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Gevokizumab in the Treatment of Autoimmune Non-Necrotizing Anterior Scleritis: Results of a Phase I/II Clinical Trial

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Gevokizumab in the Treatment of Autoimmune Non-Necrotizing Anterior Scleritis: Results of a Phase I/II Clinical Trial Gevokizumab in the Treatment of Autoimmune Non-necrotizing Anterior Scleritis: Results of a Phase I/II Clinical Trial JARED E. KNICKELBEIN, WILLIAM R. TUCKER, NIRALI BHATT, KAREN ARMBRUST, DAVID VALENT, DOMINIC OBIYOR, ROBERT B. NUSSENBLATT, AND H. NIDA SEN PURPOSE: To evaluate the safety and potential efficacy cial in treating active, noninfectious anterior scleritis and of gevokizumab, an anti-interleukin 1b (IL-1b) mono- that gevokizumab is well tolerated. Larger randomized tri- clonal antibody, in the treatment of active, noninfectious, als are warranted to assess the true efficacy of gevokizu- non-necrotizing anterior scleritis. mab in the treatment of non-necrotizing anterior DESIGN: Phase 1/2, open label, nonrandomized, pro- scleritis. (Am J Ophthalmol 2016;172:104–110. spective, single-arm pilot trial. Published by Elsevier Inc.) METHODS: Eight patients with active, noninfectious, non-necrotizing anterior scleritis with a scleral inflam- matory grade of D1toD3inatleast1eyewere ONINFECTIOUS ANTERIOR SCLERITIS, A POTEN- enrolled. In 1 patient both eyes were enrolled, for a total tially vision-threatening condition which may of 9 eyes (4 eyes with D1, 1 eye with D2, and 4 eyes N be necrotizing or non-necrotizing, is often asso- with D3). Patients received 1 subcutaneous injection ciated with systemic inflammatory diseases, such as rheu- of 60 mg gevokizumab at baseline and then every matoid arthritis, spondyloarthropathies, and 1 4 weeks for 12 weeks. Complete physical and ocular ex- granulomatosis with polyangiitis. Non-necrotizing aminations were performed at each visit. The primary anterior uveitis is categorized as nodular or diffuse outcome was at least a 2-step reduction or reduction depending on the extent and morphology of the scleral to grade 0 in scleral inflammation on a 0 to D4 scale ac- lesions. Whereas mild cases of non-necrotizing noninfec- cording to a standardized photographic scleritis grading tious anterior scleritis may be treated with oral nonste- system by 16 weeks in the study eye compared to base- roidal anti-inflammatory drugs (NSAIDs), cases of line. Secondary outcomes included changes in visual more severe non-necrotizing or any necrotizing nonin- acuity, intraocular pressure, and trends in scleral fectious scleritis require systemic corticosteroids and grading. Participants who met the primary outcome often steroid-sparing immunomodulatory therapy were eligible to continue in the study for up to 52 weeks (IMT), including antimetabolites (eg, azathioprine, 2–5 and received additional gevokizumab injections every methotrexate, mycophenolate), T-cell inhibitors 6 4 weeks until week 36, followed by 2 safety visits at (eg, cyclosporin A), cytotoxic agents (eg, cyclophos- 6 weeks 40 and 52. phamide), or biologic agents (eg, adalimumab, inflixi- 7–11 RESULTS: Seven eyes from 7 patients met the primary mab, rituximab). outcome within a median time of 2 weeks following the Several inflammatory cell types, including T and B first gevokizumab injection. No definitive changes in vi- lymphocytes, and cytokines, including TNF-a,have sual acuity or intraocular pressure were identified. There been implicated in the pathogenesis of noninfectious 12 were no serious adverse events related to the study drug. scleritis, and targeting these cells and cytokines A total of 43 adverse effects were reported, with 93% with the above-mentioned medications has proven described as mild, 95% as nonocular, and only 14% beneficial in treating this disease in small to medium- deemed possibly caused by the investigational treatment. sized cohorts. Interleukin 1b (IL-1b)isanotherinflam- CONCLUSIONS: The results of this small study suggest matory cytokine implicated in the immunopathogenesis that blockage of IL-1b using gevokizumab may be benefi- of noninfectious scleritis. Patients with diffuse anterior scleritis were found to have elevated levels of IL-1b in their serum compared with healthy controls,13 and blockade of the IL-1 receptor with anakinra has been Supplemental Material available at AJO.com. reported to improve anterior scleritis associated with Accepted for publication Sep 12, 2016. 14 From the National Eye Institute, National Institutes of Health, rheumatoid arthritis (RA). In the current study, we Bethesda, Maryland. sought to investigate the safety and potential efficacy ÃDeceased April 17, 2016. of gevokizumab, an anti-IL-1b monoclonal antibody, Inquiries to H. Nida Sen, Laboratory of Immunology, National Eye Institute, NIH, 10 Center Dr, 10/10N109, Bethesda, MD 20892; e-mail: in the treatment of active, noninfectious anterior [email protected] scleritis. 