group presentation

Question 1

What is ulcerative colitis? What are its symptoms and current treatments?

Answer 1

It is an Inflammatory Bowel disease that causes chronic inflammation in the colon and rectum. Intestinal wells become swollen and develop ulcers

symptoms: abdominal pain, uncontrolled diarrhea, bloody stools, fatigue, weight loss

current treatments: aminosalicylates, immunosuppressants, corticosteroids, biologics

Question 2

What is the pathogenesis of ulcerative colitis?

Answer 2

• multifactorial pathogenesis: genetic, environmental, microbial
• involves dysfunctional response from the innate and adaptive immune system
• multiple inflammatory cytokines are overexpressed
• amplification of the immune response leads to phenotypic expression of the disease and tissue destruction
• mediate dysfunctional cell cell interactions in innate and adaptive immune response pathways
• JAK3, a major signalling cascade downstream from cytokine and growth factor receptors, are involved in the transduction processes of IL-2R and IL-6R (including IL-12 and IL-23)

Question 3

How is tofacitinib excreted?

Answer 3

Little tofacitinib is excreted via the kidneys, most of the administered tofacitinib is eliminated via nonrenal pathways.

Question 4

What are the adverse effects of tofacitinib?

Answer 4

Tofacitinib can cross the placental barrier, and studies in animals result in fetal malformations (cardiovascular and bone malformations) when given at 100mg/kg/day)

Question 5

What are the goals of the phase 1 study? What are the AE’s that occurred?

Answer 5

Pk properties of the extended release and immediate release form; show bioequivalence of the 2 drug forms

Monitor safety

AE: 3 bowel irritation, 5 diarrhea

Question 6

In the phase 2 trial, how is the severity of UC assessed?

Answer 6

1) Mayo score (6 to 12): has 4 components, each with a subscore of 3.
- stool frequency
- rectal bleeding
- mucosal appearance at endoscopy
- physician rating of disease activity
2) Endoscopic subscore of 2 or 3

Question 7

What medications are allowed in the phase 2 trial 2 weeks before the study begins?

Answer 7

Stable dose of oral Mesalazine at least 2 weeks prior to baseline and during the

study treatment and/or glucocorticoids at least 2 weeks prior to baseline allowed

Question 8

What is the exclusion criteria for the phase 2 trial?

Answer 8

1. Subjects with other diseases of the colon that are not ulcerative colitis and can be confused with Ulcerative Colitis
2. Treatment naive subjects diagnosed with Ulcerative Colitis (without previous exposure to treatment)
3. Currently on immunosuppressive treatment
   - Intravenous corticosteroids or rectally administered corticosteroids or 5-ASA within 2 weeks prior to baseline
4. Patients who would be put at risk upon receiving tofacitinib (immunosuppressant)
   - Patients infected with HIV or Hep B or Hep C viruses
   - Current immunisation with any live virus vaccine
5. Immunocompromised patients
   - History of any lymphoproliferative disorder: Prior treatment with lymphocyte-depleting agents/therapies

Question 9

What is the primary endpoint for the phase 2 trial and what were the results?

Answer 9

• Clinical response at week 8:
  1) Decrease from baseline in mayo score of at least 3 points and at least 30 percent

) Accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute subscore for rectal bleeding of 0 or 1

-Only 15mg BID treatment group showed significant improvement in clinical response when compared to placebo

Question 10

What is the secondary endpoint for the phase 2 trial and what were the results?

Answer 10

• Clinical remission at week 8
  1) Total mayo score of 2 points or lower, with no individual exceeding 1 point
• Significant increase in clinical remission in 3mg, 10 mg and 15mg treatment groups, compared to placebo
• Endoscopic response at week 8 (decrease in baseline in endoscopy subscore by at least 1)
  1) Significant increase in endoscopic response in 15mg treatment group only, compared to placebo
• Endoscopic remission at week 8 (endoscopy subscore of 0)
  1) Significant increase in endoscopic remission in 3mg, 10mg and 15mg treatment groups, compared to placebo
• Inflammatory bowel disease questionnaire score at week 8
  1) Measures the disease specific quality of life in subjects with IBD, including ulcerative colitis, higher score indicates better quality of life
  2) Significant improvement in 15mg treatment group
• Pharmacokinetic analysis of tofacitinib was conducted and characterised in subjects with moderate to severe UC

Question 11

What were the safety results from the phase 2 study?

