SymBio Pharmaceuticals / 4582
COVERAGE INITIATED ON:

2014.10.31

LAST UPDATE:

2021.06.16

Shared Research Inc. has produced this report by request from the company discussed in the report. The aim is toprovide an “owner’s manual” to investors. We at Shared Research Inc. make every effort to provide an accurate,
objective, and neutral analysis. In order to highlight any biases, we clearly attribute our data and findings. We will
always present opinions from company management as such. Our views are ours where stated. We do not try toconvince or influence, only inform. We appreciate your suggestions and feedback. Write to us at
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Coverage

SymBio Pharmaceuticals / 4582
LAST UPDATE: 2021.06.16

Research Coverage Report by Shared Research Inc. | www.sharedresearch.jp

INDEX
How to read a Shared Research report: This report begins with the trends and outlook section, which discusses the company’s most recent
earnings. First-time readers should start at the business section later in the report.

Executive summary ----------------------------------------------------------------------------------------------------------------------------------- 3
Key financial data ------------------------------------------------------------------------------------------------------------------------------------- 5
Recent updates ---------------------------------------------------------------------------------------------------------------------------------------- 6
Highlights ------------------------------------------------------------------------------------------------------------------------------------------------------------6
Trends and outlook -----------------------------------------------------------------------------------------------------------------------------------------------9
Business ------------------------------------------------------------------------------------------------------------------------------------------------ 19
Business description -------------------------------------------------------------------------------------------------------------------------------------------- 19
Business strategy ------------------------------------------------------------------------------------------------------------------------------------------------ 22
Pipeline ------------------------------------------------------------------------------------------------------------------------------------------------------------- 25
Earnings structure ----------------------------------------------------------------------------------------------------------------------------------------------- 37
Strengths and weaknesses------------------------------------------------------------------------------------------------------------------------------------ 39
Market and value chain---------------------------------------------------------------------------------------------------------------------------- 40
Market overview ------------------------------------------------------------------------------------------------------------------------------------------------- 40
Historical performance ---------------------------------------------------------------------------------------------------------------------------- 43
Income statement ----------------------------------------------------------------------------------------------------------------------------------------------- 61
Balance sheet ----------------------------------------------------------------------------------------------------------------------------------------------------- 62
Cash flow statement -------------------------------------------------------------------------------------------------------------------------------------------- 63
Other information ---------------------------------------------------------------------------------------------------------------------------------- 64
History -------------------------------------------------------------------------------------------------------------------------------------------------------------- 64
News and topics ------------------------------------------------------------------------------------------------------------------------------------------------- 66
Major shareholders --------------------------------------------------------------------------------------------------------------------------------------------- 71
Top management ----------------------------------------------------------------------------------------------------------------------------------------------- 71
Employees --------------------------------------------------------------------------------------------------------------------------------------------------------- 71
Other ---------------------------------------------------------------------------------------------------------------------------------------------------------------- 73
Company profile ------------------------------------------------------------------------------------------------------------------------------------------------- 76

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Coverage

SymBio Pharmaceuticals / 4582
LAST UPDATE: 2021.06.16

Research Coverage Report by Shared Research Inc. | www.sharedresearch.jp

Executive summary
SymBio in-licenses drugs for development and sale
◤ SymBio Pharmaceuticals Ltd. is a specialty pharmaceutical company that buys the right to develop and commercialize drugcandidates, conducts clinical trials, and obtains manufacture and marketing approval in order to address the underserved
medical needs of patients. With its main focus on the areas of oncology, hematology, and rare diseases, the company typicallyseeks in-licensing opportunities for niche markets from pharmaceutical and biotech companies based in the US or EU.
◤ Notably, the company does not conduct basic research and outsources preclinical/clinical development, employing a fablessin-licensing approach. Using its proprietary in-house “search engine,” the company identifies, assesses and in-licenses only
quality drug candidates having proof-of-concept established in human subjects. The company first screens third-party drugcandidates being tested in clinical trials, then presents the in-licensing opportunities to its Scientific Advisory Board for further
assessment of the science behind each molecule, preclinical/clinical data, target market, and the feasibility of receiving
marketing approval from Japanese regulatory authorities.
◤ According to the company, the typical development timeline of an oncology drug in Japan from preclinical studies tomarketing approval is about 10 to 17 years. However, the company secured marketing approval for its first oncology drug
under development in Japan, Treakisym®, in only five years after in-licensing the drug. Within three years of its launch,
Treakisym® captured more than 50% of the non-Hodgkin’s lymphoma (NHL) and mantle cell lymphoma (MCL) market in
Japan.
◤ As of February 2021, the company had obtained approval for and launched Treakisym® (anticancer agent for hematologic

malignancies) for the indications of relapsed or refractory low-grade NHL and MCL, untreated (first-line treatment) andrelapsed or refractory low-grade NHL and MCL, and chronic lymphocytic leukemia (CLL). Treakisym® is listed in the Practical
Guidelines for Hematological Malignancies 2018 edited and published by Japanese Society of Hematology as the standard
treatment for relapsed or refractory low-grade B-cell NHL, MCL, and CLL, and as first-line treatment for low-grade NHL.
◤ The company obtained manufacturing and marketing approval for the ready-to-dilute (RTD) liquid formulation of Treakisym®

and began sales in January 2021. Unlike the lyophilized (freeze-dried [FD]) powder formulation of Treakisym®, the RTD
formulation eliminates the need for troublesome manual dissolution, thereby reducing burdens placed on medical personnel.
The re-examination term for the lyophilized formulation of Treakisym® ends in 2020, but by launching the RTD formulation towhich SymBio has exclusive rights, the company can extend the product life cycle of Treakisym® until 2031.
◤ Drugs in the development pipeline include Treakisym® for the indication of relapsed or refractory diffuse large B-cell

lymphoma (DLBCL), rapid infusion (RI) liquid formulation of Treakisym®, rigosertib (anticancer agent for myelodysplastic
syndromes) IV and oral formulations, and the antiviral drug brincidofovir. With regard to Treakisym® indicated for refractory or
relapsed DLBCL, in March 2021 the company obtained approval for the combination therapies of Treakisym® with rituximab,
and with rituximab and polatuzumab vedotin.

Earnings◤ FY12/20 sales were JPY3.0bn (+5.3% YoY). Product sales totaled JPY3.0bn (+5.9% YoY) and royalty revenue totaled JPY10mn(JPY26mn in FY12/19). The operating loss totaled JPY4.5bn (operating loss of JPY4.3bn). The company also reported arecurring loss of JPY4.6bn (recurring loss of JPY4.4bn) and a net loss of JPY4.1bn (net loss of JPY4.4bn).
◤ The company’s FY12/21 forecast calls for sales of JPY9.2bn (+206.4% YoY), operating profit of JPY1.4bn (operating loss of

JPY4.5bn in FY12/20), recurring profit of JPY1.4bn (recurring loss of JPY4.6bn), and net income of JPY1.1bn (net loss of
JPY4.1bn). The company expects increased product sales in Japan due to the move to sell Treakisym® in-house, and to turnprofitable at all levels on the back of sales growth and improved profit margins.
◤ In its medium-term plan (FY12/21–FY12/23), with the aims of achieving sales growth and higher profit margins, SymBio

projects sales of JPY12.4bn and net income of JPY1.8bn in FY12/23. The company expects higher sales from increased market
penetration of Treakisym® for approved indications, as well as anticipated approval of additional indication of Treakisym® forrelapsed or refractory DLBCL.

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SymBio Pharmaceuticals / 4582
LAST UPDATE: 2021.06.16

Research Coverage Report by Shared Research Inc. | www.sharedresearch.jp◤ SymBio aims to turn profitable in FY12/21. To this end, the company intends to build its own sales structure, obtain approval

for and switch to Treakisym® liquid formulations, and obtain approval for the additional indication of Treakisym® for relapsed
or refractory DLBCL. Shared Research understands that the first two of these measures (own sales structure andapproval/switch to Treakisym® liquid formulations) are key to improvement in gross profit and GPM, which in turn will help
the company achieve profitability in FY12/21. As of February 2021, the company was on track to moving into the black,having established its own sales structure and commenced sales of Treakisym® liquid formulations. SymBio also filed forapproval of the additional indication of Treakisym® for relapsed or refractory DLBCL in May 2020.

