Ozanimod Maintenance Therapy After Cyclosporine Induction in Acute Severe Ulcerative Colitis.

Ozanimod has recently received US Food and Drug Administration approval for moderate-to-severe ulcerative colitis. Treatment of acute severe colitis remains a clinical challenge, and although many patients respond to cyclosporine therapy, there remains a relative paucity of maintenance options. This case report describes the first reported, successful use of ozanimod after hospitalization for acute severe ulcerative colitis and in tandem with cyclosporine. Although a longer follow-up is required, this report shows the feasibility of ozanimod in this clinical setting.

INTRODUCTION

Ulcerative colitis is a chronic inflammatory condition of the large intestine. During the course of the disease, up to 25% of patients will develop acute severe ulcerative colitis (ASUC).[1] Treatment of patients admitted with ASUC includes intravenous corticosteroid therapy, with refractory patients receiving salvage therapy of either infliximab or cyclosporine. Our group has pioneered the use of both vedolizumab and ustekinumab as maintenance therapies after cyclosporine induction, demonstrating good effectiveness and safety.[2,3]

Recently, the US Food and Drug Administration approved ozanimod for use in patients with moderate-to-severe ulcerative colitis. Ozanimod selectively modulates the S1P1 and S1P5 receptors, which are located in endothelial cells and oligodendrocytes, respectively.[4] This results in reduced lymphocyte egress from lymph nodes and fewer circulating lymphocytes in the blood, leading to decreased inflammation and tissue damage.[5]

The transition to ozanimod after cyclosporine induction has not been previously described. In this study, we detail 2 cases of ASUC, in which cyclosporine was successfully transitioned to ozanimod maintenance therapy.

CASE REPORT

Case 1

A 23-year-old man with a history of ulcerative pancolitis refractory to therapy with infliximab, vedolizumab, tofacitinib, and ustekinumab was admitted to our center with ASUC with poor response to outpatient oral steroids. Interestingly, a year before this, he had received cyclosporine therapy as a bridge to vedolizumab. Per our institutional approach,[2] standard loading doses of vedolizumab were administered at the time of discharge at weeks 0, 2, and 6. After the third dose at week 6, oral cyclosporine was discontinued. However, he later had a disease exacerbation requiring cessation of that therapy. During this hospitalization, Clostridioides difficile infection and cytomegalovirus infection were excluded. Flexible sigmoidoscopy showed Mayo 3 inflammation involving the rectum and sigmoid (Figure 1). Laboratory results at the time of admission included hemoglobin 9.3 g/dL and albumin 3.7 g/dL. Intravenous (IV) steroids failed to improve his condition, and after 3 days, he was started on IV cyclosporine. He achieved rapid clinical remission after 3 days on IV cyclosporine and was transitioned to oral dosing of both cyclosporine and steroids and discharged on these medications and trimethoprim sulfamethoxazole for Pneumocystis jiroveci pneumonia prophylaxis. He remained on cyclosporine for 2 weeks after discharge, which was then stopped without taper, and 2 days later began ozanimod with standard 7-day titration; steroids were continued. Four months after discharge, he has weaned off corticosteroids and is in clinical and biochemical remission as evidenced by a normal C-reactive protein (CRP). This patient did not have a reduction in the absolute lymphocyte count (ALC) from baseline on follow-up laboratory testing. No adverse events related to ozanimod were observed.

Figure 1.

Colonoscopy images from the patients reported in case 1 (A) and case 2 (B) showing diffuse mucosal erythema and congestion, spontaneous mucosal bleeding, and extensive ulceration consistent with a Mayo endoscopy score of 3.

