P493 QUASAR Induction Study 1 Cumulative Response to Guselkumab in Patients With Moderately to Severely Active Ulcerative Colitis

Abstract

Background Guselkumab (GUS), an IL-23p19 antagonist, had greater efficacy than placebo (PBO) in achieving clinical response and clinical remission at Week (Wk) 12 in the randomized, controlled Phase 2b QUASAR Induction Study 1 (NCT04033445) in patients with moderately to severely active ulcerative colitis (UC).1 Patients who were not in clinical response at Wk 12 received GUS treatment through Wk 24. Here, we report GUS cumulative efficacy and safety results for Induction Study 1. Methods Eligible patients had moderately to severely active UC (modified Mayo score of 5 to 9 with a Mayo endoscopy subscore ≥2) at baseline. Patients were randomized 1:1:1 to IV GUS 200mg, 400mg, or PBO at Wks 0, 4, and 8. Patients who were not in clinical response to IV induction at Wk 12 received GUS treatment (PBO IV→GUS 200mg IV; GUS 200mg IV→GUS 200mg SC; GUS 400mg IV→GUS 200mg SC) at Wks 12, 16, and 20 and were evaluated at Wk 24 (Figure 1). Matching IV or SC PBO was administered to maintain the blind. Results Three hundred thirteen patients were randomized and treated at baseline. Demographic and disease characteristics at baseline were similar among the treatment groups, and approximately 50% had a prior inadequate response or intolerance to advanced UC therapy. At Wk 12, clinical response was achieved by 61.4% (62/101) and 60.7% (65/107) of patients randomized to GUS 200mg and GUS 400mg IV vs 27.6% (29/105) of patients randomized to PBO IV (both p<0.001). Of the patients in the GUS groups who were not in clinical response at Wk 12, 54.3% (19/35) in the GUS 200mg IV→200mg SC group and 50.0% (19/38) in the GUS 400mg IV→200mg SC group achieved clinical response at Wk 24. Clinical response at Wk 12 or 24 was achieved by 80.2% of patients who were randomized to GUS 200mg IV and 78.5% of patients who were randomized to GUS 400mg IV. For patients who received PBO IV→GUS 200mg IV, clinical response at Wk 24 (65.2%) was similar to Wk 12 clinical response following GUS 200mg IV induction (61.4%). The most frequent adverse events among all GUS-treated pts (n=274) were anemia (7.7%), headache (5.1%), worsening UC (4.4%), COVID-19 (3.6%), arthralgia (2.9%) and abdominal pain (2.6%) which are consistent with Wk 12 results. Conclusion Overall, approximately 80% of patients randomized to receive GUS achieved clinical response at Wk 12 or 24. Continued treatment with SC GUS allowed 50-54.3% of IV GUS Wk 12 clinical nonresponders to achieve clinical response at Wk 24. No new safety concerns for GUS were identified.

Combination Therapy With Guselkumab and Golimumab in Patients With Moderately to Severely Active Ulcerative Colitis: Pharmacokinetics, Immunogenicity and Drug–Drug Interactions

“…This binding prevents IL-23-mediated intracellular signaling and subsequent cytokine production from receptor-bearing cells. 5 Guselkumab is approved for the treatment of adults with psoriasis and psoriatic arthritis 6 and is currently being developed for the treatment of UC 7 and Crohn's disease. 8 The pharmacokinetics (PK) of guselkumab have been well-characterized in healthy participants and patients with plaque psoriasis, psoriatic arthritis, and palmoplantar pustulosis.…”

Segurança e eficácia de novas abordagens para o tratamento da colite ulcerativa a partir de ensaios clínicos randomizados

“…Oral A escolha pelo guselcumabe se deve à sua capacidade de inibir a sinalização de IL-23 e a consequente produção de citocinas envolvidas na fisiopatologia da colite ulcerativa. O seu uso, liberado em vários países para o tratamento de outras doenças inflamatórias, foi associado à melhora clínica e endoscópica na 12ª semana em pacientes com doença de Crohn ativa de graus moderado e grave em pacientes com resposta inadequada ou intolerância à imunossupressão ou terapia biológica (PEYRIN-BIROULET et al, 2023).…”

“…Dessa forma, 483 pacientes foram triados inicialmente, com apenas 328 pacientes diagnosticados com colite ulcerativa moderada a grave com tempo de doença mínimo de 3 meses e randomizados em grupos que receberam guselcumabe intravenoso na dose de 200 ou 400 mg (intervenção) ou placebo (controle) a cada 4 semanas. Além disso, todos os pacientes foram avaliados quanto à pontuação do escore de Mayo, frequência de evacuações, sangramentos, ocorrência de efeitos adversos, além da concentração sérica de proteína C reativa e calprotectina fecal até a 12ª semana (PEYRIN-BIROULET et al, 2023).…”

“…Pacientes de ambos os grupos que apresentaram melhora clínica ao final da 12ª ou 24ª semana foram incluídos em outro braço do estudo que avalia a terapia de manutenção, ao passo que pacientes que receberam placebo e não obtiveram resposta passaram a receber guselcumabe 200 mg intravenoso nas semanas 12, 16 e 20 do estudo (PEYRIN-BIROULET et al, 2023).…”

Inflammation induced Th17 cells synergize with the inflammation-trained microbiota to mediate host-resiliency against intestinal injury

“…Adding to human studies, murine models of colitis including IL-10 -/and T-cell transfer strongly link the IL-23:Th17 pathway with IBD 7,[12][13][14] . Evidencing the strength of this association, biologics like Ustekinumab, Risankizumab and Guselkumab which target IL-23:Th17 pathways are efficacious in IBD [15][16][17] .…”