Virologic Efficacy of Casirivimab and Imdevimab COVID-19 Antibody Combination in Outpatients With SARS-CoV-2 Infection: A Phase 2 Dose-Ranging Randomized Clinical Trial.

Importance: The monoclonal antibody combination of casirivimab and imdevimab reduced viral load, hospitalization, or death when administered as a 1200-mg or greater intravenous (IV) dose in a phase 3 COVID-19 outpatient study. Subcutaneous (SC) and/or lower IV doses should increase accessibility and/or drug supplies for patients. Objective: To assess the virologic efficacy of casirivimab and imdevimab across different IV and SC doses compared with placebo. Design, Setting, and Participants: This phase 2, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study included outpatients with SARS-CoV-2 infection at 47 sites across the United States. Participants could be symptomatic or asymptomatic; symptomatic patients with risk factors for severe COVID-19 were excluded. Data were collected from December 15, 2020, to March 4, 2021. Interventions: Patients were randomized to a single IV dose (523 patients) of casirivimab and imdevimab at 300, 600, 1200, or 2400 mg or placebo; or a single SC dose (292 patients) of casirivimab and imdevimab at 600 or 1200 mg or placebo. Main Outcomes and Measures: The primary end point was the time-weighted average daily change from baseline (TWACB) in viral load from day 1 (baseline) through day 7 in patients seronegative for SARS-CoV-2 at baseline. Results: Among 815 randomized participants, 507 (282 randomized to IV treatment, 148 randomized to SC treatment, and 77 randomized to placebo) were seronegative at baseline and included in the primary efficacy analysis. Participants randomized to IV had a mean (SD) age of 34.6 (9.6) years (160 [44.6%] men; 14 [3.9%] Black; 121 [33.7%] Hispanic or Latino; 309 [86.1%] White); those randomized to SC had a mean age of 34.1 (10.0) years (102 [45.3%] men; 75 [34.7%] Hispanic or Latino; 6 [2.7%] Black; 190 [84.4%] White). All casirivimab and imdevimab treatments showed significant virologic reduction through day 7. Least-squares mean differences in TWACB viral load for casirivimab and imdevimab vs placebo ranged from -0.56 (95% CI; -0.89 to -0.24) log10 copies/mL for the 1200-mg IV dose to -0.71 (95% CI, -1.05 to -0.38) log10 copies/mL for the 2400-mg IV dose. There were no adverse safety signals or dose-related safety findings, grade 2 or greater infusion-related or hypersensitivity reactions, grade 3 or greater injection-site reactions, or fatalities. Two serious adverse events not related to COVID-19 or the study drug were reported. Conclusions and Relevance: In this randomized clinical trial including outpatients with asymptomatic and low-risk symptomatic SARS-CoV-2, all IV and SC doses of casirivimab and imdevimab comparably reduced viral load. Trial Registration: ClinicalTrials.gov Identifier: NCT04666441.

Efficacy and safety of a single dose of casirivimab and imdevimab for the prevention of COVID-19 over an 8-month period: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: There is an unmet need for COVID-19 prevention in patient populations who have not mounted or are not expected to mount an adequate immune response to complete COVID-19 vaccination. We previously reported that a single subcutaneous 1200 mg dose of the monoclonal antibody combination casirivimab and imdevimab (CAS + IMD) prevented symptomatic SARS-CoV-2 infections by 81·4% in generally healthy household contacts of SARS-CoV-2-infected individuals over a 1-month efficacy assessment period. Here we present additional results, including the 7-month follow-up period (months 2-8), providing additional insights about the potential for efficacy in pre-exposure prophylaxis settings. METHODS: This was a randomised, double-blind, placebo-controlled trial done in the USA, Romania, and Moldova in 2020-2021, before the emergence of omicron (B.1.1.529) and omicron-lineage variants. Uninfected and unvaccinated household contacts of infected individuals, judged by the investigator to be in good health, were randomly assigned (1:1) to receive 1200 mg CAS + IMD or placebo by subcutaneous injection according to a central randomisation scheme provided by an interactive web response system; randomisation was stratified per site by the test results of a local diagnostic assay for SARS-CoV-2 and age group at baseline. COVID-19 vaccines were prohibited before randomisation, but participants were allowed to receive COVID-19 vaccination during the follow-up period. Participants who developed COVID-19 symptoms during the follow-up period underwent RT-PCR testing. Prespecified endpoints included the proportion of previously uninfected and baseline-seronegative participants (seronegative-modified full analysis set) who had RT-PCR-confirmed COVID-19 in the follow-up period (post-hoc for the timepoints of months 2-5 and 6-8 only) and underwent seroconversion (ie, became seropositive, considered a proxy for any SARS-CoV-2 infections [symptomatic and asymptomatic]; prespecified up to day 57, post-hoc for all timepoints thereafter). We also assessed the incidence of treatment-emergent adverse events. This study is registered with ClinicalTrials.gov, NCT04452318. FINDINGS: From July 13, 2020, to Oct 4, 2021, 2317 participants who were RT-PCR-negative for SARS-CoV-2 were randomly assigned, of whom 1683 (841 assigned to CAS + IMD and 842 assigned to placebo) were seronegative at baseline. During the entirety of the 8-month study, CAS + IMD reduced the risk of COVID-19 by 81·2% (nominal p<0·0001) versus placebo (prespecified analysis). During the 7-month follow-up period, protection was greatest during months 2-5, with a 100% relative risk reduction in COVID-19 (nominal p<0·0001; post-hoc analysis). Efficacy waned during months 6-8 (post-hoc analysis). Seroconversion occurred in 38 (4·5%) of 841 participants in the CAS + IMD group and in 181 (21·5%) of 842 in the placebo group during the 8-month study (79·0% relative risk reduction vs placebo; nominal p<0·0001). Six participants in the placebo group were hospitalised due to COVID-19 versus none who received CAS + IMD. Serious treatment-emergent adverse events (including COVID-19) were reported in 24 (1·7%) of 1439 participants receiving CAS + IMD and in 23 (1·6%) of 1428 receiving placebo. Five deaths were reported, none of which were due to COVID-19 or related to the study drugs. INTERPRETATION: CAS + IMD is not authorised in any US region as of Jan 24, 2022, because data show that CAS + IMD is not active against omicron-lineage variants. In this study, done before the emergence of omicron-lineage variants, a single subcutaneous 1200 mg dose of CAS + IMD protected against COVID-19 for up to 5 months of community exposure to susceptible strains of SARS-CoV-2 in the pre-exposure prophylaxis setting, in addition to the post-exposure prophylaxis setting that was previously shown. FUNDING: Regeneron Pharmaceuticals, F Hoffmann-La Roche, US National Institute of Allergy and Infectious Diseases, US National Institutes of Health.

