Medical Minute:

Updates on Emerging Oral Therapies for IBD

Supported by an educational grants from AbbVie Inc. and Bristol-Myers Squibb

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Faculty and Disclosures
Millie D. Long, MD, MPH
Associate Professor of Medicine
Director, Gastroenterology and Hepatology Fellowship Program
Vice-Chief for Education
Division of Gastroenterology and Hepatology
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Millie D. Long, MD, MPH, has disclosed that she has received consulting fees from
AbbVie, Bristol-Myers Squibb, Genentech, Janssen, Lilly, Pfizer, Prometheus, Roche,
Salix, Takeda, Target, and Theravance and funds for research support from Pfizer and
Takeda.
 A 48-year-old Man With a 6-year History of UC
and Recurrent Corticosteroid Use
 Prior meds: 5-ASA, azathioprine, steroids Flexible sigmoidoscopy
 Currently on azathioprine + IFX 5 mg/kg
(level of 17 ug/mL, no antibodies) with
primary nonresponse
 5-6 BMs/day, mild urgency, intermittent
blood, no abdominal pain
 CRP: 15 mg/dL
 He is started on a prednisone taper related
to significant active inflammation

Image courtesy of Dr Millie D. Long Slide credit: clinicaloptions.com

 The IBD Pipeline: Focus on Oral Agents
Downstream Signaling Blockade
Anti–IL-23 Lymphocyte
Inhibitors Trafficking PDE4
JAK-STAT Inhibitors Inhibitor Other
 Brazikumab Anti-integrins  Brepocitinib  Apremilast*  Fecal
 Guselkumab*  Etrolizumab (JAK1/TYK2) transplant
 Mirikizumab  PN-943  Deucravacitinib (intestinal
S1PR modulators (TYK2) microbiota
 Risankizumab* transfer)
 Amiselimod  Filgotinib
 PTG-200  SER-287
 Etrasimod  Ritlecitinib (microbiome
(JAK3/TEC) therapeutic)
 TD-1473 (oral  Stem cell
gut-selective pan- therapy
JAK) (perianal
 Upadacitinib* fistula)

*Approved for use in other indications.

ClinicalTrials.gov. Accessed June 2021. Blue = oral Slide credit: clinicaloptions.com
S1P Receptor Modulators
 Recently Approved for UC: Ozanimod
 Indicated for moderately to severely active UC Afferent lymphatic

in adults
node
‒ Previously approved for multiple sclerosis ph
S1P1
S1P2 S1P3 S1P4
S1P5 Lym T cells
‒ Dose titration: Days 1-4, 0.23 mg; Days 5-7,
XX X XX
0.46 mg; Day 8 and thereafter, 0.92 mg
X Ozanimod
 Warnings and precautions X Etrasimod
Efferent
‒ Risk of infections lymphatic

‒ Bradyarrhythmia and AV conduction delays  Recommended assessments prior to first dose:

‒ Liver injury ‒ CBC, hepatic function
‒ EKG to rule out preexisting conduction
‒ Fetal risk
abnormalities
‒ Increased blood pressure ‒ Ophthalmic evaluation if history of uveitis,
‒ Reduced pulmonary function macular edema, or diabetes

‒ Macular edema ‒ Test for varicella zoster antibodies

Ozanimod PI. Shukla. Curr Gastroentrol Rep. 2019;21:22. Slide credit: clinicaloptions.com
 S1PR Modulators

Phase III True North:

Ozanimod Induction Efficacy in UC at Wk 10
 Primary endpoint: clinical remission (Mayo score excluding PGA) at Wk 10
 Secondary endpoints: clinical response, endoscopic improvement (without friability), mucosal
healing (included histology with Geboes score)
Efficacy by Prior TNF Inhibitor Use at Wk 10
100 Efficacy at Wk 10 (Induction, ITT) 100 Prior TNF Inhibitor No Prior TNF Inhibitor
PBO (n = 216) PBO (n = 216) PBO (n = 151)
80 OZAN (n = 429) 80 OZAN (n = 429) 23.3
OZAN (n = 299)
21.0
P <.0001 P <.0001
Patients (%)

18.5
60 60 P = .008 52.5 19.8
47.8 15.7 P <.001
12.4 P <.0001 15.4
40 40 36.9 4.6 P <.0001 11.7
P <.0001 8.9 5.4 32.4 P <.001
27.3 P = .378 29.1
25.9 P <.0001 P = .195 2.3 22.1
20 18.4 20 18.5 15.4 P = .465 15.7
11.6 12.6 10.8 12.6
10.0 6.6
6 3.7 4.6 3.1 5.4 4.0
0 0
Clinical Clinical Endoscopic Mucosal Clinical Clinical Endoscopic Mucosal Clinical Clinical Endoscopic Mucosal
Remission Response Improvement Healing* Remission Response Improvement Healing Remission Response Improvement Healing

*P<.001 vs PBO whether Geboes score was ≤1.1, <2, or ≤3.1.

