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Efficacy and Safety of Intravitreal Sirolimus for Noninfectious Uveitis of the Posterior Segment

Results from the Sirolimus Study Assessing Double-Masked Uveitis Treatment (SAKURA) Program
Open AccessPublished:April 03, 2020DOI:https://doi.org/10.1016/j.ophtha.2020.03.033

      Purpose

      To evaluate the efficacy and safety of intravitreal sirolimus in the management of noninfectious uveitis of the posterior segment (NIU-PS).

      Design

      Combined analysis of 2 phase 3, randomized, double-masked, multinational, 6-month studies.

      Participants

      Adults with active NIU-PS (intermediate uveitis, posterior uveitis, or panuveitis; defined as vitreous haze [VH] ≥1.5+ on modified Standardization of Uveitis Nomenclature scale).

      Methods

      Patients were randomized 1:1:1 to receive intravitreal sirolimus 44 μg (n = 208), 440 μg (n = 208), or 880 μg (n = 177) on days 1, 60, and 120. Patients discontinued medications for NIU-PS except for systemic corticosteroids, which were tapered according to protocol. Enrollment in the 880-μg group was terminated after interim results found no significant difference in efficacy compared with the 440-μg dose.

      Main Outcome Measures

      The primary efficacy end point was the percentage of patients with VH of 0 at month 5 in the study eye without the use of rescue therapy. Secondary efficacy end points included VH of 0 or 0.5+, corticosteroid-tapering success, and changes in best-corrected visual acuity (BCVA). Safety measures included ocular and nonocular adverse events.

      Results

      A total of 592 patients were randomized. Significantly higher proportions of patients treated with 440 μg compared with 44 μg intravitreal sirolimus achieved VH of 0 (21.2% vs. 13.5%; P = 0.038) and VH of 0 or 0.5+ (50.0% vs. 40.4%; P = 0.049) at month 5. Best-corrected visual acuity was stable (absolute change <5 ETDRS letters) or improved >5 letters in 80.1% and 80.2% of patients in the 440-μg and 44-μg groups, respectively. At month 5, corticosteroids were tapered successfully in 69.6% and 68.8% of patients in the 440-μg and 44-μg groups, and among these patients, VH of 0 or 0.5+ was achieved by 43.5% and 28.1% in the 440-μg and 44-μg groups. Both doses were generally well tolerated. Mean changes from baseline intraocular pressure (IOP) in the study eye at each analysis visit were minimal in all treatment groups.

      Conclusions

      Intravitreal sirolimus 440 μg improved ocular inflammation, as measured by VH, compared with the 44-μg dose, with minimal impact on IOP, while preserving BCVA.

      Abbreviations and Acronyms:

      AE (adverse event), BCVA (best-corrected visual acuity), CI (confidence interval), CRT (central retinal thickness), ETDRS (Early Treatment Diabetic Retinopathy Study), IOP (intraocular pressure), NIU-PS (noninfectious uveitis of the posterior segment), SAE (serious adverse event), SAKURA (Sirolimus Study Assessing Double-Masked Uveitis Treatment), VH (vitreous haze)
      Uveitis is estimated to account for nearly 10% of visual impairments in developed countries, with nearly 1 in 2 patients with uveitis of the posterior segment classified as legally blind or having significant visual impairment.
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      However, these side effects are not universal and may be managed effectively by a skilled and experienced provider.
      Sirolimus is an inhibitor of the mammalian target of rapamycin with proven clinical activity in preventing organ transplant rejection.
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      Oral sirolimus has shown efficacy in preclinical models of autoimmune uveitis and in patients with severe noninfectious uveitis, but monitoring for systemic toxicity is required.
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      The efficacy, tolerability, and improvement in quality of life conveyed by this intravitreal sirolimus formulation were demonstrated in patients with active or quiescent noninfectious uveitis of the posterior segment (NIU-PS) in the phase 1 Sirolimus as a Therapeutic Approach Uveitis Study.
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      The phase 2 Sirolimus as a Therapeutic Approach Uveitis: Protocol 2 Study demonstrated that intravitreal sirolimus is well tolerated, with negligible systemic exposure even with simultaneous bilateral injections.
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      The Sirolimus Study Assessing Double-Masked Uveitis Treatment (SAKURA) Program comprised 2 phase 3, multinational, multicenter, randomized, double-masked studies (SAKURA 1 and SAKURA 2) that assessed the safety and efficacy of intravitreal sirolimus administered every other month for the treatment of active NIU-PS. Both studies evaluated intravitreal sirolimus at doses of 440 μg and 880 μg compared with a 44-μg dose serving as a low-dose active control. Results from SAKURA 1 were published previously and showed that the 440-μg dose of intravitreal sirolimus significantly reduced inflammation, as demonstrated by improvement on the vitreous haze (VH) scale compared with the 44-μg dose, while having a more favorable benefit-to-risk profile than the 880-μg dose.
      • Nguyen Q.D.
      • Merrill P.T.
      • Clark W.L.
      • et al.
      Intravitreal sirolimus for noninfectious uveitis: a phase III Sirolimus study Assessing double-masKed Uveitis tReAtment (SAKURA).
      ,
      • Nguyen Q.D.
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      • et al.
      Intravitreal sirolimus for the treatment of noninfectious uveitis: evolution through preclinical and clinical studies.
      We now report the complete analysis of data from the 6-month, double-masked treatment periods of both SAKURA 1 and SAKURA 2 (overall SAKURA Program results).

