Innovation in Inflammation: Shaping the IBD Treatment Landscape

Chair, David T. Rubin, MD, discusses inflammatory bowel disorder in this CME activity titled “Innovation in Inflammation: Shaping the IBD Treatment Landscape.” For the full presentation and complete CME information, and to apply for credit, please visit us at https://bit.ly/46X9pPT. CME credit will be available until August 25, 2025.

1. Innovation in Inflammation
Shaping the IBD Treatment Landscape

David T. Rubin, MD

Joseph B. Kirsner Professor of Medicine

Chief, Section of Gastroenterology, Hepatology & Nutrition
Co-Director, Digestive Diseases Center

University of Chicago Medicine

Chicago, Illinois

Go online to access full CME information, including faculty disclosures.

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2. Figure 1. Role of IL-23 in the Pathophysiology of IBD‘

IL-10
TGFB
ILATAJF
IL-21
IL-22
IL6
1.Korta A et al. nt J Mot Sel. 2023:24:10172. PeerView.com

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3. Figure 2. Role of IL-23 in the Pathophysiology of IBD:
Therapeutic Targets’

IL-12 Pathway IL-23 Pathway

Ustekinumab
ya

Brazikumab

Guselkumab

Mirikizumab
Risankizumab

1. Kora A ea. nt J Mo Sol 202352410172. PeerView.com

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4. Table 1. Medical Treatment Options for IBD

Therapy Treat Treatment ‘Comment
Diet EEN, PEN (CD)
5-ASA ASA (UC) Oral and rectal crea taa
Corticosteroids Prednisone, budesonide Oral and rectal (racional)
Antimetabolite Methotrexate

IM or SC or oral ($15 mg/week)
Thi

iopurines. Azathioprine, 6-mercaptopurine TPMT, NUDT15 Sons
Calcineurin inhibitors

‘Tacrolimus, cyclosporine therapies (mmune-based)

. Natalizumab (coyiv
Antiintegrin Vedolizumab (CD/UC) IV and SC maintenance |

Ustekinumab (p40:1L-12/23)

nero Mirikizumab (p19: IL-23)

Risankizumab (p19: IL-23)

Biological
therapies
NE ‘Adalimumab, certolizumab pego! Infiximab SC maintenance
‘golimumab, infliximab Biosimilars to infliximab and adalimumab
Totacitinib (JAK1,2,3) (uc)
JAK inhibitors Filgotinib (JAK1) (UC, approved in EU only)
Upadacitinib (JAK1) (coruc) “Targeted synthetic
'S1P receptor modulators Ozanimod (S1P 5), etrasimod (S1P 45) (ue) ‘small molecules

Nontraditional therapy Curcumin + ging dai

digo naturals) {UC)
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5. Figure 3. IL-23 Considerations

+ They are not all the same

Brestuma

- p40 IL-12 Susstumas IL-23
izan

- p19 Risankizumad

- pi9/CD64
+ IL-23 may favor CD more than UC

+ Cycling within class is effective
+ IL-23 is great for skin but not for joints

DS
‚Antigen IL-12Rb2 >
recognition X
m NK or T-coll
‘membrane

Re Eh
ae
Dre) esse,

11.23
heterodimer

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6. Figure 4. Risankizumab Is Superior to Ustekinumab for Achieving Clinical,
Endoscopic, and Deep Remission in Moderate to Severe CD: SEQUENCE"

Methods

+ SEQUENCE phase 3b trial: head-to-head RZB vs UST
in patients with moderate to severe Crohn's disease

+ All patients with exposure to at least one anti-TNF therapy

COA Curia! Remision EndoscopleRemisson
azar Wee at Em)
Domes E

CDA! Clinical Response

Ml, rin =: a
” a? oy a Bh Be
Conclusion: patients on RZB, compared with UST, achieve early, Ñ Pr

sustained, endoscopic, clinical, and biomarker improvement pe > > ¿>
SEAS ESAS IES

1. Dubinsky MC et al. 2024 DOW. Oral presentation 763, PeerView.com

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7. Figure 5. Risankizumab Is Effective
in Ustekinumab-Exposed and Ustekinumab-Naive Patients!

