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Background Analysis: US FDA Advisory Committee to Review Pfizer’s Xeljanz for the Treatment of Ulcerative Colitis– MAR 8, 2018 (GIDAC)

Announcement

The US FDA has scheduled a meeting of the Gastrointestinal Drugs Advisory Committee (GIDAC) for Thursday, March 8, 2018. The Committee will discuss a supplemental new drug application (sNDA) for Xeljanz (tofacitinib) tablets by Pfizer Inc. (Pfizer) for the treatment of certain adult patients with ulcerative colitis.

Indication Background

Description of Indication

Ulcerative Colitis (UC) is a form of inflammatory bowel disease that impacts the large intestine, which includes the colon and the rectum. Symptoms of UC include chronic diarrhea with blood and mucus, abdominal pain and cramping, fever and weight loss. The causes of UC are unknown, but it is believed to involve a genetic predisposition, and it may be triggered by an immune response to microbial organisms.

Product Background

Description of Product

Xeljanz (tofacitinib tablet) is a Janus kinase (JAK) inhibitor that is FDA-approved for the treatment of certain adult patients with rheumatoid arthritis and psoriatic arthritis who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs (DMARDs).

The most recent FDA-approved labeling for Xeljanz, dated December 2017, describes the mechanism of action as follows, “JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. JAK enzymes transmit cytokine signaling through pairing of JAKs (e.g., JAK1/JAK3, JAK1/JAK2, JAK1/TyK2, JAK2/JAK2). Tofacitinib inhibited the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC50 of 406, 56, and 1377 nM, respectively. However, the relevance of specific JAK combinations to therapeutic effectiveness is not known.”

Pfizer has conducted Phase 3 clinical trials that studied twice-daily oral dose regimens of 5mg, 10 mg, and 15 mg for the treatment of adult patients with  moderately to severely active UC who have demonstrated an inadequate response, loss of response, or intolerance to corticosteroids, azathioprine, 6-mercaptopurine, or tumor necrosis factor (TNF) inhibitor therapy.

Based on outcomes from the clinical development program, it appears that Pfizer will propose to only market the 5 mg and 10 mg tablets, since they discontinued their exploration of the 15 mg twice daily dose early in Phase 3 development.

Clinical Trials of Proposed Indication

Pfizer has reported that the sNDA submission includes data from three pivotal Phase 3 studies from the “OCTAVE: Oral Clinical Trials for tofAcitinib in ulceratiVE colitis” clinical development program evaluating the safety and efficacy of tofacitinib in patients with moderately to severely active UC despite previous conventional therapy or therapy with a TNF antagonist. The three Phase 3 studies are: OCTAVE Induction 1, which randomized 614 patients; OCTAVE Induction 2, which randomized 547 patients; and OCTAVE Sustain, which randomized 593 patients. The primary efficacy endpoint for OCTAVE Induction 1 and 2 was remission at Week 8. OCTAVE Sustain was a maintenance trial with a primary efficacy endpoint of remission at Week 52. Results were published in The New England Journal of Medicine in May 2017. Key excerpts are presented below, without the references to tables and appendices.

Overall Summary

In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the patients in the tofacitinib group versus 8.2% in the placebo group (P=0.007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% versus 3.6% (P<0.001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5 mg tofacitinib group and 40.6% in the 10 mg tofacitinib group versus 11.1% in the placebo group (P<0.001 for both comparisons with placebo). In the OCTAVE Induction 1 and 2 trials, the rates of overall infection and serious infection were higher with tofacitinib than with placebo. In the OCTAVE Sustain trial, the rate of serious infection was similar across the three treatment groups, and the rates of overall infection and herpes zoster infection were higher with tofacitinib than with placebo. Across all three trials, adjudicated non-melanoma skin cancer occurred in five patients who received tofacitinib and in one who received placebo, and adjudicated cardiovascular events occurred in five who received tofacitinib and in none who received placebo; as compared with placebo, tofacitinib was associated with increased lipid levels.

Patient Disposition

In the OCTAVE Induction 1 and 2 trials, patients were 18 years of age or older and had had a confirmed diagnosis of ulcerative colitis for at least 4 months. Patients had moderately to severely active disease, which was defined as a Mayo score of 6 to 12, with a rectal bleeding subscore of 1 to 3 and an endoscopic subscore of 2 or 3. Scores on the Mayo scale range from 0 to 12, and scores on each of the four subscores range from 0 to 3, with higher scores indicating more severe disease. Eligibility for the trial was based on a centrally assessed Mayo endoscopic subscore. Exclusion criteria were the presence of clinical findings suggestive of Crohn’s disease, UC limited to the distal 15 cm of colon, clinical signs of fulminant colitis, toxic megacolon, or indeterminate, microscopic, ischemic, or infectious colitis. Patients were required to have had treatment failure with or to have had unacceptable side effects from treatment with at least one of the following agents: oral or intravenous glucocorticoids, azathioprine, , infliximab, or adalimumab. Permitted concomitant medications for UC were oral aminosalicylates and oral glucocorticoids (at a maximum dose of 25 mg per day of prednisone or a prednisone equivalent), provided that the medications were administered at a stable dose throughout the induction trials; in the maintenance trial, tapering of glucocorticoids was mandatory. Prohibited concomitant therapies included TNF antagonists, azathioprine, methotrexate, and mercaptopurine.

