Steroids in UC.pptx

Dr.S.Vadivel Kumaran.,
MD(Gen.Med).,DM(Med.Gastro)

Referral Population Cohort:
Disease Distribution at Presentation
n=1116
37%
17%
46%
Farmer RG, Easley KA, Ranking GB. Dig Dis Sci 1993;38(6):1137-1146

GOALS OF THERAPY
 Inducing remission
 Maintaining remission
 Restoring and maintaining nutrition
 Maintaining patient’s quality of life
 To minimize disease and treatment complications
 Surgical intervention (selection of optimal time for surgery)

ASSESSMENT OF DISEASE SEVERITY
 Truelove and Witts classification
 Ulcerative colitis Disease Activity Index
Endoscopic assessment
Histological assessment

TRUELOVE AND WITTS
MILD MODERATE SEVERE
<4 stools/day, without or with only
small amounts of blood
Intermediate
> 6 stools/day, with blood
No fever fever > 37.5
No tachycardia HR > 90/min
Mild anemia Anemia with Hb < 75% of normal
ESR < 30 mmHg ESR> 30 mmHg

UCDAI (“Sutherland Index”)
STOOL FREQUENCY RECTAL BLEEDING MUCOSAL
APPEARANCE
PHYSICIAN GLOBAL
ASSESSMENT
0- Normal 0 – none 0 – normal 0 – normal
1- 1to2 stools/day 1- streaks of blood 1- mild friability 1- mild
2- 3to4 stools / day 2- obvious blood 2- moderate friability 2- moderate
> 4 stools / day 3- mostly blood 3- exudation,
spontaneous bleeding
3- severe

Therapeutic Pyramid for
Active UC
Severe
Moderate
Mild
IV Corticosteroids
Aminosalicylates
Surgery
Oral Steroids
AZA/6-MP
Cyclosporine
Biologicals-Infliximab/Adalimumab

INDUCTION THERAPY
Mild Disease Moderate disease Severe disease
5-Aminosalicylates 5- Aminosalicylates IV Glucocorticoids
Topical (distal colitis) Topical (distal colitis) IV Cyclosporine
Oral (distal/extensive colitis) Oral (distal/extensive colitis) IV Infliximab
Combination
Combination
Glucocorticoids
Topical (distal colitis)
Oral (distal/extensive colitis)
Combination
Azathiopurine or 6- MP

MAINTENANCE THERAPY
 5- Aminosalicylates
Topical(distal colitis)
Oral (distal colitis/extensive colitis)
 Azathiopurine or 6- mercaptopurine
 Bilologicals/Biosimilars- Infliximab/ Adalimumab
No Role for Steroids

 The treatment of active ulcerative colitis: Includes

Relapse frequency
Disease course
Response to previous medications
Extraintestinal manifestations

INDUCTION OF REMISSION
Steroids are used if there is no response to
5ASA given for period of 2 weeks
Oral glucocorticoids (Prednisolone 40-60mg/day)
form mainstay of therapy
Steroids have to be tapered once patient is stable
For 2-4 weeks by 5mg decrements per week.

STEROID DEPENDANCE
Glucocorticoids cannot be tapered to less than 10 mg
per day within 3 months of starting the medication
OR
Relapse of symptoms occur within 3 months of
Stopping glucocorticoids

SEVERE ULCERATIVE COLITIS
Oral and IV preparations of steroids form mainstay of
Medical management
MEDICATION DOSAGE IV ROUTE
PREDNISOLONE 30 MG Q 12 H
METHYL PREDNISOLONE 16-20 MG Q 8 H
HYDROCORTISONE 100 MG Q 8 H

IV steroid usage in severe ulcerative colitis resulted
In good response in 67 % cases while 27 % cases
Had to undergo colectomy due to non response
( Turner et al -Systematic review of 1991 cases of
ulcerative colitis from 1997-2003: Clinical GE/H
2007 ; 5 (1) : 103 )

TOPICAL STEROIDS
 Liquid and Foam preparations.
 For active UC distal to splenic flexure.
 Combination of topical steroid and topical mesalamine more efficacious
than either alone.