Sandborn. AIBD 2020. Abstr PO25. Slide credit: clinicaloptions.com
 S1PR Modulators

Phase III True North: Ozanimod Maintenance

Efficacy in UC at Wk 52 100
Efficacy at Wk 52 in Patients With Prior TNF Inhibitor Exposure

30.4
PBO (n = 69)
80 OZAN (n = 76)
P = .0002
18.9
18.4

Patients (%)
P = .009
Efficacy at Wk 52 (Maintenance) 60 P = .005 55.3
12.9 16.2
P = .033 P = .005
PBO (n = 227) 40 36.8
28.9
OZAN (n = 230) 24.6 23.7 22.4
20 17.4
100 10.1 10.1
5.8
19.2 0
80 P <.001 Clinical Clinical Endoscopic CS-Free Mucosal
Remission Response Improvement Remission Healing
19.4
Patients (%)

60 P <.001 Efficacy at Wk 52 in Patients Without Prior TNF Inhibitor Exposure

60 18.6 15.2 100
P <.0001 15.6 14.0
P <.001 P = .012 PBO (n = 158)
45.7 P <.001
41 80 19.4 OZAN (n = 154)
40 37
31.7 18.5 P <.001
29.6 P = .0003 62.3 16.1

Patients (%)
26.4 15.3
60 P <.001 P = .002
18.5 16.7 48.1 50
20 14.1 40.9
40 35.7 33.1
30.4
0 22.2 19.6 17.7
Clinical Clinical Endoscopic CS-Free Mucosal 20
Remission Response Improvement Remission Healing
0
Clinical Clinical Endoscopic CS-Free Mucosal
Remission Response Improvement Remission Healing

Danese. AIBD 2020. Abstr PO30. Slide credit: clinicaloptions.com

 S1PR Modulators

Phase III True North: AEs With Ozanimod Maintenance

(Wk 52)
Wk 52 AEs,2 n (%) Ozanimod Placebo
(n = 230) (n = 227)
Any AE 113 (49.1) 83 (36.6)

Common AEs (≥3%)

 ALT increased 11 (4.8) 1 (0.4)
 Headache 8 (3.5) 1 (0.4)
 Arthralgia 7 (3.0) 6 (2.6)
 Nasopharyngitis 7 (3.0) 4 (1.8)
 GGT increased 7 (3.0) 1 (0.4)

Serious AEs (≥2%) 12 (5.2) 18 (7.9)

1 (0.4) 9 (14.0)
 UC exacerbation 1 (0.4) 0
 Anemia 0 3 (1.2)
 Appendicitis/ complicated appendicitis

Severe AEs 9 (3.9) 9 (4.0)

AEs leading to d/c 3 (1.3) 6 (2.6)
 Most common AEs vs PBO were increases in ALT and headache
Danese. AIBD 2020. Abstr PO30. Slide credit: clinicaloptions.com
 S1PR Modulators

Phase II OASIS: Etrasimod in UC (Wk 12)

3.0 P = .009 60 P <.001 P = .003 Placebo (n = 50)
2.49 1-mg etrasimod (n = 52)
2.5 50
41.8 2-mg etrasimod (n = 54)
Mean MCS Score

1.93

Patients (%)
2.0 40
33
1.5
1.5 30 22.5
1.0 20 16 17.8

0.5 10 8.1

0 0
Improvement in mMCS Clinical Remission Endoscopic
Improvement
 AEs related to etrasimod were reported in 7.7%-10% of patients, with serious AEs occurring
in 3 patients receiving etrasimod 1 mg
 AEs requiring discontinuation occurred in 3 patients receiving 1 mg and 4 patients receiving 2 mg
 Most AEs (75%) were mild to moderate (grade 1/2)
Sandborn. Gastroenterology. 2020;158:550. Slide credit: clinicaloptions.com
JAK-STAT Inhibitors
 The JAK-STAT Pathway
IFN-α,
IL-2, IL-4, IL-7, IFN-β, IL-6 IL-12, EPO,
IL-9, IL-15, IL-21 IFN-ɣ family IL-23 GM-CSF

