ANALYST NET Company Report

SymBio Pharmaceuticals Ltd.
Issued: June08, 2022

（4582 Growth）

Outlook for Business Development Acceleration
Establishing itself as a specialty pharma in the area of haematology
SymBio Pharmaceuticals is entering a new phase of development, having laid thegroundwork necessary for a pharmaceutical company with a global license
specialising in haematology. This it achieved with its establishment of an in-housemarketing structure and its acquisition of the drug, brincidofovir (BCV). There has
been some loss of sales momentum in the company’s main product, Treakisym®,
due to inventory adjustments accompanying the switch to an in-house sales
structure, and as a result of the coronavirus pandemic. On the other hand, there has
been an increase in approved clinical indications, changes in formulation and thestart of in-house sales. SymBio’s operating revenues had been in negative territory
since the December 2008 period, when it licensed out Treakisym® exclusive sales
rights in Japan to Eisai and recorded a lump-sum contract payment. In 2021 thecompany at last achieved profitability, and in 2022, rising profitability on the backof growth in Treakisym® sales, should help it manage a 74.2% increase in operating
revenues, even with higher disbursements on brincidofovir R&D.
Challenging new areas (tumours/cranial nerves)
In 2022, SymBio began to expand from its global haematology specialism to theareas of cancer and the cranial nerve system. BCV is now in Phase-2 trials fordisseminated adenovirus infections after hematopoietic stem cell transplantation,
and Phase-2 trials are about to start on BK virus infections after kidneytransplantations. In addition, it now appears that BCV can be used on malignant
brain tumours and development is in the planning stages. The company seescontinued earnings growth from Treakisym® for the time being but looking ahead
it not only wants to further solidify its position as a specialist in hematology with
the introduction of new drugs in this area, but also wants to expand into new areas(infections, cancers and cranial nerves). This it hopes will allow it to evolve a
structure for alternative growth areas if earnings expansion flattens out.
Impact of generics
On February15 2022, four companies received approval for the manufacture andsale of the Treakisym® intravenous drip solution (RTD generic). In response,
SymBio has notified the four companies of concerns about patent infringement. The
patent is considered the property of the US company, Eagle Inc. which is the original
licensor of the RTD preparation. There was an earlier case of Treakisym® patent
infringement (RTD/RI formulation) in the US, with Eagle (and co-licensee Teva)
winning the court case, as a result of which generics makers cannot sell this productfor a certain period. Indolent B-cell non-Hodgkin’s lymphoma was the indication
submitted by the four companies at time of submission in February, and there are
moves to extend indications to relapsed/refractory DLBCL. However, one of thefour companies decided in May to postpone sales. Chronic lymphocytic leukemia(CLL) also has exclusive protection during the re-examination period (until 2026)
and is not included among the indications for generic products. Further, SymBio hasreceived approval for the RI formulation (10-minute infusion), which is even moreconvenient than the RTD formulation, and is pursuing a switch to RI. At the
moment, with the drug price of generics undecided, it is unclear how much of an
impact they will have, but we infer it will not immediately be very significant.
Note: This report is the English-language version of the original Japanese-language
report issued on June 8th, 2022, to which you should refer for precise details
Results

Revenues YoY
JPY-mil％

Revised Basic Report
Fair Research Inc
Tsuyoshi Suzuki

Company Outline
LocationTokyo

President

Fuminori Yoshida

EstablishedMarch 2005

Capital

JPY17,169 mil

ListedOctober 2011
www.

URL

symbiopharma.com

Industry

PharmaEmployees

141 (non-consol)

Key Indicators (June 7th, 2022)
Stock Price

JPY68952-week high

JPY2,423

52-week low
Sharesoutstanding
Trading Unit

JPY62239,553,931

Market Cap

JPY27,253mil

Dividend (est)0.0

Forecast EPS

JPY38.6

Forecast PER

17.87X

Actual BPS

JPY164.6

Actual PBR

4.19X

100 shares

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

Op. Income
JPY-mil

YoY％

Rec. Profit
JPY-milYoY％

Net Income
JPY-mil

YoY
％

EPS
JPY

Stock Price
High
Low

2017/12 Actual
2018/12 Actual

3,444
3,835

45.4
11.4

-3,947-2,656NANA-3,976-2,748NANA-3,977-2,752

NA
NA

-79.7
-165.5

335
289

196
115

2019/12 Actual

2,837

-26.0

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

NA-189.0275

150

2020/12 Actual
2021/12 Actual

2,987
8,256

5.3
176.4

-4,506
1,016

NA
NA

-4,615
1,001

NA
NA

-4,090
2,032

NA
NA

-124.1
53.0

653
2,423

243
387

2022/12 Forecast

10,992

33.1

1,770

74.2

1,750

74.8

1,480

-27.2

38.6

1/31
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 Pharmaceuticals Ltd. （4582 Growth）

2022 June 08

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
businesswithglobal company’s business model has three characteristics:
ambitions aiming for highreturns using a niche
strategy. Operating without ① Post-POC strategy
laboratories
orThe company does not itself undertake drug discovery research but investigates
manufacturing
facilities
new drug candidates developed by drug discovery ventures and pharmaceuticals
reduces much of the risk
companies around the world. Usually, proof of concept has already been
inherent in drug discovery
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 SymBio is a specialty pharma using a high return, high 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 mainly 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, and its
own expertise

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® (generic name: bendamustine), it took only five years or so togo from licensing-in (in 2005) to manufacturing and sales approval (in 2010). In
July 2018 it became the preferred drug 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 under development or at the development planning stage.

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 elements which underpin this track record are the company’s human resourcesand organisation. Hence, one-third of its 141 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 andFocus on human capital and scrutiny activities. Needless to say, the role and professional network of the company
company organisation to founder and current president, Fuminori Yoshida, are pivotal.
support networking andexpertise

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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.

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SymBio Pharmaceuticals Ltd. （4582 Growth）

2022 June 08

Establishment of an in-company sales structure

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

Members of the SAB （Scientific Advisory Board）

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

Robert Lewis

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

Tomomitsu Hotta

Honorary President, National Cancer Center,
Honorary Director, NHO Nagoya M edical
CenterM akoto Ogawa

Honorary President, Aichi Cancer Cente

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

Toshio Suda

Professor Internatinal Research Center
for M eical Science, Kumamoto Univ.

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

Toshio Heike

Director of Hyogo Prefectural
Amagasaki General M edical Cente

Tsutomu Takeuchi.

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

Senior Advisor
M atius J Rumel

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

Source: SymBio materials

3/31
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.

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SymBio Pharmaceuticals Ltd. （4582 Growth）

2022 June 08

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 (CD 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
Treakisym related events
Rigosertib related events
IONSYS® related events
BCV related events

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

4/31
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.

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SymBio Pharmaceuticals Ltd. （4582 Growth）＜Product pipeline＞

2022 June 08

SymBio’s mainstay product is Treakisym® (generic name: bendamustine) for thetreatment of malignant lymphomas. Treakisym® has been developed for a series ofadditional indications, has undergone a number of formulation changes, and is now
ready for direct sales by the company. Looking ahead, Treakisym’s profitability andmarket expansion will support the development of the company’s next mainstay
candidate, the antiviral drug brincidofovir, and will support analysis and appliedresearch (in the area of anti-tumour activity) of new modes of action of Treakisym®
and rigosertib. These represent a new stage in corporate value creation.
1. Treakisym®: (SyB L-0501 (freeze-dried injection formulation) / SyBL-1701 (RTD liquid formulation) /SyB L-1702 (liquid formulation)

NDA：New Drug Application
MA:Marketing Approval

Reference: Types of malignant lymphoma
Lymphoma is a blood disease caused by the cancerisation of immunity cells called
lymphocytes (a type of leukocyte). Its incidence reflects the ageing of society and isrising annually. There are two major types: Hodgkin’s lymphoma (HL) and nonHodgkin’s lymphoma (NHL). Most Japanese cases (94%) of malignant lymphoma are
NHL, which can be classified into the following three types depending on speed of
disease progression.
〇Indolent-B-NHL: Disease progresses annually (MALT or FL (up to grade 3a ), etc.)
FL：Follicular lymphoma,

MALT: MALT lymphoma

Follicular lymphoma accounts for 80% of indolent non-Hodgkin’s lymphoma
cases〇Medium malignancy: disease progresses monthly (MCL, DLBCL, etc.)〇High malignancy: Burkitt tumours, etc.
Among NHL cancers the most prevalent type is DLBCL (diffuse large B-cell
lymphoma). A poor prognosis is often associated with relapsed/refractory DLBCL.