Sideeffects
CUTANEOUS ENDOCRINE METABOLIC GASTROINTESTINAL
Acne Adrenal insufficiency
Electrolyte imbalance,
hypokalemia
Dyspepsia
Dysphagia /
Odynophagia
Impaired wound Healing
Cushingoid appearance
Fluid retention
MUSCULOSKELETAL
Myopathy
Osteonecrosis
Osteoporosis
Purpura, ecchymoses,
petechiae
Growth retardation
NEUROPSYCHIATRIC
Anxiety
Depression
Insomnia
Psychosis
Striae Hyperglycemia
OCULAR
Cataracts
Glaucoma
/Hyperlipedimia/
Hypertension

Mild-to-Moderate Relapses
 5-aminosalicylic acid (5-ASA) with corticosteroid formulations
 Locally acting corticosteroids – Enema, Foam, Suppositories
 Systemic corticosteroids and biologics- severe and refractory
active UC
 Locally acting corticosteroids with low bioavailability-
Budesonide and beclomethasone

Introduction
Fluticasone propionate
Prednisolone metasulphobenzoate
Beclomethasone dipropionate
Budesonide
Second generation oral corticosteroids target delivery of steroids to the site of
inﬂammation (i.e.distal small bowel and colon) thereby providing local(topical) anti-
inﬂammatory effects and potentially reducing systemic corticosteroid concentrations.
Haens GD et al. Systematic review: second-generation vs. conventionalcorticosteroids for induction of remission in ulcerative colitis. Aliment Pharmacol Ther 2016; 44: 1018–1029

Budesonide formulations
Controlled ileocolonic-release formulation (CIR)-
released in terminal ileum and ascending colon
pH dependent-release formulation
Multimatrix (MMX) formulation.

Challenges with existing Budesonide
Current formulations don’t deliver to left colon
Budesonide multi-matrix system (MMX)
technology is (presently available in India) -for
management of active mild to moderate UC
Sandborn WJ, Travis S, Moro L, et al. Once-daily budesonide MMX® extended-release tablets induce remission in patients with mild to moderate ulcerative colitis: results from the CORE I study.
Gastroenterology 2012; 143:

Structure of a MMX® Formulation
(adapted from Fiorino et al 2010)
Fiorino G, Fries W, De La Rue S, et al. New drug delivery systems in inflammatory bowel disease: MMX™ and tailored delivery to the gut. Current medicinal chemistry 2010; 17: 1851-1857.

Drug Delivery in the Ileum and the entire Colon
(adapted from Fiorino et al 2010)
Fiorino G, Fries W, De La Rue S, et al. New drug delivery systems in inflammatory bowel disease: MMX™ and tailored delivery to the gut. Current medicinal chemistry 2010; 17: 1851-1857.
1. Gastro-protective layer protects the dosage form from
the acidic environment of the stomach. When the
dosage form travels through the GI tract, the
duodenum pH is too low to promote hydrolysis of the
acrylic copolymers
2. In the lower part of the small intestine, the protective
layer is lost
3. The intestinal fluid comes in contact with the
hydrophilic matrix polymers. Due to relaxation of the
polymeric chains, the tablet starts to swell until a
viscous gel matrix is formed, which includes the inert
small lipophilic matrices. As the gel matrix dissolves,
budesonide is gradually released from the internal
lipophilic matrices in a controlled fashion

Budesonide MMX-9 mg
MMX® is a unique technology
Targeted drug delivery to entire colon
Specifically useful for budesonide
To reach beyond the ileo-caecal area
To maintain benefits of efficacy
combined with minimal systemic effects
Brunner M, Ziegler S, DiStefano AFD et al. Br J Clin Pharm 2005:61;31-8
Mean (SD) plasma conc. after single dose of budesonide-
MMX with transit through various gut regions
Dispersion of 153Sm-labelled
budesonide MMX® tablets
in the colon approximately 7h after
drug administration

Indication & Dosage: Budesonide MMX
•Induction of remission in patients with mild-
to-moderate active UC
•It is taken as a single 9 mg tablet once daily for
up to 8 weeks
Is taken orally in the morning, with or without
food
Must not be broken, crushed or chewed
CORTIMENT MMX Prescribing Information
Budesonide, a topically acting glucocorticoid with low systemic bioavailability and a topical
anti-inflammatory effect

Comparison in Delivery of Locally-Released Oral Budesonide
Therapies, Enemas and Colonic Release System

