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A Phase 2 study to assess the safety, immunogenicity and recommended dose of DS-5670a (COVID-19 vaccine) in Japanese healthy adults

A Phase 2 study to assess the safety, immunogenicity and recommended dose of DS-5670a in Japanese healthy adults

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[Part 1 and Part 2] The mean (standard deviation [SD]) age was 42.6 (13.00) years in the 30 ug group and 41.9 (11.91) years in the 60 ug group. The percentage of males was 52.5% (21/40) in the 30 ug group and 47.5% (19/40) in the 60 ug group. The mean (SD) BMI was 22.72 (3.143) kg/m^2 in the 30 ug group and 22.13 (2.339) kg/m^2 in the 60 ug group. Although the presence of prior medical history and/or underlying conditions was imbalanced between the 30 and 60 ug group in Part 2, there were no appreciable differences in the other demographic factors. The demographic data of the immunogenicity analysis set and the pharmacokinetic analysis set were the same as those of the safety analysis set. [3rd administration part] The mean (SD) age of subjects was 43.2 (11.75) years, the percentage of males was 51.7% (15/29), and the mean (SD) BMI was 22.18 (1.939) kg/m^2. The demographic data of the immunogenicity analysis set were similar to those of the safety analysis set.

[Part 1 and Part 2] A total of 80 subjects (30 ug group 40 subjects, 60 ug group 40 subjects) were administered the investigational drug, and pharmacokinetics were evaluated in 20 of them (30 ug group 10 subjects, 60 ug group 10 subjects). Out of the 80 subjects, 79 completed the observation period (up to Day 57) (30 ug group 40 subjects, 60 ug group 39 subjects), and one subject (60 ug group) withdrew consent and discontinued the clinical trial. The completion rate of the one-year follow-up period was 58.8% (47/80) for the subjects who completed, and 41.3% (33/80) for the subjects who discontinued. Among the 33 subjects who discontinued, 29 discontinued due to transitioning to the 3rd administrationpart. [3rd administration part] Out of the 39 subjects who were administered DS-5670a 60 ug twice in Part 1 or Part 2, all 29 subjects who gave re-consent were enrolled in the 3rd administration part and were administered the investigational drug. There were no subjects who discontinued the clinical trial during the observation period (up to Day 29). The completion rate of the one-year follow-up period was 93.1% (27/29) for the subjects who completed, and 6.9% (2/29) for the subjects who discontinued.

[Part 1 and Part 2] The incidence of adverse events was 92.5% (37/40) in the 30 ug group and 100.0% (40/40) in the 60 ug group, and the incidence of adverse reactions was 92.5% (37/40) in the 30 ug group and 100.0% (40/40) in the 60 ug group. The incidence of injection-site adverse events was 90.0% (36/40) in both the 30 ug group and the 60 ug group. The main injection-site adverse event was injection-site pain (92.5% in the 30 ug group and 90.0% in the 60 ug group). The incidence of systemic adverse events was 62.5% (25/40) in the 30 ug group and 80.0% (32/40) in the 60 ug group. The main systemic adverse event was myalgia (50.0% in the 30 ug group and 57.5% in the 60 ug group). There were no deaths, other serious adverse events, or adverse events leading to discontinuation. During the follow-up period, there was no safety concerns. [3rd administration part] By Day 29 after the third administration of the investigational drug in the 3rd administration part, all participants experienced adverse events and adverse reactions. Solicited injection-site adverse events were observed in 96.6% of participants, and solicited systemic adverse events were observed in 72.4% of participants. All solicited injection-site adverse events and solicited systemic adverse events were considered adverse reactions. The main solicited injection site adverse events were injection-site pain and injection-site warmth. Severe solicited injection-site adverse events were observed in 3 participants, all of which were injection-site erythema. The main solicited systemic adverse events were fatigue, myalgia, and headache. There were no severe solicited systemic adverse events. There were no deaths, other serious adverse events, or adverse events leading to discontinuation. During the follow-up period, there was no safety concerns.

