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Objective The objective of this study was to evaluate the long-term safety and efficacy of sarilumab over 5 years in patients with RA refractory to TNF inhibitors (TNFis). Methods Patients in the 24-week randomized controlled trial (RCT) TARGET (NCT01709578) who received double-blind placebo or sarilumab 150 or 200 mg every 2 weeks (q2w), plus conventional synthetic DMARDs (csDMARDs), were eligible to receive open-label sarilumab 200 mg q2w plus csDMARDs in the open-label extension (OLE), EXTEND (NCT01146652). OLE dose reduction to 150 mg q2w was permitted per investigators’ judgement or protocol-mandated safety concerns. Safety and efficacy were assessed through treatment-emergent adverse events (AEs), laboratory abnormalities and clinical DASs. All statistics are descriptive. Results Of 546 patients, 454 (83%) were treated with sarilumab in the OLE. The cumulative observation period was 1654.8 patient-years (PY; n = 521); 268 patients (51%) had ≥4 years’ exposure. Incidence rates per 100 PY of AEs, and AEs leading to discontinuation, infection and serious infection were 160.4, 8.1, 57.8 and 3.9, respectively. Neutropenia was the most common AE (15.3 per 100 PY). An absolute neutrophil count of 1 TNFi failure, and similar for patients who either remained on 200 mg or reduced to 150 mg. Conclusion In patients with RA refractory to TNFi, sarilumab’s long-term term safety profile was consistent with previous clinical studies and post-marketing reports. Efficacy was sustained over 5 years. Trial registration TARGET, ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01709578, NCT01709578; EXTEND, ClinicalTrials.gov, https://www.clinicaltrials.gov/ct2/show/NCT01146652, NCT01146652.

BackgroundThe novel calcineurin inhibitor voclosporin was approved in 2021 for the treatment of adult patients with active lupus nephritis (LN) in combination with background immunotherapy. Voclosporin has a favorable metabolic profile and a consistent dose-concentration relationship, eliminating the need for therapeutic drug monitoring.The Phase 2 AURA-LV and Phase 3 AURORA 1 studies demonstrated that the addition of voclosporin to mycophenolate mofetil (MMF) and low-dose steroids led to significantly higher complete renal response rates in AURA-LV at 24 weeks (32.6% vs 19.3%; odds ratio [OR] 2.03; p=0.046) and in AURORA 1 at 52 weeks (40.8% vs 22.5%; OR 2.65; pObjectivesThe European League Against Rheumatism and European Renal Association (EULAR/ERA) published updated treatment recommendations for LN with targeted reductions in proteinuria over the course of the first year of therapeutic intervention.1 Here we report on a post-hoc analysis of pooled data from the similarly designed 48-week AURA-LV and 52-week AURORA 1 studies based on these updated response criteria.MethodsAURA-LV and AURORA 1 enrolled patients with biopsy-proven active lupus nephritis (Class III, IV, or V ± III/IV) and proteinuria ≥1.5 mg/mg (≥2 mg/mg for Class V). Pooled data included 268 patients in the voclosporin (23.7 mg BID) group and 266 patients in the control group, with all patients receiving MMF (target dose 1 g BID) and low-dose steroids (target dose 2.5 mg/day by week 16 according to protocol-defined steroid taper). We assessed the following EULAR/ERA treatment targets: ≥25% reduction in urine protein creatinine ratio (UPCR) by 3 months, ≥50% reduction in UPCR by 6 months, UPCR ≤0.7 mg/mg by 12 months, and steroid dose ≤7.5 mg/day by 3, 6, and 12 months.ResultsWithin the first 3 months of treatment, 78.4% of patients in the voclosporin group and 62.4% of patients in the control group achieved ≥25% reduction in UPCR (odds ratio [OR] 2.25; 95% confidence interval [CI] 1.52, 3.33; p90%) of patients in both groups had achieved the recommended steroid dose, with 89.6% and 82.8% in the voclosporin and control groups, respectively, on the recommended dose at 12 months. The proportion of patients meeting all three UPCR targets during the one-year study period and having a steroid dose ≤7.5 mg/day at 12 months was 37.3% in the voclosporin group and 23.3% in the control group (OR 2.11; CI 1.43, 3.10; p=0.0001).ConclusionThe addition of voclosporin to a background regimen of MMF and low-dose steroids in patients with LN significantly increased the likelihood of achieving the 3-, 6-, and 12-month UPCR targets of therapy recommended by EULAR/ERA.References[1]Fanouriakis, A. et al. 2019 Update of the Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA–EDTA) recommendations for the management of lupus nephritis. Ann. Rheum. Dis. 79, 713–723 (2020).Figure 1.Integrated AURA-LV and AURORA 1 Analysis on the Achievement of UPCR Treatment Targets and Use of Low-Dose Steroids per EULAR/ERA Lupus Nephritis RecommendationsDisclosure of InterestsHans-Joachim Anders: None declared, Ray Federico Shareholder of: Aurinia Pharmaceuticals Inc., Employee of: Aurinia Pharmaceuticals Inc., Simrat Randhawa Shareholder of: Aurinia Pharmaceuticals Inc., Employee of: Aurinia Pharmaceuticals Inc., Henry Leher Shareholder of: Aurinia Pharmaceutical Inc., Employee of: Aurinia Pharmaceutical Inc.