Detailed Efficacy Results

In the OCTAVE Induction 1 and 2 trials, the primary efficacy end point was remission (a total Mayo score of ≤2, with no subscore >1 and a rectal bleeding subscore of 0) at 8 weeks, and the key secondary end point was mucosal healing (a Mayo endoscopic subscore of ≤1) at 8 weeks. In the OCTAVE Sustain trial, the primary end point was remission at 52 weeks; key secondary end points were mucosal healing at 52 weeks and remission that was sustained (i.e., occurring at both 24 and 52 weeks) and glucocorticoid-free (i.e., occurring without the administration of glucocorticoids for ≥4 weeks before the assessment) among patients who were in remission at maintenance-trial entry.

In the OCTAVE Induction 1 trial, 614 patients underwent randomization: 122 were assigned to receive placebo, 476 to receive tofacitinib at a dose of 10 mg twice daily, and 16 to receive tofacitinib at a dose of 15 mg twice daily. In the OCTAVE Induction 2 trial, 547 patients underwent randomization: 112 were assigned to receive placebo, 429 to receive tofacitinib at a dose of 10 mg twice daily, and 6 to receive tofacitinib at a dose of 15 mg twice daily.

In the OCTAVE Sustain trial, 593 patients underwent randomization: 198 were assigned to receive placebo, 198 to receive tofacitinib at a dose of 5 mg twice daily, and 197 to receive tofacitinib at a dose of 10 mg twice daily. The majority (88%) of patients in the OCTAVE Sustain trial had received tofacitinib during the induction trial, and 30% were in remission at maintenance-trial entry.

In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the patients (88 of 476) in the 10 mg tofacitinib group versus 8.2% (10 of 122) in the placebo group (P=0.007) — a difference of 10.3 percentage points (95% confidence interval [CI], 4.3 to 16.3). In the OCTAVE Induction 2 trial, remission at 8 weeks occurred in 16.6% of the patients (71 of 429) in the 10 mg tofacitinib group versus 3.6% (4 of 112) in the placebo group (P<0.001) — a difference of 13.0 percentage points (95% CI, 8.1 to 17.9). In both trials, the treatment effect was similar between those who had received previous treatment with a TNF antagonist and those who had not.

In the OCTAVE Induction 1 and 2 trials, the key secondary end point of mucosal healing at 8 weeks occurred in significantly more patients in the 10 mg tofacitinib groups than in the placebo groups. … In the OCTAVE Sustain trial, mucosal healing at 52 weeks occurred in significantly more patients in the 5 mg tofacitinib group (37.4% of patients [74 of 198]) and in the 10 mg tofacitinib group (45.7% [90 of 197]) than in the placebo group (13.1% [26 of 198]) (P<0.001 for both comparisons).

The mean IBDQ (Inflammatory Bowel Disease Questionnaire) total scores at baseline were between 120 and 127 in the induction trials and between 166 and 167 in the maintenance trial. The proportion of patients with an IBDQ score indicative of remission (i.e., a score of ≥170) and the proportion of patients with an IBDQ score indicative of a treatment response (i.e., a score ≥16 points higher than the baseline score in the induction trial) were significantly larger with tofacitinib than with placebo at weeks 4 and 8 in both induction trials (P≤0.008 for all comparisons).

Detailed Safety Results

In the OCTAVE Induction 1 trial, adverse events occurred in 56.5% of the patients (269 of 476) in the 10 mg tofacitinib group and in 59.8% (73 of 122) in the placebo group. …

In the OCTAVE Sustain trial, adverse events occurred in 72.2% of the patients (143 of 198) in the 5 mg tofacitinib group, 79.6% (156 of 196) in the 10 mg tofacitinib group, and 75.3% (149 of 198) in the placebo group. The most frequently reported adverse events in any treatment group in the maintenance trial (excluding worsening UC) were nasopharyngitis, arthralgia, and headache.

In the OCTAVE Induction 1 trial, serious adverse events occurred in 3.4% of the patients in the 10 mg tofacitinib group and in 4.1% in the placebo group. The corresponding percentages in the OCTAVE Induction 2 trial were 4.2% and 8.0%. In the OCTAVE Sustain trial, serious adverse events occurred in 5.1% of the patients in the 5 mg tofacitinib group, 5.6% in the 10 mg tofacitinib group, and 6.6% in the placebo group.

In the OCTAVE Induction 1 and 2 trials, the proportion of patients who discontinued treatment because of adverse events was similar in the placebo groups and the tofacitinib groups. In the OCTAVE Sustain trial, the proportion was larger in the placebo group than in the tofacitinib groups.