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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.

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SymBio Pharmaceuticals Ltd. （4582 Growth）

2022 June 08

Distribution of malignant lymphomas 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

2.0

Burkitt tumours

1.3

T/NK cell tumours

18.1

Hodgkin lymphoma

5.9

Others

3.8

Treakisym
indicated

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 et al., “Difference in incidence and trends ofhaematological malignancies in Japan and the United States”, British Journal of
Haematology, 2014

(1) History of indications and development
Among various malignant lymphomas Treakisym® is indicated for the following
four:〇Relapsed/refractory indolent-B-NHL and MCL (approved in October 2010)〇Untreated indolent-B-NHL and MCL (approved in December 2016)〇Chronic lymphocytic leukemia (CLL) (approved in August 2016)〇r/rDLBCL (approved in March 2021)
Note: Not indicated for untreated DLBCL (off-label)

Treakisym® was approved
within 5 years of being
licensed in, and newclinical indications havebeen added since thenAfter its first approval in2010,
Telomelysin®
received approval for two
further indications in 2016

Treakisym® was first developed in Germany in 1971. In December 2005 SymBio
acquired sole development and merchandising rights in Japan from the Astellas
European subsidiary, Astellas Pharma (now known as Astellas Deutschland GmbH)and underwent clinical trial development. In October 2010, a mere 5 years after
licensing-in, Treakisym® was approved for the treatment of r/r indolent-B-NHL andMCL and sales began in December. Further, in August 2016 chronic lymphatic
leukemia (CLL), and in December untreated indolent-B-NHL and MCL received
approval. In July 2018, with respect to indolent-B-NHL, MCL and CLL,
Treakisym® was for the first time listed as a standard therapy option in the
Hematopoietic Tumor Clinical Practice Guidelines 2018 Edition (edited by: Japan
Society of Hematology). It thus became a standard treatment both in name andpractice. As a result of its new status, the market penetration of Treakisym® rose,completely surpassing R-CHOP, which had been the standard treatment, and in
6/31

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.

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SymBio Pharmaceuticals Ltd. （4582 Growth）

2022 June 08

with a consequent increase 2018, from the market launch in August, achieved sales in Japan of JPY8.5 billion
in
level
of
market (approved drug price basis).
penetration
Behind this was the demonstrated superiority of the B-R therapy, combining
Becamethestandard Treakisym® and rituximab, over what had been the standard therapy, the R-CHOP
treatment in July 2018
therapy (see comparative charts below).
Comparative study of the CHOP-R and B-R therapies

Source: SymBio company briefing (showing better results for the B-R therapy)
Note: CHOP-R therapy
Chemotherapy that combines the molecular targeted drug rituximab with theanticancer drugs cyclophosphamide, doxorubicin hydrochloride, vincristine
sulfate, and the steroid prednisolone.

Subsequently, there was some stagnation in domestic sales, to JPY8.1 billion in
authorised drug price terms in 2020, due to inventory fluctuations caused by productquality problems with the supplier and the switchover to direct selling. However,sales rebounded after the approval in March 2021 of the B-R therapy and thePolivy®+BR therapy for the treatment of r/r DLBCL.
There was then a short-term
decline in sales, followed by Until the development of multi-agent chemotherapies (such as the CHOP therapy)
a recovery due to the there was no effective treatment for DLBCL or especially r/r DLBCL. CHOP was
expansion of indications to developed in the 1970’s but, while DLBCL ceased to be incurable, efficacy fell short.
include r/r DLBCLIn 1997, the R-CHOP therapy using Rituxan (generic name rituximab) was
The B-R therapy has fewer approved, demonstrating a far better survival period than CHOP. However, this isside effects and has a high not effective in about one-third of patients who suffer relapses, and is therefore an
response ratearea of high unmet medical need. In addition, many malignant lymphoma patientsare of advanced years and the possible side effects of the multi-agent chemotherapy
used in R-CHOP are of great concern. On the other hand, the B-R therapy comeswith fewer side effects and greater responsiveness, allowing it to more rapidly make
30% market penetration inroads into the r/r DLBCL market. While it was introduced only as recently as theachieved in a short time after second half of 2021, it has already captured around 30% of the market and islaunchexpected to capture 60%.
7/31
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.

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SymBio Pharmaceuticals Ltd. （4582 Growth）

2022 June 08

Reference:
Results of the Phase-3 trials of the B-R therapy targeting r/r DLBCL wereannounced at the European Hematology Association conference (EHA) in June
2020. The overall response rate (ORR) reported was a high 76.3%, and thecomplete response rate (CR) was 47.4%. An important finding was the efficacy inelderly patients (age 65 and over) for whom HSC transplantation was not thestandard therapy. In addition, it was reported that the complete response for nonGCB DLBCL’s, which have a poor prognosis, was 39%.

Results of Phase-3 trials of the B-R therapy targeting r/r DLBCL
Complete response rate: 47.4%, overall response rate: 76.3%

Source: SymBio company briefing(2) Competitive environment
Review of the competitive As noted earlier, Treakisym® has established itself as the main treatment in the area
environmentof haematological cancers. However, this area has seen the arrival of a variety of
new therapies in recent years. In addition, in February 2022, there appeared a new
reality in the shape of regulatory approval of Treakisym® generics. This requires are-evaluation of Treakisym’s competitive environment.

Whileacombination
therapy of Revlimid® and
Rituxan (R-R theapy) has
recently been approved forthe treatment of indolent-BNHL, there has been nochange in the standard
therapy status of the B-R
therapy① Indolent-B-NHL (low grade B-cell non-Hodgkin’s lymphoma)
For indolent-B-NHL, the combination therapies (BR therapy and B-G therapy) of
Treakisym® and an anti-CD20 antibody (rituximab, trade name Rituxan) or
obinutuzumab (trade name: Gazyva) are the standard and recommended treatment
options in the main clinical practice guidelines for hematopoiesis. In January 2020,a therapy combining lenalidomide (trade name: Revlimid®) and rituximab (R-R
therapy) was approved for relapsed / refractory indolent-B-NHL. Revlimid® is athalidomide derivative and may be teratogenic, so appropriate control procedures
have been established. Treatment should be selected based on the individual patient's
condition and the drug’s characteristics, but the B-R therapy is still considered oneof the standard therapies.
Reference: In the AUGMENT tests which underpinned approval of the RR therapy,
the median progression-free survival (PFS) for RR was 39.4 months, well above the14.1 months of rituximab alone. While no direct comparison can be made, in thecomparative tests of the CHOP-R therapy and B-R therapy mentioned earlier, the BR therapy registered a median PFS of 69.5 months.

Treatments for r/r DLBCL
include both the B-R therapy
and now the P-BR therapy.
The latter uses lower dosesof Treakisym®

② Relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL)In June 2019 the FDA announced the expedited approval of a three-drug therapy (PBR) for the treatment of transplant-ineligible relapsed or refractory diffuse large Bcell lymphoma (r/r DLBCL). This therapy consists of the B-R therapy of
bendamustine (Treakisym®) + rituximab (Rituxan®) together with the anti-CD79b
antibody drug-conjugate polatuzumab vedotin (product name: Polivy®, developedby Genentech and Roche). In Japan, an application for approval of the combined B8/31

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.

