[Federal Register Volume 78, Number 25 (Wednesday, February 6, 2013)]
[Notices]
[Pages 8544-8546]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2013-02611]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


National Center for Advancing Translational Sciences (NCATS): 
Cooperative Research and Development Agreement (CRADA) and Licensing 
Opportunity for Small Molecule Agonists of the Relaxin Hormone Receptor 
(RXFP1) for Treatment of Heart Failure and Fibrosis

SUMMARY: The National Center for Advancing Translational Sciences 
(NCATS), the National Institutes of Health (NIH), is seeking 
Cooperative Research and Development Agreement (CRADA) partners to 
collaborate in the final stages of lead optimization, in vitro and in 
vivo evaluation, and preclinical development of a novel series of 
potent, selective, and orally bioavailable small molecule agonists of 
the relaxin hormone receptor, RXFP1, for the treatment of heart failure 
and fibrosis. Interested potential CRADA collaborators will receive 
detailed information on the current status of the project after signing 
a confidentiality

[[Page 8545]]

disclosure agreement (CDA) with NCATS.

DATES: Interested candidate partners must submit a statement of 
interest and capability to the NCATS point of contact before March 8, 
2013 for consideration. Guidelines for the preparation of a full CRADA 
proposal will be communicated shortly thereafter to all respondents 
with whom initial confidential discussions will have established 
sufficient mutual interest. CRADA applications submitted after the due 
date may be considered if a suitable CRADA collaborator has not been 
identified by NIH among the initial pool of respondents. Licensing of 
background technology related to this CRADA opportunity is also 
available to potential collaborators.

ADDRESSES: Questions about licensing opportunities of related 
background technology should be addressed to Lauren Nguyen-Antczak, 
Ph.D., Licensing and Patenting Manager, Office of Technology Transfer, 
NIH, 6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-
3804, Telephone: (301) 435-4074; Email: [email protected]. 
Respondents interested in licensing will be required to submit an 
``Application for License to Public Health Service Inventions.'' An 
executed CDA will be required to receive copies of the patent 
applications.

FOR FURTHER INFORMATION CONTACT: Further details of this CRADA 
opportunity and statement of interest please contact Lili Portilla, 
M.P.A., Acting Director, Office of Policy, Communications and Strategic 
Alliances, National Center for Advancing Translational Sciences, NIH, 
6701 Democracy Blvd., Suite 900, Bethesda, MD 20892-4874; Telephone: 
(301) 402-0304; E-Mail: [email protected] or Dr. Krishnan Balakrishnan, 
Technology Transfer Manager, NCATS, Telephone: (301) 217-2336; Email: 
[email protected].

SUPPLEMENTARY INFORMATION: NIH seeks to ensure that technologies 
developed by NIH are expeditiously commercialized and brought to 
practical use. The purpose of a CRADA is to find a partner to 
facilitate the development and commercialization of a technology or 
small molecule compounds that are in an early phase of development. 
Respondents interested in submitting a CRADA proposal should be aware 
that it may be necessary for them to secure a patent license to the 
above-mentioned patent in order to be able to commercialize products 
arising from a CRADA. 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.
    Recombinant relaxin hormone has been extensively investigated for 
the treatment of acute heart failure and is currently in phase III 
clinical trials for this indication. Related to its antifibrotic role 
in pregnancy, relaxin appears to be unique in promoting the active 
remodeling of heart lesions. However, this remodeling capacity of the 
natural hormone is difficult to study in chronic settings due to the 
short half-life and the need for intravenous administration of the 
recombinant hormone. The clinically observed physiological effects of 
relaxin are mediated through its interaction with a G protein-coupled 
receptor (RXFP1) leading to the modulation of several signal 
transduction pathways. Activation of RXFP1 by relaxin induces (1) up-
regulation of the endothelin system which leads to vasodilation; (2) 
extracellular matrix remodeling through regulation of collagen 
deposition, MMPs and TIMPs expression, and overall tissue homeostasis; 
(3) a moderation of inflammation by reducing levels of inflammatory 
cytokines, such as TNF-[beta] and TGF-[beta]; and, (4) angiogenesis by 
activating transcription of VEGF. The development of small-molecule 
agonists of RXFP1 would have numerous benefits and will allow 
investigating additional therapeutic applications where chronic 
administration is required. NCATS has identified a series of small-
molecule agonists of RXFP1 which are potent, highly selective, easy to 
synthesize, and with reasonable metabolic and physical properties. Our 
molecules display similar efficacy as the natural hormone in several 
functional assays. Mutagenesis studies have mapped the specific regions 
responsible for relaxin receptor activation by these compounds to an 
allosteric site on the receptor. Finally, these compounds display good 
in vivo pharmacokinetic properties and are currently being evaluated in 
vivo.
    Under the CRADA, further in vitro and in vivo ADME and activity 
studies will be conducted on current and new small molecule leads, 
using rodent and non-rodent species. Pharmacokinetics and PEP image 
studies in monkey are on-going to better characterize compound tissue 
distribution. But further in vivo characterization of select compounds 
is needed and will be part of the CRADA program. Based on the results 
of these experiments and other data, the program will then develop a 
target product profile. The chemical series might be further improved 
to address specific aspects of this target product profile and, if 
necessary, to optimize its physical properties and formulation. The 
CRADA scope will also include studies beyond candidate selection 
including all aspects of pre-clinical studies such as toxicity studies, 
and chemistry GMP scale up of select compound(s) and manufacture of 
controls leading to a successful IND application. Collaborators should 
have experience in the pre-clinical development of small molecules and 
with the successful submission of IND applications to the FDA for 
cardiovascular and/or fibrotic diseases.
    The full CRADA proposal should include a capability statement with 
a detailed description of (1) Collaborators' chemistry expertise in the 
area of modulation of small molecule physical properties and 
formulation of small molecules, and their ability to manufacture 
sufficient quantities of chemical compounds according to FDA guidelines 
and under GMP; (2) expertise with cardiovascular and/or fibrotic 
diseases; (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 molecule 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.

Publications

    1. ``Identification of small molecule agonists of the relaxin 1 
receptor by utilizing a homogenous cell-based cAMP assay,'' Chen CZ, 
Southall N, Xiao J, Marugan JJ, Ferrer M, Agoulnik A, Zheng W, 
Journal Biomolecular Screening, Accepted.
    2. Identification and optimization of small molecule agonists of 
the relaxin hormone receptor RXFP1,'' Xiao J, Chen CZ, Huang Z, 
Agoulnik IU, Ferrer M, Southall N, Hu X, Zheng W, Agoulnik AI, and 
Marugan JJ, Nature-Communications, Submitted.

Patent Status:

    ``Modulators of the Relaxin receptor 1'', Marugan JJ, Xiao J, 
Ferrer M, Chen CZ, Southall N, Zheng W, Agoulnik A, Agoulnik IU, 
U.S. Patent Application  61/642,986, NIH Reference 
 E-072-2012/0-US-1.


[[Page 8546]]


    Dated: January 30, 2013.
Christopher P. Austin,
Director, National Center for Advancing Translational Sciences, 
National Institutes of Health.
[FR Doc. 2013-02611 Filed 2-5-13; 8:45 am]
BILLING CODE 4140-01-P