Purpose
To evaluate the safety and potential efficacy of gevokizumab, an anti-interleukin 1β (IL-1β) monoclonal antibody, in the treatment of active, noninfectious, non-necrotizing anterior scleritis.
Design
Phase 1/2, open label, nonrandomized, prospective, single-arm pilot trial.
Methods
Eight patients with active, noninfectious, non-necrotizing anterior scleritis with a scleral inflammatory grade of +1 to +3 in at least 1 eye were enrolled. In 1 patient both eyes were enrolled, for a total of 9 eyes (4 eyes with +1, 1 eye with +2, and 4 eyes with +3). Patients received 1 subcutaneous injection of 60 mg gevokizumab at baseline and then every 4 weeks for 12 weeks. Complete physical and ocular examinations were performed at each visit. The primary outcome was at least a 2-step reduction or reduction to grade 0 in scleral inflammation on a 0 to +4 scale according to a standardized photographic scleritis grading system by 16 weeks in the study eye compared to baseline. Secondary outcomes included changes in visual acuity, intraocular pressure, and trends in scleral grading. Participants who met the primary outcome were eligible to continue in the study for up to 52 weeks and received additional gevokizumab injections every 4 weeks until week 36, followed by 2 safety visits at weeks 40 and 52.
Results
Seven eyes from 7 patients met the primary outcome within a median time of 2 weeks following the first gevokizumab injection. No definitive changes in visual acuity or intraocular pressure were identified. There were no serious adverse events related to the study drug. A total of 43 adverse effects were reported, with 93% described as mild, 95% as nonocular, and only 14% deemed possibly caused by the investigational treatment.
Conclusions
The results of this small study suggest that blockage of IL-1β using gevokizumab may be beneficial in treating active, noninfectious anterior scleritis and that gevokizumab is well tolerated. Larger randomized trials are warranted to assess the true efficacy of gevokizumab in the treatment of non-necrotizing anterior scleritis.
Noninfectious anterior scleritis, a potentially vision-threatening condition which may be necrotizing or non-necrotizing, is often associated with systemic inflammatory diseases, such as rheumatoid arthritis, spondyloarthropathies, and granulomatosis with polyangiitis. Non-necrotizing anterior uveitis is categorized as nodular or diffuse depending on the extent and morphology of the scleral lesions. Whereas mild cases of non-necrotizing noninfectious anterior scleritis may be treated with oral nonsteroidal anti-inflammatory drugs (NSAIDs), cases of more severe non-necrotizing or any necrotizing noninfectious scleritis require systemic corticosteroids and often steroid-sparing immunomodulatory therapy (IMT), including antimetabolites (eg, azathioprine, methotrexate, mycophenolate), T-cell inhibitors (eg, cyclosporin A), cytotoxic agents (eg, cyclophosphamide), or biologic agents (eg, adalimumab, infliximab, rituximab).
Several inflammatory cell types, including T and B lymphocytes, and cytokines, including TNF-α, have been implicated in the pathogenesis of noninfectious scleritis, and targeting these cells and cytokines with the above-mentioned medications has proven beneficial in treating this disease in small to medium-sized cohorts. Interleukin 1β (IL-1β) is another inflammatory cytokine implicated in the immunopathogenesis of noninfectious scleritis. Patients with diffuse anterior scleritis were found to have elevated levels of IL-1β in their serum compared with healthy controls, and blockade of the IL-1 receptor with anakinra has been reported to improve anterior scleritis associated with rheumatoid arthritis (RA). In the current study, we sought to investigate the safety and potential efficacy of gevokizumab, an anti-IL-1β monoclonal antibody, in the treatment of active, noninfectious anterior scleritis.