Efficacy and Safety of Sarilumab in Hospitalized Patients With Coronavirus Disease 2019: A Randomized Clinical Trial.

BACKGROUND: Open-label platform trials and a prospective meta-analysis suggest efficacy of anti-interleukin (IL)-6R therapies in hospitalized patients with coronavirus disease 2019 (COVID-19) receiving corticosteroids. This study evaluated the efficacy and safety of sarilumab, an anti-IL-6R monoclonal antibody, in the treatment of hospitalized patients with COVID-19. METHODS: In this adaptive, phase 2/3, randomized, double-blind, placebo-controlled trial, adults hospitalized with COVID-19 received intravenous sarilumab 400 mg or placebo. The phase 3 primary analysis population included patients with critical COVID-19 receiving mechanical ventilation (MV). The primary outcome was proportion of patients with ≥1-point improvement in clinical status from baseline to day 22. RESULTS: There were 457 and 1365 patients randomized and treated in phases 2 and 3, respectively. In phase 3, patients with critical COVID-19 receiving MV (n = 298; 28.2% on corticosteroids), the proportion with ≥1-point improvement in clinical status (alive, not receiving MV) at day 22 was 43.2% for sarilumab and 35.5% for placebo (risk difference, +7.5%; 95% confidence interval [CI], -7.4 to 21.3; P =.3261), a relative risk improvement of 21.7%. In post hoc analyses pooling phase 2 and 3 critical patients receiving MV, the hazard ratio for death for sarilumab vs placebo was 0.76 (95% CI, .51 to 1.13) overall and 0.49 (95% CI, .25 to .94) in patients receiving corticosteroids at baseline. CONCLUSIONS: This study did not establish the efficacy of sarilumab in hospitalized patients with severe/critical COVID-19. Post hoc analyses were consistent with other studies that found a benefit of sarilumab in patients receiving corticosteroids. CLINICAL TRIALS REGISTRATION: NCT04315298.

Pharmacokinetics and Pharmacodynamics of Subcutaneous Sarilumab and Intravenous Tocilizumab Following Single-Dose Administration in Patients With Active Rheumatoid Arthritis on Stable Methotrexate.

We assessed pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD relationships of interleukin-6 (IL-6), soluble IL-6 receptor, and C-reactive protein (CRP) in serum, and absolute neutrophil count (ANC) in blood following single doses of subcutaneous sarilumab versus intravenous tocilizumab (NCT02097524) from patients with rheumatoid arthritis (RA) who are inadequate responders to methotrexate (MTX) and on a stable dose of MTX. Patients with RA randomized (1:1:1:1) to single-dose sarilumab (150 or 200 mg subcutaneously) or tocilizumab (4 or 8 mg/kg intravenously) were included (n = 101), and PK, PD, and PK/PD relationships and safety were assessed over 6 weeks postdose. PK profiles for both drugs are described by parallel linear and nonlinear target-mediated clearance pathways. PD markers showed similar onset of effect during the first week postdose, regardless of dose or route of administration. CRP and ANC decreased, with median postdose nadirs at 7-15 days for CRP and 3-5 days for ANC. Both drugs at low and high doses achieved the same nadir for ANC and a similar return toward baseline within 2 weeks postdose, suggesting a saturation of effect. Safety profiles of sarilumab and tocilizumab were generally similar. In conclusion, despite differences in PK, the onset of the decrease in CRP (efficacy) and ANC (safety) after a single dose were similar for subcutaneous sarilumab and intravenous tocilizumab. PD effects and safety were consistent with previous studies.

Safety and efficacy of inactivated varicella zoster virus vaccine in immunocompromised patients with malignancies: a two-arm, randomised, double-blind, phase 3 trial.