Strengths and weaknesses
Shared Research thinks SymBio’s strengths include its unique drug candidate selection process, strong product development
team, and business strategy focusing on niche markets. Weaknesses include its dependence on a single individual and product(see Strengths and weaknesses).

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SymBio Pharmaceuticals / 4582
LAST UPDATE: 2021.06.16

Research Coverage Report by Shared Research Inc. | www.sharedresearch.jp

Key financial data
Income statement(JPYmn)Sales

FY12/11Par.
1,883

FY12/12Par.
1,955

FY12/13Par.
1,532

FY12/14Par.
1,955

FY12/15Par.
1,933

FY12/16Par.
2,368

FY12/17Par.
3,444

FY12/18
Par.
3,836

FY12/19
Par.
2,838

FY12/20Par.
2,987

FY12/21Est.
9,151
206.4%

YoY

29.8%

3.9%

-21.6%

27.6%

-1.1%

22.5%

45.4%

11.4%

-26.0%

5.3%

Gross profit

658

593

318

527

583

904

1,031

1,173

865

867

YoY
GPM

-45.7%
35.0%

-9.9%
30.3%

-46.4%
20.8%

65.6%
26.9%

10.7%
30.2%

55.1%
38.2%

14.1%
29.9%

13.7%
30.6%

-26.3%
30.5%

0.2%
29.0%

-2,067-1,700-1,681-1,303-2,552-2,127-3,947-2,656-4,302-4,506

-

-

-

-

-

-

-

-

-

-

14.9%

-2,095-1,729-1,601-1,110-2,630-2,317-3,977-2,749-4,377-4,616

1,350

YoY

-

-

-

-

-

-

-

-

-

-

-

RPM

-

-

-

-

-

-

-

-

-

-

14.8%

1,149

Operating profit
YoY
OPM

Recurring profit

Net income

1,361-2,105-1,733-1,605-1,116-2,632-2,313-3,978-2,753-4,376-4,090

YoY

-

-

-

-

-

-

-

-

-

-

-

Net margin

-

-

-

-

-

-

-

-

-

-

12.6%

19,131-574.4
1,381.1

19,131-362.4
1,018.8

30,634-277.2957.9

30,634-145.0835.2

32,391-325.0510.2

46,531-235.3434.4

54,049-319.1200.0

20,560-165.5212.2

26,438-189.0143.1

38,203-124.1
105.8

6,511
7,178
17
48
13
7,256
309
646
5
651
6,606

4,840
5,421
14
57
11
5,502
330
599
4
602
4,900

7,264
7,634
9
37
8
7,687
251
3
254
7,433

6,591
7,290
49
49
66
7,454
306
488
2
490
6,964

4,261
4,827
53
53
52
4,984
320
551
2
552
4,432

5,719
6,685
75
77
42
6,878
322
942
451
1,394
5,485

2,947
4,037
47
100
69
4,252
604
1,011
1
1,013
3,239

4,821
6,038
57
73
71
6,239
726
1,336
1
1,338
4,902

3,911
4,887
75
70
241
5,274
121
872
2
874
4,400

3,849
5,815
77
81
302
6,275
665
1,615
2
1,617
4,657

-

-

-

-

-

-

-

-

-

-

-2,074-117
4,611-1,659-411-1-1,677-1,332
4,057-1,266314
544-2,272
1,489-3-1,960-44
3,658-3,817-78
1,164-2,325-26
4,272-4,351-216
3,740-4,122
-160
4,222

#REF!
-39.4%
91.0%-27.2%-30.2%
89.1%-24.3%-26.3%
96.7%-14.7%-15.8%
93.4%-42.3%-48.3%
88.9%-39.0%-50.4%
79.7%-71.5%-102.6%76.2%-52.5%-77.8%
78.6%-76.0%-107.4%83.4%-70.8%-104.7%74.2%

Per share data (JPY)
Shares issued (year-end; '000)
EPS
EPS (fully diluted)
Dividend per share
Book value per share
Balance sheet (JPYmn)
Cash and cash equivalents
Total current assets
Tangible fixed assets
Investments and other assets
Intangible fixed assets
Total assets
Accounts payable
Short-term debt
Total current liabilities
Long-term debt
Total fixed liabilities
Total liabilities
Net assets
Total interest-bearing debt
Statement of cash flows (JPYmn)
Cash flows from operating activities
Cash flows from investing activities
Cash flows from financing activities
Financial ratios
ROA (RP-based)
ROE
Equity ratio

30.1-

Source: Shared Research based on company data
Note: Figures may differ from company materials due to differences in rounding methods.
Note: The company conducted a four-to-one reverse stock split in July 2019. Earnings per share in the FY12/19 earnings forecast reflects the effect of the reverse stock
split.

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Coverage

SymBio Pharmaceuticals / 4582
LAST UPDATE: 2021.06.16

Research Coverage Report by Shared Research Inc. | www.sharedresearch.jp

Recent updates
Highlights
On June 16, 2021, Shared Research updated the report following interviews with SymBio Pharmaceuticals Ltd.

On June 7, 2021, the company announced that Chimerix, Inc. obtained FDA approval of brincidofovir as a medical
countermeasure for the treatment of smallpox.
Chimerix announced in its press release dated June 4, 2021 that FDA approved brincidofovir (generic name; BCV) tablets and oralsuspensions, antiviral formulations for the treatment of smallpox for adult and pediatric patients including neonates.
As part of bioterrorism countermeasures, Chimerix developed oral BCV formulations as medical countermeasures for thetreatment of smallpox, with continued funding and support from the Biomedical Advanced Research and Development Authority(BARDA) within the U.S. Department of Health and Human Services (HHS). With this FDA approval, Chimerix intends to proceedwith negotiations with BARDA toward a procurement agreement to support national preparedness.
SymBio obtained global exclusive development, manufacturing, and marketing rights for BCV from Chimerix in September 2019
regarding all indications except for the prevention and treatment of smallpox. Global development of BCV intravenous injectionis underway in patients with adenovirus (AdV) infections developed after hematopoietic stem cell transplantation.

On May 19, 2021, the company announced that polatuzumab vedotin has been added to the NHI drug price list.
Chugai Pharmaceutical Co., Ltd. announced that its genetically engineered polatuzumab vedotin indicated for the treatment ofrelapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) has been added to the NHI drug price list and that it beganselling the drug. Accordingly, Treakisym® can now be used in the combination therapy of genetically engineered polatuzumab
vedotin, bendamustine, and genetically engineered rituximab (the combination therapy of the latter two also referred to as BR
therapy).

On May 13, 2021, the company announced earnings results for Q1 FY12/21; see the results section for details.

On May 10, 2021, the company announced that it has filed for approval of the rapid infusion (RI) method for Treakisym®
intravenous formulation.
The company has submitted an application for partial change to the approved matters of Treakisym® ready-to-dilute (RTD)
intravenous formulation 100mg/4ml to allow its use with the rapid infusion (RI) method.

On April 28, 2021, the company announced that it has obtained approval for the use of Treakisym® RTD liquid formulation in
combination with rituximab and polatuzumab vedotin as treatment for r/r DLBCL.
The company has obtained approval of a partial change to the approved matters of its anticancer agent Treakisym®
ready-to-dilute (RTD) intravenous formulation (non-proprietary name: bendamustine hydrochloride) pertaining to the drug’s
efficacy/effectiveness, administration, and additional dosage (90mg/sqm of bendamustine hydrochloride) for use in combination
with genetically engineered rituximab and genetically engineered polatuzumab vedotin (“Pola-BR therapy”) as treatment for
relapsed or refractory diffuse large B-cell lymphoma (“r/r DLBCL”).

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SymBio Pharmaceuticals / 4582
LAST UPDATE: 2021.06.16

Research Coverage Report by Shared Research Inc. | www.sharedresearch.jp

On the same day, the company announced that it has obtained approval for the use of Treakisym® RTD liquid formulation in
combination with rituximab as treatment for r/r DLBCL.
The company has obtained approval of a partial change to the approved matters of its anticancer agent Treakisym®
ready-to-dilute (RTD) intravenous formulation (non-proprietary name: bendamustine hydrochloride) pertaining to the drug’s
efficacy/effectiveness, administration, and additional dosage (120mg/sqm of bendamustine hydrochloride) for use incombination with rituximab (“BR therapy”) as treatment for r/r DLBCL.

