ANALYST NET Company Report

SymBio Pharmaceuticals Ltd
Issued July 14,2023(4582 GROWTH)

Aiming to become a truly global specialty pharma
2023 likely to be a climacteric

Revised Basic Report

2023 is shaping up to be a critical year for SymBio, with the market for
Treakisym®, long its major earner, starting to be eroded by generics. At the sametime, in May 2023, brincidofovir (BCV), which SymBio has positioned as a pillar
of future global expansion, has established POC for humans in is first indication(disseminated adenoviral infection after hematopoietic stem cell transplantation).
Subsequent indications (BK virus infection after kidney transplantation,
resistant/refractory CMV infection after hematopoietic stem cell transplantation ororgan transplantation) are also providing opportunities to promote in-housedevelopment. Additionally, in 2023 SymBio has concluded cooperative researchand development agreements (CRADA) with two institutes within the National
Institutes of Health (NIH), the National Institute of Neurological Disorders andStroke (NINDS) and the National Institute of Allergy and Infectious Diseases(NIAID). This means that research can be pursued using the US national budget,and facilities, intellectual property, and human resources owned by NINDS and
NIAID. That is why CRADA can only be concluded for projects that may lead to aparadigm shift, concluding these two CRADA is quite epoch-making. SymBio
retains sole ownership of any licenses stemming from the research results.

Fair Research Inc
Tsuyoshi Suzuki

Company Outline
Location

Employees

121 (consol.)President
Established
CapitalListedURL

BCV market estimated at JPY45 billion
The BCV market for disseminated adenoviral infections after hematopoietic stem
cell transplantation, which is expected to be launched in 2028, is estimated at JPY6
billion. The BCV market for BK virus infections after kidney transplantation, which
is being developed, is JPY24 billion. Then there is the BCV market forresistant/refractory CMV infections after hematopoietic stem cell transplantation ororgan transplantation, estimated at JPY15 billon. The total market size, therefore,
is JPY45 billion, and the BCV pipeline value for these markets alone we posit at
between JPY41.9 billion and JPY60.4 billion. The company’s next targets arecancers caused by viral infections (NK/T cell lymphoma, glioblastoma, etc.) andneurodegenerative diseases caused by viral infections (multiple sclerosis,
Alzheimer's dementia). It goes without saying that the market for these is extensive.
Global specialty pharma status by 2030
For the time being, while the Treakisym® market contracts, SymBio will focus on
its own global development of BCV for infectious diseases after hematopoietic stem
cell transplantation or organ transplantation. However, if neurodegenerative diseaseresearch is successful, a global partnership is possible around 2024 or 2025.
Looking further ahead, after 2030 the company plans to enter into full-scale
development in the area of cancers caused by viral infections and neurodegenerative
diseases caused by exposure to viral infections. It will not be easy to do all of thisat the same time, but if successful, there is no doubt that a very large market awaits.
The support of investors who approve of SymBio's strong development drive willbe essential.

IndustryTokyo
Fuminori
YoshidaMarch 2005
JPY 17,568 mil
Oct. 2011www.
symbiopharma.
com
PharmaKey Indicators (July 13, 2023)
Share Price

JPY42252-week high

JPY88152-week low
Sharesoutstanding
Trading unit

JPY35739,827,256

Market cap

JPY16,807 mil

Dividend (est)0.0

Forecast EPS

JPY-9.36

Forecast PERNM

Actual BPS

JPY205.4

Actual PBR

2.05X

100 shares

Note: EPS, PER, BPS and PBR based onshares outstanding, excl. treasury shares

YoY
％

Op.
Income
JPY mil

YoY％

Rec. Profit
JPY milYoY％

Net Income
JPY mil

YoY
％

EPS
JPY

3,835

11.4

-2,656NA-2,748NA-2,752NA-165.5

289

115

2,837

-26.0

-4,301NA-4,376NA-4,376

NA-189.0

275

150

2,987

5.3

-4,506NA-4,615NA-4,090NA-124.1

653

243

8,256

176.4

1,016

NA

1,001

NA

2,032

NA

53.0

2,423

387

2022/1 Actual

10,008

NM

1,963

NM

1,999

NM

1,179

NM

30.2

1,284

610

2023/1 Forecast

7,000

-30.1

-331

NA

-351

NA

-370

NA

-9.4

Results

Revenues
JPY mil

2018/12 Actual
2019/12 Actual
2020/12 Actual
2021/12 Actual

Stock Price JPY
High

Low

1/30
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmacuticals Ltd.(4582 GROWTH)

Issued July 14,2023

Company overview and management philosophy
SymBio Pharmaceuticals Ltd. is a global specialty pharma with a focus on rare
conditions with strong medical need in the areas of cancer and hematology, to which
the major pharmaceutical companies have paid little attention. The company’s
The
companyisa involvement extends from clinical trials, rather than from the high-risk area of drug
pharmaceuticalventure discovery, through to sales activity undertaken by the company itself. The
business with ambitions to company’s business model has three characteristics:
become a global specialty
pharma, aiming for high ① Post-POC strategy
returns and operating in a
The company does not itself undertake drug discovery research but investigates
niche sector without labs or
new drug candidates developed by drug discovery ventures and pharmaceuticals
manufacturing facilities tocompanies around the world. Usually, proof of concept has already been
reduce risk
established. By insisting on prior evidence of efficacy and safety in humansubjects the company reduces the development risks of new drug candidates.
＜Business model＞② A specialty pharma using a high return, high market share niche strategy
The company focuses its efforts on drugs for relatively rare conditions in, forexample, cancer and hematology, where the need is high, but where the major
pharmaceuticals companies are relatively unrepresented. Using this niche
strategy, the company seeks high market share and high returns. Until 2020, thecompany’s business model involved entering into licensing agreements
covering new drug candidates it had selected, developing them in Japan andthen licensing out to other pharmaceuticals companies. Since 2021, however, it
has set up its own sales function in Japan and has established itself as a pharma
specialising in hematology.
③ Global licensor
Further, in September 2019, SymBio acquired exclusive rights (development,
production and sales) to brincidofovir (BCV), a product with global
applications. SymBio has thus evolved from a company seeking licenses inJapan to one providing licenses around the world, firstly in Asia, including
China, and also the US and Europe.

The key to returns is thecompany’s network of drug
discovery companies, andthecompany’sownexpertise

SymBio is a rare bio-venturein that it already has a
product on the market,
which took only five years
from inception to regulatory
approval

The success of this business model owes much to the company’s network of pharmacollaborators around the world and the company’s own expertise. Hence, thecompany’s track record. Normally, it takes some 10-20 years to bring a drug frombasic research to the market. In terms of the probability of success, some estimatessuggest that, counting from the chemical compound stage, it is less than 1/30,000,
and even from the POC stage, it is only around 7-8%. In the case of SymBio’s first
product, Treakisym® it took only five years or so to go from licensing-in (in 2005)
to manufacturing and sales approval (in 2010). In July 2018 it became the preferreddrug for the treatment of malignant lymphomas. In the 17 years since the company
was founded SymBio has introduced 6 products, 3 of which are now underdevelopment or at the development planning stage.
The elements which underpin this track record are the company’s human resourcesand organisation. Hence, one-third of its 121 employees are engaged in research anddevelopment, and the company also boasts a Scientific Advisory Board consistingof specialists, including Nobel Prize candidates, to support its drug search andscrutiny activities. Needless to say, the role and professional network of the company
founder and current president, Fuminori Yoshida, are pivotal.

2/30This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmacuticals Ltd.(4582 GROWTH)

Issued July 14,2023

Establishment of an in-company sales structure

Focus on human capital andcompany organisation to
support networking andexpertise

Source: SymBio: “Matters pertaining to the management plan and company growthpotential”, April 2022

SAB (Scientific Advisory Board） Members

George M orstyn(Chair)Previously Senior Vice Pres.. (Global
Development) of Amgen and CM O

Robert Lewis

Former Senior Vice President at Aventis,
and CEO of Bridgewater ResearchInstitute

Tomomitsu Hotta

Chairman, Foundation for Promotion ofCancer Research
Honorary President, National Cancer Center,
Honorary Director, NHO Nagoya M edical
CenterM akoto Ogawa

Honorary President, Aichi Cancer Center

Toshio Suda

Professor Internatinal Research Center for
M eical Science, Kumamoto Univ,
Professor at Singapore National
University's cancer research insituteToshio Heike

Director of Hyogo Prefectural Amagasaki
General M edical Center, Emeritus
Professor, Kyoto University

Emeritus Professor, Kyoto University
Tatsutoshi Nakahata Director, Central Institute for Experimental
Animals

Tsutomu Takeuchi.

Emeritus Professor, Keio University,
Vice Chancellor, Saitama M edical University.

M D, Texas university Anderson Cancer
Yasukazu Takahashi Centre Leukemia Dept. Assistant Professor,
Dept. of genomic medicine

Senior Advisor
M atius J Rumel

M edical Director Clinic for hematology andM edical Oncology, Justus-Liebig University

Source: SymBio

3/30
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmacuticals Ltd.(4582 GROWTH)

Issued July 14,2023

Significant events
2005/3

SymBio established2005/12Acquires from Astellas in Germany the exclusive rights in Japan for the development and sale of bendamustine

2008/8Concludes with Eisai an agreement on the sale in Japan of freeze-dried bendamustine

2010/10

Acquires approval for manufacture and sale of Treakisym® (freeze-dried bendamustine) in Japan

2010/12Starts sales of Treakisym®

2011/7

Concludes rigosertib licensing agreement with US company Onconova Therapeutics Inc.

