Phase 2 candidates
The primary endpoint in most of the phase 2 trials is change in ppFVC capacity from baseline to week 24. The following investigative therapies are in phase 2 trials:
Bexotegrast (PLN-74809), an oral, small molecule, dual-selective inhibitor of alphav/beta6 and alphav/beta1 (NCT04396756).
BBT-877, described as a potent autotaxin (ATX) inhibitor, demonstrated its ability to inhibit lysophosphatidic acid (LPA) production by as much as 90 percent (NCT05483907).
CC-90001, an oral, once-daily c-Jun N-terminal kinases (JNK) inhibitor. JNKs have been implicated in the underlying mechanisms of fibrosis, including epithelial cell death, inflammation and polarization of profibrotic macrophages, fibroblast activation, and collagen production (NCT03142191).
C21 targets the underlying fibrosis in IPF by stimulating the protective arm of the renin-angiotensin system. It also has an upstream effect by promoting alveolar repair by which it can reduce fibrosis formation, stabilize disease, and increase lung capacity (NCT04533022).
CSL312 (garadacimab) is a humanized anti-FXIIa monoclonal antibody administrated intravenously (NCT05130970).
Cudetaxestat, a noncompetitive autotaxin inhibitor (NCT05373914).
Bersiposocin/DWN12088, an inhibitor of prolyl-tRNA synthetase 1 (PARS1), which is suspected to control the pathologic accumulation of collagen containing high amounts of proline in fibrotic diseases (NCT05389215).
ENV-101, a small-molecule inhibitor of the Hedgehog (Hh) signaling pathway, which plays a key role in IPF. This agent was originally developed to target Hh-driven cancers (NCT04968574).
GKT137831 (setanaxib) inhibits nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) isoforms. (NCT03865927).
HZN-825, a lysophosphatidic acid receptor 1 (LPAR1) antagonist. (NCT05032066)
Ifetroban, a potent and selective thromboxane-prostanoid receptor (TPr) antagonist, which exhibits a high affinity for TPr on platelets, vascular and airway smooth muscle, and fibroblasts, and lacks agonistic activity (NCT05571059).
INS018_055, a small-molecule, oral antifibrotic candidate notable for being the first entirely AI-generated drug to enter phase 2 trials. Trial enrollment started in October (NCT05975983, NCT05983920)
Jaktinib dihydrochloride monohydrate, an oral JAK1, JAK2, and JAK3 inhibitor (NCT04312594).
Leramistat, an anti–tumor necrosis factor (TNF) agent (NCT05951296).
LTP001, an oral, selectively deuterated form of pirfenidone designed to retain the antifibrotic and anti-inflammatory activity of pirfenidone with a differentiated pharmacokinetic profile (NCT05497284, NCT05321420).
ME-015 (suplatast tosilate) aims to stabilize ion channels in the neuronal endings in the lungs that mediate IPF-related cough (NCT05983471).
Nalbuphine, a small-molecule, dual-mechanism treatment for chronic cough in IPF. It acts as both a mu opioid receptor antagonist and a kappa opioid receptor agonist (NCT05964335). The CANAL trial, complete last year, is evaluating an extended-release formulation (NCT04030026).
NP-120 (ifenprodil), a small-molecule N-methyl-D-aspartate (NMDA) receptor antagonist, specifically targets the NMDA-type subunit 2B (GluN2B) (NCT04318704).
Orvepitant, a selective antagonist for the NK₁ receptor, is being evaluated to treat IPF-related cough (NCT05815089).
RXC007 (zelasudil), a Rho-associated coiled-coil–containing protein kinase 2 (ROCK2) selective inhibitor, was granted FDA orphan drug designation in August 2023 (NCT05570058).
Saracatinib, a selective Src kinase inhibitor originally developed for oncological indications (NCT04598919).
SHR-1906, an intravenous treatment, inhibits binding of a target protein to a variety of cytokines and growth factors, affects downstream signaling pathways, and reduces cell proliferation and migration (NCT05722964).
TTI-101, an oral, small-molecule inhibitor of signal transducer and activator of transcription (STAT3), which has been found to accumulate in the lungs of IPF patients (NCT05671835).
VAY736 (lanalumab), a BAFF-R inhibitor (NCT03287414).
Vixarelimab, a human monoclonal oncastatin M receptor beta antibody (NCT05785624).
Some investigative programs, however, didn’t make it out of phase 2. The trial evaluating inhaled GB0139, a selective functional antagonist of G-protein–coupled receptor 84, which plays a key role in fibrosis, failed to meet its primary endpoint (NCT03832946). Likewise, oral GLPG1205 failed to show a significant difference in FVC decline vs. placebo (NCT03725852). The program to develop SAR156597, also known as romilkimab, was halted (NCT02345070). ND-L02-s0201n, an siRNA oligonucleotide drug designed to inhibit heat shock protein 47 (HSP47), which regulates collagen synthesis and secretion that causes fibrosis, didn’t show the expected efficacy (NCT03538301).