Rationale: Idiopathic pulmonary fibrosis (IPF) is characterized by excessive deposition of type 1 collagen. 68Ga-CBP8, a type 1 collagen positron emission tomography (PET) probe, measures collagen accumulation and shows higher collagen deposition in patients with IPF. Bexotegrast (PLN-74809) is an oral, once-daily, dual-selective inhibitor of αvβ6 and αvβ1 integrins under late-stage evaluation for treatment of IPF. Objectives: Evaluate changes in type 1 collagen in the lungs of participants with IPF following treatment with bexotegrast. Methods: In this Phase 2 (NCT05621252), single-center, double-blind, placebo-controlled study, adults with IPF received bexotegrast 160mg or placebo for 12 weeks. Primary endpoint was the change in whole-lung standardized uptake value (SUV) of 68Ga-CBP8 PET. Changes in lung dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters, forced vital capacity (FVC), cough severity, and biomarkers of collagen synthesis and progressive disease were also assessed. Measurements and Main Results: Of 10 participants, 7 received bexotegrast and 3 placebo. At Week 12, mean change from baseline in top quartile of 68Ga-CBP8 whole-lung SUV was −1.2% with bexotegrast vs 6.6% with placebo; greatest mean changes were observed in subpleural lung regions in both groups (bexotegrast, −3.7%; placebo, 10.3%). DCE-MRI demonstrated numerically increased peak enhancement and faster contrast washout rate in bexotegrast-treated participants, suggesting improvements in lung microvasculature and decreased extravascular extracellular volume. Bexotegrast treatment resulted in numerical improvements in FVC, cough severity, and biomarker levels. Conclusions: The reduced uptake of 68Ga-CBP8 in the lungs of participants with IPF indicates an antifibrotic effect of bexotegrast, suggesting the potential for favorable lung remodeling.

Background: Overexpression of integrins αvβ6 and αvβ1 activates latent TGF-β in IPF. Bexotegrast (PLN-74809), an oral, once-daily, dual-selective inhibitor of αvβ6 and αvβ1, may provide a novel IPF treatment via localized TGF-β inhibition. Aims and objectives: Report long-term safety and tolerability, and durability of effects on FVC and fibrotic markers for bexotegrast 320 mg. Methods: Participants were randomized: bexotegrast 320 mg (n=21) or placebo (n=8) for at least 24 but less than 48 weeks. Primary endpoints: safety and tolerability. Exploratory endpoints: change in FVC and Quantitative Lung Fibrosis (QLF) score at Week 24. Results: No drug-related serious treatment-emergent adverse effects (TEAEs) occurred: most were mild and unrelated to study drug. The most common TEAE was diarrhea (31.8% bexotegrast, 37.5% placebo), mainly observed in participants on background therapy. No discontinuations occurred due to TEAEs after Week 12. Through Week 40, serious AEs (SAEs) occurred in 9.1% (bexotegrast) and 12.5% (placebo): one fatal SAE (bexotegrast) was unrelated to study drug (acute respiratory failure, following a cardiac ablation). FVC decline was reduced in bexotegrast-treated participants vs. placebo at Week 12, with 50% of participants on bexotegrast showing improvement at Week 24. 89% of bexotegrast participants with improvement in FVC at Week 12 maintained this at Week 24. At Week 24, 71% of bexotegrast participants had stable/improved disease by QLF vs. 33% on placebo. Conclusions: Bexotegrast 320 mg showed favorable safety and tolerability up to 40 weeks, and physiologic and radiographic evidence of an antifibrotic effect up to Week 24. Phase 2b evaluation is planned for mid-2023.

RATIONALE: Integrins α v β 6 and α v β 1 are upregulated in the lungs of patients with idiopathic pulmonary fibrosis (IPF), playing a key role in promoting transforming growth factor beta (TGF-β) activation and fibrosis.PLN-74809 is an oral, once-daily (QD), highly selective inhibitor of integrins α v β 6 and α v β 1 that was well tolerated in >180 healthy participants in Phase 1 studies at doses up to 320 mg.PLN-74809 showed antifibrotic activity (reduction in collagen deposition [Ashcroft Score]) in animal models of lung fibrosis and in live precision-cut lung tissue slices from patients with IPF, and reduced TGF-β activation in the lungs of healthy participants when dosed at 40 mg once daily.METHODS: INTEGRIS-IPF (PLN-74809-IPF-202; NCT04396756) is a Phase 2a, randomized, doseranging, double-blind, placebo-controlled study evaluating the safety, tolerability, and pharmacokinetics (PK) of PLN-74809 administered over 12 weeks in participants with IPF (ATS/ERS/JRS/ALAT, 2018).Approximately 84 participants with IPF will be enrolled in three planned ascending PLN-74809 dose groups (40 mg, 80 mg, or 160 mg QD), with a 3:1 randomization ratio (active:placebo) and stratification based on use of standard of care (SoC) therapy (pirfenidone or nintedanib [yes/no]).Key eligibility criteria include ≥40 years of age; forced vital capacity (FVC) ≥45% of predicted; diffusing capacity of the lung carbon monoxide ≥30%; forced expiratory volume in one second/FVC ratio ≥0.7; if receiving SoC, must be on stable regimen for ≥3 months; and no recent acute IPF exacerbation in the previous 6 months.RESULTS: The primary endpoint is the evaluation of PLN-74809 safety and tolerability, and the secondary endpoint is the assessment of PK across a dose range.Exploratory endpoints will measure change in FVC, Quantitative Lung Fibrosis score, cough symptoms via visual analog scale, and selected biomarkers over 12 weeks of treatment.Research sites will enroll across 10 participating countries from Australasia, Europe, and North America.CONCLUSIONS: This Phase 2a, randomized, dose-ranging study will evaluate the safety, tolerability, and PK of PLN-74809 for treatment of IPF.