2011/10

Listed on JASDAQ

2015/8Onconova re-designs rigosertib tests and starts joint international Phase 3 (INSPIRE ) trials

2015/10The Medicines Company in the US acquires sole development and sales rights in Japan for IONYS® post
operative self-administered pain medicine

2016/5

Treakisym® approved for additional indication in Japan - chronic lymphocytic leukemia

2016/8

Approval given for expanded indications in Japan for low-malignity non-Hodgkin's lymphoma and mantle cell
lymphoma2017/9Acquires from US company Eagle Pharmaceuticals the sole rights in Japan to develop and sell bendamustine
liquid formulation (RTD and RI preparations)

2017/10

Petition seeking arbitration for damages due to non-performance of The Medicines Company's agreement on
license for IONSYS®

2017/11IONSYS® agreement cancelled

2018/7

Approval of Treakisym® and Gazaiba® combined treatment for follicular lymphoma (CD20 positive)

2018/7

Treakisym® listed for the first time in the Hematopoietic Tumor Clinical Practice Guidelines (2018 Edition) as afirst-line treatment for malignant lumphomas

2019/3Treakisym® approved as pre-treatment for Kymriah CAR-T treatment of r/r acute lymphocytic leukemia

2019/9Acquires sole global license for development, manufacture and sale of the anti-viral agent BCV from the US
company, Chimerix (excludes smallpox)

2020/8Top-line results of internatonal joint Phase 3 (INSPIRE) trials on rigosertib show no significant difference fromphysician-chosen treatment

2020/9Approval given for the Treakisym® RTD formulation on existing indications

2020/9IONSYS® arbitration handed down: SymBio to receive half the costs of arbitration-related costs

2020/12

SymBio takes over sales of Treakisym®

2021/1Enters agreement with the Institute of Medical Science, Tokyo University on joint research into discovering new
indications for which bendamustine and rigosertib night be indicated2021/3Phase 2 trials start in the US to test BCV targeting adenovirus infections following HSC transplants

2021/3

Combined Treakisym® and Rituxan® therapy approved for treatment of r/r DLBCL

2021/3

Combination of Treakisym® Rituxan® and Polivy® approved

2021/4Treatisym RTD liquid formulation approved for r/r DLBCL treatment

2021/4Development of BCV targeting adenovirus infections in children given fast track examination status

2021/5

Application submitted for approval of Treakisym® RI formulation

2021/8Among the adenovirus targets of BSV was that for pediatric cases - Phase-2 FPI administrations

2022/2Treakisym® RI formulation approved

2022/2Treakisym® generics approved

2022/6

Towa pharm. starts sales of Treakisym generic targeing r/r DLBCL

2022/6

BCV: FPI in Australian Phase-2 for BK infection following kidney transplant

2022/11

Towa and Pfizer generics approved for Treakisym® RI administration

2022/12

BCV: Ｒesearch results of effect of ＢCV on NK/T-cell lymphoma published by ASH

2022/12Filed a lawsuit against Pfizer and Towa Pharmaceuticals seeking an injunction to stop the manufacture andsale of generics and compensation for damages

2022/12

BCV: Concluded a research agreement with Tufts University to verify the effects of BCV on Alzheimer's
disease caused by HSV-1 infection using a 3D brain model2023/32023/42023/5

BCV: Concluded a joint R&D agreement with the National Institute of Neurological Disorders and Stroke(NINDS) Target: multiple sclerosis caused by EBVBCV : Concluded a behavioral R&D agreement with the US National Institute of Allergy and Infectious
Diseases. Subject: Treatment effect on EBV disease
BCV: Establishes human POC for AdV infection after hematopoietic stem cell transplantation

Source: Compiled by Fair Research Inc. using SymBio’s securities reports and otherfilings

4/30
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmacuticals Ltd.(4582 GROWTH)＜Product pipelines＞

Issued July 14,2023

１．Brincidofovir （SyB V-1901）

SymBio’s next mainstay product pipeline is the antiviral agent, brincidofovir (BCV),a highly active agent for multi-viral infections developed by the US company
Nextleading
product
Chimerix. SymBio plans to develop BCV to target diseases in four areas. Firstly, incandidate:brincidofovir
the area of hematopoietic stem cell transplantation, adenoviral infections and(BCV)cytomegaloviral infections following such transplantations. Secondly, in the area oforgan transplantations, BK viral infections following kidney transplantations.
Thirdly, in the area of cancers caused by viral infections, NK/T-cell lymphoma,
cytomegalovirus-infected GBM, etc. And fourthly, in the area of brain neurodegenerative diseases caused by exposure to viruses, such as EB virus-associatedmultiple sclerosis and herpes simplex virus type 1 (HSV-1) infection Alzheimer's
dementia.

NDA: New Drug Application, MA: Marketing Approval
Source: SymBio Pharmaceuticals website

In 2019 the company
licensed in the highly active
anti-multiviral agent BCV
fromthe US company,
Chmerix

As a strategic product to succeed Treakisym®, SymBio announced on October 1st2019 that it had acquired exclusive global licensing rights (development,
manufacturing and sales) to BCV from Chimerix, Inc. for all diseases except
smallpox. Until this time SymBio’s business had involved acquiring licenses
overseas and undertaking development mainly for the Japanese market. This
contract, however, allows it to evolve into a provider of licenses for development
globally. (Subsequently, on May 16th 2022, Chimerix announced that it would
transfer the license for BCV to Emergent BioSolutions Inc. However, the rights
acquired by SymBio will not be affected.)① Disseminated adenoviraltransplantation

First target indication for
BCV
isdisseminatedadenoviral infection after
hematopoietic stem celltransplantation

infection

after

hematopoietic

stem

cell

Adenovirus infections after hematopoietic stem cell transplantation and BK virus
infections after kidney transplantations are currently in Phase-2. It is generally thecase that in hematopoietic stem cell transplantation and organ transplantation,
irradiation and immunosuppressive agents are used to suppress rejection, which
5/30This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmacuticals Ltd.(4582 GROWTH)

Issued July 14,2023

makes patients susceptible to infection from viruses. Conventionally, other antiviral
agents such as cidofovir (CDV) and foscarnet (FOS) have been used, but there havebeen concerns about nephrotoxicity as a side effect. BCV has low nephrotoxicity
and is therefore an important product that will support SymBio's goal of becominga specialty pharma in the hematology field.
Development recap
Decision reached in August2020 that the first target
shouldbeadenovirus
infections
following
hematopoietic stem celltransplantation

IND application for Phase
2a clinical trlials in March
2021,
FDA
fast-track
designation in April, FPI in
August(a) Decision on development policy
After the Global Scientific Advisory Board meetingheld in February 2020, SymBio
decided to prioritise adenoviral infections after hematopoietic stem celltransplantation as the first development target in August 2020 and that tests onchildren would be given priority. In addition, since safety had already been
confirmed using data from Chimerix, it was decided to start with a Phase-2 dosage
study (development for adults to begin once POC in the pediatric trials wasestablished.)(b) Clinical trials
IND application to conduct Phase-2a joint international trials made on March 10th
2021 and the development program for pediatric adenovirus infections accorded
fast-track designation by the FDA on April 26th. FPI (first-patient-in) was on August
16th 2021. IND application for UK clinical trials made in January 2022.

The clinical trial was designed to study (Phase-2a ATHENA study; 4 cohorts, about
Structure: 4 groups, about 6 6 subjects in each cohort) and confirm safety and tolerability by successively
cases eachincreasing the doses.
1st cohort BCV

0.2mg/1kg body weight. Twice per week for at least 4 weeks

2nd cohort BCV 0.3mg/1kg body weight. Twice per week for at least 4 weeks
3rd cohort

BCV 0.4mg/１kg body weight. Twice per week for at least 4 weeks

4th cohort

BCV 0.4mg/１kg body weight. Once per week for at least 4 weeks（ｃ）POC in humans established
Confirmed POC in human On May 29th, 2023, SymBio submitted to the FDA clinical data for a total of 24
subjects in 24 cases up to the patients (8 in the first cohort, 9 in the second cohort, and 7 in the third cohort) andthird cohort in May 2023
announced that, as a result, POC (proof of concept) had been confirmed.
Consequently, with the 3rd cohort completed, the administration schedule for the
4th cohort is being considered, and discussions are underway with the FDA prior toStarts discussions with FDA
the start of a Phase-3 clinical trial.
as Phase-3 approaches
If all goes well, Phase-3 (several hundred cases) will start in the first half of 2024,
Phase-3 to start in 2024 with
an application for approval will be submitted to the FDA in 2026-2027, and market
market launch around 2027launch will be in 2027-2028.
2028

6/30
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmacuticals Ltd.(4582 GROWTH)

Issued July 14,2023② BK viral infection after kidney transplantation
SymBio plans to move development beyond viral infections following
haematopoietic stem cell transplantation to viral infections after organtransplantation. Organ transplants are more common in Europa and North America
SymBio’s second target than in Japan. For example, while some 1,600 kidney transplantations are carried
indication is BK viral out annually in Japan, 20,000 are carried out in the US and around the same number
infections after kidney in the five major European countries. Of these, an estimated one-third contract thetransplantation
BK virus or the CMV (cytomegalovirus). While the number of infections is quite
low (560) in Japan, in the US + 5 main countries of Europe the total is around 15,000
cases annually.

