Introduction

OZA, an oral selective sphingosine 1-phosphate receptor modulator, is approved for the treatment of moderately to severely active ulcerative colitis and is under investigation for CD. Clinical, endoscopic, and histologic improvements were observed after 12 wk of treatment with OZA in pts with moderately to severely active CD in the phase 2 STEPSTONE study. Differential decreases in circulating lymphocytes were observed in STEPSTONE, with reductions in T and B cells; however, natural killer cells and monocytes were unaffected. Circulating MBCs have not been widely studied in CD.

Aims & Methods

This exploratory analysis of STEPSTONE assessed the association between levels of circulating lymphocyte subsets and OZA efficacy. Pts received OZA 0.92 mg for 12 wk. Lymphocyte subsets were evaluated using multicolor flow analysis on blood samples collected before treatment and at Week (W) 12; differences between Day 1 and W12 were analyzed by Wilcoxon signed-rank tests. Change in disease activity from baseline to W12 was determined for Simple Endoscopic Score for Crohn’s Disease, size of ulcers, extent of ulcerated surface, extent of affected surface, presence of narrowing, Crohn’s Disease Activity Index (CDAI), Robart’s Histopathology Index (RHI), Geboes Histology Activity Score (GHAS), and stool frequency. Efficacy outcomes (ie, clinical response, clinical remission, endoscopic response, endoscopic remission, global GHAS remission, RHI remission, and RHI mucosal healing) were evaluated at W12. Associations of lymphocyte subset levels with disease activity changes and efficacy outcomes were assessed using Spearman’s correlation and logistic regression, respectively.

Results

Of the 69 pts enrolled, 52 had disease activity, efficacy outcome, and flow cytometry data at baseline and W12 and were included in this analysis. Most lymphocyte subsets assessed were significantly associated with 1 or 2 efficacy outcomes, whereas nonswitched MBCs were significantly associated with most outcomes, including endoscopic response-25, endoscopic response-50, endoscopic remission, global GHAS remission, and RHI mucosal healing (Table). Baseline levels of nonswitched MBCs were significantly correlated with change from baseline to W12 in extent of affected surface (Spearman’s rho = –0.44, P<0.05), RHI (Spearman’s rho = –0.34, P<0.05), and GHAS (Spearman’s rho = –0.47, P<0.05). Changes in levels of nonswitched MBCs were significantly correlated with change from baseline to W12 in CDAI (Spearman’s rho = 0.38, P<0.05), RHI (Spearman’s rho = 0.37, P<0.05), GHAS (Spearman’s rho = 0.43, P<0.05), and stool frequency (Spearman’s rho = 0.43, P<0.05).

Conclusion

After 12 wk of OZA treatment, higher levels of nonswitched MBCs at baseline were associated with endoscopic and histologic improvement, and reductions in nonswitched MBCs were associated with decreases in clinical and histologic disease activity. These data implicate nonswitched MBCs, which are involved in T cell–dependent immune responses and some inflammatory diseases, as a marker associated with OZA response in CD.

