COMPANY RESEARCH AND ANALYSIS REPORT

SymBio Pharmaceuticals Limited
4582
Tokyo Stock Exchange Growth Market

24-May-2022
FISCO Ltd. Analyst

Yuzuru SatoFISCO Ltd.
https://www.fisco.co.jp

COMPANY RESEARCH AND ANALYSIS REPORTFISCO Ltd.
https://www.fisco.co.jp

SymBio Pharmaceuticals Limited

24-May-2022

4582 Tokyo Stock Exchange Growth Market

https://www.symbiopharma.com/ir_e/■ Index■Summary---------------------------------------------------------------------------------------------------------------------------------------------------------------------------- 01
1. Result trend of FY12/21...............................................................................................................................

01

2. Trends in the development pipeline. . ............................................................................................................

01

3. Outlook for FY12/22. . ............................. ......................................................................................................

02■Company profile---------------------------------------------------------------------------------------------------------------------------------------------------------- 03■Trends in the development pipeline--------------------------------------------------------------------------------------------------------- 06
1. TREAKISYM® (generic name: bendamustine hydrochloride). ......................................................................

06

2. Brincidofovir (BCV) (intravenous formulation/oral formulation). ....................................................................

10

3. Rigosertib (intravenous formulation/oral formulation). ..................................................................................

16■Results trends--------------------------------------------------------------------------------------------------------------------------------------------------------------- 17
1. Summary of FY12/21 results. . ......................................................................................................................

17

2. Financial condition................................. ......................................................................................................

19■Outlook-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- 20
1. Outlook for FY12/22. . ............................. ......................................................................................................

20

2. Future business strategy........................ ......................................................................................................

22

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COMPANY RESEARCH AND ANALYSIS REPORTFISCO Ltd.
https://www.fisco.co.jp

SymBio Pharmaceuticals Limited

24-May-2022

4582 Tokyo Stock Exchange Growth Market

https://www.symbiopharma.com/ir_e/■ Summary
The field of development for BCV expanded from viral infection tobrain tumors and cranial nerve disease, and its growth potential
substantially improved
SymBio Pharmaceuticals Limited <4582> (hereafter, also “the Company”) is a bio-venture progressing developmentsfrom the clinical trial stage, targeting indications for oncology, hematology, and rare diseases for which there arefew patients but medical needs are high. The main development pipeline includes TREAKISYM®, for which it isexpanding indications as a treatment for malignant lymphoma; rigosertib, which it in-licensed from Onconova
Therapeutics, Inc. <ONTX> (hereafter, Onconova) (U.S.); and the antiviral drug brincidofovir (BCV) in-licensed fromChimerix Inc. <CMRX> (U.S.).
1. Result trend of FY12/21
In the FY12/21 results, net sales increased 176.4% year-on-year (YoY) to ¥8,256mn and operating profit was¥1,016mn (compared to a loss of ¥4,506mn in the same period in the previous fiscal year). This was due to theshift to the in-house sales structure for TREAKISYM® from December 2020 and then in March 2021, it expanded
the indication areas for TREAKISYM® by obtaining approval for the manufacturing and marketing authorization,
allowing the product to be used in the bendamustine-rituximab (BR) therapy and in the polatuzumab vedotin plus
bendamustine-rituximab (P+BR) therapy to treat recurrent/refractory diffuse large B-cell lymphoma (hereafter, r/r
DLBCL). Also, in addition to the shift to the in-house sales structure, it made progress in switching to the RTD
formulation (liquid type) from FD formulation (lyophilized powder intravenous type), causing the gross profit margin
to greatly increase, rising from 29.0% in the same period in the previous fiscal year to 70.2%, which was a major
factor behind the Company becoming profitable.
2. Trends in the development pipeline
In February 2022, the Company received marketing approval for TREAKISYM® Liquid Formulation Rapid Infusion(RI) administration (which reduces the infusion time from the original 60 minutes to 10 minutes). It is expected that
RI administration will significantly reduce the burden on healthcare professionals and patients, and also lead tofurther sales increases. The Company is also working to maximize product value by, for instance, launching joint
research with academia to explore the possibility of expanding to new applications through combination therapy
with rigosertib and with existing drugs. It also announced in February 2022 that four pharmaceutical companies hadreceived manufacturing and marketing approval for generic versions of RTD formulation products. The Company
consulted with U.S. company Eagle Pharmaceuticals, Inc. <EGRX> (“Eagle”), the license holder, and declared its
intention to take legal action in the event that patent infringement was discovered. It is FISCO’s view that becauseof the Company’s shift in sales to RI administration, even if sales of generic products were launched, the impact
would be limited.

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COMPANY RESEARCH AND ANALYSIS REPORTFISCO Ltd.
https://www.fisco.co.jp

SymBio Pharmaceuticals Limited

24-May-2022

4582 Tokyo Stock Exchange Growth Market

https://www.symbiopharma.com/ir_e/

Summary

As for BCV (intravenous formulation), the Company began phase II of global joint clinical trials indicated for adenovirus infections after hematopoietic stem cell transplantation in 3Q FY12/21 and may possibly advance to phase
III in 2023 if these trials proceed smoothly. It also plans to begin global joint clinical trials indicated for BK virus(BKV) infections after kidney transplantation in the second half of FY12/22. Additionally, it was discovered throughacademic research papers that BCV could be expected to help treat glioblastoma or multiple sclerosis stemmingfrom cytomegalovirus (CMV) infection, and the Company has unveiled a policy of advancing development in thesefields going forward. Because these are refractory diseases, there are still no effective treatments. Therefore, if theCompany succeeds at development, future development trends will be given attention all the more because themarket value of BCV may surpass ¥100bn.
3. Outlook for FY12/22
In FY12/22 results, the Company’s forecast calls for net sales to increase 33.1% YoY to ¥10,992mn and for operating
profit to increase 74.2% to ¥1,770mn. The increase in net sales will largely result from the full-year contribution
from net sales of TREAKISYM® for r/r DLBCL. Furthermore, all sales have been switched to RTD formulation/RI
administration since the start of the fiscal year, and the gross profit margin is projected to rise even further to 80.0%.
SG&A expenses are projected to increase 46.9% YoY to ¥7,026mn. Among these, R&D expenses are projected
to increase 76.0% to ¥3,056mn, mainly centered on expenses for BCV clinical trials. In 1Q, net sales are likely tofall slightly short of the target due to the impact of the novel coronavirus (COVID-19), but will be viewed as having
proceeded according to the target from the perspective of profit. Since the Company is enhancing its humanresource systems through a U.S. subsidiary that will serve as an integrated base for global clinical trials, it plans totransition to consolidated financial statements beginning in FY12/22.
Key Points
TREAKISYM® will expand indications to r/r DLBCL and sales are forecast to continue growing through receiving
approval for RI administration• BCV expanded target treatment fields as a unique drug combining both antiviral and anti-cancer activity• In FY12/22 results, continued increase of sales and profit projected through increased sales of products for r/r
DLBCL and an increase in the gross profit margin•

Results trends（¥mn）

Net sales（left）

Operating profit (loss) （right）

15,000

（¥mn）
4,000

1,770
12,000

2,000

1,016

9,000
6,000

0
-2,656

10,992-4,301

3,000
3,835

-4,506

2,837

2,987

FY12/19

FY12/20-2,0008,256-4,0000-6,000FY12/18

FY12/21

FY12/22 E

Source: Prepared by FISCO from the Company’s financial results

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COMPANY RESEARCH AND ANALYSIS REPORTFISCO Ltd.
https://www.fisco.co.jp

SymBio Pharmaceuticals Limited

24-May-2022

4582 Tokyo Stock Exchange Growth Market

https://www.symbiopharma.com/ir_e/■ Company profile
A bio-venture that conducts developments from the clinical trial
stage, targeting the fields of oncology, hematology, and rarediseases
SymBio Pharmaceuticals is a bio-venture founded by the current Representative Director and President Chief
Executive Officer Fuminori Yoshida in March 2005. For its business strategy, its basic policy is to conduct development and provision of new drugs for underserved therapeutic areas in which development has not been progressed
due to the small numbers of patients. One of its features is a business model that aims to achieve highly efficientand rapid drug discovery within the areas targeting oncology, hematology, and rare diseases, which are fields withhigh medical needs, by in-licensing development candidates for which POC* for humans has been obtained, andconducting development from the clinical trial stage.
*	POC (proof of concept): when the usefulness and efficacy of a new drug candidate compound is recognized following its
administration to animals or humans during research and development

