A randomised, placebo-controlled phase 3 study to evaluate the efficacy and safety of ASP0113, a DNA-based CMV vaccine, in seropositive allogeneic haematopoietic cell transplant recipients

Abstract

Background: Cytomegalovirus (CMV) is a complication of allogeneic haematopoietic cell transplantation (allo-HCT). ASP0113, a DNA-based vaccine, contains two plasmids encoding human CMV glycoprotein B and phosphoprotein 65 (pp65). We assessed ASP0113 in CMV-seropositive allo-HCT recipients.

Methods: In this phase 3, randomised, placebo-controlled study, CMV-seropositive allo-HCT recipients were randomly assigned (1:1) via interactive response technology to receive five injections of 1 mL of 5 mg/mL ASP0113 or placebo. The pharmacist and designated staff were unblinded. Masked syringes maintained the blind for patients and study personnel. Efficacy and safety analyses included patients who received ≥1 dose of ASP0113/placebo. The primary efficacy endpoint was the proportion of allo-HCT recipients with composite all-cause mortality and adjudicated CMV end-organ disease (EOD) by 1 year post-transplant. ClinicalTrials.gov: NCT01877655 (not recruiting).

Findings: Patients were recruited between Sept 11, 2013 and Sept 21, 2016. Overall, 501 patients received ≥1 dose of ASP0113 (n = 246) or placebo (n = 255). The proportion of patients with composite all-cause mortality and adjudicated CMV EOD by 1 year post-transplant was 35.4% (n = 87) with ASP0113 and 30•2% (n = 77) with placebo (odds ratio 1.27; 95% confidence interval: 0.87 to 1.85; p = 0.205). Incidence of injection site-related treatment-emergent adverse events (TEAEs) was higher with ASP0113 than placebo. Overall incidence and severity of other TEAEs was similar between groups. T-cell response to pp65 increased over time and was greater with placebo than ASP0113 (p = 0.027).

Interpretation: ASP0113 did not reduce overall mortality or CMV EOD by 1 year post-transplant. Safety findings were similar between groups.

Funding: Astellas Pharma Global Development, Inc .

Conflict of interest statement

Dr Ljungman reports grants, personal fees and non-financial support from 10.13039/501100004948Astellas personal fees from Vical, during the conduct of the study; personal fees from AiCuris, grants from Merck, grants from Shire, outside the submitted work. Dr Bermudez reports other from Astellas, during the conduct of the study. Dr Logan reports other from Astellas, during the conduct of the study; other from Novartis, outside the submitted work. Dr Kharfan-Dabaja reports other from Seattle Genetics, other from Alexion Pharmaceuticals, other from Incyte, personal fees from Daiichi Sankyo, personal fees from Pharmacyclics, outside the submitted work. Dr Chevallier has nothing to disclose. Dr Martino reports other from Astellas, during the conduct of the study. Dr Wulf reports personal fees from Astellas, during the conduct of the study. Dr Selleslag reports personal fees from Astellas Pharma Global Development, Inc., personal fees from GlaxoSmithKline, personal fees from MSD, personal fees from Pfizer, during the conduct of the study. Dr Kakihana reports personal fees from Chugai Pharmaceutical Co. Ltd, personal fees from Kyowa Hakko Kirin, personal fees from Bristol-Myers Squibb, personal fees from Takeda Pharmaceutical Co., personal fees from Dainippon Sumitomo Pharma, outside the submitted work. Dr Langston has nothing to disclose. Dr Lee reports grants from Astellas, during the conduct of the study; grants from GSK, personal fees from MSD, personal fees from Pfizer, personal fees from Gilead, personal fees from SL Vaxigen, outside the submitted work. Dr Solano reports grants from Astellas Pharma Global Development, Inc., during the conduct of the study; personal fees from Gilead, personal fees from Mitsubishi Tanabe Pharma, outside the submitted work. Dr Okamoto reports grants, personal fees and other from Astellas Pharma, during the conduct of the study. Dr Smith reports personal fees from Astellas Pharma, during the conduct of the study. Dr Boeckh reports grants from Astellas Pharma Global Development Inc, during the conduct of the study; grants and personal fees from Gilead, grants and personal fees from Merck, grants and personal fees from Takeda, grants and personal fees from Vir Bio, personal fees from Allovir, personal fees from GlaxoSmithKline, personal fees from Moderna, personal fees from Oxford Immunotec, personal fees from Evrys Bio, personal fees from Helocyte, grants from Lophius Biosciences, outside the submitted work. Dr Wingard reports personal fees from Astellas Pharma Global Development, Inc., during the conduct of the study; personal fees from Allovir, personal fees from Ansun, personal fees from Celgene, personal fees from Cidara, personal fees from Merck, personal fees from Pluristem, personal fees from Shire, outside the submitted work. Dr Cywin reports personal fees from Astellas, during the conduct of the study, and is an employee of Astellas. Dr Fredericks reports personal fees from Astellas, during the conduct of the study; personal fees from Astellas, outside the submitted work; and is an employee of Astellas. Dr Lademacher reports personal fees from Astellas, during the conduct of the study, and is an employee of Astellas. Dr Wang reports other from Astellas, during the conduct of the study; other from Astellas Pharma global Development, outside the submitted work; and employment by Astellas. Dr Young reports personal fees from Astellas, during the conduct of the study, and is an employee of Astellas. Dr Maertens reports personal fees and non-financial support from 10.13039/501100004948Astellas, grants, personal fees and non-financial support from 10.13039/100004334Merck, personal fees and non-financial support from 10.13039/100004319Pfizer, personal fees and non-financial support from Basilea, personal fees and non-financial support from F2G, personal fees and non-financial support from 10.13039/100010643Cidara, grants, personal fees and non-financial support from 10.13039/100005564Gilead, outside the submitted work.

