[Federal Register Volume 81, Number 214 (Friday, November 4, 2016)]
[Notices]
[Pages 76949-76950]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-26628]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


National Institute of Aging (NIA), National Institute of Mental 
Health (NIMH), and National Center for Advancing Translational Sciences 
(NCATS): Cooperative Research and Development Agreement (CRADA) and 
Licensing Opportunity for Ketamine for the Treatment of Depression and 
Other Anxiety-Related Disorders

AGENCY: National Institutes of Health, HHS.

ACTION: Notice.

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SUMMARY: The National Institute of Aging (NIA), National Institute of 
Mental Health (NIMH), and National Center for Advancing Translational 
Sciences (NCATS) of the National Institutes of Health (NIH), University 
of Maryland at Baltimore (UMB) and their collaborators are seeking 
Cooperative Research and Development Agreement (CRADA) partners to 
collaborate in the preclinical and clinical development of ketamine 
metabolite (2R, 6R-HNK) for the treatment of depression and other 
anxiety-related disorders.

DATES: Interested candidate partners must submit a statement of 
interest and capability, no more than five pages long, to the NCATS 
point of contact before January 3, 2017 for consideration.

FOR FURTHER INFORMATION CONTACT: Information on licensing and co-
development research collaborations, and copies of the U.S. patent 
applications listed below may be obtained by contacting: Attn: Sury 
Vepa, Ph.D., J.D., Senior Licensing and Patenting Manager, National 
Center for Advancing Translational Sciences, NIH, 9800 Medical Center 
Drive, Rockville, MD 20850, Phone: 301-217-9197, Fax: 301-217-5736, or 
email [email protected]. A signed Confidential Disclosure 
Agreement may be required to receive copies of the patent applications.

SUPPLEMENTARY INFORMATION: As per the Anxiety and Depression 
Association of America, Major depressive disorder affects 14.8 million 
people in America, including children, adults, and the elderly. A 
number of therapies currently exist to treat depression, although they 
suffer drawbacks such as requiring weeks to take action. One particular 
therapy includes the approved drug, ketamine, which has demonstrated 
robust and acute antidepressant activity. However, its efficacy is 
bridled with significant disadvantages including its addictive 
potential and its dissociative activities. This is the case even when 
administered at low doses, which limits the potential widespread use of 
ketamine as an antidepressant medication.
    In order to improve the treatment of depression, it is important to 
explore the mechanism by which ketamine exerts its antidepressant 
effects. That is precisely what the NIH and UMB scientists and 
collaborators are investigating, and have found that the metabolism of 
ketamine is critical to its antidepressant effects, and that the 
(2R,6R)-2-amino-2-(2-chlorophenyl)-6-hydroxycyclohexanone ((2R,6R)-
hydroxynorketamine (HNK)) metabolite, reversed depression-like 
behaviors in mice without triggering anesthetic, dissociative, or 
addictive side effects associated with ketamine. Specifically, the 
researchers found that the

[[Page 76950]]