Answer 11

No significant increase in AE when compared to placebo. 2 patients has post operation and anal abscess respectively.

Question 12

What are the main results from the phase 2 study?

Answer 12

15mg twice daily of tofacitinib daily achieved significant improvements in the primary outcome of induction of a clinical response as well as in the secondary outcomes of induction of a clinical response and remission. This trial is focused in tofacitinib as an inductive therapy, the effectiveness in maintenance therapy is unknown.

Question 13

What are the 3 studies in the phase 3 trial?

Answer 13

2 phase 3 trials for induction therapy

1 phase 3 trial for maintenance therapy

Question 14

What is the inclusion criteria in the phase 3 study?

Answer 14

● 18 years or older

● Confirmed diagnosis (with endoscopic or radiographic and histological documentation, biopsy report) of Ulcerative Colitis for at least 4 months.

● Moderately to severely active disease

○ Mayo score of 6 to 12

○ Rectal bleeding subscore of 1 to 3

○ Endoscopic subscore of 2 or 3

● Treatment failure with existing drugs for Ulcerative Colitis or have side effects while taking at least one of the following oral or intravenous drugs:

○ Oral glucocorticoids

○ Azathioprine or 6-mercaptopurine (6-MP)

○ Anti-TNF therapy: Infliximab, Adalimumab

Question 15

What is the permitted concomitant medications for UC?

Answer 15

Induction trials: Oral aminosalicylates and oral glucocorticoids (at a maximum dose of 25mg per day of prednisolone or equivalent).

Sustain trials: Tapering of glucocortids required

Question 16

What is the exclusion criteria in the phase 3 trials?

Answer 16

● Presence of indeterminate colitis, microscopic colitis, ischemic colitis, infectious colitis, or clinical findings suggestive of Crohn’s disease, clinical signs of fulminant colitis or toxic megacolon→ other diseases of the colon that is not Ulcerative Colitis and can be confused with Ulcerative Colitis

● Subjects without previous treatment for Ulcerative Colitis (treatment-naive)

● Subjects with Ulcerative Colitis limited to the distal 15cm of colon (not severe enough)

● Prohibited concomitant therapies (those on immunosuppressive treatments)

○ TNF antagonists within 8 weeks prior to baseline

○ Azathioprine, Methotrexate, Mercaptopurine within 2 weeks prior to baseline

Question 17

How are subjects randomized in the phase 3 trial?

Answer 17

● Subjects with Mayo score of ≥ 6, rectal bleeding subscore ≥ 1, endoscopic subscore ≥ 2 and fulfil all other inclusion/ exclusion criteria will be randomized

● Randomization stratified by

○ For OCTAVE Induction 1 & 2 trials: according to prior treatment with anti-TNF therapy, glucocorticoid use at baseline and geographic region

○ For OCTAVE Sustain Trial, according to induction-trial group assignment and remission status at maintenance-trial entry

● A computer generated randomization schedule will be used to assign subjects to treatment

Question 18

How is efficiency measured in the phase 3 trial?

Answer 18

● Decrease from induction-trial baseline in the total Mayo score of ≥ 3 points and ≥ 30%

● With an accompanying decrease in the rectal bleeding subscore of ≥ 1 point or an absolute rectal bleeding subscore ≤ 1

Question 19

What are the results in terms of primary and secondary endpoints for the induction trials?

Answer 19

• Primary: In both trials, the % of patients in remission is higher in the 10mg tofacitinib group than the placebo group
• Secondary: In both trials:
• Mucosal healing occurred in significantly more patients in the 10mg tofacitinib group than placebo group
• Improvement of partial mayo score (ie. Total mayo score without endoscopic subscore) from baseline, which also occurred more significantly in the 10mg tofacitinib group than placebo group

Question 20

What are the adverse events that occurred in the phase 3 induction trials?