Disclosure

The study was funded by Bristol Myers Squibb, Princeton, NJ, USA.
SHar, CW, YH, and RM: employees and/or shareholders of Bristol Myers Squibb.
BGF: consulted for AbbVie, ActoGeniX, Albireo, Amgen, AstraZeneca, Avaxia Biologics, Baxter, Biogen Idec, Boehringer Ingelheim, Bristol Myers Squibb, Calypso, Celgene, Elan, Eli Lilly, enGene, Ferring Pharmaceuticals, Roche/Genentech, gIcare Pharma, Gilead, Given Imaging, GlaxoSmithKline, Ironwood, Janssen, Johnson & Johnson, Lexicon, Merck, Millennium, Nektar, Novo Nordisk, Pfizer, Prometheus Laboratories, Protagonist, Sanofi, and UCB; director at Robarts Clinical Trials.
SHan: consulted for AbbVie, Actavis, Boehringer Ingelheim, Bristol Myers Squibb, Caremark, Celgene, Ferring Pharmaceuticals, Janssen, Merck, Pfizer, Salix, Sanofi-Aventis, Shire, and UCB.
SV: received research funding from AbbVie, Galapagos, Johnson & Johnson, Pfizer, and Takeda; received consulting and/or speaking fees from AbbVie, Abivax, AbolerIS, AgomAb, Alimentiv, Arena, AstraZeneca, Avaxia, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Cytoki Pharma, Eli Lilly, Falk Pharma, Ferring, Galapagos, Genentech/Roche, Gilead, GlaxoSmithKline, Hospira, IMIDomics, Janssen, Johnson & Johnson, Materia Prima, MiroBio, Morphic Therapeutic, MRM Health, MSD, Mundipharma, Pfizer, ProDigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillotts Pharma AG, and Zealand.
SG: received research funding from AbbVie and GlaxoSmithKline; served as a lecturer for AbbVie, Celgene, Eli Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Pfizer, and Takeda; served as a consultant for AbbVie, Bristol Myers Squibb, Janssen, Novo Nordisk, Pfizer, Roche, and Takeda.
JY: employee and shareholder of Laboratory Corporation of America Holdings.
DCW: received honoraria as a speaker, consultant, and/or advisory board member from AbbVie, Arena, Celgene/Bristol Myers Squibb, Janssen, Pfizer, Prometheus, Takeda, and UCB.
GD: served as an advisor for AbbVie, Agomab Therapeutics, Alimentiv, Applied Molecular Therapeutics, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Cytoki, Eli Lilly, Exeliom, Ferring, Galapagos, GlaxoSmithKline, Gossamer Bio, Immunic, Johnson & Johnson, Pfizer, Polpharma, ProciseDx, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Seres, Takeda, Tillotts, and Versant; received speaker fees from AbbVie, Bristol Myers Squibb, Eli Lilly, Galapagos, Johnson & Johnson, Pfizer, Takeda, and Tillotts.

Introduction

The GALAXI-1 study (NCT03466411) is a phase 2b study that evaluated guselkumab (GUS), a selective interleukin-23 p19 subunit antagonist, in patients with moderate-to-severe Crohn’s disease (CD).

Aims & Methods

We assessed clinical, endoscopic, and safety outcomes through 3 years in patients receiving maintenance therapy with GUS in the GALAXI-1long-term extension (LTE) study. Upon completing the treat-through Week 48 phase 2 study, patients continued in the LTE receiving 1 of 3 maintenance regimens that were assigned at randomization: GUS 100 mg subcutaneous (SC) every 8 weeks (q8w), GUS 200 mg SC every 4 weeks (q4w), or ustekinumab (UST) 90 mg SC q8w. Key efficacy endpoints assessed at Week 144 included CD Activity Index (CDAI) clinical remission, patient-reported outcome (PRO)-2 remission, and endoscopic response. Efficacy analysis sets are defined in Table 1. Safety analyses included all treated patients. The study was not powered to evaluate efficacy differences between individual GUS doses or GUS vs UST.

Results

Overall, the average duration of follow-up from baseline through Week 152 was 100.9 weeks in the combined GUS group (n=220) and 102.7 weeks in the UST group (n=114); 151 patients randomized to GUS and 48 patients randomized to UST were treated in the LTE. Study drug discontinuations in the combined GUS group from Week 48 through Week 152 were due to adverse events (AE, n[%]: 6[4]), lack of efficacy (2[1.3]), surgery 1[0.7]), lost to follow-up (4[2.6]), protocol deviation (1[0.7]), pregnancy (1[0.7]), refusal (1[0.7]), and patient withdrawal (9[6]); in the UST randomized group, due to AE (1[2.1]), patient withdrawal (3[6.3]), and other (1[2.1]). Among all randomized patients in the combined GUS group (including those who did not enter the LTE; primary efficacy analysis set), 54.1% were in clinical remission, 51.4% were in PRO-2 remission, and 34.7% were in endoscopic response at Week 144 (Table 1). Percentages of patients who achieved these outcomes at Week 144 among those who entered the LTE (LTE efficacy analysis set) and among those with available data at each visit (observed case analysis set) in the combined GUS group and UST reference arm are summarized in Table 1. In the combined GUS group, serious adverse events (SAEs, n[%]: 35[15.9]) and serious infections (12[5.5]) were infrequent. Most infections were not serious, mild to moderate in severity, and most resolved without drug withdrawal. No cases of active tuberculosis, opportunistic infections, anaphylactic/serum sickness reactions, major adverse cardiovascular event, or death occurred during the LTE.