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SymBio Pharmaceuticals Ltd. （4582 Growth）

2022 June 08

R and Polivy® therapy was submitted by Chugai in July 2020, and approved in
March 2021. While the amount of Treakisym® required for the B-R therapy alone
is 120mg per dose, for the three-drug therapy it is 90mg.
Reference: P-BR therapy vs B-R therapy (r/r DLBCL)
There is data showing that the complete response (CR) rate for P-BR is 40%(GO29365 study; Phase-1b/2. Source: Sehn LH e al., J Clin Oncol, 2019). In
addition, Phase-2 trials in Japan (P-DRIVE trials) produced a CR rate of 34.3%.
The CR rate for the B-R therapy, whose cohort was included in the GO29365
study, was 17.5%. Elsewhere, the Phase-3 results targeting the B-R therapy on
r/rDLBCL and released by SymBio, produced a 47.4% CR rate, a 76.3% overall
response rate (ORR), and a median overall survival rate (mOS) of 29.2 months.
(Note: 70% of the patients on whom genetic analysis was conducted were of the
non-GCB type; 57.5% of the patients in the B-R therapy GO29365 study cohort
were non-GCB).
GO29365 Trial
Pola-BR

SymbioB-R

B-R(90mg/㎡）(120mg/㎡）

ORR(％）

70.0

32.5

76.3

CR(％）

57.5

20.0

47.4

ｍOS

12.4

4.7

29.2

(month)( ) dose of Treaksym

Source: Sehn LH et al, J Clin Oncol 2019, and SymBio IR materials

Since there is no superiority
of one over the other both
could become mainstream

Since the two patient cohorts have different backgrounds we cannot make asimple comparison. Also, in the GO29365 B-R therapy trials the Treakisym® dose
administered was 90mg/m2, while the Treakisym® dose administered in the
Phase-3 B-R trials released by SymBio was 120mg/m2. This means that thedifference in response, for the same B-R therapy, could be due to the difference indosage. It is not at present possible to say one is superior to the other.

In any event, the P-BR therapy and the B-R therapy will probably be mainly
indicated for r/r DLBCL.
In December 2021, Chugai Pharmaceutical submitted an application for the P-RCHP
therapy targeting first-line DLBCL (Treakisym® non-indicative). However,clinicians are divided on how to evaluate the clinical test results since there was onlya small difference from R-CHOP in OS terms. It is unclear at the present time
whether or not disease recurrence is lower using P-RCHP. If recurrence is lower,
then the r/r DLBCL market could shrink and the proportion of refractory patients
resistant to treatment would rise. It is believed that, after first-line P-RCHP, the PBR therapy will not be effective in second-line or subsequent refractory or relapsed
cases.

The use of Treakisym®
prior to CAR-T is now very
rare, but this should have
only a small impact because
the use of CAR-T itself isrelatively limited.

③ The CAR-T therapy
In the area of r/r DLBCL treatments CAR-T therapies are becoming more widely
accepted, with such CAR-T therapies as Kymriah®, Yescarta® and Breyanzi®
having already received approval. CAR-T is a T cell with a CAR (chimeric antigen
receptor) that specifically binds to the cancer antigen CD19 on the surface oftumorised B cells. T cells specifically attack cancerous B cells, and the response rateis thought to be in the area of 70-90%.
Previously, it was thought that bendamustine (Treakisym®) could be used as a
9/31This 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.

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2022 June 08

pretreatment for the CAR-T therapy. Today, however, various guidelines andreviews have recommended that the use of Treakisym® be avoided in pre-treatment,such that there are now very few cases of the P-BR and BR therapies being usedprior to CAR-T.
However, the target patients for CAR-T therapy are currently limited mostly to those
who are not indicated for transplantation (mainly third-line). In addition, the use of
autologous cells in CAR-T therapy requires sophisticated technology andequipment, and is time-consuming. It is also extremely expensive (said to be inexcess of JPY30 million per procedure) and can only be carried out at facilities that
can handle adverse events, such as cytokine release syndrome. The use of CAR-T
therapy is thus likely to be extremely limited.
④ Appearance of generics
Appearance of a generic
On February 15 2022, four companies (Pfizer Inc., Meiji Seika Pharma, KOA ISEI
RTD formulation
Co. Ltd., and Towa Pharmaceutical) were approved to manufacture and market
generic versions of the Treakisym® RTD intravenous infusion. At the time ofPatents protecting the RTD regulatory approval in February, the four companies generics were indicated forformulation belong to the indolent-B-NHL and MCL, but not r/r DLBCL. Recently, however, procedures
US company, Eagle
undertaken suggest that a move is underway to add r/r DLBCL as an indication(Towa Pharmaceutical on June 1). CLL has exclusive protection during the reIn the United States, sales of examination period (until 2026) and cannot be included in the indications for genericgenerics are not possible for products.
a certain period

In reaction, on February 25, SymBio released a document in which it notified the
In Japan, one of the four four companies of concerns about patent infringement. It is thought that the patent
generic makers has decided in question belongs to the US company, Eagle Pharmaceuticals Inc., which was theoriginal licensor of the RTD formulation. There was a previous instance of patent
to postpone sales
infringement involving the Bendeka® RT formulation in the US. The court decisionin that case enjoined the generics makers from selling the product for a prescribedperiod of time. In Japan, on May 11, Meiji Seika Pharma announced it was
postponing the posting of standard drug prices from the original June date. The risk
poised by generic products is receding, with one of the four generic makers deciding
to postpone sales.
Switching to the more userfriendly RI administration In February 2022, SymBio obtained approval for the RI formulation, which is evenwill provide a protective more convenient than the RTD formulation, and is proceeding with the switch fromwall against competition
one to the other. As pricing of the generic is at present undecided, any impact isunclear, but it is felt that there is unlikely to be a significant impact in the near term.
SymBio has not made any changes to its 2022 management plan.
Reference: New formulations
Until December 2020 the Treakisym® on the market was the freeze-dried (FD)formulation manufactured by Astellas Deutschland GmbH. In 2020, 10 years had
passed since Treakisym® was approved and from 2021 there was a risk ofcompetition from generics. Preparations have therefore been made to extend the
product’s life to 2031 by means of new formulations.
As a first step, in September 2017 SymBio announced it was licensing in ready-todilute (RTD) and rapid infusion (RI) Treakisym formulations from the US company,
Eagle Pharmaceuticals Inc. While the conventional FD formulation has theadvantage of room-temperature storage, it is time consuming and troublesome
because of the need to dissolve in a solvent and to dilute in physiological salineprior to administration. In the case of a liquid formulation, while refrigerated
storage is necessary, the burden on medical staff is reduced because it only requires
dilution in physiological saline. The switch to a liquid formulation should alsomean an appreciable reduction in costs.

10/31
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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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2022 June 08

Since the RTD formulation is the same in terms of efficacy and method ofadministration as the FD formulation, additional tests were deemed unnecessary.
A submission was filed with drug stability data in September 2019 and approval
was given for the existing indications in September 2020 with sales beginning on
January 12, 2021. In April 2021 approval of an additional indication, r/r DLBCL,
was received also for the RTD formulation. SymBio expected the RTD liquid
formulation to rise from 20% if sales in January-March 2021 to around 80% by
year end.

Comparison of the FD, RTD and RI (10-minute administration) formulations

Source: SymBio results meeting
Note: Having launched a freeze-dried formulation in the US in 2014, Teva
Pharmaceutical Industries, in January 2016 launched an RI preparation (productname: Bendeka® (10-minute infusion), licensed in from Eagle Pharmaceuticals. In
only two years, the BENDEKA® replaced 97% of the TREANDA® market.

Since the RI formulation (10 minutes infusion) has a different concentration andadministration time, a number of clinical tests to confirm safety and investigate
pharmacokinetics was undertaken before submitting an application in May 2021. In
February 2022 approval was given for all indications. With its 10-minuteadministration time and low salt content it is regarded as particularly suitable for the
many elderly patients with malignant lymphomas. With the introduction of theseliquid formulations, the product’s life cycle will be extended until the end of 2031.

The development of oral
PI3K inhibitors tareting
haemological cancers has
stagnated due to problems
with safety and effectiveness

Reference: PI3K inhibitors
In the field of hematological cancer, PI3K inhibitors have attracted attention aseasy-to-administer oral agents. In the United States, four PI3K inhibitors havebeen approved in the field of hematological cancer since idelalisib was authorisedin 2014.
All of these qualified for accelerated examination based on Phase-2 studies andbecame subject to revalidation of efficacy and safety in post-marketing validation
studies. As a result of this re-verification, approval has been withdrawn for someidelalisib indications, and approvals/ applications have been withdrawn for anumber of other drugs. In view of these results, the FDA has changed its stancesuch that in future randomised control trials are required for PI3K applications.
There has thus been a major change in the outlook for zandelisib, for which an
application via accelerated examination was planned using Phase-2 data.
Developments currently underway in Japan include pasaraclib (Phase-2),
zandelisib (Phase-3), and duvelisib (submission completed). Pasaraclib Phase-2
targets third-line follicular lymphoma, and zandelisib Phase-3 targets second-line
follicular lymphoma. Telomelysin® is also indicated for first-line, thus marginally
improving sales prospects. The indications for duvelisib are the extremely limited
fields of third-line CLL/SLL.