Answer 20

● In both trials, the percentage of patients with infections of any severity were higher in the 10mg tofacitinib group than in placebo group

● Most of the infections were mild or moderate in severity, with serious infections occurring in only 1.3% and 0.2% of the patients receiving tofacitinib in trial 1 and 2 respectively and no patients in placebo

● No cases of herpes zoster infection were serious adverse events or resulted in discontinuation

Question 21

What are the conclusions for the phase 3 induction trials?

Answer 21

● In comparison to placebo group, Tofacitinib (10mg, twice daily) group experienced:

1. Significantly higher rates of remission at 8 weeks
2. Significantly higher rates of mucosal healing and clinical response at 8 weeks
3. Significantly greater improvements in health-related quality of life and partial Mayo score at 2 weeks (first assessment of partial Mayo score after baseline assessment)

Question 22

What is the inclusion criteria for the phase 3 sustain trials?

Answer 22

○ ≥3 point decrease in induction-trial baseline Mayo Score, which is ≥30%

■ ≥1 point decrease in rectal bleeding subscore OR

■ Absolute rectal bleeding subscore of 0 or 1

-tapering of glucocorticoids to achieve steroid free status

Question 23

What are the primary and secondary endpoints for the sustain trial?

Answer 23

● Primary Endpoint: Remission at 52 weeks

● Secondary Endpoints: Mucosal healing at 52 weeks, maintenance of remission at 24 and 52 weeks

Question 24

What are the efficacy results for the sustain trial (primary and secondary endpoints)?

Answer 24

1. Efficacy: primary endpoint (remission at 52 weeks)

• Significantly higher % of patients in treatment groups were in remission compared to placebo
• Between treatment groups, 10mg treatment showed a slightly higher % of patients in remission compared to the 5 mg treatment group

1. Efficacy: secondary endpoints

• Significantly higher % of patients in treatment groups attaining secondary endpoints compared to placebo
• Between treatment groups, 10mg treatment showed a slightly higher % of patients attaining secondary endpoints compared to the 5mg treatment group

Question 25

What are the safety events in the sustain trial?

Answer 25

-Safety (adverse event) * Total % adverse events were not significantly different across the 3 groups (\*includes worsening UC) * % of AE that led to discontinuation was twice in the placebo group compared to treatment group (\*includes worsening UC) * Most common AE reported in both placebo and treatment groups were nasopharyngitis, arthralgia and headache (\*excludes worsening UC) - Safety (infections) * Treatment groups have slightly elevated incidence of infections (expected since tofacitinib is an immunosuppressant) - Safety (cancer related AE’s) ● Nonmelanoma skin cancers occurred in four patients in the sustain trial: Three from the 10-mg tofacitinib group, one from the placebo group ● Ductal breast carcinoma occured in one patient in the sustain trial ● Very unlikely due to tofacitinib exposure: Nonmelanoma skin cancer cases * The patients from the 10-mg tofacitinib group have a history of nonmelanoma * skin cancer * All four patients had prior exposure to thiopurine: Ductal breast carcinoma case * Patient was in placebo group throughout induction and maintenance trials

Question 26

What is the conclusion from the sustain trial?

Answer 26

● Efficacy: Tofacitinib was efficacious as a maintenance drug for ulcerative colitis ■ Treatment groups had significantly higher % of patients who reached the primary and secondary endpoints ● Safety ○ Long term usage of tofacitinib did not show additional or unexpected adverse events, other than those seen in previous trials

Question 27

How is the phase 4 trial carried out?

Answer 27

Patients quality of life and safety events recorded in a web application. Primary endpoints is a qualitiative questionnaire known as simple clinical colitis activity index Secondary endpoint is mayo score.

Question 28

What are the criticisms of the study?

Answer 28

* In the phase 3 induction trial, oral aminosalicylates and glucocorticoids were permitted concomitant mediations. This leads to ambiguity in degree of contribution of concomitant medication and tofacitinib in patient recovery. * Also, endoscopic subscore is an imprecise and subjective proxy for mucosal healing because it is difficult to determine severity. A fecal biomarker like fecal calprotectin and lactoferrin might be better. * Also, the toxicity of nervous system should be quantified since JAK1 is targeted. However, the high specificity of tofacitinib to JAK3 reduces the likelihood of toxicity.