The first development candidate to be in-licensed was the anticancer agent bendamustine hydrochloride (hereafter,
bendamustine hydrochloride; product name in Japan: TREAKISYM®) indicated for malignant lymphoma that wasdeveloped by Astellas Pharma GmbH (Germany), for which the Company concluded an exclusive development andmarketing rights agreement for Japan in December 2005. With the development code SyB L-0501 (FD formulation),
the Company began the phase I clinical trial in 2006 for indications for recurrent/refractory low-grade non-Hodgkin’s
lymphoma (NHL) and mantle cell lymphoma (MCL), and in 2010, it acquired manufacturing and marketing approval.
It progressed licensing activities during this time, and in 2007, it expanded the target areas for the exclusive
development and marketing rights in China, South Korea, Taiwan, and Singapore. Then with Eisai Co., Ltd. <4523>
it concluded licensing agreements for Japan in 2008 and for South Korea and Singapore in 2009. Due to changes inEisai’s business strategy, the domestic licensing agreement was terminated on the deadline of December 9, 2020,
and the Company transitioned to its own sales system. It has also terminated the agreements for South Korea andSingapore during FY12/21. In addition, with the progress made in the switch from the FD formulation to the RTD
formulation, the Company terminated the marketing agreements for China and Taiwan during FY12/21.
TREAKISYM® was launched in the Japanese market in December 2010, and since then, the Company has progressed its development to expand its indications. In 2016, it acquired marketing approval for chronic lymphocytic
leukemia (CLL) and untreated (first line of treatment) low-grade NHL/MCL, and then in March 2021, it acquired
approval for r/r DLBCL, so sales are expected to increase from the rise in the number of patients for which it isindicated. Also, in 2017, it concluded an exclusive development and marketing rights agreement for Japan with
Eagle Pharmaceuticals, Inc. <EGRX> (U.S.) for the TREAKISYM® liquid type RTD formulation/RI administration(development codes: SyB L-1701/SyB L-1702)*.
*	The FD formulation, which the Company has purchased from Astellas Pharma up to the present time, has to be dissolved at
a medical site at the time of use (which requires about 3 hours, including the adjustment time). But this work is not requiredwith the liquid formulation, so it has the advantage of greatly reducing the burden placed on medical practitioners. Also, theonly difference between the RTD formulation and the RI administration is the volume of diluted physiological saline, which isdiluted to 250ml in the RTD formulation and to 50ml in the RI administration. Therefore, for the intravenous injection time,
the RTD formulation takes the same time as the FD formulation, which is 60 minutes, but the RI administration reduces
this to only 10 minutes, greatly reducing the burden on the patient.

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COMPANY RESEARCH AND ANALYSIS REPORTFISCO Ltd.
https://www.fisco.co.jp

SymBio Pharmaceuticals Limited

24-May-2022

4582 Tokyo Stock Exchange Growth Market

https://www.symbiopharma.com/ir_e/

Company profile

Also, as the second in-licensed product, the Company concluded an exclusive development and marketing rights
agreement in 2011 for Japan and South Korea with Onconova for rigosertib (development codes: SyB L-1101(intravenous formulation) / SyB C-1101 (oral formulation)) as a development candidate indicated for myelodysplastic
syndrome (MDS)*. Moreover, in September 2019, it concluded an exclusive global development, manufacturing,marketing, and licensing agreement with Chimerix for BCV for all viral diseases excluding smallpox. The featuresof BCV are that compared to cidofovir (CDV; unapproved in Japan), it has high antiviral efficacy and safety and iseffective against multiple DNA viruses.
*	M DS is a disease in which the patient cannot produce normal blood cells due to abnormalities in the hematopoietic
stem cells in their bone marrow, causing a decrease in normal blood cells and symptoms such as anemia, infection, andhemorrhage. It is also an intractable disease that is highly likely to transition to acute myeloid leukemia, and frequently
occurs in the elderly.

Technology in-licensing agreements
TREAKISYM®

Rigosertib sodium

Brincidofovir

Development codes

Name

SyB L-1701 (RTD formulation)/
SyB L-1702 (RI administration)

SyB L-1101(Intravenous formulation)/
C-1101(Oral formulation)

SyB V-1901(Intravenous formulation)

In-licensing partner

Eagle Pharmaceuticals (U.S.)

Date agreement was
September 2017 / Product patent period
concluded / agreement or the market-exclusive period, whichever
periodis longer

Content of the main
agreements

Onconova Therapeutics (U.S.)

Chimerix (U.S.)

July 2011 / 10-year period from the first
product sales (7 years in South Korea),
the market-exclusive period, or the patentvalidity period, whichever is longest, in eachcountry

September 2019 / Each royalty period is
10 years from the start of sales, the patent
period, or the market-exclusive period,
whichever is longest, for each product’s
indication and for each country. The
agreement deadline is when the final royalty
period expires

Exclusive development and marketing rights Exclusive development rights and marketing Exclusive global license agreementin Japanrights in Japan and South Korea
concerning the rights to develop,
manufacture, and commercialize BCV in all
DNA virus indications excluding smallpox

Source: Prepared by FISCO from the Company’s securities report and news releaseWe encourage readers to review our complete legal statement on “Disclaimer” page.

04 23

COMPANY RESEARCH AND ANALYSIS REPORTFISCO Ltd.
https://www.fisco.co.jp

SymBio Pharmaceuticals Limited

24-May-2022

4582 Tokyo Stock Exchange Growth Market

https://www.symbiopharma.com/ir_e/

Company profile

History
Date
March 2005
December 2005

Summary
Established SymBio Pharmaceuticals Limited at Minato-ku, Tokyo
Concluded a license agreement with Astellas Pharma GmbH (Germany) to acquire exclusive development and marketing rights inJapan for anti-cancer agent Bendamustine Hydrochloride

March 2006

Obtained manufacturer’s license (packaging, labeling and storage) from Tokyo Metropolitan Government

March 2007

Concluded a license agreement with Astellas Deutschland GmbH (Germany) to acquire development and marketing rights in
China, Taiwan, South Korea and Singapore for anti-cancer agent SyB L-0501

August 2008

Concluded a license agreement with Eisai Co., Ltd. to grant co-development and marketing rights in Japan for anti-cancer agent
SyB L-0501

March 2009

Concluded sublicense agreement with Cephalon, Inc. (U.S.) to grant development and marketing rights in China for anti-cancer
agent SyB L-0501

May 2009

Concluded a license agreement with Eisai to grant co-development and marketing rights in South Korea and Singapore for
anticancer agent SyB L-0501

September 2010

Launched SYMBENDA® (generic name: bendamustine hydrochloride) in Singapore for the treatment of low-grade non-Hodgkin’s
lymphoma and chronic lymphocytic leukemia

October 2010

Acquired manufacturing and marketing approval of anti-cancer agent for malignant lymphoma TREAKISYM® in Japan (launched
in December 2010)

July 2011

Concluded a license agreement with Onconova Therapeutics, Inc. for anti-cancer agents SyB L-1101/SyB C-1101

October 2011

Launched SYMBENDA® (generic name: bendamustine hydrochloride) in South Korea for the treatment of chronic lymphocytic
leukemia and multiple myeloma

October 2011

Listed on Osaka Securities Exchange JASDAQ Growth Market

February 2012

Launched INNOMUSTINE® in Taiwan for the treatment of low-grade non-Hodgkin’s lymphoma and chronic lymphocytic leukemia

October 2015

Concluded a licensing agreement with The Medicines Company (U.S.) to acquire exclusive development and marketing rights inJapan for post-operative, self-administered pain-management medication, SyB P-1501 (the agreement ended in November 2017)

May 2016

Established SymBio Pharma USA, Inc. at Menlo Park, California, USA

August 2016

Acquired manufacturing and marketing approval of anti-cancer agent for malignant lymphoma TREAKISYM® in Japan for the
additional indication of chronic lymphocytic leukemia

December 2016

Acquired manufacturing and marketing approval of anti-cancer agent for malignant lymphoma TREAKISYM® in Japan for the
additional indication of first-line treatment of low-grade non-Hodgkin’s lymphoma and mantle cell lymphoma

September 2017Concluded a license agreement with Eagle Pharmaceuticals, Inc. to acquire development and marketing rights in Japan forbendamustine liquid formulations (RTD formulation and RI administration) *RTD: Ready-to-dilute, RI: Rapid Infusion

October 2017

Filed for arbitration for damages against The Medicines Company (U.S.) due to the non-fulfillment of the licensing agreement

July 2018

TREAKISYM® was newly listed as the standard treatment for malignant lymphoma in the 2018 edition of the Japan Society of
Hematology’s Guidelines for the Treatment of Hematopoietic Tumors,

September 2019Concluded an exclusive global license agreement with Chimerix Inc. (U.S.) concerning the rights to develop, manufacture, andcommercialize the antiviral drug, brincidofovir (excluding smallpox)

September 2020

In the final arbitration ruling for the claim for damages filed against The Medicines Company (U.S.) due to the non-fulfillment of
a licensing agreement, the Company will receive from the Medicines Company 50% of its expenses relating to the arbitration
proceedings, including attorneys’ fees.