In the OCTAVE Induction 1 and 2 trials, the percentages of patients with infections of any severity were higher in the 10 mg tofacitinib groups (23.3% and 18.2%, respectively) than in the placebo groups (15.6% and 15.2%). In the OCTAVE Sustain trial, infections occurred in 35.9% of the patients in the 5 mg tofacitinib group, 39.8% in the 10-mg tofacitinib group, and 24.2% in the placebo group. In all three trials, the majority of infections were mild or moderate in severity. In the OCTAVE Induction 1 and 2 trials, serious infections occurred in 6 patients (1.3%) and 1 patient (0.2%), respectively, in the 10 mg tofacitinib groups and in no patients in the placebo groups. In the OCTAVE Sustain trial, serious infections occurred in 2 patients (1.0%) in the 5 mg tofacitinib group, 1 (0.5%) in the 10 mg tofacitinib group, and 2 (1.0%) in the placebo group. In the OCTAVE Induction 1 and 2 trials, herpes zoster infection occurred in 3 patients (0.6%) and 2 patients (0.5%), respectively, in the 10 mg tofacitinib groups and in 1 (0.8%) patient and no patients in the placebo groups. In the OCTAVE Sustain trial, herpes zoster infection occurred in 3 patients (1.5%) in the 5 mg tofacitinib group, 10 (5.1%) in the 10 mg tofacitinib group, and 1 (0.5%) in the placebo group. No cases of herpes zoster infection were serious adverse events or resulted in discontinuation; most affected one dermatome or two adjacent dermatomes. One patient in the 10 mg tofacitinib group in the OCTAVE Induction 2 trial had cytomegalovirus colitis. No cases of tuberculosis were reported in the three trials.

In the OCTAVE Induction 1 trial, 1 patient in the 10 mg tofacitinib group had a serious adverse event of intestinal perforation. The patient had had cytomegalovirus colitis approximately 3 months before the start of the trial and had been receiving concomitant therapy with oral prednisone (20 mg daily) at baseline. The patient underwent colectomy and had a perforation in the descending colon, which had been affected by colitis. In the OCTAVE Induction 2 trial, 1 patient in the placebo group had a serious adverse event of intestinal perforation. No patients in the OCTAVE Sustain trial had adverse events of intestinal perforation.

In the induction trials, non-melanoma skin cancers occurred in 2 patients: 1 patient in the 10 mg tofacitinib group in the OCTAVE Induction 1 trial who had a history of non-melanoma skin cancer received a diagnosis of squamous-cell carcinoma of the skin, and 1 patient in the 10-mg tofacitinib group in the OCTAVE Induction 2 trial received a diagnosis of basal-cell carcinoma of the skin. In the OCTAVE Sustain trial, non-melanoma skin cancers occurred in 4 patients: 3 patients in the 10 mg tofacitinib group who had a history of non-melanoma skin cancer received a diagnosis of squamous-cell carcinoma (2) or basal-cell carcinoma (1), and 1 patient in the placebo group received a diagnosis of basal-cell carcinoma. All the patients with non-melanoma skin cancer had previous exposure to thiopurines. No patients in the induction trials had cancer other than non-melanoma skin cancer. One patient in the OCTAVE Sustain trial had invasive ductal breast carcinoma; this patient received placebo during both the induction trial and the maintenance trial.

Across all three trials, 5 patients who received tofacitinib had adjudicated cardiovascular events. One patient in the 10 mg tofacitinib group in the OCTAVE Induction 1 trial died from aortic dissection.

In the induction and maintenance trials, the proportion of patients with abnormal lipid and creatine kinase levels was generally larger in the tofacitinib groups than in the placebo groups. Across the three trials, lipid levels (total cholesterol, low-density lipoprotein, and high-density lipoprotein) increased with tofacitinib, and the increase plateaued after approximately 4 weeks. There were no reported cases of myopathy or rhabdomyolysis associated with the elevated creatine kinase levels among patients who received tofacitinib. Across the three trials, 2 patients who received tofacitinib (both in the induction trials) had absolute lymphocyte counts of less than 500 per cubic millimeter that were confirmed by two sequential measurements; both patients had low absolute lymphocyte counts at baseline (640 and 650 per cubic millimeter).

The ClinicalTrials.gov identifiers for OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain, are NCT01465763, NCT01458951, and NCT01458574, respectively.

Regulatory Background

US Regulatory Background

March 2018 – PDUFA date

July 13, 2017 – Pfizer announced the FDA’s acceptance of the sNDA.

November 6, 2013 - Initial approval date of Xeljanz for the treatment of certain patients with rheumatoid arthritis.

The current indication of Xeljanz and its extended -release formulation, Xeljanz XR, labeling, dated December 2017, is:

1.1 Rheumatoid Arthritis

·      XELJANZ/XELJANZ XR (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs).

·      Limitations of Use: Use of XELJAN Z/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

1.2 Psoriatic Arthritis

·      XELJANZ/XELJANZ XR (tofacitinib) is indicated for the treatment of adult patients with active psoriatic arthritis who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs (DMARDs).

·      Limitations of Use: Use of XELJAN Z/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

The product is approved with a Boxed Warning: SERIOUS INFECTIONS AND MALIGNANCY, and the FDA has required a Medication Guide.

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: Pfizer Inc. Drug Name: tofacitinib Drug Class: Janus kinase (JAK) inhibitor Indication: Ulcerative colitis


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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.