On April 26, 2021, the company announced that the US Food and Drug Administration has granted fast track designation to
intravenous formulation of antiviral agent brincidofovir.
The company announced that it has received fast track designation from the US Food and Drug Administration (FDA) for its
development program for intravenous formulation of antiviral agent brincidofovir (BCV IV) for the treatment of adenovirus (AdV)
infections in pediatric patients.
The FDA’s fast track designation is a process intended to expedite the review of new drugs that are expected to be effective intreating serious or potentially life-threatening diseases as well as diseases with high unmet medical needs, with the goal ofaccelerating the process from development to review. Receiving this designation provides more opportunities for consultation
with the FDA including clinical trial consultations, and if clinical trials show positive efficacy and safety results, accelerated
approval through priority reviews may be obtained.
SymBio has begun a global phase II clinical trial in the US and the UK for disseminated AdV infection and AdV infection in
immunocompromised patients, an area with high unmet medical needs as there currently exists no effective treatment. This
study will confirm the appropriate dosage and administration for pediatric patients. The company plans to conduct a global study
as the next phase for approval applications.

On the same day, the company announced that Onconova Therapeutics, Inc. has dosed the first patient in an
investigator-initiated phase II study of rigosertib in recessive dystrophic epidermolysis bullosa-associated squamous cell
carcinoma.
According the company’s statement, its US licensor of anticancer drug rigosertib, Onconova Therapeutics, Inc., announced on
April 22, 2021 (US EST) that the first patient has been dosed in an investigator-initiated phase II study to assess the efficacy andsafety of rigosertib in patients with recessive dystrophic epidermolysis bullosa (RDEB)-associated locally advanced/metastatic
squamous cell carcinoma (SCC).
On March 29, 2021, the company announced that it has applied for approval to extend the shelf life of Treakisym® RTD liquid
formulation.
The company submitted an application for partial change to the approved matters of the RTD formulation (ready-to
dilute-formulation; only requires diluting the drug before use, no dissolution required) of Treakisym® intravenous fluid with theaim of extending its shelf life.

On March 25, 2021, the company announced that it has filed for approval of the RTD liquid formulation of Treakisym® used in
combination with rituximab and with rituximab and polatuzumab vedotin, for the treatment of relapsed or refractory diffuse large
B-cell lymphoma.

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SymBio Pharmaceuticals / 4582
LAST UPDATE: 2021.06.16

Research Coverage Report by Shared Research Inc. | www.sharedresearch.jp

The company submitted an application for partial change to the approved matters of the RTD formulation (ready-to-diluteformulation that only requires diluting the drug before use [no dissolution required]) of Treakisym® intravenous injection used inbendamustine-rituximab combination therapy (BR therapy) in patients with relapsed or refractory diffuse large B-cell lymphoma(r/r DLBCL). At the same time, the company also submitted an application for partial change to the approved matters of the RTD
formulation for use in bendamustine-rituximab-polatuzumab vedotin combination therapy targeting r/r DLBCL.

On March 23, 2021, the company announced that it had obtained approval for Treakisym® used in combination with rituximab
and polatuzumab vedotin to treat patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL).
The company obtained approval of a partial change to the approved matters of anticancer agent Treakisym® 25mg and 100mg
vials (lyophilized powder for intravenous infusion; generic name: bendamustine hydrochloride) for use in combination withrituximab and polatuzumab vedotin to treat r/r DLBCL.
On the same day, based on results of clinical trials in Japan and overseas to evaluate combination therapy of Treakisym® andrituximab (BR therapy) with polatuzumab vedotin, Chugai Pharmaceutical Co., Ltd. obtained manufacturing and marketing
approval for polatuzumab vedotin targeting r/r DLBCL.
As noted below, the phase III clinical trial of BR therapy targeting r/r DLBCL obtained favorable results in the response rate
(primary endpoint), which exceeded expectations. On March 23, 2021, the company obtained approval of a partial change tothe approved matters. Once polatuzumab vedotin is added to the NHI drug price list and goes on sale, Treakisym® can be used in
the combination therapy of polatuzumab vedotin and BR therapy.
The latest approval is for the lyophilized formulation of Treakisym® to treat r/r DLBCL. SymBio commented that it plans to apply
this week for a partial change to the approved matters of the RTD formulation of Treakisym® to treat r/r DLBCL.

On the same day, the company announced that it had obtained approval for Treakisym® used in combination with rituximab totreat patients with r/r DLBCL.
The company obtained approval of a partial change to the approved matters of anticancer agent Treakisym® 25mg and 100mg
vials (lyophilized powder for intravenous infusion; generic name: bendamustine hydrochloride) for use in combination withrituximab (BR therapy) to treat r/r DLBCL, relating to indication and additional dosage regimen (bendamustine hydrochloride
120mg/m2).
The latest approval is based on results of the phase III clinical trial targeting r/r DLBCL, which demonstrated favorable results inprimary endpoints, with response rates exceeding expectations.
This approval is for the lyophilized formulation of Treakisym® for r/r DLBCL. The company plans to apply for a partial change tothe approved matters of the RTD formulation of Treakisym® for r/r DLBCL by March 27, 2021.

On March 11, 2021, the company announced its submission of an investigational new drug (IND) application for a phase II
clinical trial of the injectable antiviral agent brincidofovir as a treatment for adenovirus infections in children.
The company has submitted an IND application to the Food and Drug Administration of the US to start a phase II study of theantiviral injection brincidofovir, primarily in pediatric patients with adenovirus infections.
For previous releases and developments, please refer to the News and topics section.

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SymBio Pharmaceuticals / 4582
LAST UPDATE: 2021.06.16

Research Coverage Report by Shared Research Inc. | www.sharedresearch.jp

Trends and outlook
Quarterly trends and results
FY12/20

Cumulative

FY12/21(JPYmn)

Q1

Q2

Q3

Q4

Q1

Sales

551

1,361

2,333

2,987

1,420

YoY

-65.8%-32.1%

16.2%

5.3%

157.6%

Gross profit
YoY
GPM

128

330

611

867

1,010

-79.0%
23.2%-37.7%
24.2%

8.5%
26.2%

0.2%
29.0%

690.9%
71.1%

SG&A expenses

1,090

2,170

3,753

5,373

1,221

YoY
SG&A ratio-9.6%
197.6%-14.7%
159.5%-8.4%
160.9%

4.0%
179.9%

12.0%
85.9%

-962

-1,840-3,142-4,506

-211

-

-

-

-

-

-991

-1,883-3,221-4,616

-209

-

-

-

-

-

Net income-992-1,885-2,694-4,090-210

YoY
Net margin

-

-

-

-

-

Operating profit
YoY
OPM

Recurring profit
YoY
RPM

FY12/20

Quarterly(JPYmn)Sales
YoY

Gross profit
YoY
GPM

Q2

Q3

Q4

Q1

551
-65.8%
128809
105.7%
202

972
281

654
-21.1%
256

1,420
157.6%
1,010-79.0%
23.2%

25.0%

738.4%
28.9%-15.2%
39.1%

690.9%
71.1%

1,090

1,080

1,583

1,620

1,221

YoY
SG&A ratio-9.6%
197.6%-19.4%
133.5%

1.8%
162.9%

51.8%
247.5%

12.0%
85.9%

-962
-

-878
-

-1,302--1,364
-

-211
-

YoY
OPM

Recurring profit
YoY
RPM

Net income
YoY
Net margin

FY12/21
Q3

Q4% of Est.
15.5%

FY Est.
9,151
206.4%

-

1,361
14.9%

-

1,350
14.8%

-

1,149
12.6%

FY12/21

Q1

SG&A expenses

Operating profit

Q2

-

-

-

-

-

-991
-

-892
-

-1,338--1,395
-

-209
-

-

-

-

-

-

-992
-

-893
-

-809
-

-1,396
-

-210
-

-

-

-

-

-

Q2

Q3

Q4

Q3

Q4

Q3

Q4

Source: Shared Research based on company data
Note: Figures may differ from company materials due to differences in rounding methods.
“-”denotes YoY change of over 1000%.