BACKGROUND: Patients who are immunocompromised because of malignancy have an increased risk of herpes zoster and herpes zoster-related complications. We aimed to investigate the efficacy and safety of an inactivated varicella zoster virus (VZV) vaccine for herpes zoster prevention in patients with solid tumour or haematological malignancies. METHODS: This phase 3, two-arm, randomised, double-blind, placebo-controlled, multicentre trial with an adaptive design was done in 329 centres across 40 countries. The trial included adult patients with solid tumour malignancies receiving chemotherapy and those with haematological malignancies, either receiving or not receiving chemotherapy. Patients were randomly assigned (1:1) to receive four doses of VZV vaccine inactivated by γ irradiation or placebo approximately 30 days apart. The patients, investigators, trial site staff, clinical adjudication committee, and sponsor's clinical and laboratory personnel were masked to the group assignment. The primary efficacy endpoint was herpes zoster incidence in patients with solid tumour malignancies receiving chemotherapy, which was assessed in the modified intention-to-treat population (defined as all randomly assigned patients who received at least one dose of inactivated VZV vaccine or placebo). The primary safety endpoint was serious adverse events up to 28 days after the fourth dose in patients with solid tumour malignancies receiving chemotherapy. Safety endpoints were assessed in all patients who received at least one dose of inactivated VZV vaccine or placebo and had follow-up data. This trial is registered (NCT01254630 and EudraCT 2010-023156-89). FINDINGS: Between June 27, 2011, and April 11, 2017, 5286 patients were randomly assigned to receive VZV vaccine inactivated by γ irradiation (n=2637) or placebo (n=2649). The haematological malignancy arm was terminated early because of evidence of futility at a planned interim analysis; therefore, all prespecified haematological malignancy endpoints were deemed exploratory. In patients with solid tumour malignancies in the modified intention-to-treat population, confirmed herpes zoster occurred in 22 of 1328 (6·7 per 1000 person-years) VZV vaccine recipients and in 61 of 1350 (18·5 per 1000 person-years) placebo recipients. Estimated vaccine efficacy against herpes zoster in patients with solid tumour malignancies was 63·6% (97·5% CI 36·4 to 79·1), meeting the prespecified success criterion. In patients with solid tumour malignancies, serious adverse events were similar in frequency across treatment groups, occurring in 298 (22·5%) of 1322 patients who received the vaccine and in 283 (21·0%) of 1346 patients who received placebo (risk difference 1·5%, 95% CI -1·7 to 4·6). Vaccine-related serious adverse events were less than 1% in each treatment group. Vaccine-related injection-site reactions were more common in the vaccine group than in the placebo group. In the haematological malignancy group, VZV vaccine was well tolerated and estimated vaccine efficacy against herpes zoster was 16·8% (95% CI -17·8 to 41·3). INTERPRETATION: The inactivated VZV vaccine was well tolerated and efficacious for herpes zoster prevention in patients with solid tumour malignancies receiving chemotherapy, but was not efficacious for herpes zoster prevention in patients with haematological malignancies. FUNDING: Merck & Co, Inc.

Immunogenicity of Sarilumab Monotherapy in Patients with Rheumatoid Arthritis Who Were Inadequate Responders or Intolerant to Disease-Modifying Antirheumatic Drugs.

INTRODUCTION: This open-label study evaluated the immunogenicity, safety, and efficacy of sarilumab monotherapy in patients with active, moderate-to-severe rheumatoid arthritis (RA) and inadequate response or intolerance to prior conventional synthetic disease-modifying antirheumatic drugs. METHODS: Adults with RA (n = 132) were randomized to receive subcutaneous sarilumab (150 [n = 65] or 200 mg [n = 67]) every 2 weeks (q2w) for 24 weeks. Endpoints included incidence of antidrug antibodies (ADAs) at week 24, safety, and efficacy. RESULTS: Persistent ADAs occurred in eight patients (12.3%) receiving sarilumab 150 mg q2w, seven of whom (10.8%) had neutralizing antibodies (NAbs), and in four patients (6.1%) receiving sarilumab 200 mg q2w, two of whom (3.0%) had NAbs; all exhibited low antibody titers. Infections and neutropenia were the most common adverse events (AEs). There were three serious AEs, no reports of anaphylaxis, and few hypersensitivity reactions (e.g., rash) with no notable differences in hypersensitivity reactions in ADA-positive patients relative to ADA-negative patients. Changes in absolute neutrophil count, alanine aminotransferase level, and platelet count were consistent with interleukin-6 signaling blockade and in agreement with previous observations. At week 24, overall American College of Rheumatology 20%/50%/70% improvement criteria responses were 73.8%/53.8%/29.2%, respectively, with sarilumab 150 mg q2w and 71.6%/50.7%/29.9% with sarilumab 200 mg q2w. No patients with an ADA-positive response showed loss of efficacy. CONCLUSIONS: ADA titers were low and persistent ADAs and NAbs occurred relatively infrequently in both sarilumab dose groups. ADA did not meaningfully impact the safety or efficacy of either dose of sarilumab over 24 weeks. TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT02121210. FUNDING: Sanofi Genzyme and Regeneron Pharmaceuticals, Inc. Plain language summary available for this article.

Safety and tolerability of subcutaneous sarilumab and intravenous tocilizumab in patients with rheumatoid arthritis.