Case 2

A 41-year-old woman with a history of left-sided ulcerative colitis with previous poor response to adalimumab, infliximab, vedolizumab, and tofacitinib was admitted with ASUC refractory to both oral and IV steroids. Her admission laboratory results included hemoglobin 12 g/dL, albumin 3.7 g/dL, and CRP 40 mg/L. Flexible sigmoidoscopy revealed Mayo 3 inflammation involving the rectum and sigmoid (Figure 1). A gastrointestinal infectious panel was negative including for C. difficile, and biopsies were negative for cytomegalovirus infection. She was started on IV cyclosporine and by day 4 of admission was in clinical remission with normalization of inflammatory markers. She was transitioned to oral cyclosporine and steroids and discharged on these and P. jiroveci pneumonia prophylaxis. She did have nausea and vomiting related to cyclosporine, which was stopped after a week of outpatient therapy, and 2 days later, ozanimod was started with initial titration; prednisone 30 mg was continued. Presently, the patient has weaned off oral steroids, is on alternate day topical steroids, and remains in clinical and biochemical remission (as evidenced by a normal CRP) 4 months after discharge. Of note, follow-up laboratory results 1 month after treatment initiation showed an ALC of 518 cells/μL representing an 80% reduction from her baseline ALC. No adverse events related to ozanimod were observed.

DISCUSSION

We demonstrate the feasibility of using ozanimod as maintenance therapy after induction of remission with cyclosporine in patients with ASUC. Cyclosporine is an effective therapy in patients hospitalized with ASUC and is an attractive option in the setting of hypoalbuminemia, in which there is a pharmacodynamic challenge for monoclonal antibodies due to protein loss. In addition, an elevated CRP has been associated with reduced response to infliximab.[6-8] Because many patients present after having failed multiple therapies, more options for maintenance after cyclosporine induction are required, especially those with unique modes of administration and mechanisms of action. Ozanimod is an attractive option in this setting as a synthetic targeted small molecule that is administrated orally and has a good safety profile as evidenced in the phase 3 clinical trials.[9] It is important to note that in both these cases we used tandem therapy, in which cyclosporine was discontinued before starting ozanimod (Figure 2). Cyclosporine has a short half-life, so we did not worry about the cumulative immune suppression of these 2 agents.

Figure 2.

The proposed treatment algorithm for the transition from cyclosporine to ozanimod maintenance therapy in acute severe colitis. IV, intravenous.

The safety and efficacy of ozanimod was studied in the phase 3 True North study. Treatment emergent adverse events included increased liver enzymes, headaches, nasopharyngitis, arthralgia, and 1 case of macular edema.[9] None of these treatment emergent adverse events were noted in our patients during the follow-up period. We report that one of our patients had a significant reduction in peripheral ALC. This has been described in the clinical trials and is expected considering the mechanism of action of ozanimod. Despite this reduction, no associated increased risk of severe infection has been described.[9] It remains unknown whether a reduction in ALC is associated with improved treatment outcomes. Although not specifically recommended in the label, routine laboratory follow-up seems prudent.

This is the first reported use of ozanimod after hospitalization for ASUC and in tandem with cyclosporine. We show that this therapeutic strategy is feasible, effective, and safe. A longer follow-up and further study of this therapy is required to better understand the role of this treatment.

DISCLOSURES

Author contributions: NA Cohen and DT Rubin conceptualized and designed the study, NA Cohen and D. Choi acquired the data, NA Cohen analyzed/interpreted the data and drafted the manuscript, and SR Dalal and DT Rubin critically revised the manuscript. NA Cohen is the article guarantor.

Financial disclosure: NA Cohen has served as a consultant for Seres Therapeutics. SR Dalal has served as a consultant for Pfizer and is on the speaker's bureau for AbbVie. D. Choi has served on the speaker bureau for Janssen Pharmaceuticals and has served as a consultant for Bristol-Myers Squibb. DT Rubin has received grant support from Takeda and has served as a consultant for AbbVie, AltruBio, Allergan, Arena Pharmaceuticals, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene/Syneos, GalenPharma/Atlantica, Genentech/Roche, Gilead Sciences, InDex Pharmaceuticals, Ironwood Pharmaceuticals, Iterative Scopes, Janssen Pharmaceuticals, Lilly, Materia Prima, Pfizer, Prometheus Biosciences, Reistone, Takeda, and Techlab. He is also the cofounder of Cornerstones Health and GoDuRn, LLC and is on the Board of Trustees of the American College of Gastroenterology.

Informed consent was obtained for this case report.