11/31
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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.

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2022 June 08

２． Brincidofovir（SyB V-1901）

Brincidofovir (BCV) is a highly active multiviral infection drug developed by the
US company, Chimerix Inc.

In 2019 SymBio licensed infrom the US company
Chimerix rights to the highly
activeantiviral
agent
brincidofovir

On October 1 2019 SymBio announced it had acquired from Chimerix Inc. exclusive
global license rights (development, manufacture and sale) to brincidofovir (BCV)
for all indications except smallpox. It is intended as the company’s strategic productsuccessor to Treakisym®. Until now SymBio has obtained licenses overseas anddeveloped them in the Japanese market. The contract with Chimerix allows it tolicense out development products globally. (On May 16, 2022 Chimerix announced
it had transferred the BCV license to Emergent BioSolutions Inc., but this has noeffect on the rights acquired by SymBio.)（１） Principal features of brincidofovir
Brincidofovir is highly Compared to other anti-viral drugs such as cidofovir (CDV) and Foscarnet (FOS),
activeagainstvarious BCV is highly active and effective against multiple infectious diseases.
infections
Brincidofovir (BCV) is highly active across a broad spectrum

Source: Chimerix documents
Note: EC50 (the concentration at which a drug or antibody shows a 50% maximum
response from the lowest value) indicates that the lower the number, the higher theactivity. In the above chart, EC50 is color-coded depending on the level. Green has
high activity and red has low activity. The left-most BCV column is green for various
viruses = has a broad spectrum.

12/31
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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.

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2022 June 08

Reference: cidofovir (CDV)
Was approved by the FDA in 1996 for the treatment of cytomegalovirus retinitis in
AIDS patients. CDV is a cytosine nucleotide analog which inhibits the replicationof DNA viruses such as adenovirus, papillomavirus, and polyomavirus as well as
the herpesvirus family. CDV is also effective against ganciclovir (GCV) resistance(UL97 gene mutation) and is thought to be of use when foscarnet (FOS) cannot be
administered due to the development of GCV resistance. It is not approved inJapan.

As can be discerned from the previous figure, cidofovir (CDV) has a similar levelof activity across as broad a spectrum as BCV. However, while CDV is nephrotoxic
and difficult to handle, BCV has low toxicity and is very safe despite being highly
active.
(2) BCV mode of action
Brincidofovir (BCV) has a structure in which a fatty chain (hexadecyloxypropyl: HDP)

Further,
nephrotoxicity, is bonded to cidofovir (CDV) and is rapidly taken into a lipid bilayer membrane andwhich is a common problem efficiently translocated into cells. The compound whose fatty chain is cleaved byin antiviral agents, is low
metabolism by intracellular phospholipase and the generated activated form (CDV-PP:
CDV diphosphate) is retained in the cell for a protracted period, resulting in a dramatic
improvement in antiviral activity. In addition, because HDP binding does not cause
accumulation of renal tubular epithelial cells by the OAT-1 transporter and the low levelof CDV released into the blood, nephrotoxicity, a fundamental problem of CDV, isreduced (because CDV does not have lipid tails it becomes a substrate of OAT-1 andaccumulates in renal urinary duct epithelial cells, with nephrotoxicity the likely
outcome).

Source: SymBio IR materials(3) Targeted disease areas
SymBio’s development strategy for BCV focuses on the “blank therapeutic spaces”
for which existing antiviral agents have not been approved. However, although there
SymBio targets the blank are many antiviral agents for which CMV (cytomegalovirus) is indicated, anti-CMV
therapy spaces in a “blue agents for glioblastoma (GBM), which is a malignant brain tumor, also constitute a"blank therapeutic spaces". This field is also considered a promising development
ocean strategy”
target.

13/31
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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.

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2022 June 08

Many blank therapeutic spaces awaiting drug solutions
CMV
Brincidofovir
Maribavir●

Letermovir●

Foscarnet●

Cidofovir●

Ganciclovir

●

AdV

BKV

EBV

〇

〇

〇

●：Approved〇：Development Target
However,

CMV-GBM is「Blank treatment area」

Source: SymBio results meeting, February 2022

The first of these blankspaces is disseminatedadenovirus infection after
hematopoietic stem celltransplantation① Disseminated adenovirus infection after HSC transplantation
In general, in the case of hematopoietic stem cell (HSC) transplantations and organtransplantations, irradiation and immuno-suppressants are used to suppress
rejection, thus rendering the patient vulnerable to infection. It used to be that CDV,FOS or some other anti-viral drug was used to offset this, but with the attendant riskof a nephrotoxic side-effects. Hence, the importance of BCV, which has low risk ofnephrotoxicity, to SymBio's goal of becoming a specialty pharmaceuticals company
in the region of hematology.

SymBio originally planned to use BCV to target viral infections after HSC
transplantations, an area with poor prognosis, high lethality, and of strong unmet
medical needs. After a meeting of the company’s Global Advisory Board in February2020 it was decided that the first development target would be adenovirus infections
contracted after HSC transplantation, and that tests on children would be given
particular priority. Since Chimerix data had already confirmed safety, the first stepwould be Phase 2 dosing tests, after which, when trials on children had begun, adultDevelopment from Phase-2 dosing tests would start.
has already begun in the US
and UK
SymBio submitted an IND application for the BCV Phase-2 trials for adenovirus
infection after HSC transplantation to the US FDA on March 10, 2021 (registration
number NCT04706923). In addition, on April 26, the FDA gave fast track
After
fast-tracking
for examination status to development programs for pediatric adenovirus infections. On
children, Phase-2 for adults August 16, 2021, SymBio succeeded in registering its first patient (FPI) for Phase2 joint international trials of the anti-viral brincidofovir intravenous preparation
will commence in 2022
(BCV IV) for treatment of child adenovirus infections (AdV infections). In January2022, an application to conduct clinical trials was submitted in the UK. Firstly, four
The next phase is scheduled groups of six patients each will receive stepped increases in doses to test safety andto start in the first half of tolerance. The trials are scheduled for completion in the second half of 2022 or early20242023. Phase-2 trials targeting adults will also begin in 2022. If all goes according toplan, Phase-3 with several hundred participants will start in the first half of 2024, an
NDA will be submitted in 2026-2027, and product launch will occur in 2027-2028.
Reference: Number of HCT transplantations

It is estimated that worldwide there are some 78,000 HSC transplantations a year,of which around 43,000 are autologous (using the bone marrow of family
members) and therefore less subject to rejection. There are some 35,000
allogeneic transplants using the bone marrow of non-family donors with the same
white cell type, for whom immunoreactions need to be controlled to suppress
rejection, and which are highly vulnerable to viral infection. These are on the rise.
14/31
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.

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2022 June 08

Number of HCT transplantations

Source: SymBio results meeting, February 2020

② BK virus infections after kidney transplants
The second “blank space” is In addition to work on infections following hematopoietic stem cell transplants the
BK
viral
infections company is also planning to extend its efforts into viral infections at the time offollowing kidney transplants organ transplants. Organ transplants are more common in the West than in Japan.
For example, while some 1,600 kidney transplants are carried out annually in Japan,
20,000 are carried out in the US and around the same number in the five major
European countries. Of these, an estimated one-one-third contract the BK virus
infection and the CMV (cytomegalovirus) infection. While the number of infections
is a quite low 560 in Japan, in the US + 5 main countries of Europe the total is around
15,000 cases annually.
SymBio is scheduled to begin development in Australia, Japan and one other country
Phase-2
scheduledtoduring 2022. Apparently, for the Phase-2 dosage trials they are thinking of a scalecommence in Australia andsimilar in size to the adenovirus Phase-2 trials. The company plans to do the early
elsewhere in the first half oftrials itself, but the organ transplants are outside its area of expertise, and there are2022
not enough cases in Japan. For those reasons it is thinking seriously of partneringwith a European or US company to promote development and sales in the area oforgan transplants.
Development of targets forviral infections after organtransplantation needs to bepromoted with western
pharmaceutical companies
as partners

Potential market for SOT transplantations

Source: SymBio: Matters concerning business plans and growth potential

15/31
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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.

