ulcerative collitis update

1. MODERATOR :DR U K NATH ( ASSOC PROFF, DEPT. OF
MEDICINE ,JMCH
PRESENTER: DR. SUDIP ROY , 1ST YR PGT, MEDICINE
ORIGINAL ARTICLE PUBLISHED IN NEJM ON OCT 8, 2021

2. INTRODUCTION
• UC is one of the two major types of IBD.
• India has highest incidence of IBD in Asia ~9.3 per lakh population with 95% C.I.
• With increase in urbanisation in the country the incidence and prevalence of this disease is
slowly but surely rising posing a imminent issue .
• Amino-salicylates are not effective in severe UC, and long term use or high dosage of
glucocorticoids are associated with infection , infusion reactions and cancers.
• New biologic drugs and JAK inhibitors have low long-term efficacy.
• Hence , the need for new oral treatment for UC , that are safe , durable and glucocorticoid
sparing .

3. ULCERATIVE COLITIS
• Chronic disease that is characterised by a dysregulated immune response and chronic
inflammation in rectal and colonic mucosa.
• Urban areas and higher socio-economic classes have higher prevalence .
• Bimodal in onset -2nd to 4th decades and 7th to 9th decades.
• Classified based on Montreal classification of extent and severity of UC.
• Rectal or rectosigmoid is involved primarily.
• Diarrhea , rectal bleed , tenesmus , passage of mucus and abdominal cramps are main clinical
featues.
• Sigmoidoscopy, fecal calprotectin, fecal lactoferrin and biopsy are usedcfor evaluation.

4. ETIOLOGY AND PATHOGENESIS
• Genetic : >60 different gene defects are associated in polygenic manner with IBD.
Eg ATG16L1 , ITLN-1, etc
• Commensal microbiota: Increase in inflammation inducing microorganisms like
EIEC, EAEC or decrease in microorganisms that hinder inflammation like
faecalibacterium prausnitzii.
• Defective immune regulation: loss of oral tolerance to dietary antigens and
commensal microbiota due to alternation or deletion of certain cytokines
responsible for immunosuppression like IL-2, IL-10, TGF-B or interference with IEC
barrier eg mucus glycoprotein, NF-kB.

6. OZANIMOD
• Sphingosine-1-phosphate receptor modulator.
• Binds with high affinity to S1P-1 and S1P-5 receptors , leading to internalisation
of S1P receptors in lymphocytes and prevention of the lymphocytes mobilization
to inflammatory site.
• Dosage : day1-4 -0.23 mg per day
day 5-7 –0.46 mg per day
day 8 onwards 0.92 mg per day
• Other S1P modulators – fingolimod, Siponimod , ponesimod.

7. CHEMICAL STRUCTURE OF OZANIMOD

9. METHODS
• Multicentric
• International (285 sites in 30 countries).
• Randomised
• Parallel group
• Double blind
• Placebo controlled
• Designed and steering by members of steering committee in collaboration with
sponsor(Bristol-Myers-Squibb)

10. INCLUSION CRITERIA
1. Male or female from age 18 to 75.
2. Diagnosed case of UC at least 3 months prior to trial by clinical, endoscopic and
histological evidence.
3. Have active UC ; defined as MAYO SCORE 6-12; with endoscopic sub-score >=2,
rectal bleed sub-score >=1, stool frequency sub-score >=1.
4. Must be currently receiving either oral amino-salicylates
(>3wks);prednisolone(<20mg/day) or budesonide for at least 2 weeks.

11. INCLUSION CRITERIA CNTD…
5. Have undergone a colonoscopy or sigmoidoscopy in last 2 years or willing to
undergo colonoscopy at time of screening.
6. Males and females of childbearing age must be willing to use adequate birth
control measures during trial.
7. Must have documentation of VZV IgG Antibody positive status or complete
VZV vaccination at least 30 days prior to trial.
8. Provide written informed consent and ready to be compliant with the trial
protocol schedule.