In June 2022, the company
submitted a clinical trial
protocol for international
joint Phase-2 to the PMDA.
In August, it also submitted
a clinical trial protocol to theAustralian authorities
First administrations
Australia
startedDecember 2022

inin

SymBio is planning to begin product development in Australia, Japan and one othercountry and on June 14th 2022, submitted to the PMDA an application to conduct
Phase-2 joint international clinical trials of BCV on BK viral infections after kidneytransplantations. Additionally, on August 22nd 2022, the company submitted theapplication for clinical trials plan to the Australian Therapeutic Goods
Administration (TGA). In these joint international trials, dose-setting tests are firstcarried out, and the plan is to have 3 groups of 12 cases each. The beginning ofadministrations in Australia was announced on December 13th 2022. Phase-2 isscheduled for completion in the first half of 2025.
1st cohort BCV 0.3mg/1kg body weight. Twice/week, 8-14 weeks
2nd cohort BCV 0.4mg/1kg body weight. Twice weekly, 8-14 weeks
3rd cohort (expanded cohort) BCV recommended dose twice weekly, 8-14 weeks

Protocol: 3 groups
Phase-2
completion
H1/2025
The company plans to promote its own in-house product development, but organtransplantations are outside SymBio’s s area of expertise, and there are not enoughcases in Japan. For these reasons, it is thinking of partnering with a European or US
Promoting in-house productpharmaceutical company to promote development and sales in the area of organ
development
transplantations.
BCV injections:planned development timeline
Present

Year
Quarter

2022
1Q

2Q

Adv infection after
hematopoietic stem celltransplant

3Q

2023
4Q

1Q

2Q

3Q

1Q

2Q

3Q

2025
4Q

1Q

2Q

2026

3Q

4Q

1Q

2Q

3Q

4Q

Ph2 clinical

BKV infection after organtransplant

Ph2 clinical

CMV infection after
hematopoietic stem celltransplant

Ph1b clinicalPre-clinical

EBV multiple sclerosis

HSV-1
Alzheimer's dementia

CMV-GBM

2024
4Q

Ph1 clinicalPre-clinicalPre-clinicalPh1 clinicalPh1 clinical: Establish animal POC：Establish POC in humans

Source: SymBio company briefing, February 2023

7/30
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmacuticals Ltd.(4582 GROWTH)

Issued July 14,2023③ CMV infections after hematopoietic stem cell transplantation
SymBio is considering starting Phase-1b trials for cytomegalovirus infection after
haematopoietic stem cell transplantation by the end of 2023. Development of the
CMV infection following
drug had already been put on the back burner because of the earlier development of
haematopoietic stem cell
Takeda's maribavir for the same CMV indication, but physicians who conducted thetransplantation has emerged
clinical trials on maribavir requested a BCV trial for those patients (44.3%) who
as the next target indication
showed resistance to maribavir, and the decision was made to pursue development
in relapsed and refractory CMV infection.
Restance emerges in almost
half the cases treated with
Maribavir efficacy
maribavir
・Limited effectiveness of existing antivirals, including maribavir
・Problems include possible toxicity, resistance and cross tolerance
Maribavir international Phase-3 clinical trials
2021 Nov. SOLSICE study: Approved by FDA for r/r CMV infection after SOT

For the 44.3% of patients
who are resistant tomaribavir there is noeffective treatment

Trial results・Achieved the required proportion of patients who saw clearance of CMV 8 weeks after administration
・But 44.3% were resistant and showed no effect・Even after the virus became undetectable resistance devleloped, 23% relapsed after 6 weeks and 30% afer 12 weeks

Source: SymBio company briefing, February 2023

Unlike maribavir, BCV is thought to be resistant to mutations. The target moleculeof maribavir is a protein kinase called U97, which is prone to resistance mutations,whereas the target molecule of BCV and CDV is a virus-derived DNA polymerase
Unlike maribavir, BCV is called UL54, which is essential for viral replication, so resistance mutations are
regarded as unlikely to cause unlikely to occur. In fact, clinical trials of BCV have not detected mutations
resistance mutations
associated with resistance.
④Hematological malignancies (NK/T-cell lymphoma, etc.) and solid tumors(GBM, etc.)(a) Hematological malignancies
The EB virus was the first human cancer virus isolated from Burkitt's lymphoma, atype of blood tumor (1964), and is known to be associated with various cancers. Its
involvement in nasopharyngeal cancer, Hodgkin's lymphoma, NK/T-cell lymphoma,
etc. has been documented. However, instead of infection = carcinogenesis, changes
The EB virus is linked to in the genes of infected cells by EB virus are involved in carcinogenesis.
blood tumours
As a result of joint research by SymBio and the National Cancer Center ofSingapore, the therapeutic effect of BCV (non-clinical) for rapidly progressing
Therapeutic effect of BCV NK/T cell lymphoma, for which no effective treatment has been established so far,againstNK/Tcell was released by ASH (the American Society of Hematology) in December 2022.
lymphomaetc.
wasannounced by ASH in 2022 NK/T-cell lymphoma is a malignant lymphoma derived from NK cells or T cells. It
occurs primarily in the perinasal and cutaneous areas as extranodal NK/T-cell
lymphoma. This disease is more common in East Asia and South America than in
NK/T cell lymphomas occur Europe and the United States. In Europe and the United States, it accounts for less
8/30
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmacuticals Ltd.(4582 GROWTH)

Issued July 14,2023

frequently in East Asia and than 1% of non-Hodgkin's lymphoma, while in East Asia (China) it accounts forSouth America
about 10%. Most NK/T-cell lymphomas are EB virus-positive.
Most patients are EB virus
positive

Distribution of NK/T lymphoma patients

Source: ASH, December 2022

While by no means fully elucidated, the carcinogenic mechanism probably goes asfollows. In NK/T-cell lymphoma cancer cells, the EB virus is latently infectious and
The EB virus is involved in expresses a variety of EB virus proteins such as EBNA-1, EBNA-2, LMP-1 andtumor
malignancy
via LMP-2. When EBNA-1 is expressed, p53 is inhibited and apoptosis of cancer cells
various pathways
is suppressed. LMP-1activates NF-κB and this also suppresses apoptosis. It isthought that LMP-2 is involved in carcinogenesis via the P13K or MAPK pathways.
EBV promotes maligancy
EBNA-1＝＞P53 instability＝＞apoptosis
EBNA-2＝＞MYC、LMP-1/2 promotion of expression＝＞cell mmortalised
LMP-1 ==＞NF-κB activation＝＞apoptosis suppression

LMP-2 ＝PI3K pathway /MAPK pathway activation=>involvement in carcinogenesis

BCV has been found not only to suppress the expression of a group of genes (MYC)that promotes tumour malignancy by the EB virus, but also to destroy tumour cells
BCV not only suppresses the and induce immunogenic cell death, which activates cancer immunity. This could
expression of a group of also lead to a beneficial effect in combination with immunotherapy, such as withgenes that promote tumour anti-PD-1 inhibitors.
malignancy, but also induces
immunogenic cell death
Therapeutic efficacy of BCV
Tumour size

The effect of a therapy
combiningBCV
withimmunotherapy, such as
anti-PD-1 inhibitor, could bepromising

BCV injection⇒Involved in inhibiting expression of MYC(cancer gene)

BCV Group

Source: SymBio company briefing, February 2023

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Note: Immunogenic cell death
When cancer cells die, the cells are destroyed and their contents are released, which
signals to dendritic cells, a type of immune cell, that cancer cells have been
destroyed, teaching effector memory T cells how to recognise cancer cells andallowing the immune system to act. This type of cell death is called 'immunogenic
cell death'.

TheInternational
Conference on Malignant
Lymphoma in June 2023
also
confirmedtheeffectiveness of BCVIn April 2023, SymBio
completed a CRADA with
NIAID in the US to examine
the effect of BCV on EB
virus-associatedlymphoproliferative
disorders

In addition, a presentation at the International Conference on Malignant Lymphoma
in June 2023 demonstrated that high sensitivity to BCV is highly correlated with low
expression of TLE1 (cancer suppressor), worse prognosis in patients with NK/T-cell
lymphomas, and increased expression of oncogenes such as MYC.
Further, in April 2023, SymBio concluded a joint R&D agreement (CRADA) with
the US National Institute of Allergy and Infectious Diseases (NIAID) to conduct
non-clinical studies to evaluate BCV’s effect on EB virus-associatedlymphoproliferative disorders.

（ｂ）Solid tumours (GBM)
Glioblastoma (GBM) is the most common malignant brain tumour and an area ofHalf of all glioblastoma seriously unmet medical need. It has a survival time of only 15-20 months and a 5(GBM) patients test positive year survival rate of less than 5%. Approximately 50% of patients are known to be
CMV positive. Various therapeutic agents are currently under development, but
for CMV
there are no therapeutic drug candidates targeting CMV.
ResearchatBrown
University in the US has
demonstrated a mechanism
by which CMV infection
promotes the growth of
GBM cancer cells

Although the CMV-brain tumour mechanism is not fully understood, research at
Brown University, has demonstrated in a mouse model that CMV infection enhances
NF-κB signaling, leading to increased expression of the angiogenic PDGF-D factor,
which promotes GBM cancer cell growth. It has also been found experimentally thatthe antiviral drug cidofovir (CDV) inhibits CMV reactivation and improves survival
in CMV-infected mice （ The Journal of Clinical Investigation 2019, Sean E.
Lawler Sean et al.).