BackgroundVoclosporin (VCS), a novel calcineurin inhibitor, was approved in the US in January 2021 for the treatment of adult patients with active lupus nephritis (LN) in combination with background immunosuppressive therapy. The Phase 3 AURORA 1 study showed that the addition of VCS to mycophenolate mofetil (MMF) and low-dose steroids in patients with LN significantly increased rates of complete renal response at 52 weeks.ObjectivesHere we report the results of the completed continuation study, AURORA 2, which assessed the long-term safety and tolerability of VCS compared to placebo in patients with LN receiving treatment for an additional 24 months following completion of the AURORA 1 studyMethodsKey inclusion criteria for the parent AURORA 1 study included a diagnosis of biopsy-proven active LN (Class III, IV, or V ± III/IV), proteinuria ≥1.5 mg/mg (≥2 mg/mg for Class V) and estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m2. Patients who completed AURORA 1 and who elected and were eligible to enter AURORA 2 continued on the same blinded therapy as at the end of AURORA 1 (either VCS or placebo twice daily in combination with MMF and low-dose steroids). Safety and tolerability were monitored, and eGFR, serum creatinine (SCr), and urine protein creatinine ratio (UPCR) were also assessed.ResultsIn total, 116 and 100 patients in the VCS and control arms enrolled in AURORA 2, with 92 (79.3%) and 73 (73.0%) patients in each respective arm receiving treatment to the end of AURORA 2. There were no unexpected safety signals in the VCS arm compared to control, with similar rates of serious adverse events reported in both arms (VCS [18.1%] vs. control [23.0%]; Table 1). Eight patients in each arm experienced serious adverse events of infection; serious coronavirus infections were observed in 2 patients in the voclosporin arm and 5 patients in the control arm. There were 4 and 2 adverse events by preferred term of renal impairment reported in the VCS and control arms, respectively, none of which were considered serious, and no reports of acute kidney injury by preferred term in either arm. There were no deaths in the VCS arm during AURORA 2; four deaths were reported in the control arm (pulmonary embolism [n=1], coronavirus infection [n=3]). Mean eGFR and SCr levels remained stable through the end of AURORA 2. The difference between the VCS and control arms in LS mean change from baseline in eGFR was 2.7 mL/min/1.73 m2 at 4 weeks following study drug discontinuation (Figure 1). The mean reductions in UPCR observed in patients treated with VCS in AURORA 1 were maintained in AURORA 2 with no increase in UPCR noted at the follow-up visit 4 weeks after study drug discontinuation.Table 1.Overall Summary of Adverse EventsControl(n=100)Voclosporin(n=116)n (%)n (%)Any AE80 (80.0)100 (86.2) Renal Impairment2 (2.0)4 (3.4) Acute Kidney Injury00Treatment-related AE21 (21.0)28 (24.1)Serious AE23 (23.0)21 (18.1)Serious Treatment-related AE2 (2.0)1 (0.9)AE Leading to Study Drug Discontinuation17 (17.0)11 (9.5)Death4 (4.0)0Treatment-related Death00Figure 1.LS Mean eGFR over TimeConclusionVoclosporin was well-tolerated over 3 years of treatment with no unexpected safety signals detected. Further, eGFR remained stable throughout the study period, and the significant and meaningful reductions in proteinuria achieved in AURORA 1 were maintained. These data provide evidence of a long-term treatment benefit of VCS in patients with LN.Includes adverse events starting on or after the first dose of study drug in AURORA 2 up to 30 days after the last dose and all events of death reported during study follow-up. Adverse events were aggregated by System Organ Class and Preferred Term and coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 20.0. AE, adverse event.Disclosure of InterestsAmit Saxena Speakers bureau: Aurinia Pharmaceuticals Inc., Consultant of: Aurinia Pharmaceuticals Inc., Y.K. Onno Teng Consultant of: Aurinia Pharmaceuticals Inc., Chris Collins Shareholder of: Aurinia Pharmaceuticals, Employee of: Aurinia Pharmaceuticals, Nicole England Shareholder of: Aurinia Pharmaceuticals, Employee of: Aurinia Pharmaceuticals, Henry Leher Shareholder of: Aurinia Pharmaceuticals, Employee of: Aurinia Pharmaceuticals

