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A Randomized Phase 2A Clinical Trial Pioneering the Utility of an eNAMPT-Reducing Therapy in ARDS/VILI: the PUERTA Trial

Award Number: R44HL145930
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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A Randomized Phase 2A Clinical Trial Pioneering the Utility of an eNAMPT-Reducing Therapy in ARDS/VILI: the PUERTA Trial - ABSTRACT The serious unmet need to address the excessive mortality observed in patients with Acute Respiratory Distress Syndrome (ARDS) has been brought sharply into focus by the current COVID-19 pandemic. In this R-44 application, Aqualung Therapeutics will address this therapeutic gap by utilizing a novel, humanized monoclonal antibody, ALT-100 mAb, which binds/neutralizes a novel ARDS target, eNAMPT (extracellular nicotinamide phosphoribosyltransferase), to reduce ARDS/VILI severity. We have shown that eNAMPT functions as a DAMP (tissue damage-associated molecular pattern) that binds Toll-like receptor 4 (TLR4) to elicit profound NFkB- driven inflammation, processes we have shown to be involved in pathobiology of ARDS and mechanical ventilator-induced lung injury (VILI). Importantly, we demonstrated that eNAMPT is a highly druggable ARDS target with the ALT-100 mAb profoundly attenuating the cytokine storm and inflammatory lung injury in preclinical models of ARDS/VILI including a porcine model of septic shock-induced ARDS/VILI. We completed GLP IND-enabling pharmacokinetic (PK) studies (T1/2 half-life of 12-14 days) and toxicity studies (rats/pigs) which failed to identify any discernable level of toxicity even up to 50 mg/kg of ALT-100 mAb (28 day study). Importantly, we have completed CMC and a 200L cGMP Bioreactor run (expression 6 gms/L) generating sufficient mAb for completion of a first-in-human (FIH) Phase 1A safety ascending dose study clinical trial in healthy volunteers (beginning June 2022) and the Phase 2 A safety/efficacy study called PUERTA (Pioneering the Utility of eNAMPT-Reducing Therapies in ARDS/VILI) in ARDS subjects with sepsis, septic shock, trauma, bacterial or viral pneumonia, or COVID-19 infection. We anticipate FDA Investigational New Drug approval in Q2 2022 for the ALT-100 mAb as an ARDS therapeutic intervention. This R-44 award will support the PUERTA P2A trial of ALT-100 mAb in 90 severely hypoxemic subjects (2:1, ALT-100:placebo) with the diagnosis of moderate-to-severe ARDS (P/F <200) who are immediately treated with mechanical ventilation (MV), with high flow nasal O2 (HFNO) or non-invasive ventilation (NIV i.e. BIPAP/CPAP). SA #1 will assess safety, tolerability, and PK of ALT-100 mAb at 2 dose levels (1mg/kg or 4 mg/kg) compared to placebo. SA #2 will assess the capacity for ALT-100 mAb to reduce ventilator requirements (# ventilator-free days), the incidence of multi-organ failure (MOF), the need for MV in HFNO/NIV-treated ARDS subjects, and reductions in plasma cytokines i.e. pharmacodynamic effects [PD] SA #3 will assess predictive capacity of plasma eNAMPT levels and NAMPT SNPs in identifying PUERTA subjects who respond to single dose treatment with ALT-100. The R-44 PUERTA trial, overseen by our CRO, Prevail Infoworks and conducted at 5 academic clinical sites, will directly address the unmet need for novel ARDS therapies and confirm eNAMPT as a highly druggable therapeutic target for ARDS. Successful achievement of R-44 milestones will lead to further investigation of ALT-100 mAb in larger pivotal P2b/P3 studies to determine efficacy of treatment with ALT-100 mAb to reduce ARDS/VILI mortality.


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 = -$185,221 )
2026	2024	AQUALUNG THERAPEUTICS, CORP	450 OCEAN DR APT 1205	JUNO BEACH	FL	33408	PALM BEACH	USA	Lung Diseases Research	000	5	3/20/2026	NON-COMPETING CONTINUATION	-$185,221
														Subtotal = -$185,221

Issue Date FY: 2025 ( Subtotal = -$542,406 )
2025	2024	AQUALUNG THERAPEUTICS, CORP	450 OCEAN DR APT 1205	JUNO BEACH	FL	33408	PALM BEACH	USA	Lung Diseases Research	000	5	5/13/2025	NON-COMPETING CONTINUATION	-$542,406
														Subtotal = -$542,406

Issue Date FY: 2024 ( Subtotal = $1,500,000 )
2024	2024	AQUALUNG THERAPEUTICS, CORP	450 OCEAN DR APT 1205	JUNO BEACH	FL	33408	PALM BEACH	USA	Lung Diseases Research	000	5	9/11/2024	NON-COMPETING CONTINUATION	$1,500,000
														Subtotal = $1,500,000

Issue Date FY: 2023 ( Subtotal = $1,500,000 )
2023	2023	AQUALUNG THERAPEUTICS, CORP	450 OCEAN DR APT 1205	JUNO BEACH	FL	33408	PALM BEACH	USA	Lung Diseases Research	000	4	9/8/2023	COMPETING CONTINUATION	$1,500,000
														Subtotal = $1,500,000

Grand Total All Awards = $2,272,373

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A Randomized Phase 2A Clinical Trial Pioneering the Utility of an eNAMPT-Reducing Therapy in ARDS/VILI: the PUERTA Trial

Award Number: R44HL145930

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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