Introduction

Fistulating peri-anal Crohn’s disease can affect approximately 20% of patients and have a major impact on quality of life. Despite being an important area of unmet clinical need, there is a paucity of evidence for most medical treatments and a lack of dedicated clinical trials for perianal Crohn’s disease. Current studies also report a high level of heterogeneity for outcomes with both treatments and placebo - making interpretation of the available data challenging for both clinical practice and design of clinical trials. Use of Bayesian methodology offers an attractive solution to help address some of these challenges. We sought to conduct a Bayesian prior elicitation exercise to determine the efficacy of licensed medical therapies for fistulating perianal Crohn’s disease.

Aims & Methods

A formal Bayesian prior elicitation meeting was convened. This was composed of a group of 11 gastroenterologists and 5 statisticians. Consensus priors were developed leveraging both published data and expertise of the gastroenterologists, to determine one-year fistula remission rates for seven options of licensed medical treatments based on five different mechanisms of action (anti-TNF, anti-integrin, anti-IL12/23, anti-IL-23, and JAK inhibitor). Consensus priors on the efficacy of each of seven treatment options was determined relative to an elicited consensus prior for placebo control. The log-odds ratio for efficacy for each of the seven therapy options versus placebo control was also established.

Results

Consensus priors were obtained for seven medical treatments for likelihood of fistula remission at one year. The prior mean, together with a 90% prior credible interval, of the one-year fistula remission rate was 0.22 (0.05, 0.46) for placebo, 0.58 (0.09, 0.96) for intravenous infliximab, 0.39 (0.06, 0.82) for adalimumab, 0.53 (0.09, 0.93) for subcutaneous infliximab, 0.24 (0.03, 0.60) for intravenous vedolizumab, 0.44 (0.05, 0.90) for upadacitinib, 0.34 (0.04, 0.77) for ustekinumab, and 0.36 (0.04, 0.82) for risankizumab. When assessing treatment effect on the log-odds ratio scale, oral upadacitinib and subcutaneous infliximab had the strongest “priors”, with the highest probability for likely efficacy, alongside intravenous infliximab.

Conclusion

We have conducted, to the best of our knowledge, the first formal Bayesian prior elicitation exercise for efficacy of medical therapies in perianal Crohn’s disease. These priors developed for the efficacy of licensed medical therapies can be internationally validated and potentially taken forward for planning of dedicated clinical trials. Importantly, these results could be used to enhance the design and analysis of clinical trials for fistulating perianal Crohn’s disease. Notable potential benefits from these findings include: improved estimation of treatment efficacy, reduction in the required sample sizes, and with minimisation or even avoidance of placebo control arms for future dedicated fistulating perianal Crohn’s disease clinical trials.

Disclosure

NMN declares educational/travel grants and/or speaker fees from AbbVie, Bristol Myers Squibb, Celltrion, Dr Falk Pharma, Ferring, Galapagos, J&J, Lilly, Pfizer, Pharmacosmos, Takeda and Tillotts Pharma AG. RC reports personal fees from AbbVie, Galapagos, Lilly outside the submitted work, and grants from Celltrion, Ferring, Tillotts Pharma outside the submitted work; and fees from advisory board membership of AbbVie, Bristol Myers Squibb outside the submitted work. SD reports personal fees from AbbVie, Ferring, Janssen, Takeda outside the submitted work; and grants from AbbVie, Dr Falk, Janssen, outside the submitted work; and fees from advisory board membership of AbbVie outside the submitted work. HG has received speaker fees from: Janssen, Ferring, Takeda, and AbbVie, and consultancy fees from. AbbVie, Galapagos. KBK reports serving as a speaker, a consultant, and/or an advisory board member for Abbvie, Falk, Galapagos, Janssen, and Takeda. JOL reports personal fees from AbbVie, Atlantic Healthcare, Bristol Meyer Squibb, Celgene, Celltrion, Engytix, Eli Lilly, Ferring, Galapagos, Gilead, GSK, Janssen, MSD, Norgine, Pfizer, Shire, and Takeda outside the submitted work; and grants from AbbVie, Ferring, Gilead, Takeda, and Shire outside the submitted work. GWM declares consultancy fees/grant funding from AbbVie, AstraZeneca and Janssen; all outside the submitted work. KVP reports personal fees from AbbVie, DrFalk, Galapagos, Janssen, PredictImmune, Pfizer, Takeda outside the submitted work; and grants from AbbVie, Celltrion, Dr Falk, Ferring, Janssen, Takeda, Tillotts Pharma outside the submitted work; and fees from advisory board membership of AbbVie, Galapagos, Janssen, Pfizer outside the submitted work. SS reports consulting fees from Takeda, AbbVie, Merck, Ferring, Pharmacosmos, Warner Chilcott, J&J Innovative Medicine, Dr Falk Pharma, Biohit, TriGenix, Celgene, and Tillots Pharma outside the submitted work; payment or honoraria from AbbVie, Takeda, Celltrion, Pfizer, Biogen, AbbVie, J&J Innovative Medicine, Merck, Warner Chilcott, Dr Falk Pharma, outside the submitted work; and is co-director of research for the South Asian IBD Alliance. TR has received research/educational grants and/or speaker/consultation fees from Abbvie, Arena, Aslan, AstraZeneca, Boehringer-Ingelheim, BMS, Celgene, Eli Lilly, Ferring, Galapagos, Gilead, GSK, Heptares, LabGenius, Janssen, MonteRosa, Mylan, MSD, Novartis, Numab, Pfizer, Roche, Sandoz, Takeda, UCB, and XAP Therapeutics. SS reports person fees from Abbvie, Celltrion, Dr. Falk, Ipsen, Janssen, Takeda outside the submitted work. ALH has received consultancy fees from AbbVie, Bristol Myers Squibb, Celltrion, Galapagos, Johnson & Johnson, Takeda, Pfizer, and Lilly; has received honoraria from AbbVie, Bristol Myers Squibb, Celltrion, Galapogos, Johnson & Johnson, Takeda, Pfizer, Lilly; and has received support for attending meetings or travel from AbbVie, Bristol Myers Squibb, Celltrion, Galapagos, Johnson & Johnson, Takeda, Pfizer, and Lilly; all outside of the submitted work. MP reports personal fees from Janssen and Takeda outside the submitted work; and grants from AstraZeneca, Galapagos, Gilead, Pfizer outside the submitted work. All other authors declare no conflicts of interest.

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.

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