Combining Budesonide with MMX® Technology
1. Teshima C, Fedorak RN. Inflamm Bowel Dis 2008.
2. Edsbäcker S, et al. Aliment Pharmacol Ther 2003.
3. Marshall JK. Advanced Therapy of Inflammatory Bowel Disease 2011.
4. Travis SP et al. Gut. 2014.
UC, ulcerative colitis; MMX, multi matrix.
Properties of Budesonide
Properties of Budesonide coupled with MMX®
technology4
• Topical activity1
• Most of the drug is released in the ileum
and caecum2,3
• Potential for reduced side effects1
• Topical activity
• Efficacy of conventional steroids with targeted drug
delivery to the entire colon
• Potential for minimised systemic side effects
Oral budesonide is not well distributed in the colon and therefore MMX technology can
favour the delivery of the drug to the entire colon with minimised systemic side effects4
3

Conclusions
• The first and only orally administered topical gluco-corticosteroids targeting the
entire colon
• It allows the release of the tablet at pH >7, delivering budesonide right into the
distal gastrointestinal tract (GI), the main site of inflammation in UC
• Unlike conventional corticosteroids which significantly suppresses HPA, it has
lower bioavailability due to high first- pass liver metabolism (90%)
• The single dose of Budesonide MMX offers better patient compliance and hence
adherence to the therapy

Adapted from Danese S, et al. Aliment Pharmacol Ther 2014;39:1095-1103
Integrating budesonide MMX into treatment algorithms
for mild to moderately active ulcerative colitis

Review of Evidence…S.E.C
Safety Efficacy Convenience

CORE I and II trials Study Design
1. Sandborn WJ, Travis S, Moro L et al. Once-daily budesonide MMX(R) extended-release tablets induce remission in patients with mild to moderate ulcerative colitis: results from the CORE I study.
Gastroenterology. 2012;143(5):1218-1226
2. Travis SP, Danese S, Kupcinskas L et al. Once-daily budesonide MMX in active, mild-to-moderate ulcerative colitis: results from the randomised CORE II study. Gut. 2014;63:433-441
Efficacy and safety evaluation of Budesonide MMX 9mg and 6 mg in patients with active,
mild-to-moderate UC compared to placebo
DESIGN Randomized, double-blind, double-dummy, placebo-controlled, multi-center, parallel-group trials
PATIENT
POPULATION
Adults (18 - 75 years) with active, mild-to-moderate UC
(UCDAI*: 4 - 10 inclusive) (with confirmed histology)
• CORE I: USA, Canada, Mexico, and India
• CORE II: Western Europe, Eastern Europe, Russia, Israel, and Australia
UCDAI, Ulcerative Colitis Disease Activity Index
*UCDAI score components: stool frequency, rectal bleeding, mucosal appearance and physician rating of disease activity

Robust study Design
SCREENING
Colonoscopy with biopsy and
central histopathology review
(screening)
SAFETY FOLLOW-UP
Colonoscopy with biopsy and
central histopathology review
(day 56)
R
A
N
D
O
M
I
S
A
T
I
O
N
Budesonide MMX
9 mg
Budesonide MMX
6 mg
Placebo
Reference arm
CORE I: Measalamine (Asacol®) 2.4 g
or
CORE II: Controlled Ileal Release
Budesonide Entocort® 9 mg
56-days
Double-blind treatment
14 day safety
follow-up
2 - 16 days
Screen period
8 WEEKS ONCE-DAILY DOSING:
* 2 days wash out

CORE I and II trials: Assessments
 Full colonoscopy (not flexible sigmoidoscopy)1,2
 Baseline stool tests to exclude infectious colitis
 Blood and urine samples (laboratory parameters, plasma cortisol)
 Evaluation of patient diaries
 Mucosal biopsy samples (x3 from most severe lesions on colonoscopy)
 UCDAI*, CAI, EI and IBD-QoL questionnaire
 Pill count to determine compliance
 AE reporting, vital signs and physical examination
AE, adverse event; CAI, clinical activity index; EI, endoscopic index; IBD-QoL, inflammatory bowel disease quality of life

CORE I & II Pivotal Trials: Primary efficacy endpoint
Combined clinical AND endoscopic remission at
week 8
UCDAI score ≤1
Sub-scores of 0 for both rectal bleeding and
stool frequency
No mucosal friability on colonoscopy
≥1-point reduction from baseline in the EI score
3. Sandborn WJ, Danese S, Kupcinskas L et al. Induction of clinical and colonoscopic remission of mild-to-moderate ulcerative colitis with budesonide MMX 9 mg: pooled analysis of two phase 3 studies.
Aliment Pharmacol Ther. 2015;41:409–418