The possible mechanisms of action of BCV on GBM include an anti-tumour effect,in which BCV changes intracellularly into CDV-PP and inhibits the replication cycle
BCV may have an anti- of tumour cells, inducing apoptosis, and a malignant growth suppression effect, intumoureffect and the which BCV inhibits CMV reactivation and suppresses tumour growth.
ability to inhibit malignancy
growthSymBio is currently evaluating the anti-tumour potential of BCV in collaboration
with the University of California and is also working with Brown University toNowconducting
non- evaluate the anti-tumour effect and the effect on tumour malignancy of BCV, withclinical studies,with results expected by the end of 2023. Thereafter, a Phase-1 is planned to start in 2024.
Phase-1 due to begin in 2024
10/30
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SymBio Pharmacuticals Ltd.(4582 GROWTH)

Issued July 14,2023⑤ Expansion into the field of neurodegenerative diseases.
Some neurodegenerative brain diseases are thought to be caused by inflammation
due to viral infection. SymBio is currently conducting pre-clinical studies on
Someneurodegenarative
multiple sclerosis and Alzheimer's dementia.
diseases thought due to
inflammation due to viral
infection
Schedule for development of treatment for neurodegenerative diseases
Now
conducting
nonclinical studies on multiple
sclerosis(MS)andAlzheimer’s dementia

Multiple sclerosis
Trial type

TesterBasic

NIH/Symbio

Protocol
Q3/2022（underway）

Animal model

NIH/SymBio

2023/Q3～

Clinical (human)

NIH/SymBio

2024/Q2～

Alzheimer's dementia
Trial type

Tester3D brain model

Tufts Univ.

Protocol2022/Q4（underway）

Animal model

SymBio2023/Q4～

Clinical (human)

Jointly with partner

2025/Q1～

Alzheimer's dementia
Trial type
TesterTufts Univ.

Protocol2022/Q4（underway）

Animal model

SymBio2023/Q4～

Clinical (human)

Jointly with partner

2025/Q1～

3D brain model

Source: SymBio company briefing. February 2023

MS considered a new target
since February 2022
CRADA concluded
NINDS in 2023

with(a)Multiple sclerosis
In February 2022 the company announced that it was considering MS, an
autoimmune disease, as a new target indication for BCV. In August 2022 it
concluded a cooperative research and development agreement (CRADA) with
NINDS, which belongs to the National Institutes of Health in the US, to evaluate theantiviral effect of BCV against the EB virus. Under this agreement, Symbio was toprovide NINDs with BCV to conduct non-clinical tests for evaluation of potential
effect of BCV against diseases caused by EB. Further, in March 2023, SymBio
concluded a CRADA with the National Institute of Neurological Disorders andStrokes (NINDS) to test the efficacy of BCV in-vitro and in animal models using
cells derived from patients with multiple sclerosis with EB virus infection. In thesecond half of 2023, more advanced experiments using animal models (marmosets)
is scheduled, with plans to start clinical trials (Phase-1) in the second half of 2024.
It is expected that at this stage the major pharmaceutical companies will pay closer
attention.

Development will proceed
to animal models from late2023 and to human Phase1clinical trials in 2024, at
which point a potential
global partnership is in theoffingReference: Multiple sclerosis

An autoimmune disease subject to repetitive relapses and remissions in which
lymphocytes attack the myelin covering the axons of nerve cells and demyelinate
them, causing various neurological symptoms (e.g. motor, visual, sensory and urinary
disorders) as information is not transmitted smoothly in the demyelinated nerves.
Lesions occur sporadically in the brain, spinal cord, and optic nerve, and recur atintervals of one month or longer. The number of patients in Japan, including
neuromyelitis optica patients, is about 18,000, but it is said that there are 3 million
cases worldwide, mainly in Europe and the United States. There is no fundamental
treatment, and steroid pulse therapy which suppresses inflammation with steroids
and immunomodulators that suppress the activity of lymphocytes are used.

Source: multiple sclerosis.jp

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SymBio Pharmacuticals Ltd.(4582 GROWTH)

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The mechanism by which EB virus causes multiple sclerosis (MS) is not fully
understood, but an association with EB virus is supported by epidemiological studies.
A Harvard University research team analyzed a sample of more than 10 million U.S.
military service adults and found that 955 were diagnosed with MS during military
service. Studying these 955 cases it was found that the incidence of post-EB virus
infections were 32-times greater than with other viral infections. （Science Magazine,
January 13, 2022:,”Longitudinal analysis reveals high prevalence of Epstein-Barrvirus associated with multiple sclerosis”）

A research team at Stanford University has recently put forward a powerful new
hypothesis explaining the mechanism of MS onset by the EB virus (Nature, January
24 2022: “Clonally Expanded B cells in Multiple Sclerosis Bind EBV EBNA1 andGlial CAM”) According to this hypothesis, the EB virus transcription factor,
EBNA1, and the glial cell adhesion molecule, GlialCAM, in the brain are
structurally similar, leading the lymphocytes that produce autoantibodies which
recognize both to migrate to the center, accidentally damaging their own myelin,leading to the onset of multiple sclerosis. This hypothesis is supported by theeffectiveness of blocking the transfer of lymphocytes into the central nervous system(sphingosin 1- phosphate receptor agonist) or blocking the migration of lymphocytes
from the lymph nodes (anti-α4 integrin antibody) and the effectiveness of moleculartargeted drugs such as the anti-CD20 antibody (ocrevus) in targeting B-cells.
SymBio believes that if our understanding of this mechanism is correct, theprogression of MS can be inhibited by promptly eliminating the EB virus with BCV
after the onset of MS. Currently, the scale of the market for multiple sclerosis drugs
is about JPY1.5 trillion, and perhaps JPY 2 trillion if steroids are included. SymBio
expects that BCV will be added as a combination drug offering a new mechanism.
Major Multiple Sclerosis Drugs (2020)(JPYbillion)
Mechanism

Product

Company

Anti-CD20 antibody

Ocrevus

Biogen/Roche/Genentech

492.2

Activation of Nrf2 pathway

Techfidera

Biogen422.2

Gilenya/Imusera

Novartis/Tanabe-Mitsubishi Pharm

324.6

DHOD inhibition

Aubagio

Sanofi249.1

Anti-α4 integrin antibody

Tysabri

Biogen/Biogen Japan

207.8

S1P receptor activation

Worldwide Sales

Source: SymBio results meeting materials, February 2022（b）Alzheimers dementia disease
Recently, evidence has been accumulating that herpes simplex virus type 1 (HSV-1)
VSV
activates
herpes is involved in the onset of Alzheimer's disease (Nikkei-FT Conference on Infectious
simplex virus type-1 and Diseases: October 24th 2022: Nikkei News Paper). According to the article, research
amyloid β accumulates
at Tufts University has raised the possibility that the VSV (varicella-zoster virus)
activates HSV-1 and leads the tau protein and amyloid β to accumulate, reducing thefunctioning of nerve cells. In particular, it has been pointed out that carriers of the
APOE4 gene are receptive. Research at Oxford University has also shown that when
HSV-1 is present in the brain the combination with APOE4 increases susceptibility
to Alzheimer’s.

Pre-clinical trials underway
to test the effectiveness of
BCV using the Tufts
University 3-D brain model

On 19th December 2022, SymBio concluded a contract research agreement with
Tufts University and began a pre-clinical study to test the effect of BCV using Tufts
University’s 3-D brain model of the herpes simplex virus (HSV). Longer term theaim is to develop anti-viral drugs to treat Alzheimer’s. Anti-amyloid-β fibre
antibodies such as Lecanemab are currently under the spotlight as a treatment for
12/30

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Alzheimer's disease, but SymBio is hoping BCV can respond a wider variety ofstages than those at which these antibodies are successful.
Note: 3-D Brain Tissue ModelAn experimenting system in which human neural stem cells are cultured using collagen-filled
porous silk protein sponge as a base material, and then proliferated and differentiated into afunctional network of neurons and glial cells that are also susceptible to viral infection. In thissystem, electrophysiological functions, amyloid-β fibril formation due to HSV infection,neuroinflammation, etc. can be evaluated under conditions exclusive of other factors.

・Amyloid β accumulation
・Gliosis, higher or lower inflammation
・3D-Brain Model

・Brain dysfunction

Filled with silk sponge to replicate complex 3-D structure of neurons,different reactions compared with 2-D model

Source: SymBio company briefing. February 2023

Additionally, in November 2022 SymBio concluded a material transfer agreementwith Pennsylvania State University, and non-clinical trials have been started to test
Efficacy against illnesses the effect of BCV on models of polyoma viral infections The polyomavirus is a
caused by a variety of other double-stranded DNA virus that causes serious diseases. Existing antiviral drugs areviruses is also being mostly ineffective. The BK virus and the JC virus are both polyoma viruses.
examined
Review 1: Characteristics of brincidofovirCompared to other antiviral agents such as cidofovir (CDV) and foscarnet (FOS) BCV

BCV stands out against is highly active and effective against multiple viruses.
other agents because it is
BCV - highly active and broad spectrum
highly active and broad
spectrum

Source: Chimerix Inc.
Note: the lower the EC50 (half maximal effective concentration of a drug or
antibody) the higher the activity. In the chart, green indicates high activity andred indicates low activity. BCV on the far left is green for various viruses = hasa broad spectrum.

