Moderna Announces Additional Positive Phase 1 Data from Cytomegalovirus (CMV) Vaccine (mRNA-1647) and First Participant Dosed in Phase 2 Study
New interim analysis after third and final vaccination shows continued boosting of neutralizing antibody titers in both seronegative participants (exceeding seropositive baseline levels 10-fold at 90 and 180 µg) and seropositive participants (exceeding baseline levels by 20- to 40-fold at 90 and 180 µg)
Phase 2 interim data at three months, expected in 2H 2020, intended to inform Phase 3 dose selection
Pivotal Phase 3 study manufacturing and planning already underway; study start expected in 2021
CMV is the most common infectious cause of birth defects in the U.S.; there is no approved vaccine to prevent CMV
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“Prevention of CMV in women of childbearing age is an urgent unmet need, which we believe positions our wholly owned mRNA-1647 program as a potential blockbuster commercial opportunity. mRNA-1647 is the first mRNA vaccine for an infectious disease to enter a Phase 2 clinical trial,” said Stéphane Bancel, Moderna’s chief executive officer. “These new data, after the third vaccination, represent another critical clinical milestone in our CMV vaccine program and we are extremely pleased with this continued progress as we move into late-stage development, prepare for a pivotal Phase 3 study as quickly as possible and ensure commercial readiness.”
mRNA-1647 comprises six mRNAs encoding two antigens in one vaccine, and is designed to protect against CMV infection. Of the six mRNAs, five encode the subunits of the CMV pentamer complex and one mRNA encodes the glycoprotein B (gB) protein, both of which are highly immunogenic. Both pentamer and gB proteins are essential for CMV to enter epithelial cells, which is the first step in CMV infection. mRNA-1647 is designed to produce an immune response to both pentamer and gB antigens to prevent CMV infection.
The second interim analysis of the Phase 1 trial reports safety and immunogenicity of the first three dose levels (30, 90 and 180 µg) through seven months (one month after the third vaccination) and the highest dose level (300 µg) through three months (one month after the second vaccination). Neutralizing antibody titers were assessed in two assays utilizing epithelial cells and fibroblasts, which measure immune response to pentamer and gB antigens, respectively.
Safety data were consistent with those reported at the three-month interim analysis. The vaccine was generally well-tolerated and there were no vaccine-related serious adverse events (SAEs). The most common solicited local adverse reaction (AR) across all vaccinations was injection site pain (54-100% of a given treatment group). The most common solicited systemic ARs reported overall were headache, fatigue, myalgia and chills. Fever was reported in 0-55% of CMV-seronegative treatment groups and in 8-67% of CMV-seropositive treatment groups. The most common Grade 3 solicited ARs were in CMV-seropositive participants, and were fatigue (0-27% of a given treatment group), chills (0-27% of a given treatment group) and fever (0-33% of a given treatment group). In general, the highest solicited systemic AR rates were reported after the second vaccination, were more frequent in the CMV-seropositive compared to the CMV-seronegative group, and tended to correlate to dose. As reported in the previous interim analysis, one related Grade 4 adverse event (AE) has been observed, which was an isolated lab finding of elevated partial thromboplastin time (PTT), which was elevated at baseline (Grade 1) and self-resolved on the next lab test with no associated clinical findings.
In the CMV-seronegative group at seven months:
- Neutralizing antibody titers continued to increase after the third vaccination in both epithelial cell and fibroblast assays.
- Neutralizing antibody titers against epithelial cell infection were greater than 10-fold higher than CMV-seropositive baseline titers at the 90 and 180 µg dose levels after the third vaccination, compared to 3-fold to 5-fold higher after the second vaccination.
- Neutralizing antibody titers against fibroblast infection increased to 1.4-fold higher than CMV-seropositive baseline titers at the 90 and 180 µg dose levels after the third vaccination, compared to titers that were comparable to CMV-seropositive baseline titers after the second vaccination.
In the CMV-seropositive group at seven months:
- Neutralizing antibody titers continued to increase after the third vaccination in both epithelial cell and fibroblast assays.
- Third vaccination boosted neutralizing antibody titers against epithelial cell infection to levels of 22-fold to 40-fold over baseline across treatment groups, compared to 10-fold to 19-fold over baseline after the second vaccination.
- Third vaccination boosted neutralizing antibody titers against fibroblast infection to levels of 4-fold to 6-fold over baseline across treatment groups, compared to 2-fold to 4-fold over baseline after the second vaccination.
Samples from a subset of CMV-seronegative participants from the 30, 90 and 180 µg dose levels demonstrated T-cell reactivity against the gB antigen at all doses. Pentamer-based T-cell assays remain in development.