CORE I & II Pivotal Trials: : Secondary and
exploratory efficacy endpoints
Secondary Endpoints
 Clinical improvement at week 8, defined as: ≥3-point improvement in UCDAI from
baseline
 Endoscopic improvement at week 8, defined as ≥1-point reduction in the
endoscopy
sub-score of the UCDAI from baseline
Exploratory endpoints
 Symptom resolution at week 8
 Rectal bleeding and stool frequency UCDAI sub-scores = 0

CORE I & II Trials: Primary efficacy endpoint:
Results
Combined Clinical and Endoscopic Remission at week 8
7.4
17.9*
13.2
12.1
4.5
17.4**
8.3
12.6
6.2
17.7***
10.9
0
5
10
15
20
25
Placebo Asacol®/ Entocort®
CORE I CORE II Pooled Data
Budesonide MMX 9 mg
vs. Placebo
*p = 0.0143
**p = 0.0047
***p = 0.0002
%
of
Patients
(mITT)
Budesonide MMX 9
mg
Budesonide MMX
6 mg
mITT, modified intention to treat
In the CORE I and CORE II studies and in the pooled analysis, clinical and endoscopic remission
at week 8 were significantly higher with Budesonide MMX 9 mg O.D. compared with placebo
5-ASA/Budesonide

CORE I & II Trials: Secondary efficacy endpoint:
Results
Clinical Improvement: ≥3 point reduction in overall UCDAI score
24.8
33.3§
30.6
33.9
33.7
42.2§§
25.7
33
28.6
37.5§§§
28.3
0
5
10
15
20
25
30
35
40
45
50
Placebo Asacol® /
Entocort®
Budesonide MMX 9
mg vs. Placebo
Not Significant
Odds Ratios:
§1.52 (0.87 - 2.65)
§§1.44 (0.80 - 2.57)
§§§1.50 (1.04 - 2.24)
%
of
Patients
(mITT)
In the CORE I and CORE II studies and in the pooled analysis, clinical improvement at week 8 was
numerically, but not statistically greater with Budesonide MMX OD compared with placebo
Budesonide MMX 9
mg
Budesonide MMX
6 mg 5-ASA/Budesonide

33.1
41.5§
35.5
33.1
31.5
42.2§§
25.7
36.9
32.4
41.8§§§
30.9
0
5
10
15
20
25
30
35
40
45
50
Placebo Asacol® / Entocort®
CORE I & II Trials: Secondary efficacy endpoints: Results
Endoscopic Improvement: ≥1 point reduction in mucosal appearance subscores
In the CORE I and CORE II studies and in the pooled analysis, endoscopic improvement at
week 8 was numerically, but not statistically greater with Budesonide MMX compared with
placebo
%
of
Patients
(mITT)
Budesonide MMX
9 mg vs. Placebo
Not Significant
Odds Ratios:
§1.43 (0.85 - 2.42)
§§1.59 (0.88 - 2.86)
§§§1.50 (1.02 - 2.21)
N=103
N=121 N=89 N=210 N=123 N=109 N=232 N=121 N=109 N=230 N=124
Budesonide MMX 9
mg
Budesonide MMX 6 mg
5-
ASA/Budesonide

16.5
28.5* 28.9*
25
11.2
23.9*
13.8
18.4
14.3
26.3*
21.7
0
5
10
15
20
25
30
Placebo Asacol® / Entocort®
CORE I & II Trials: Exploratory efficacy endpoints: Results
Symptom resolution: 0 for both stool frequency and rectal bleeding subscores
In the CORE I and CORE II studies and in the pooled analysis, symptom resolution at
week 8 was significantly higher with Budesonide MMX OD compared with placebo
%
of
Patients
(mITT)
Budesonide MMX
9 mg vs. Placebo
*p < 0.05
N=123 N=232 N=121 N=230
N=121 N=89 N=210 N=109 N=109 N=124 N=103
Budesonide MMX 9
mg
Budesonide MMX 6 mg 5-
ASA/Budesonide