Methods UST-Nalve Patients More Likely to Achieve SFCR
+ Prospective, single-center cohort; patients with CD treated with RZB at Week 12; However, NO Difference in Absolute HBI Score,
+ Inclusion: HBI 25, fecal calprotectin (FC) >25019/g, or evidence of RUE ZU U SZ SEC RME an TIesimenE RER
active disease (ileocolonoscopy or cross-sectional imaging) Hal Over Time Sterold-Free Clinical Remission
+ HBl assessed at weeks 2, 4, 8, 12, 26, 52, and FC 2) 100) p=0 2
KR 7
Results E
+ N= 102; 46 (45%) UST naive, 56 (55%) UST experienced 3
+ UST-experienced group had longer disease duration, higher o
rates of surgery, exposure to higher number of advanced a au me
therapies, higher baseline HB Proportion Remaining on RZB
+ Of patients in steroid free clinical remission (SFCR) at week 12, EX ps OP usTnane
persisting SFCR rates were up to 90% and 76% at week 26 and we Bos: =
week 52 SFCR; no difference with prior UST exposure a sb

a
Conclusion

+ UST-experienced patients treated with RZB have similar treatment
persistence & SFCR rates as UST-naive patients

Wonk 12" Wook 26” Wook 2

4. Zinger Act a. 2024 DOW. Abstract 1177, PeerView.com

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8. Figure 6. Risankizumab Phase 3 Data From INSPIRE and
COMMAND Study in Moderately to Severely Active UC13

Methods

+ Moderately to severely active UC with clinical response to RZB
induction (INSPIRE) proceeded to double-blind, placebo-contolled
withdrawal COMMAND maintenance study

+ 1:1:1 randomization to placebo, RZB 180mg or 360 mg SC QEW
for 52 weeks

+ Patients not achieving response at week 12 randomized 1:1:1
(1.200 mg IV x 3 vs RZB 180 mg SC vs 360 mg SC)

Results

+ Refractory population, 75% failed TNF, 14% failed JAKi

+ Of patients without clinical response at week 12, most had clinical
response by week 24 wilh another 12 weeks of SC

+ Nonew safely data: elevated liver enzymes in RZB 360 mg
‘demonstrated without significant liver injury

Conclusions

+ RZB SC maintenance was superior to placebo for clinical
remission and other key clinical, endoscopic, and histological-
endoscopic endpoints in responders to 12-week RZB induction

+ Early improvements in symptoms, including bowel urgency and
biomarkers, were seen within 4 weeks of first IV induction dose

+ RZB was well tolerated, with no new safety concems observed

Patents, %

fe Week 52 Endoscopic and Y

ME mm

OU + MOMATRT— ATIR

Histologic Outcomes Remission|

Pan

Cas

‘Week 52 Cinca! Remission

[Weck 52 Patent Reported =]

4. Schreiber Seta 2024 DOW. Abstract 904.2. Panaccione Ret al. 2024 DOW. Abstract 04. 3, Siegel Cet al 2024 DOW. Abstract Su1770.

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9. Figure 7. Mirikizumab Is Noninferior to Ustekinumab in Achieving
Clinical Remission in Moderately to Severely Active CD: Phase 3 VIVID 112

Background: Mirikizumab, a p19-directed anti-IL-23 antibody, is more effective than placebo in patients with moderate to severe Crohn's disease
Methods

+ Secondary endpoints on the comparisons of mirikizumab to ustekinumab from the phase 3, randomized, double-blind, double-dummy, active- and
placebo-controlled, reat through study: VIVID-1

+ Multipliity-adjusted week 52 secondary endpoints: clinical remission by CDA! (noninferiority, 10% margin) and endoscopic response (superiority)

+ Nonmultiplicty-adjusted week 52 secondary endpoints: endoscopic-histologic response (absence of epithelial neutrophils, epithelial damage erosions or
ulceration, or 250 decrease in GHDAS)