Background:Sarilumab is a human IL-6 receptor (IL-6R) inhibitor approved for the treatment of adults with moderate to severely active rheumatoid arthritis (RA). In the TARGET study (NCT01709578), sarilumab plus conventional synthetic disease-modifying antirheumatic drugs (DMARDs) significantly improved signs and symptoms of RA and physical function versus placebo in patients refractory to tumor necrosis factor (TNF) inhibitors.Objectives:Here we report the long-term safety and efficacy of subcutaneous (SC) sarilumab over 5 years in patients who continued treatment in the open-label extension study (OLE), EXTEND (NCT01146652).Methods:Patients who received double-blind placebo, sarilumab 150 mg, or sarilumab 200 mg every 2 weeks (q2w) in the 24-week randomized controlled trial (RCT) were eligible to receive open-label sarilumab 200 mg q2w in the OLE, with dose reduction to 150 mg q2w permitted to manage laboratory abnormalities or per investigator’s discretion. Safety outcomes are presented for the OLE population for the follow-up from RCT baseline through OLE cut-off date. Efficacy assessments included Clinical Disease Activity Index (CDAI) score and the proportion of responders (CDAI ≤10 and ≤2.8) over time.Results:Of the 546 patients randomized in the RCT, 454 (83%) entered and were treated with sarilumab 200 mg in the OLE (original placebo group n = 156; sarilumab 150 mg n = 145; sarilumab 200 mg n = 153). Demographics and disease characteristics at OLE baseline were similar across groups (mean age 53.2 years; 81% female; mean RA duration [SD] 11.8 years [8.9]). At the time of data cut-off (January 15, 2019), 199/546 (36%) patients had discontinued: 100 (18%), 68 (13%), and 27 (5%) due to treatment-emergent adverse events (AEs), other reasons, and lack of efficacy, respectively. Cumulative exposure to sarilumab through the RCT and OLE (n=521) was 1654.8 patient-years (PY), and 268 patients (51%) had ≥4 years’ exposure. The rates per 100 PY of AEs, serious AEs, AEs leading to discontinuation, and AEs leading to death were 160.4, 10.2, 8.1, and 0.3, respectively. The most common AEs were neutropenia and injection site erythema (15.3 and 11.9 per 100 PY). Absolute neutrophil count 3(Grade 3–4 neutropenia) was observed in 74 patients (14.2%) and normalized on treatment in 48 (9.2%). Alanine aminotransferase >3× the upper limit of normal was observed in 46 patients (8.8%) and normalized on treatment in 25 (4.8%). Infections and serious infections occurred at rates of 57.8 and 3.9 per 100 PY, respectively. Clinical efficacy was sustained through 5 years of the OLE (Table). At OLE Week 240 (n = 95) mean change (SD) in CDAI from RCT baseline was −31.2 (14.6).Table .Proportion of responders*Original RCT groupPlacebo +DMARD(n=156)Sarilumab 150 mg +DMARD(n=145)Sarilumab 200 mg +DMARD(n=153)CDAI ≤2.8, n (%) OLE baseline21 (13)26 (18)23 (15) After 192 weeks’ follow-up17 (11)28 (19)28 (18)CDAI ≤10, n (%) OLE baseline62 (40)75 (52)76 (50) After 192 weeks’ follow-up57 (37)61 (42)66 (43)*Nonresponder imputationConclusion:The safety profile of sarilumab was consistent with results of Phase 3 trials, IL-6R inhibition, and SC administration, and no new safety signals were identified over 5 years of follow-up in patients with RA refractory to TNF inhibitors. Clinical efficacy was sustained through 5 years’ follow-up.Acknowledgments:Study funding and medical writing support (Joseph Hodgson, PhD, Adelphi Communications Ltd, Macclesfield, UK) provided by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc. in accordance with GPP3 guidelines.Disclosure of Interests:Roy Fleischmann Grant/research support from: AbbVie, Akros, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer, IngelhCentrexion, Eli