OBJECTIVE: Safety and efficacy of mAbs blocking the IL-6 receptor have been established in RA. This is the first analysis examining safety and tolerability of sarilumab and tocilizumab administered as single or multiple doses in patients with RA within the same study. METHODS: In ASCERTAIN, patients were randomized 1: 1: 2 to 24 weeks' double-blind sarilumab 150 or 200 mg every 2 weeks s.c. or tocilizumab 4 mg/kg every 4 weeks i.v., increased to 8 mg/kg if clinically indicated. In Study 1309, patients were randomized 1: 1: 1: 1 to single-dose open-label sarilumab 150 or 200 mg s.c. or tocilizumab 4 or 8 mg/kg i.v. RESULTS: In ASCERTAIN, incidence of treatment-emergent adverse events was similar between sarilumab and tocilizumab. The most common treatment-emergent adverse events were the following: sarilumab: neutropenia [6 patients (12.2%) in the 150 mg group and 8 (15.7%) in the 200 mg group], nasopharyngitis [6 (12.2%) and 3 (5.9%)], and injection-site erythema [4 (8.2%) and 4 (7.8%)]; tocilizumab: accidental overdose [9 (8.8%)], upper respiratory tract infection [7 (6.9%)] and nausea [7 (6.9%)]. Laboratory changes in both studies included decreased neutrophils and platelets and increased transaminases and lipids. In Study 1309, incidence of absolute neutrophil count <1.0 giga/l was similar between sarilumab and tocilizumab, and occurred more frequently in the higher dose groups. No association between decrease in absolute neutrophil count and increased incidence of infection was observed in either study. CONCLUSION: No clinically meaningful differences in treatment-emergent adverse events were observed between sarilumab and tocilizumab. Laboratory changes with sarilumab were within the same range as those with tocilizumab. TRIAL REGISTRATION NUMBERS: ASCERTAIN (NCT01768572); Study 1309 (NCT02097524).

Inactivated varicella zoster vaccine in autologous haemopoietic stem-cell transplant recipients: an international, multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Recipients of autologous haemopoietic stem-cell transplants (auto-HSCT) have an increased risk of herpes zoster and herpes zoster-related complications. The aim of this study was to establish the efficacy and safety of an inactivated varicella zoster vaccine for the prevention of herpes zoster after auto-HSCT. METHODS: In this randomised, double-blind, placebo-controlled phase 3 trial, participants were recruited from 135 medical centres (ie, stem-cell transplant centres and hospitals) in North America, South America, Europe, and Asia. Patients were eligible if they were aged 18 years or older, scheduled to receive an auto-HSCT within 60 days of enrolment, and had a history of varicella infection or were seropositive for antibodies to varicella zoster virus, or both. Exclusion criteria included a history of herpes zoster within the previous year of enrolment, and intended antiviral prophylaxis for longer than 6 months after transplantation. Participants were randomly assigned according to a central randomisation schedule generated by the trial statistician, to receive either the inactivated-virus vaccine from one of three consistency lots, a high-antigen lot, or placebo, stratified by age (<50 vs ≥50 years) and intended duration of antiviral prophylaxis after transplantation (≤3 months vs >3 to ≤6 months). Participants, investigators, trial staff, and the funder's clinical and laboratory personnel were masked to group assignment. Participants were given four doses of inactivated vaccine or placebo, with the first dose 5-60 days before auto-HSCT, and the second, third, and fourth doses at about 30, 60, and 90 days after transplantation. The primary efficacy endpoint was the incidence of herpes zoster, confirmed by PCR or adjudication by a masked clinical committee, or both, assessed in all participants randomly assigned to the vaccine consistency lot group or placebo group who received at least one dose of vaccine and had auto-HSCT. Safety was assessed in all randomised participants who received at least one dose of vaccine and had follow-up data. A prespecified vaccine efficacy success criterion required the lower bound of the 95% CI be higher than 25% for the relative reduction of the hazard ratio of herpes zoster infection in participants given the vaccine from one of the consistency lots compared with those given placebo. This trial is registered on ClinicalTrials.gov (NCT01229267) and EudraCT (2010-020150-34). FINDINGS: Between Dec 7, 2010, and April 25, 2013, 560 participants were randomly assigned to the vaccine consistency lot group, 106 to the high-antigen lot group, and 564 to the placebo group. 249 (44%) of patients in the vaccine consistency lot group, 35 (33%) in the high-antigen lot group, and 220 (39%) in the placebo group discontinued before study end, mostly because of death or withdrawal. 51 participants were excluded from the primary efficacy endpoint analyses because they did not undergo auto-HSCT or were not vaccinated, or both (22 [4%] in the vaccine consistency lot group, and 29 [5%] in the placebo group). Mean follow-up for efficacy was 2·4 years (SD 1·3) in the vaccine consistency lot group and 2·3 years (SD 1·3) in the placebo group. 42 (8%) of 538 participants in the vaccine consistency lot group (32·9 per 1000 person-years) and 113 (21%) of 535 in the placebo group (91·9 per 1000 person-years) had a confirmed case of herpes zoster. The estimated vaccine efficacy was 63·8% (95% CI 48·4-74·6), meeting the pre-specified success criterion. For the combined vaccine groups versus the placebo group, the proportion of patients with serious adverse events (216 [33%] of 657 vs 181 [33%] of 554; risk difference 0·2%, 95% CI -5·1 to 5·5) and serious vaccine-related adverse events (five [1%] vs five [1%]; risk difference 0·1%, -1·4 to 1·1) were similar. Vaccine-related injection-site adverse events occurred more frequently in participants given vaccine than those given placebo (191 [29%] vs 36 [7%]; risk difference 22·6%, 95% CI 18·5-26·6; p<0·0001). INTERPRETATION: This study shows for the first time in a large phase 3 trial that early vaccination of auto-HSCT recipients during the peri-transplant period can be effective for the prevention of an opportunistic infection like herpes zoster and that the vaccine is well tolerated. FUNDING: Merck & Co., Inc.

