Clinical remission by legacy vs. FDA definitions: Definition justification and results from UNIFI Study

Background: Ustekinumab (UST), an interleukin-12/23 blocker, was evaluated as induction and maintenance for moderate-severe ulcerative colitis (UC). Clinical remission was analysed using a US-specific definition (FDA) excluding the PGA (Physician's Global Assessment) and the legacy definition which includes the PGA to accommo Da te regional regulatory preference. Methods: Patients (pts) were randomised to receive a UST intravenous (IV) induction dose (either 130 mg [n = 320] or approximating 6 mg/kg [n = 322]), or PBO (n = 319). Responders to UST IV induction were randomised to SC maintenance of 90 mg UST (either every 12 weeks [n = 172] or every 8 weeks [n = 176]), or PBO (n = 175). The primary endpoint for induction (Week 8) and maintenance (Week 44) was clinical remission. In a prior UC induction study with golimumab, 87.5% had >3 stools per Da y at baseline and stool number ≤3 aligned with what approximately 98% of patients reported as normal. FDA clinical remission definition was developed after FDA requested PGA removal (ie, absolute stool number ≤3 [aligned with upper limit of normal stool number in the general population], Mayo rectal bleeding subscore 0, and Mayo endoscopy subscore 0/1). This differed from the legacy definition (total Mayo score ≤2 points, with no individual subscore >1). Using golimumab and infliximab UC study Da ta, FDA definition was assessed for agreement with legacy definition, treatment effect, and clinical meaningfulness using the Inflammatory Bowel Disease Questionnaire and the 36-item short form health survey as anchor variables. UNIFI remission was analysed using both definitions. Results: The FDA definition demonstrated high concor Da nce, specificity and sensitivity with the legacy definition with a similar treatment effect, and defined patients who had clinically meaningful benefit. In the UNIFI study, Week 8 clinical remission rates among patients receiving IV UST at either 130 mg or ∼6 mg/kg were significantly higher than PBO patients by both legacy (15.6%, 15.5%, and 5.3%, respectively p < 0.001 for both doses) and FDA definitions (16.6%, 18.9%, and 6.3%, respectively; p < 0.001 for both doses). Week 44 clinical remission rates among patients randomised to q12wk or q8wk UST were significantly higher than PBO patients by both legacy (38.4%, 43.8%, and 24.0%, respectively; p = 0.002 q12wk and p < 0.001 q8wk) and FDA definitions (39.5%, 42.6%, and 24.6% respectively; p = 0.002 q12wk and p < 0.001 q8wk). Conclusions: Using either legacy or FDA remission definition, IV UST induced remission and SC UST maintained remission in UST induction responders with moderately-to-severely active UC. Importantly, the FDA definition with absolute stool number ≤3 is clinically meaningful, easily understood by physicians and patients, and is not based on patients' distant recall of normal stool pattern.