December 2020

Start of own sales of TREAKISYM®

January 2021

Concluded a joint research agreement with The Institute of Medical Science, The University of Tokyo to search for new indications
for bendamustine and rigosertib

March 2021

Submitted an IND application to the FDA in the U.S. for a global joint clinical trial indicated for adenovirus infections (in infants)
after hematopoietic stem cell transplantation

March 2021

Acquired marketing approval for a TREAKISYM® and rituximab combination therapy (BR therapy) and TREAKISYM®, rituximab,
and polatuzumab vedotin combination therapy (P-BR therapy) indicated for r/r DLBCL

April 2021

Obtained marketing approval of the RTD formulation of TREAKISYM® for its use in BR and P+BR therapy for the treatment of r/r
DLBCL

August 2021

Reached First Patient In (FPI) in a phase II global joint clinical trial of BCV indicated for adenovirus infections after hematopoietic
stem cell transplantation

February 2022

Obtained approval for a partial change to the manufacturing and marketing approval for the RI administration of TREAKISYM®

Source: Prepared by FISCO from the Company’s securities report and website

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COMPANY RESEARCH AND ANALYSIS REPORTFISCO Ltd.
https://www.fisco.co.jp

SymBio Pharmaceuticals Limited

24-May-2022

4582 Tokyo Stock Exchange Growth Market

https://www.symbiopharma.com/ir_e/■ Trends in the development pipeline
TREAKISYM® will expand indications to r/r DLBCL and sales are
forecast to continue growing through receiving approval for RI
administration
1. TREAKISYM® (generic name: bendamustine hydrochloride)
TREAKISYM® is an anticancer agent for malignant lymphoma. Malignant lymphoma is a disease in which lymphocytes, which are a type of white blood cell, undergo canceration (tumorification) and lumps (masses) can grow inlymph nodes distributed throughout the body and organs other than lymph nodes (such as the stomach, intestines,
thyroid, spinal cord, lung, liver, skin, and eyes). It is the most frequent disease among blood cancers, with patients inJapan surpassing 30,000 annually, and the number of patients requiring treatment is predicted to increase gradually
going forward as the elderly population grows. Malignant lymphoma is mainly divided into Hodgkin’s lymphoma (HL)and non-Hodgkin’s lymphoma (NHL), with about 90% of cases in Japan being NHL. It is classified into low-grade,medium-grade, and high-grade according to the progression rate of the symptoms, and there are various diseasetypes.
Types of non-Hodgkin’s lymphoma
Type according to grade
Low grade: Indolent lymphoma(progresses yearly)

Non-Hodgkin’s lymphoma type (disease type)
Follicular lymphoma (grade 1, 2), MALT lymphoma, lymphoplasmacytic lymphoma
Mycosis fungoides, Sezary syndrome, chronic lymphocytic leukemia / small lymphocytic lymphoma, etc.

Medium grade: Aggressive lymphoma Follicular lymphoma (grade 3), mantle cell lymphoma, diffuse large B-cell lymphoma(progresses monthly)
Peripheral T cell lymphoma, extranodal NK / T cell lymphoma, adult T cell leukemia / lymphoma (chronictype), etc.
High grade: Highly aggressive
lymphoma (progresses weekly)

Burkitt’s lymphoma, acute lymphocytic leukemia / lymphoblastic lymphoma
Adult T-cell leukemia / lymphoma (acute type, lymphoma type), etc.

Source: Prepared by FISCO from National Cancer Center Japan materials

Estimated number of malignant lymphoma patients(Number ofpeople)140,000
119,390

112,410120,000
99,7900-14 years

100,000
80,00060,00045,49037,32015-44 years

30,73045-54 years
34,04030,54055-64 years

31,71065-74 years

40,000

0

9,920
8,550
2015-19

21,02020,03019,42020,000630

11,6708,760

590

2020-24

12,0908,520

75 years or
older
560

2025-29

Note: Number of patients who required treatment during these periods
Source: Estimations by the Company based on cancer information service data from the National Cancer Center Japan

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COMPANY RESEARCH AND ANALYSIS REPORTFISCO Ltd.
https://www.fisco.co.jp

SymBio Pharmaceuticals Limited

24-May-2022

4582 Tokyo Stock Exchange Growth Market

https://www.symbiopharma.com/ir_e/

Trends in the development pipeline(1) Expansion of indications
As its sales strategy for TREAKISYM®, the Company has been working to sequentially expand its indications. It
acquired marketing approval for recurrent/refractory low-grade non-Hodgkin’s lymphoma (NHL) and mantle cell
lymphoma (MCL) in October 2010, chronic lymphocytic leukemia (CLL) in August 2016 and untreated (first line oftreatment) low-grade NHL/MCL in December 2016. Also, in July 2018, TREAKISYM® and rituximab combination
therapy (BR therapy) was newly listed in the Japan Society of Hematology’s Guidelines for the Treatment of
Hematopoietic Tumors, and it has come to be recommended as the standard treatment option for all indications
for which it has been approved. So TREAKISYM® has come to be positioned as the standard treatment for
malignant lymphoma in both name and reality.
Other than the above, for CD20-positive follicular lymphoma (FL), which is a typical type of low-grade NHL, theCompany acquired approval in July 2018 for partial changes relating to combination use with a new anti-CD20
antibody formulation, in addition to rituximab, and combination therapy with obinutuzumab* 1 was added as atherapy option. Furthermore, in March 2019, it acquired approval for partial changes relating to pre-treatment
with tumor-specific T-cell infusion therapy* 2, and for the first time in Japan, TREAKISYM® can be used as a
pre-treatment for the CAR T-cell therapy*3 Kymriah® intravenous drip*4.
*1	Obinutuzumab (GAZYVA®; sold by Chugai Pharmaceutical Co., Ltd.): similar to rituximab, which is recommended in
the treatment guidelines domestically and overseas as a therapeutic drug for NHL, it is a glycosylated modified type II
anti-CD20 monoclonal antibody that binds to CD20, a protein that expresses on B cells other than stem cells and plasma
cells, and it directly attacks and destroys the B cells it targets together with the body’s immune system.
*2	Tumor-specific T-cell infusion therapy: a therapy administered to patients after artificially applying and multiplying cancer
specificity outside the body to the cancer patient’s own T cells (a type of lymphocyte).
*3	CAR T-cell therapy (chimeric antigen receptor T-cell therapy): among tumor-specific T-cell infusion therapies, this is atherapy to introduce, amplify, and infuse into the gene-coding T cells the chimeric antigen receptors (CAR) that combine
the antigen-binding site of the antibody that recognizes the membrane antigen on the tumor cell and the T-cell receptor’s
intracellular domain.
*4	Kymriah® intravenous drip (generic name: tisagenlecleucel; sold by Novartis Pharma KK as the first CAR-T therapy
approved in Japan. In March 2019, it acquired manufacturing and marketing approval indicated for recurrent/refractory
CD19-positive B cell acute lymphoblastic leukemia (B-ALL) and recurrent/refractory CD19 positive DLBCL.

Then in March 2021, it announced the acquisition of marketing approval for r/r DLBCL *1. In addition to the
combination therapy (BR therapy) with rituximab developed by the Company, the combination therapy with
polatuzumab vedotin (P-BR therapy)*2 developed by Chugai Pharmaceutical Co., Ltd. <4519> was also approved.
Through these marketing approvals, the number of patients TREAKISYM® is indicated for has greatly expanded(actual sales started from 2Q FY12/21).
*1	The standard treatment for untreated DLBCL is to provide a combination therapy of rituximab and chemotherapy, but
recurrence is seen in approximately 40% of patients. Also, autologous stem cell transplantation (ASCT) is recommended
as one treatment for r/r DLBCL, but for approximately half of patients, the relief chemotherapy provided prior to ASCT
is not successful and ASCT cannot be provided. Moreover, there are many patients for whom ASCT is not suitable as atreatment, such as due to their age or complications, and it has yet to be established as the standard treatment.
*2	Polatuzumab vedotin: an anti-CD79b antibody drug compound developed by Roche <ROG>using the antibody drug
conjugate technologies of Seattle Genetics Inc. (U.S.), in which humanized anti-CD79b monoclonal antibodies and tubulin
polymerization inhibitors are combined with a linker. CD79b proteins are expressed specifically on many B cells, and thisis a promising target in terms of developing new therapies. It is considered that polatuzumab vedotin binds with CD79b
while suppressing the effects on normal cells and destroys B cells through the delivered chemotherapy agent.

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COMPANY RESEARCH AND ANALYSIS REPORTFISCO Ltd.
https://www.fisco.co.jp

SymBio Pharmaceuticals Limited

24-May-2022

4582 Tokyo Stock Exchange Growth Market

https://www.symbiopharma.com/ir_e/

Trends in the development pipeline

Details of malignant lymphomas

Source: Reprinted from the business plan and items relating to growth potential

The results of the phase III clinical trial for BR combination therapy indicated for r/r DLBCL announced by theCompany were excellent, with a complete response rate of 47.4% and an overall response rate of 76.3%. In
particular, it seems that medical specialists were surprised by the level of the complete response rate for persons
aged 76 years and older, which was 36.4%. There was no effective treatment for r/r DLBCL until now, and amulti-drug combination therapy that combines multiple anticancer agents (3 to 6 types) was administered as relief
chemotherapy. However, it had strong side effects and little effectiveness. For these reasons, it is highly likely thatthe use of BR therapy and P-BR therapy, which have few side effects and high effectiveness, will spread as thestandard therapies and sales of TREAKISYM® are forecast to further increase. The choice of whether to use BR
therapy or P-BR therapy depends on the doctor’s decision, based on factors such as the patient’s symptoms
and gene type*.
*	In BR therapy, TREAKISYM® 120mg/m2 (body surface area) is administered once a day for 2 consecutive days, and thennot administered for 19 days. This constitutes one cycle, and it is administered for a maximum of six cycles while observing
the patient’s condition. In P-BR therapy, the dosage is 90mg/m2.