Two years of sarilumab in patients with rheumatoid arthritis and an inadequate response to MTX: safety, efficacy and radiographic outcomes.

Objectives: To examine 2-year safety, efficacy and radiographic outcomes of sarilumab in adults with RA and inadequate response to MTX (MTX-IR). Methods: In the randomized, placebo-controlled MOBILITY trial, MTX-IR patients received subcutaneous sarilumab (150 or 200 mg) or placebo every 2 weeks (q2w) plus MTX for up to 1 year. Upon study completion, patients could enrol in the open-label, long-term extension study (EXTEND, NCT011046652), in which all patients received sarilumab 200 mg q2w plus MTX. Dose reduction to 150 mg q2w was allowed for abnormal laboratory findings and per investigator's discretion. Results: Of 1197 patients participating in MOBILITY, 901 entered EXTEND. Over the 2-year period, treatment-emergent adverse events (TEAEs) and serious AEs occurred at rates of 279.6 events per 100 patient-years and 16.6 events per 100 patient-years, respectively. The most common TEAEs were neutropenia, injection site erythema, increased alanine aminotransferase and upper respiratory tract infections. After 1 year in the open-label, long-term extension, disease activity reached similar levels regardless of initial treatment. Modified total Sharp scores at year 1 were maintained through year 2. Best radiographic outcomes were observed in patients initially randomized to sarilumab 200 mg q2w. After dose reduction, 89.4% of patients continued the study through 2 years. Conclusion: Sarilumab safety through year 2 was consistent with IL-6 receptor blockade. Clinical response was similar irrespective of initial treatment, and radiographic progression stabilized. Patients initiated on sarilumab 200 mg q2w had the best radiographic outcomes. Dose reduction allowed most patients to continue with the study.

Usability and Patient Preference Phase 3 Study of the Sarilumab Pen in Patients with Active Moderate-to-Severe Rheumatoid Arthritis.

INTRODUCTION: Sarilumab is a human monoclonal antibody that blocks the interleukin-6 receptor alpha (IL-6Rα). The phase 3 SARIL-RA-EASY study (EASY) assessed the robustness of an autoinjector (pen) for administering sarilumab when used by adults with active moderate-to-severe rheumatoid arthritis (RA) who are candidates for anti-IL-6R therapy in an unsupervised real-world setting. METHODS: EASY was a 12-week, multicenter, randomized, open-label, parallel-group usability study of the sarilumab pen and prefilled syringe. Patients were randomized 1:1:1:1 to sarilumab 150 or 200 mg every 2 weeks (q2w) administered via pen or syringe, plus background disease-modifying antirheumatic drugs. Patients reported their ability to remove the pen cap and initiate and complete injections; negative responses were defined as product technical complaints (PTCs). The primary endpoint was the number of validated product technical failures (PTFs; PTC with a validated technical cause). This study was not powered to demonstrate bioequivalence or differences in efficacy among groups. RESULTS: A total of 217 patients were randomized. There were 600 successful injections with the sarilumab pen in 108 patients and no pen-associated PTFs. One PTC was observed (the pen was mistakenly activated before injection). At week 12, 88% of patients indicated the pen was "easy" to use, and 98% reported they were "satisfied" with the pen. Proportions of patients achieving an American College of Rheumatology 20/50/70 response and a 28-joint disease activity score by C-reactive protein < 2.6 were similar at each dose between the pen and syringe groups, as were the pharmacokinetics. There were no clinically meaningful differences in adverse events (AEs), serious AEs, and AEs leading to discontinuation in the pen and syringe groups. The most common treatment-emergent AEs were infections and neutropenia. CONCLUSION: This study demonstrated the ease of use and robustness of the sarilumab pen when used by patients with RA in an unsupervised setting. Pharmacokinetics, safety, and efficacy were generally similar for the pen and syringe groups (NCT02057250). FUNDING: Sanofi Genzyme and Regeneron Pharmaceuticals, Inc. TRIAL REGISTRATION: Clinicaltrials.gov identifier, NCT02057250.