      Methods

       Patients

      Eligible patients were 18 years of age or older and had an investigator-determined diagnosis of active NIU-PS, defined as a VH score of 1.5+ or more on the modified Standardized Uveitis Nomenclature scale, a best-corrected visual acuity (BCVA) of 19 or more Early Treatment of Diabetic Retinopathy Study (ETDRS) letters (Snellen equivalent, 20/400 or better) in the study eye, and a BCVA of 20/200 or better in the nonstudy fellow eye. In the SAKURA Program, active NIU-PS included intermediate uveitis, posterior uveitis, and panuveitis. If an anterior uveitis component was present, it had to be less than the posterior component. Key ocular exclusion criteria included infectious uveitis, a primary diagnosis of anterior uveitis, uncontrolled glaucoma (defined as IOP >21 mmHg while receiving medical therapy), use of intravitreal or posterior sub-Tenon’s corticosteroid injections, a history of vitrectomy in the study eye, other significant ocular disease that could compromise vision in the study eye, intraocular surgery within 90 days before baseline, or ocular or periocular infection in either eye. All systemic immunosuppressive agents other than corticosteroids were required to be discontinued by 30 days before the first administration of the study medication on day 1. Systemic (oral) corticosteroid treatment was allowed, but was to be tapered rapidly in patients whose overall prednisone-equivalent dose at day 1 was more than 5 mg/day according to the following schedule: dose reduced by 10 mg every week until a dose of 40 mg/day is reached, then reduced by 5 mg every week until a dose of 20 mg/day is reached, and then reduced by 2.5 mg every week until stopping.

       Study Design

      Both SAKURA 1 and SAKURA 2 were phase 3 randomized, double-masked, multinational studies conducted under a single protocol. SAKURA 1 enrolled 347 patients from May 31, 2011, through March 29, 2013, at 103 sites in 15 countries, and SAKURA 2 enrolled 245 patients from April 4, 2013, through March 23, 2016, at 81 sites in 17 countries. Most patients in SAKURA 1 and SAKURA 2 were enrolled in India (33.1% and 34.3%, respectively) and the United States (31.7% and 31.0%, respectively), with the remaining patients enrolled in the European Union, Latin America, Israel, and Japan. Both studies were conducted in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki; the SAKURA Program was registered at ClinicalTrials.gov (identifier, NCT01358266). An ethics committee or institutional review board at each participating site approved the study protocol before patients were enrolled, and all patients provided written informed consent before participating in any study-related procedures. United States study sites complied with provisions of the Health Insurance Portability and Accountability Act.
      Both studies included a 6-month, double-masked treatment period, during which eligible patients were randomized (1:1:1) to intravitreal sirolimus 44 μg, 440 μg, or 880 μg administered via a 20-μl injection in the study eye on days 1, 60, and 120. If the patient had bilateral NIU-PS, the eye with the greater VH score on day 1 was selected as the study eye. For patients in whom both eyes had the same VH scores, the right eye was chosen as the study eye. If the fellow eye showed uveitis or active uveitis developed at any point during the study, the investigator could choose to initiate standard-of-care local therapy for that eye. Patients were randomized following a permuted-block randomization scheme stratified by geographic region and baseline VH score of the study eye, using an interactive response system. All doses were supplied in identical packages to ensure study patients and investigators remained masked.
      The study protocol was amended to terminate further enrollment in the 880-μg treatment arm after an analysis of the SAKURA 1 results found no significant difference in efficacy between the 440-μg and 880-μg doses.
      • Nguyen Q.D.
      • Merrill P.T.
      • Clark W.L.
      • et al.
      Intravitreal sirolimus for noninfectious uveitis: a phase III Sirolimus study Assessing double-masKed Uveitis tReAtment (SAKURA).
      The decision was made to avoid exposing study patients to a higher intravitreal sirolimus dose that did not offer any additional benefit. This protocol amendment was instituted in March 2014 and as a result, 60 patients enrolled during SAKURA 2 were randomized in a 1:1 ratio to receive intravitreal sirolimus 44 μg or 440 μg. Patients randomized to 880 μg before implementation of the amendment completed the 6-month treatment period, but efficacy analyses were deemed exploratory in nature. The otherwise identical designs of the 6-month, double-masked treatment period allowed for combined analysis of the 2 studies.

       Assessments

      Patients were evaluated on days 1, 14, and 30 and monthly thereafter during the double-masked treatment visits. Slit-lamp biomicroscopy was performed at each visit to evaluate eye structures and VH, which was categorized using a modified Standardization of Uveitis Nomenclature scale that included a VH score of 1.5+.
      • Nguyen Q.D.
      • Merrill P.T.
      • Clark W.L.
      • et al.
      Intravitreal sirolimus for noninfectious uveitis: a phase III Sirolimus study Assessing double-masKed Uveitis tReAtment (SAKURA).
      The BCVA was recorded at each visit using ETDRS methods. OCT, fluorescein angiography, and fundus photography were performed for both eyes at baseline and at month 5. To assess safety, full ocular assessments, adverse events (AEs), and IOP were evaluated at each visit. Investigators were required to report increases in IOP of 10 mmHg or more occurring within 40 minutes of intravitreal injections as an AE and increases in IOP of more than 35 mmHg persisting for 7 days or more as a serious adverse event (SAE). Clinical laboratory tests, measurement of vital signs, and physical examinations were conducted at baseline and month 5.
      Use of systemic corticosteroids at day 1 was allowed for patients who were already receiving these agents. However, for patients receiving a more than 5-mg/day prednisone-equivalent dose at day 1, the systemic corticosteroid was tapered rapidly according to the mandatory tapering schedule previously described.