BACKGROUND & AIMS:The development of accurate non-invasive tests to detect and measure the extent of fibrosis and disease activity in patients with non-alcoholic steatohepatitis (NASH) - the progressive phenotype of non-alcoholic fatty liver disease (NAFLD) - is of great clinical importance. Herein, we aimed to validate the performance of PRO-C3 and ADAPT for the detection of moderate/severe fibrosis within the CENTAUR screening population. METHODS:PRO-C3 was assessed in plasma from the screening population of the phase IIb CENTAUR study (NCT02217475) in adults with NASH and liver fibrosis. The relation between PRO-C3 and histologic features of NASH was evaluated, as well as the demographics of patients with high and low levels of PRO-C3. The diagnostic ability of PRO-C3, as a standalone marker or incorporated into ADAPT, to identify patients with F≥2 and NASH was estimated using receiver-operating characteristic analysis and logistic regression models. RESULTS:A total of 517 individuals with matched biopsy and PRO-C3 measurements were included. Patients with PRO-C3 levels ≥20.2 ng/ml showed increased levels of insulin, HOMA-IR, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and platelet count compared to patients with low PRO-C3 (p <0.05). PRO-C3 increased stepwise with increasing liver fibrosis, lobular inflammation, hepatocyte ballooning, steatosis, and NAFLD activity score (p <0.05), and could distinguish between NAFL and NASH (p <0.0001). PRO-C3 was independently associated with fibrosis and NASH when adjusted for clinical confounders. ADAPT outperformed Fibrosis-4, AST-to-platelet ratio index, and AST/ALT ratio as a predictor of advanced fibrosis and NASH (p <0.001). CONCLUSION:PRO-C3 was associated with NAFLD activity score and fibrosis. ADAPT outperformed other non-invasive scores for detecting NASH. These data support the use of PRO-C3 and ADAPT as diagnostic tools to identify patients with NASH eligible for inclusion in clinical trials. CLINICAL TRIAL NUMBER:NCT02217475 LAY SUMMARY: PRO-C3 is a serological biomarker associated with liver disease activity and fibrosis. Its performance for the detection of disease activity and fibrosis is improved when it is incorporated into the ADAPT score. Herein, we showed that ADAPT was better at selecting patients with non-alcoholic steatohepatitis for inclusion in clinical trials than other non-invasive scores.