12. EXCLUSION CRITERIA
1. Have severe extensive colitis.
2. Diagnosis of crohns or indeterminate colitis .
3. Positive stool examination for pathogens like C. difficile, ova or cysts.
4. Pregnancy, lactation or B-hcg positive status.
5. Clinically relevant hepatic , neurologic, pulmonary , ophthalmological, cardiac,
endocrine , psychiatric or any other major systemic disease like to interfere with
protocol or interpretation of results.

13. EXCLUSION CRITERIA CNTD…
6. Type 1 DM or uncontrolled Type 2 DM (HbA1C > 9%).
7. History of uveitis or macular edema .
8. Known active bacterial, viral or fungal infection.
9. History of cancer or any immunodeficiency status.
10. History of alcohol or drug abuse within 1 year prior to study.

14. STATISTICAL ANALYSIS
• Clinical remission was analysed with use of a two-sided Cochran-Mantel-Haenszel
test at 5% significance level.
• Data was analysed using SAS software for windows version (9.4).
• Quantitative data were presented as standard deviation (SD) while qualitative
data was presented as numbers.
• A p-value <0.05 was considered statistically significant.

15. TRIAL END-POINTS
Induction period
• Primary efficacy end point :
Proportion of patients in clinical remission at week 10.
• Secondary efficacy end points :
Proportion of patient with clinical response in week 10.
Proportion of patient with endoscopic improvement at week 10.
Proportion of patients with mucosal healing at week 10.

16. TIAL END-POINTS CNTD…
Maintainenece period
• Primary efficacy end-points :
Proportion of patients in clinical remission at week 52.
• Secondary efficacy end-points :
Clinical response at week 52
Endoscopic improvement at week 52
Mucosal healing at week 52

17. THE END POINTS CNTD…
Proportion of patients with durable clinical response.
Proportion of patients in remission at week 52 in the subset of patients who were
in remission at week 10.
Proportion of patients in corticosteroid free remission.

18. ADVERSE EVENTS
COMMON
1. Headache
2. Bradycardia and cardiac conduction
abnormalities
3. Fevers and chills
4. Respiratory involvement
5. Macular edema
6. Elevated aminotransferases level
SERIOUS
1. Absolute lymphocyte count decrease
by a mean of ~54% . 17 patients had
count < 200 cells per cu.mm
2. Cancer~ 4 patients were detected
with carcinoma during the trial.
3. One death occurred in a patient with
h/o ischemic CMP and prolonged
tobacco abuse.

19. RESULTS
• Study period- May 2015 to June 2020.
SCREENING
1831
ENROLLED
1012
COHORT 1
OZANIMOD :429
PLACEBO :216
COHORT 2
OZANIMOD :367
(OPEN LABEL)
INDUCTION PERIOD 10 WEEKS
COHORT 1 and 2 underwent
RANDOMISATION
OZANIMOD 230
PLACEBO 227
MAINTAINENCE PERIOD TILL 52 WEEKS

21. OZANIMOD PLACEBO
18.4% 6.0%
CLINICAL REMISSION AT WEEK 10 (p<0.001)
OZANIMOD PLACEBO
37% 18.5%
CLINICAL REMISSION AT WEEK 52 (p<0.001)

22. DISCUSSION
• In patients with moderate to severe active ulcerative colitis , once daily oral
formulation of ozanimod shows significant clinical improvements compared to
placebo.
• Cancer , opportunistic infections and macular edema were observed in patients
receiving ozanimod , but incidence were low.
• There was no incidence of bradycardia or AV conduction abnormality due to
mitigation of the 7-day –dose escalation schedule.
• Serious complication related to the study was less than 2%.
• AST levels were higher in ozanimod groups , but discontinuation due to hepatic
complication was <1%.

23. STRENGHT OF STUDY
• Large and diverse sample size.

24. LIMITATIONS OF STUDY
• Long term data collection.
• Expensive drug.

25. TAKE HOME MESSAGE
• Patients of moderate to severe active ulcerative colitis ; not controlled by the
usual prescribed drugs ; can be treated with ozanimod for induction or
maintenance therapy as it has better outcome and is also corticosteroid sparing
leading to better compliance.

26. SIMILAR STUDIES