Tofacitinib: A Novel Addition to Your Toolkit

Bhargav Patel, Mercer University College of Pharmacy

Ulcerative colitis is a chronic inflammatory disease of the large intestine characterized by symptoms that include abdominal pain and bloody diarrhea. Patients may present with this condition between 15-30 years of age with standard treatment depending on the extent of involvement, disease severity, and other factors. [1] Medications such as corticosteroids, tumor necrosis factor (TNF) antagonists, and aminosalicylates are proposed to assist with remission and maintenance medications may follow to prevent with a relapse. [2] Tofacitinib is an oral, small-molecule Janus kinase (JAK) inhibitor developed to treat rheumatoid arthritis and is also being investigated for the treatment of ulcerative colitis. Preferential inhibition of JAK1/JAK3 may cause interference in the JAK-STAT signaling pathway and prevent signaling to multiple immunological mediators such as Interleukin (IL)-2, IL-4, and interferon–γ. [3]

 

Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis [4]
Design Multicenter, randomized, double-blind, placebo-controlled:

OCTAVE Induction 1; N= 598

OCTAVE Induction 2; N= 541

OCTAVE Sustain; N= 593

Objective To evaluate the efficacy of tofacitinib as induction and maintenance therapy for ulcerative colitis
Study Groups OCTAVE Induction 1: placebo (n= 122); tofacitinib 10 mg twice daily (n= 476)

OCTAVE Induction 2: placebo (n= 112); tofacitinib 10 mg twice daily (n= 429)

OCTAVE Sustain: placebo (n= 198); tofacitinib 5 mg twice daily (n= 198); tofacitinib 10 mg twice daily (n= 197)

Methods Patients 18 years of age or older and with a confirmed diagnosis of ulcerative colitis for at least 4 months with moderate to severely active disease (defined with a Mayo score of 6-12 [ranges from 0-12], with a rectal bleeding subscore of 1-3 [ranges from 0-3] and an endoscopic subscore of 2-3 [ranges from 0-3]) with higher scores indicating more severe disease were selected.

Patients who had presence of Crohn’s disease, received rescue therapy, ulcerative colitis limited to the distal colon, signs of fulminant colitis, or other kinds of colitis were excluded. Concomitant therapies with TNF antagonists, azathioprine, methotrexate and mercaptopurine were prohibited.

Clinical response was defined as a decrease from induction-trial baseline total Mayo score of at least 3 points and at least 30%, with an accompanying decrease in rectal bleeding subscore of at least 1 point.

Duration OCTAVE Induction 1 and 2: 8 weeks

OCTAVE Sustain: 52 weeks

Primary Outcome Measure OCTAVE Induction 1 and 2: remission (a total Mayo score of ≤2, with no subscore >1 and a rectal bleeding subscore of 0) at 8 weeks

OCTAVE Sustain: remission at 52 weeks

Secondary Outcome Measure OCTAVE Sustain: sustained remission (remission by week 24 and sustained until week 52)
Baseline Characteristics
OCTAVE Induction 1 OCTAVE Induction 2 OCTAVE Sustain
Placebo Tofacitinib 10 mg Placebo Tofacitinib 10 mg Placebo Tofacitinib 5 mg Tofacitinib 10 mg
Male, % 63.1 58.2 49.1 60.4 58.6 52 55.8
Mean age, years (SD) 41.8 (15.3) 41.3 (14.1) 40.4 (13.2) 41.1 (13.5) 43.4 (14.0) 41.9 (13.7) 42.9 (14.4)
Remission at maintenance trial entry, n (%) 29.8 32.8 27.9
Total Mayo Score (SD) 9.1 (1.4) 9 (1.4) 8.9 (1.5) 9 (1.5) 3.3 (1.8) 3.3 (1.8) 3.4 (1.8)
Partial Mayo Score (SD) 6.5 (1.2) 6.3 (1.2) 6.4 (1.2) 6.4 (1.3) 1.8 (1.4) 1.8 (1.3) 1.8 (1.3)
Median Duration of disease, years 6 6.5 6.2 6 7.2 6.5 6.8

 

Results
OCTAVE Induction 1
Placebo Tofacitinib 10 mg Difference (95% CI) p value
Remission, % 8.2 18.5 10.3 (4.3-16.3) 0.007
Clinical response, % 32.8 59.9 27.1 (17.7-36.5) <0.001
Change from baseline in total Mayo score at week 8 (SD) -1.8 (0.3) -3.8 (0.1) -1.9 (-2.5–1.4) 0.001
 

OCTAVE Induction 2

Placebo Tofacitinib 10 mg Difference (95% CI) p value
Remission, % 3.6 16.6 13 (8.1,17.9) <0.001
Clinical response, % 28.6 55 26.4 (16.8,36) <0.001
Change from baseline in total Mayo score at week 8 (SD) -2.1 (0.3) -3.7 (0.1) -1.6 (-2.2,-1) <0.001
 

OCTAVE Sustain

Placebo Tofacitinib 5 mg Difference compared to placebo (95% CI) p value Tofacitinib 10 mg Difference compared to placebo (95% CI) p  value
Remission, % 11.1 34.3 23.2 (15.3-31.2) <0.001 40.6 29.5 (21.4-37.6) <0.001
Sustained remission, % 5.1 22.2 17.2 (10.6-23.7) <0.001 25.4 20.3 (13.5-27.1) <0.001
Clinical response, % 20.2 51.5 31.3 (22.4-40.2) <0.001 61.9 41.7 (32.9-50.5) <0.001

 

Adverse Events Common Adverse Events:

OCTAVE Induction 1: worsening ulcerative colitis (2.3%), nasopharyngitis (7.1%), arthralgia (2.9%), and headache (7.8%)

OCTAVE Induction 2: worsening ulcerative colitis (3%), nasopharyngitis (4.9%), arthralgia (2.6%), and headache (7.7%)

OCTAVE Sustain: tofacitinib 5 mg: worsening ulcerative colitis (18.2%), nasopharyngitis (9.6%), arthralgia (8.6%), and headache (8.6%); tofacitinib 10 mg: worsening ulcerative colitis (14.8%), nasopharyngitis 13.8%), arthralgia (8.7%), and headache (3.1%)

Serious Adverse Events:

OCTAVE Induction 1: serious infection (1.3%), intestinal perforation (0.2%), and cardiovascular event (0.4%)

OCTAVE Induction 2: serious infection (0.2%), cardiovascular event (0.4%)

OCTAVE Sustain: serious infection (0.5%), cardiovascular event (0.5%)

Percentage that Discontinued due to Adverse Events: OCTAVE 1 Induction (3.8%), OCTAVE 2 Induction (4%), OCTAVE Sustain (9.3%)
Study Author Conclusions Tofacitinib was more effective at induction and maintenance therapy than placebo in patients with moderately to severely active ulcerative colitis.

 

Tofacitinib stands out from other biologics due to the preserved plasma levels after oral administration that can be an improvement to patient compliance and comfort. The trial’s short duration of follow-up might have led to adverse events going unreported leading to false assumptions of this drug being safer than expected. The Mayo score used to indicate remission is a quantified score based on the interpretation of endoscopic findings, which can be inconsistent and affect the outcome of trials.  

References

[1] Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med 2011;365:1713–25.

[2] Kornbluth A. & Sachar D. B. Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 105, 501–23 (2010).

[3] Danese S, Grisham M, Hodge J, Telliez JB. JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines. Am J Physiol Gastrointest Liver Physiol. 2016;310:G155–G162.

[4] Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2017;376:1723-1736.

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