Breakdown of SG&A expenses
FY12/20

Cumulative(JPYmn)
SG&A expenses
YoY

FY12/21

Q1

Q2

Q3

Q4

Q1

1,090

2,170

3,753

5,373

1,221
12.0%

-9.6%

-14.7%

-8.4%

4.0%

R&D expenses

438

834

1,745

2,267

473

YoY

-7.1%

-13.4%-11.5%

-7.2%

8.0%

651

1,336

2,008

3,107

747

-11.1%-15.5%

-5.6%

14.0%

14.7%

SG&A expenses excl. R&D
YoY

FY12/20

Quarterly(JPYmn)
SG&A expenses
YoY

FY12/21

Q1

Q2

Q3

Q4

Q1

1,090

1,080

1,583

1,620

1,221
12.0%

-9.6%

-19.4%

1.8%

51.8%

R&D expenses

438

396

911

522

473

YoY

-7.1%

-19.4%

-9.7%

11.0%

8.0%

SG&A expenses excl. R&D
YoY

Q2

651

685

672

1,098

747

-11.1%-19.3%

23.2%

83.9%

14.7%

Q2

Source: Shared Research based on company data
Note: Figures may differ from company materials due to differences in rounding methods.

09/77

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SymBio Pharmaceuticals / 4582
LAST UPDATE: 2021.06.16

Research Coverage Report by Shared Research Inc. | www.sharedresearch.jp

Q1 FY12/21 results▷

Sales:▷

Operating loss: JPY211mn (loss of JPY962mn in Q1 FY12/19)▷

Recurring loss:

JPY4.6bn (loss of JPY991mn in Q1 FY12/19)▷

Net loss:

JPY4.1bn (loss of JPY992mn in Q1 FY12/19)

JPY1.4bn (+157.6% YoY)

Sales increased 157.6% YoY to JPY1.4bn, largely due to the transfer of sales from Eisai Co., Ltd. to the company’s own sales force.
The business alliance agreement for Treakisym® concluded with Eisai expired on December 9, 2020, and SymBio started
independently marketing Treakisym® in Japan on December 10, 2020. With this change, the product is shipped topharmaceutical wholesalers instead of to Eisai. This allows the company to receive not only the gross profit it received previously(the company’s sales to Eisai minus cost of sales), but also the gross profit earned by Eisai through December 9, 2020 (i.e., thedifference between the shipment price from Eisai to pharmaceutical wholesalers and the price Eisai paid the company to source
the product).
Earnings were partially hindered by medical care delays due to the COVID-19 outbreak since late 2020 and constraints on sales
activities due to tighter restrictions on facilities visitations, but considering the clearance of market inventory of the lyophilized(freeze-dried [FD]) powder formulation of Treakisym® sold by Eisai prior to the switch to the company’s own sales force inDecember 2020, demand for Treakisym® was strong in Q1.
For Q2, although there are lingering impacts of the clearance of market inventory distributed prior to the switch to the company’own sales force, there will be minimal impact on sales overall, and the company says that it anticipates sales growth on the
additional indications for relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) that were approved on March 23, 2020.
Gross profit was JPY1.0bn (+690.9% YoY), and GPM was 71.1% (+47.9pp YoY). The company attributes GPM growth to the shift
to its own marketing system and the launch of Treakisym® Ready-To-Dilute (RTD) formulation in January 2021. In Q1, sales ofTreakisym® lyophilized formulations surpassed those of Treakisym® RTD formulations

Reasons why in-house marketing of Treakisym® contributed to GPM improvement: Switching from marketing through Eisai (based the marketing
agreement with Eisai) to doing its own marketing meant that products are shipped to pharmaceutical wholesalers instead of to Eisai starting from
December 10, 2020. This allows the company to receive not only the gross profit it received previously (the company’s sales to Eisai minus cost of
sales), but also the gross profit earned by Eisai through December 9, 2020 (i.e., the difference between the shipment price from Eisai to pharmaceuticalwholesalers and the price Eisai paid the company to source the product).

GPM rises due to switching from the lyophilized formulation to the RTD formulation of Treakisym®: The company sourced the lyophilized formulation ofTreakisym® from Astellas Deutschland, but the liquid formulations (RTD and RI formulations) are supplied by Eagle Pharmaceuticals. The company saysthat the GPM on liquid formulations of Treakisym® is higher than the GPM on the lyophilized formulation.

Although SG&A expenses increased, losses at the operating profit level on down shrank thanks to the effect of sales growth.
SG&A expenses increased 12.0% YoY to JPY1.2bn.
▷

R&D expenses increased 8.0% YoY to JPY473mn. This included expenses for conducting clinical trials of Treakisym® andbrincidofovir injections.

▷Excluding R&D expenses, SG&A expenses rose 14.7% YoY to JPY747mn. The switch to in-house sales drove up the cost of
sales. Yet, the results were below the company’s forecast for SG&A expenses (excluding R&D expenses) of JPY3.6bn(+15.1% YoY), as the shift to online sales activities and other factors curbed the expenses.

Overview of business progress
In FY12/21, progress in main businesses are as follows:

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In June 2021, Chimerix, Inc. (licensor of brincidofovir) obtained FDA approval of brincidofovir tablets and oral suspensions as
antiviral formulations for the treatment of smallpox.

▷

In May 2021, SymBio submitted approval application for Treakisym® rapid infusion (RI) liquid formulation.

▷

In April 2021, the company obtained approval of Treakisym® ready-to-dilute (RTD) liquid formulation for use in combination
with rituximab and in combination with rituximab and polatuzumab vedotin for the treatment of refractory or relapsed diffuse
large B-cell lymphoma (r/r DLBCL).

▷In March 2021, the company obtained approval of Treakisym® for use in combination with rituximab, and in combination withrituximab and polatuzumab vedotin for the treatment of r/r DLBCL.

▷In March 2021, the company submitted an Investigational New Drug (IND) application for phase II clinical study ofbrincidofovir injection in pediatric patients with adenovirus infections.

▷

In January 2021, the company launched Treakisym® RTD liquid formulation.

Domestic
Preparations for in-house sales organization begin
The business alliance agreement between SymBio and Eisai Co., Ltd. under which Eisai acts as a sales agent expired in December
2020, and the company switched to in-house sales for domestic sales of Treakisym®.
The company has thus far deployed a nationwide network of marketing representatives as well as hematology experts to covereach region to establish a highly productive internal sales organization capable of making proposals that fit the needs of eachregion. With the termination of its alliance agreement with Eisai, in September 2020, the company concluded a basic agreementwith Suzuken Co., Ltd and Toho Pharmaceutical Co., Ltd for the procurement and sale of pharmaceuticals to achieve nationwide
distribution. The company has established two distribution centers, one in Eastern Japan and the other in Western Japan, undermanagement by S.D. Collabo Co., Ltd.
During Q1, in January 2021, the company launched sales of the ready-to-dilute (RTD) formulation of Treakisym®, for which it
obtained manufacturing and marketing approval in September 2020.
On March 23, 2021, the company obtained approval of a partial change to the approved matters of the lyophilized (freeze-dried)
powder formulation of Treakisym® for use in bendamustine-rituximab combination therapy (BR therapy) and in
bendamustine-rituximab-polatuzumab vedotin combination therapy (Pola-BR therapy) to treat r/r DLBCL patients. The
lyophilized powder formulation of Treakisym® can be used in BR therapy (120mg/sqm as bendamustine hydrochloride) rightaway, and it can also be used in Pola-BR therapy (90mg/sqm as bendamustine hydrochloride) once polatuzumab vedotin isadded to the NHI drug price list (listed in May 2021) .
On April 28, 2021, the company obtained approval of a partial change to the approved matters of Treakisym® RTD liquid
formulation for use in BR and Pola-BR therapy as treatment for r/r DLBCL.

Stable product supply
With the launch of sales of Treakisym® RTD formulation in January 2021, the company now markets both Treakisym® in both RTD
formulation and lyophilized powder formulation.
SymBio imports lyophilized Treakisym® for injection from Astellas Deutschland (consolidated subsidiary of Astellas Pharma) andTreakisym® RTD formulation from Eagle Pharmaceuticals Inc. In Q1, secondary packaging and quality tests were applied toimported batches, resulting in stable quality, and as of May 2021, inventories had maintained proper levels to enable stableproduct supply.
On the supply front, the company is aiming for 91% completion of the switchover from the lyophilized formulation to the RTD
formulation of Treakisym®.

