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A Novel Gyrase Inhibitor for the Treatment of Drug-susceptible and Multidrug-resistant Mycobacterium tuberculosis Infections

Award Number: R44AI131749
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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A Novel Gyrase Inhibitor for the Treatment of Drug-susceptible and Multidrug-resistant Mycobacterium tuberculosis Infections - ABSTRACT Tuberculosis (TB), caused by the bacterial pathogen Mycobacterium tuberculosis (Mtb), remains a leading cause of death in the world today despite the availability of therapeutic drugs for more than sixty years. The disease also exacts a significant economic toll in countries where it is prevalent, often in poorer areas of the world. Multidrug-resistant TB (MDR-TB and XDR-TB) is an increasing problem, with nearly one half million cases worldwide per year, adding to the difficulty of controlling this disease. Therefore, effective new drugs, with novel mechanisms of action that can be included in treatment regimens for both drug-susceptible and MDR-TB are urgently needed. Spero Therapeutics has in- licensed SPR720, formerly Vertex VXc-486, an inhibitor of the B subunit (GyrB) ATPase activity of the essential DNA replication gyrase enzyme, that possesses excellent in vitro anti-mycobacterial activity and in vivo efficacy in mouse models of TB infection. GyrB ATPase represents a relatively naïve drug target and, therefore, pre-existing resistance to drugs against this target should be rare in patients. The scope of this application includes additional mouse infection model studies to assess treatment efficacy when SPR720 is included in drug regimens that contain an increased dose level of rifampin for drug-susceptible TB and in combinations with existing standard-of-care drugs used for MDR-TB. For the former, a goal in this proposal is to shorten the duration of treatment while for MDR-TB, goals are to identify new drugs to replace those to which isolates are no longer susceptible and also hopefully shorten duration of treatment. Additional profiling of SPR720 indicated favorable drug-like properties including good pharmacokinetics (PK) in multiple animal species, no significant off-target or cytotoxic findings, and no significant toxicities in non-GLP studies in two animal species. In this proposal, we will also work to improve the oral drug formulation as well as assess toxicity in a six-month rat GLP toxicity model in anticipation of future human dosing regimens. In parallel, outside of the scope of this proposal, Spero will run additional studies to complete a full IND-enabling package with an IND filing planned in 2017. Based on the microbiology results and other strong preclinical data to date, Spero believes that this compound is poised for rapid progression into the clinic as a new agent to treat mycobacterial infections and is committed to progressing this compound through full clinical development and entry into the marketplace.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2020 ( Subtotal = -$158 )
2020	2018	SPERO LEGACY STI, INC	675 MASSACHUSETTS AVE STE 14	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	2	4/22/2020	NON-COMPETING CONTINUATION	-$158
														Subtotal = -$158

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	SPERO LEGACY STI, INC	675 MASSACHUSETTS AVE STE 14	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	2	11/1/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $425,178 )
2018	2018	SPERO LEGACY STI, INC	675 MASSACHUSETTS AVE STE 14	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	2	2/23/2018	NON-COMPETING CONTINUATION	$425,178
														Subtotal = $425,178

Issue Date FY: 2017 ( Subtotal = $564,718 )
2017	2017	SPERO THERAPEUTICS, INC.	675 MASSACHUSETTS AVE STE 14	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	1	2/22/2017	NEW	$564,718
														Subtotal = $564,718

Grand Total All Awards = $989,738

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A Novel Gyrase Inhibitor for the Treatment of Drug-susceptible and Multidrug-resistant Mycobacterium tuberculosis Infections

Award Number: R44AI131749

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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