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whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
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Reference: Cidofovir - CDV

Also, BCV is very safe

The FDA approved CDV in 1996 for the treatment of cytomegalovirus retinitis in
AIDS patients. CDV is a cytosine nucleotide analog that inhibits the replication of
not only herpesviridae but also DNA viruses such as adenovirus, papillomavirus, andpolyomavirus. CDV is also effective against ganciclovir (GCV) resistance (UL97 genemutation) and is considered useful when foscarnet (FOS) cannot be used when GCV
resistance emerges. It has not been developed in Japan, where it is not approved. As
is clear from the above chart, CDV is close to BCV in terms of activity level andspectrum width but is nephrotoxic and difficult to handle. BCV, meanwhile, has low
toxicity and is safe despite its high activity.
Review 2: BCV’s mode of action
Brincidofovir (BCV) has a structure in which a fatty chain (hexadecyloxypropyl:
HDP) is attached to CDV, which is rapidly incorporated into the lipid bilayer andefficiently transferred into the cell, after which the fatty chain is detached bymetabolism by intracellular phospholipase and the activated form (CDV-PP: CDV
diphosphate) produced is retained intracellularly for a protracted period. This results
in a compound with dramatically improved antiviral activity. Additionally, due to
HDP binding, OAT-1 transporter-mediated accumulation in renal tubular epithelial
cells does not occur, and the level of CDV released into the blood is low, thus avoiding
the nephrotoxicity problem of CDV. (Since CDV does not have a fatty chain, it acts asa substrate for OAT-1 and accumulates in renal tubular epithelial cells, resulting in
nephrotoxicity.)

Source: SymBio Pharmacueticals I.R documents

14/30
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whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
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SymBio Pharmacuticals Ltd.(4582 GROWTH)

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２．Development of rigosertib (SyB L-1101 injection and SyB C-1101 oral)
Rigosertib
wasbeing Rigosertib was originally developed to target MDS (myelodysplastic syndromes),
developedfor However, it failed to meet its primary endpoint in Phase-3 international joint trials
myelodysplastic syndromes (INSPIRE trials)) in August 2020.
until it was discontinued.
Consideration is now being
given to development using
a different mode of action

Onconova, the licensor, isfocusing on rigosertib’s
RAS inhibitory function
Source: SymBio web pageNow, however, the focus has shifted to its function as a RAS inhibitor, with therigosertib licensor, Onconova Therapeutics, pursuing the development of cancer
drugs.
Rigosertib’s action mechanism

Source: Daniel A Ritt et al, 「Inhibition of Ras/Raf/MEK/ERK Pathway Signaling
by a Stress-induced Phospho-regulatory Circuit」 Mol Cell 2016 Dec
Rigosertib's microtubule inhibitory effect activates JNK and is thought to act on the
Ras/Raf/MEK/ERK pathway.

In September 2021, Onconova released Phase-1 partial interim results of a study(Phase-1/2a) of a combination of rigosertib (oral) and anti-PD-1 antibody nivolumab(Optdivo®) for non-small cell lung cancer (NSCLC) with KRAS mutation.
The patient subjects were all KRAS mutation NSCLC patients who had at least one
experience of treatment with anti-PD-1 antibody. For NSCLC patients, anti-PD-1
antibodies such as Opdivo® are targeted at patients with a PD-L1 expression rate of
50% or higher, but among patients with a PD-L1 expression rate of 50% or higher,
only about 45% respond to anti-PD-1 antibodies. In other words, even if the antiPD-1 antibody (Opdivo®) is indicated for treatment by genetic testing, it is noteffective in 55% of patients receiving first-line therapy. There is an unmet medical
need here, and it is also a field where pharma companies are competing.
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As a result, of the 12 subjects, 2 had not yet reached the evaluation stage, and 3 werediscontinued due to side effects, etc., so 7 patients were available for evaluation, 2of whom had a partial response (PR). 1 had stable disease (SD), with a disease
control rate of 43%. Partial responses were observed in patients with mutations in
the G12C segment as well as in the G12V segment among KRAS mutations. No
unexpected or serious side effects were observed.
In NSCLC, KRAS mutations are observed in approximately 20% of patients, ofwhich the most frequent (approximately 13%) are mutations in the G12C segment.
LUMAKRAS (generic name sotorasib, AMGEN accelerated approval in May2021), the world's first approved KRAS inhibitor, is an inhibitor of the G12C
mutation. US-based Mirati is also developing the KRAS (G12C) inhibitor adagrasibfor NSCLC, and has also begun developing a KRAS (G12D) inhibitor for pancreaticcancer. However, both AMGEN's drug and Mirati's drug bind to a specific mutatedportion of KRAS and act only on that mutation. On the other hand, rigosertib isthought to have multiple mechanisms of action, such as RAS signal inhibition andmicrotubule destabilization.
SymBio is cooperating with academic institutions (such as Tokyo University and
Kyoto University) on further research into new modes of action for rigosertib andTreakisym® (bendamustine) and seeking out novel uses and new indications.
Possibilities for t combining rigosertib and Treakisym® (bendamustine)

SymBio is collaboratingwith academia in researchon new modes of action

Source: SymBio company briefing

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SymBio Pharmacuticals Ltd.(4582 GROWTH)

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３. Treakisym® (SyB L-0501 (freeze-dried injection formulation/SyB L-1701(RTD liquid formulation)/ Treakisym® (SyB L-1702 liquid formulation)
Treakisym® (generic name: bendamustine) developed by SymBio was the first drug
Symbio guided Treakisym® for malignant lymphoma in Japan. Treatment using Treakisym® is now established
to its status as a standard as one of the standard therapies for malignant lymphoma.
drugformalignantlymphomas in Japan

Source: SymBio home page

Treakisym® is indicated for the following four malignant lymphomas:〇 Relapsed/refractory indolent-B-NHL and MCL (approved Oct. 2010)
Treakisym® is indicated for
low-grade
B-cellnon〇 Treatment-naïve indolent B-NHL and MCL (approved Dec. 2016)
Hodgkin's
lymphoma,〇 Chronic lymphocytic leukemia (CLL) (approved Aug. 2016)
mantle cell lymphoma,
chronic
lymphocytic〇 Relapsed/refractory DLBCL (approved March 2021)
leukemia,
andrelapsed/refractory DLBCL Note: naïve DLBCL: Not eligible for treatment
Reference: Types of malignant lymphoma
Lymphoma is a blood disease that occurs when lymphocytes (a type of white bloodcell), which act as immune cells, become cancerous. Lymphoma is mainly divided into
Hodgkin’s lymphoma (HL) and non-Hodgkin's lymphoma (NHL). In the case ofJapanese malignant lymphoma, 94% are considered to be NHL. NHL is classified
according to the rate of progression of the disease into three categories:〇 Low-grade (indolent-B-NHL): Disease progresses on a yearly basis (such as MALT
and FL (up to grade 3a):
FL：Follicular lymphoma, MALT: MALT lymphoma
Follicular lymphoma accounts for about 80% of low-grade B-cell non-Hodgkin's
lymphoma〇 Intermediate grade: progression of disease on a monthly basis (MCL, DLBCL, etc.)
MCL: mantle cell lymphoma, DLBCL: diffuse large B-cell lymphoma〇 High grade: Weekly progression (such as Burkitt lymphoma)
Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL, but it has
a poor prognosis and a high rate of relapse/refract (r/rDLBCL).

17/30
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whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
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SymBio Pharmacuticals Ltd.(4582 GROWTH)

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Distribution of malignant lymphoma by type (Japan)
(%)
DLBCL

45.3

Follicular lymphoma

13.5

M alt lymphoma

7.2

Non-Hodgkin
Chronic lymphcytic leukemia/SLL
lymphoma

3.2

M antle cell lymphoma

Treakisym
indicated

2.0

Burkitt tumours

1.3

T/NK cell tumours

18.1

Hodgkin lymphoma

5.9

Others3.8
Indolent lymphoma
M edium-high malignancy

Note: Among DLBCL's indicated for r/r DLBCL, 1st-Line DLBCL - off-label
Further, splenic green band B-cell lymphoma, lymph plasma cell lymphoma, and nodalline green band B-cell lymphoma belonging to other categories are also indicated.

Source: Compiled from Chihara D et al, “Differences in incidence and trends ofhaematological malignancies in Japan and the United States” British Journal of
Haematology. 2014

SymBiointroduced ① History of development
Treakisym to Japan in Looking back briefly at the history of development, Treakisym® was developed in
December 2005
Germany in 1971. In December 2005, SymBio acquired exclusive development andmarketing rights in Japan from Astellas Pharma's European subsidiary, Astellas
Acqured first indication Pharma (current name: Astellas Deutschland GmbH) and conducted clinical trials.
approval five years after In October 2010, just five years after its introduction, it was approved for theindication of relapsed/refractory indolent-B-NHL and MCL, and sales began inlicensing in
December. In August 2016, it was approved for chronic lymphocytic leukemia(CLL), and in December 2016, it was additionally approved for treatment-naïve
Established as a standard indolent-B-NHL and MCL. Furthermore, in July 2018, indolent-B-NHL, MCL, andtherapy in 2018
CLL, for which Treakisym® had been approved, were newly included as standard
treatment options in the 2018 edition of the Clinical Practice Guidelines for
Hematopoietic Malignancies (edited by the Japanese Society of Hematology).
Market penetration of Treakisym® increased as it was established as one of thestandard therapies, completely surpassing the R-CHOP therapy, which had been theSales boost in 2021 from conventional standard therapy, and domestic sales in 2018, the eighth year since its
launch, expanded to JPY8.5 billion (NHI drug price basis). There was subsequently
approval of r/rDLBCL
some temporary stagnation in sales due to quality issues at the manufacturer andinventory fluctuations as the company switched to its own sales system (domestic
sales in 2020: JPY8.1 billion, NHI drug price basis), but in March 2021, approval
was given for the B-R therapy and P-BR therapy (Polivy® + B-R therapy) for diffuse
large B-cell lymphoma (r/rDLBCL), opening the way for sales to again expand.
SymBiohasbeen SymBio has also been developing more user-friendly formulations. Until December
developinguser-friendly 2020, Treakisym® was a freeze-dried formulation (FD formulation) manufactured
dosing formulations
by Astellas Deutschland GmbH. In September 2017, SymBio announced thelicensing-in of a Treakisym liquid formulation (RTD - Ready to Dilute) from Eagle
Pharmaceuticals Inc. in the United States. Although the conventional FD
formulation has the advantage of storage at room temperature, it requires the workof dissolving in a solvent and dilution with physiological saline before
RTD formulation approved administration, which takes time and effort. On the other hand, liquid preparationsin September 2020, leading must be refrigerated, but they have the advantage of reducing the work-load bysimple dilution with physiological saline, which shortens the preparation. Further,to signficant cut in costs
the switch to a liquid formulation can provide substantial savings of the sales-cost
ratio. Since the efficacy and administration of the RTD formulation are the same as
for the FD formulation, no additional clinical trials were necessary. Providing only
18/30
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SymBio Pharmacuticals Ltd.(4582 GROWTH)