[Part 1 and Part 2] Safety Evaluation Refer to "Adverse events" section. Immunogenicity Evaluation The serum SARS-CoV-2 neutralizing activity geometric mean titers (GMTs) was higher in the 60 ug group compared to the 30 ug group on Day 43 (14 days after the second administration) for all strains, and on Day 57, the GMTs were similar between the 30 ug and 60 ug groups. The seroconversion rates (defined as proportion of subjects with >=4-fold rise) in the neutralizing activity on Day 43 and Day 57 were 92% or higher for the original strain, 94% or higher for the Delta strain, and 39% or higher for the Omicron strain. The geometric mean concentration (GMC) of receptor binding domain (RBD)-binding IgG antibody was higher in the 60 ug group than the 30 ug group at all time points after administration. There was a correlation between the serum neutralization titers and the serum RBD-binding IgG concentration. The serum SARS-CoV-2 neutralizing activity (against the original strain) reached its peak on Day 43 (14 days after the second administration) in both Part 1 and Part 2, and then gradually declined over time. Throughout the follow-up period, the values of the serum SARS-CoV-2 neutralizing activity were generally higher in the DS-5670a 60 ug group compared to the DS-5670a 30 ug group. Pharmacokinetic Evaluation The median Tmax of MAFB-7566a was approximately 14 to 23 hours after the first administration and approximately 23 hours in both groups after the second administration. The mean Cmax and AUClast of MAFB-7566a increased with the dose of DS-5670a after both the first and second administrations. The mean Cmax and AUClast of MAFB-7566a after the second administration were lower than those after the first administration. The plasma concentration of cationic lipid was below the limit of quantification in most time points in the 30 ug group and in more than half of the time points in the 60 ug group after both the first and second administrations. The median Tmax of cationic lipid was approximately 23 to 24 hours in both groups after both the first and second administrations. The mean Cmax and AUClast of cationic lipid increased with the dose of DS-5670a after both the first and second administrations. The mean Cmax and AUClast of MAFB-7566a after the second administration were lower than those after the first administration. The plasma concentration of PEG lipid was below the lower limit of quantification at all measured time points. [3rd administration part] Safety Evaluation Refer to "Adverse events" section. Immunogenicity Evaluation For all staints, the GMT of serum neutralizing activity decreased before the third administration compared to 28 days after the second administration. GMT increased on Day 15 and Day 29 compared to before the third dose. The lower limits of the 95% confidence interval (CI) of the geometric mean fold rise (GMFR) on Day 15 and Day 29 based on before the third administration, 14 days after the second administration and 28 days after the second administration were above 1.0 for all strains. The seroconversion rates were above 95% for the original strain, above 90% for the Delta variant, and above 85% for the Omicron strain. The GMC of anti-RBD IgG antibody titer decreased before the third administration compared to 28 days after the second administration. GMC increased on Day 15 and Day 29 compared to before the third administration. The lower limits of the 95% CI of the GMFR based on Day 15 and Day 29 based on before the third administration and 28 days after the second administration were above 1.0 for all strains. The GMFR based on 14 days after the second administration was close to 1.0 on Day 15 and Day 29, with the 95% CI crossing 1.0. The seroconversion rates were 100.0% on both Day 15 and Day 29. The serum neutralizing activity against SARS-CoV-2 (original strain) 12 months after the third administration were higher than those 6 months after the second administration in Part 1 and Part 2.

It is considered appropriate to select DS-5670a 60 ug as the recommended dose for initial vaccination, as the tolerability was good with both 30 ug and 60 ug doses administered twice intramuscularly and DS-5670a 60 ug demonstrated higher serum neutralizing activity against SARS-CoV-2. Furthermore, additional administration of DS-5670a 60 ug is expected to enhance the preventive effect against SARS-CoV-2 infection.

Aug. 31, 2023

https://www.sciencedirect.com/science/article/pii/S0264410X23008241?via%3Dihub

No

https://jrct.niph.go.jp/latest-detail/jRCT2071210086

Inoguchi Akihiro

DAIICHI SANKYO Co.,Ltd.

1-2-58, Hiromachi, Shinagawa-ku, Tokyo

dsclinicaltrial@daiichisankyo.co.jp

Contact for Clinical Trial Information

DAIICHI SANKYO Co.,Ltd.

1-2-58, Hiromachi, Shinagawa-ku, Tokyo

+81-3-6225-1111

dsclinicaltrial@daiichisankyo.co.jp

Complete

Nov. 06, 2021

Interventional

randomized controlled trial

double blind

uncontrolled control

parallel assignment

prevention purpose

1) Japanese
2) Healthy adults aged >=20 and <65 years at the time of informed consent (Part 1 and Part 2)
3) Body Mass Index (BMI) is >=17.5 and <30.0 kg/m^2 (at screening )
4) Subjects who can follow the compliance requirements during clinical trials, undergo medical examinations and tests specified by the protocol, and report symptoms, etc
5) Subjects who received DS-5670a 60 ug twice intramuscularly in Part 1 or Part 2 of this study and 6 months have passed (3rd administration part)

1) Having a history of anaphylaxis or severe allergies due to food, cosmetics, medicines, or vaccination.
2) Having alcohol or drug dependence.
3) Having a history of immunodeficiency or having a close relative with congenital immunodeficiency.
4) Having a history of SARS-CoV-2 infection.
5) Having fever of >=39.0 C or symptoms of suspected anaphylaxis such as systemic rash within 2 days after past vaccination.
etc.

Both

Prevention of infectious disease by Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)

Part 1 and Part 2: Administer 30 or 60 ug of DS-5670a intramuscularly twice.
3rd administration part: Administer 60 ug of DS-5670a intramuscularly once.

Safety: Adverse events, specific adverse events, laboratory data, weight, vital signs and 12-lead ECGs

Immunogenicity: Neutralizing antibodies against SARS-CoV-2 levels in blood, Anti-IgG levels in blood
Pharmacokinetics: Plasma concentration of MAFB-7566a and constituent lipids of LNP

+81-92-283-7701

Nov. 05, 2021

none