metabolite does not inhibit the non-competitive glutamatergic N-methyl-
D-aspartate (NMDA) receptor, and it exerts rapid actions that activate 
the [alpha]-amino 3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) 
receptors. Results indicate a non-NMDA receptor dependent mechanism 
underlying ketamine's antidepressant properties, which involve 
bioactivity of a specific metabolite (2R, 6R-HNK) could be exploited 
for drug development. Additionally, the researchers have established 
appropriate salt, crystal and polymorph forms of the agent and multiple 
methods of synthesis. Full ADME and polypharmacology assessment is 
complete as well as pre-formulations studies.
    To expedite the research, development and commercialization of 
2R,6R-hydroxynorketamine (a metabolite of ketamine), the National 
Institutes of Health, UMB and their collaborators are seeking one or 
more CRADA and/or license agreements with appropriate pharmaceutical or 
biotechnology companies in accordance with the regulations governing 
the transfer of Government-developed technology and its public sector 
objectives, as outlined below. The purpose of a CRADA is to find a 
partner to collaborate in the development and commercialization of a 
technology that is in early phases of clinical development. Under the 
CRADA, key activities related to the clinical development of 2R,6R-HNK 
as a therapeutic to treat a variety of mental health conditions 
including depressive disorders will be performed. Collaborators should 
have proven experience in drug development with specialized expertise 
within depression and/or related mental health disorders. Owing to 
NIH's commitment to public dissemination of data, a key criterion will 
be that all outcomes from the collaborative effort will be published 
including the outcomes of all clinical trials. Further, it is the goal 
of NIH, UMB and other collaborators to develop the technology to the 
fullest extent (as therapeutic for multiple clinical indications 
including, but not limited to, anxiety, suicidal ideation, anhedonia, 
PTSD, addiction, neuropathic pain, among others).
    How to Apply: Interested potential CRADA collaborators will receive 
detailed information on the current status of the project after signing 
a confidentiality disclosure agreement (CDA) with NIH, UMB and other 
collaborators. Interested candidate partners must submit a statement of 
interest and capability, no more than five pages long, to the NCATS 
point of contact before January 3, 2017 for consideration. Guidelines 
for the preparation of a full CRADA proposal will be communicated by 
the NIH to respondents that have demonstrated sufficient mutual 
interests and capabilities that indicate the partnering entity will 
appropriately and substantially contribute to the proposed 
collaboration. Capability statements submitted after the due date may 
be considered if a suitable CRADA collaborator has not been identified 
by NIH and UMB among the initial pool of respondents.
    Respondents interested in submitting a CRADA proposal should be 
aware that it may be necessary for them to secure a patent license to 
the background-patent applications in order to commercialize products 
arising from a CRADA. Licensing of background technology patent rights 
related to this CRADA opportunity and claimed in the pending patent 
applications are available for either exclusive or non-exclusive 
licensing and licensing by NIH is subject to 35 U.S.C. 207 and 37 CFR 
part 404. CRADA partners are afforded an option to negotiate an 
exclusive license from the NIH for inventions arising from the 
performance of the CRADA research plan.
    The full CRADA proposal should include a capability statement with 
a detailed description of: (1) Collaborator's Expertise with mental 
health disorders such as depression, (2) Collaborators' expertise in 
preclinical development efforts including toxicology and chemistry, 
manufacturing and controls (CMC), (3) Expertise in regulatory affairs, 
particularly at the IND filing and early stage clinical trials stages, 
(4) Collaborator's ability to support, directly or through contract 
mechanisms, and upon the successful completion of relevant milestones, 
the ongoing pharmacokinetics and biological studies, long term toxicity 
studies, process chemistry and other pre-clinical development studies 
needed to obtain regulatory approval of a given therapy so as to ensure 
a high probability of eventual successful commercialization and; (5) 
Collaborator's ability to provide adequate funding to support some pre-
clinical studies of the project as well as clinical trials.

Publications

Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, 
Manickavasagom A, Yuan P, Pribut HJ, Singh NS, Dossou KSS, Fang Y, 
Huang X-P, Mayo CL, Wainer IW, Albuquerque EX, Thompson SM, Thomas 
CJ, Zarate CA, Gould TD. NMDA receptor inhibition-independent 
antidepressant actions of a ketamine metabolite. Nature, May 4, 
2016, doi: 10:1038/nature17998.

Patent Status

    (1) ``Use Of (2R,6R)-HNK, (S)-Dehydronorketamine and (R,S)-ketamine 
metabolites in the treatment of depression and neuropathic pain''; 
Irving W. Wainer, Ruin Moaddel, Michel Bernier, Carlos A. Zarate, Mary 
Tanga, Marc C. Torjman, Michael Goldberg; Assignees: National Institute 
of Aging (NIA), National Institute of Mental Health (NIMH), SRI 
International, University of Medicine and Dentistry of New Jersey 
(UMDNJ); U.S. Provisional Patent Application # 61/547,336; Filed: 
October 14, 2011; NIH Reference # E-092-2011.
    (2) ``Methods of using (2S,6S)-HNK and (2R,6R)-HNK to treat various 
depressive disorders and anxiety disorders''; Craig Thomas, Todd D. 
Gould, Irving W. Wainer, Carlos A. Zarate, Ruin Moaddel, Patrick 
Morris, Panos Zanos; Assignees: National Institute of Aging (NIA), 
National Institute of Mental Health (NIMH), National Center for 
Advancing Translational Sciences (NCATS), University of Maryland at 
Baltimore (UMB); U.S. Provisional Patent Application # 62/313317; 
Filed: March 25, 2016; NIH Reference #E-036-2016.
    (3) ``Crystal forms and methods of synthesis of (2R, 6R)-HNK and 
(2S,6S)-HNK''; Craig Thomas, Patrick Morris, Carlos A. Zarate, Ruin 
Moaddel, Todd D. Gould, Panos Zanos; Assignees: National Center for 
Advancing Translational Sciences (NCATS), National Institute of Mental 
Health (NIMH), National Institute of Aging (NIA), University of 
Maryland at Baltimore (UMB); U.S. Provisional Patent Application #62/
313309; Filed: March 25, 2016; NIH Reference #E-116-2016.

    Dated: October 31, 2016.
Pamela McInnes,
Deputy Director, Office of the Director, National Center for Advancing 
Translational Sciences.
[FR Doc. 2016-26628 Filed 11-3-16; 8:45 am]
 BILLING CODE 4140-01-P