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Background and aims: The thiopurine drugs, azathioprine (AZA) and 6-mercaptopurine, are established in the treatment of infl ammatory bowel diseases (IBD). Polymorphisms in thiopurine S-methyltransferase (TPMT) gene have been associated with adverse drug reactions (ADRs) to AZA. Methods: The aim of this study was to evaluate TPMT polymorphisms and AZA-related toxicity in a Slovak cohort of 220 IBD patients treated with AZA. In every patient, the dose and duration of AZA therapy, concomitant 5-aminosalicylate (5-ASA) medication, frequency, type, time to onset, dose of ADR and concomitant 5-ASA at the onset of ADR were recorded. Each patient was also genotyped for the presence of variant TPMT alleles (*2,*3A,*3B,*3C). Frequency, type and circumstances of ADRs were compared according to TPMT status. Results: Of the 220 patients, 205 (93.2 %) were wild-type (TPMT*1/*1), one (0.5%) carried a TPMT*1/*3C allele, 13 (5.9 %) carried TPMT *1/*3A allele and one was homozygous for TMPT *3A allele. No TPMT *2 mutation was found. The incidence of adverse drug reactions was 62/205 (30.2 %) in the wild-type group as compared to 13/15 (86.7 %) in the TPMT mutation group, p=2.10-5. Leukopenia (WBC< 3.0*10^9/L) occurred in 21/205 (10.2 %) patients with wild type TPMT versus 11/15 (73.3 %) patients with TPMT mutations, p=0.000001. There was no signifi cant difference between TMPT groups in gastrointestinal or other ADRs. No impact of 5-ASA on the incidence and severity of AZA adverse drug reactions was observed. Conclusion: The incidence of leukopenia in TPMT mutant patients was signifi cantly higher and more severe as compared to TPMT wild type patients. We observed no impact of concomitant 5-ASA therapy on AZA induced toxicity (Tab. 4, Fig. 2, Ref. 37).

Background and Aims Ontamalimab, a fully-human monoclonal antibody targeting MAdCAM1, induced remission in patients with moderate-to-severe ulcerative colitis (UC) in TURANDOT. We assessed long-term safety, tolerability and efficacy of ontamalimab in TURANDOT II. Methods TURANDOT II was a phase 2, multicentre, open-label (OL) study in patients with moderate-to-severe UC who completed TURANDOT on placebo or ontamalimab. Patients were randomized to 75mg or 225mg ontamalimab every 4 weeks for 72 weeks (OL1). Dosage could be increased to 225mg from week 8 at the investigator’s discretion. All patients then received 75mg every 4 weeks for 72 weeks (OL2), followed by 6-month safety follow-up. The primary objective was safety, measured by adverse events (AEs), serious AEs (SAEs) and AEs leading to withdrawal. Mucosal healing (MH; centrally read endoscopy) was assessed. Results Of 330 patients, 180 completed OL1; 94 escalated to 225mg; 127 completed OL2. Overall, 36.1% experienced drug-related AEs. The most common SAE (10.0%) was worsening/ongoing UC; 5.5% of patients had serious infections, the most common being gastroenteritis (0.9%). One death and four cancers (all unrelated to ontamalimab) occurred. No PML/lymphoproliferative disorders occurred. Geometric mean hsCRP and faecal calprotectin decreased across OL1 in both dose groups. The proportion of patients assigned placebo in TURANDOT achieving MH increased from 8.8% (6/68) at baseline to 35.3% at week 16 (24/68; non-responder imputation). The corresponding increase in the ontamalimab group was from 23.3% (61/262) to 26.7% (70/262). Conclusions Ontamalimab was well tolerated up to 144 weeks in patients with moderate-to-severe UC, with good safety and efficacy.

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