class therapeutic program to treat dry aged-related macular degeneration from Columbia University in collaboration with NIH. Available at: http://www.prnewswire.com/news-releases/lin-bioscience-licenses-first-in-class-therapeutic-program-to-treat-dry-aged-related-macular-degeneration-from-columbia-university-in-collaboration-with-nih-300386708.html#continue-jump. Accessed January 6, 2017.
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