Results’ :~50% biologic experienced
CDAI Clinical Remission at Week 52 zx Endoscopic Response at Week 52 — Endoscopic-Histologic Response at Week 52

races three man en A waiter More Mai tne
Conclusions

+ Mirikizumab achieved noninferionty to ustekinumab for clinical remission by CDAI
+ Mirikizumab showed numerically greater rates for several endpoints in the bio-failed, including endoscopic response
+ Mirikizumab achieved significant greater rates of endoscopic-histologic response in the bio-failed (nominal P)
1. D'Hnens G et al 2024 DOW. Abstract 985. 2 Sands Bel al 2024 DDW. Abarat Su1001 PeerView.com

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10. Figure 8. Guselkumab Maintenance Therapy Is More Effective Than
Placebo in Moderate to Severe UC: Phase 3 QUASAR Maintenance!

tor that blocks IL-23 and binds to CD64, a receptor on cells that produce IL-23

Background: Guselkumab (GUS) is a dual-acting IL-23p19 inhit
Methods

Randomized-withdrawal, double-blind, placebo-controlled study in patients with moderate to severely active UC
Inadequate response/intolerance to conventionalladvanced therapy

Clinical response to GUS IV induction
Randomized 1:1:1 to SC GUS 200 mg Q4W, GUS 100 mg Q8W, or placebo (GUS withdrawal)

Target Population

Adults, moderate to
‘severely active UC:
Baseline modified Mayo

Results score of 510.9
Primary Endpoint: Clinical Remission at Week 44 Major Secondary Endoscopic Endpoints at Week 44 | "in ct! bleeding
M Placebo (guseikumab withdrawal) MM Guseikumab 100 mg SC Q8W. I Gusekumab 200 mg SC GW = Mayo endoscopic subscore
2296 ES)
# 18295 (85% 0120981) Rn Pan cae
E — \ pee Px001
| — 5zs2 05%, as
is Per — Pen zer Endoscopic improvement:
¿Sw aos 518 an PE MES = ort with no ratty
SE Fr. Histo-ndoscopie mucosal
8 EM Improvement: Risto
improvement (Geboes
Ë 2 ‘cing sytem) aná
ES Erdoseope improvement
Endoscopie Wite-Andoscople Endoscopie

Improvement Mucosal Remission
improvement (MES=0)

Conclusions
+ In moderately to severely active UC, maintenance therapy with both GUS SC regimens was efficacious in patients who responded

to GUS IV induction
+ Primary endpoint and all nine major secondary endpoints were met by both GUS SC maintenance regimens. ,
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1. Rubin DT eta, 2024 DDW. Abstract 758.

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11. Figure 9. Guselkumab Is More Effective Than Placebo in
Moderately to Severely Active Crohn’s Disease: Phase 3 GALAXI 2 & 31

Methods: GALAX! 2 & 3 are identical 48-week, randomized, double-blind, double-dummy, placebo- and active-comparator (ustekinumab)
treat-through registrational trials assessing the efficacy and safety of guselkumab in patients with moderately to severely active Crohn's disease

Results
Week 12 Clinical Response and Week 48 Weck 12 Clinical Response and Weck 48 Major secondary endpoint:
Endoscople Response ‚Clinical Remission Eficacy of guselkumab
100 2328 2308 sn asa 2350 IV induction
P< 001 P< 001 g P<.001 P<001
r O
2337 2279 3 238 ama co} nse
Ea E 70 | At Avon Y Endoscople Response Week 12
= £Se0 so) e sw
5 382 304 sé 5
B ze ig"
Ex as
ha Ea SE o
2 a se
= o o Eo.
‘OALANI2 GALAXIA GALAKI2 GALAN 3
I Placebo IM Susekumab 200 mg IV GW IM Gusetkumad 200 mg IV as ¿ 2
=> 100 mg SC asi 200 mg SC AW a
hc Ban 10 get cn am in CON CDA EO le Gains
non LEEDS CET

