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Targeting the eNAMPT/TLR4 pathway to reduce Inflammatory Bowel Disease severity

Award Number: R42DK135208
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/19/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Targeting the eNAMPT/TLR4 pathway to reduce Inflammatory Bowel Disease severity - ABSTRACT Inflammatory bowel disease (IBD) is a debilitating disease (without curative therapies) that is critically influenced by dysregulated inflammatory pathways. This A0 R42 STTR application focuses on a highly novel humanized monoclonal antibody (mAb), ALT-100, to target and neutralize eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a damage-associated molecular pattern protein (DAMP) that robustly activates innate immunity-driven inflammatory pathways via ligation of the Toll-like receptor 4 (TLR4). We speculate the eNAMPT-neutralizing ALT-100 mAb to be a strategy to address the unmet need for therapies that limit inflammatory bowel injury/fibrosis and reduce the severity of IBD. Published and unpublished data strongly support involvement of eNAMPT in human IBD pathobiology. First, NAMPT RNA and protein expression are significantly increased in intestinal tissues from IBD patients and are highly upregulated by IBD-relevant stimuli including growth factors and cytokines. Second, plasma/serum eNAMPT levels are elevated in IBD subjects and correlate with disease severity and responses to anti-TNFa therapies. Thirdly, NAMPT polymorphisms (SNPs), previously linked to inflammatory disease severity in ARDS and pulmonary hypertension (PH), associate with IBD severity in GWAS studies. Lastly, compellingly published data demonstrate eNAMPT is a highly druggable target, with ALT-100 mAb profoundly attenuating multiple preclinical systemic inflammation/organ injuries (ARDS, PH, radiation-induced fibrosis, cancer). Importantly, ALT-100 mAb reduces preclinical IBD severity, colon inflammation and fibrosis. The feasibility of ALT-100 mAb as an IBD therapy is supported by completed acute IND-enabling pharmacokinetic (PK) studies and 28-day toxicity studies showing the IV ALT-100 mAb formulation has a T1/2 half-life of 10 days and is without discernable toxicity (rats and pigs). In addition, we have completed CMC manufacturing development (stable cell line, Research/Master Cell Banks) and a 200L GMP Bioreactor run (expression 6 gms/L) of the IV ALT-1000 mAb formulation (10mg/mL). We anticipate FDA IND submission for ARDS in May 2022. In PHASE I of this R-42 STTR PHASE I/II Fast Track application, Specific Aims #1/2 will assess pharmacodynamic (PD) properties of ALT-100 mAb in well-established acute (7 days) and chronic (28 days) preclinical DSS-induced murine colitis models and optimize ALT-100 mAb dosing (0.4 mg/kg, 1mg/kg, 4 mg/kg) and route of delivery (IV vs subQ) using IV formulations (10 mg/mL) and subQ formulations (100 mg/mL). In PHASE II studies conducted in rats and minipigs, Specific Aim #3 will characterize the pharmacokinetic (PK) characteristics of the subQ and IV ALT-100 mAb formulations and Specific Aim #4 will evaluate chronic subQ ALT-100 mAb toxicokinetic properties. Successful completion of these PHASE I/ II STTR studies will establish ALT-100 mAb as a viable IBD therapeutic and enable the submission of an FDA IND application to allow Aqualung to conduct IBD clinical trials that address ALT-100 mAb as a novel therapeutic to address the unmet needs in subjects with severe IBD, especially in subjects who fail biologic therapies.


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: 2026 ( Subtotal = -$97,663 )
2026	2024	AQUALUNG THERAPEUTICS, CORP	450 OCEAN DR APT 1205	JUNO BEACH	FL	33408	PALM BEACH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	12/10/2025	NON-COMPETING CONTINUATION	-$97,663
														Subtotal = -$97,663

Issue Date FY: 2024 ( Subtotal = $975,215 )
2024	2024	AQUALUNG THERAPEUTICS, CORP	450 OCEAN DR APT 1205	JUNO BEACH	FL	33408	PALM BEACH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	7/16/2024	NON-COMPETING CONTINUATION	$975,215
2024	2022	AQUALUNG THERAPEUTICS, CORP	450 OCEAN DR APT 1205	JUNO BEACH	FL	33408	PALM BEACH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/11/2024	NEW	$0
														Subtotal = $975,215

Issue Date FY: 2023 ( Subtotal = $975,215 )
2023	2023	AQUALUNG THERAPEUTICS, CORP	450 OCEAN DR APT 1205	JUNO BEACH	FL	33408	PALM BEACH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	8/15/2023	EXTENSION WITH OR WITHOUT FUNDS	$975,215
2023	2022	AQUALUNG THERAPEUTICS CORP.	1790 EAST RIVER #205	TUCSON	AZ	85718	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/27/2023	NEW	$0
														Subtotal = $975,215

Issue Date FY: 2022 ( Subtotal = $269,233 )
2022	2022	AQUALUNG THERAPEUTICS CORP.	1790 EAST RIVER #205	TUCSON	AZ	85718	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/19/2022	NEW	$269,233
														Subtotal = $269,233

Grand Total All Awards = $2,122,000

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Targeting the eNAMPT/TLR4 pathway to reduce Inflammatory Bowel Disease severity

Award Number: R42DK135208

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/19/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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