Methods
This was a phase I/II nonrandomized, prospective, single-center study that evaluated subcutaneous gevokizumab (XOMA, Berkeley, California, USA) as a treatment for active, noninfectious, non-necrotizing anterior scleritis. The study protocol was reviewed and approved by the Institutional Review Board of the National Institutes of Health, a HIPAA-compliant institution, and all procedures conformed to the tenets of the Declaration of Helsinki (Clinical Trials registration: NCT01835132 ; NEI protocol ID: 13-EI-0102). Informed consent was obtained from all participants at the time of enrollment. Patients received 1 subcutaneous injection of 60 mg gevokizumab at baseline and then every 4 weeks for 12 weeks. Participants could continue taking ≤20 mg/day prednisone or equivalent during the study. All other immunosuppressive medications had to be stopped upon receiving the first injection of gevokizumab. Participants who met the primary outcome measure, as defined below, and did not develop a severe scleritis complication (eg, corneal complications) that caused vision loss >20 ETDRS letters were eligible to continue in the first extension phase of the study. In this extension phase, participants received 6 additional gevokizumab injections every 4 weeks until week 36 followed by 2 safety visits at weeks 40 and 52. After 52 weeks, patients were eligible for a second extension phase in which they would receive gevokizumab injections at weeks 52, 54, 58, and 62 and then as needed for flares of scleritis at the investigator’s discretion until week 110. However, the implementation of the second extension was delayed, with an average of 10.2 months (range 7.5–14 months) interruption between the last injection under the first extension phase and the reintroduction of treatment under the second extension phase.
Inclusion and Exclusion Criteria
Inclusion criteria included age ≥18 years and a diagnosis of active, noninfectious, non-necrotizing anterior scleritis. The study eye was required to have ≥1+ scleritis in at least 1 quadrant based on a standardized grading system, the NEI Scleritis Grading Scale, and visual acuity of 20/640 or better. If both eyes met the criteria for the study eye, both eyes were analyzed and evaluated. Participants on systemic anti-inflammatory therapy (including corticosteroids) must not have had a dose escalation in any of their immunosuppressive treatments within the last 4 weeks prior to enrollment. Participants must not have received another systemic biologic immunosuppressive agent (eg, infliximab, daclizumab, etanercept, adalimumab, or anakinra) within the last 3 months or rituximab or an alkylating agent (eg, cyclophosphamide) within the last 12 months prior to enrollment. Exclusion criteria included any active infection requiring treatment, a history of tuberculosis (TB), human immunodeficiency virus (HIV), hepatitis B or C, or a history of cancer (other than a nonmelanoma skin cancer or carcinoma in situ of the cervix) diagnosed within the last 5 years. Also, eyes with periocular or intravitreal steroid injection within the last 6 weeks prior to enrollment, dexamethasone intravitreal implant (Ozurdex) within the last 6 months prior to enrollment, fluocinolone intravitreal implant (Retisert) within the last 3 years prior to enrollment, or intraocular surgery of any kind in the last 4 weeks prior to enrollment were excluded.
Ophthalmic and Medical Evaluations
At all visits, participants underwent a complete physical and ocular examination that included visual acuity assessment using the standardized Early Treatment Diabetic Retinopathy Study (ETDRS) refraction protocol, vital signs, concomitant medications assessment, adverse event assessment, intraocular pressure, slit-lamp examination, dilated fundus examination, standardized scleral photographs, complete blood count with differential, basic metabolic panel, urine pregnancy testing in female participants, and urinalysis.
Primary, Secondary, and Safety Outcomes
The primary outcome was at least a 2-step reduction or reduction to grade 0 in scleral inflammation in the study eye (or eyes, if both eyes met study eye criteria) in at least 1 quadrant according to a standardized photographic scleritis grading system developed at NEI, on or before the week 16 visit as compared to baseline. Two separate investigators evaluated the primary outcome, which was based on scores from the clinical examination and not scleral photographs of the participant. If there was a difference in the grading between the 2 investigators, then the difference was discussed between the investigators and an opinion was reached by consensus. The secondary outcomes included mean and median change in visual acuity via ETDRS at all follow-up visits, changes in intraocular pressure, and trends in scleral grading. Safety outcomes included the number and severity of systemic and ocular toxicities and adverse events and the proportion of participants with loss of ≥15 ETDRS letters at any follow-up visit.
Study Drug Administration
All participants received 4 subcutaneous injections of 60 mg gevokizumab administered at baseline and at weeks 4, 8, and 12. At week 16, participants were assessed for eligibility in the extension phase of the study. Participants were eligible for the extension phase if they did not develop a severe scleritis complication (eg, corneal complications) that caused vision loss >20 ETDRS letters during the first 16 weeks of the study, if they showed a 2-step reduction or reduction to grade 0 in scleral inflammation in the study eye (or eyes, if both eyes met study criteria) on or before week 16 (primary outcome), and if they elected to participate in the extension phase of the study. Six of 8 participants continued into the extension phase, and the remaining 2 participants did not meet the study primary outcome. No additional injections were given outside the scheduled injections.
