Description:
099 Inhalational 5A Apolipoprotein A-I Mimetic Peptide for the Treatment of Asthma (SBIR-TT)
Fast-Track proposals will be accepted.
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Direct-to-Phase II proposals will not be accepted.
Number of anticipated awards: 2
Budget (total costs):
Phase I: up to $225,000 for up to 12 months
Phase II: up to $1,500,000 for up to 24 months
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Summary
New treatments are needed for severe asthmatics who do not respond to standard therapy with inhaled steroids, especially those with a “type 2 low” phenotype, such as individuals with neutrophil-predominant inflammation. This solicitation is for the development and early commercialization of an inhalational formulation of the 5A apolipoprotein A-I (apoA-I) mimetic peptide that can be administered to asthmatic subjects in Phase I clinical trials and subsequently developed into a new treatment for severe asthma.
ApoA-I is the major protein component of high-density lipoproteins, which mediates reverse cholesterol transport out of cells by interacting with the ATP-binding cassette subfamily member 1 (ABCA1). ApoA-I also has anti-inflammatory, anti-oxidant, and immunomodulatory properties. NHLBI investigators have shown that systemic administration of the 5A apoA-I mimetic peptide, which is a bi-helical peptide that recapitulates the α-helical structure of apoA-I and mediates reverse cholesterol transport out of cells by interacting with ABCA1, attenuates the induction of airway inflammation, mucous cell metaplasia, and airway hyperresponsiveness in house dust mite (HDM)-challenged mice. In addition, they have shown that apoA-I has a protective effect in allergic asthma. Apoa1-knockout mice, which were sensitized and challenged with ovalbumin (OVA), have increased neutrophilic airway inflammation that was primarily mediated by increased G-CSF expression, with associated increases in type 1 (IFN-γ, TNF-α) and Th17 (IL-17A) cytokines. The increased neutrophilic airway inflammation in the OVA-challenged Apoa1-knockout mice was inhibited by intranasal administration of the 5A apoA-I mimetic peptide. Lastly, serum apoA-I levels are positively correlated with FEV1 in atopic asthmatic subjects, which suggests that circulating apoA-I may improve airflow obstruction. These murine and human translational studies serve as the conceptual basis for developing the 5A apoA-I mimetic peptide into a novel inhalational treatment for severe asthma.
Project Goals
The overall goal of this project is to prepare, in both manufacturing processes and preclinical evaluation, an inhalational 5A apoA-I mimetic peptide that will be the subject of a future Investigational New Drug (IND) application to the US Food and Drug Administration (FDA) focused on the treatment of type 2 low phenotype asthma patients, such as those with neutrophil-predominant inflammation. Successful submission and allowance to proceed of the IND will enable the company to collaborate on the conduct of a clinical trial with intramural clinicians at the NIH Clinical Center, at the company’s discretion. During review, preference will be given to companies or teams with a demonstrated prior ability to successfully bring either a peptide therapeutic or an inhalational therapeutic to, at a minimum, Phase 1 clinical studies in the US.
Additional Project Information
This is an SBIR Technology Transfer (TT) contract topic from the NHLBI. This is a program whereby inventions from the NHLBI Division of Intramural Research (DIR) are licensed on an exclusive or non-exclusive basis to qualified small businesses with the intent that those businesses develop these inventions into commercial products that benefit the public. The contractor funded under this NHLBI SBIR TT contract topic shall work closely with the NHLBI inventor(s) of this technology, who will assist in pre-clinical experiments and will perform a clinical trial using the offeror’s product. The NHLBI inventor(s) will provide assistance in a collaborative manner with provision of 5A apoA-I mimetic peptide for SBIR Phase I comparability studies, experimental designs and techniques, clinical considerations, and discussions during the entire award period.
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An SBIR TT contractor will automatically be granted a royalty-free, non-exclusive license to make and use, but not to sell or offer to sell, for background inventions covered by the NIH-owned patent rights only within the scope and term of the award. However, an SBIR offeror or SBIR contractor can apply for an exclusive or non-exclusive commercialization license to make, use, and sell products or services incorporating the NIH background invention(s). Offerors submitting an SBIR contract proposal in response to this solicitation are strongly encouraged to concurrently submit an application for a commercialization license to such background invention(s). Under the NHLBI SBIR TT program, the SBIR contract award process will be conducted in parallel with, but separate from, the review of any applications for a commercialization license. The criteria to determine eligibility of an offeror to receive a commercialization license will depend on their technical eligibility to receive the SBIR award but will be assessed independently of the SBIR process.