104 PUBLISHED BY ELSEVIER INC. 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2016.09.017 METHODS cancer or carcinoma in situ of the cervix) diagnosed within the last 5 years. Also, eyes with periocular or intravitreal THIS WAS A PHASE I/II NONRANDOMIZED, PROSPECTIVE, steroid injection within the last 6 weeks prior to enroll- single-center study that evaluated subcutaneous gevokizu- ment, dexamethasone intravitreal implant (Ozurdex) mab (XOMA, Berkeley, California, USA) as a treatment within the last 6 months prior to enrollment, fluocinolone for active, noninfectious, non-necrotizing anterior scleritis. intravitreal implant (Retisert) within the last 3 years prior The study protocol was reviewed and approved by the Insti- to enrollment, or intraocular surgery of any kind in the last tutional Review Board of the National Institutes of Health, 4 weeks prior to enrollment were excluded. a HIPAA-compliant institution, and all procedures conformed to the tenets of the Declaration of Helsinki OPHTHALMIC AND MEDICAL EVALUATIONS: At all (Clinical Trials registration: NCT01835132; NEI protocol visits, participants underwent a complete physical and ID: 13-EI-0102). Informed consent was obtained from all ocular examination that included visual acuity assessment participants at the time of enrollment. Patients received using the standardized Early Treatment Diabetic Retinop- 1 subcutaneous injection of 60 mg gevokizumab at baseline athy Study (ETDRS) refraction protocol, vital signs, and then every 4 weeks for 12 weeks. Participants could concomitant medications assessment, adverse event assess- continue taking <_20 mg/day prednisone or equivalent dur- ment, intraocular pressure, slit-lamp examination, dilated ing the study. All other immunosuppressive medications fundus examination, standardized scleral photographs, had to be stopped upon receiving the first injection of gevo- complete blood count with differential, basic metabolic kizumab. Participants who met the primary outcome mea- panel, urine pregnancy testing in female participants, and sure, as defined below, and did not develop a severe scleritis urinalysis. complication (eg, corneal complications) that caused vision loss >20 ETDRS letters were eligible to continue PRIMARY, SECONDARY, AND SAFETY OUTCOMES: The in the first extension phase of the study. In this extension primary outcome was at least a 2-step reduction or reduc- phase, participants received 6 additional gevokizumab in- tion to grade 0 in scleral inflammation in the study eye jections every 4 weeks until week 36 followed by 2 safety (or eyes, if both eyes met study eye criteria) in at least 1 visits at weeks 40 and 52. After 52 weeks, patients were quadrant according to a standardized photographic scleritis eligible for a second extension phase in which they would grading system developed at NEI,15 on or before the week receive gevokizumab injections at weeks 52, 54, 58, and 16 visit as compared to baseline. Two separate investigators 62 and then as needed for flares of scleritis at the investiga- evaluated the primary outcome, which was based on scores tor’s discretion until week 110. However, the implementa- from the clinical examination and not scleral photographs tion of the second extension was delayed, with an average of the participant. If there was a difference in the grading of 10.2 months (range 7.5–14 months) interruption be- between the 2 investigators, then the difference was tween the last injection under the first extension phase discussed between the investigators and an opinion was and the reintroduction of treatment under the second reached by consensus. The secondary outcomes included extension phase. mean and median change in visual acuity via ETDRS at all follow-up visits, changes in intraocular pressure, and INCLUSION AND EXCLUSION CRITERIA: Inclusion trends in scleral grading. Safety outcomes included the criteria included age >_18 years and a diagnosis of active, number and severity of systemic and ocular toxicities and noninfectious, non-necrotizing anterior scleritis. The study adverse events and the proportion of participants with eye was required to have >_1þ scleritis in at least 1 quadrant loss of >_15 ETDRS letters at any follow-up visit. based on a standardized grading system, the NEI Scleritis 15 Grading Scale, and visual acuity of 20/640 or better. If STUDY DRUG ADMINISTRATION: All participants both eyes met the criteria for the study eye, both eyes received 4 subcutaneous injections of 60 mg gevokizumab were analyzed and evaluated. Participants on systemic administered at baseline and at weeks 4, 8, and 12. At anti-inflammatory therapy (including corticosteroids) week 16, participants were assessed for eligibility in the must not have had a dose escalation in any of their immu- extension phase of the study. Participants were eligible nosuppressive treatments within the last 4 weeks prior to for the extension phase if they
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