Studies have shown that IL-12, 22 and 23 are involved in IBD pathogenesis with IL-12 and 23 playing a crucial role in the maintenance of inflammation.47 It is suggested that IL-12 is involved in the initiation of intestinal inflammation caused by epithelial barrier disruptions and works together with IL-23 to maintain chronicity.48 However, there has been more recent research suggesting that IL-12 possesses some anti-inflammatory activity in animal models.49 Table 2 summarises the phase 3 studies of the current cytokine inhibitors being tested for UC and CD.
Ustekinumab biosimilar
Ustekinumab is a fully human IgG1 monoclonal antibody that blocks the biological activity of interleukin-12 and interleukin-23 through their common p40 subunit.50 It was the first anti-IL drug developed and approved for CD and UC, given intravenously for the first dose and then subsequently given subcutaneously.50 51 The ustekinumab patents are due to expire in September 2023 in USA and in January 2024 in Europe,52 allowing for biosimilars to be brought into the market. Seven different biosimilars of ustekinumab (BAT2206, CT-P43, FYB202, NeuLara, ABP654, SB17, AVT04) are currently in development and going through phase 1–3 trials, although all publicly available information on these clinical trials thus far involves patients with plaque psoriasis.53 The European Medicines Agency has approved the application for AVT04 in patients with plaque psoriasis and is expected to be released in the second half of 2023.
Rani therapeutics has partnered with Celltrion to develop an oral drug delivery programme for a ustekinumab biosimilar, RT-111.54 This is designed to be a capsule, RaniPill, that is, ingested into the stomach and once it reaches the intestine, the capsule injects the drug into the intestinal wall. The RaniPill intends to replace subcutaneous or intravenous injection of biologics and drugs with oral dosing and is designed to administer drugs with bioavailability that is comparable to a subcutaneous injection. While initial phase 1 trials have shown promising results, further work is still needed to determine its future within the IBD armamentarium.
In the meantime, there are other monoclonal antibodies that are being developed to specifically target IL-23 through their subunit p19.
Risankizumab
This is a new humanised monoclonal antibody that has only recently been released in the UK and the USA for use in moderate to severely active CD.55 56 This was following the release of two induction studies (ADVANCE and MOTIVATE)57 and one maintenance study (FORTIFY),58 which demonstrated that subcutaneous risankizumab was a safe and efficacious treatment for both induction and maintenance of CD. At week 52, greater clinical remission and endoscopic response rates were reached with 360 mg risankizumab versus placebo (clinical: 52% vs 41%, respectively; endoscopic: 47% vs 22%, respectively). Adverse event rates were similar among groups with worsening disease, arthralgia and headache the most frequently reported in all treatment groups.
A phase 3 induction study (INSPIRE) for patients with UC is currently ongoing. AbbVie has released an early press statement with preliminary results demonstrating that risankizumab has met the primary endpoint of clinical remission at week 12 compared with placebo (20.3% vs 6.2%, respectively, p<0.00001).59 The patients enrolled in this study were intolerant or showed inadequate response to conventional and/or advanced therapies. Key secondary endpoints were also met at week 12, including endoscopic improvement (36.5% vs 12.1%, p<0.00001) and histological endoscopic mucosal improvement (24.5% vs 7.7%, p<0.00001).
Mirikizumab
Mirikizumab is a humanised IgG4 monoclonal antibody that is administered intravenously or subcutaneously every 4 weeks and studies have explored induction doses of 200 mg, 600 mg and 1000 mg. The phase 2 trial for patients with UC demonstrated mirikizumab to be effective in inducing a clinical response after 12 weeks (50 mg: 15.9%, p=0.066; 200 mg: 22.6%, p=0.004; 600 mg: 11.5%, p=0.142 vs placebo 4.8%).60 The subsequent phase 3 study (LUCENT-2) met its primary endpoint with clinical remission achieved by 63.6% from the treatment arm 200 mg vs 36% from the placebo arm at week 40 (p<0.001).61 Furthermore, the rates of corticosteroid-free remission, endoscopic remission and histological endoscopic mucosal remission were all superior in the treatment arm compared with the placebo, regardless of patients receiving previous advanced therapy. Similarly, D’Haens et al conducted two randomised control phase 3 trials of mirikizumab in UC with an induction dose of 300 mg for 12 weeks followed by maintenance dose of 200 mg. Significantly higher percentages of patients in the mirikizumab group compared with the placebo group had clinical remission at week 12 (24.2% vs 13.3%, p<0.001) and at week 40 (49.9% vs 25.1%, p<0.001).62
The phase 2 study for CD (SERENITY) has also shown superiority in its primary endpoint of inducing endoscopic response at week 12 with intravenous mirikizumab (200 mg: 25.8%, p=0.079; 600 mg: 37.5%, p=0.003; 1000 mg: 43.8%, p<0.001 vs placebo 10.9%). Patients who responded were rerandomised to either intravenous or subcutaneous 300 mg. Endoscopic response at week 52 was 58.5% and 58.7% in the intravenous and subcutaneous groups, respectively.63 The frequency of serious adverse events and discontinuations were higher in the non-randomised maintenance cohort with the most commonly reported adverse events being headache, weight gain and nasopharyngitis. The phase 3 study (VIVID) is ongoing.
Guselkumab
The humanised IgG1 monoclonal antibody, guselkumab, is being investigated for its intravenous use in CD with results from the GALAXI-1 phase 2 study.64 Of the patients recruited, 50% had refractory disease to prior biological therapy. At week 12, all three dose regimens (200 mg, 600 mg and 1200 mg at weeks 0, 4 and 8) of guselkumab induced greater clinical and endoscopic improvements compared with placebo, with a favourable safety profile. Preliminary results from the phase 3 induction study outcomes for patients with UC (QUASAR) has shown a significantly greater proportion of patients treated with either 200 mg or 400 mg guselkumab achieved the study’s primary endpoint of clinical response compared with placebo at week 12 (200mg: 61.4%, p<0.001; 400 mg: 60.7%, p<0.001; placebo: 27.6%).65 Adverse events were similar in both treatment and placebo groups, with no reports of serious infections, malignancy or death.
The VEGA trial was a proof-of-concept study that explored the combination use of guselkumab with golimumab in UC.66 In this study, patients were randomly assigned (1:1:1) to either combination therapy (subcutaneous golimumab at weeks 0, 2, 6 and 10 followed by subcutaneous guselkumab at week 0, 4 and 8 and then 8 weekly thereafter), golimumab monotherapy or guselkumab monotherapy. At week 12, 83% in the combination group achieved clinical response compared with 61% in the golimumab monotherapy group and 75% in the guselkumab monotherapy group. At week 50, however, this reduced to 63% in the combination group, 76% in the golimumab group and 65% in the guselkumab monotherapy group.
Brazikumab
Brazikumab is an IgG2 monoclonal antibody which has gone through phase 2 trials in both CD67 and UC.68 To recruit into the CD study, patients had to have failed a TNFα-inhibitor. Clinical response at week 8 demonstrated significant improvement in patients receiving 700 mg brazikumab subcutaneously every 4 weeks compared with placebo (49.2% vs 26.7%, p=0.010), however, this was not sustained at week 24 (53.8% vs 57.7%). EXPEDITION was the long-term phase 2 study exploring the use of brazikumab in UC. The company affiliated with brazikumab, AstraZeneca, released a press statement in June 2023 announcing the discontinuation of the brazikumab IBD programme, which includes the phase IIb/III INTREPID trial for CD and the EXPEDITION trial for UC and their respective open-label extension trials.69 The cause for the study discontinuation is unknown.