CORE I & II: Pooled Safety Analysis
Preferred Term, n (%)
Placebo
N = 258
Budesonide MMX
9 mg
N = 255
Budesonide MMX
6 mg
N = 254
Any AEs 138 (53.5) 144 (56.5) 154 (60.6)
Colitis Ulcerative 36 (14.0) 34 (13.3) 42 (16.5)
Headache 27 (10.5) 29 (11.4) 37 (14.6)
Nausea 11 (4.3) 13 (5.1) 12 (4.7)
Abdominal Pain 15 (5.8) 9 (3.5) 7 (2.8)
Diarrhea† 11 (4.3) 3 (1.2) 7 (2.8)
Flatulence† 5 (1.9) 6 (2.4) 8 (3.1)
Nasopharyngitis 6 (2.3) 4 (1.6) 13 (5.1)
Similar Side effects profile compared to placebo
* Incidence of a TEAE ≥ 5% in any group (Safety Population)

Review of Cochrane Collaboration (2015)
1. Sherlock ME, MacDonald JK, Griffiths AM et al. Oral budesonide for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2015;10:CD007698. doi: 10.1002/14651858.CD007698.pub3
2. Travis SP, Danese S, Kupcinskas L, et al. Once-daily budesonide MMX in active, mild-to-moderate ulcerative colitis: results from the randomised CORE II study. Gut. 2014;63:433-441
3. Sandborn WJ, Travis S, Moro L, et al. Once-daily budesonide MMX(R) extended-release tablets induce remission in patients with mild to moderate ulcerative colitis: results from the CORE I study. Gastroenterology.
2012;143(5):1218-1226
4. Rubin DT, Cohen RD, Sandborn WJ et al. Budesonide MMX(r) 9 mg for inducing remission in patients with mild-to-moderate ulcerative colitis not adequately controlled with oral 5-asa. Abstract number:A-1402.
Presented (OP011) at 10th congress of ECCO, 20.02.2015

Clinical effectiveness endpoints at the end of
treatment
Danese S, Hart A, Dignass A, et al. A multicentre prospective cohort study assessing the effectiveness of budesonide MMX® (Cortiment®MMX®) for active, mild-to-moderate ulcerative
colitis. United European gastroenterology journal 2019; 7: 1171-1182
Budesonide MMX is safe, effective and well tolerated in patients with UC.

Effectiveness and tolerability of budesonide-
MMX in ulcerative colitis: A real-life experience
 Multicentre retrospective cohort study conducted in 82 patients at four tertiary IBD
centres in Italy
 The primary outcome was clinical remission at the end of 2 months of budesonide-MMX
therapy
 Clinical remission was achieved in 50% of patients and clinical response in
2.4% of patients, while 40.2% of patients showed no response (47.6%)
 Budesonide-MMX is commonly used in combination with other therapies, both for acute
disease flares and for partial response to therapy
Maconi G, Mezzina N, Landi S, et al. Use, effectiveness and tolerability of budesonide-MMX in ulcerative colitis: A real-life experience. United European gastroenterology journal 2019; 7:
1164-1170.

Overview of guidelines
 AGA suggests adding either oral prednisone or budesonide MMX in mild–moderate UC
refractory to optimized oral and rectal 5-ASA, regardless of disease extent
 BSG guidelines strongly recommend with moderate quality evidence that topically-acting
oral corticosteroids such as budesonide MMX can be used as alternative treatments for
those wishing to avoid systemic corticosteroids
Indian Society of Gastroenterology Consensus on management of UC clearly states
that oral steroids with low systemic bioavailability (budesonide) are available in
India. However, presently available budesonide preparation in India is designed
for release in the distal ileum and right colon and is not suitable for use in patients
with UC
1. Ramakrishna BS et al. Indian Society of Gastroenterology consensus on ulcerative colitis. Indian J Gastroenterol 2012; 31: 307-323. 2012/10/26.
2. Lamb CA, Kennedy NA, Raine T, et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut 2019; 68: s1-s106
3. Ko CW et al. AGA clinical practice guidelines on the management of mild-to-moderate ulcerative colitis. Gastroenterology 2019; 156: 748-764

Conclusions
 Budesonide MMX has a positive benefit-risk profile for 8 weeks of treatment in active,
mild to moderate UC providing a safer and effective steroidal treatment options that
effectively targets the main site of UC with a low risk for systemic side effects and better
patient compliance
Budesonide-MMX is well tolerated and efficacious in mild-to-moderate UC, with
available data supporting the hypothesis that low bioavailability and targeted
delivery of budesonide limit side effects

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