Safety and Immunogenicity of Inactivated Varicella-Zoster Virus Vaccine in Adults With Autoimmune Disease: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

BACKGROUND: Immunogenicity and safety of inactivated zoster vaccine (ZVIN) were evaluated in adults with autoimmune disease. METHODS: Adults with autoimmune disease treated with immunosuppressive therapy (biologic or nonbiologic) were randomized to receive 4 doses of ZVIN, ZVIN containing a higher quantity of antigen, or placebo. To measure varicella-zoster virus (VZV)-specific immune responses using glycoprotein enzyme-linked immunosorbent assay (gpELISA) and interferon-gamma enzyme-linked immunospot (IFN-γ ELISPOT), blood samples were collected at baseline, post-doses 2, 3, and 4. The primary hypothesis was that ZVIN would elicit significant VZV-specific immune responses, measured by gpELISA or ELISPOT, at approximately 28 days post-dose 4. Safety and tolerability was assessed through 28 days post-dose 4. RESULTS: ZVIN elicited a statistically significant VZV-specific immune response approximately 28 days post-dose 4, measured by gpELISA (estimated geometric mean fold rise from baseline [GMFR] = 1.6 [95% confidence interval [CI], 1.4,1.7], P value < .0001) and IFN-γ ELISPOT (estimated GMFR = 2.0 [95% CI, 1.6,2.6], P value < .0001); both results met the prespecified success criterion. Overall, 57% (164/289) of all ZVIN and 21% (13/62) of placebo recipients reported ≥1 injection-site adverse events (AEs), and 52% (149/289) and 47% (29/62) reported ≥1 systemic AEs, respectively. Eight ZVIN and 1 placebo recipients experienced serious AEs, including 2 events (ZVIN group) determined by the investigator to be vaccine related (keratitis; amnesia). Overall frequency of AEs decreased with subsequent doses of vaccine. CONCLUSIONS: In adults with autoimmune disease, ZVIN was well tolerated and elicited statistically significant VZV-specific immune responses approximately 28 days post-dose 4, measured by gpELISA and IFN-γ ELISPOT. CLINICAL TRIALS REGISTRATION: NCT01527383.

Safety and immunogenicity of inactivated varicella-zoster virus vaccine in adults with hematologic malignancies receiving treatment with anti-CD20 monoclonal antibodies.

BACKGROUND: Immunocompromised patients can experience significant morbidity and occasional mortality from complications associated with herpes zoster (HZ), but live attenuated HZ vaccine is contraindicated for these patients. Inactivated zoster vaccine (ZVIN) is in development for prevention of HZ in immunocompromised patients. However, there are limited data in the literature regarding the effect of anti-CD20 monoclonal antibodies on vaccine-related cell-mediated immune response. This study evaluated safety and immunogenicity of ZVIN in patients with hematologic malignancies (HM) receiving anti-CD20 monoclonal antibodies (alone or in combination chemotherapy regimens) and not likely to undergo hematopoietic cell transplant (HCT) (n=80). METHODS: This was an open-label, single-arm, multicenter Phase I study (NCT01460719) of a 4-dose ZVIN regimen (∼30days between doses) in patients ⩾18years old. Blood samples were collected prior to dose 1 and 28days Postdose 4 to measure varicella zoster virus (VZV)-specific T-cell responses using interferon-γ enzyme-linked immunospot (IFN-γ ELISPOT). The primary hypothesis was that ZVIN would elicit significant VZV-specific immune responses at ∼28days Postdose 4, with a geometric fold rise (GMFR) >1.0. All vaccinated patients were evaluated for adverse events (AE) through 28days Postdose 4. RESULTS: ZVIN elicited a statistically significant VZV-specific immune response measured by IFN-γ ELISPOT at 28days Postdose 4 (GMFR=4.34 [90% CI:3.01, 6.24], p-value<0.001), meeting the pre-specified success criterion. Overall, 85% (68/80) of patients reported ⩾1 AE, 44% (35/80) reported ⩾1 injection-site AE, and 74% (59/80) reported ⩾1 systemic AE. The majority of systemic AEs were non-serious and considered unrelated to vaccination by the investigator. Frequencies of AEs did not increase with subsequent doses of vaccine. No recipient of ZVIN had rash polymerase chain reaction (PCR) positive for VZV vaccine strain. CONCLUSIONS: In adults with HM receiving anti-CD20 monoclonal antibodies, ZVIN was well-tolerated and elicited statistically significant VZV-specific T-cell responses ∼28days Postdose 4. CLINICALTRIALS.GOV identifier: NCT01460719.

Cellular and Humoral Responses to a Second Dose of Herpes Zoster Vaccine Administered 10 Years After the First Dose Among Older Adults.

BACKGROUND: Herpes zoster vaccine (ZV) was administered as a second dose to 200 participants ≥ 70 years old who had received a dose of ZV ≥ 10 years previously (NCT01245751). METHODS: Varicella zoster virus (VZV) antibody titers (measured by a VZV glycoprotein-based enzyme-linked immunosorbent assay [gpELISA]) and levels of interferon γ (IFN-γ) and interleukin 2 (IL-2; markers of VZV-specific cell-mediated immunity [CMI], measured by means of ELISPOT analysis) in individuals aged ≥ 70 years who received a booster dose of ZV were compared to responses of 100 participants aged 50-59 years, 100 aged 60-69 years, and 200 aged ≥ 70 years who received their first dose of ZV. The study was powered to demonstrate noninferiority of the VZV antibody response at 6 weeks in the booster-dose group, compared with the age-matched first-dose group. RESULTS: Antibody responses were similar at baseline and after vaccination across all age and treatment groups. Both baseline and postvaccination VZV-specific CMI were lower in the older age groups. Peak gpELISA titers and their fold rise from baseline generally correlated with higher baseline and postvaccination VZV-specific CMI. IFN-γ and IL-2 results for subjects ≥ 70 years old were significantly higher at baseline and after vaccination in the booster-dose group, compared with the first-dose group, indicating that a residual effect of ZV on VZV-specific CMI persisted for ≥ 10 years and was enhanced by the booster dose. CONCLUSIONS: These findings support further investigation of ZV administration in early versus later age and of booster doses for elderly individuals at an appropriate interval after initial immunization against HZ. CLINICAL TRIALS REGISTRATION: NCT01245751.

