loading
loading
NIH grant 1R44HL184806-01: Development of a Novel Integrin Antagonist for the Treatment of Pulmonary Hypertension
Institute: {'code': 'HL', 'abbreviation': 'NHLBI', 'name': 'National Heart Lung and Blood Institute', 'admin_org_id': '12500068', 'admin_funding_url': ''}. PI: John Cavin Kraft. Award: $605981.
Start: 2026-09-05T00:00:00.
PROJECT SUMMARY/ABSTRACT
The long-term goal of this project is to develop a long-acting injectable (LAI) α5β1 integrin inhibitor therapy for
Pulmonary Arterial Hypertension (PAH; Group 1 PH) and/or Pulmonary Hypertension associated with
Idiopathic Pulmonary Fibrosis (IPF-PH; Group 3 PH). Although several symptom-relieving PAH therapies are
marketed, only sotatercept is a potentially disease-modifying PAH therapy, however sotatercept does not
improve cardiac output (CO). PAH remains life-limiting and mortality is high with a 5-year survival rate of ~57%.
Sotatercept’s inability to improve CO, lack of anti-fibrotic activity, and unclear long-term safety profile in PAH
patients are key limitations. For IPF-PH patients (Group 3 PH), treprostinil, a vasodilator, is the only approved
therapy and mortality is still exceptionally high with a 5-year survival rate of ~23%. Therefore, there is a high
unmet medical need for more effective disease-modifying therapies for both PAH and IPF-PH. Accumulating
evidence suggests the α5β1 integrin is a pivotal driver of PH pathology, and α5β1 is emerging as a novel
therapeutic target for PH with disease modifying potential. In lung and heart cells from PAH patients, α5β1 is
upregulated. Blockade of α5β1 inhibited the pro-proliferative and apoptosis-resistant phenotype of Group 1 and
3 PH patient pulmonary arterial smooth muscle cells (PASMCs) and precision-cut lung slices (PCLS). In the
gold-standard Sugen/hypoxia rat PAH model, α5β1 blockade improved CO and had anti-fibrotic activity, unlike
with treatment with the rodent sotatercept analog (RAP-011). Thus, α5β1 inhibition has potential as a novel
disease-modifying therapeutic approach for both Group 1 and 3 PH patients. Lila Biologics has developed
LILA-003, a potent and highly selective de novo α5β1 miniprotein inhibitor that reduces the pro-proliferative
and apoptosis-resistant phenotype of PASMCs from both Group 1 and 3 PH patients. In addition, Lila has
developed technology to extend the plasma half-life of proteins for long acting injectables (LAIs) that allow
infrequent subcutaneous (SC) injection, with projected monthly human dosing based on non-human primate
(NHP) pharmacokinetics (PK). The overall objective of this current application is to demonstrate that Lila’s
anti-α5β1 LAI has disease-modifying activity in the Sugen/hypoxia PAH rat model and ex vivo organotypic lung
slices from Group 1 and 3 PH patients, and to conduct IND-enabling toxicology studies. In Phase I, we will: 1)
Optimize cross-species cell-based potency of α5β1 inhibitor candidates, 2) Optimize α5β1 inhibitor PK
in transgenic mice with hFcRn receptors & NHPs to support LAI human PK, and 3) Demonstrate in vivo
efficacy in a rat Sugen/hypoxia PAH model. In Phase II, we will: 1) Demonstrate ex vivo efficacy in Group
1 & 3 PH patient PCLS, 2) Develop/optimize cell lines for manufacture of material to support
IND-enabling toxicology, and 3) Complete IND-enabling toxicology studies in rats & NHPs. Overall, this
work will help preclinically develop the first anti-α5β1 LAI, which could significantly improve the lives of tens of
thousands of patients suffering from PH through its novel disease-modifying activity.document fetched 2026-09-13 02:45