       Study End Points

      The primary efficacy end point was the proportion of patients with a VH score of 0 at month 5 based on the modified Standardization of Uveitis Nomenclature scale. Key secondary efficacy end points included the proportion of patients with a VH score of 0 or 0.5+ at month 5 and the corticosteroid-tapering success rate, defined as the proportion of patients receiving a prednisone-equivalent dose of more than 5 mg/day at baseline who were tapered to 5 mg/day or less at month 5. Additional secondary efficacy end points, also evaluated at month 5, included the changes from baseline in BCVA and central retinal thickness (CRT; measured by OCT) and use of rescue therapy (see Supplemental Material, available at www.aaojournal.org, for rescue therapy criteria), consisting of any treatment that could have a therapeutic effect on NIU-PS before month 5.

       Statistical Analysis

      Calculations performed a priori estimated a total sample size of approximately 600 patients for the overall SAKURA Program would provide more than 80% power, assuming a difference between 440-μg and 44-μg doses of 16% or more. Efficacy end points were evaluated in the intention-to-treat population, which comprised all randomized patients. For responder rate analyses (such as VH response rate), patients who received rescue therapy before month 5 were considered nonresponders. The primary efficacy end point was analyzed using the Fisher exact test in SAKURA 1 and the Pearson’s chi-square test in SAKURA 2. This change in the statistical analysis of the primary end point was made after termination of the 880-μg study arm to increase the study power of SAKURA 2. For the overall SAKURA Program analysis, the difference in primary end point attainment between the 440-μg and 44-μg groups also was assessed using Pearson’s chi-square tests. Statistical comparison between the 880-μg and 44-μg groups was performed on an exploratory basis. Missing VH data were imputed using the last observation carried forward approach.
      The key secondary end point of the proportion of patients with VH scores of 0 or 0.5+ was analyzed using the same methods used for the primary end point. Corticosteroid-tapering success was evaluated in all randomized patients who were taking systemic corticosteroids at baseline at a prednisone-equivalent dose of more than 5 mg/day (intention-to-taper population). Continuous secondary efficacy variables, including changes from baseline in VH score and BCVA, were assessed using a mixed-effects model for repeated measures, with baseline score as a covariate, and with study (SAKURA 1 or SAKURA 2), geographic region (United States and Latin America or rest of the world), treatment, visit, and treatment-by-visit interaction as fixed effects.
      A prespecified subgroup analysis of the primary efficacy end point was made by age (<65 years vs. ≥65 years), gender, race, anatomic location of uveitis in the study eye (intermediate uveitis, posterior uveitis, or panuveitis), presence of anterior segment inflammation, intention-to-taper corticosteroid status at baseline, and presence of macular edema at baseline (CRT ≥300 μm vs. <300 μm).
      Adverse events and IOP were summarized using descriptive statistics for the safety population, which comprised all randomized patients who received at least 1 dose of study drug. All safety end points were assessed at month 6.
      Statistical testing of efficacy end points was conducted at a significance level of 0.05 (2-sided). All statistical analyses were performed with the SAS software version 9.3 or higher (SAS Institute, Inc., Cary, NC).

       Study Oversight

      The SAKURA Program Data Safety and Monitoring Committee met periodically to conduct an independent review of unmasked aggregated and individual-level data related to treatment safety, data integrity, and overall study conduct. The SAKURA Program Study Steering Committee, which consisted of key investigators, met periodically with study investigators, coordinators, and staff to discuss issues regarding patient recruitment and retention, protocol amendments, AEs, and other study-related issues.

