Skyrizi vs. Entyvio in Patients with Crohn's Disease

To create an alert for the Global Brand Director of Entyvio at Takeda to inform the latest development, highlighting the relevance of the news and its implications for Takeda

1. AbbVie presents positive topline results from the Phase-3 maintenance study (FORTIFY) showing Skyrizi SC achieves co-primary endpoints at week-52 in patients with moderate-severe Crohn’s disease Sources: 1. AbbVie Press Release 2. PRNewswire 3. NCT03105102 4. NCT03105128 5. NCT03104413 Skyrizi® ( risankizumab ): IL-23 inhibitor developed by AbbVie in partnership with BI [02-Jun-2021] Phase-3 maintenance results show patients with Crohn's disease receiving risankizumab (Skyrizi®) achieved endoscopic response and clinical remission at one year 1,2 Endpoints Skyrizi SC (180mg) (N=157) Skyrizi SC (360mg) (N=141) Skyrizi IV (N= 164) (Control group) Endoscopic Response (ER) (Primary endpoint - US Plan ) 47% (P<0.001) 47% (P<0.001) 22% Clinical Remission (CDAI) (Primary endpoint - US Plan ) 55% (P<0.001) 52% (P<0.001) 41% Clinical Remission (SF/AP) (Primary endpoint – OUS Plan) 46% (P>0.005) 52% (P<0.001) 40% Endoscopic Remission (ER) (Secondary endpoint - OUS) 30% (P<0.001) 39% (P<0.001) 13% Deep Remission (Secondary endpoint - OUS) 25% (P<0.001) 29% (P<0.001) 10% FORTIFY Efficacy Results @ WK-52 BI – Boehringer Ingelheim , SC – Subcutaneous, IV – Intravenous, WK – Week, CDAI – Crohn’s disease activity index, SF/AP – S tool frequency/Abdominal pain , OUS – Outside US, RCT – Randomized controlled trial Skyrizi SC (360 mg, @ every WK-8) Met co-primary endpoints in both the US / Outside the US (OUS) analysis plan Nearly half of patients achieved both the primary endpoints FORTIFY Safety Results @ WK-52 : No new safety risks were observed – nearly consistent with the known safety profile of risankizumab Rates of serious adverse events were 12.3% and 13.4% in subjects treated with Skyrizi 180 or 360mg respectively, vs. 12.5% in control group Skyrizi SC (180 mg, @ every WK-8) Met co-primary endpoints in the U.S. analysis plan, but not in the OUS analysis plan The FORTIFY study [NCT03105102] 3 evaluated two doses: 180mg and 360mg of subcutaneous (SC) Skyrizi in moderate-severe Crohn’s patients Multi-centre, randomized, double-blind, control group, 52-week Phase 3 open-label extension study (US, EU, UK, Japan, Canada, China) Two analysis plans for clinical remission: Crohn's disease activity index (CDAI) for the US analysis plan, and stool frequency and abdominal pain (SA/AP) the outside of the US analysis plan — due to regulatory requirements in the different regions

2. Sources: 1. AbbVie Press Release 2. Skyrizi - Advance/Motivate 3. Skyrizi Approval 4. Entyvio SC – SmPC 5. Entyvio Website Skyrizi SC vs. Entyvio SC: As Crohn’s Disease Maintenance Therapy SC – Subcutaneous, WK – Week, OUS – Outside the US Skyrizi SC shows better compliance rate as compared to Entyvio SC Skyrizi SC ( 180 / 360mg) at every 8-weeks [ once in 2-months ] 1 Entyvio SC (108mg) at every 2-weeks [ twice in a month ] 4 COMPLIANCE Skyrizi SC reported more significant clinical endpoints – with quicker onset of action as compared to Entyvio SC Clinically significant endpoints evaluated such as Endoscopic Response and Clinical Remission [both are primary endpoints] 1 Skyrizi SC (360mg) achieved both co-primary and secondary endpoints 1 Skyrizi has faster onset of action [starts to work within 4-weeks ] 2 Clinical Remission was only evaluated as primary endpoint 5 Secondary endpoints (Clinical Response) was not statistically significant [52% Entyvio vs. 44.8% placebo] 5 At week-6 considered to reflect early onset of action 5 CLINICAL OUTCOMES Skyrizi SC has higher chance to get launched in the US market – before Entyvio SC Expected approval in Q2-2022 3 : Skyrizi SC (360 mg, @WK-8) met co-primary endpoints in both the US / OUS analysis plan Approved in EU, Canada, Australia; However Entyvio SC has been rejected by the US FDA COMMERCIAL DATA Skyrizi SC and Entyvio SC – both have comparable safety profile Safety profile of both tested doses of Skyrizi SC was in-line with prior data [ no new safety risks were reported ] 1 Favorable safety profile with ' No-box warning ‘ 5 SAFETY PROFILE Skyrizi SC Entyvio SC Entyvio will face significant competition from AbbVie’s Skyrizi which has higher compliance, favorable clinical outcomes with faster-onset of action, and comparable safety profile Lead/ Superiority Negative/ Inferiority

3. Sources: 1. Seeking Alpha Skyrizi SC vs. Entyvio SC: Recommendations AbbVie’s Skyrizi has competitive edge over Entyvio based on new late-phase 3 clinical data: 1. Better compliance with Skyrizi as subcutaneous formulation is taken 'once in 2-months' whereas Entyvio SC is prescribed 'twice in a month' 2. Might have higher acceptance within HCPs as more significant clinical endpoints were evaluated in Skyrizi trial (such as endoscopic response, deep remission) 3. Skyrizi has faster onset-of-action : Quicker onset-of-action is a leading parameter for HCPs as one-third patients were found to be non-responder to biologics 4. High probability for the US launch before Entyvio ; Also AbbVie’s strong relationship with payers to secure positive formulary positioning “ AbbVie's replacements for Humira (Skyrizi and Rinvoq ) are rapidly growing and will eventually make up for the drop in sales as generics begin to pressure Humira ” [Seeking Alpha, Jun-04, 2021] 1

4. 2.