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

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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.