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formulation safety data an application was submitted in September 2019 andapproval for the existing indications was received in September 2020, with sales
beginning on January 12th 2021. In April 2021, the RTD formulation was also
Approval given for time- approved for r/rDLBCL. In addition, regarding the RI administration that can besaving RI administration in administered in a shorter time, using Bendeka 10-minute administration licensed
February 2022
from Eagle Pharmaceuticals in the US, the concentration and administration time
are different, so the company had to confirm safety and pharmacokinetics. Clinical
trials were conducted, an application was filed in May 2021, and all indications wereapproved in February 2022. The administration time is shortened to 10 minutes andthe salt content is low, so it is positioned as a formulation suitable for malignant
lymphoma patients, many of whom are elderly.
Comparison of FD, RTD, and RI (10-minute administration) formulations

Source: SymBio results meeting②

Emergence of generics and Symbio’s response<Evolution of generics in the market>
In February 2022 a number
The entry of Treakisym® generics into the market started in February 2022. Onofgenerics(RTD
February 15th 2022, Pfizer (Japan) Meiji Seika Pharma, Kowaisei and Towa
preparations) were given
Pharmaceutical received approval for the manufacture and sale of a generic
FDA approval
Treakisym® intravenous dip (RTD formulation). It is relatively easy in Japan, which
has a policy of encouraging the take-up of generic drugs, to have a generic approved
through the inclusion of a different ingredient to the original drug’s composition.
However, this can create patent infringement problems.
On February 25th 2022, SymBio notified the four companies of concerns about
patent infringement. The patent in question, which has also been recognized inJapan, is the property of Eagle Pharmaceuticals Inc., a US company, which is theoriginal licensor of the RTD formulation and RI administration. There was aprevious instance in the US of patent infringement involving the Treakisym
Bendeka® RI administration. The court in that case found for Eagle Pharmaceuticals(the licensor was Teva) and enjoined the generics makers from selling the productThree of these companies for a prescribed period. On February 28th 2022, approval was given for the RI
decided to put off sales, but formulation, which is even more convenient to administer than the RTD formulation,
Towa went ahead
and SymBio began encouraging a switch. On May 11, Meiji Seika Pharma
announced it was putting off the posting of drug prices scheduled for June and some
generic makers followed Meiji Seika Pharma. With this, the risk posed by generics
receded somewhat, however one company, Towa, got as far as posting prices andIndications approved for the starting sales.
19/30
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whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmacuticals Ltd.(4582 GROWTH)

Issued July 14,2023

generics were expanded to The indications approved for the four generics makers in February covered indolent
include r/rDLBCL in June B-NHL and MCL, but not r/r DLBCL. In June, Towa received approval for the2022
additional indication of r/r DLBCL. Meanwhile, CLL is covered by exclusive
protection during the reexamination period (until 2026) and cannot be included in
the indications for generic products. At that time, the P-BR therapy was not approved
In November 2022, Towafor the treatment of r/r DLBCL.
and Pfizer received
approval for generic RI
administration, also
However, on November 9th 2022 Towa Pharmaceuticals and Pfizer (Japan) received
approved for use in P-BR
approval for an RI generic, and Pfizer began sales on December 16th. The indications
therapy
approved for Pfizer included P-BR for r/r DLBCL (in February 2023 Towa was also
permitted to use it in P-BR therapy). In response, SymBio filed a lawsuit against
In December 2022, SymBio Towa Pharmaceutical on 16th December 2022 for an injunction against the
filed a lawsuit against Towa manufacture and sale of generic products, and compensation for damages, claiming
and Pfizer for patent possible patent infringement with regard to the RI administration. In addition, on
infringement
26th December, a similar lawsuit was filed against Pfizer.

As of 2022 the effect ofgenerics on sales was around
JPY200 million
However, due to the entry of
Pfizer with its stong brandpower into the market, andto the approval for use in PBR therapy, which has
become the mainstream
therapy for r/rDLBCL, sales
in 2023 are expected to fall
30% to JPY7 billion

With the gradual penetrationof generics and official dug
price revisions sales in 2024
are forecast to come in at
JPY4-5 billion, and in 2025
at JPY4-5 billion<Effect on sales>
As for 2022, the impact on sales due to the entry of generics seems to had been
limited to about JPY200 million. In August 2022, SymBio lowered its initial sales
forecast of JPY10,992 million by about JPY990 million to JPY10,003 million,
estimating the effect of generics on sales at only around JPY200 million. SymBio
made its forecast based on details of each medical facility’s generic adoption level,
the use of new anticancer drugs, inpatient-outpatient ratio, parent organization of the
facility (public hospitals are under pressure to adopt generics), the existence orotherwise of accounts for freeze-drying agents (FD formuation), pharmacy
department sensitivity to distributors’ recommendations, medical facility sensitivity
to proposals by MRs (Treakisym Manager – TM), in addition to RI administration
usage level and timing of switch to RTD. The sales forecast for the third quarter was
JPY2,476 million and for the fourth quarter was JPY2,654 million, but the actual
sales for the third quarter was JPY2,481 million, demonstrating, as expected, theaccuracy of the estimates. As of mid-October, some 20 medical facilities had
confirmed delivery of generics, suggesting a cautious stance toward their adoption.
In December 2022, however, Pfizer with its strong brand power, entered the market.
Additionally, Treakisym® RI administration and generics were approved in themainstream P-BR treatment of r/rDLBCL. This has necessitated a more cautious
view of Treakisym® sales. SymBio expects sales of Treakisym® in 2023 to drop
30% year-on-year to around JPY7 billion. In addition, it seems that sales in 2024 areexpected to come in at around JPY5-6 billion yen due to drug price revisions, andsales in 2025 are expected to be JPY4-5 billion yen.
Sales forecast of Treakisym®

120

100

80

60

40

20

0

2020

2021

2022

2023

2024

2025

Source: Compiled by Fair Research Inc. from interviews

20/30
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmacuticals Ltd.(4582 GROWTH)
SymBio’s plan is to stabilise
sales by focusing on
expanding
Treakisym’s
share in the r/rDLBCL area

Issued July 14,2023

Of course, in the field of hematology and oncology, there is a deep-rooted, relatively
cautious attitude toward generics that have a slightly different composition to
Treakisym®. In addition, the market share of the B-R therapy and P-BR therapy
targeting r/rDLBCL is still only about half, so we can expect an increase inprescriptions due to market share expansion. More specifically, in the treatment of
r/rDLBCL, the B-R therapy and P-BR therapy began making inroads in late-line 3rd
and 4th line stages but came to be increasingly used in the 2nd line and earlier stages.
The company’s sales force is focusing on expanding market share in the r/rDLBCL
field. Through these efforts, it is hoped that sales of Treakisym® will stabilise at the
JPY4 billion level from 2026 onwards.
r/rDLBCL market

others3%

Multi-agent
combination
therapy
45％

BR 1%

PBR

52% market share intransplant ineligible 2nd-Line

Source: SymBio company briefing, February 2023
B: bendamustine=Treakisym®
Reference:
No. of cases for treatment with Treakisym® (annual)① r/r indolent-B-NHL
around 9,000 cases② CLL
around600 cases③ 1st-Line indolent-B-NHL around 6,000 cases④ r/r DLBCL
around 10,000 cases
Source: Compiled by Fair Research Inc. from interviews
In the area of follicular lymphoma (FL), which accounts for about three-quarters of➂1st-Line indolent-B-NHL, Treakisym®’s market share is around 70%.
Focular Lymphoma market
10%

15%
40%

8%

BG
G-CHOPBR
R-CHOP

27%

In FL 1st-line, market
share 67%(=BG+BR)

Source: SymBio company briefing, February 2023

21/30
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whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmacuticals Ltd.(4582 GROWTH)

Issued July 14,2023<Potential market size for Brincidofovir (BCV) market sizenext major product＞
We will here look at the size of three areas which demonstrate SymBio’s in-housedevelopment policy: ① Disseminated adenoviral infection after hematopoietic
stem cell transplantation; ② BK virus infection after renal transplantation; ③Resistant/refractory CMV infection after hematopoietic stem cell or organtransplantation. The company also plans to develop for blood cancers, such as NK/Tcell lymphoma, in-house, but we do not speculate on size of market because thedevelopment plan is not yet clear. Glioblastoma (GBM), a type of solid cancer, iscalculated only for reference.
On the other hand, neurodegenerative diseases (multiple sclerosis and dementia of
the Alzheimer's type) are outside SymBio's current area of expertise. Collaboration
with leading external pharmaceutical companies would be essential and we are
currently not including such diseases in our calculation.
The number of target
patients is 2,000 for
disseminated AdV infection,
8,000 for BKV infection,and10,000for
resistant/refractory
CMV
infection

The number of patients in the fields targeted by BCV is approximately 2,000 for ①
disseminated adenoviral infection after hematopoietic stem cell transplantation, ②approximately 8,000 for BK virus infection after kidney transplantation, and ③ anestimated approximately 5,000 people each with refractory CMV infection andresistant/refractory CMV infection after organ transplantation.