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SymBio Pharmaceuticals Ltd. （4582 Growth）

2022 June 08③ Development directed at malignant brain tumours (GBM)
The third “blank space” is Glioblastoma (GBM) is the most common malignant brain tumor and is an area ofmalignant brain tumours extremely high unmet needs, with a survival rate of only 15 to 20 months and a 5(glioblastoma)
year survival rate of 5% or less. It is known that about 50% of GBM patients are
CMV (cytomegalovirus) positive. Various drug therapies are these days being
developed for various conditions but there is no drug development candidate
In this area there is currently
targeting CMV.
no prospective drug forCMV (cytomegalovirus)

While the CMV-brain tumour mechanism is certainly not fully understood, researchusing a mouse model conducted at Brown University shows that CMV infection
enhances the NF-κB signal, leading to increased expression of PDGF-D, anangiogenetic factor, which promotes the growth of GBM cancer cells. It has also
been found that the antiviral agent cytomegalovirus (CDV) inhibits CMV
We now know that CMV
infection promotes the reactivation in CMV-infected mice and improves survival rates. （The Journal of
Clinical Investigation, 2019, Sean E Lawler et al.)growth of GBM
SymBio is now considering whether or not to develop BCV as a treatment for GBM
based on this and separate research. The mechanism of action of BCV against GBM
consists of BCV converting to CDV-PP in the cell. It has an antitumor effect that
BCV has an anti-tumour inhibits the replication cycle of tumor cells and induces apoptosis, with BCV
effect and is able to inhibiting the reactivation of CMV. It is thought to have the effect of suppressing
constrain the degree of malignancy that suppresses tumor growth. It is inferred that BCV’s malignancy
suppression has the effect of controlling tumour growth.
malignancy
SymBio is now doing joint research with California University on evaluating theanti-tumour potential of BCV. It is also working with Brown University to evaluate
Joint research now being BCV’s anti-tumour effectiveness and its tumour malignancy suppression effect. As
underaken
withthe soon as the data from this research is available a decision will be made on what the
University of California and next stage should be.
Brown University

The fourth ‘blank space’
involves the search for atherapyformultiplesclerosis④ Expansion into the field of neurovirology (multiple sclerosis)
The EC50 value of BCV against the Epstein-Barr virus (EB virus) is significantly
lower than that of other antiviral agents, and BCV is known to have extremely highantiviral activity against the EB virus. The EB virus is also known as humanherpesvirus 4, and 95% of adults get infected with it. It is almost entirely symptom
free and is inactive in lymphocyte B cells in a latent state. However, in some people
it is thought to cause blood cancers and other intractable diseases (such as
autoimmune diseases). In particular, there is a clinically clear association with someblood and pharyngeal cancers.

The EB virus is a neoplastic
virus and is attracting
attention as a cause ofmultiple sclerosis
SymBio in February 2022 announced it was considering making multiple sclerosis(MS), one type of autoimmune disease, a new target indication of BCV.

16/31
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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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2022 June 08

Reference: multiple sclerosis
For reasons which are unclear, lymphocytes attack and demyelinate the myelin that covers theaxons of nerve cells, preventing the smooth transmission of information to the nerves where
demyelination has occurred. This causes various neurological symptoms (motor disorders,visual disorders, sensory disorders, and urinary disorders.). It is an autoimmune disease withrepetitive recurrence and remission. Lesions occur throughout the brain, spinal cord, and optic
nerve, and relapse at intervals of one month or longer. It affects around 18,000 people in Japan,
but it is estimated there are about 3 million sufferers worldwide, mainly in Europe and theUnited States. There is no definitive cure. but steroidal pulse therapy to suppress inflammation
with steroids, and immunomodulators to suppress lymphocyte activity are used.

Source: Multiple sclerosis.jp

Epidemiological research
papers have been publishedpointing to a strong
connection between the EB
virus and MS

Transcription factors oflymphocytes(B
cells)
infected with the EB virus
are analogous in structure to
glia cell adhesion factors inthe brain

The mechanism by which the EB virus causes MS is not fully understood, but
epidemiological surveys have supported the association. A Harvard research teamanalyzed a sample of more than 10 million serving U.S. military personnel, andfound that 955 cases were diagnosed with MS during military service. Analysis ofthese 955 cases found that the risk of contracting MS after being infected with theEB virus was 32 was times higher than that of other viral infections.（Science,
January13 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 EB virus (Nature, January 24
2022: “Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and Glial
CAM”) According to this hypothesis, the EB virus transcription factor, EBNA1, andthe glial cell adhesion molecule, GlialCAM, in the brain are structurally similar,
leading the lymphocytes that produce autoantibodies which recognize both tomigrate to the center, accidentally damaging their own myelin, leading to the onsetof multiple sclerosis (MS).

Auto-antibodies that interact
with
the
EB
virus This hypothesis is supported by the effectiveness of blocking the transfer of
inadvertently damage nerve lymphocytes into the central nervous system (sphingosin 1 (SP1) phosphate receptor
axons
agonist) or blocking the of lymphocytes from the lymph nodes (anti-α4 integrin
antibody) and the effectiveness of molecular-targeted drugs such as the anti-CD20
BCV eliminates the EB antibody (ocrevus) in targeting B-cells. SymBio believes that if this mechanism isvirus, thus stimying progress correct, the progression of MS can be inhibited by promptly exterminating the EB
virus with BCV after the onset of MS. At present, the value of the market for multipleof the mutliple sclerosis
sclerosis treatments is thought to be JPY1.5 trillion, or JPY2 trillion if steroid
treatments are included. SymBio expects that BCV will be added as a concomitant
Considering now whether or drug with a new mechanism and is considering conducting applied research withnot to proceed
overseas experts on BCV in the field of neurological disorders. In the second half of2022 a decision will be made on business development.
The EB virus may also be a Further, SymBio is focusing on the possibility that the after-effects of the new
sequela of the coronavirus, coronavirus infection (long COVID symptoms: fatigue, brain fog, rash, etc.) may be
17/31
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2022 June 08

suggesting BCV may have a caused by the reactivation of the EB virus by an inflammatory reaction after COVID
wide range of applications in infection. In July 2021, Professor Gold of the World Health Organization noted in
the field of the cranial nerves The Journal of Pathogens that most patients with long COVID symptoms haveregistered positive for EB virus reactivation, versus only 10% in the control group.
SymBio has not decided whether or not to make long COVID a target of research,
but BCV has the potential to extend its application range beyond MS to the cranial
nerve area.
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, February 2022

18/31
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.

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SymBio Pharmaceuticals Ltd. （4582 Growth）

Rigosertib was developed
for MDS until suspended.
Now consideration is being
given to developing it withthe focus on other modes ofaction2022 June 08

3. Development of rigosertib (injection and oral formulations)
Rigosertib was first developed to treat myelodysplastic syndrome (MDS) but failed
to achieve its primary endpoint at international joint Phase-3 INSPIRE trials (August2020). Now, however, the focus is on its function as a RAS inhibitor, and its
development is being promoted as a cancer drug, particularly by the licensor,
Onconova Therapeutics.
Rigosertib mode of action

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-inhibiting action is thought to activate JNK and act on theRas / Raf / MEK / ERK pathway.

In September 2021 Onconova released interim results of the Phase-1 part of trials
Onconova focusing on the (Phase1/2a) of a therapy combining oral rigosertib and the anti-PD-1 antibody
RAS–inhibitory function
nivolumab (Opdivo®) for the treatment of non-small cell lung cancer (NSCLC) with
KRAS mutation.
The subjects were NSCLC patients with KRAS mutations and all had had at least
one experience of treatment with an anti-PD-1 antibody. For NSCLC patients, antiPD-1 antibodies such as Opdivo® are targeted at patients with a PD-L1 expression
ratio of 50% or higher. However, of the patients with a PD-L1 expression rate of
50% or more, only about 45% respond to the anti-PD-1 antibody. In other words,
even if selected for treatment with the anti-PD-1 antibody (Opdivo) by genetic
testing, it is ineffective as a first-line treatment in 55% of cases. There is clearly anunmet medical need here and an area of great competition between companies.
In terms of test results, of the 12 cases tested 2 had not yet reached the evaluation
stage, and 3 were terminated due to side-effects, leaving 7 patients who could be
evaluated. Of these, 2 showed a partial response (PR) and 1 showed stability of
disease (SD), making for a disease control rate of 43%. Looking at partial response
subjects, both KRAS G12C and KRAS G12V mutations were observed. No
unexpected serious side effects were observed.
KRAS mutations have been observed in about 20% of NSCLC cases, of which themost common (13%) is G12C mutation. The first KRAS inhibitor recognizedanywhere was the G12C mutation inhibitor, LUMAKRAS (generic name Sotorasib
19/31
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.