      Results

       Patients

      A total of 592 patients were randomized in the overall SAKURA Program and comprised the intention-to-treat population: 208 in each of the 44-μg and 440-μg groups and 177 in the 880-μg group (Fig 1). One patient inadvertently was randomized twice and received intravitreal sirolimus 880 μg in each eye. Safety data from both treatment courses for this patient were included in the safety analysis, but efficacy data from the second treatment were excluded from the intention-to-treat population to maintain the independence of samples for the efficacy analyses. Most patients completed study assessments at month 6; only 23 patients (3.9%) discontinued before month 5, most frequently because of adverse events (n = 8; 1.3%) or withdrawn consent (n = 8; 1.3%).
      Figure thumbnail gr1
      Figure 1Flowchart showing the patient disposition in the overall Sirolimus Study Assessing Double-Masked Uveitis Treatment (SAKURA) Program. ∗After SAKURA 1 found the 880-μg dose did not offer a significant benefit over the 440-μg dose, the protocol was amended to terminate further randomization into the 880-μg dose group. One patient was randomized twice, both times to the 880-μg dose, and received 1 treatment course in each eye; both treatment courses were included in the safety population, but only the first one was included in the intention-to-treat (ITT) population. Three patients received the wrong doses during the double-masked treatment period and were classified by the maximum dose received for the safety analyses. Three patients were randomized but never received any study medication and were not included in the safety population. Patients completed and exited the study earlier than the defined analysis visit window. IVT = intravitreal.
      Overall, the study cohort had a mean age of 45.2 years; 57.9% were women (Table 1). The mean time since diagnosis of uveitis in the study eye was 43.5 months, with uveitis classified as intermediate uveitis in 219 patients (37.0%), panuveitis in 195 patients (32.9%), and posterior uveitis in 178 patients (30.1%). Most patients (n = 514; 86.8%) had a baseline VH score of 1.5+ (34.3%) or 2+ (52.5%) in the study eye. Systemic corticosteroids were used by 129 patients (21.8%). The dose at baseline was more than 40 mg/day in 11 patients, more than 20 to 40 mg/day in 40 patients, 10 to 20 mg/day in 49 patients, 6 to less than 10 mg/day in 10 patients, and 5 mg/day or less in 19 patients. Demographic and clinical characteristics did not differ significantly among dose groups, except for the higher proportion of patients taking systemic corticosteroids at baseline in the 440-μg group compared with the 44-μg group (26.4% vs. 16.8%; P = 0.020).
      Table 1Baseline Demographics and Clinical Characteristics in the Overall Sirolimus Study Assessing Double-Masked Uveitis Treatment (SAKURA) Program
      Intravitreal Sirolimus Dose (μg)
      44 (n = 208)440 (n = 208)880 (n = 176)
      Age at randomization (yrs)
       Mean (SD)43.64 (14.858)46.27 (14.093)45.69 (14.293)
       Median43.1547.1047.20
       Minimum–maximum18.2–83.618.1–78.418.1–74.3
      Age group (yrs), no. (%)
       <65188 (90.4)191 (91.8)153 (86.9)
       ≥6520 (9.6)17 (8.2)23 (13.1)
      Female gender, no. (%)113 (54.3)117 (56.3)113 (64.2)
      Race, no. (%)
       White93 (44.7)99 (47.6)79 (44.9)
       Nonwhite115 (55.3)109 (52.4)97 (55.1)
      Baseline vitreous haze score of study eye
       Mean (SD)1.96 (0.490)1.95 (0.473)1.98 (0.484)
       1.5+, no. (%)72 (34.6)75 (36.1)56 (31.8)
       2+, no. (%)110 (52.9)105 (50.5)96 (54.5)
       3+ or 4+, no. (%)26 (12.5)28 (13.5)24 (13.6)
      Bilateral uveitis, no. (%)124 (59.6)128 (61.5)107 (60.8)
      Anatomic location of uveitis in study eye, no. (%)
       Intermediate83 (39.9)67 (32.2)69 (39.2)
       Panuveitis64 (30.8)74 (35.6)57 (32.4)
       Posterior61 (29.3)67 (32.2)50 (28.4)
      Disease duration of uveitis of study eye (mos)
       Mean (SD)46.44 (66.547)37.49 (47.719)47.27 (65.130)
       Median19.0518.9521.65
       Minimum–maximum0.2–411.70.3–216.70.1–346.6
      Baseline BCVA of study eye (ETDRS letters), no. (%)
       ≤70127 (61.1)126 (60.6)119 (67.6)
       >7081 (38.9)82 (39.4)57 (32.4)
      Baseline use of systemic corticosteroids, no. (%)35 (16.8)55 (26.4)
      P = 0.020, comparison between 440 μg and 44 μg (low dose). All other comparisons were not significantly different.
      39 (22.2)
      BCVA = best-corrected visual acuity; EDTRS = Early Treatment of Diabetic Retinopathy Study; SD = standard deviation.
      P = 0.020, comparison between 440 μg and 44 μg (low dose). All other comparisons were not significantly different.