Safety, tolerability, and immunogenicity of zoster vaccine in subjects on chronic/maintenance corticosteroids.

BACKGROUND: This randomized, placebo-controlled study assessed the safety, tolerability, and immunogenicity of live virus zoster vaccine (ZV) in individuals receiving chronic/maintenance systemic corticosteroid therapy (daily dose equivalent of 5-20mg prednisone) for ≥2 weeks prior to vaccination and ≥6 weeks postvaccination. METHODS: Subjects were followed for adverse experiences (AEs), exposure to varicella or herpes zoster (HZ), or development of varicella/varicella-like or HZ/HZ-like rashes for 42 days postvaccination (primary safety follow-up period) and for serious AEs (SAEs) through Day 182 postvaccination (secondary follow-up period). Varicella-zoster virus (VZV) antibody titers by glycoprotein enzyme-linked immunosorbent assay (gpELISA) were measured at baseline and at Week 6 postvaccination. RESULTS: The proportions of subjects reporting systemic AEs and SAEs were similar in both groups. A higher percentage of subjects reported injection-site AEs in the ZV group (21.5%) than in the placebo group (12.1%). One SAE of ophthalmic HZ (onset Day 16 postvaccination) was reported in the ZV group and deemed vaccine-related by the study investigator; however, PCR testing confirmed the presence of wild-type (not vaccine strain) VZV. Geometric mean titer (GMT) at 6 weeks postvaccination was higher for ZV recipients than placebo recipients, with estimated geometric mean fold rises (GMFR) of 2.3 (CI: 2.0, 2.7) and 1.1 (CI: 1.0, 1.2) respectfully. CONCLUSIONS: In adults ≥60 years old on chronic/maintenance corticosteroids, ZV was generally well tolerated and immunogenic. The VZV-specific gpELISA antibody GMT at 6 weeks postvaccination and the GMFR from baseline to 6 weeks postvaccination were higher in the ZV group than in the placebo group.

Long-term persistence of zoster vaccine efficacy.

BACKGROUND: The Shingles Prevention Study (SPS) demonstrated zoster vaccine efficacy through 4 years postvaccination. A Short-Term Persistence Substudy (STPS) demonstrated persistence of vaccine efficacy for at least 5 years. A Long-Term Persistence Substudy (LTPS) was undertaken to further assess vaccine efficacy in SPS vaccine recipients followed for up to 11 years postvaccination. Study outcomes were assessed for the entire LTPS period and for each year from 7 to 11 years postvaccination. METHODS: Surveillance, case determination, and follow-up were comparable to those in SPS and STPS. Because SPS placebo recipients were offered zoster vaccine before the LTPS began, there were no unvaccinated controls. Instead, SPS and STPS placebo results were used to model reference placebo groups. RESULTS: The LTPS enrolled 6867 SPS vaccine recipients. Compared to SPS, estimated vaccine efficacy in LTPS decreased from 61.1% to 37.3% for the herpes zoster (HZ) burden of illness (BOI), from 66.5% to 35.4% for incidence of postherpetic neuralgia, and from 51.3% to 21.1% for incidence of HZ, and declined for all 3 outcome measures from 7 through 11 years postvaccination. Vaccine efficacy for the HZ BOI was significantly greater than zero through year 10 postvaccination, whereas vaccine efficacy for incidence of HZ was significantly greater than zero only through year 8. CONCLUSIONS: Estimates of vaccine efficacy decreased over time in the LTPS population compared with modeled control estimates. Statistically significant vaccine efficacy for HZ BOI persisted into year 10 postvaccination, whereas statistically significant vaccine efficacy for incidence of HZ persisted only through year 8.

Fold rise in antibody titers by measured by glycoprotein-based enzyme-linked immunosorbent assay is an excellent correlate of protection for a herpes zoster vaccine, demonstrated via the vaccine efficacy curve.

BACKGROUND: The phase III Zostavax Efficacy and Safety Trial of 1 dose of licensed zoster vaccine (ZV; Zostavax; Merck) in 50-59-year-olds showed approximately 70% vaccine efficacy (VE) to reduce the incidence of herpes zoster (HZ). An objective of the trial was to assess immune response biomarkers measuring antibodies to varicella zoster virus (VZV) by glycoprotein-based enzyme-linked immunosorbent assay as correlates of protection (CoPs) against HZ. METHODS: The principal stratification vaccine efficacy curve framework for statistically evaluating immune response biomarkers as CoPs was applied. The VE curve describes how VE against the clinical end point (HZ) varies across participant subgroups defined by biomarker readout measuring vaccine-induced immune response. The VE curve was estimated using several subgroup definitions. RESULTS: The fold rise in VZV antibody titers from the time before immunization to 6 weeks after immunization was an excellent CoP, with VE increasing sharply with fold rise: VE was estimated at 0% for the subgroup with no rise and at 90% for the subgroup with 5.26-fold rise. In contrast, VZV antibody titers measured 6 weeks after immunization did not predict VE, with similar estimated VEs across titer subgroups. CONCLUSIONS: The analysis illustrates the value of the VE curve framework for assessing immune response biomarkers as CoPs in vaccine efficacy trials. CLINICAL TRIALS REGISTRATION: NCT00534248.