© 2021 The Authors.

Figures

Fig. 1

Trial profile *Randomisation was blinded, so allocation to treatment group could not influence the likelihood of receiving treatment. †The FAS consisted of all randomised patients who received at least one dose of randomly assigned study drug. ‡The SAF consisted of all randomised patients who received at least one dose of study drug. §The IAS included all patients who received at least one dose of study drug and for whom at least one post-transplant immunogenicity measurement was available. AE=adverse event; FAS=full analysis set; IAS=immunogenicity analysis set; SAF=safety analysis set.

Fig. 2

Time to composite of all-cause mortality and adjudicated CMV EOD (full analysis set) *Parameter estimate from a Cox proportional hazards model with treatment and randomisation strata. p-value based on Cox proportional hazards model parameter estimate for the treatment effect. Circles indicate censored observations. CMV=cytomegalovirus; EOD=end-organ disease; HR=hazard ratio.

Fig. 3

(A) Time to first protocol-defined CMV viraemia through 1 year post-transplant. (B) Time to first use of adjudicated CMV-specific antiviral therapy after first study vaccine injection through 1 year post-transplant *Parameter estimate from a Cox proportional hazards model with treatment and randomisation strata, adjusting for death as a competing risk. p-value based on Cox proportional hazards model parameter estimate for the treatment effect. Circles indicate censored observations. CMV=cytomegalovirus; HR=hazard ratio.

Fig. 4

T-cell response to pp65 (immunogenicity analysis set) Data are mean and standard deviation. Interaction and overall p-value are based on the repeated measure model with post-baseline T-cell response to pp65 values on the 10 based log scale as the outcome variable, randomisation stratum, treatment, time, and treatment by time interaction as the explanatory variables. The self-consistent sandwich correlation structure was used. As zero values are possible these were replaced by 1 before taking the log transform of the pp65 values. *p-value is based on Wilcoxon rank sum test at each visit. Circles indicate censored observations. Time intervals on the x-axis are not equal. ELISpot=enzyme-linked immune absorbent spot; PBMC=peripheral blood mononuclear cell; pp65=phosphoprotein 65; SFU=spot-forming units.

Fig. 5

gB antibody levels (immunogenicity analysis set) Data are mean and standard deviation. Interaction and overall p-value are based on the repeated measure model with post-baseline gB antibody level values on the 10 based log scale as the outcome variable, randomisation stratum, treatment, time, and treatment by time interaction as the explanatory variables. The self-consistent sandwich correlation structure was used. Time intervals on the x-axis are not equal. *p-value is based on Wilcoxon rank sum test at each visit. Circles indicate censored observations. gB=glycoprotein B; RU=relative units.