       Efficacy Outcomes

      As previously reported for SAKURA 1,
      • Nguyen Q.D.
      • Merrill P.T.
      • Clark W.L.
      • et al.
      Intravitreal sirolimus for noninfectious uveitis: a phase III Sirolimus study Assessing double-masKed Uveitis tReAtment (SAKURA).
      the primary efficacy end point (VH = 0 at month 5) was achieved by a significantly greater proportion of patients receiving intravitreal sirolimus 440 μg compared with those receiving the 44-μg dose (22.8% vs. 10.3%; P = 0.025, Fisher exact test, adjusted for multiplicity; P = 0.010, chi-square test), whereas the difference in response rate between the 880-μg and 44-μg dose groups was not statistically significant (16.4% vs. 10.3%; P = 0.183, Fisher exact test, adjusted for multiplicity; P = 0.169, chi-square test). In SAKURA 2, the VH of 0 response rates at month 5 were 19.1%, 17.6%, and 13.3% with intravitreal sirolimus 440 μg, 44 μg, and 880 μg, respectively (P = 0.783 for comparison of 440-μg and 44-μg groups; P = 0.485 for comparison of 880-μg and 44-μg groups). In the overall SAKURA Program, the VH of 0 response rate was significantly greater with the 440-μg dose compared with the 44-μg dose (21.2% vs. 13.5%; P = 0.038), whereas the response rate with the 880-μg dose was not significantly different compared with the low-dose group (Fig 2). Subgroup analysis of the overall SAKURA Program data showed that intravitreal sirolimus 440 μg exhibited a higher VH of 0 response rate at month 5 compared with the 44-μg dose across most demographic and baseline characteristics, with the exception of patients with good vision at baseline (BCVA >75 letters; Snellen equivalent, >20/32; Fig 3). Among patients with baseline BCVA of 75 ETDRS letters or fewer, VH of 0 response was significantly lower in the 44-μg group (n = 154) compared with the 440-μg group (n = 157): 8.4% versus 20.4% (P = 0.003). In contrast, VH of 0 response was comparable among patients with baseline BCVA of more than 75 ETDRS letters: 27.8% in the low-dose group (n = 54) and 23.5% in the 440-μg group (n = 51; P = 0.619). Of note, results from each of the studies comprising the overall SAKURA Program also showed a significantly lower proportion of patients with BCVA of 75 ETDRS letters or fewer achieving VH of 0 in the 44-μg group compared with the 440-μg group (SAKURA 1, 7.1% vs. 19.0% [P = 0.024]; SAKURA 2, 10.0% vs. 21.8% [P = 0.052]).
      Figure thumbnail gr2
      Figure 2Graph showing the primary efficacy analysis (vitreous haze [VH] of 0 at month 5) in the combined intention-to-treat population. aPatients receiving rescue therapy before month 5 were classified as nonresponders. bUnadjusted P value from Pearson’s chi-square test. ITT = intention-to-treat.
      Figure thumbnail gr3
      Figure 3Graph showing subgroup analysis of the primary efficacy end point (vitreous haze [VH] of 0 at month 5) in patients treated with intravitreal sirolimus 440 μg or 44 μg. Orange squares and whiskers indicate the mean difference in response rates for the 2 doses and 95% confidence intervals (CIs). The vertical dotted line corresponds to no difference between the 2 doses; squares to the right of this line indicate that a higher proportion of patients treated with 440 μg achieved VH of 0 at month 5 than those treated with 44 μg. BCVA = best-corrected visual acuity; CRT = central retinal thickness; SCS = systemic corticosteroid.
      After the 880-μg dose group was discontinued, between-group comparisons for the overall SAKURA Program focused on intravitreal sirolimus 440 μg versus 44 μg. The key secondary efficacy end point of VH of 0 or 0.5+ (i.e., no or trace ocular inflammation) was achieved by 104 of 208 patients (50.0%) in the intravitreal sirolimus 440-μg group compared with 84 of 208 patients (40.4%) in the low-dose group (P = 0.049). The median time to achievement of the first occurrence of VH of 0 or 0.5+ without being rescued also favored the 440-μg dose over the 44-μg dose (84 vs. 93 days; P = 0.017).
      Corticosteroid-tapering success, another key secondary efficacy end point, was evaluated in the subset of patients in the SAKURA Program who were receiving a prednisone-equivalent dose of more than 5 mg/day at baseline. Corticosteroid-tapering success at month 5 was achieved by 32 of 46 patients (69.6%) treated with intravitreal sirolimus 440 μg compared with 22 of 32 patients (68.8%) in the low-dose group (P = 0.94). Among patients who achieved corticosteroid-tapering success, all except 1 patient in each group were able to taper corticosteroids completely to 0 mg/day at month 5 without use of rescue therapy. Corticosteroid-tapering success plus reaching a VH of 0 or 0.5+ was achieved by 20 of 46 patients (43.5%) in the intravitreal sirolimus 440-μg group and 9 of 32 patients (28.1%) in the low-dose group (P = 0.168). A post hoc analysis revealed corticosteroid-tapering success plus VH of 0 response was achieved by 23.9% in the intravitreal sirolimus 440-μg group versus 3.1% in the low-dose group (P = 0.012).
      Overall, BCVA was stable or improved at month 5 in most patients in each group. The proportion of patients who improved by 5 letters or more from baseline to month 5 was 48.4% (90/186) with intravitreal sirolimus 440 μg and 44.9% (84/187) with the 44-μg dose, whereas the proportion with stable BCVA (i.e., absolute change <5 letters) was 31.7% (59/186) with the 440-μg dose and 35.3% (66/187) with the 44-μg dose. The change from baseline in BCVA at month 5 was most pronounced in patients with the worst baseline BCVA (≤20/100). The median change in ETDRS letters was 14.5 letters for these patients in the 440-μg group versus 8.0 letters in the 44-μg group (P = 0.432; n = 32 in each group). The median change at month 5 among patients with baseline BCVA between better than 20/100 and 20/40 or worse was 5 ETDRS letters in both the 440-μg group (n = 79) and the 44-μg group (n = 83). In the mixed-effects model for repeated measures, the change from baseline in BCVA favored the 440-μg dose over the 44-μg dose early in the treatment course, with a significant difference observed at 2 weeks (mean improvement, 4.9 vs. 2.7 letters; P = 0.020; Fig 4).
      Figure thumbnail gr4
      Figure 4Graph showing change from baseline best-corrected visual acuity (BCVA) by study visit. ETDRS = Early Treatment Diabetic Retinopathy Study; LS = least-squares; SE = standard error of the mean. aP = 0.02; P values for other time points were not significant.
      Macular edema (defined as CRT ≥300 μm) was present at baseline in 68 patients (32.7%) in the 440-μg group and 65 patients (31.3%) in the 44-μg group in the SAKURA Program. Among the subset with macular edema, 57 patients in the 440-μg group and 56 patients in the 44-μg group had OCT data at month 5. A post hoc analysis showed that the mean change in CRT from baseline in this subgroup was –20.4% and –12.4% in the 440-μg and 44-μg groups, respectively (P = 0.144; Table 2). The decrease in CRT with intravitreal sirolimus 440 μg was particularly pronounced in patients without an epiretinal membrane at baseline: –35.9% and –7.0% in the 440-μg (n = 12) and 44-μg (n = 16) groups, respectively (P = 0.047).
      Table 2Changes in Central Retinal Thickness (in Micrometers) in the Sirolimus Study Assessing Double-Masked Uveitis Treatment (SAKURA) Program
      44 μg440 μg
      Baseline
       No.6568
       Mean (SD)507.9 (160.8)501.7 (160.4)
      Month 5
       No.5657
       Mean (SD)419.6 (180.7)382.3 (216.5)
      CRT change at month 5 (%)
       No.5657
       Mean (SD)
      P = 0.144 for comparison between 440 and 44 μg (low dose).
      –12.4 (36.8)–20.4 (41.5)
      CRT = central retinal thickness; SD = standard deviation.
      P = 0.144 for comparison between 440 and 44 μg (low dose).
      Regarding the use of rescue therapy, only 34 of 208 patients (16.3%) in the 440-μg group and 37 of 208 patients (17.8%) in the 44-μg group received rescue therapy before month 5 (P = 0.700).