BACKGROUND:Chronic alcohol consumption is associated with neuroinflammation, neuronal damage, and behavioral alterations including addiction. Alcohol-induced neuroinflammation is characterized by increased expression of proinflammatory cytokines (including TNFα, IL-1β, and CCL2) and microglial activation. We hypothesized chronic alcohol consumption results in peripheral immune cell infiltration to the CNS. Since chemotaxis through the CCL2-CCR2 signaling axis is critical for macrophage recruitment peripherally and centrally, we further hypothesized that blockade of CCL2 signaling using the dual CCR2/5 inhibitor cenicriviroc (CVC) would prevent alcohol-induced CNS infiltration of peripheral macrophages and alter the neuroinflammatory state in the brain after chronic alcohol consumption.METHODS:C57BL/6J female mice were fed an isocaloric or 5% (v/v) ethanol Lieber DeCarli diet for 6 weeks. Some mice received daily injections of CVC. Microglia and infiltrating macrophages were characterized and quantified by flow cytometry and visualized using CX3CR1eGFP/+ CCR2RFP/+ reporter mice. The effect of ethanol and CVC treatment on the expression of inflammatory genes was evaluated in various regions of the brain, using a Nanostring nCounter inflammation panel. Microglia activation was analyzed by immunofluorescence. CVC-treated and untreated mice were presented with the two-bottle choice test.RESULTS:Chronic alcohol consumption induced microglia activation and peripheral macrophage infiltration in the CNS, particularly in the hippocampus. Treatment with CVC abrogated ethanol-induced recruitment of peripheral macrophages and partially reversed microglia activation. Furthermore, the expression of proinflammatory markers was upregulated by chronic alcohol consumption in various regions of the brain, including the cortex, hippocampus, and cerebellum. Inhibition of CCR2/5 decreased alcohol-mediated expression of inflammatory markers. Finally, microglia function was impaired by chronic alcohol consumption and restored by CVC treatment. CVC treatment did not change the ethanol consumption or preference of mice in the two-bottle choice test.CONCLUSIONS:Together, our data establish that chronic alcohol consumption promotes the recruitment of peripheral macrophages into the CNS and microglia alterations through the CCR2/5 axis. Therefore, further exploration of the CCR2/5 axis as a modulator of neuroinflammation may offer a potential therapeutic approach for the treatment of alcohol-associated neuroinflammation.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease with no approved treatments. C‐C chemokine receptor types 2 and 5 (CCR2/CCR5) play an important role in inflammation and fibrosis and are potential therapeutic targets for PSC. We evaluated the efficacy and safety of cenicriviroc (CVC), a dual antagonist of CCR2 and CCR5, for the treatment of PSC. This was a single‐arm, open‐label, exploratory study of CVC in adults with a clinical diagnosis of PSC, serum alkaline phosphatase (ALP) ≥1.5 times the upper limit of normal (ULN), with or without inflammatory bowel disease, across eight sites in the United States and Canada. The primary endpoint was percent change in ALP over 24 weeks; key secondary efficacy endpoints were proportion of participants who achieved ALP normalization and overall response (decrease to <1.5 times the ULN or 50% decrease). Of the 24 participants, 20 completed the study. The mean age was 43 years, 50% were female, and the mean body mass index was 25 kg/m2. From a median ALP baseline of 369 U/L (range: 173, 1,377 U/L), a median absolute reduction of 49.5 U/L (range: −460, 416 U/L) was achieved at week 24, corresponding to a median reduction of 18.0% (range: −46%, 89%). No participant achieved ALP normalization or a 50% decrease; 2 participants (10%) achieved a reduction in ALP to < 1.5 times the ULN, and 4 had ≥25% increase. Twenty participants (83.3%) reported at least one adverse event; most were mild to moderate in severity. The most frequent events were rash, fatigue, and dizziness. Conclusion: After 24 weeks of CVC treatment, adults with PSC achieved a modest reduction (median 18%) in the surrogate endpoint of ALP. CVC was well tolerated, and no new safety signals were observed. ClinicalTrials.gov identifier: NCT02653625.

While virologically suppressive combination antiretroviral therapy (cART) has improved the outlook for persons‐with‐HIV (PWH), clinically significant cognitive impairment remains prevalent in otherwise effectively treated PWH. Underlying pathogenesis mechanisms include neuroinflammation, ongoing HIV replication in the central nervous system (CNS), and the contribution of lifestyle factors. At present, no proven interventions exist for the management of cognitive disorders in PWH. Cenicriviroc is a novel inhibitor of C‐C chemokine receptor type 5 (CCR5) and type 2 (CCR2) and is expected to have antiretroviral and anti‐inflammatory activity. Thus, cenicriviroc is a potential intervention for management of cognitive disorders in PWH. We assessed cerebrospinal fluid (CSF) exposure of cenicriviroc following 8 weeks cART intensification with cenicriviroc in PWH with symptomatic cognitive impairment. Cognitively impaired PWH with suppressed plasma HIV RNA on cART were eligible. Our definition of cognitive impairment included the presence of patient‐reported symptoms of cognitive impairment and formal clinical neuropsychological testing confirming cognitive impairment. Exclusion criteria included major depression and current use of CCR5 inhibitors. Paired CSF and plasma sampling were collected for cenicriviroc concentration assessment at baseline and after 8 weeks. Cenicriviroc concentration was determined using reverse phase high‐performance liquid chromatography, interfaced with a mass spectrometer. The EC90 for cenicriviroc 1 is 0.17 ng mL, and the lower limit of quantification (LLOQ) for CSF cenicriviroc concentration (0.24 ng mL) was utilised as the target concentration. Where exposure of cenicriviroc was below the LLOQ, a value 0.24 ng mL was imputed. CSF:serum albumin ratio was used as a surrogate measure of blood‐brain barrier integrity. Patient‐reported outcome measurements (PROMs) including Patient Health Questionnaire–9 item depression scale (PHQ‐9) and computerised cognitive testing (CogstateTM) were assessed. Of seven subjects enrolled, four completed all study procedures. Reasons for early discontinuation included fatigue, headache, depression, and nausea, all possibly related to cenicriviroc. All adverse events occurred within 4 weeks of commencing cenicriviroc, and all three subjects had discontinued cenicriviroc by week 6. Symptoms resolved within 7 days of cenicriviroc discontinuation in all three subjects.