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SymBio Pharmaceuticals Ltd. （4582 Growth）

2022 June 08

from AMGEN, given expedited approval in May 2021). Also in the area of NSCLC,
progress is being made by the American company, Mirati Therapeutics, in thedevelopment of adagrasib, a KRAS (G12D) inhibitor, and work has begun on thedevelopment of a KRAS (G12D) inhibitor targeting pancreatic and other cancers.
However, AMGEN and Mirati’s medicines both bind with specific KRAS mutations
and act exclusively on them. On the other hand, rigosertib probably has multiple
action mechanisms, such as RAS signal inhibition and microtubule destabilisation
and, as described above, a response can be obtained regardless of the particular
SymBio now cooperating
KRAS mutation. Rigosertib is therefore considered to have the potential for wider
with academia on new
applications.
modes of action
SymBio has been cooperating with academia (Institute of Medical Science of the
The future direction will University of Tokyo, Gunma University) on research into novel modes of action of
become clear in the second rigosertib and Treakisym® (bendamustine) and will make a decision on where to go
half of 2022
from here in the second half of 2022.

Possibilities offered by therapies combining rigosertib and Treakisym®
(bendamustine)

Source: SymBio company briefing

20/31
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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.

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SymBio Pharmaceuticals Ltd. （4582 Growth）<Potential market for thecompany’s main
products>
For the three indications ofrelapsed/refractory indolentB-NHL, CLL and untreatedindolent-B-NHL, Treakisym
sales in 2021 came in at
JPY6.13 billion, and for r/r
DLBCL, JPY2.13 billion

If we count in increased
marketpenetrationof
untreatedfollicularlymphoma, which accounts
for approximately 80% of
untreated indolent-B-NHL,andincreased
marketpenetration of relapsed /refractory DLBCL, thenpeak sales should come in at
JPY12.3 billion (JPY15
billion on a regulated pricebasis)

2022 June 08

１． Potential market for Treakisym®
Here we look at the market size of SymBio products on the assumption that theeffect of patent problems is minor, and that the switch to 10-minute RI
administrations will blunt the impact of generics. The market for Treakisym® isexpected to grow mainly in those fields where clinical indications were expanded in
2021. Up to 2021 the areas that had been approved and sales begun were: ①
Relapsed/refractory indolent-B-cell NHL/MCL; ② Chronic lymphocytic leukemia(CLL); ➂ untreated indolent-B-cell NHL/MCL. The sales value (net basis) of
Treakisym® for indications ① to ➂ totaled JPY6.13 billion in 2021. We believethat in the areas ① and ② market penetration by Treakisym® has already beenachieved, but market penetration for untreated follicular lymphoma, which accounts
for 80% of untreated indolent-NHL, currently has a market penetration of only 50%.
Looking ahead, this is likely to rise to 75% in the future. We therefore see peak net
sales of JPY7.3 billion (regulated price basis: JPY8.7 billion). Further, sales ofTreakisym® for r/r DLBCL, which was approved as recently as March 2021, totaled
JPY2.13 billion (net basis) in 2021, and the current market penetration is estimatedat about 30%. SymBio is looking to secure a 60% market penetration in this segment
and expects it to be a main driver of market growth. Peak net sales could come to
JPY5 billion (and around JPY6 billion on a regulated price basis). Overall peak sales
should come in at JPY15 billion, or JPY12.3 billion on a net basis.
Number of Treakisym-indicated cases (annual)① r/r indolent-B-NHL② CLL③

1st-line indolent-B-NHL④ r/r DLBCL

around 9,000 casesaround 600 casesaround 6,000 casesaround 10,000 cases

Source: Fair Research Inc. using SymBio data

21/31
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.

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SymBio Pharmaceuticals Ltd. （4582 Growth）

2022 June 08

２． Potential market size for brincidofovir（BCV）
The number of potential
patients could be 2,000 for
disseminated AdV infection,
8,000 for BKV infection,and 30,000 for malignant
brain tumors

Here, we consider the market size for disseminated adenovirus infections after
hematopoietic stem cell transplantation, BK virus infections after kidneytransplantation, and malignant brain tumors (GBM). For these, SymBio has
indicated a policy of in-house development.
SymBio has estimated the following patient numbers: 2,000 for disseminatedadenovirus infections after hematopoietic stem cell transplantation; 8,000 for BKV
virus infections after kidney transplantation; and 30,000 for malignant brain
tumours. The total comes to around 40,000 patients.
Comparison of patient numbers for brincidofovir and maribavir
40,000 cases

Cancers:
CMV -brain
tumours

30,000SOT :BKV infections after
kidney transplantation

Assuming a cost per case of
JPY3 million: JPY300
billion for the two infections
alone, and JPY1.2 trillion
including malignant brain
tumours

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 Maribavir based on IR Material 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 Marrow Transplantation 2016, Bone Marrow 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 IR materials, February 2022

Assuming that the drug cost per case is JPY3 million by comparing with otherantiviral drugs, total sales is estimated at about JPY1.2 trillion. However, as of 2022,
limiting our estimate to diffused AdV following hematopoietic stem cell transplant,
now undergoing Phase-2 clinical trials, sales comes to JPY60 billion. For BKV
infections following liver transplants, expected to start Phase-2 clinical trials in thefirst half of 2022, sales of around JPY240 billion is expected. As of 2022, JPY300
billion of the market is still subject to Phase-2 trials.
In passing, according to Takeda Pharmaceutical, the maribavir market has a valueof USD700-800 million (JPY840-960 billon, assuming JPY120/USD).

22/31
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.

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SymBio Pharmaceuticals Ltd. （4582 Growth）

Calculation based on
number of suppositions

2022 June 08

Reference: modeling value of the product pipelinea We here estimate (using the DCF method) the value of the Treakisym® andbrincidofovir pipelines. In view of the fact the company is now profitable we set a
discount rate of 8%.

The discount rate was set at ① Treakisym® assumptions
8% to reflect the company’s In line with our earlier comments, we assume that peak sales will occur in the fourth
emergence into profitability year after market launch and will maintain that level for the next 3-4 years, before
shrinking at 5% per year and, from 2031, shrinking rapidly at 10% per year.
We have set the Treakisym®
cost ratio at 20%
From 2021 Treakisym® sales channels moved in-house, and should in subsequent
years be moved almost entirely to the liquid RTD formulation. Liquid formulations
will have, we assume, a cost advantage over the conventional formulations. After
Annualselling
costs
switching, we assume the cost ratio, including the payment of royalties to Eagle,
assumption JPY2 billion
should be in the area of 20%. We assume milestones of JPY550 million will bepayable in each of 2023 and 2024, and annual sales costs we assume will come toaround JPY2 billion② Brincidofovir assumptions
There are a lot of
Making estimates concerning brincidofovir (BCV) are complicated by the number
uncertainties
affectingof uncertainties. We therefore restrict our calculation to disseminated AdV infections
calculation of the BCV
following hematopoietic cell transplants, currently in Phase-2, and BKV infections
pipeline value
following liver transplants. As noted earlier we are assuming market sizes of,respectively, JPY60 billion and JPY240 billion. In terms of the development
Target diseases are limited to schedule, the disseminated AdV treatment is slightly ahead, with Phase-2 expected
the above-mentioned AdV to occur by 2023, and Phase-3, embracing 400 people, occurring between 2024 andand BKV infections. Launch 2027. We are assuming an NDA submission will be made in 2027 and market launchdates are assumed to be 2028 we anticipate will occur in 2028. For the BKV infections, Phase-2 trials we expect
and 2030, respectively
to begin in 2022 for completion in 2024. Phase-3 (1,200 subjects), we anticipate will
last from 2025 to 2028 with submission of an NDA in 2029 and market launch in2030.
Weassumeroyalty
payments to Chimerix ofUnder the licensing-in contract with Chimerix Inc., SymBio is to pay Chimerix
12%
milestones of USD180 million (including the USD5 million contractual lump sum)and royalties. It has been revealed that the royalties rate will be a two-digitWeareassuming percentage. In the pipeline calculation we assume 12%. Meanwhile, in the case ofdevelopment of AdV will be disseminated AdV infections, SymBio will go it alone until Phase-3, after which it
done in-house up to Phase-3, will license out development and sales rights to a global pharma. With respect toand BKV will be developed BKV infections, after establishing POC (after completing Phase-2) there will be awith a partner from Phase-3. licensing-out. It may be that the development costs of Phase-3 will be shared. We
SymBio’sshareof assume that SymBio’s share of development costs (Phases 2 and 3) will be JPY8developmentcosts
we billon for disseminated AdV infections and JPY13 billion for BKV infections. The
assume will be JPY8 billion milestone associated with the licensing-out is assumed to be JPY25 billion, which
and
JPY13
billion is a quarter of peak sales, and 50% of sales will be received as gross profit. Since
respectively
the effectiveness of BCV in humans has already been established we have set
probability of success at 60-80%.
We assume the milestone
receivable from the sales In addition to existing drugs there will be annually recurring basic R&D costs tolicensee will be one quarter fund the search for new drug candidates and costs associated with company-wide
administration. We assume the former at JPY600 million and the latter at JPY1.6
of peak sales
billion, for a total of JPY2.2 billion.