(2) RTD formulation /RI administration
Sales of the RTD formulation, which is the TREAKISYM® liquid type, began in January 2021, and the full switchfrom the FD formulation was completed in December of the same year. The switching rate increased fromapproximately 20% in March 2021 to slightly less than 50% by June, and increased to slightly less than 60% as
of September. Sales were started initially for existing indications except for r/r DLBCL, but it acquired marketing
approval for r/r DLBCL in April 2021 and it is currently being sold for all existing indications.
The Company also received marketing approval for the RI formulation in February 2022. As of March 2022, it
had obtained informal consent to switch to RI administration from approximately 90% of the medical institutions
with which it conducts business, and projects that the switch to RI administration will proceed smoothly going
forward. RI administration reduces the infusion time from the original 60 minutes to 10 minutes, thereby making
it possible to significantly reduce the burden on healthcare professionals and patients. In particular, reducing theadministration time is a major advantage for outpatients. Therefore, at FISCO we think that it is highly likely thatthe use of the RI formulation will spread even more at medical facilities conducting multi-drug combination therapy.

We encourage readers to review our complete legal statement on “Disclaimer” page.

08 23

COMPANY RESEARCH AND ANALYSIS REPORTFISCO Ltd.
https://www.fisco.co.jp

SymBio Pharmaceuticals Limited

24-May-2022

4582 Tokyo Stock Exchange Growth Market

https://www.symbiopharma.com/ir_e/

Trends in the development pipeline

Sales progress of TREAKISYM®
Drug

Indication

SyB L-0501(FD lyophilized powder formulation)

r/r low-grade NHL/MCL
CLLFirst-line low-grade NHL/MCL
r/r DLBCL

Approved for sale in October 2010
Approved for sale in August 2016
Approved for sale in December 2016
Approved for sale in March 2021

Progress

SyB L-1701(RTD liquid formulation)

Already approved indications

Marketing approval in September 2020
(Marketing approval for relapsed and refractory DLBCL in April 2021)

SyB L-1702(RI liquid formulation)

Already approved indications

Applied for marketing approval in May 2021

Source: Prepared by FISCO from the Company’s results briefing materials and website(3) Impact of generic drugs
In February 2022, it was announced that four companies (Pfizer Inc., Meiji Seika Pharma Co., Ltd., KOA ISEICO., LTD., and TOWA PHARMACEUTICAL CO., LTD. <4553>) had received marketing approval for genericdrugs using RTD formulation as a brand-name drug. There are two indications, which are low-grade NHL/MCL
and pre-treatment with tumor-specific T-cell infusion therapy. Recurrent/refractory DLBCL, for which are there
many patients, will not be included this time. That being said, more than 30% of the target fields will impacted
by generic drugs, and there is a possibility that NHI price listings will be given and that sales will begin roughly inJune 2022. However, Eagle has obtained a formulation patent and several use patents related to RI administration.
The Company, which holds exclusivity rights for these patents domestically, has sent a written notification to thefour companies regarding its concerns over patent infringement, and requested an appropriate response. It has
also declared its intention to take legal action in cooperation with Eagle in the event that patent infringement is
discovered.
The formulation patent for RTD formulation determines the density of components (bendamustine, glycol, andantioxidants) and the component ratio, among other things. Although the components of the generic drugs madeby the four companies differ from what is listed in the patent, it is not necessarily the case that this difference alone
clears them of patent infringement, and it appears that judgement will be made based on a comprehensive view
including use patents. In fact, in the U.S., Mylan <MYL> and three other companies had tried to sell generic drugs
for RTD formulation, but at a trial held in August 2021, the court ruled in favor of Eagle and declared that its patent
was valid until 2031. However, it cannot be denied that a different ruling may possibly be made in Japan, so theCompany must be mindful of business risks. Although RTD formulation/RI administration are products subject toprice maintenance premiums*, and the prices are being maintained, if sales of generic drugs are launched, it ispossible that they will no longer be applicable starting from the year when prices are revised, and that the priceof the drugs will fall more than 10%.
*	Price maintenance premiums (premium to promote the development of new drugs and eliminate off-label use) are premiums
applied to new drugs that meet certain criteria during the period of drug price revisions. This is a system in which drug
prices are maintained or made difficult to lower until the patents expire in an aim to promote the creation of innovative new
drugs and the development of unauthorized or off-label drugs.

Based on factors including the fact that indications of generic drugs make up only a little more than 30% of
TREAKISYM® and that the Company’s product competitiveness will substantially increase by switching to RI
administration, which enables rapid infusion, FISCO believes that even if sales of generic drugs are launched,
the impact on FY12/22 results will be limited. Furthermore, it appears that the Company’s future policies and theimpact on results will become clear in the second half of 2022.

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09 23

COMPANY RESEARCH AND ANALYSIS REPORTFISCO Ltd.
https://www.fisco.co.jp

SymBio Pharmaceuticals Limited

24-May-2022

4582 Tokyo Stock Exchange Growth Market

https://www.symbiopharma.com/ir_e/

Trends in the development pipeline(4) Future development plans
For TREAKISYM®, going forward, the Company will progress joint research with academia to search for new
indications, and its policy is to work to further increase business value. Specifically, in January 2021 it concluded
a joint research agreement with The Institute of Medical Science, The University of Tokyo, and they are conducting
research into new treatments through possible developments not only for blood cancer, but also for solid cancers
and other types of cancer, and also through combinations with other drugs, while utilizing AI technologies. In
addition, in August of the same year it concluded a joint research agreement with Kyoto University, and they areprogressing research into its inhibitory effect on LUBAC, which it has been suggested is involved in refractory
activated B cell type (ABC) DLBCL.
In January 2022, the Company concluded a joint research agreement with the University of Tokyo to establish asocial collaboration course entitled “Molecular Oncology” and also initiated an investigator-led phase II clinical trial
indicated for autologous hematopoietic stem cell transplantation in patients with r/r DLBCL through BR therapy,
pursuant to an agreement between SymBio and Saitama Medical University.

BCV expanded target treatment fields as a unique drug combining
both antiviral and anti-cancer activity
2. Brincidofovir (BCV) (intravenous formulation/oral formulation)(1) Overview and licensing agreement
BCV is a lipid conjugate of cidofovir (CDV), which is known as a treatment of cytomegalovirus (CMV) retinitis. BCV
is an antiviral drug candidate whose features are that it has higher antiviral activity, exhibits antiviral activity against
a wider range of viruses. In addition, academic research has recently uncovered that BCV has high anti-cancer
activity, and it is gaining attention as a development candidate to enhance a niche area with high unmet medical
needs where treatments have not yet been established.
Comparison of antiviral activity (EC50)
Virus

BCV

CDV

Maribavir

Letermovir

Ganciclovir

Foscarnet

Acyclovir

ADV

0.02

1.3

-

>10

4.5-33Inactive

>100

BKV

0.13

115

-

-

>200

Inactive

>200

EBV

0.03

65.6

0.63

>10

0.9

<500

6.2

CMV

0.001

0.4

0.31

0.005

3.8

50-800>200

Note: E
 C50 (the concentration at which a drug or antibody shows a 50% maximum response from the lowest value) indicates that the lower thevalue, the higher the activity. BCV possesses high antiviral activity for all viruses.
Source: Prepared by FISCO from the Company’s results briefing materials

BCV has a structure that conjugates a lipid chain into CDV, which allows for more efficient uptake of BCV into
cells than CDV alone. Once inside target cells, the lipid chain is cleaved, releasing CDV, which is then converted
to its active form of cidofovir diphosphate (CDV-PP), which fulfills the role of inhibiting viral DNA replication. Dataobtained from in vivo tests and other studies shows that BCV has a much higher antiviral replication effect than
CDV and other antiviral drugs through these action mechanisms. In terms of the safety profile, CDV has risks
for side effects such as strong nephrotoxicity, including renal dysfunction caused by the accumulation of CDV in
renal tubular epithelial cells. However, because the lipid conjugation of BCV brings no accumulation of CDV in
renal tubular epithelial cells, BCV has the outstanding feature of reducing the risk of nephrotoxicity associatedwith CDV. CDV has been granted fast-track designation by the FDA for the prevention of cytomegalovirus andthe treatment of adenovirus, while in Europe, the EMA has granted orphan drug designation for the same viruses.