Jak1 Jak3 Jak2 Jak1 Jak2 Jak 2 Jak 2

Jak1
TYK2 TYK2 Jak 2 TYK2

 4 JAKs (1, 2, 3, and TYK2) and 7 STATs (1-6,  Selectivity of JAK inhibitors may have important
including 5A and 5B)1 clinical implications3, eg
‒ Risk of infection, especially zoster, increased by JAK 1
 Release inflammatory cytokines; important or JAK 3 inhibitors
targets for autoimmune diseases, including ‒ Reductions in reticulocyte count related to JAK 2
IBD1 inhibition and neutrophil count to JAK 1, JAK 2, and
TYK 2 inhibitors
 Tofacitinib: “pan JAK” inhibitor currently ‒ Increase in hemoglobin seen with JAK-1 specific
available for UC2 filgotinib not seen with tofacitinib

1. Cordes. World J Gastroenterol. 2020;26:4055. 2. Tofacitinib PI. 3. Winthrop. Nature Rev Rheumatol. 2017;13:234. Slide credit: clinicaloptions.com
 JAK-STAT Inhibitors

Phase III U-ACHIEVE: Efficacy and Safety

of Upadacitinib Induction in UC (Wk 8)
Primary and Secondary Endpoints Upadacitinib 45 mg QD Placebo
P Value
at Wk 8, % (n = 319) (n = 154)
Clinical remission (primary endpoint)* 26 5 <.001
Clinical response* 73 27 <.001
Endoscopic improvement 36 7 <.001
Histologic-endoscopic mucosal
30 7 <.001
improvement

*Per Adapted Mayo Score.

 Safety profile was consistent with previous phase III safety findings across other
indications, with no new safety risks observed
 Most common AEs for upadacitinib included acne, increased blood creatine
phosphokinase, nasopharyngitis
pharmabiz.com/NewsDetails.aspx?aid=134085&sid=2. Slide credit: clinicaloptions.com
 JAK-STAT Inhibitors

Phase III U-ACCOMPLISH: Efficacy and Safety

of Upadacitinib Induction in UC (Wk 8)
Primary and Secondary Endpoints Upadacitinib 45 mg QD Placebo P Value
at Wk 8, % (n = 341) (n = 174)
Clinical remission (primary endpoint)* 33 4 <.001
Clinical response* 74 25 <.001
Endoscopic improvement 44 8 <.001
Histologic-endoscopic mucosal
37 6 <.001
improvement

*Per Adapted Mayo Score.

 Safety profile was consistent with previous phase III safety findings across other
indications, with no new safety risks observed
 Most common AEs for upadacitinib included acne, anemia, increased blood
creatine phosphokinase
prnewswire.com/news-releases/second-phase-3-induction-study-confirms-upadacitinib-rinvoq-improved-clinical-endoscopic-and-
histologic-outcomes-in-ulcerative-colitis-patients-301231986.html. Slide credit: clinicaloptions.com
 JAK-STAT Inhibitors

Phase II CELEST: Upadacitinib in Patients With CD

and Prior TNF Inhibitors or Immunosuppressants (Wk 52)
 Continued clinical remission and endoscopic response were observed with upadacitinib at Wk 52
 Upadacitinib safety profile was consistent with previous studies in RA

Clinical Remission Endoscopic Remission

100 100

80 80
63

Patients (%)
Patients (%)

60 60
38 41 38
40 30 30 29 32 40
25 25 25 24 26
21
16
20 20 10

0 0
Responders Clinical Responders Responders Clinical Responders
Upadacitinib 3 mg BID Upadacitinib 6 mg BID Upadacitinib 12 mg BID Upadacitinib 24 mg BID

Sandborn. Gastroenterology. 2020;158:2123. Slide credit: clinicaloptions.com

 JAK-STAT Inhibitors

Phase IIb/III SELECTION: Filgotinib Induction

in Moderately to Severely Active UC
 SELECTION comprised 3 studies: 2 induction studies and 1 maintenance PBO
FIL 100 mg
 Current analysis focused on induction studies, which enrolled biologic-naive (n = 659) and FIL 200 mg
biologic-experienced patients (n = 689)
Clinical Remission at Wk 10 Endoscopic Remission at Wk 10 Histologic Remission at Wk 10
50 50 50 ∆19.0
45 ∆10.8 45 45 P = .0002 ∆11.4
40 P = .0157 40 40 35.1
∆7.2 ∆7.8
Patients (%)

Patients (%)