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Anticancer agents: (SyB L-0501[lyophilized injection]/SyB L-1701 [RTD]/SyB L-1702 [RI] (generic name: bendamustine hydrochloride,
product name: Treakisym®)
The anticancer agent Treakisym® is used in malignant lymphomas, indicated for untreated low-grade non-Hodgkin’s lymphoma
and mantle cell lymphoma (marketing approval obtained in December 2016), refractory or relapsed low-grade NHL and MCL(October 2010), and chronic lymphocytic leukemia (August 2016).
The combination therapy of Treakisym® and rituximab (BR therapy) was newly included in the Practical Guidelines for
Hematological Malignancies 2018 published by Japanese Society of Hematology as a standard treatment option, which applies toall of the approved indications. This has seen Treakisym® establish its position as a standard treatment for lymphatic cancer.
Also, SymBio obtained approval for partial change to the approved matters of Treakisym® in July 2018. Treakisym® can now be
used in combination with new anti-CD20 antibodies and not just rituximab for the treatment of CD20-positive follicularlymphoma, the most common histological type of low-grade NHL. This allows the company to provide patients a new treatment
option: combination therapy with obinutuzumab. In March 2019, SymBio obtained approval for partial change to the approved
matters of Treakisym® to enable its use as a pretreatment agent in tumor-specific T cell infusion therapy. This allows Treakisym® tobe used as a pretreatment agent for Kymriah® intravenous infusion, which was the first chimeric antigen receptor T-cell (CAR-T)
therapy approved in Japan. Growing use of Treakisym® as a pretreatment agent in regenerative medicine has solidified its
positioning as standard therapy for malignant lymphomas.
In the phase III clinical study of Treakisym® administered in BR therapy for the treatment of r/r DLBCL, the company submitted an
application for partial change to approved matters in May 2020 and obtained approval in March 2021. In April 2021, it obtained
approval for a partial change to the approved matters of Treakisym® RTD liquid formulation for use in BR and Pola-BR therapy astreatment for r/r DLBCL. The company has conducted a follow-up study with overall survival as the primary endpoint, because
evaluating the survival data (e.g., overall survival and progression-free survival) for Treakisym® administered in BR therapy is
crucial for establishing Treakisym® as a treatment for DLBCL. It is now making preparations to publicize the results of that study.
Also, after Chugai Pharmaceutical Co., Ltd. applied for manufacture and marketing approval for polatuzumab vedotin in
combination with BR therapy to treat r/r DLBCL in June 2020, the company applied for approval for a partial change to theapproved matters of Treakisym® for use in Pola-BR therapy and obtained approval in March 2021. With the approvals obtained by
Chugai and SymBio, once polatuzumab vedotin is added to the NHI drug price list, Treakisym® will be able to be used in Pola-BRtherapy. At present there are no effective treatments for the additional indication of r/r DLBCL, which is usually treated by a
combination of anticancer agents as salvage chemotherapy, so development of a highly effective but safe new drug would be
ideal. Since BR therapy is already being used in the West to treat r/r DLBCL, patient organizations and related academic societies
have petitioned MHLW so that it can be used in Japan as soon as possible.
The company concluded an exclusive licensing agreement in Japan with Eagle Pharmaceuticals (based in New Jersey, US) in
September 2017 for the RTD and rapid infusion (RI) formulations of Treakisym® (the RI formulation reduces administration time).
Manufacturing and marketing approval of the RTD formulation was obtained in September 2020, and the company launched it inJanuary 2021. The company has concluded clinical trials to confirm safety of the RI formulation and applies for approval in May
2021. Unlike the current lyophilized powder formulation, the RTD formulation reduces the workload of medical professionals,
because it eliminates the need for troublesome manual dissolution. The RI formulation can be administered in just 10 minutes
versus 60 minutes for the current lyophilized injection and RTD formulation. This reduces the burden on patients and healthcare
professionals, providing significant value added. Multiple patent protections in the form of a liquid product license will enable
the extension of the product life of Treakisym® to 2031.

Anticancer agents: SyB L-1101 [IV]/SyB C-1101 [oral] (generic name: rigosertib sodium)
Onconova Therapeutics, Inc., the licensor, conducted a global phase III trial (INSPIRE study) across more than 20 countries
addressing higher-risk myelodysplastic syndromes (higher-risk MDS) with overall survival as the primary endpoint. The target ispatients who do not respond to the current standard treatment with hypomethylating agents, relapse after treatment under thecurrent standard of care, or are intolerant to hypomethylating agents. In August 2020, Onconova announced a comparator trial

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to physicians’ choice of treatment failed to achieve the primary endpoint. The company leads clinical trials conducted in Japanand is looking to apply the knowledge gleaned from additional analysis of the INSPIRE study to rigosertib development going
forward.
Regarding the oral formulation of rigosertib, Onconova completed a phase I/II clinical trial for the drug used in combination withazacytidine, whose results suggested the efficacy and safety of the combination therapy. To verify the tolerability and safety of
the high-dose oral formulation of rigosertib as an initial treatment for higher-risk MDS among Japanese patients, SymBio began aphase I clinical trial in Japan in June 2017 and completed patient enrollment in June 2019.

Antiviral drug: SyB V-1901 (generic name: brincidofovir）
In September 2019, SymBio concluded an exclusive global license agreement with Chimerix Inc. (hereafter Chimerix) for
brincidofovir (SyB V-1901, hereafter BCV IV and BCV Oral), an antiviral drug in intravenous and oral forms). The company
acquired exclusive global rights to develop, manufacture, and market BCV for all diseases except smallpox.
The company has concluded that it would prioritize global development of BCV IV (mainly in Japan, the US, and Europe) to treat
adenovirus (AdV) infections in patients receiving hematopoietic stem cell transplantation to address an unmet medical need. In
March 2021, the company submitted of an investigational new drug (IND) application to the Food and Drug Administration(FDA) of the US with the goal of obtaining permission for the launch of a phase II clinical trial for a phase II clinical trial of BCV IV asa treatment for adenovirus infections that primarily occur in children (although also in adults). In April 2021, the company
received granted fast track designation from the FDA.
Based on safety and efficacy data acquired from its study, the company plans to review the drug’s efficacy against dsDNA viral
infections in patients receiving hematopoietic stem cell transplantation and extend its target indications to include multiviral
infections. By exploring the potential for expanding target disease areas to viral infections related to organ transplants (including
kidney transplants), the company aims to grow the market for and maximize the business value of BCV. Clinical trials by Chimerix
have demonstrated superior, broad-spectrum antivirus activity of BCV Oral against dsDNA viruses, raising expectations for its
potential as a safe and effective therapy to prevent and treat a range of viral infections in patients receiving hematopoietic stem
cell transplantation.
Chimerix announced in June 2021 that the FDA approved BCV tablets and oral suspensions in adult and pediatric patients
including neonates for the treatment of smallpox.

Overseas
The company marketed SyB L-0501 in China and Hong Kong, and product sales were in line with the company’s plans.

In-licensing of drug candidates
The company is currently focusing on unrolling global development plans for antiviral drug brincidofovir it in-licensed in
September 2019. It is constantly looking into multiple licensing deals and looking for and evaluating promising in-licensing drugcandidates.

For details on previous quarterly and annual results, see the Historical performance section.

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Full-year company forecast
FY12/20(JPYmn)Sales
Gross profit
Gross profit margin

FY12/21

1H Act.
1,361
330

2H Act.
1,626
537

FY Act.
2,987
867

FY Est.
9,151
6,957
76.0%

24.2%

33.0%

29.0%

SG&A expenses

2,170

3,203

5,373

5,596

SG&A ratio

159.5%

197.0%

179.9%

61.2%

834
1,336
-1,8401,433
1,770-2,666

2,267
3,107-4,506

2,019
3,577
1,361
14.9%

R&D expenses
Excluding R&D expenses
Operating profit
Operating profit margin

Recurring profit
Recurring profit margin

Net income
Net margin

-

-

-

-1,883-2,733-4,616

1,350

-

-

-

14.8%

-1,885-2,205-4,090

1,149

-

-

-

12.6%

Source: Shared Research based on company data.
Note: Figures may differ from company materials due to differences in rounding methods.