Target patient population comparison between brincidofovir and maribavir
40,000 cases

Cancers:
CMV -brain
tumours
30,000SOT :BKV infections after
kidney transplantation

HSC transplants:
Disseminated AdV
infections 2,000

25,000 cases

HSC transplant:
1st line CMV
infections
15,000Maribavir

8,000

5,000

BCV

Maribavir

5,000

SOT
r/r CMV infections
HSC transplants
r/r CMV infections

Figures for M aribavir based on IR M aterial by Takeda Pharm. 2019 Nov 21
Global data for GBM is based on forecast incidence of cases of GBM in US, EU5, China and Japan (2027)
HCT data based on Bone M arrow Transplantation 2016, Bone M arrow Transplantation 2019
SOT data is based on International Report on Organ Donation and Transplantation Activities, executive summary 2019, April 2021 and Transplantation 2012

Source: SymBio company briefing, February 2022

BCV’s target patients forresistant/refractory
CMV Of the CMV infections after hematopoietic stem cell transplantation, the first-line
portion (approximately 15,000 patients) is not indicated for BCV. BCV’s target ismarivavir-resistant patients
resistant/refractory CMV infections. About half of the patients withare 5,000
resistant/refractory CMV infection after hematopoietic stem cell transplantation orafter organ transplantation (approximately 10,000 in total) show maribavir
resistance. Therefore, BCV’s target patients for resistant/refractory CMV are
approximately 5,000.
Assuming the drug cost per Assuming, by referencing other antiviral agents, that the drug cost for one case iscase is JPY3 million, then JPY3 million, then:for three viral infectons thetotal value comes to JPY45① Disseminated adenoviral infection after hematopoietic stem cellbilliontransplantation: 2,000 patients×JPY3 million＝JPY6 billion
22/30
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmacuticals Ltd.(4582 GROWTH)

Issued July 14,2023② BK virus infection after kidney transplantation:
8,000 patients×JPY3 million＝JPY24 billion③Resistant/refractory CMV infection after hematopoietic stem cell or organtransplantation: 5,000 patients×JPY3 million＝JPY15 billion
From the above we posit a total value for ①～③ of JPY45 billon. However, worth
noting is that there is a lot of room for expanded indications in other areas.
For reference purposes, weestimate a value for GBM
of JPY90 billion
We infer a very large market
forcancers
andneurodegenerative diseases
caused by viruses

Reference:
Glioblastoma（GBM）: 30,000 patients×JPY3 mil＝JPY90 billion.
Multiple sclerosis (MS): Current market valued at JPY2 trillion

Reference: Pipeline value<Pipeline Value>

Here we calculate estimated pipeline values for Treakisym® and for brincidofovir
using the DCF methodology. Given inroads made by generics, and hence reduced
On the basis of a number of earnings power, we accord Treakisym® a discount rate of 10% (8% in our previous
variables we accord a report).
tentative 10% discount rate(a) Preconditions for the Treakisym® pipeline value calculation
The size of the Treakisym® market will decrease to JPY7 billion in 2023, JPY5-6
billion yen in 2024, and JPY4-5 billion yen in 2025 due to the impact from the
Treakisym® sales outlook emergence of generics. Thereafter, it will continue to decline slightly until 2031, frommust take into account the which point it is assumed that it will shrink rapidly (annual rate of 10%).
entry of generics

It is assumed that the sales structure went in-house from 2021, and will mostly switch
to liquid formulations (RI administration) from 2023 onwards. In addition, we assume
Sales promition costs for the that the unit cost rate for liquid formulations would be around 20%, even withyear set at JPY1 billion
royalties paid to Eagle Industries. Milestone payments to Eagle have already been
completed. Sales promotion costs are posited at around JPY1 billion per year due tostreamlining of the sales system.
(b) Preconditions for brincidofovir (BCV)
It is difficult to calculate for BCV because of the number of uncertain elements.
Therefore, for reference purposes only, our calculation relates to: ① disseminated
There are too many adenoviral infection after hematopoietic stem cell transplantation; ② BK virus
uncertainties in the BCV infection after kidney transplantation; and ③ resistant/refractory CMV infection
pipeline to make a value after hematopoietic stem cell transplantation or organ transplantation.
estimate<Value of markets targeted>
The foregoing are given values of: ①JPY6 billion; ②JPY24 billion；and ③
JPY15 billion.
Target diseases are restricted
to AdV infection after
hematopoietic stem cell <Development schedule and development costs>
transplantation,
BKV
Since SymBio has not disclosed actual development cost figures or the timing of
infectionafterkidneyregulatory approval or market launch, Fair Research Inc. has made its own predictionstransplantation,and(below). Investors should bear in mind that changes may be made.
resistant/refractory
CMV
23/30
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmacuticals Ltd.(4582 GROWTH)
infection
after
hematopoietic stem celltransplantation or organtransplantation

Issued July 14,2023

Assumptions for BCV development costs and development schedule
2023
AdV

2024

SOTーAdV Ph22025

Ph3 start Ph3
5

BKV

ZOT-BKV

Ph2

5
Ph2

SOT-r/rCMV

Ph1b

7
Ph1b

1

Ph3
10

4
Ph1b-Ph2

5

5
Ph1b

ZOT-r/rCNV

1

Assuming BCV targeting
AdV
infections
after
hematopoietic stem celltransplantation is launchedin 2028 and further launches
are made in succession

Sub totals
BCV Total

2027

2028

Applic.&approval

Launch

Ph3

Ph3

2029

2030

2031

2032

2033

（JPY-100mil）
2034
Image of Ph-3
scale
Ph3:100 cases＋Historical data

10

Ph2 finish Ph3

11
CMV

2026

10
Ph2

15
Ph2

Applic. &approval

Ph2-Ph355Ph1b Ph1b-Ph2
5
5

Ph3:200
cases+Historicaldata

Launch

15
Ph3

10

10

Ph3

Applic.&approval

Ph3

5

5

10
Ph2-Ph3
10

Ph2

Ph2

Ph3:150 cases＋Historical data

LaunchPh3

Applic. & Launch

10

10 approval

1

5

6

10

10

15

15

20

10

10

17

17

20

30

25

30

15

20

10

10

Source: Fair Research Inc.

<Milestones>
SymBio is to pay Chimerix a total of $180 million in milestone payments (including
There are still USD175 a $5 million contract fee) and royalties. Details of the timing and amounts ofmillionin
milestone milestone payments have not been disclosed, but for the purposes of the calculation
payments outstanding to we are assuming that payments will be made at the time each clinical indication islaunched, and when sales reach a certain level.
Chimerix<Royalties and manufacturing costs>
The company has simply said that sales royalties to Chimerix will be at the doubledigit percentage level. For the purpose of this calculation, we are assuming12%. The
We are assuming that
manufacturing cost rate has also not been released, so for calculation purposes weroyalties of 12% will be paid
are assuming a conservative 20%.
to Chimerix

Aiming to establish in-housesales structure for Europe
and the US<Sales costs>
In addition, SymBio is considering a plan to set up a sales structure in Europe andthe US in order to establish itself also as a specialty pharmaceutical company
overseas. The alternative would be out-licensing the sales rights after in-housedevelopment. The number of transplant centers to be covered is about 35 in Japan,
while there are around 75 in the US and about 90 in Europe. In order to build andmaintain such a sales structure, we posit annual sales promotion expenses ofapproximately JPY 1 billion in both regions. In Japan this would mean adding about
JPY500 million to current Treakisym® sales promotion expenses of JPY1 billion.
Finally, since BCV efficacy in humans has already been established we posit
probability of success at 60-80%.

Sales Promotion costs in
Europe and the US would
come to JPY1 billion foreach region, and an
additional JPY500 million
Finally, it is necessary to consider company-wide costs, such as new drug candidate
for Japan
discovery and basic R&D, and general admin costs. We posit JPY2.5 billion for
R&D costs related to routine discovery and company management.

(c) Results of trial calculation
Calculating the discounted present value under the above preconditions yields the
Treakisym® value: JPY18.7
results shown in the table below. The value of Treakisym® (before tax) is estimatedbillion (before tax)
at JPY18.7 billion, a significant decrease from the previous estimate (JPY55.7
billion) due to the impact of generics and changes in the discount rate. The value of
BCV value adjusted for BCV is estimated at JPY41.9 billion with a success probability of 60% because theprobability of success: underlying premise has been changed to in-house development and in-house sales.
JPY41.9-60.4 billion
24/30
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmacuticals Ltd.(4582 GROWTH)

After deducting comapanywide costs value still comesto JPY35.6-54.1 billion
The value will further
increase on expansion into
the fields of maligant brain
tumours and cranial nerve
disordersIssued July 14,2023

The combined value of Treakisym® and BCV comes to an estimated JPY60.6
billion, but if company-wide costs are subtracted, the pipeline value (before tax)
comes to an estimated JPY35.6 billion. Assuming an 80% probability of success, thevalue of brincidofovir is JPY60.4 billion, resulting in: Treakisym® + BCV company-wide costs = JPY54.1 billion. Although not included in the trial
calculations on this occasion, the value of the pipeline will further increase as further
indications for BCV are added (GBM, multiple sclerosis, etc.) and applications suchas rigosertib are factored in. Even after considering factors such as the tax rate,
SymBio’s market capitalisation of under JPY20 billion as of July 03, 2023 is
probably too low.