       Post Hoc Analysis

      The SAKURA Program used a low-dose control rather than a placebo control, which may have affected the magnitude of the effect seen with the 440-μg dose. To test this hypothesis, a post hoc comparison was performed involving untreated fellow eyes that met VH of 1.5+ or more inclusion criteria at baseline (n = 96), assuming the response observed in fellow eyes potentially could resemble a placebo response. During the SAKURA Program, fellow eyes were allowed local treatments. For this post hoc analysis, any treatment other than the study drug or topical corticosteroids was considered rescue therapy. A VH response of 0 at month 5 was achieved by 21.2% patients in the 440-μg group, which was significantly higher than what was reported in the untreated fellow eyes (9.4%; P = 0.012). The VH of 0 response in fellow eyes was lower than, but not significantly different from, that in the 44-μg group (13.5%; P = 0.311).

       Safety

      Overall, AEs were reported in 82.1% of patients in the 44-μg group, 83.9% in the 440-μg group, and 86.0% in the 880-μg group during the double-masked treatment period. Adverse events suspected by the investigator to be related to either the study medication or treatment procedure were reported in 44.9%, 47.8%, and 53.9% of the 44-μg, 440-μg, and 880-μg groups, respectively. The most common ocular AEs reported in the double-masked period up to month 6 by all patients were increased IOP (17.1%), iridocyclitis (15.4%), uveitis (12.2%), conjunctival hemorrhage (10.8%), and eye pain (9.0%). Table 3 lists ocular SAEs occurring in 2% or more of patients in any group, as well as several ocular SAEs of special interest (increased IOP, cataract, retinal detachment, and endophthalmitis). There was a slight dose-dependent increase in ocular SAEs associated with inflammatory reactions: worsening uveitis (which includes the Medical Dictionary for Regulatory Activities terms uveitis, iridocyclitis, vitritis, intermediate uveitis, and choroiditis) was reported in 6.3%, 6.8%, and 9.6% of patients in the 44-μg, 440-μg, and 880-μg groups, respectively. Cataracts were reported as ocular SAEs in 1.0%, 0.5%, and 2.2% of the 44-μg, 440-μg, and 880-μg groups, respectively. Mean changes in IOP at each study visit were not clinically significant (Fig 5). Surgeries related to IOP increases were performed in 2 patients (1.0%) in the 44-μg group, 4 patients (2.0%) in the 440-μg group, and 3 patients (1.7%) in the 880-μg group. Of these 9 patients, 6 reported glaucoma or ocular hypertension as part of their medical history at baseline (1 in the 44-μg group, 2 in the 440-μg group, and 3 in the 880-μg group).
      Table 3Ocular Serious Adverse Events of Interest in the Study Eye During the 6-Month Double-Masked Treatment Period in the Overall Sirolimus Study Assessing Double-Masked Uveitis Treatment (SAKURA) Program
      Table depicts SAEs occurring in ≥2% of patients in any group as well as SAEs of special interest.
      Intravitreal Sirolimus Dose (μg), No. (%)
      44 (n = 207)440 (n = 205)880 (n = 178)Overall (n = 590)
      Patients with any ocular SAEs29 (14.0)33 (16.1)35 (19.7)97 (16.4)
      Worsening uveitis
      Includes Medical Dictionary for Regulatory Activities preferred terms uveitis, choroiditis, iridocyclitis, vitritis, and intermediate uveitis.
      13 (6.3)14 (6.8)17 (9.6)44 (7.5)
      Sterile endophthalmitis0 (0)1 (0.5)7 (3.9)8 (1.4)
      Endophthalmitis0 (0)1 (0.5)0 (0)1 (0.2)
      Transient drug depot in visual axis2 (1.0)2 (1.0)4 (2.2)8 (1.4)
      Increased intraocular pressure2 (1.0)3 (1.5)1 (0.6)6 (1.0)
      Cataract
      Includes Medical Dictionary for Regulatory Activities preferred terms cataract, cataract cortical, and cataract subcapsular.
      2 (1.0)1 (0.5)4 (2.2)7 (1.2)
      Retinal detachment2 (1.0)1 (0.5)0 (0)3 (0.5)
      SAE = serious adverse event.
      Table depicts SAEs occurring in ≥2% of patients in any group as well as SAEs of special interest.
      Includes Medical Dictionary for Regulatory Activities preferred terms uveitis, choroiditis, iridocyclitis, vitritis, and intermediate uveitis.
      Includes Medical Dictionary for Regulatory Activities preferred terms cataract, cataract cortical, and cataract subcapsular.
      Figure thumbnail gr5
      Figure 5Graph showing mean change from baseline in intraocular pressure at each study visit in the safety population. BL = baseline; SE = standard error of the mean; W = week.
      The overall incidence of nonocular AEs was comparable among the 3 dose groups (38.2%, 36.1%, and 32.6% for the 44-μg, 440-μg, and 880-μg groups, respectively). Headache and nasopharyngitis were the only nonocular AEs that occurred in more than 3% of patients; neither was considered to be related to the study drug. No clinically relevant changes were found in laboratory parameters or vital signs, consistent with the minimal systemic exposure of sirolimus after intravitreal administration.