Earnings outlook
The company’s FY12/21 forecast calls for sales of JPY9.2bn (+206.4% YoY), operating profit of JPY1.4bn (operating loss of
JPY4.5bn in FY12/20), recurring profit of JPY1.4bn (recurring loss of JPY4.6bn), and a net income of JPY1.1bn (net loss of
JPY4.1bn).

▷

The company expects increased product sales in Japan due to the move to sell Treakisym® in-house and obtaining approval for,and beginning sales of Treakisym® for the additional indication of relapsed or refractory diffuse large B-cell lymphoma (DLBCL).
 Sales increase resulting from move to sell Treakisym® in-house: The business alliance agreement with Eisai for Treakisym®
expired on December 9, 2020, and SymBio began independently marketing Treakisym® in Japan on December 10.
Switching from marketing through Eisai (based on the marketing agreement with Eisai) to doing its own marketing meantthat products are shipped to pharmaceutical wholesalers instead of to Eisai. This allows the company to receive not only
the gross profit it received previously (the company’s sales to Eisai minus cost of sales), but also the gross profit earned by
Eisai through December 9, 2020 (i.e., the difference between the shipment price from Eisai to pharmaceutical wholesalers
and the price Eisai paid the company to source the product).
 Obtaining approval for, and beginning sales of Treakisym® for the additional indication of relapsed or refractory DLBCL:The company targets sales of JPY2.6bn on an NHI drug reimbursement price basis for Treakisym® indicated for DLBCL.

▷The company expects to turn profitable at all profit levels on the back of sales growth.

▷

It forecasts gross profit of JPY7.0bn (+702.6% YoY) with a GPM of 76.0% (+47pp YoY). The increase in gross profit is due tohigher sales and GPM. The GPM rise is due to starting in-house sales of Treakisym® and switching to the RTD formulation of the
product.
 GPM rise due to starting in-house sales of Treakisym®: As noted above, switching from marketing through Eisai (based on
the marketing agreement with Eisai) to doing its own marketing meant that products are shipped to pharmaceuticalwholesalers instead of to Eisai. This allows the company to receive not only the gross profit it received previously (thecompany’s sales to Eisai minus cost of sales), but also the gross profit earned by Eisai through December 9, 2020 (i.e., thedifference between the shipment price from Eisai to pharmaceutical wholesalers and the price Eisai paid the company tosource the product). Before December 9, 2020, the company was selling the lyophilized formulation of Treakisym® to
Eisai at a GPM of around 30%. Shared Research understands that from December 10 onward, by doing its own marketing,
the GPM on Treakisym® would go up to around 70%.
 GPM rise due to switching from the lyophilized formulation to the RTD formulation of Treakisym®: The company sourced
the lyophilized formulation of Treakisym® from Astellas Deutschland, but the liquid formulations (RTD and RI formulations)
are supplied by Eagle Pharmaceuticals. The company commented that the GPM on liquid formulations of Treakisym® will

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be higher than the GPM on the lyophilized formulation. By the end of 2021, the company targets an RTD product sales
share of 91% of total Treakisym® sales.

▷

SymBio expects SG&A expenses of JPY5.6bn (+4.1% YoY).
 The company plans R&D expenses of JPY2.0bn (-10.9% YoY). It will proceed with development of Treakisym® for theindication of relapsed or refractory DLBCL, Treakisym® liquid formulations, and rigosertib, as well as antiviral drug
brincidofovir. The company made a milestone payment on obtaining approval of the RTD formulation of Treakisym® in
FY12/20, but no milestone payments are expected in FY12/21.
 SG&A expenses excluding R&D expenses are estimated to be JPY3.6bn (+15.1% YoY). The company will reinforce its
in-house sales structure and prepare to expand its business overseas so that it can turn profitable in FY12/21 and sustain
earnings expansion thereafter.

The main pipeline development plans are as follows.

Treakisym®
The company targets Treakisym® sales of JPY11.3bn in FY12/21 on an NHI drug reimbursement price basis (JPY8.0bn in FY12/20).

▷

Sales growth of Treakisym® for approved indications: The company targets Treakisym® sales of JPY4.1bn as first-line therapy for
low-grade non-Hodgkin’s lymphoma and JPY4.6bn for other indications (NHI reimbursement price basis) in FY12/21.

▷

Sales growth of Treakisym® for added indication: SymBio applied for approval of the additional indication of relapsed or
refractory DLBCL for Treakisym® in May 2020, and expects to obtain approval and launch in Q2 FY12/21. The company targets
Treakisym® sales of JPY2.6bn for the indication of DLBCL.

▷

Extended product life cycle: The company began sales of the RTD formulation of Treakisym® in Q1 FY12/21. By the end of 2021,
the company targets a 91% sales share of the RTD formulation of total Treakisym® sales. It plans to begin sales of the RI
formulation in 1H FY12/22.

Oral rigosertib and rigosertib injection▷

SymBio is continuing to develop intravenous rigosertib formulation. Onconova, the licensor of anticancer drug rigosertib,announced in August 2020 that its global phase III trial (INSPIRE study) in patients with higher-risk myelodysplastic syndromes(higher-risk MDS) intolerant of treatment with hypomethylating agents failed to meet its primary endpoints. SymBio engages
in clinical development of rigosertib in Japan, and plans to use the knowledge obtained from genomic analysis of the INSPIRE
study in future development of rigosertib.

Antiviral drug brincidofovir
Regarding the intravenous formulation of brincidofovir (BCV IV), after a review at the global advisory board held in February 2020,
the company concluded that it would prioritize global development of BCV IV (mainly in Japan, the US, and Europe) to treat
adenovirus (AdV) infections in patients receiving hematopoietic stem cell transplantation to address an unmet medical need. As
of February 2021, the company was preparing to begin clinical trials of the liquid formulation of BCV for dose determination inchildren.

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Long-term outlook
Medium-term plan (FY12/21–FY12/23)
SymBio announced a three-year medium-term plan for FY12/21 through FY12/23 along with the FY12/20 results.
Medium-term plan targets
FY12/20

FY12/21

FY12/22

FY12/23(JPYmn)

Act.

Est.

TargetTarget

Sales

2,987

9,151

10,985

12,369YoY

5.3%

206.4%

20.0%

12.6%

-4,506

1,361

1,738

2,099
20.8%

Operating profit
YoY

-

-

27.7%

Operating profit margin

-

14.9%

15.8%

17.0%

1,350

1,727

2,088
20.9%

Recurring profit-4,616

YoY

-

-

27.9%

Recurring profit margin

-

14.8%

15.7%

16.9%

1,149

1,470

1,778

Net income-4,090

YoY

-

-

27.9%

21.0%

Net margin

-

12.6%

13.4%

14.4%

Source: Shared Research based on company data

Targets in medium-term plan (FY12/21–FY12/23)
Sales
SymBio expects product sales of Treakisym® to account for the bulk of sales.

▷

Product sales targets reflect the recent pace of market penetration and sales trends, which feed into the company’s revised
sales growth rates calculated over the medium-term plan period.

▷

Sales through FY12/20 were booked based on product shipment sales to the sales distributor, Eisai. From FY12/21 onward,
sales will be booked on product shipment sales to pharmaceutical wholesalers from the company’s own in-house salesorganization.

▷

In estimating sales from FY12/21 onward, SymBio disclosed targets assuming increased product sales of Treakisym® as it
expects to gain approval of the drug as a treatment for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in Q2
FY12/21.

