Clinical Development of a Cytomegalovirus DNA Vaccine: From Product Concept to Pivotal Phase 3 Trial

Abstract

2013 marks a milestone year for plasmid DNA vaccine development as a first-in-class cytomegalovirus (CMV) DNA vaccine enters pivotal phase 3 testing. This vaccine consists of two plasmids expressing CMV antigens glycoprotein B (gB) and phosphoprotein 65 (pp65) formulated with a CRL1005 poloxamer and benzalkonium chloride (BAK) delivery system designed to enhance plasmid expression. The vaccine's planned initial indication under investigation is for prevention of CMV reactivation in CMV-seropositive (CMV⁺) recipients of an allogeneic hematopoietic stem cell transplant (HCT). A randomized, double-blind placebo-controlled phase 2 proof-of-concept study provided initial evidence of the safety of this product in CMV⁺ HCT recipients who underwent immune ablation conditioning regimens. This study revealed a significant reduction in viral load endpoints and increased frequencies of pp65-specific interferon-γ-producing T cells in vaccine recipients compared to placebo recipients. The results of this endpoint-defining trial provided the basis for defining the primary and secondary endpoints of a global phase 3 trial in HCT recipients. A case study is presented here describing the development history of this vaccine from product concept to initiation of the phase 3 trial.

Keywords: CMV end organ disease (EOD); benzalkonium chloride (BAK); cytomegalovirus (CMV); glycoprotein B (gB); hematopoietic cell transplant (HCT); phosphoprotein 65 (pp65); plasmid DNA vaccine; poloxamer CRL1005.

Figure 1

Clinical development timeline of ASP0113 (TransVax) from product concept in 2002 to initiation of a phase 3 trial in 2013. Initiation of various activities is shown in blue diamonds; regulatory activities are shown above the timeline and all others below the timeline. Horizontal blue lines and arrows depict the duration of the indicated activities. Development activities that continued and/or were refined during clinical development are shown in rectangular boxes within the large dotted arrow. Abbreviations: IND, investigational new drug application; FDA, U.S. Food and Drug Administration; EMA, European Medicines Agency; GLP, good laboratory practices; QC, quality control; DS, drug substance.