Treakisym® value JPY55.2
billion (before tax)

③ Results of calculation
The results of our discounted present value calculations using the above suppositions
are shown in the table below. Using a discount rate of 8%, we posit a value before
tax of JPY55.2 billion for Treakisym®. The value calculation for BCV is
23/31

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.

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SymBio Pharmaceuticals Ltd. （4582 Growth）

2022 June 08

complicated but on the basis of various assumptions and given a 60% probability ofsuccess we posit a value of JPY26.7 billion. The combined value of Treakisym®
The value of BCV isand BCV therefore comes to JPY81.9 billion. Deducting company-wide costs
JPY26.7-42.7 billion after
produces a pipeline value (before tax) of JPY54.4 billion.
taking probability of successinto consideration
Pipeline value calculations (before tax)

Value at the JPY50 billon
level
after
deductingcompany costs

Prob. of success 100%

Prob. of success 80%(100 mil.JPY)
Prob. of success 60%

---

---

Treakisym®

552

BCV (AdV+BKV alone)

571

427

267

Sub-total

1,123

979

819

-275
-275
-275
Expanding into the area of Company costs
Total
704
544
848
malignant brain tumours andcranialnerveswould
produce an even higher Source: calculations by Fair Research Inc.
value
Note: Please note that pipeline value and market value are not directly comparable

Although not included in the above calculations, pipeline value would be higher iffurther indications for brincidofovir (malignant brain tumors, multiple sclerosis,etc.) and rigosertib were included

24/31
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.

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SymBio Pharmaceuticals Ltd. （4582 Growth）<Earnings andmanagement plan>
Turned profitable in 2021

Sales revenue in 2021 rose
because of in-house sales
andexpandedclinicalindications.
However,
expectations for the year not
met due to the effect of
COVID-19 on inventories

2022 June 08

Sales of products and income from licenses are the sources of SymBio’s earnings.
Apart from the period ending December 2008, when it received a lump sum forlicensing out Treakisym® sole domestic sales rights to Eisai and went into the black,it had always operated at a loss. However, when it brought the sales function inhouse in 2021 it again turned profitable.
1. 2021 results
Revenues in the 12/2021 year came to JPY8,256 million, a big increase on previous
years. Until the previous year the company had been wholesaling through Eisai butfrom 2021 this function came in house. Nevertheless, COVID-19 caused
postponements and delays to treatment (around JPY400 million foregone), andbecause of absorbing the Eisai inventories which had built up in the market (JPY450
million foregone), sales failed to reach the JPY9,151 million originally projected. In
addition, the cost ratio improved significantly from the previous year (71.0%) to29.7% due to self-sale, but the switch from the FD formulation to the RTD
formulation caused an inventory valuation loss from the FD formulation of JPY330
million. Also, due to the delayed switch to the RTD formulation, the improvementin the cost ratio was reduced by about 5.7 percentage points from initialexpectations.

Big improvement in the cost
ratio. However, due to theswitch to the liquid
formulation an inventory
Revenues and financial structureevaluation loss was made on
the FD product, and bcause
2015
2016
2017
the switch was later than
expected the improvement Sales
1,933
2,368
3,444
of goods
1,933
2,137
3,444
was narrower than originally Sale
License income
0231
0
projected
Cost of sales
1,483
1,737
2,413

(JPY-mil）
2018

2019

2020

2021

3,835
3,809
25

2,838
2,811
27

2,987
2,977
10

8,256
8,256
0

Initial plan
9,151
9,151
0
2,194

Actual

2,662

1,973

2,120

2,456

Rate

76.7%

73.3%

70.1%

69.4%

69.5%

71.0%

29.7%

24.0%

SG&A
of which, R&D

3,135
2,035
1,100

3,031
1,667
1,364

4,978
3,017
1,961

3,828
1,832
1,996

5,166
2,442
2,724

5,373
2,266
3,107

4,784
1,736
3,048

5,596
2,019
3,577

Op. profit-2,552-2,127-3,947-2,656-4,302-4,506

1,016

1,361

Rec.profit-2,630-2,317-3,976-2,748-4,377-4,615

1,001

1,350

Pre-tax profit-2,628-2,309-3,974-2,748-4,372-4,086

Net profit-2,632-2,313-3,978-2,752-4,376-4,090

2,302

1,149

Current assetsof which, cash etc.
Fixed assets
Current liabs
Fixed liabs
of which, debt
Net assetsof which, shareholders equityof which, stock acquisition rights

4,827
4,261
158
551
2
0
4,432
4,132
300

6,685
5,719
193
942
451
450
5,485
5,054
431

4,037
2,947
216
1,011
1
0
3,239
2,702
537

6,038
4,821
200
1,336
1
0
4,901
4,372
530

4,887
3,910
386
872
1
0
4,400
3,779
620

5,815
3,848
459
1,615
2
0
4,657
4,037
620

6,747
3,860
1,705
1,518
189
0
6,745
6,226
519

Income from issue and exercise ofstock acquisition rights

0

687

1,178

4,301

3,771

4,244

0

Income from issue of CB's

0

3,000

0

0

0

0

くexcl. R&D>

(Ref)

Event
Cost ofIONSYS
licensing in

Cost of BCV
licensing in
Cost of liquid
Treakisym
licensing in

In-house sales
structure0In-house sales start
Formulation change improved cost of goods

RTD milestone Loss on FD inventory
In-house sales
Receipt of court
structure
Deferred tax capitalisedaward

Source: Compiled by Fair Research Inc. from securities report filings

Research and development spending in 2021 stood at JPY1,736 million, below the
Increased efficiency of R&D
2020 level of JPY2,424 million. 2020 spending includes the milestone payment
activities help reduce R&D(around JPY500 million) made in respect of the RTD formulation’s approval.
costs
Adjusting for this leaves a decrease of about JPY200 million. It is inferred that thisis the result of promoting the efficiency of R & D activities due to the increase in
The arrival of profitability expenses associated with the establishment of an in-house sales system. Non-R&D
means the availabilty of sales and administration expenditure in 2021 came to JPY3,048 million, about thedeferred tax assets and a same level as the previous year. As a result, operating income came in at JPY1,016
25/31This 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.

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SymBio Pharmaceuticals Ltd. （4582 Growth）
steep rise in net profits

2022 June 08

million. In addition, as the company had made a profit it was able to activate
JPY1,270 million in deferred tax assets, boosting net income to JPY2,032 million.
Quarterly sales and outlook

Cash reserves stay at the
JPY3.8 billion level

Source: SymBio “Matters concerning the business plan and growth potential”
Note: Actual sales was JPY2,315 million in the first quarter of 2022, in line withexpectations

Reflecting the arrival of profitability at the company, net assets at the end of 2021
rose JPY2.08 billion and cash maintained the JPY3.8 billion level.