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10 23

COMPANY RESEARCH AND ANALYSIS REPORTFISCO Ltd.
https://www.fisco.co.jp

SymBio Pharmaceuticals Limited

24-May-2022

4582 Tokyo Stock Exchange Growth Market

https://www.symbiopharma.com/ir_e/

Trends in the development pipeline

How BCV works

Source: Reprinted from the Company’s website

Chimerix had been developing an oral formulation of BCV, but it discontinued development because it did not
obtain statistically significant results in the phase III clinical trials, and as there were some side effects, including
diarrhea. Subsequently, Chimerix was looking for a partner to whom it could out-license BCV to concentrate
its management resources in the anticancer agent field, and in September 2019, the Company and Chimerix
concluded a licensing agreement for the global manufacture, marketing and development (excluding smallpox) of
BCV. The key point for the Company’s decision to in-license BCV was that it has excellent safety and functionality(high antiviral activity against a wide range of viruses), and it judged that its development was highly likely to be a
success. Also, its target diseases are “rare diseases,” and “niche areas with high unmet medical needs,” are not
only consistent with the Company’s development targets, but are also the same blood disease areas targeted by
TREAKISYM®, so it judged that synergies for sales would be great.
In terms of the reason why Chimerix failed to develop an oral formulation, the Company thinks that as the drug
absorption rate from the digestive organs was low, it was necessary to administer a large dosage. The Company
believes that an intravenous formulation could have the same effect as an oral formulation at just 10% of thedosage, so it thinks there is a lower risk of side effects and a higher probability of success. This agreement covers
both the intravenous formulation and the oral formulation, as the Company believes that going forward, there is apossibility that it can resolve these issues through new improvements to the drug. Of the viral infectious diseases,
the reason why smallpox alone is excluded from the agreement is that the U.S. government needs to maintainits ability to manufacture and stockpile a smallpox treatment independently within the country as a measure tocounter bioterrorism*.
*	In June 2021, Chimerix announced that the U.S. FDA approved its New Drug Application (NDA) for BCV Oral as a medical
countermeasure for smallpox.

This licensing agreement is noted for being a global licensing agreement and for covering manufacturing rights. The
use of a licensing agreement covering manufacturing rights stems from a TREAKISYM® quality defect issue that
occurred in 2019. The Company understands that controlling manufacturing rights on its own and constructing
systems to limit business risks to the best of its ability benefit all stakeholders, including patients, and is criticalin order to aim for growth as a global specialty pharmaceutical company.

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11 23

COMPANY RESEARCH AND ANALYSIS REPORTFISCO Ltd.
https://www.fisco.co.jp

SymBio Pharmaceuticals Limited

24-May-2022

4582 Tokyo Stock Exchange Growth Market

https://www.symbiopharma.com/ir_e/

Trends in the development pipeline

Target indications of these developments include viral infections after hematopoietic stem cell transplantation ororgan transplantation, in addition to brain tumors, which the results of university research show are derived fromcytomegalovirus infection, and the Company indicates its intention to advance development through antibodies for
multiple sclerosis which has been revealed to largely be caused by the EV virus. In October 2021, the Company
commenced operations of SymBio Pharma USA, which will serve as an integrated development base in the U.S.
(the company was established in 2016, but had been in a dormant state). The Company hired a talented individualwith the expertise and experience to smoothly advance clinical trials on a global scale as the vice president. It plans
to increase the number of personnel from 3 in March 2022 to 10 by around 2025, and enhance its development
systems.
Furthermore, in relation to the BCV licensing agreement, the Company paid a lump-sum contract payment of $5
million USD (approx. ¥540mn) to Chimerix, the original developer, in FY12/19. According to the agreement, as a
future milestone, the Company will pay a maximum of $180 million USD (approx. ¥19.4bn) as a two-digit royalty
payment corresponding to net sales of goods.
(2) Development plansa) Adenovirus infections after hematopoietic stem cell transplantation
For the initial development target of BCV (formulation), the Company initiated a phase II global joint clinical trial inAugust 2021 indicated for infants (but including adults) with adenovirus infections after hematopoietic stem celltransplantation (scheduled number of patients: 24 cases) in the US. Adenovirus is a naturally existing virus thatcauses infectious diseases such as pharyngitis, tonsilitis, conjunctivitis, gastroenteritis, and hemorrhagic cystitis
through the infection of areas including the respiratory organs, eyes, intestines, and urinary organs. Althoughcases of able-bodied individuals developing serious complications after being infected are rare, there is a highrisk of serious complications when patients’ immunity is lowered after hematopoietic stem cell transplantation,and there are still no treatments, so there is a strong desire for the development of treatments or preventative
drugs. Every year, there are 35,000 cases of hematopoietic stem cell transplantation around the world, among
which there are approximately 2,000 patients infected with adenovirus (Source: Bone Marrow Transplantation
2016, Bone Marrow Transplantation 2019).
In the phase II trial, drug dosage is divided into four groups, and aspects such as safety, tolerability, and efficacy
are evaluated and the recommended dosage for the next trial is determined. As of March 2022, the trial has
advanced to Group II. Going forward, the Company will strive to increase the pace through measures such asadditional trial facilities in the U.S. and launching trials in the UK, and aims to complete phase II within the year.
At the current stage, there are no reports of adverse events occurring, and if the trial progresses smoothly, it ispredicted that the Company will progress to the phase III clinical trial in 2023. It is also possible that the Company
will conclude a partner agreement and advance to the phase III clinical trial depending on the results of phase II.
b) BKV virus infections after kidney transplantation
As the second pipeline, the Company is moving ahead with preparations in order to begin phase II global joint
clinical trials indicated for BK virus infections after kidney transplantation in the second half of 2022. Although
trial protocols and number of patients have not yet been determined, it is assumed that they will be similar to theclinical trial for adenovirus infections after hematopoietic stem cell transplantation. The initial plan was to advancetrials in Japan and Australia, but trials may be conducted in other countries as well depending on the situation.

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12 23

COMPANY RESEARCH AND ANALYSIS REPORTFISCO Ltd.
https://www.fisco.co.jp

SymBio Pharmaceuticals Limited

24-May-2022

4582 Tokyo Stock Exchange Growth Market

https://www.symbiopharma.com/ir_e/

Trends in the development pipeline

Kidney transplantation is the only definitive treatment for end-stage renal disease. It is FISCO’s view that the
number of patients worldwide who require transplantation surgery is approximately 100,000. Because immunity
is lowered following kidney transplantation, cases of infection are frequent; the incidence rate is less than 15%
for BKV, less than 20% for CMV, and less than 10% for the varicella-zoster virus. For BKV, nearly 100% of evenable-bodied individuals are infected during infancy, and although there are no issues as long as the individual isin healthy condition, in a state where immunity is lowered after organ transplantation, the virus becomes active,
causing illnesses such as hemorrhagic cystitis and interstitial nephritis. Furthermore, there are even cases in which
failure of the newly transplanted kidney occurs if symptoms worsen. There are 8,000 patients with BKV infections
every year (Source: International Report on Organ Donation and Transplantation Activities Executive Summary
2019, April 2021 & Transplantation 2012). Currently, immunosuppressive drugs and CMV anti-infective agentsare prescribed as symptomatic therapy, but the results are limited, so BKV infection is a disease with a high levelof unmet medical needs for which treatment has yet to be established.
Potential needs for kidney and liver transplantation(Unit: people)
U.S.

EU

Kidney transplantation

39,51528,053

Liver transplantation

13,07010,754Japan

Other countries

Total

1,827

30,702100,097395

11,56535,784

Source: Prepared by FISCO from the Company’s results briefing materialsc) CMV infection in brain tumors (GBM)
In other news, research related to antitumor efficacy is progressing in overseas academia. Specifically, it enteredinto a collaborative research agreement with the National Cancer Centre Singapore (NCCS) to explore anti-tumor
efficacy and mechanisms in EB virus (EBN)* positive lymphoma in September 2021. Also in September of thatyear, a non-clinical study was initiated to investigate anti-tumor efficacy against brain tumors at the Brain Tumor
Center within the Department of Neurological Surgery at the University of California, San Francisco. Additionally,in March 2022, the Company has also announced the initiation of a non-clinical study to investigate anti-tumor
efficacy against brain tumors associated with CMV infections in collaboration with Brown University in the U.S.
*	EBV is known for infecting roughly 50% of five-year-olds and nearly 95% of adults. Nearly all EBV infections are asymptomatic, while some result in hematological cancer or auto-immune diseases. EBV typically infects B lymphocytes and lies
hidden within the cell, inactive, but becomes active due to some sort of environmental change.