      Discussion

      The results from the overall SAKURA Program demonstrate that the 440-μg dose of intravitreal sirolimus had the most favorable benefit-to-risk profile, with the primary end point of VH score of 0 at month 5, as well as the clinically relevant end point of VH of 0 or 0.5+ at month 5, being achieved by significantly greater percentages of patients in the 440-μg dose group compared with the 44-μg dose group. The uveitis community recognizes that VH does not always exist in eyes with active uveitis. When it does occur, most likely active inflammation is present that can be challenging to improve. In the SAKURA Program, the overall primary outcome of reaching VH of 0 was 21.2% in the 440-μg group compared with 13.5% in the 44-μg group (P = 0.038). Reduction in haze does not always lead to an immediate or linear improvement in vision; rather, haze reduction is aimed at improving ocular status from being overtly inflamed. Visual acuity is not always a reliable marker of uveitic disease activity and has not been used as a primary end point in uveitis clinical trials, unlike in other ocular studies. In the SAKURA Program, despite the statistically significant reduction in VH, no statistically significant difference was found in visual acuity between the 2 groups, and the study was not powered to detect a change in visual acuity. Uveitis specialists managing patients typically will use additional biomarkers of ocular inflammation such as vitreous cells and retinal vascular leakage, which were not primarily assessed in the SAKURA Program.
      The improvement in VH with the 440-μg dose was supported further by consistent improvements across the many secondary end points. In addition, results of a post hoc analysis involving untreated fellow eyes suggest that intravitreal sirolimus 44 μg (low dose) may have some therapeutic activity, as evidenced by the greater proportion of eyes achieving VH of 0 response in this group compared with fellow eyes (13.5% vs. 9.4%, respectively). We performed this post hoc analysis using fellow eyes as the potential placebo arm. In doing so, we recognize potential caveats and limitations. It is possible intravitreal sirolimus may have had an effect on the fellow eye, although pharmacokinetic studies have shown negligible systemic exposure after intravitreal administration of sirolimus.
      • Mudumba S.
      • Bezwada P.
      • Takanaga H.
      • et al.
      Tolerability and pharmacokinetics of intravitreal sirolimus.
      Administration of intravitreal sirolimus to one eye therefore would not be expected to have an effect on the fellow eye. Additionally, an effect in the fellow eye likely would have resulted in the difference in VH haze reduction being even less between the 2 eyes. In the overall SAKURA Program study population, a statistically greater proportion of patients were receiving systemic corticosteroids at baseline in the 440-μg group compared with the 44-μg group. If we assume the fellow eye population had a similar presentation, more ceiling effect may have been the case in the 44-μg group.
      In the SAKURA Program, patients discontinued biologics and other noncorticosteroid therapies at least 30 days before administration of intravitreal sirolimus. For those receiving systemic corticosteroids at a prednisone-equivalent dose more than 5 mg/day at baseline, a corticosteroid-tapering regimen was initiated during the intravitreal sirolimus treatment period, with nearly 70% of patients in the intention-to-taper subgroup achieving successful tapering of systemic corticosteroids at month 5. Consequently, the results from the overall SAKURA Program support the use of intravitreal sirolimus predominantly as monotherapy.
      Most of the study population (80%) in the SAKURA Program did not require systemic corticosteroids at baseline. Inflammation in patients with uveitis may improve or fluctuate with minimal or no treatment. It is challenging to compare the effect of intravitreal sirolimus versus the natural history of uveitis. The study inclusion and exclusion criteria were developed carefully to minimize the impact of this inherent difficulty on the study results. Even with such a potential challenge of natural improvement, which would have made it even more difficult to attribute VH reduction to the effect of the drug, statistically different outcomes still were found favoring the 440-μg over the 44-μg dose.
      The use of local corticosteroid therapy is a recognized alternative to systemic administration, especially for unilateral or asymmetric cases of NIU-PS. The Multicenter Uveitis Steroid Treatment Trial compared the effectiveness of a local corticosteroid implant with standard systemic corticosteroids (plus immunosuppression when indicated) in the treatment of NIU-PS.
      Multicenter Uveitis Steroid Treatment (MUST) Trial Research Group
      Randomized comparison of systemic anti-inflammatory therapy versus fluocinolone acetonide implant for intermediate, posterior, and panuveitis: the Multicenter Uveitis Steroid Treatment Trial.
      After 6 months, the proportion of patients with active uveitis declined from 78% to 21% in the local implant group, compared with a decline from 75% to 44% in the systemic therapy group. However, the benefits of treatment in the local implant group were counterbalanced by high rates of increased IOP, glaucoma requiring surgical intervention, and cataract development. Extended follow-up showed the mean visual acuity beginning to decline in the implant group after 5 years. By year 7, the change in visual acuity from baseline favored systemic therapy by a mean of 7.1 letters (95% confidence interval, 2.1–12 letters; P = 0.006). However, these findings were limited by a 30% loss to follow-up.
      Multicenter Uveitis Steroid Treatment (MUST) Trial and Follow-Up Research Group
      Association between long-lasting intravitreous fluocinolone acetonide implant vs systemic anti-inflammatory therapy and visual acuity at 7 years among patients with intermediate, posterior, or panuveitis.