Lilly, EMD Serono, Genentech, Gilead, Janssen, Merck, Nektar, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche, Samsung, Sandoz, Sanofi Genzyme, Selecta, Taiho, UCB, Consultant of: AbbVie, ACEA, Amgen, Bristol-Myers Squibb, Eli Lilly, Gilead, GlaxoSmithKline, Novartis, Pfizer, Sanofi Genzyme, UCB, Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme, Karina Maslova Shareholder of: Sanofi Genzyme, Employee of: Sanofi Genzyme, Henry Leher Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., Amy Praestgaard Employee of: Sanofi Genzyme, Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma

Background:A proportion of adult patients with rheumatoid arthritis (RA) are refractory to tumor necrosis factor inhibitors (TNFi), and treatment with subsequent biologics is commonly associated with reduced response. Sarilumab is a human IL-6 receptor inhibitor approved for the treatment of adults with moderate to severely active RA. In the Phase 3 TARGET study (NCT01709578), significant improvements in the signs and symptoms of RA and physical function were shown with sarilumab plus conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) versus placebo in patients refractory to TNFi.Objectives:To investigate long-term safety and efficacy of subcutaneous sarilumab over 5 years in patients with 1 or >1 TNFi treatment failure prior to their enrollment in TARGET, who continued onto the open-label extension (OLE) study, EXTEND (NCT01146652).Methods:In the 24-week randomized controlled trial (RCT), patients received placebo, sarilumab 150 mg, or sarilumab 200 mg every 2 weeks (q2w), and were eligible to receive open-label sarilumab 200 mg q2w in the OLE. Dose reduction to 150 mg q2w was permitted per investigator’s discretion, or to manage laboratory abnormalities. Safety outcomes are presented for the entire follow-up period from RCT baseline through the OLE. Efficacy was assessed using Clinical Disease Activity Index (CDAI) score.Results:Of the 546 patients randomized in the RCT, 454 (83%) entered the OLE, of whom 339 had 1 TNFi failure and 115 had >1 TNFi failure. Patients with >1 TNFi failure were older and had a longer duration of RA than patients with 1 TNFi failure (mean age [SD] 55.3 [12.6] and 52.5 [11.9] years, mean RA duration [SD] 13.9 [9.1] and 11.1 [8.8] years, respectively). Kaplan–Meier estimates of the probability of continuation at 5 years were similar between groups: 48% and 54% for patients with >1 and 1 TNFi failure, respectively. At the time of data cut-off (January 15, 2019) 199/546 patients (36%) had discontinued through the RCT and OLE. The rates per 100 patient-years of treatment-emergent adverse events (AEs) and AEs leading to discontinuation for patients with >1 and 1 TNFi failure were 290.6 and 197.9, and 6.5 and 8.1, respectively. Clinical efficacy of sarilumab was sustained in the OLE through 5 years in both groups, regardless of initial treatment in the RCT (Table).TableMean CDAI and proportion of CDAI respondersTreatment allocation in 24-week RCTPlacebo+DMARDSarilumab 150 mg+DMARDSarilumab 200 mg+DMARD(n=156)(n=145)(n=153)TNFi failures1>11>11>1CDAI, mean (SD)RCT baseline43.7 (12.7)42.5 (10.3)42.0 (13.0)44.3 (13.5)42.1 (13.5)48.5 (13.0)Change after 216 weeks’ follow-up−30.9 (17.5)−32.6 (15.2)−33.3 (15.8)−33.1 (12.7)−30.3 (13.6)−36.0 (18.1)CDAI ≤10, n (%)*OLE baseline48 (42)14 (33)59 (53)16 (47)56 (49)20 (51)After 216 weeks’ follow-up24 (21)10 (24)29 (26)7 (21)29 (25)8 (21)*Nonresponder imputationConclusion:The long-term safety and efficacy of sarilumab were similar in patients with 1 or >1 prior TNFi failure over 5 years’ follow-up. Clinical efficacy could be sustained through 5 years of treatment.Acknowledgments:Study funding and medical writing support (Joseph Hodgson, PhD, Adelphi Communications Ltd, Macclesfield, UK) provided by Sanofi Genzyme (Cambridge, MA, USA) and Regeneron Pharmaceuticals, Inc. (Tarrytown, NJ, USA) in accordance with GPP3 