CMV infections are discovered in nearly half the cases of GBM (glioblastoma) which has a particularly high degreeof malignancy among brain tumors. The reactivation of CMV causes inflammation in cells, and creates a hypoxic
state, thereby increasing the VEGF which is a growth factor related to the formation of new blood vessels, and it
has been indicated that this may accelerate the multiplication of cancer cells. The standard treatments for GBM
are surgical operations, radiation therapy, and chemotherapy, but the average life expectancy is between 15 to 20
months, and the survival rate after five years is extremely low at under 5%, so it is becoming a field where there
is a strong desire for the development of effective treatments. Although there are currently many GBM treatments
in development, there are none which target both CMV and brain tumors, so if BCV is proven to be effective, itis predicted that its market value will increase significantly. It is thought that the number of GBM patients aroundthe world is approximately 30,000*.
*	Company estimates based on GlobalData: Forecast of incident cases of GBM in US, 5EU, China and Japan (2027)

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13 23

COMPANY RESEARCH AND ANALYSIS REPORTFISCO Ltd.
https://www.fisco.co.jp

SymBio Pharmaceuticals Limited

24-May-2022

4582 Tokyo Stock Exchange Growth Market

https://www.symbiopharma.com/ir_e/

Trends in the development pipeline

The Company is currently examining the results of two non-clinical studies underway at U.S. universities andworking to determine whether or not will it will progress to clinical trials. The results of the non-clinical studies
are projected to be confirmed in 2022, and it is predicted that the Company will initiate phase II trials in 2023 if
things go smoothly.
d) Multiple sclerosis
The possibility is emerging that BCV will be developed as a treatment for multiple sclerosis. This is because it
has been discovered that EBV is associated as being one cause behind the onset of multiple sclerosis. Multiple
sclerosis is one type of neurological disease that causes functional impairments in areas such as the brain, spinal
cord, and optic nerve due to inflammation of the central nervous system or optic nerve for some reason or another.
As resurgence and remission occur over and over in repeated cycles, vision, limb functions, and cognitive abilities
will decline if symptoms develop further. There are many patients in North America and Europe, with approximately
3 million people around the world and approximately 18,000 in Japan.
Multiple items are being sold as treatments, including Ocrevus which is an anti-CD20 antibody, and the scopeof scales surpasses a total of ¥1.5tn. However, because the cause of onset had been unclear, there are only
symptomatic treatments to hold back the progression of the disease, and root treatments have not yet beendeveloped, so even now many companies are advancing development.
Companies with highest ranking net sales for multiple sclerosis treatments
Mechanism

Name

Sales company

Global net sales(¥bn)

Anti-CD20 antibodies

Ocrevus

Biogen/Roche/Genentech

492.2

Immunoregulation

Tecfidera

Biogen422.2

Sphingosine 1-phosphate receptor activation

GILENYA/ IMUSERA

Mitsubishi Tanabe Pharma Corporation/ Novartis

324.6

Inhibition of dihydroorotate dehydrogenase

AUBAGIO

Sanofi249.1

Anti-α4 Integrin antibody

TYSABRI

Biogen/ Biogen Japan

207.8

Source: Prepared by FISCO from the Company’s results briefing materials

A paper published by a research team from the U.S.’s Harvard University in January 2022, which was based on an
analysis of data from 1,000 patients with multiple sclerosis among the more than 10 million currently enlisted U.S.
soldiers, revealed that the risk of onset is substantially higher for patients with a history of EBV infection, and that
EBV is the main cause of onset for multiple sclerosis. Furthermore, according to a research paper published bya research team from the U.S.’s Stanford University in January of this year, the nuclear antigen of EBV resembles
the antigen of glia cells, which proves that EBV is the mechanism which triggers multiple sclerosis through B-cells
that have multiplied after EBV infection. This shows that the development of symptoms after the onset of multiple
sclerosis can be prevented through treatment by quickly eliminating EBV.
The Company has declared a policy of advancing developments indicated for multiple sclerosis based on theseacademic research findings, and intends to formulate a development strategy in 2022. It is already in the processof advancing talks with renowned medical institutions in the same field about joint research. There are a large
number of multiple sclerosis patients and the scale of clinical trials will be large, so it is thought that in the event
the Company advances development, it will do so by concluding a partner agreement at a relatively early stage.
With no other companies working to develop antiviral treatments, this may gain attention as a new approach.

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14 23

COMPANY RESEARCH AND ANALYSIS REPORTFISCO Ltd.
https://www.fisco.co.jp

SymBio Pharmaceuticals Limited

24-May-2022

4582 Tokyo Stock Exchange Growth Market

https://www.symbiopharma.com/ir_e/

Trends in the development pipeline

Progress status of BCV clinical trials
Drug

SyB V-1901(Intravenous
formulation)

Indication

Progress

Adenovirus infections in patients withimmunodeficiency after hematopoietic stem cell Global joint clinical phase II trial being conducted (U.S. and UK)
transplantation (infants and adults)
BKV infection after kidney transplantation

Plans to initiate phase II clinical trial in second half of 2022 (Japan andAustralia)

GBM from CMV infections

Non-clinical studies in progress

Source: Prepared by FISCO from the Company’s results briefing materials and websitee) Results of joint research with the National Institute of Infectious Diseases
On February 24, 2022, the Company published the results of joint research with the National Institute of Infectious
Diseases on BCV. In summary, based on the results of verifying the antiviral activity of BCV against 17 different
serotypes of adenoviruses of previously unknown responsiveness, they were able to confirm approximately
200-fold antiviral activity in all cases compared to CDV. The research showed BCV to exhibit a high level ofantiviral activity, particularly against D54 or B11, which are known in Japan to cause hemorrhagic cystitis after
epidemic keratoconjunctivitis or hematopoietic stem-cell transplantation. Because there are no drugs approved
as treatments for adenovirus, there is an emerging possibility that the Company will advance developments
indicated for these diseases.
f) Underlying market value of BCV
In terms of antiviral treatments, maribavir (LIVTENCITY) from Takeda Pharmaceutical Company Limited <4502>
received U.S. marketing approval in November 2021 as a treatment for refractory or resistant CMV infection* afterorgan or hematopoietic stem-cell transplantation. According to estimates by Takeda Pharmaceutical Company
Limited, every year approximately 200,000 adults around the world undergo transplantation surgery, and it
is understood that roughly 25% of these people face the risk of CMV infection. With the number of indicatedpatients, including those with first-line CMV infections after hematopoietic stem-cell transplantation, at 25,000,
Takeda Pharmaceutical Company Limited projects net sales to reach between $700 and 800mn USD during thepeak of maribavir. The number of patients indicated for BCV, which this company develops, is approximately
40,000 when including patients with brain tumors from CMV infections, and if patients with multiple sclerosis arealso included, the potential market value of BCV will surpass ¥100bn, and attention will be given to development
trends going forward.
*	Four types of antiviral treatments (ganciclovir, valganciclovir, foscarnet, and cidofovir) are indicated for refractory or resistant
CMV infections

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15 23

COMPANY RESEARCH AND ANALYSIS REPORTFISCO Ltd.
https://www.fisco.co.jp

SymBio Pharmaceuticals Limited

24-May-2022

4582 Tokyo Stock Exchange Growth Market

https://www.symbiopharma.com/ir_e/

Trends in the development pipeline

Strengths of BCV

Source: From the Company’s results briefing materials

Is exploring the possibilities of developing rigosertib throughcombinations with other drugs, including TREAKISYM®
3. Rigosertib (intravenous formulation/oral formulation)
Rigosertib is an anticancer agent candidate that has unique multi-kinase inhibitory action (which causes cancer cells
to die by inhibiting the multiple kinases involved in cancer cell proliferation, invasion, and metastasis). Its licensor,
Onconova, has conducted the global joint phase III clinical trials (INSPIRE trial) with the overall survival period as
the primary endpoint for high-risk myelodysplastic syndrome (MDS) recurring after treatment, for which sufficient
treatment efficacy cannot be obtained through the current standard treatment of hypomethylating drugs as it shows
resistance to such drugs. In August 2020, it was announced that the primary endpoint had not been achieved incomparison to the doctor-selected therapy.
The Company is responsible for clinical development in Japan, and its policy is to search for new disease targets,
including from the findings obtained from the INSPIRE trial’s additional analysis. Specifically, through the joint
research agreements concluded with the Institute of Medical Science, The University of Tokyo, and Gunma University,
they are creating new treatments through combination therapies for bendamustine and rigosertib and their combined
use with other existing drugs, and searching for new disease targets, including in treatment areas other than the
oncology area, while utilizing AI technologies. The Company intends to formulate a new rigosertib development
plan in 2022.

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16 23

COMPANY RESEARCH AND ANALYSIS REPORTFISCO Ltd.
https://www.fisco.co.jp

SymBio Pharmaceuticals Limited

24-May-2022

4582 Tokyo Stock Exchange Growth Market

https://www.symbiopharma.com/ir_e/

Trends in the development pipeline

Also, for the development of the rigosertib oral formulation, in September 2021 Onconova announced the interim
results for the doctor-led phase 1/2a clinical trial (combined used with immune checkpoint inhibitors) for progressive
KRAS* mutated NSCLC (non-small cell lung cancer, stage IV). Positive results were obtained showing antitumor
activity in the combination therapy, which suggest the possibility that the effectiveness of immune checkpoint
inhibitors is increased by their combination use with the rigosertib oral formulation, and development trends fromnow on will be closely watched. The Company has completed the phase I clinical trial in Japan in 2019 to confirm
the safety of a high dosage of a single drug and its tolerability among Japanese people.
*	KRAS is a cancer gene. The KRAS gene usually inhibits the replication of cells, but when a mutation of the KRAS geneoccurs, a signal for cells to replicate is continually sent out, which causes cancerous cells to actively replicate. Patientswith mutated KRAS genes have been identified in a certain percentage of patients with certain forms of cancer, includingcolorectal cancer and lung cancer.