Transition to in-house sales structure
SymBio has entrusted Treakisym® sales to Eisai until end-FY12/20. During this period, product shipments to Eisai are being
booked as sales. However, Eisai’s exclusive sales period expires in FY12/20, and from FY12/21 SymBio will switch to selling
Treakisym® in-house. Up to and including FY12/20, Shared Research assumes that the price of shipments to Eisai will be around
50% of the NHI drug price. With the transition to an in-house sales structure in FY12/21, though, Shared Research thinks the pricethat SymBio charges to wholesalers will rise to roughly 90% of the NHI drug price. Thus even if volume remains largely
unchanged, the company expects higher selling prices to drive sharp YoY sales growth in FY12/21.
Based on data supplied by Eisai, sales of Treakisym® were JPY7.7bn (+6.3% YoY) in FY03/20. In contrast, SymBio’s product sales
stood at JPY2.8bn in FY12/19. The fiscal year ends of the two companies differ by three months, SymBio’s product sales include
overseas sales, and at Eisai, there is a time lag between product procurement and sales. Broadly speaking, however, we can inferthat Eisai’s gross profit is roughly Eisai’s sales minus SymBio’s sales, so once SymBio begins its own sales of Treakisym®, it is ourunderstanding that the company will be gaining the equivalent of Eisai’s portion of gross profit.
As noted, the company plans to shift to its own sales organization and switch product shipments from Eisai to pharmaceuticalwholesalers in FY12/21. In the run-up to this it will be necessary to reduce Eisai’s inventories toward the end of FY12/20. Sales ofTreakisym® based on an NHI drug price should remain solid, reflecting actual market demand, but SymBio plans to stop shipping
to Eisai with a target date of end-1H FY12/20. It expects FY12/20 sales to decline by a commensurate amount.

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Addition of an indication of relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL)The company plans to seek approval of the additional indication of r/r DLBCL for Treakisym® in Q2 FY12/21. It aims to commence
sales of Treakisym® for this indication in Q3 FY12/21, with a view to growing Treakisym® product sales in FY12/21 onward. The
company says that its sales target range for FY12/22 is based on an estimated market penetration rate due to the additional
indication.
As reference for the anticipated impact of adding the indication of r/r DLBCL, the company estimates that the number of patients
being treated for relapsed or refractory low-grade NHL and MCL in Japan is 9,336 and the number of patients with untreatedlow-grade NHL and MCL is 6,967, for a total of 16,303. For these indications, SymBio’s FY12/19 sales target was JPY10.1bn on an
NHI drug price basis. By comparison, the company estimates that the number of Japanese patients with r/r DLBCL is 18,672.
In FY12/21, the company targets Treakisym® sales (on an NHI drug reimbursement price basis; same below) of JPY11.3bn(JPY8.0bn in FY12/20), breaking down into JPY8.7bn for approved indications and JPY2.6bn for the DLBCL indication.
Treakisym® indicated for DLBCL will begin contributing to earnings in FY12/21. The full-year contribution of this product(indicated for DLBCL) in FY12/22 and FY12/23, as well as its higher market penetration rate will likely boost overall sales.

Gross profit under the medium-term plan
The FY12/21 full-year forecast calls for a rise in GPM to 76.0% (+47pp YoY), which is due to starting in-house marketing of
Treakisym® and switching to the RTD formulation of the product. The company assumes that progress in switching to liquid
formulations of Treakisym® during the medium-term plan period will gradually raise the GPM.

▷

Based on historical performance, Shared Research understands that the gross profit margin was about 30% for Treakisym®
shipments to Eisai prior to December 10, 2020. As outlined earlier, on December 10, 2020, SymBio transitioned to in-housesales of Treakisym®, rather than entrusting them to Eisai. The company now ships Treakisym® to pharmaceutical wholesalersinstead of to Eisai. The gross profit earned prior to the transition remains, but is augmented by the gross profit that had
previously gone Eisai’s way (difference between the procurement price paid by Eisai and the price on shipments from Eisai towholesalers). Shared Research estimates that the transition to in-house sales will lift SymBio’s gross profit margin to around70%.

▷

SymBio is likely to further boost the gross profit margin by procuring Treakisym® from a different source. The company
procures lyophilized Treakisym® from Astellas Deutschland, but procures the liquid formulations (RTD and RI formulations)from Eagle Pharmaceuticals. The company expects GPM to be higher for the liquid formulations than for the lyophilized
product. The company targets 91% sales share of the RTD formulation of total Treakisym® sales at end-FY12/21 and 95% at
end-FY12/22.

SG&A expenses under the medium-term plan
The company expects a gradual increase in SG&A expenses, including milestone payments and clinical trial expenses. SG&A
expenses are largely broken down to R&D spending and other SG&A expenses.

▷

The company calculated R&D expenses based on the latest development plans for its existing pipeline comprising Treakisym®,
rigosertib, and antiviral drug brincidofovir.
 The company forecasts R&D expenses of JPY2.0bn (-10.9% YoY) in FY12/21. It made a milestone payment of around
JPY500mn for the RTD formulation of Treakisym® in FY12/20 after obtaining approval, but plans no milestone payment in
FY12/21.
 The company plans milestone payments for Treakisym® RTD formulation and antiviral drug brincidofovir in FY12/22 andFY12/23. It also expects an increase in clinical trial expenses for brincidofovir in FY12/22 onward.

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The company does not assume any upfront payments for in-licensing drug candidates outside its existing pipeline after
brincidofovir, an antiviral drug, although it will continue to evaluate and investigate them.

▷

Other SG&A expenses comprise primarily Treakisym® sales and marketing, production and distribution, business development,
and management related costs. From FY12/21, SymBio assumes costs associated with operating its own sales organization forsales of Treakisym®. It forecasts an increase primarily in personnel expenses due to a higher medical representative headcountand higher expenses due to more activities. The company forecasts JPY3.6bn (+15.1% YoY) in SG&A expenses other than for
R&D in FY12/21, assuming an increase in sales promotion and other expenses. It does not anticipate a large increase in
expenses in FY12/22 onward, having established its own sales structure.

Net income
In the previous medium-term plan announced in February 2020, the company forecast net income exceeding recurring profit in
FY12/21 and FY20/22 to reflect the reduction in loss carried forward from FY12/21 onward on tax effect accounting. Heeding theadvice of accounting auditors, the new medium-term plan was formulated by removing income taxes adjustment factors for
FY12/21 onward.

Personnel plans
SymBio completed the formation of its 62-member nationwide sales structure in FY12/20. It plans to allocate the bare minimumof necessary personnel in other parts of the organization and is budgeting for personnel expenses accordingly. The company
plans to increase personnel expenses for global expansion of brincidofovir, an antiviral drug, and reflected this in personnel
expenses.

Funding plans
Regarding funding plans, the company will work toward strengthening its financial base so that it can respond in a flexible andnimble way to the need for funds according to business developments.
Shared Research thinks that once the company has turned profitable at net income level in FY12/21, there will be no need to raise
funds through the issue of shares. In December 2020, SymBio concluded a JPY3.0bn syndicated loan (committed credit line)
agreement with MUFG Bank, Ltd. as the arranger and agent to have a flexible funding structure in place.

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Business
Business description
SymBio obtains rights to develop and market new drug candidates from biotech companies in the US and EU
President and CEO, Fuminori Yoshida, established SymBio in March 2005 to address underserved medical needs in Japan and theAsia Pacific region, with main focus on oncologic, hematologic and autoimmune diseases. The company aspires to be a leading
specialty pharmaceutical company in the Asia Pacific region. Its strategic approach to drug development negates the need forcostly and time-consuming investment in earlier-stage R&D activities with an in-house search and evaluation team to identify andassess only quality drug candidates having proof-of-concept established in human subjects.

Strategy Overview (details to follow)◤ Post proof-of-concept: The company reduces product development risk by focusing on drug candidates undergoing clinicaldevelopment with preclinical/clinical data establishing safety and efficacy in human subjects.
◤ Screening: The company uses an in-house search and evaluation team to screen and evaluate drug candidates having a highunmet medical in Japan and other Asia Pacific markets with the potential to secure marketing approval in a shorter clinicaldevelopment period. A select number of drug candidates will then undergo rigorous review by the company’s Scientific
Advisory Board (SAB).
◤ Fabless: The company outsources preclinical/clinical studies and manufacturing to reduce fixed costs.
◤ Niche market: The company targets drugs with the potential to receive orphan drug designation and thus, secure a longer

marketing exclusivity period due to high unmet medical needs—including oncology, hematology, and rare diseases—andsmaller patient populations. Larger pharmaceutical companies may be reluctant to develop drugs in niche markets due tolimited sales potential—SymBio sees an opportunity to avoid intense competition in the marketplace by focusing on thedevelopment of orphan or ‘orphan-like’ drugs.
◤ Global expansion: The company identifies and capitalizes on opportunities to grow sales by acquiring the right to develop

drug candidates in Japan and other international markets.