2. 2022 outlook
We are assuming that sales in 2022 will rise 33.1% on a YoY basis to JPY10.992
billion, driven by the expansion of approved indications in March 2020 to include
r/r DLBCL. The cost ratio is expected to fall to 20% in anticipation of the completionof switching to the liquid formulation (RTD/RI), and gross profits will reach 80%.
Regulated prices for generics are due to be posted in June 2022 but any effect will
not be apparent until late in the second half. SymBio is not changing its forecast forWith the switch to liquid 2022 sales.
formulations
complete,further improvement in the Elsewhere, SG&A expenses are scheduled to come in at JPY7,026 million, an
cost ratio
increase of JPY2,241 million on the previous year. Of this, an expected JPY3,056
million is for R&D, an increase of JPY1,319 million. This is mainly due to a
Any impact from generics ballooning of BCV-related outlays, including the start of BK virus clinical trials inwill not be felt until the Australia in the second quarter of 2022. All the same, the expectation is for operating
revenues to hit JPY1,770 million, an increase of 74.2%. The operating profit margin
second halfshould come in at 16.1%.
While there will be asignificant increase in R&D
outlays due to the full-scale
In 2022, sales are expected
to increase by 33.1%, driven
by such factors as continued
growth in demand in the
DLBCL. segment

26/31
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.

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SymBio Pharmaceuticals Ltd. （4582 Growth）
development of BCV, thecompany can still manage a
74.2% increase in profits

2022 June 08

2022 outlook (management plan)(JPY-mil)

2021

2022

2022-１Q(Actual）(Forecast）(Actual)Sales
Gross sales profits
Margin
SG&A

8,256
5,800
70.3%
4,784

10,992
8,796
80.0%
7,026

2,315
1,898
82.0%
1,388

of which, R&D

1,736

3,056

469

（BCV-related）
Op. profit
Op. profit margin
Rec. profit
Net profit

408

1,269

NA

1,016

1,770

509

12.3%

16.1%

22.0%

1,016
2,032

1,750
1,480

478
163

Source: Compiled by Fair Research Inc using SymBio medium-term management
plan and security report filings
Reference: Committed line of credit (upper limit JPY3 billion) extended from
December 2020 to March 2022

Company evolves fromfinancing that relies solely
on equity finance: working
capital to be sourced frombank borrowing

The company has normally relied on equity finance in the form of new share
warrant issues to secure corporate funds. In December 2020, however, with theprospect of turning profitable, the company concluded committed line of credit
contracts (upper limit JPY3 billion) with two banks. It intends from now on toborrow cash to cover operational requirements. In March 2022, the contracts
were rolled over with a new upper limit of JPY3.15 billion.
Reference： First quarter 2022 results
In the Q1/2022 results released on May 12 2022, sales came in at JPY2.315
billion, roughly in line with expectations. The formulation change seems to beproceeding smoothly with the RTD formulation accounting for in excess of 99%
of sales as of March end, 2022. As a result of the formulation switch and of theswitch to in-house sales the gross profit margin came in at 82%. Then, despite
boosting SG&A expenses by 13.8% YoY, operating revenues totaled JPY509
million. It also appears that, as of the end of April, more than 93% of medical
institutions were on the way to switching to the RI formulation.

3. New source of capital – Heights Capital Management Inc makes aninvestment approach
The company received an
approach from an investor
whose selection strategy
involves
cultivating
investment targets after firstdeveloping good relations

The company plans to raisea total of JPY2.19 billion for
BCV development, theacquisition of new licenses,
and M&A

On May 16, 2022 SymBio announced a new JPY2.19 billion fund raising. The
methodology chosen was the issue of 1 million new shares and the equivalent of 2
million shares in new share subscription rights, both to be placed in a third-party
allotment to CVI Investments Inc, managed by Heights Investment CapitalManagement Inc. Heights is part of the Susquehanna International Group, which
has a track record of over a hundred investments in biotech, including in Japan, andwhose investment approach involves developing long term relations with potential
investment targets.
Heights made contact with SymBio around October 2021 and, after subsequentconsideration, SymBio judged Heights could be a long-term equity partner well
positioned to help accelerate future growth. Judging there would be little risk of adownside effect on the stock price, it accepted an investment proposal. The exercise
price for the new share options is set at JPY785 (no adjustment clause) and an
exercise period of five years from June 2, 2022 to June 1, 2027. The new shares werepriced at JPY662 on issue.
27/31This 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.

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SymBio Pharmaceuticals Ltd. （4582 Growth）

2022 June 08

As for uses of funds, a total of JPY1,785 million is allocated to BCV development,with JPY1,219 million going into direct spending, and JPY576 million into indirect.
In addition, the company plans to spend around JPY395 million on the acquisitionof new licenses, M&A and other investment activities. It is possible these will bedirected at new products in the area of SymBio’s specialization, haematologicalcancers.

A financing to put future growth on solid foundations(JPY-mil)Funds raised by issue
Expenditure period Totaland exercise of warrants

Funds raised by new share issue

Expenditure period

Dev. funds for the antiviral drug, BCV direct expenditures

432.002022/7～2022/10

787.00 2022/10～2023/3

1,219.00

Dev. funds for the antiviral drug, BCV indirect expenditures

190.002022/7～2022/10

386.00 2022/10～2023/3

576.00395.76395.76

Funds for new license acquisitions
and M&A to secure long-term growth

Total

-

622.001,568.76

2022/7～2023/3

2,190.76

Source: SymBio notification on May 16, 2022 concerning the third party allotment of
new shares and the issue of No.58 new share subscription rights

28/31
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.

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SymBio Pharmaceuticals Ltd. （4582 Growth）

2022 June 08

SymBio in 2020 built an in-house sales structure and acquired brincidofovir, thereby
laying the groundwork for the company’s growth as a haematology-specialised
pharma with a global license. Then, in 2021 it expanded the diseases for which its
For the time being the main product, Treakisym®, was indicated to r/r DLBCL, and since 2021 its finances
company will retain strong have moved firmly into the black. We believe that until sales peak, Treakisym® will
earnings growth momentum retain strong profit growth momentum, reflecting the product’s high profit margin.
Conclusions

Meanwhile, the develomentofbrincidofovir
willproceed and the company
will evolve from a pharma
specialising in haematology
to one embracing tumours
and cranial nerve ailments

Looking ahead, even when Treakisym® reaches peak sales and profit growth flattens
out, the company can expand the number of products in its blood field specialism
and target viral infections after hematopoietic stem cell transplantation and kidneytransplantation. Thus, regulatory approval and the launch of brincidofovir (BCV)
will emerge as the next growth driver. Further, even as the RI formulation patent
expires in 2031 the development area of brincidofovir will be expanding to areas of
oncology, such as malignant brain tumours, and in the neurological disease field,
such areas as multiple sclerosis. Thus, further expansion of business value willremain possible.
Brincidofovir development will soon start in earnest and there is a possibility thatearnings growth momentum will slow down. However, the receipt of investment
funds from Heights Capital Management will not only support the promotion of
BCV development but will provide the funds necessary for the company’s
acquisition of new licenses. That investment, then, further strengthens thefoundation for future and more rapid growth.
The business value of the pipelines is about JPY55.2 billion (before tax) for
Treakisym® alone, and JPY26.7-42.7 billon for brincidofovir in the field ofdisseminated AdV infection after hematopoietic stem cell transplantation and BKV
infection after kidney transplantation. However, the value is immeasurable if we
consider the expansion of indications to malignant brain tumours and multiple
sclerosis.

Source: SymBio company briefing, February 2022

29/31
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.

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SymBio Pharmaceuticals Ltd. （4582 Growth）

2022 June 08

Fair Research Inc
BIZ SMART Kayabacho, Shinkawa 1-3-21
Chuo-ku
Tokyo 104-0033
Email: info@fair-research-inst.jp

30/31This 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.

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SymBio Pharmaceuticals Ltd. （4582 Growth）

2022 June 08

Disclaimer□This report is prepared by Fair Research Inc. ("Fair Research") for the purpose of providing information toinvestors for fees under a contract with a covered company, and not for solicitation of securities trading.
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is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Also, views and forecasts set forthin the report represent judgment by Fair Research at the time of issue of the report, and may be changed without
notice.
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31/31
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.

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