Pulmonary arterial hypertension (PAH) is a fatal disease (without curative therapies) that is critically influencedby dysregulated inflammatory pathways. This A1 R42 Fast Track STTR application focuses on eNAMPT (extra-cellular nicotinamide phosphoribosyltransferase) as a novel, highly attractive PAH target. Aqualung Therapeuticshas developed a humanized eNAMPT-neutralizing mAb, ALT-100, to address the unmet need for therapies thatimprove right ventricular (RV) dysfunction/failure and PAH survival. Circulating eNAMPT is a damage-associ-ated molecular pattern protein (DAMP) that robustly activates innate immunity-driven inflammatory pathwaysvia ligation of the Toll-like receptor 4 (TLR4). Our published/unpublished data strongly support involvement ofeNAMPT in the pathobiology of human PH. First, we have reported that NAMPT RNA and protein expressionand secretion are significantly increased in PBMCs and in remodeled lung vessels from PAH patients with theseprocesses highly upregulated by PAH-relevant stimuli, including growth factors and hypoxia via HIF-2α signaling.Second, plasma eNAMPT levels are elevated and correlate with RV dysfunction in PAH subjects. Thirdly,NAMPT polymorphisms (SNPs), previously linked to inflammatory severity including ARDS mortality, are asso-ciated with PAH severity, including cardiac catherization indices of RV dysfunction in a large PAH GWAS. Lastly,we have compellingly demonstrated that eNAMPT is a highly druggable target, with the eNAMPT-neutralizingmAb, ALT-100, profoundly attenuating and reversing preclinical PAH vascular remodeling and indices of RVheart failure. Supporting the feasibility of ALT-100 as a PAH therapy, we have completed non-IND-enablingpharmacokinetic (PK) studies demonstrating that IV-delivered ALT-100 mAb exhibits a T1/2 half-life of 12-14 daysand 28-day toxicity studies in rats demonstrated that up to 50 mg/kg of ALT-100 is without discernable toxicity.We have completed stable cell line development, generated both Research and Master Cell Banks, and havecompleted a 200L GMP Bioreactor run (expression 6 gms/L); a titer assuring very low Cost of Goods and marketentry at a low price point. ALT-100's acute IND-enabling studies for the indication of ARDS will to be completedby November 2021, again facilitating a successful FDA IND application for PAH. STTR PHASE I is designed tooptimize route of delivery (SubQ vs IM) and dosing of ALT-100 mAb and further validate ALT-100 as an effectivestrategy in two preclinical PAH rat models (monocrotaline, hypoxia/Sugen) (SA #1). We will provide proof-of-concept genomic data validating ALT-100 targeting of the eNAMPT/TLR4 pathway in rat lung tissues and PBMCsas the mechanism by which ALT-100 significantly halts PAH progression and potentially reverses the severity ofPAH (SA #2). PHASE II studies conducted in rats and minipigs will characterize the PK and pharmacodynamic(PD) characteristics of the ALT-100 mAb (SA #3) and ALT-100 toxicokinetic properties (SA #4). Successfulcompletion of these PHASE I/ II STTR studies will enable submission of an FDA IND application whose approvalwill allow rapid movement to conducting PAH clinical trials that address the significant unmet need in PAH.
Public Health Relevance Statement: PUBLIC HEALTH RELEVANCE - NARRATIVE
Pulmonary Arterial Hypertension is a debilitating often fatal disease without a cure, a serious unmet need. The
inflammatory protein, eNAMPT (extracellular nicotinamide phosphoribosyltransferase), is a key driver of
unchecked inflammation and a highly novel therapeutic target and candidate gene in PAH. Our Phase I/II goals
are to validate and optimize the eNAMPT- neutralizing humanized mAb, ALT-100, as a therapeutic strategy for
PAH, and to complete IND-enabling studies that will facilitate ALT-100 development in human PAH trials.
Project Terms: | | | 