NIH grant: A Novel Water-Soluble, Orally-Active Peptide Therapeutic for Interstitial Lung Disease Derived from the Caveolin-1 Scaffolding Domain (1R44HL186828-01)

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NIH grant 1R44HL186828-01: A Novel Water-Soluble, Orally-Active Peptide Therapeutic for Interstitial Lung Disease Derived from the Caveolin-1 Scaffolding Domain
Institute: {'code': 'HL', 'abbreviation': 'NHLBI', 'name': 'National Heart Lung and Blood Institute', 'admin_org_id': '12500068', 'admin_funding_url': ''}. PI: STANLEY R HOFFMAN. Award: $920624.
Start: 2026-09-05T00:00:00.
Abstract
Our long-term goal is to fill the unmet need for treatments for Interstitial Lung Diseases (ILD). Caveolin-1 is a
promising therapeutic target in fibrotic diseases. The profibrotic effects of caveolin-1 deficiency in cells and
mouse models are suppressed by a peptide equivalent to its active site (caveolin-1 scaffolding domain, CSD).
We showed the beneficial effects of CSD using models for lung, skin, heart, and kidney fibrosis. CSD almost
completely blocks the dramatic increases in fibrosis, microvascular leakage, inflammatory cell infiltration, and
organ function deficits in these models. Pathological changes in otherwise untreated aged mice are also
reversed by CSD. Thus, CSD can reverse pre-existing disease. However, CSD lacks key pharmacologic
properties for drug development. In successful feasibility studies, we undertook rational steps (devising CSD
fragments, making them water soluble, comparing their efficacy) to select a Lead Compound (W94-101). Both
subcutaneous (sc) and oral W94-101 delivery were effective in mouse disease models. Our Lead Compound
selection and demonstration of oral efficacy puts us in strong position to successfully perform the next logical
steps in W94-101 drug development. Aim 1: Efficacy Studies:1a) Mouse Model Systems of ILD. We will
determine the minimum beneficial dose of W94-101 via both sc and oral delivery using two mouse model
systems. Lung Function and Thriftiness (a measure of well-being) will be the Primary Readouts. The use of
non-terminal Lung Function assays will allow us to show that the beneficial effects of W94-101 on Lung
Function and Thriftiness occur in parallel. 1b) Use of human fibrotic lung tissue. A well-characterized ex vivo
culture model (to detect W94-101’s inhibition of pre-existing Col I overproduction) will be used. Aim 2: Labcorp
Studies: 2a) Select Delivery Route for IND-enabling studies in animals. LabCorp, a leading CRO, will first
perform standalone pharmacokinetic (PK) studies comparing sc and oral delivery of W94-101 to determine
circulating exposure levels. These data, along with the efficacy dose dependence data (Aim 1a), will indicate
the best delivery route for drug development. If each route provides equal exposure levels and efficacy, we will
select oral delivery as it provides the best compliance in human patients. 2b) IND-enabling Studies. Prior to
clinical trials, IND-enabling studies must be completed: toxicology and safety, PK and stability, and ADME
(absorption, distribution, metabolism, excretion). In rat and dog studies, W94-101 will be delivered via the route
determined in Aim 2a. Results meeting industry standards will establish W94-101’s safety profile and
tolerability and provide a safety margin for use in humans while demonstrating sufficient pharmacological
activity to justify clinical trials. In the future, to prepare for clinical trials we will recruit investors and industry
partners, obtain SBIR Phase IIB funding, complete IND-enabling studies, choose a vendor for W94-101 cGMP
synthesis, and develop a regulatory strategy to prepare for an FDA meeting by the end of Phase IIB.

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