Progress on sales of rigosertib
Drug

Indication

Progress

SyB L-1101 (Intravenous formulation) Recurrent/refractory high-risk MDS single drug
SyB L-1101 (Oral formulation)

Global joint phase III clinical trial Currently conducting
additional analysis

Recurrent/refractory high-risk MDS single drug

Completed the phase I clinical trial in Japan

Untreated high-risk MDS (combined use with AZA)

Completed the global joint phase I/II clinical trial

Source: Prepared by FISCO from the Company’s results briefing materials and website■ Results trends
In the FY12/21 results, become profitable for the first time throughthe increase in sales of TREAKISYM®
1. Summary of FY12/21 results
In the FY12/21 results, net sales increased 176.4% YoY to ¥8,256mn, operating profit was ¥1,016mn (compared
to a loss of ¥4,506mn), ordinary profit was ¥1,001mn (a loss of ¥4,615mn), and profit was ¥2,032mn (a loss of¥4,090mn), and the Company become profitable for the first time since its foundation.
FY12/21 results(¥mn)
FY12/20
Results

FY12/21

vs. net sales

Initialforecast

Results

vs. net sales

YoY
ChangeYoY% changevs. plan
ChangeNet sales

2,987

-

9,151

8,256

-

5,269

176.4%-894

Gross profit

866

29.0%

6,957

5,800

70.2%

4,933

569.1%-1,156

SG&A expenses

5,373

179.9%

5,596

4,784

57.9%

-588

-11.0%-811

R&D expenses

2,266

75.9%

2,019

1,736

21.0%

-530

-23.4%-282

Other SG&A expenses

3,106

104.0%

3,577

3,047

36.9%

-58

-1.9%

-529

Operating profit (loss)-4,506-150.9%

1,361

1,016

12.3%

5,522

-

-344

Ordinary profit (loss)-4,615-154.5%

1,350

1,001

12.1%

5,617

-

-348

529

-

-

0

-

-529

-

0

-4,090-136.9%

1,149

2,032

24.6%

6,122

-

883

Extraordinary profit (loss)
Profit (loss)

Source: Prepared by FISCO from the Company’s financial results

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17 23

COMPANY RESEARCH AND ANALYSIS REPORTFISCO Ltd.
https://www.fisco.co.jp

SymBio Pharmaceuticals Limited

24-May-2022

4582 Tokyo Stock Exchange Growth Market

https://www.symbiopharma.com/ir_e/

Results trends

Net sales increased significantly, mainly because in December 2020 the Company transitioned to an in-housestructure for sales of TREAKISYM®* and as its indications were expanded to r/r DLBCL, for which there are many
patients. The gross profit margin also rose greatly, from 29.0% in the same period in the previous fiscal year to70.2%, including due to the transition to the in-house sales structure and the progress made in switching from theFD formulation to the RTD formulation. As a result, gross profit increased 569.1% YoY to ¥5,800mn. On the other
hand, an inventory loss of ¥331mn of the FD formulation was recorded in 4Q primarily as a result of the switch fromthe FD to RTD formulation.
*	For its distribution system, in September 2020 the Company concluded agreements with Suzuken Co., Ltd. <9987> andTOHO PHARMACEUTICAL CO., LTD., a consolidated subsidiary of Toho Holdings Co., Ltd. <8129>, and it became theirgeneral agent. It is also outsourcing logistics to S.D Collabo Co., Ltd., which is a subsidiary of Suzuken (one logistics basein both eastern and western Japan).

Conversely, SG&A expenses decreased 11.0% YoY to ¥4,784mn, mainly due to the decline in R&D expenses.
R&D expenses declined ¥530mn YoY, although within this amount, ¥520mn was due to an absence of the RTD
formulation milestone payment recorded in the previous fiscal year, and on excluding this factor, R&D expenses
were basically unchanged YoY. Other SG&A expenses decreased ¥58mn due to a curb on other expenses despite
the rise in sales costs following the transition to the in-house sales system. As a result of the above, operating profit
increased ¥5,522mn YoY.
Looking at how net sales trended on a quarterly basis, although making a full-scale transition to an in-house sales
structure from 1Q FY12/21 has caused net sales to increase, net sales from Eisai in 4Q FY12/20 were ¥1.9bn, so
sales have in actuality decreased compared to the previous quarter. This decrease was mainly because market
inventory of TREAKISYM® was greater than anticipated, and because the number of patients receiving treatment
slowed due to the impact of COVID-19. In 2Q, market inventory was depleted, and sales for r/r DLBCL began
in earnest in 3Q, which has led net sales to increase further, expanding to ¥2,703mn in 4Q. 4Q operating profit
decreased slightly from the previous quarter to ¥591mn, but this was primarily due to the recording of ¥331mn ofvaluation loss.
Looking at the Company’s plan, net sales fell short by ¥894mn. ¥450mn of this amount was due to market inventory
being greater than anticipated, and ¥400mn was because the number of patients receiving treatment failed to growas people refrained from consultations due to COVID-19. Although the Company was able to curb SG&A expenses
more than it had been planned, operating profit fell short by ¥344mn due in part to the recording of valuation loss.
On the other hand, profit managed to exceed the plan by ¥883mn partially through the recording of ¥1,275mn indeferred tax assets.

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18 23

COMPANY RESEARCH AND ANALYSIS REPORTFISCO Ltd.
https://www.fisco.co.jp

SymBio Pharmaceuticals Limited

24-May-2022

4582 Tokyo Stock Exchange Growth Market

https://www.symbiopharma.com/ir_e/

Results trends

Quarterly result trends（¥mn）

Net sales

Operating profit (loss)

4,000
3,000
2,000
1,000

2,703

2,406
1,420

971

809

551

1,726

654

619

591

15
0
-210
-1,000-961-878-1,302-1,3633Q

4Q-2,000

1Q

2Q

FY12/21

1Q

2Q

3Q

4Q

FY12/22

Source: Prepared by FISCO from the Company’s financial results

Has entered a phase for expanding profitability in FY12/22, andfundraising is expected to be mainly borrowings from financial
institutions
2. Financial condition
At the of end of FY12/21, total assets were up ¥2,178mn compared to the end of the previous fiscal period to¥8,452mn. Looking at the main change factors, in current assets, there were increases of accounts receivable-tradeof ¥1,740mn and advance payments of ¥149mn, but there were decreases of semi-finished goods of ¥412mn,
accrued consumption taxes of ¥314mn, and merchandise and finished goods of ¥146mn. In non-current assets,deferred tax assets increased ¥1,275mn.
Total liabilities were up ¥89mn compared to the end of the previous fiscal period to ¥1,707mn. The main change
factors were increases in accrued consumption taxes of ¥516mn, and income taxes payable of ¥301mn, provision
for product changeover of ¥186mn, but decreases in accounts payable-trade of ¥595mn, and accounts payable of¥130mn. Net assets increased ¥2,088mn to ¥6,745mn. This was mainly due to an increase of ¥2,032mn in retained
earnings due to the recording of profit and increases in share capital of ¥112mn and capital surplus of ¥113mn
following the exercise of stock acquisition rights. As a result, the equity ratio rose 9.3 percentage points, from 64.3%
at the end of the previous period to 73.7%.
At the end of March 2022, the Company renewed its syndicate loan (commitment line) agreement with three banks.
The upper limit has been set at ¥3.15bn with the commitment period set to last until April 4, 2024.

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19 23

COMPANY RESEARCH AND ANALYSIS REPORTFISCO Ltd.
https://www.fisco.co.jp

SymBio Pharmaceuticals Limited

24-May-2022

4582 Tokyo Stock Exchange Growth Market

https://www.symbiopharma.com/ir_e/

Results trends

Balance sheet and management indicator(¥mn)
FY12/18

FY12/19

FY12/20

FY12/21

Change

6,038

4,887

5,815

6,747

932

4,821

3,910

3,848

3,860

11

200

386

459

1,705

1,245

Total assets

6,239

5,273

6,274

8,452

2,178

Total liabilities

1,337

873

1,617

1,707

89

-

-

-

-

-

4,901

4,400

4,657

6,745

2,088

70.1%

71.7%

64.3%

73.7%

9.3pt

Current assets(Cash and deposits)
Non-current assets(Interest-bearing debt)
Net assets
Management indicator
Equity ratio

Source: Prepared by FISCO from the Company’s financial results■ Outlook
In FY12/22 results, continued increase of sales and profit projected
through increased sales of products for r/r DLBCL and an increasein the gross profit margin
1. Outlook for FY12/22
In FY12/22 results, the Company’s forecast calls for net sales to increase 33.1% YoY to ¥10,992mn, operating profit
to increase 74.2% to ¥1,770mn, ordinary profit to increase 74.8% to ¥1,750mn, and profit to decrease 27.2% to¥1,480mn. Sales and profit are projected to increase mainly through expanded sales of products for r/r DLBCL. It
cannot be precisely determined which indications TREAKISYM® is being used for, but by inferring through analogy
from sales and outlooks for drugs used in combination, products for r/r DLBCL were launched effectively beginningin 3Q FY12/21, so the Company forecasts approximately ¥4.0bn in FY12/22 which will be a little less than a two-foldincrease YoY. In addition, it forecasts sales increases through share expansion in target fields and increases in thenumber of treatments. The impact of generic drugs has not been incorporated into the plan at this time.
Outlook for FY12/22(¥mn)
FY12/21
Results

FY12/22vs. net sales

Company
forecast

vs. net sales

Change% change

Net sales

8,256

-

10,992

-

2,735

33.1%

Gross profit

5,800

70.2%

8,796

80.0%

2,995

51.7%

SG&A expenses

4,784

57.9%

7,026

63.9%

2,241

46.9%

R&D expenses

1,736

21.0%

3,056

27.8%

1,319

76.0%

408

4.9%

1,269

11.5%

861

211.0%

Other SG&A expenses

3,047

36.9%

3,970

36.1%

922

30.3%

Operating profit

1,016

12.3%

1,770

16.1%

753

74.2%

Ordinary profit

1,001

12.1%

1,750

15.9%

748

74.8%

Profit

2,032

24.6%

1,480

13.5%

-552

-27.2%[BCV]

Source: Prepared by FISCO from the Company’s financial results

We encourage readers to review our complete legal statement on “Disclaimer” page.