To apply for a license to commercialize this NIH invention, an SBIR offeror or contractor must submit a license application to the NHLBI Licensing and Patenting Manager: Cristina Thalhammer-Reyero; thalhamc@nih.gov; (301) 435-4507. A license application and model license agreements are available at http://www.ott.nih.gov/sites/default/files/documents/pdfs/licapp.pdf and http://www.ott.nih.gov/forms-model-agreements#MLA
This license application provides NIH with information about the potential licensee, some of the terms desired, and the potential licensee's plans for development and/or commercialization of the invention. License applications will be treated in accordance with Federal patent licensing regulations as provided in 37 CFR Part 404. A further description of the NIH licensing process is available at http://www.ott.nih.gov/licensing-process. NIH will notify an SBIR offeror who has submitted an application for an exclusive commercialization license if another application for an exclusive license to the background invention is received at any time before such a license is granted.
NHLBI will share any unpublished patent applications with offerors subject to their agreement to the terms and execution of a confidential disclosure agreement.
Any invention developed by the contractor during the course of the NIH TT contract period of performance will be owned by the contractor subject to the terms of Section 5.5 Technical Data Rights in this Request For Proposals.
Relevant NIH Publications and Patent Applications
Sethi AA, Stonik JA, Thomas F, Demosky SJ, Amar M, Neufeld E, Brewer HB, Davidson WS, D'Souza W, Sviridov D, Remaley AT. Asymmetry in the lipid affinity of bihelical amphipathic peptides. A structural determinant for the specificity of ABCA1-dependent cholesterol efflux by peptides. J Biol Chem 2008;283:32273-32282. http://www.jbc.org/content/283/47/32273.long
Amar MJ, D’Souza W, Turner S, Demosky S, Sviridov D, Stonik J, Luchoomun J, Voogt J, Hellerstein M, Remaley AT. 5A apolipoprotein mimetic peptide promotes cholesterol efflux and reduces atherosclerosis in mice. J Pharmacol Exp Ther 2010;334:634-641. http://jpet.aspetjournals.org/content/334/2/634.long
Tabet F, Remaley AT, Segaliny AI, Millet J, Yan L, Nakhla S, Barter PJ, Rye KA, Lambert G. The 5A apolipoprotein A-I mimetic peptide displays anti-inflammatory and anti-oxidant properties in vivo and in vitro. Arterioscler Thromb Vasc Biol 2010;30:246-252. http://atvb.ahajournals.org/content/30/2/246.long
Yao X, Dai C, Fredriksson K, Dagur PK, McCoy JP, Qu X, Yu ZX, Keeran KJ, Zywicke GJ, Amar MJ, Remaley AT, Levine SJ. 5A, an apolipoprotein A-I mimetic peptide, attenuates the induction of house dust mite-induced asthma. J Immunol 2011;186:576-583. http://www.jimmunol.org/content/186/1/576.long
Dai C, Yao X, Keeran KJ, Zywicke GJ, Qu X, Yu ZX, Dagur PK, McCoy JP, Remaley AT, Levine SJ. Apolipoprotein A-I attenuates ovalbumin-induced neutrophilic airway inflammation via a granulocyte colony-stimulating factor-dependent mechanism. Am J Respir Cell Mol Biol 2012;47:186-195. http://www.atsjournals.org/doi/abs/10.1165/rcmb.2011-0322OC?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed#.Vusaa-nVtNE
Barochia AV, Kaler M, Cuento RA, Gordon EM, Weir NA, Sampson M, Fontana JR, MacDonald S, Moss J,
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Manganiello V, Remaley AT, Levine SJ. Serum apolipoprotein A-I and large high-density lipoprotein particles are positively correlated with FEV1 in atopic asthma. Am J Respir Crit Care Med 2015;191:990-1000. http://www.atsjournals.org/doi/abs/10.1164/rccm.201411-1990OC?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed#.VusakunVtNE
Issued Patents, expiring 10/14/2025: NIH Reference Number E-114-2004/0 (https://www.ott.nih.gov/technology/e-114-2004)
• US 7,572,771, issued August 11, 2009;
• US 8,071,746, issued December 6, 2011;
• US 8,148,323, issued April 3, 2012;
• EP 05815961.7, issued May 26, 2010;
• JP 2007-536912, issued September 21, 2012
Phase I Activities and Expected Deliverables
A Phase I award should be used to demonstrate that a comparable 5A apoA-I mimetic peptide can be synthesized and attenuate allergen-induced airway inflammation when administered by a pulmonary route in a pre-clinical asthma model.