Varicella-zoster virus-specific antibody responses in 50-59-year-old recipients of zoster vaccine.

Prevaccination and 6-week postvaccination samples from the immunogenicity substudy (n = 2269) of the zoster vaccine (ZV) efficacy trial (N = 22 439) in 50-59-year-old subjects were examined for varicella-zoster virus-specific antibody responses to vaccination. The varicella-zoster virus geometric mean titer (GMT) and geometric mean fold rise were higher in ZV recipients than in placebo recipients (GMT, 660.0 vs 293.1 glycoprotein enzyme-linked immunosorbent assay units/mL [P < .001], respectively; geometric mean fold rise, 2.31 vs 1.00 [P < .025]). In each group there was a strong inverse correlation between postvaccination GMT and risk of subsequent herpes zoster. Although these data provide strong evidence that relates ZV-induced antibody and the risk of herpes zoster, a protective threshold was not determined. Clinical Trials Registration. NCT00534248.

Varicella-zoster virus-specific enzyme-linked immunospot assay responses and zoster-associated pain in herpes zoster subjects.

Varicella-zoster virus (VZV)-specific cell-mediated immunity (CMI) responses were compared over time following an episode of herpes zoster (HZ) with those of age-, race-, and gender-matched healthy controls (HC) without HZ, using a validated gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay. The zoster brief-pain inventory (ZBPI) was used to assess zoster-associated pain. HZ patients (n = 140) had significantly higher IFN-γ ELISPOT responses to VZV antigen than did HC (n = 140). ELISPOT geometric mean count (GMC) responses (with 95% confidence intervals [CI]) for subjects who presented within 72 h were as follows: for HZ patients ≥ 60 years of age, at day 0 the GMC was 110 and at week 2 the GMC was 235; for HZ patients 21 to 59 years of age, at day 0 the GMC was 111 and at week 2 the GMC was 198; for HC ≥ 60 years of age, at day 0 the GMC was 19 and at week 2 the GMC was 18; and for HC 21 to 59 years of age, at day 0 the GMC was 59 and at week 2 the GMC was 56. The mean pain score (95% CI) across age groups at 1 week postrash (n = 106) was 6.0 (5.5, 6.5) and at 2 weeks postrash (n = 119) was 3.5 (2.9, 4.0). The percentage of HZ patients with substantial pain (score ≥ 3) at 6 weeks postrash increased with age from 8% for patients 21 to 49 years of age to 16% for patients 50 to 59 years of age to 22% for patients ≥ 60 years of age. The VZV-specific CMI response was substantially boosted by an episode of HZ, as measured by ELISPOT results. Older adults had lower VZV-specific cellular immunity than younger subjects at baseline, but the boosting effect of HZ was substantial for all age groups. HZ patients experienced considerable zoster-associated acute (1 to 2 weeks after rash) pain across age groups, while chronic pain increased with age.

Efficacy, safety, and tolerability of herpes zoster vaccine in persons aged 50-59 years.

BACKGROUND: Herpes zoster (HZ) adversely affects individuals aged 50-59, but vaccine efficacy has not been assessed in this population. This study was designed to determine the efficacy, safety, and tolerability of zoster vaccine for preventing HZ in persons aged 50-59 years. METHODS: This was a randomized, double-blind, placebo-controlled study of 22 439 subjects aged 50-59 years conducted in North America and Europe. Subjects were given 1 dose of licensed zoster vaccine (ZV) (Zostavax; Merck) and followed for occurrence of HZ for ≥1 year (mean, 1.3 years) postvaccination until accrual of ≥96 confirmed HZ cases (as determined by testing lesions swabs for varicella zoster virus DNA by polymerase chain reaction). Subjects were followed for all adverse events (AEs) from day 1 to day 42 postvaccination and for serious AEs (SAEs) through day 182 postvaccination. RESULTS: The ZV reduced the incidence of HZ (30 cases in vaccine group, 1.99/1000 person-years vs 99 cases in placebo group, 6.57/1000 person-years). Vaccine efficacy for preventing HZ was 69.8% (95% confidence interval, 54.1-80.6). AEs were reported by 72.8% of subjects in the ZV group and 41.5% in the placebo group, with the difference primarily due to higher rates of injection-site AEs and headache. The proportion of subjects reporting SAEs occurring within 42 days postvaccination (ZV, 0.6%; placebo, 0.5%) and 182 days postvaccination (ZV, 2.1%; placebo, 1.9%) was similar between groups. CONCLUSIONS: In subjects aged 50-59 years, the ZV significantly reduced the incidence of HZ and was well tolerated. CLINICAL TRIALS REGISTRATION: NCT00534248.