# Preclinical Development of a Novel eNAMPT-Neutralizing mAb for Pulmonary Hypertension

> **NIH NIH R42** · AQUALUNG THERAPEUTICS CORP. · 2022 · $259,613

## Abstract

ABSTRACT
Pulmonary arterial hypertension (PAH) is a fatal disease (without curative therapies) that is critically influenced
by 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 Therapeutics
has developed a humanized eNAMPT-neutralizing mAb, ALT-100, to address the unmet need for therapies that
improve 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 pathways
via ligation of the Toll-like receptor 4 (TLR4). Our published/unpublished data strongly support involvement of
eNAMPT in the pathobiology of human PH. First, we have reported that NAMPT RNA and protein expression
and secretion are significantly increased in PBMCs and in remodeled lung vessels from PAH patients with these
processes 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-neutralizing
mAb, ALT-100, profoundly attenuating and reversing preclinical PAH vascular remodeling and indices of RV
heart failure. Supporting the feasibility of ALT-100 as a PAH therapy, we have completed non-IND-enabling
pharmacokinetic (PK) studies demonstrating that IV-delivered ALT-100 mAb exhibits a T1/2 half-life of 12-14 days
and 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 have
completed a 200L GMP Bioreactor run (expression 6 gms/L); a titer assuring very low Cost of Goods and market
entry at a low price point. ALT-100’s acute IND-enabling studies for the indication of ARDS will to be completed
by November 2021, again facilitating a successful FDA IND application for PAH. STTR PHASE I is designed to
optimize route of delivery (SubQ vs IM) and dosing of ALT-100 mAb and further validate ALT-100 as an effective
strategy 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 PBMCs
as the mechanism by which ALT-100 significantly halts PAH progression and potentially reverses the severity of
PAH (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...

## Key facts

- **NIH application ID:** 10489982
- **Project number:** 1R42HL164300-01
- **Recipient organization:** AQUALUNG THERAPEUTICS CORP.
- **Principal Investigator:** Joe G. N. Garcia
- **Activity code:** R42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $259,613
- **Award type:** 1
- **Project period:** 2022-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10489982

## Citation

> US National Institutes of Health, RePORTER application 10489982, Preclinical Development of a Novel eNAMPT-Neutralizing mAb for Pulmonary Hypertension (1R42HL164300-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10489982. Licensed CC0.

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