Conclusion: The GALAX! 2 & 3 studies independently established short-term and long-term TB combined guseiumao
efficacy of guselkumab in moderate to severely active Crohn's disease 200 mg IV

1. Panaccione Ret

2024 DOW. Abstract 10570, PeerView.com

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12. Figure 10. Guselkumab Is More Effective Than Ustekinumab in
Moderately to Severely Active Crohn’s Disease: Phase 3 GALAXI 2 & 31

Methods: GALAX! 2 8 3 are identical 48-wk, randomized, double-blind, double-dummy, placebo- and active-comparator (ustekinumab)
treat-through registrational trials assessing the efficacy and safety of guselkumab in patients with moderately to severely active Crohn's disease

Results Wk 48 Major Secondary Endpoints
266 ans ans aza
. Pot Fr Frot SER Cinieal Response: 2100-pont reduction rom
FA sn a ia azeine in DAL ce COAT 2160
#
7° Pa Po Pau Ps ai 7 à aa,
i from bazeine in SES-CD or SESCD $2
E nic Remisson: CDA! <150
Es Endosopi Remission: SES-CO 4 an à
E 22 pom! reduction rom bassine and no
H ubeosre greater han À in any heal
H component
E

lin Remission Wk 48 and
ndo Response ondo Remission ‘lin Remission Wk 48
Endo Response WK48 Endo Re wasn Re 5

I Gu5 209 mg1v au 100 mg 50 a I GUS 200 mg1V am 209 mgscam BE ust-6 mong 99 mg 50 aew

Conclusion: Pooled analyses demonstrated superiority of guselkumab over ustekinumab in prespecified major secondary endpoints at wk 48

1. Panaccione R et al. 2024 DDW. Abstract 1057. PeerView.com

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13. Figure 11. Anti-IL-23 Biologics Effective in Pediatric IBD: Mirikizumab
in UC (Phase 2 SHINE) and Risankizumab in Real-World CD Multicenter*?

O
Aim: SHINE: phase 2 multicenter open-label study aimed to explore the efficacy =
of mirikizumab in children with moderate to severe UC Aim: assess real-world effectively and safety of RZB
Methods Results in pediatric CD
Re" Methods:
CE ES MAIS ENT Espoo + Multicenter retrospective review
u | + Al received RZB at adult dosing (600 mg IV, 360 mg SC)
A &
Results
Emol + N= 53; mean age 16.3, median 3.7 years since dx,
91% failed 1+ advanced therapy
En + Median 15 6 weeks follow-up
et + 89% treatment persistence (5 patients PNR)
+ No drug-related AE reported
o.
Sn Week 52 Efficacy Endpoints
In Weck 12 Responders
rauen PE Ê aa Postinaucion Outcomes ont Outcomes
tat tng 0 Core) 5 = E
A [| : A I N 3 A |
SS IÓ o ES = on
ion: Mirikizumab is effective in children AS Ga Groans
with moderate-to-severe UC

1. Kaplan Jet al. 2024 DOW. Abstract Su1800, 2. Spencer EA et al. 2024 DDW. Abstract Mo2038, PeerView.com

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14. Figure 12. Mirikizumab Improved Bowel Urgency, Abdominal Pain, and
Fatigue in Pediatric Patients With Moderate to Severe UC: Phase 2 SHINE-11
Patients in All Age Groups Reported Improved Bowel Urgency NRS Score

Bowel Urgency NRS Scores

Le Pan pen

Ih
ii

CS

tonta aire Pes
Bowel ge Mos so 0)
ance ee

ts in All Age Groups Reported Fatigue NRS Score

ES si Fatigue NRS Scores.
Conetusion JT dr
+ Mirikizumab demonstrated improvements in N Hey Bios 2
abdominal pain, bowel urgency, and fatigue ER # He 8 3
following induction and maintenance treatment E +
in pediatric patients with moderate to severe is o. Bee

UC, supporting evidence for the pivotal phase 3

pediatric SHINE-2 study ee
A. Dubinsky Metal. DDW 2024. Abstract Su1808, PeerView.com

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