About the September 7, 2022
Announcements— Leading Global in Gene medicine —September 2022

About COVID-19 DNA Vaccine

We decided to use the technology cultivated in R&D of our world-first genetherapy product using plasmid DNA to develop a COVID-19 DNA vaccine.

Experience of developing andcommercializing HGF genetherapy productDevelopment ofCOVID-19 DNAVaccine

within the body

Integrate the necessary
genetic information into theplasmid

Using plasmid expression
in the body

Plasmid DNA
technology cultivated ingene therapy productThe insertion of a gene into a circular DNA
molecule called a plasmid that is found inbacteria such as E. coli and theadministration of this plasmid DNA causes
the production of proteins the body needs
A large amount of plasmid DNA can becultivated through introduction into E-colibacteria, enabling rapid large-scale plasmid
production

Research at
Osaka University

Source: WHO website

3After deciding to develop a DNA vaccine for the original Wuhan strain of COVID-19,
we began conducting a non-clinical trial for the initial vaccine from March 2020 andcompleted administration for a Phase 2/3 Clinical Trial by March 2021
Since August 2021, we have also been conducting a Phase 1/2 Clinical Trial using avaccine with a higher drug concentration than the initial vaccine

Mar. 2020

Initial vaccine

Nov. 2020

Mar. 2021

Non-clinical

Phase 1/2

Phase 2/3

trial

Clinical Trial

Clinical Trial

High-concentration
vaccineAug. 2021 Nov. 2021

Aug. 2022

Phase 2/3
observation andanalysis

Phase 1/2
Clinical Trial

Phase 1/2

observation
and analysis

4Previous DNA vaccine

SafetyImmunogenicity◎△Discontinued development of previousDNA vaccine and started research
into improved DNA vaccineImproved DNA vaccine

Formulation for intranasal
Review of platform
deliveryimmuneresponse,preventing multiplication of the virus
Improvementof plasmid
Stimulate a broad immuneandimpeding
spreadand
expression
efficiency
transfer efficiency

response to prevent viral
replication and spread

5

Utilization of Stanford University's "Gold-Nanostar Octopod" Technology
At Stanford University, progress is being made on research into an intranasal formulation of the vaccine which
will induce a broader immune response, potentially preventing multiplication of the virus and impeding its spreadwith respect to viral lung diseases.
An intranasal formulation of the vaccine was prepared using plasmid DNA with the genome sequence of theoriginal Wuhan strain, and an experiment using mice confirmed a surge in serum antibodies (IgG, IgA, and IgM).
The intranasal formulation was found to demonstrate neutralizing activity not only against the Wuhan strain but
also against variants such as the β variant and histological analyses revealed cellular and humoral immune
responses against the spike protein in the lymph nodes and spleen.
Based on these findings, we will start development to prepare a formulation for intranasal delivery based on thelatest variants.

■ Outline of Sponsored Research Agreement
Name

Stanford University

Location

California, USAResearch period

Approx. 3 years

Research expenditure

Approx. 3 million USD
6

R&D of intranasal formulation for a safe, highly effective vaccine[What is intranasal delivery?]
The viruses and bacteria which cause respiratory diseases such as COVID-19, influenza and thecommon cold enter the body through the mucosal membranes of the "upper respiratory tract" (nose,mouth and throat) and the "gastrointestinal tract" (intestine, etc.).
The upper respiratory and gastrointestinal tracts have a mucosal immune system, which attacks
viruses to protect the body from infection.
How is it infected?

Production of IgA antibodies (a type of antibody secreted into mucosal membranes) in the nose andthroat may help prevent infection itself and intranasal delivery could create immunity in the part of

the respiratory tract that is the site of infection.
7

HGF Gene Therapy ProductIn March 2019, we obtained marketing approval with conditions and time limit in Japan, claiming
improvement of lower limb ischemic ulcers in patients suffering from chronic arterial occlusion as theefficacy, effect, or performance
Phase 3 Clinical Trial for approval of the additional indication of chronic arterial occlusive disease with rest
pain in Japan
Phase 2 Clinical Trial in the US for arteriosclerosis obliterans with lower limb ulcer in patients with chronicarterial occlusion■ Conditional and time-limited approval system
Project(Nonproprietary name)Area

HGF gene therapy product(BeperminogeneJapanperplasmid)

Indications

Basicresearch

Nonclinicaltrial

Conditional/timeApproval/rlimited
Phase Phaseeview
approval
12

SaleApproved

On saleClinical trial

Ulcer associated withchronic arterial occlusive
diseases

Postmarketing
Formalsurveillance approval

On going■ Standard approval system
Project

HGF gene therapy product(Beperminogeneperplasmid)

Area

Indications

Japan

Chronic arterial occlusive
diseases
Rest pain

Ulcer associated with
Unitedchronic arterial occlusive
Statesdiseases

NonBasic
clinicalresearch
trial

Clinical trial
Phase 1

Phase 2Phase 3

Approval/rApprovaleview

On going

P2b(On going)

9The results of the Phase 3 Clinical Trial of the HGF gene therapy product for the additional
indication of chronic arterial occlusive disease with rest pain showed that we failed to meet theprimary endpoints for rest pain

■ Conditional and time-limited approval system
Project(Nonproprietary name)Area

HGF gene therapy product(BeperminogeneJapanperplasmid)

Indications

Basicresearch

Nonclinicaltrial

Conditional/timeApproval/rPhase Phase
limitedeview
12
approval

Sale

Approved

On saleClinical trial

Ulcer associated withchronic arterial occlusivediseases

PostFormal
marketingapproval
surveillance
On going■ Standard approval system
Project

HGF gene therapy product(Beperminogeneperplasmid)

AreaIndications

Japan

Chronic arterial occlusive
diseases
Rest painUlcer associated withUnitedchronic arterial occlusive
Statesdiseases

NonBasic
clinicalresearch
trial

Clinical trial
Phase 1

Phase 2Phase 3On going

Approval/rApproval
eview

Discontinuationof development

P2b(On going)10

We will push ahead as planned with preparations to apply to obtain the approval of the HGF
gene therapy product in Japan, with improvement of lower limb ischemic ulcers in patients
suffering from chronic arterial occlusion as the stated efficacy, effect, or performance.
We will in the US of the HGF gene therapy product for the treatment of lower limb icontinue

with the Phase 2 Clinical Trial schemic ulcers in patients with chronic arterial occlusion andpush ahead with development aiming to quickly progress through the clinical trial stages.

■ Conditional and time-limited approval system
Project(Nonproprietary name)Area

Indications

HGF gene therapy product(Beperminogeneperplasmid)

JapanUlcer associated withchronic arterial occlusivediseases

Basicresearch

Conditiona
Clinical trialNonApproval/re l/timeclinicalviewlimited
Phase 1 Phase 2
trial
approval
Approved

SaleOn sale

Postmarketing
Formalsurveillance approval

On going

Continued
implementation■ Standard approval system
Project

HGF gene therapy product(Beperminogeneperplasmid)

Area

Indications

Japan

Chronic arterial occlusive
diseases
Rest pain

Ulcer associated withUnitedchronic arterial occlusive
Statesdiseases

Application being
prepared

NonBasic
clinicalresearch
trial

Clinical trial
Phase 1

Phase 2Phase 3

Approval/rApproval
eview

Discontinuationof development
P2b(On going)

Continuedimplementation11

Leading Global in Gene Medicine

AnGes's website
https://www.anges.co.jp/en/