The specific deliverables would be:
• Synthesis of a non-GMP grade 5A apoA-I mimetic peptide for comparability studies with the 5A peptide that was previously utilized by NHLBI investigators. NHLBI investigators can provide reference test material for comparability studies.
• Dose ranging animal studies will be performed to reproduce experiments showing that the 5A apoA-I mimetic peptide significantly suppresses house dust mite (HDM)-induced airway inflammation. Three doses of the 5A apoA-I mimetic peptide or control peptide, 0.1, 1, and 10 mg/kg, in 10 μl of saline, will be administered by pulmonary delivery, 5 days per week for 4 weeks and compared to an untreated group that receives pulmonary delivery of the vehicle alone (e.g., saline). Inhibition of airway inflammation in HDM-challenged mice by pulmonary delivery of the 5A apoA-I mimetic peptide will be assessed by quantifying the number of eosinophils in bronchoalveolar lavage fluid. A greater than 25% reduction will be considered significant. NHLBI investigators had previously sensitized and challenged A/J mice by intranasal instillation of 25 μg of HDM in 10 μl of saline, 5 days per week, for 4 weeks and concurrently administered either the 5A apoA-I mimetic peptide (1 mg/kg/day) or a control peptide (that represented the scrambled sequence of an apolipoprotein E mimetic peptide). The 5A apoA-I mimetic peptide should be delivered via a pulmonary route in the morning and the HDM should be administered in the afternoon. NHLBI investigators performed three independent experiments with 10 mice per group (J Immunology, 2011, 186: 576).
Phase II Activities and Expected Deliverables
A Phase II award should be used to develop an inhaled formulation of the 5A apoA-I mimetic peptide for future use in human clinical trials. In addition, the deliverables will include stability testing of the inhaled formulation of the 5A apoA-I mimetic peptide and early pre-clinical animal studies. These deliverables will initiate safety testing and regulatory development of an inhaled formulation of the 5A apoA-I mimetic peptide.
The specific deliverables would be:
• Generation and synthesis of an inhaled GMP formulation of both the 5A apoA-I mimetic peptide and control peptide.
• Development and validation of GLP-bioanalytical test methods for the inhaled formulation of the GMP-grade 5A apoA-I mimetic peptide.
• GLP stability testing of the inhaled formulation of the GMP-grade 5A apoA-I mimetic peptide. The awardee should have expertise in peptide chemistry and analysis and devise a plan that adequately assesses
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stability of the α-helical structure of the 5A apoA-I mimetic peptide, demonstrates that no chemical changes have occurred (e.g., hydrolysis, deamidation, oxidation, etc.), as well as performs cGMP release and serum stability assays.
• GLP toxicity studies to establish the NOAL (no observed adverse effect level) and MTD (maximum tolerated dose) of the inhaled 5A apoA-I mimetic peptide in the rat using GMP-grade 5A apoA-I mimetic peptide and appropriate controls (e.g., vehicle, control peptide).
• Acute GLP respiratory and systemic PK/TK studies in rats (males and females) using the GMP-grade 5A apoA-I mimetic peptide and appropriate controls (e.g., vehicle, control peptide).
• Daily repeat GLP dosing respiratory and systemic PK/TK studies in rats (male and female) using the GMP-grade 5A apoA-I mimetic peptide for a minimum of 14 days and appropriate controls (e.g., vehicle, control peptide).
• Generation of a development plan to support a successful IND application to the FDA for an inhaled formulation of the 5A apoA-I mimetic peptide. The development plan will address: (i) CMC manufacturing of the inhaled formulation of the 5A apoA-I mimetic peptide, (ii) pre-clinical studies, and (iii) Phase 1 clinical trials. The development plan will be discussed at a pre-IND meeting with the FDA and modified as necessary.
Offerors are encouraged to consider the NHLBI Phase IIB Bridge (http://1.usa.gov/1q9yTyP) and Phase IIB Small Market Award (http://1.usa.gov/1v0Wxn1) programs to support additional development beyond Phase II.
