P573 The safety profile of upadacitinib maintenance therapy in ulcerative colitis in the Phase 3 U-ACHIEVE study is consistent with that in approved indications

Abstract

Background The oral, small-molecule, selective and reversible Janus kinase inhibitor upadacitinib (UPA) is approved for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), moderate-to-severe atopic dermatitis (AD) and ankylosing spondylitis, and is under investigation in ulcerative colitis (UC). This assessment reviewed adverse event (AE) data for UPA maintenance therapy in UC in the context of the known long-term safety profile of UPA in its approved indications. Methods Safety data were collated from patients with UC who responded to 8 weeks’ induction treatment with UPA 45 mg once daily (QD) and were enrolled in U-ACHIEVE to receive maintenance treatment (UPA 15 mg, 30 mg QD or placebo) for ≤52 weeks. Treatment-emergent AEs (TEAEs) were defined as AEs with an onset on or after the first dose, and ≤30 days after the last dose, of study drug. Safety data were also collected from two AD (15 and 30 mg doses), six RA (15 mg dose in all, 30 mg dose in four) and two PsA (15 and 30 mg doses) Phase 3 trials. Exposure-adjusted event rates were calculated for TEAEs and AEs of special interest (AESIs). Results Data were available for 746 patients with UC who received 8 weeks’ induction with UPA 45 mg and were randomised to maintenance treatment as follows: placebo, n=245; UPA 15 mg, n=250; UPA 30 mg, n=251. Rates of any AEs, serious AEs, severe AEs and AEs leading to treatment discontinuation were lower with both UPA doses versus placebo (Table 1). No deaths occurred. Rates of the above AE categories in patients with UC who received maintenance treatment with UPA 15 or 30 mg were within the ranges previously reported in AD, RA and PsA, apart from neutropenia (Table 1). AESI rates in UC were generally similar with UPA and placebo, except for higher rates of herpes zoster, creatine phosphokinase elevation, hepatic disorder, and venous thromboembolism (VTE), but lower rates of anaemia, with UPA (Table 2). Non-melanoma skin cancer was reported only with UPA 30 mg. One adjudicated major cardiovascular event was reported in each of the placebo and UPA 30 mg arms. VTE only occurred with UPA treatment (two events per arm). Based on the limited number of patients exposed, and apart from a higher VTE rate, AESI rates in the UC maintenance study were generally similar to those reported in patients receiving long-term treatment with UPA 15 or 30 mg QD in AD, RA or PsA. Conclusion The safety profile of UPA maintenance treatment in UC is consistent with that in its approved indications. Although VTE rates were higher in UC, background VTE risk is known to be increased in UC versus AD, RA and PsA. This review identified no new important safety risks.

Integrating new and emerging therapies into inflammatory bowel disease clinical practice

“…Preliminary results from the U-ACCOMPLISH trial, a randomized, placebo-controlled trial in patients with moderate to severe UC, reported a significantly higher proportion of patients receiving upadacitinib achieved clinical remission when compared to placebo (33.5% and 4.1%, respectively) [10]. The safety profile of upadacitinib in UC appears similar to that in other approved indications [11].…”

Evaluating Upadacitinib in the Treatment of Moderate-to-Severe Active Ulcerative Colitis: Design, Development, and Potential Position in Therapy

“…Likewise, onset of SAEs was higher in the placebo group (21.9 cases per person-years) than the UPA 15 mg (12.6 cases per person-years) and UPA 30 mg (10.6 cases per person-years) groups. 35 AEs leading to treatment discontinuation were reported in 6 cases per 100 person-years in both UPA 15 mg and UPA 30 mg arms, compared to 20.3 cases per 100 person-years of the placebo group. Most frequently reported AEs were nasopharyngitis, elevation of creatine phosphokinase, UC exacerbation, upper respiratory tract infection, arthralgia, and anemia, as reported in Table 4 .…”

“…VTE was reported only with UPA treatment (1.0–1.1 cases per 100 person-years). 35 No deaths occurred in the induction and maintenance studies. Safety events were stratified based on plasma exposure to UPA.…”

JAK inhibitors: A new dawn for oral therapies in inflammatory bowel diseases

“…The incidence rate of VTE for upadacitinib was 1.1 per 100 patient-years; in the case of filgotinib, one PE episode was reported in the 100 mg dose arm, and two DVTs were reported in the placebo arm (80,81). At this moment, it is unknown if this is a drug class adverse event or due to inhibition of a specific pathway, data that must be confirmed in long-term studies; therefore, it cannot be established that selective JAK-1 inhibition is a measure to decrease the risk of VTE.…”