guidelines.Disclosure of Interests:Roy Fleischmann Grant/research support from: AbbVie, Akros, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer, IngelhCentrexion, Eli Lilly, EMD Serono, Genentech, Gilead, Janssen, Merck, Nektar, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche, Samsung, Sandoz, Sanofi Genzyme, Selecta, Taiho, UCB, Consultant of: AbbVie, ACEA, Amgen, Bristol-Myers Squibb, Eli Lilly, Gilead, GlaxoSmithKline, Novartis, Pfizer, Sanofi Genzyme, UCB, Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme, Karina Maslova Shareholder of: Sanofi Genzyme, Employee of: Sanofi Genzyme, Henry Leher Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., Amy Praestgaard Employee of: Sanofi Genzyme, Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma

Background:Rheumatoid arthritis (RA) patients who achieve a response to therapy but fail to reach low disease activity (LDA) or remission (partial responders) may decline treatment changes for fear of clinical worsening and losing their achieved response. Little is known about the likelihood of worsening after switching therapy in partial responders, and this limits patients’ ability to make informed treatment decisions.Objectives:This post hoc analysis of the open-label extension (OLE) of MONARCH (NCT02332590) assesses the effects of switching from adalimumab to sarilumab in patients with RA who achieved a partial response to adalimumab but not remission or LDA.Methods:MONARCH was a 24-week, head-to-head monotherapy trial comparing sarilumab with adalimumab. At study end, patients randomized to adalimumab were switched to sarilumab 200 mg q2w for the OLE. Partial responders to adalimumab were defined as patients who had improved more than the minimal clinically important difference (MCID) in the Clinical Disease Activity Index (CDAI) during MONARCH, but who continued to have moderate to high disease activity (CDAI >10) at OLE baseline (BL). MCID was defined as a CDAI decrease ≥12 from a BL CDAI >22 or ≥6 from a BL CDAI >10 to ≤22. Response following treatment switch was assessed by change in CDAI and other outcomes from OLE BL to OLE Week 24. The effect of switching was analyzed descriptively and categorized: worsening = CDAI increase ≥6; improvement = CDAI decrease ≥6; stable = CDAI absolute change Results:Of 369 patients enrolled in MONARCH, 320 (87%) entered the OLE; 155 were switched from adalimumab to sarilumab, and of these, 91 were partial responders, who had a mean (SE) CDAI at OLE BL of 19.56 (0.86). Mean (SE) improvement in CDAI from OLE BL to OLE Week 24 in these patients was 7.37 (1.10). At OLE Week 24, only 6% of adalimumab partial responders had worsened after switching to sarilumab, while 57% had improved; the remaining 37% maintained stable disease activity. Analyses of other efficacy measures—patient and physician global assessments, disease activity score 28-joint erythrocyte sedimentation rate, and swollen and tender joint counts—demonstrated similar results: improvement was seen in 27–78% and worsening in 2–17%. No new safety signals emerged during the OLE. The adverse event profile among patients switching from adalimumab to sarilumab was consistent with the established safety profile of sarilumab.Conclusion:Among adalimumab CDAI partial responders who switched to sarilumab, there was a low likelihood of clinical worsening, while more than half of such patients achieved clinically meaningful improvement. Similar results were observed for other efficacy measures. This small risk of worsening coupled with the substantial likelihood of improvement after switch may help alleviate patients’ concerns around loss of response and help inform shared decision-making.Acknowledgments:Study funding and medical writing support (Gregory Bezkorovainy, Adelphi Communications, New York) were provided by Sanofi Genzyme (Cambridge, USA) and Regeneron Pharmaceuticals, Inc. (Tarrytown, USA) in accordance with Good Publication Practice (GPP3) guidelines. Amy