As patents expire, the development of biosimilars may increase, opening up new opportunities to compare efficacies of these drugs.
With emerging biologics for patients with ulcerative colitis who are refractory to conventional medical treatment, a recent literature review emphasized the need to compare various options when determining the optimal treatment plan.
Ulcerative colitis is a chronic, inflammatory disease characterized by diarrhea, rectal bleeding, and abdominal pain, urgency, and tenesmus. Therapeutic goals of treatment include the induction and maintenance of remission as well as symptom management. Biologic agents are recommended in patients with moderate-to-severe ulcerative colitis in whom conventional therapy, such as corticosteroids, aminosalicylates, or immunomodulators, is contraindicated or has failed.
The currently approved biologics for ulcerative colitis include anti-tumor necrosis factor a (TNFa) agents infliximab, adalimumab, and golimumab, as well as vedolixumab and ustekinumab. In the literature review, investigators conducted an initial search with the drug names as keywords, in addition to “UC” and “clinical trial.” They identified 62 studies to include.
The randomized, double-blinded ACT-1 and ACT-2 trials were among the first to show the efficacy of infliximab compared to placebo in moderate-to-severe ulcerative colitis. In ACT-1, clinical remission at week 8 was significantly higher in the infliximab group compared to placebo, and similar findings were observed in ACT-2. In both trials, no significant differences were found between the efficacy of 2 compared doses, and the 5 mg/kg dose is the initial preferred dose based on safety and pharmacoeconomic data.
Many patients experience a loss of response to infliximab over time, and this was observed in the ACT-1 trial with clinical remission reducing from 69% at week 8 to 45% at week 54. However, following dose intensification, 66.7% continued to maintain long-term clinical remission.
Adalimumab is well-established as a safe and effective treatment. The multicenter, double-blind, placebo-controlled ULTRA trials 1, 2, and the open-label extension ULTRA-3 found that treatment with adalimumab maintained rates of remission (63.6%), mucosal healing (59.9%), and improved quality of life on up to 4 years of therapy.
Comparing treatment efficacy between adalimumab and infliximab found lower remission rates in ULTRA-1 and -2 compared to those found in the ACT-1 and -2 trials, but greater mucosal healing in the ULTRA trials. The lower remission rates in the ULTRA trials could be explained by 40% of patients having received previous treatment with infliximab, whereas in the ACT trials, all patients were anti-TNF naïve.
Golimumab is another safe and effective treatment for moderate-to-severe ulcerative colitis. The phase 3 double-blinded PURSUIT-SC trial found that subcutaneous golimumab effectively induced clinical remission, mucosal healing, and increased quality of life at 6 weeks compared to placebo in anti-TNF-naïve patients. Its efficacy and safety were also highlighted in the GO-COLITIS trial, although early induction response was greater and sustained response was lower compared to the PURSUIT trial.
The PURSUIT-M trial found that remission and response rates were maintained at 30 and 54 weeks of treatment. More recently, the long-term extension of PURSUIT-M showed maintained clinical benefit at up to 3 additional years, with 63% of patients remaining on golimumab treatment after 228 weeks.
Many trials have shown the efficacy of vedolizumab in ulcerative colitis, the most significant being the GEMINII study, which demonstrated greater response rate and clinical remission in vedolixumab compared with placebo. However, the investigators noted that approximately 80% of participants in the GEMINII trial were Caucasian in both the vedolixumab and placebo cohorts, and its efficacy may not be representable in other ethnicities.
Despite a lack of direct comparison between different interventions in ulcerative colitis, the VARSITY trial compared adalimumab with vedolizumab, and found greater clinical remission in vedolizumab compared with adalimumab (31.3% vs 22.5%). Additionally, vedolizumab had a lower failure rate and higher discontinuation-free survival than adalimumab in infliximab-failed patients in a real-world setting. However, patients who previously had no response to anti-TNF therapy were eligible for the VARSITY trial, potentially lowering the overall efficacy of adalimumab.
Finally, the authors examined literature around the anti-interleukin-12/23 drug ustekinumab. The UNIFI study compared various doses of ustekinumab with placebo in patients with moderate-to-severe ulcerative colitis who either had an inadequate response or unacceptable adverse effects (AEs) with anti-TNF treatments, vedolizumab, or conventional therapies. Results showed that those receiving ustekinumab were more likely to achieve clinical remission compared to placebo at the end of both the induction trial and the maintenance trial.
However, the authors noted that those who did not respond to ustekinumab in the induction trial were not entered into the maintenance trial. Had they completed this, the clinical remission for ustekinumab would most likely have been different; however, the study was strengthened by its double-blinding, randomization, and large sample size.
Due to the long-term and systemic AEs associated with corticosteroids, biologics may be the preferred option in the future for acute treatment of ulcerative colitis. Although aminosalicylates will most likely remain first-line treatments for maintaining remission, the authors emphasized the need to compare different biological and non-biological treatments when determining the optimal treatment plan for patients.
Additionally, as the patents on Entyvio (Takeda), Simponi (Janssen), Humira (AbbVie), and Stelara (Janssen) expire soon, the development of biosimilars for ulcerative colitis may increase, allowing more studies to compare the efficacies of these drugs. Other administration routes can also be studies, which may increase the bioavailability at the preferred sites in the colon.
Awan H, Fatima U, Eaw R, Knox N, and Alrubaiy L. The Efficacy of Currently Licensed Biologics for Treatment of Ulcerative Colitis: A Literature Review. Cureus. 2023 Apr; 15(4):e37609. doi:10.7759/cureus.37609