      The systemically administered anti–tumor necrosis factor monoclonal antibody adalimumab may be another noncorticosteroid option for consideration in patients with NIU-PS based on the efficacy shown in the VISUAL trials, which found significant reductions in the risk of treatment failure (defined as occurrence of new, active inflammatory lesions, 2-step increase in anterior chamber cell of vitreous haze grade, or worsening of visual acuity ≥15 ETDRS letters) of 50% in patients with active uveitis
      • Jaffe G.J.
      • Dick A.D.
      • Brézin A.P.
      • et al.
      Adalimumab in patients with active noninfectious uveitis.
      and 57% of those with inactive uveitis
      • Nguyen Q.D.
      • Merrill P.T.
      • Jaffe G.J.
      • et al.
      Adalimumab for prevention of uveitis flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial.
      compared with those treated with placebo. Serious AEs and AEs leading to treatment discontinuation were more common among patients receiving adalimumab compared with those receiving placebo in patients with active disease,
      • Jaffe G.J.
      • Dick A.D.
      • Brézin A.P.
      • et al.
      Adalimumab in patients with active noninfectious uveitis.
      and adequate monitoring for potential systemic adverse events is required.
      • Jaffe G.J.
      • Dick A.D.
      • Brézin A.P.
      • et al.
      Adalimumab in patients with active noninfectious uveitis.
      • Nguyen Q.D.
      • Merrill P.T.
      • Jaffe G.J.
      • et al.
      Adalimumab for prevention of uveitis flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial.
      • Bessette A.P.
      • Sharma S.
      Adalimumab for noninfectious uveitis.
      The rates of ocular and nonocular AEs in the SAKURA Program generally were comparable between the treatment groups. Iridocyclitis was the most common ocular AE in both groups, which was not unexpected, given that patients with uveitis involving the anterior segment were eligible for the study and topical corticosteroids were discontinued before sirolimus treatment. Ocular inflammation-related AEs, such as uveitis, were among the most commonly reported AEs, likely reflecting the progression of underlying disease. Ocular SAEs observed with intravitreal sirolimus generally were manageable and resolved without sequelae. Importantly, a low incidence of increased IOP was found. Because the study excluded patients with uncontrolled glaucoma (defined as IOP >21 mmHg while receiving medical therapy), the potential safety of intravitreal sirolimus in patients with high IOP needs further evaluation.
      Systemic exposure to intravitreal sirolimus is minimal, supported by pharmacokinetic data (Rosberger D, et al. Pharmacokinetics of intravitreal sirolimus in non-infectious uveitis (NIU) of the posterior segment: results from a subset of SAKURA Study 1 subjects. Paper presented at: ARVO Annual Meeting; May 3–7, 2015; Denver, CO), and is reflected in the low occurrence of nonocular AEs reported during the SAKURA Program (e.g., headache and nasopharyngitis). Such findings represent a potential advantage of intravitreal sirolimus over immunosuppressive and biologic therapies that are administered systemically.
      Additional data are needed to characterize better the efficacy of intravitreal administration of sirolimus 440 μg in the management of NIU-PS. However, taken together, the efficacy and safety results from the SAKURA Program suggest that this treatment may provide multiple clinically relevant benefits to patients with NIU-PS, including early and sustained control of active inflammation; improvement or preservation of vision, or both; low overall need for rescue therapy; potential corticosteroid-sparing properties; low rates of cataracts; and increased IOP occurrences.
      As shown in SAKURA 1, the reduction in VH achieved with 880 μg was not significantly different compared with the 440-μg dose.
      • Nguyen Q.D.
      • Merrill P.T.
      • Clark W.L.
      • et al.
      Intravitreal sirolimus for noninfectious uveitis: a phase III Sirolimus study Assessing double-masKed Uveitis tReAtment (SAKURA).
      The reason for such a result is not known. Based on preclinical ocular pharmacokinetic studies, it is possible that drug exposure in the target tissues becomes saturated at a dose level close to 440 μg and that no additional benefit can be obtained with higher doses. Alternatively, it is possible the higher dose may be more beneficial in a different population of patients with uveitis.
      Several study limitations should be considered. At the time the SAKURA Program was started, the decision was made to use a low dose (44 μg) of intravitreal sirolimus as an active control because difficulties were encountered in selecting a locally administered active control approved for worldwide use. Most patients were corticosteroid free at randomization; therefore, assessment of the potential steroid-sparing benefit of intravitreal sirolimus was limited by the small sample size. The SAKURA Program entry criteria did not require the presence of macular edema, which limited assessment of treatment effects on this parameter. SAKURA 1 showed a statistically significant beneficial effect for the 440-μg over the 44-μg dose, and SAKURA 2 showed a similar trend, but the difference did not reach statistical significance. The combined results continue to show statistical benefits. Therefore, we have a study with positive results (SAKURA 1) and one with equivocal results (SAKURA 2). Hence, a third study is needed to assess the efficacy of the 440-μg dose further.
      In conclusion, the SAKURA Program demonstrated that administration of intravitreal sirolimus every other month may lead to improvement in ocular inflammation in patients with active NIU-PS. The overall benefit-to-risk profile of the 440-μg dose supports its potential use as a locally delivered, noncorticosteroid, immunoregulatory therapy for NIU-PS. The third study is expected to address some of the limitations of the SAKURA Program and to characterize further the efficacy and safety profile of intravitreal sirolimus 440 μg in the treatment of active NIU-PS.

      Acknowledgment

      Writing and editorial assistance supported in part by Santen, Inc., Emeryville, California.

      Supplementary Data

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