petesicatib (RG7625) / Roche - LARVOL DELTA

Spatial T1-Mapping of Cardiac Fibrosis Identifies Causal Protein Drivers through Deep Learning and Mendelian Randomization (AHA 2025) - "eQTL SMR identified LMF1 (p=8.3×10-5), JMJD6 (p=1.7×10-4), RIT1 (p=3.96×10-4). Targets with existing inhibitors include CTSS (VBY-036, RO5459072), PDE5A (sildenafil, tadalafil), and ENPP2 (ONO-8430506, PF-8380, IOA-289).Conclusions AI-derived spatial fibrosis phenotypes using VAE decomposition of T1 maps reveal hidden prognostic information and region-specific biological drivers invisible to conventional mean T1 analysis, identifying causal protein targets (FOLH1, ENPP2, CTSS, PDE5A) amenable to existing inhibitors for precision anti-fibrotic therapies."

Cardiovascular • Congestive Heart Failure • Coronary Artery Disease • Fibrosis • Heart Failure • Immunology • CTSS • DLG2 • ENPP2 • FABP4 • FOLH1 • LEP • PDE5A • RIT1 • TMPRSS6 • TNFRSF1A

A randomized, double-blind, placebo-controlled, parallel group study on the effects of a cathepsin S inhibitor in primary Sjögren's syndrome. (PubMed, Rheumatology (Oxford)) - P2a | "There was no clinically relevant improvement in ESSDAI score (primary end point), and no apparent benefit in favor of RO5459072 in any of the secondary endpoints. Further work is needed in order to understand the mechanisms of MHC-II-mediated immune stimulation in pSjS."

Clinical • Journal • Immunology • Rheumatology • Sjogren's Syndrome • CTSS

Population pharmacokinetic analysis of RO5459072, a low water-soluble drug exhibiting complex food-drug interactions. (PubMed, Br J Clin Pharmacol) - "The population PK model supported that dissolution- and solubility-limited absorption from the proximal and distal intestine alone explains the non-linear PK of RO5459072 in fasted state and the linear PK in fed state. This work together with the PBPK analysis raised our confidence in the understanding of this complex PK."

Clinical • Journal • PK/PD data

Differential effects of specific cathepsin S inhibition in biocompartments from patients with primary Sjögren syndrome. (PubMed, Arthritis Res Ther) - "CatS activity in tear fluid seems to be a relevant biomarker for pSS disease activity. Conversely, CatS inhibition diminishes T cell and associated monokine responses towards relevant autoantigens in pSS. Thus, CatS inhibition may represent a promising novel treatment strategy in pSS."

Biomarker • Clinical • Journal • Dermatology • Dermatopathology • Immunology • Infectious Disease • Psoriasis • Sjogren's Syndrome • Tetanus

Sjögren's syndrome: Old and new therapeutic targets. (PubMed, J Autoimmun) - "Biological agents previously implemented in successful therapeutic outcomes in rheumatoid arthritis (RA), such as anti-TNF agents, anakinra, tocilizumab and rituximab failed to reach primary outcomes in randomized double-blind controlled trials in the context of SS. Abatacept and belimumab, already licensed for the treatment of RA and lupus respectively, as well combination regimens of both rituximab and belimumab hold some promise in alleviation of SS-specific complaints, but data from large controlled trials are awaited...While targeting of cathepsin-S (Petesicatib), inducible costimulator of T cells ligand (prezalumab), and lymphotoxin beta receptor (baminercept) failed to fulfil the primary outcome measures, preliminary results from two randomized placebo controlled trials on CD40 blockade (Iscalimab) and B-cell activating factor receptor (Ianalumab) inhibition resulted in significant reduction of SS disease activity, with a favorable so far safety profile. Results..."

Journal • Review • CD40 • IL2

"$RHHBY discontinuations: RG6109 undiscl ADC; RG6123 anti-CEA MAb; RG6146 bromodomain inh; RG6148 undisclosed (Her2+ breast cancer); RG7625 cathepsin S inh" (@JacobPlieth)