20 23

COMPANY RESEARCH AND ANALYSIS REPORTFISCO Ltd.
https://www.fisco.co.jp

SymBio Pharmaceuticals Limited

24-May-2022

4582 Tokyo Stock Exchange Growth Market

https://www.symbiopharma.com/ir_e/

Outlook

The gross profit margin is forecast to rise from 70.2% in the previous period to 80.0% because the switch to RTD
formulation/RI administration has been fully completed since the beginning of the period. The exchange rate has
been progressing around ¥123 per U.S. dollar, moving toward a weakened yen since the formulation of the plan
when it was ¥110 per U.S. dollar. However, purchases from Eagle for the fiscal year under review have mostly alreadybeen reserved, so profits will largely be unaffected.
The Company projects SG&A expenses to increase 46.9% YoY to ¥7,026mn. Among these, R&D expenses areprojected to increase 76.0% to ¥3,056mn. The main factors behind this increase include expenses for BCV clinical
trials in addition to the recording of expenses for the operation of its U.S. company that will serve as an integrated
development base, and an increase in fees for joint research with academia. The Company projects that other SG&A
expenses will increase 30.3% to ¥3,970mn. This increase is mainly due to the inclusion of a ¥550mn milestone
payment to Eagle which will occur once total net sales of RTD formulation have reached a certain level. Additionally,
discussions are underway to in-license new development candidates, but these have not been incorporated into
the results forecast. With regard to domestic sales and employees whose duties are not directly related to sales,
the Company intends to maintain its levels from the end of the previous period. Although there is a possibility thatoverseas business expenses may increase due to the continually weakening yen, the Company’s view is that these
expenses are within a range where they can be offset by a curb on expenses.
The main factor behind the decrease in profit is the elimination of the impact of deferred tax assets recorded in theprevious period. Its U.S. company will increase from the current structure of 3 to 4 people, and plans to expand
its scale up to a dozen or more employees by around 2025 because it will actively promote development overseas
going forward.
The Company displays its outlook on a quarterly basis, and forecasts net sales in FY12/22 to increase 67.8% YoY
to ¥2,383mn in 1Q. As for the actual status of sales, it is thought that they will fall slightly short of the plan due tothe impact of patients refraining from consultations because of COVID-19, but it appears that they will proceed
according to plan on a profit basis through a curb on expenses.

Trends and outlook for quarterly net sales
（¥mn）
3,500
3,000
2,406
1,900

1,900

1,726

1,700

1,600

2,982

2,383

2,500

2,000

2,771 2,856

2,703

1,420

1,500
1,000
500
0
1Q

2Q

3Q

FY12/20

4Q

1Q

2Q

3Q

FY12/21

4Q

1Q

2Q

3Q

4Q

FY12/22

Note: Figures up to 4Q FY12/20 are net sales of Eisai
Source: Prepared by FISCO from the Company’s results briefing materials

We encourage readers to review our complete legal statement on “Disclaimer” page.

21 23

COMPANY RESEARCH AND ANALYSIS REPORTFISCO Ltd.
https://www.fisco.co.jp

SymBio Pharmaceuticals Limited

24-May-2022

4582 Tokyo Stock Exchange Growth Market

https://www.symbiopharma.com/ir_e/

Outlook

Advance development of BCV and aim for growth as a global
specialty pharmaceutical company
2. Future business strategy
In the three-year Mid-Range Plan that the Company announced in February 2021, the numerical results targets forthe plan’s final fiscal year of FY12/23 were net sales of ¥12,369mn, operating profit of ¥2,099mn, ordinary profit of¥2,088mn, profit of ¥1,778mn, and earnings per share of ¥46.5. However, because of the expansion of indicationsof brincidofovir, the Company is in the middle of formulating a new research development plan and has decided not
to disclose a plan for FY12/23.
In terms of expenses, R&D expenses are predicted to increase up to the low ¥4.0bn range in FY12/23. This isbecause although these expenses were set to be roughly ¥3.8bn in the initial plan, there is an emerging possibility
that the Company will newly initiate clinical trials indicated for brain tumors (glioblastoma) from CMV infections as
a pipeline for BCV development. The Company intends for personnel structures to be maintained in their current
state in Japan, while increasing personnel appropriately at its U.S. company.
Mid-Range Plan (announced in February 2021)(¥mn)
FY12/21Plan

FY12/22
TargetFY12/23
TargetNet sales

9,151

10,985

12,369Operating profit (loss)

1,361

1,738

2,099

Ordinary profit (loss)

1,350

1,727

2,088

Profit (loss)

1,149

1,470

1,778

Earnings per share (¥)

30.1

38.5

46.5

Source: Prepared by FISCO from the Company’s announcement material

In the long term, the Company is forming a policy to aim for growth as a global specialty pharmaceutical company.
Specifically, in addition to initiatives aimed at expanded sales of TREAKISYM®, the Company’s strategy involves
establishing POC in four niche areas with high unmet medical needs through BCV, and expanding its overseas
business while considering entering partnership agreements. As for BCV, in order to carry out a stable supply ofhigh-quality products, the Company plans to maximize profit by conducting in-house manufacturing (manufacturingconsignment) and also uncover fundamental business values contained by each pipeline while advancing joint
research with academia and others, and bridging that to maximization of business values, while simultaneously
working on in-licensing new development candidates.
The Company has set “Local & Global” and “50 and 50 in 30” as the management keywords. These keywords signify
taking a dramatic leap forward as a global pharmaceutical company by successfully guiding the development of BCV
with the aim of increasing the percentage of total sales from overseas sales to 50% by 2030. At FISCO, we expectthat the Company’s corporate value will substantially improve if it succeeds at developing BCV as a treatment foradenovirus infection after hematopoietic stem-cell transplantation or organ transplantation, and as a treatment forbrain tumors or cranial nerve disease caused by this virus, and are focused on future development trends.

We encourage readers to review our complete legal statement on “Disclaimer” page.

22 23

COMPANY RESEARCH AND ANALYSIS REPORTFISCO Ltd.
https://www.fisco.co.jp

SymBio Pharmaceuticals Limited

24-May-2022

4582 Tokyo Stock Exchange Growth Market

https://www.symbiopharma.com/ir_e/

Outlook

The Company’s strategies

Source: From the Company’s results briefing materials

We encourage readers to review our complete legal statement on “Disclaimer” page.

23 23

Disclaimer
FISCO Ltd. (“FISCO”) offer stock price and index information for use under the approval of theTokyo Stock Exchange, the Osaka Stock Exchange and Nikkei Inc.
This report is provided solely for the purpose of offering information, and is not a solicitationof investment nor any other act or action.
FISCO prepared and published this report based on information which it considered reliable;
however, FISCO does not warrant the accuracy, completeness, fitness nor reliability of thecontents of this report or the said information.
The issuers’ securities, currencies, commodities, securities and other financial instruments
mentioned in this report may increase or decrease in value or lose their value due to influence
from corporate activities, economic policies, world affairs and other factors. This report does
not make any promises regarding any future outcomes. If you use this report or any information
mentioned herein, regardless of the purpose therefor, such use shall be made based on yourjudgment and responsibility, and FISCO shall not be liable for any damage incurred by you asa result of such use, irrespective of the reason.
This report has been prepared at the request of the company subject hereto based on theprovision of information by such company through telephone interviews and the like. However,
the hypotheses, conclusions and all other contents contained herein are based on analysis
by FISCO. The contents of this report are as of the time of the preparation hereof, and are
subject to change without notice. FISCO is not obligated to update this report.
The intellectual property rights, including the copyrights to the main text hereof, the data
and the like, belong to FISCO, and any revision, reprocessing, reproduction, transmission,
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is strictly prohibited.
FISCO and its affiliated companies, as well as the directors, officers and employees thereof,
may currently or in the future trade or hold the financial instruments or the securities of issuersthat are mentioned in this report.
Please use the information in this report upon accepting the above points.

◾ For inquiry, please contact: ◾

FISCO Ltd.
5-13-3 Minami Aoyama, Minato-ku, Tokyo, Japan 107-0062
Phone: 03-5774-2443 (IR Consulting Business Division)
Email: support@fisco.co.jp