Conclusion

Durable clinical and endoscopic efficacy was maintained over time through Week 144 of the LTE. The safety profile of GUS was consistent with that of the approved indications. Most infections were not serious and did not result in discontinuation, while incidence rates of SAEs and serious infections were generally low.

Disclosure

Anita Afzali, M.D. is a consultant, speaker, clinical investigator, and advisory board member for Janssen
Silvio Danese, M.D. is a consultant and speaker for Janssen
Remo Panaccione, M.D. is a consultant, clinical investigator, and speaker for Janssen
Brian G. Feagan, M.D. is a consultant, speaker, member of a data safety monitoring board, and advisory board member for Janssen
David T. Rubin, M.D. is a consultant for Janssen
Bruce E. Sands, M.D. is a consultant and speaker for Janssen
Walter Reinisch, M.D. is a clinical investigator, speaker, and advisory board member for Janssen
Julián Panés, M.D. is a consultant, speaker, clinical investigator, advisor, and member of a data safety monitoring board for Janssen
Aparna Sahoo, D.O. is an employee of Janssen
Natalie A. Terry, M.D. is an employee of Janssen
Leonardo Salese, M.D. is an employee of Janssen
Chris Corbett, M.Sc. is an employee of Janssen
Tadakazu Hisamatsu, M.D. is a clinical investigator for Janssen
Jane M. Andrews, M.D. is a clinical investigator and consultant for Janssen
Geert R D’Haens, M.D. is a consultant for Janssen

Introduction

Intraductal Papillary Mucinous Neoplasias (IPMN) are cystic neoplasias of the ducts of the pancreas. They usually occur at advanced age and can progress to invasive adenocarcinomas. While there are morphological and spatial features to assess the progression risk, a mutational footprint defining the progression risk remains to be identified. IPMNs often harbor an activating mutation of either GNAS or KRAS or both, but neither interaction nor signaling crosstalk is well understood.

Aims & Methods

Here, we use a patient-derived induced pluripotent stem cell (iPSC) model system, harboring either a wildtype or mutant GNAS with an inducible oncogenic KRAS^G12D cassette. Various iPSC genotypes were differentiated towards the pancreatic lineage including pancreatic duct-like organoids, followed by subsequent transplantation onto the porcine urinary bladder (PUB) for long-term culture. Dysplasia, mucin expression and cyst size were subsequently analysed.

Results

Already 2 weeks post transplantation, a substantial amount of CK7/CK19 positive pancreatic ductal structures were found in all grafts with a strong cystic phenotype driven by a GNAS^R201C background. The phenotype was still present 8 weeks after transplantation. The induction of KRAS^G12D for 6 weeks resulted in an increased ductal lumen, which was further boosted by GNAS^R201C. In addition, a strong GNAS^R201C dependent expression of Mucin 2, a marker for the intestinal IPMN subtype was documented. Quantification of dysplastic ductal structures revealed an increase in low grade dysplasia driven either by KRAS^G12D or GNAS^R201C. Combination of both mutations was associated with a strong increase in the amount of high grade dysplastic ductal structures. In ductal structures a pro-proliferative phenotype driven by GNAS^R201C background was observed. The amount of p21 positive nuclei was highly increased by KRAS^G12D, while it was significantly attenuated in ductal cells with a double mutated KRAS^G12D GNAS^R201C background, showing a decreased amount of oncogene induced senescence. This was recapitulated in vitro in pancreatic ductal organoids.

Conclusion

The first results show an effect of GNAS^R201C on early dysplasia formation and a further boost of KRAS^G12D driven dysplasia and high-grade dysplasia formation. Additionally, the increased proliferative and decreased senescent phenotype hints at a GNAS^R201C driven bypass of oncogene induced senescence. Our genuine patient-derived iPSC model featuring an endogenous GNAS^R201C locus will allow us to closely investigate the early formation of IPMNs and timewise resolve their transition towards an invasive phenotype to further unravel the mechanisms of IPMN formation and the collaborative pro-oncogenic signaling of KRAS^G12D with GNAS^R201C.