Pipeline trial calculation (before tax)
(JPY-100 mil）
Prob. Of success Prob. of success Prob. of success
100%
80%
60%
Treakisym®

187

BCV

788

604

419

Sub-total

975

791

606

company-wide costs

-250

-250

-250

Total

725

541

356

---

---

Discount rate set at 10%
BCV targets: SOT-AdV、ZOT-BKV、SOT-r/rCMV and ZOT-r/rCMV

Source: Fair Research Inc.
Note: No direct comparison of pipeline value and market capitalisation ispossible

25/30
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmacuticals Ltd.(4582 GROWTH)

Issued July 14,2023<Medium term outlook>

Medium term earnings trajectory

Achieved profitability in
2021, but profit declined in
2022 due to emergence ofgenerics and expansion of
BCV development

SymBio achieved profitability in 2021. In 2022, however, the appearance in themarket of generic versions of Treakisym®, the company’s mainstay product, cast
doubts on the idea that it could secure profit growth from expanded sales ofTreakisym® while pursuing development of its next mainstay, BCV. Sales for the
first indication of BCV (disseminated AdV infection after hematopoietic stem celltransplantation) are expected around 2028, and sales other than Treakisym® cannot
be expected until then. It is therefore probably better to consider the profit trajectory
not only for 2023 but for the three years to 2025.

The company forecasts anoperating loss of JPY330
million in 2023. However,since this is based onconservative assumptions,
there is the possibility of abetter outcome

First, in the company's forecast for 2023, sales are expected to decline to JPY7
billion, and operating income is expected to turn into a deficit of JPY331 million.
The main factors at work here are a sharp drop in sales, an increase in SG&A
expenses, and higher production costs. R&D expenses will increase by about
JPY825 million, mainly related to BCV, and although SG&A expenses other thanR&D expenses will be reduced, overall SG&A expenses will increase by JPY220
million. However, amid concerns about the future of Treakisym®, it is essential tostrengthen development of the next mainstay product, BCV. The company expects
the cost of sales ratio in 2023 to come in at 21.1%. The ratio in 2022 is ostensibly
24.1%, but this includes the sales milestone payment of JPY550 million to Eagle.
Excluding this, the ratio is 18.6%. In addition, the cost ratio in the first quarter of2023 was 19.5%. The company expects the cost of sales ratio to rise due to falling
drug prices, but this appears to be a somewhat conservative expectation. In addition,
it is expected that there will be room for further reductions in SG&A expenses, andin the final analysis, it is possible that operating profit will be close to zero.
2023 Company management plan
（JPY mil）
2021

2022

（JPY mil）

2023

2022

2023

（company forecast）

Jan-March

Jan-March

Sales

8,256

10,008

7,000

2,315

1,544

Cost of goods
COGS ratio

2,456
29.7%

2,408
24.1%

1,474
21.1%

417
18.0%

301
19.5%

1,388
495

1,192
549

excl. milestone payments

18.6%
Greatly reduced by
the change to liquid
formulation

SG&A
of which, R&D（BCV related）

4,784
1,736
NA

deteoriation due to
NHI price revision

5,636
2,554

5,857
3,380

1,111

1,739

Op. revenues

1,016

1,963

-331

509

51

Net profit

2,032

1,179

-370

163

4

Source: Fair Research Inc., using company earnings reports

From 2024, Treakisym®
sales will decline and BCV
development will be in fullswing.
Thereisanexpectation that in 20242025 there will be revenues
from the global partnershiptargeting neurodegenerative
disorders

For 2024, it appears that further inroads made by generics and revisions to official
prices will depress sales to the JPY5-6 billion level. Meanwhile, in terms of R&D
expenses, there will be further progress in BCV development (such as Phase-3
clinical trials for AdV infections), while the cost of establishing clinical facilities for
BKV infection after kidney transplantation will level off. It seems likely therefore
that there will be no change on 2023 levels. By the end of 2024, or at the latest by2025, SymBio aims to conclude a joint research and development agreement with a
global mega-pharmaceutical company in the area of neurodegenerative diseases
based on the results of non-clinical trials to date. SymBio expects JPY10 billion indevelopment cooperation funds through this global partnership.
26/30

This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmacuticals Ltd.(4582 GROWTH)

Assuming that development
cooperation funds from theglobal partnering are JPY2
billion for 5 years, there is apossibility that the company
will avoid falling deeply into
the red in 2024 and 2025

Issued July 14,2023

Sales of BCV for its first indication, disseminated AdV infection after hematopoietic
stem cell transplantation, are expected in 2028, until which time sales of products
other than Treakisym are unlikely. The prospective development collaboration fee istherefore essential to complete the in-house development of BCV (for purposes
other than neurodegenerative diseases).
It is not possible to predict how many billions of yen will be disbursed in incrementsof JPY100 million from this development cooperation fund. However, if we assume
that JPY2 billion will be paid in 5-year increments (2024-2028), the company should
not encounter serious losses in in 2024 and 2025.
Medium term earnings
Medium term

JPY100-mil

2023

Sales
Treakisym

2024

2025

70.0 50～60

40～50

20

Development fees from partnering

20

Gross profit

0.0 59～67

R&D
BCV : infections following SOT,ZOT
Others

33.8
17.4
16.4

32
17
15

35
20
15

Sales costs

24.6

24

24

Milestone payments to Chimerix

0.0

0

0

Operating revenues

-3.3

4～12

51～59

-6～4

Close to zero
Source: calculations by Fair Research Inc.

However,if
BCVdevelopment targets are
expandedbeyondexpectations, or if BCV
development
accelerates,
then losses for the company
could also grow

However, if the scope of BCV development expands or accelerates more than
expected, the deficit will increase. Please note that the amount will vary dependingon the scale and timing of development cooperation funds from the global
partnering. From 2026 onwards, there are many uncertain factors, such as the
expansion of BCV development and whether sales of Treakisym® will stabilize,
making it difficult to forecast earnings over the medium term.

Currently (as of the end of March 2023), cash and deposits on the balance sheet
stand at around JPY5,939 million, and we can expect development cooperation
funds of about JPY10 billion through the global partnering. However, for SymBio,
Given SymBio’s strong
which has a strong drive to develop products, it is not possible to predict whether
product development drivethese funds will be sufficient.
available funds may not be
sufficient

27/30
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmacuticals Ltd.(4582 GROWTH)＜Conclusion＞

Issued July 14,2023

Conclusions

2023 repesents a major 2023 could turn out to be a major turning point for SymBio. The company has forclimaceric for SymBio
many years nurtured the market for Treakisym®, which has become its biggest
earner, but generics have begun eating into this in a big way in 2023. Meanwhile,the company has positioned BCV as its next pillar of global growth and, in May
Major inroads being made2023, established POC in humans for BCV’s first indication, disseminatedby generics
adenovirus infection following hematopoietic stem cell transplantation. Subsequent
indications (BK virus infection after kidney transplantation, resistant/refractory
POC achieved for IV BCV CMV infection after hematopoietic stem cell transplantation or organ
in humanstransplantation) are also providing opportunities for in-house development.

Research can now be
promoted using US statefunding and using thefacilities,
intellectual
properties and personnel of
NINDS and NIAID

In 2023, SymBio concluded cooperative research and development agreements(CRADA) with two research institutes belonging to the National Institutes of Health(NIH), the National Institute of Neurological Disorders and Stroke (NINDS) and the
National Institute of Allergy and Infectious Diseases (NIAID). Signing CRADA
with two institutes coming under the aegis of NIH, he world’s largest life sciences
and medical research institute, means that research will be promoted using the US
national budget, research facilities, intellectual property, and human resources
owned by NINDS and NIAID. That is why CRADA can only be concluded withprojects that will lead to paradigm shifts. In addition, the licenses ensuing from theresearch are controlled solely by SymBio.

For the time being, thecompany will pursue global
development targeting posttransplantation infectious
diseases

For the time being, SymBio plans to concentrate on developing BCV for infectious
diseases after hematopoietic stem cell transplantation or organ transplantation for
the global market. After 2030, the company then plans to enter into full-scale
development in the area of cancers caused by viral infection and in the area ofneurodegenerative diseases caused by exposure to viral infection. It will not be easy
to pursue these targets simultaneously, but if successful, there is no doubt that a very
From 2030 onwards, it will
large market awaits. The support of investors who value SymBio’s development
participate fully in the area
ambitions is essential.
ofcancers
andneurodegenerative disorders
caused mainly by exposure
to viral infections
SymBio business development - image+Our Future

Exposure to virus neurodegenerative disorders
EBV infection：MS
HSV-1 infection：Alzheimer

Present

Blood cancers
Treakisym®
focused pipeline
strengthening

2023

Organ transplant
BKV infection
CMV infection

Hematopoietic
stem celltransplant
AdV infection

EBV infection：Long-Covid

Virus Infections
Blood cancers
CMV-GBM
EBV-Lymphoma
HPV-H&N

CMV infection

2030

2040

Source: company briefing, February 2023

28/30
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmacuticals Ltd.(4582 GROWTH)

Issued July 14,2023

Fair Research Inc.
BIZ SMART Kayabacho
Shinkawa 1-3-21
Chuo-ku
Tokyo 103-0033

Email: info@fair-research-inst.jp

29/30
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmacuticals Ltd.(4582 GROWTH)

Issued July 14,2023

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