Results
Nine eyes from 8 patients (Patient 2 had both eyes enrolled) with noninfectious anterior scleral inflammation ranging from +1 to +3 were enrolled (4 patients with +1, 1 patient with +2, and 4 patients with +3). The average age was 59.9 years (range 34–81 years), and there were 4 female and 4 male patients ( Table 1 ). All patients had previously been treated with systemic therapy (details listed in Table 1 ). Patient 8 had scleral inflammation recalcitrant to several immunosuppressive agents, including infliximab, adalimumab, and rituximab. Two patients had identifiable systemic disease associations (Patient 2 had RA and Patient 8 had systemic lupus erythematosis and Sjogren syndrome).
| Patient | Demographics | Prior Systemic Treatments | Systemic Associations | Concomitant Steroids |
|---|---|---|---|---|
| 1 | 62-year-old white man | Oral corticosteroids, mycophenolate mofetil (off both at the time of enrollment) | None | None |
| 2 | 50-year-old black woman | Oral corticosteroids (off prior to enrollment), methotrexate (last dose 15 mg 1 month prior to enrollment) | Rheumatoid arthritis | Topical prednisolone acetate BID |
| 3 | 34-year-old white woman | Intravenous corticosteroids (off prior to enrollment) | None | None |
| 4 | 75-year-old black man | Indomethacin (50 mg/day stopped ∼4 months prior to enrollment) | None | Topical loteprednol TID |
| 5 | 65-year-old white man | Ibuprofen (off prior to enrollment), methotrexate (last dose 10 mg 5 days prior to enrollment), mycophenolate mofetil (1250 mg BID stopped upon enrollment), infliximab (off prior to enrollment) | None | Topical loteprednol BID |
| 6 | 61-year-old black man | Intravenous corticosteroids (off prior to enrollment) | None | None |
| 7 | 81-year-old white man | Indomethacin (50 mg TID stopped upon enrollment) | None | None |
| 8 | 51-year-old white woman | Oral corticosteroids (prednisone 7.5 mg/day), adalimumab (off for 3 months prior to enrollment), cyclosporine (off prior to enrollment), azathioprine (off prior to enrollment), methotrexate (off prior to enrollment), mycophenolate mofetil (off prior to enrollment), rituximab (off prior to enrollment) | Systemic lupus erythematosus, Sjogren syndrome | Oral prednisone (max dose 7.5 mg/day), topical loteprednol QID |
Seven eyes from 7 patients met the primary outcome within 16 weeks (median 2 weeks) following the first gevokizumab injection ( Figures 1 and 2 ). Among the 7 eyes that met the primary outcome, there were 3 eyes with +3, 1 eye with +2, and 3 eyes with +1 scleral inflammation at baseline. Most patients maintained the initially achieved positive response, although some patients experienced new activity in previously uninvolved quadrants (Patients 2 and 5).
Six patients who met the primary outcome at week 16 were continued in the first extension phase of the study (Patients 1, 3, 5, 6, 7, and 8). Although the right eye of Patient 2 met the primary outcome, the more severely affected left eye did not substantially improve with treatment; therefore, she was not continued in the extension phase to allow for alternative therapy. Patient 4 (1 study eye) failed to meet the primary outcome by week 16. In general, eyes that responded by week 16 maintained their response through week 52 ( Figure 2 ). Three patients (Patients 1, 7, and 8) continued into the second extension phase of the study. The last treatment of the first extension phase occurred on week 36 with no treatments administered on weeks 40 or 52, which were safety visits. Implementation of the second extension phase was delayed, and there was an average of 10.2 months (range 7.5–14 months) interruption between the last treatment under the first extension phase and the reintroduction of treatment under the second extension phase. The second extension phase was planned for reinduction injections (0, 2, 6, and 10 weeks) followed by pro re nata injections, with study visits occurring every 8 weeks after the reinduction. At the start of the second extension phase, all 3 patients had recurrent scleral inflammation (grades 1+ to 2+). All 3 patients experienced a reduction to grade 0 in at least 1 quadrant after a single gevokizumab injection during the second extension phase ( Figures 2 and 3 ). All patients received 4 treatments as part of the “reinduction” in the second extension phase; however, the trial was discontinued early by the company owing to the company’s decision to cease development activities in ophthalmology.