This interim analysis also reports the first data from the 300 µg dose level through three months (one month after the second vaccination), which continued to show consistent dose-dependent increases in neutralizing antibodies against epithelial cell infection and against fibroblast infection in both CMV-seronegative and CMV-seropositive participants. Safety and tolerability at the 300 µg dose level was comparable to that observed at the 180 µg dose level.
“These data are significant because they show that after a third dose, mRNA-1647 continues to increase durable immune responses that exceed the levels of those with natural CMV infection,” said
The findings from this interim analysis build on the previously reported interim analysis of safety and immunogenicity through one month after the second vaccination in the three lower dose levels announced at the Company’s R&D Day in
First Participant Dosed in Phase 2 Study
The first participant has been dosed in the randomized, observer-blind, placebo-controlled, dose-confirmation Phase 2 study, which will investigate the safety and immunogenicity of mRNA-1647 in approximately 252 healthy adults in the U.S. at three dose levels (50, 100 and 150 μg) in both CMV-seronegative and CMV-seropositive participants administered in a three-dose vaccination schedule (0, 2 and 6 months). This Phase 2 study will test the intended Phase 3 formulation, which contains the same proprietary lipid nanoparticle (LNP) used in the Phase 1 study. The first interim analysis will evaluate safety and immunogenicity at three months (one month after the second vaccination) and is intended to inform Phase 3 dose selection. mRNA-1647 is the first mRNA vaccine for an infectious disease to enter a Phase 2 clinical trial.
About the Planned Phase 3 Study
With the seven-month Phase 1 data and the launch of the Phase 2 study, the Company is actively preparing for a global randomized, observer-blind, placebo-controlled Phase 3 pivotal study to evaluate the efficacy of mRNA-1647 against primary CMV infection.
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About mRNA-1647
mRNA-1647 comprises six mRNAs encoding two antigens in one vaccine, and is designed to protect against CMV infection. Of the six mRNAs, five encode the subunits of the CMV pentamer complex and one mRNA encodes the glycoprotein B (gB) protein, both of which are highly immunogenic. The pentamer complex is important for CMV entry into a variety of cells, including epithelial cells, while gB is important for entry into all susceptible cells including fibroblasts. A vaccine that produces an immune response against both pentamer and gB has the potential to prevent CMV entry into a range of target cell types and thus prevent primary and congenital infections. Unlike a protein-based vaccine, mRNA-1647 instructs the body’s own cells to manufacture the antigens, resulting in functional antigens that mimic those presented to the immune system by CMV during a natural infection. Preclinical data previously published in Vaccine showed that vaccination with mRNA-1647 in animal models elicited potent and durable neutralizing antibody titers.
About Cytomegalovirus (CMV)
CMV is a common pathogen and member of the herpesvirus family. Congenital (present at or before birth) CMV infection results when infected mothers transmit the virus to their unborn child, and it is the leading infectious cause of birth defects in
CMV is spread through saliva, breastmilk, mucus and urine and is common in healthy babies and toddlers; as a result, young children can be a major source of infection for pregnant women, particularly mothers, daycare workers, preschool teachers, therapists and nurses. Efforts to create a vaccine began in the 1970s, and in 1999 the
About Moderna’s Prophylactic Vaccines Modality
To date,
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Special Note Regarding Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended including, initiating clinical trial sites outside of the U.S. for mRNA-1647; planning for a pivotal Phase 3 study for mRNA-1647; exploration of three development candidates for potential global health; and the Company’s belief that it can reduce the burden of CMV infection, including in women of childbearing age. In some cases, forward-looking statements can be identified by terminology such as “will,” “may,” “should,” “expects,” “intends,” “plans,” “aims,” “anticipates,” “believes,” “estimates,” “predicts,” “potential,” “continue,” or the negative of these terms or other comparable terminology, although not all forward-looking statements contain these words. The forward-looking statements in this press release are neither promises nor guarantees, and you should not place undue reliance on these forward-looking statements because they involve known and unknown risks, uncertainties, and other factors, many of which are beyond Moderna’s control and which could cause actual results to differ materially from those expressed or implied by these forward-looking statements. These risks, uncertainties, and other factors include, among others: the results and timing of the Phase 2 study; the results of testing the Phase 3 formulation; the timing of the proposed Phase 3 study and those risks and uncertainties described under the heading “Risk Factors” in Moderna’s most recent Annual Report on Form 10-K filed with the
1 Congenital CMV and Hearing Loss.
2 Schleiss et al.
3 Congenital CMV and Birth Defects.
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