Praestgaard (Sanofi Genzyme employee) contributed to the statistical analysis for this abstract.Disclosure of Interests:Jeffrey Curtis Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Janssen, Lilly, Myriad, Pfizer, Regeneron, Roche, UCB, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Janssen, Lilly, Myriad, Pfizer, Regeneron, Roche, UCB, Daniel Aletaha Grant/research support from: AbbVie, Novartis, Roche, Consultant of: AbbVie, Amgen, Celgene, Lilly, Medac, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi Genzyme, Speakers bureau: AbbVie, Celgene, Lilly, Merck, Novartis, Pfizer, Sanofi Genzyme, UCB, Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Kerri Ford Shareholder of: Sanofi Genzyme, Employee of: Sanofi Genzyme, Hubert van Hoogstraten Shareholder of: Sanofi, Employee of: Sanofi, Henry Leher Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., Karthinathan Thangavelu Shareholder of: Sanofi Genzyme, Employee of: EMD Serono, Sanofi Genzyme, Vivian Bykerk: None declared

This study examined the effect of an angiostatic agent on the growth of a highly vascularized intraocular tumor.A murine uveal melanoma cell line (99E1) was transplanted intracamerally into athymic nude BALB/c mice. Mice were treated topically three times per day beginning on the day of tumor transplantation and continuing through day 28. Groups included (a) 1% anecortave acetate, (b) vehicle control, or (c) no treatment. Tumor growth was scored clinically according to the volume of anterior chamber occupied by tumor. Intraocular tumor weights were determined on days 10, 14, 21, and 28. The effect of the test agents on tumor cell proliferation was examined in vitro by [3H]thymidine incorporation.Tumors grew progressively in untreated mice and mice treated with the vehicle; tumors filled the entire eye by day 20 and frequently perforated the globe by day 21. By contrast, tumors treated with anecortave acetate grew significantly slower (P0.025) and did not perforate the eye. On days 21 and 28 the net tumor weight of the AL-3789-treated animals was 40% to 30% of controls (P0.05). Tumor inhibition was presumably due to the angiostatic properties of anecortave acetate because the compound did not affect tumor cell proliferation in vitro.The topical ocular administration of anecortave acetate restricted the growth of a highly vascularized angiogenic intraocular tumor.

Recrudescence is a common and troubling feature of Acanthamoeba keratitis and suggests that corneal infection with this organism fails to stimulate the systemic immune apparatus. The present study examined the cell-mediated and humoral immune responses to Acanthamoeba keratitis in the Chinese hamster. Corneal infection with A. castellanii failed to induce either delayed-type hypersensitivity (DTH) or serum IgG antibody against parasite antigens. The failure to induce cell-mediated and humoral immunity did not result in anergy or tolerance since subsequent intramuscular (i.m.) immunization with parasite antigens elicited robust DTH and IgG antibody responses. The inability of corneal infections to induce primary cell-mediated immune responses was due to the absence of resident antigen-presenting cells in the central cornea because induction of Langerhans cell (LC) migration into the central cornea prior to infection with Acanthamoeba promoted the development of parasite-specific DTH. Although the presence of resident LC did not promote the development of a primary humoral immune response, subsequent i.m. immunization elicited heightened parasite-specific IgG antibody production which was indicative of an anamnestic response. Collectively, the results indicate that in the absence of resident antigen-presenting cells, corneal infection with Acanthamoeba fails to stimulate primary cell-mediated or humoral immunity. Induction of peripheral LC into the central corneal epithelium promotes the development of parasite-specific DTH, but does not exacerbate corneal disease.