Strategies for fibrosis resolution

Regenerative Macrophage Therapy: targeting chronic inflammation and fibrosis with a multimodal approach

Lara Campana, SVP and Co-Founder, Resolution Therapeutics

Abstract: Chronic inflammatory diseases with a fibrotic component are on the rise, and collectively are characterised by chronic damage, which fuels a chronic inflammatory response. In turn, the chronic inflammatory response is responsible for excessive extracellular matrix (ECM) deposition and insufficient ECM turnover. Examples of such conditions are interstitial lung disease (ILD), end-stage liver disease (ESLD) and chronic kidney disease. Thus far, these diseases have been characterised by poor clinical outcomes, compounded by scarcity of available medical therapies, and key limitations of surgical therapies such as solid organ transplantation (e.g., organ shortage, complexity of the surgery and need for lifelong immunosuppression). Macrophages with a regenerative phenotype display anti-inflammatory and anti-fibrotic properties, which drive organ regeneration, positioning them as ideal therapeutics for patients with chronic fibro-inflammatory diseases. In fact, ESLD is a disease where the dysfunctional microenvironment has continuously hampered attempts at replacement cell therapy using hepatocytes. Subverting the therapeutic hypothesis, Regenerative Macrophage Therapy (RMT) aims to correct the dysfunctional microenvironment, thereby allowing the remaining hepatocytes to restore some of the metabolic function of the damaged liver. Resolution Therapeutics has developed an autologous RMT platform to target inflammatory and fibrotic conditions, and it is targeting ESLD as its first indication. To increase the anti-inflammatory and anti-fibrotic properties required for treating this population, IL10 and MMP9 were selected as payloads to engineer our first regenerative macrophage asset, RTX001. Payloads were selected following screening of candidate payloads with the potential to enhance its anti-inflammatory and anti-fibrotic mechanism of action (MoA)5,6. In this presentation, we will outline our strategy for testing of safety, biodistribution and pharmacology of RTX001 in preclinical models, with a particular focus on the importance of measuring systemic markers of MoA. Safety and biodistribution studies in immunocompromised models were key to receive approval for the initiation of EMERALD, a Phase 1/2 study testing a multi dose regime of autologous RTX001 in patients with ESLD. Pharmacology studies in immunocompetent models will be key to support MoA plausibility for Phase 3/pivotal filings, and they are also key to provide scientific plausibility to our potency assay strategy. We were able to conduct preclinical pharmacology studies utilising immunocompetent CDAA-HFD models thanks to the development of a mouse (m)RTX001 surrogate. In these models, mRTX001 was effective after a single dose at reducing fibrosis, local and systemic inflammation, thus confirming MoA from in vitro studies. In conclusion, our data show that well-planned studies are necessary to show safety, biodistribution and pharmacology of multimodal RMTs such as RTX001. The data obtained showed that RTX001 is poised to be well-tolerated and to deliver clinical benefit in patients with ESLD. Interim analyses of the Phase 1/2 EMERALD study are expected in Q3 2026 and Q1 2027. Further preclinical studies will be conducted to show whether RMT can be utilised therapeutically in models of other fibroinflammatory diseases with similar pathogenesis as ESLD, such as lung fibrosis.

Targeting CCN proteins: Navigating the balance between antifibrotic efficacy and clinical tolerability

Ole J. Kaasboell, Co-founder and CSO, Tribune Therapeutics

Abstract: CCN family members CCN1, CCN2, and CCN4 are established drivers of fibrosis. Among emerging targets, CCN2—previously known as connective tissue growth factor (CTGF)—is notable because multiple clinical studies have demonstrated that its inhibition can reduce human fibrosis. Because CCN proteins play vital roles during embryogenesis but are minimally active in healthy adults, therapeutic targeting of this pathway is expected to be a highly tolerated intervention.

Tribune Therapeutics is advancing TRX-44, a first-in-class albumin fusion designed to mimic CCN5, the endogenous anti-fibrotic member of the CCN family. Primate PK studies confirm no signs of target-mediated drug disposition, supporting a predictable therapeutic window. Its favorable safety profile is further supported by GLP toxicology studies in rats and monkeys, which showed no dose-related toxicities.

Antifibrotic activity is robustly validated in high-fidelity IPF patient-derived models, including airway basal cell-derived bronchospheres and precision-cut lung slices. In these systems, TRX-44 drives concentration-dependent displacement of pro-fibrotic ligands and reduces soluble osteopontin, a biomarker of prognosis in IPF.

The clinical transition of TRX-44 is supported by a PD biomarker strategy aimed at exploiting several facets of CCN biology. The presentation will share key data from Tribune’s work developing PD biomarkers to support the clinical transition of TRX-44.

Lanifibranor a pan-PPAR agonist in MASH: Vascular and fibrotic remodeling

Guillaume Wettstein, Head of translational science, Inventiva Pharma

Abstract: Lanifibranor is a pan-peroxisome proliferator-activated receptor (pan-PPAR α/δ/γ) agonist under phase III clinical development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). Its therapeutic potential is largely attributed to its metabolic, anti-inflammatory, and anti-fibrotic properties. For the first time in phase 2 trial a MASH asset has hit on both endpoints- resolution of MASH without worsening of fibrosis and Improvement of fibrosis without worsening of MASH. Moreover, it is only lanifibranor that has statistically significant benefit on fibrosis at 6 months.

Fibrosis progression in MASH, is driven by sustained hepatic lipotoxicity, chronic inflammation, and stellate cell activation and can ultimately lead to cirrhosis, with extensive tissue remodelling, architectural distortion, and the development of portal hypertension (PH). Lanifibranor has been designed to target the 3 PPAR isoform in a moderate and balanced manner to address the core pathophysiological drivers of disease progression namely lipid dysregulation, Insulin resistance, inflammatory signalling, and fibrogenesis.

PH and cirrhotic remodeling in MASH are not driven by a single pathway but by the convergence of three interconnected processes: progressive fibrogenesis mediated by activated hepatic stellate cells (HSCs), sinusoidal capillarization reflecting loss of normal liver sinusoidal endothelial cell (LSEC) phenotype, and extrahepatic vascular dysfunction characterized by splanchnic vasodilation and pathological angiogenesis. Lanifibranor’s pan-PPAR agonism, spanning all three isoforms, positions it to act on each of these drivers simultaneously providing a mechanistic basis for lanifibranor’s potential to modify the trajectory of compensated Advanced Chronic liver Disease (cACLD) due to MASH.