Patients (%)
35 35 ∆8.6 35 P = .019
∆3.8
30 P = .0103 30 30 P = .0672 ∆5.2
P = .3379 26.1 P = .0047 ∆1.3
23.8
25 ∆5.2 25 P = .4269 25 P = .1286 19.8
19.1 ∆2.1
20 15.3 P = .0645 20 ∆0.0
20 16.1
15 11.5 15 P = .3495 12.2 15 13.7
9.5 P = .9987 8.5
10 10 5.8 10
4.2 3.6 2.1 2.1 3.4
5 21/
137
53/
277
64/
245
27/
285
30/
262
5 16/ 30/
245
5 22/
137
66/
277
86/
245
12/
142
38/
285
52/
262
6/142 5/137 277 3/142 6/285 9/262
0 0 0
Biologic Naive Biologic Biologic Naive Biologic Biologic Naive Biologic
Experienced Experienced Experienced
 Filgotinib induction was well tolerated, with similar rates of AEs and serious AEs across all
doses and placebo
Feagan. Lancet. 2021;397:2372. Slide credit: clinicaloptions.com
 JAK-STAT Inhibitors

JAK-STAT Inhibitors: Safety Considerations

 Upadacitinib2
‒ Currently approved for RA
‒ Label warns of serious infections
(including herpes zoster),
malignancy, thrombosis, GI
perforation
 Filgotinib3
‒ MANTA-RAy study to evaluate
effect of filgotinib on semen
parameters in adult males

1. https://www.fda.gov/safety/medical-product-safety-information/xeljanz-xeljanz-xr-tofacitinib-drug-safety-communication-initial-safety-tr
ial-results-find-increased
. 2. Upadacitinb PI. 3. NCT03926195.
 A 48-year-old Man With a 6-year History of UC
and Recurrent Corticosteroid Use
 Prior meds: 5-ASA, azathioprine, Flexible sigmoidoscopy
steroids
 Currently on azathioprine + IFX 5 mg/kg
(level of 17 ug/mL, no antibodies) with
primary nonresponse
 5-6 BMs/day, mild urgency, intermittent
blood, no abdominal pain
 CRP: 15 mg/dL
 He is started on a prednisone taper
related to significant active
inflammation
Image courtesy of Dr, Millie D. Long Slide credit: clinicaloptions.com
 Clinical Trials: The Human Perspective
Flexible sigmoidoscopy
 Prior meds: 5-ASA, azathioprine, steroids
 Currently on azathioprine + IFX 5 mg/kg (level of 17 ug/mL, no
antibodies) with primary nonresponse
 5-6 BMs/day, mild urgency, intermittent blood, no abdominal pain
 CRP: 15 mg/dL
 Started on a prednisone taper related to significant active
inflammation
 Enrolled in a trial of a selective JAK inhibitor, once prednisone at a stable dosage of 15 mg/daily
‒ Achieved clinical remission by week 12
‒ Sigmoidoscopy revealed mucosal healing
‒ Steroid taper enacted per study protocol
‒ Patient in steroid-free clinical and endoscopic remission at week 48 assessment
Image courtesy of Dr, Millie D. Long Slide credit: clinicaloptions.com
Conclusions
 A number of oral agents are in late-stage development for IBD
 Among the S1P receptor modulators
‒ Ozanimod recently approved for UC; phase III efficacy at Wk 52 included clinical response of 60% vs 41% for PBO and
clinical remission of 37% vs 18.5% for PBO; safety considerations include risk of infection, bradyarrhythmia, liver injury,
and macular edema

‒ Etrasimod phase II efficacy at wk 12 in UC included improvement in modified MCS of 2.49 vs 1.5 for PBO and clinical
remission of 33% vs 8.1% for PBO; most AEs were mild to moderate (grade 1/2)

 Among the JAK-STAT inhibitors

‒ Upadacitinib phase III efficacy in UC at wk 8 included clinical response of 74% vs 25% for PBO and clinical remission of
33% vs 4% for PBO; phase II efficacy in CD at wk 52 included clinical remission of 63% and endoscopic remission of 38%
among responders; safety profile was consistent with previous studies in other indications

‒ Filgotinib phase IIb/III efficacy in UC at wk 10 included clinical remission of 26.1% vs 15.3% for PBO and endoscopic
remission of 12.2% vs 3.6% for PBO; rates of AEs were similar to placebo

‒ Awaiting further data on whether selective JAK-STAT inhibitors will have a better safety profile than tofacitinib

Slide credit: clinicaloptions.com

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