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.