P117 Pharmacodynamic activity of JNJ-67484703 in rheumatoid arthritis, ulcerative colitis and Sjogren’s disease: results of a phase II proof of biology trial

Abstract Background/Aims PD-1 is an inhibitory receptor expressed on activated T cells and at high levels on T follicular and peripheral helper (Tfh/Tph) cells. Tfh/Tph are enriched in autoimmune diseases and support B cell function. JNJ-67484703 agonises PD-1 and depletes cells with high PD-1 levels. The aim was to investigate the biological effects of multiple doses of JNJ-67484703 in disease-relevant tissues in participants with rheumatoid arthritis (RA), ulcerative colitis (UC) and Sjogren’s disease (SjD). Methods This phase 2 open label trial aimed to recruit 15 patients in each of 3 disease groups (RA, UC and SjD) to receive 7 doses of subcutaneous JNJ-67484703 at weeks 0, 1, 2 and then every 2 weeks until week 10. Within each disease, participants were allocated to one of two doses with predicted non-overlapping exposures: 3 mg/kg (n = 10) or 0.5 mg/kg (n = 5). Synovium, gut or minor salivary gland biopsies were taken at weeks 0 and 12. The primary outcome was change in proportion of Tfh/Tph in disease relevant target tissue, measured by scRNAseq and analysed with Bayesian hierarchical modelling. Results A total of 37 patients were recruited (RA n = 17, UC n = 5 and SjD n = 15). Two RA participants withdrew by choice prior to second biopsy and were replaced. Three UC patients withdrew from active treatment due to unsatisfactory response but provided end of treatment biopsies. Combining all disease cohorts, there was a 28% and 43% posterior probability of a decrease in Tfh/Tph over time in disease tissues at the lower and higher doses, respectively; however pre-planned sensitivity analyses showed large variation dependent on disease. The greatest effect was observed in the 3 mg/kg RA cohort, with a 96% posterior probability of Tfh/Tph decrease over time (median change in percentage, -0.14 per week; Credible Interval, -0.30, 0.02). Tfh/Tph decrease was accompanied by median reductions in the following: proportion of scRNAseq IFNγ+CD4+ T cells, total T and B cell counts per mm2 as assessed by immunofluorescence, Krenn synovitis score, CRP, CXCL13 and serum amyloid A (SAA). A trend for median reduction in DAS-28(CRP) score from baseline was observed at Week 12: -0.6 (IQR -2.1, 0.0) with 0.5 mg/kg and -1.8 (IQR -2.1, 0.0) with 3 mg/kg treatment. Change in tissue Tfh/Tph correlated with change in DAS-28(CRP). For SjD and UC, no decrease over time in Tfh/Tph cells or histological improvement were observed. The majority of adverse events were grade 1 (mild; 91.7%) or grade 2 (moderate; 8.0%). There were no serious adverse events or deaths. Conclusion In RA, but not SjD or UC, 3 mg/kg JNJ-67484703 was associated with a reduction in Tfh/Tph in target tissue and other parameters of tissue inflammation, demonstrating the value of early proof of biology studies. Disclosure B.A. Fisher: Consultancies; BAF has undertaken consultancy for Novartis, BMS, Servier, Galapagos, Roche, UCB, Sanofi, Janssen, AstraZeneca, Otsuka, Amgen, Kiniksa, Cullinan, Quell and OneFour Bio. Grants/research support; BAF has received research funding from Janssen, Servier, Galapagos, Celgene and Novartis. J. van der Wiel: None. J.D. Turner: None. Y. Liu: Grants/research support; YSL has received research funding from GSK, Johnson & Johnson and SynAct.. T. Hosack: None. J. Young: None. S. Al-Taei: None. A. Baranskaya: None. F. Humby: Member of speakers’ bureau; FH has been a speaker for UCB, Roche, Pfizer and Genentech. Grants/research support; FH has received research funding from Pfizer. J. McMurray: None. S. Gilbert: Grants/research support; SG has received research funding from AstraZeneca. C. Shave: Grants/research support; CS has received research funding from UCB. D. Gardner: None. S. Nayar: None. S.J. Bowman: Consultancies; SJB has undertaken consultancy for Abbvie, Amgen, Argenx, Artivabio, Aurinia, Avoro, Bain, BMS, EcoR1, Iqvia, J&J/Janssen, Kiniksa, Novartis and Scitaris. A. Rowe: None. C.D. Buckley: Consultancies; CJB has undertaken consultancy for GSK, Roche, Johnson & Johnson, AbbVie, Takeda, Pfizer and Eli-Lilly.. Shareholder/stock ownership; CJB is a shareholder for Mestag Therapeutics. Member of speakers’ bureau; CJB has been a speaker for GSK.. Grants/research support; CJB has received research funding from Roche, Johnson & Johnson, GSK, Takeda, Pfizer and Celsius. A.G. Richter: Member of speakers’ bureau; AGR has been a speaker for CSL, Takaeda, MSD, and AstraZeneca.. Grants/research support; AGR has received research funding from GSK and Oxford Immunotec. M.J. Loza: Corporate appointments; ML is an employee of Johnson & Johnson. S.J. Marciniak: Corporate appointments; SJM is an employee of Johnson & Johnson. W. Ng: Consultancies; WFN has undertaken consultancy for Novartis, Johnsons & Johnsons Innovations, Bristol Myers Squibb, Sanofi, Argenx, IQVIA, Quotients, Resolves Therapeutics, Veloxis and EQT. A. Pratt: Grants/research support; AP has received research funding from GSK. S. Travis: Consultancies; Alimentiv; Apexian; Apollo; Arcturis; AstraZeneca; BMS; Clario; Cosmo; Endpoint Health; EQrX; Equillium; Ferring; Galapagos; Genentech/Roche; Gilead; GSK; Janssen; Lilly; Mestag; Microbiotica; ONO; Pf. Shareholder/stock ownership; Satisfai Health Inc. Member of speakers’ bureau; BMS, Ferring, Janssen, Lilly, Pfizer, Sun Pharma, Takeda. Grants/research support; AbbVie, Celgene, Celsius, Galapagos, Johnson & Johnson, Lilly, Pfizer, Takeda, and Vifor.. V. Homer: None. A. Filer: Consultancies; AF has undertaken consultancy for Johnson & Johnson and Sonoma. Grants/research support; AF has received research funding from BMS, Roche, UCB, Nascient, Mestag, GSK, Johnson & Johnson and Synact..