The company have in-licensed new drug candidates after rigorously evaluating them.
According to the company, the development of a drug—from preclinical studies to approval—usually takes 10 to 17 years. A
newly developed chemical compound has a 1/100,000 chance of securing regulatory approval. By contrast, the company’s first
product, Treakisym®, received approval for domestic production only five years after signature of the License Agreement. The
company achieved sales of JPY4.2bn in Japan in the third year after launch (FY12/13), equivalent to a market share of over 50%.
An example of the company’s ability to identify and pursue quality in-licensing opportunities with proof-of-concept established isthe license agreement signed for the development and commercialization right to rigosertib—currently in joint global phase III
clinical trials. In July 2011, once phase II clinical trials in the US established the drug’s proof-of-concept, SymBio secured an
exclusive right to all indications for rigosertib in Japan and South Korea from Onconova within seven months from the initial
meeting between the two companies. The following year, Baxter International Inc. entered into an agreement with Onconova forthe commercialization rights to rigosertib in Europe with a USD50mn upfront payment and USD337.5mn in pre-commercial
milestones tied to MDS and pancreatic cancer indications (in addition to an existing equity investment with Onconova of
USD55mn), a market that is approximately twice the size of Japan.

Products under development: Treakisym® (FD), Treakisym® (RTD and RI), rigosertib (injection and oral), andbrincidofovir
Additional indications for Treakisym®
For patients that have developed resistance to other drugs, Treakisym® is safer and more efficacious than existing treatments. As
outlined below, the company has gained approval in Japan for the indications of refractory or relapsed low-grade non-Hodgkin’s

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lymphoma and mantle cell lymphoma, chronic lymphocytic leukemia, and first-line treatment of low-grade non-Hodgkin’s
lymphoma and mantle cell lymphoma.

▷

Refractory or relapsed low-grade non-Hodgkin’s lymphoma and mantle cell lymphoma: After designation as an orphan drug
(drug for the treatment of rare diseases), Treakisym® won marketing approval for this indication in October 2010.

▷

Chronic lymphocytic leukemia: SymBio received approval for this to be added as indication for Treakisym® in August 2016.

▷

First-line treatment of untreated low-grade non-Hodgkin’s lymphoma and mantle cell lymphoma: The company gained
approval for this to be added as indication for Treakisym® in December 2016.

As of February 2021, phase III clinical trials for the fourth indication of relapsed or refractory DLBCL had been completed, with thetrial confirming a positive overall response rate (the primary endpoint of the study) exceeding expectations (November 2019).
The company filed for manufacture and marketing approval in May 2020 and expects to obtain approval in 1H FY12/21.

Treakisym® (RTD and RI formulations)
In September 2017, Eagle Pharmaceuticals and SymBio concluded a license agreement that licenses to SymBio rights to develop,
market, and sell Eagle’s bendamustine hydrochloride ready-to-dilute (RTD) and rapid infusion (RI) products in Japan. Securing
products to replace existing freeze-dried (FD) product (whose exclusive sales rights in Japan expire in 2H 2020) had been apriority for the company. SymBio obtained approval for the RTD formulation in September 2020 and launched it in January 2021.
With this, it aims to promote a switch in clinical settings from the current lyophilized powder formulation to RTD and RI
formulations that lighten the workload for medical professionals, at the same time curtailing uptake of Treakisym® generics (filingfor approval of generics will be possible from 2H 2020, although Shared Research believes that even if generics launch it will not
be until around 2022). Because it has exclusive rights to sell the RTD and RI formulations in Japan, SymBio will be able to extend
Treakisym®’s product lifecycle until 2031.

Rigosertib
Rigosertib is a treatment for myelodysplastic syndromes (MDS). According to the company, rigosertib may be used alone or—due
to its safety—in combination with other anticancer drugs. The drug is being developed in both intravenous (IV) and oral forms.
In February 2014, Onconova completed phase III clinical trials of rigosertib (injection) in patients with relapsed or refractory MDS
in Europe, and its efficacy was proven in subgroup analysis. SymBio also completed patient registration for phase I domestic
clinical trials in January 2015. In August 2015, Onconova initiated global phase III clinical trials for patients with higher-risk MDS
who had failed to respond to the standard therapy with hypomethylating agents (HMAs) or relapsed in more than 20 countries,
and announced in August 2020 that they had failed to meet the primary endpoints in comparison with physician’s choice. In
Japan, the company conducted joint global phase III clinical trials in cooperation with Onconova. SymBio says it will utilize theknowledge obtained from additional analysis of the global phase III clinical trials in future development of rigosertib.
For the oral form of the drug, Onconova completed phase I/II clinical trials targeting first-line treatment of higher-risk MDS, whichsuggested efficacy and safety of rigosertib-azacitidine combination therapy. SymBio initiated the phase I clinical trial of rigosertib
monotherapy for higher-risk MDS in Japan in June 2017 and completed patient enrollments in June 2019.

Brincidofovir
Brincidofovir is an antiviral drug formed by conjugating a lipid chain (hexadecyloxypropyl, or HDP) of specified length tocidofovir (an antiviral drug already approved and marketed in the EU and the US, but not approved in Japan). It has a novel
mechanism of action, which is attributed to its being a lipid conjugate, and can be taken up into cells with enhanced efficiency
compared to cidofovir (i.e., brincidofovir has higher cell membrane permeability). Once inside a cell, brincidofovir transforms
into a direct-acting agent and inhibits viral replication, demonstrating high antiviral effect. It is also easy to use as it has a low riskof nephrotoxicity, which is a side effect of cidofovir, hence making brincidofovir a novel, highly active anti-multiviral drug. It is
expected to become an effective treatment for a wide spectrum of infectious diseases caused by DNA viruses, including
cytomegalovirus (CMV) and other herpes viruses, adenoviruses, BK virus, papillomaviruses, and smallpox virus.

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In September 2019, SymBio entered an exclusive global license agreement with Chimerix Inc. for brincidofovir. As a result, thecompany acquired exclusive worldwide rights to develop, market, and manufacture brincidofovir for all indications except
smallpox. As of February 2021, the company was preparing for dose determination trials of brincidofovir liquid formulation
targeting adenovirus infection in children.

Revenue source: Treakisym® sales
Revenue mainly comes from product sales of Treakisym®. Operating losses have persisted since the company’s founding with the
exception of FY12/08 when the company booked operating profit due to a one-time contract payment from Eisai for an exclusive
domestic right to sell Treakisym®.
For FY12/21, the company expects JPY1.4bn operating profit (versus a JPY4.5bn operating loss in FY12/20) and JPY1.1bn net
income (net loss of JPY4.1bn in FY12/20). The company began in-house sales of Treakisym® in December 2020 and sales of the
RTD formulation in January 2021. It also expects to obtain approval for the additional indication of relapsed or refractory DLBCL in
FY12/21, which are all factors expected to contribute toward sales growth and GPM improvement. The company therefore
forecasts a turn to profitability at operating profit level in FY12/21.
Over the course of the medium-term plan (FY12/21–FY12/23), the company targets operating profit of JPY2.1bn in FY12/23 andexpects to continue posting operating profit over the medium term thereafter.

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Business strategy
Unlike conventional pharmaceutical companies, SymBio does not conduct basic research or develop its own drug candidates inlabs or clinics. Rather, it in-licenses drug candidates from pharmaceutical and biotech companies based in the US or EU.
The company focuses on developing drugs that have strong safety and efficacy data in clinical trials, providing an opportunity todevelop new drugs more likely to succeed and secure regulatory approval with the use of bridging data whenever possible toshorten development timelines. Because the company does not conduct basic research, the company can obtain approval andstart selling a drug within five to six years of securing the development and commercialization right. The company increases the
chance that drug candidates it in-licenses will be approved in the future through an effective in-house screening process andrigorous evaluation by the company’s Scientific Advisory Board.
The overall aim is to reduce development risk, streamline expenses, and expand revenue opportunities. This hinges on thefollowing five strategies, namely post proof-of-concept, screening, fabless, niche market, and global expansion.

Post-POC strategy: SymBio targets compounds with an established proof-of-concept
The pharmaceutical business requires substantial financial commitment in terms of upfront investment, not to mention thenumber of years of development required in order to realize a return on the investment and the high risk of failure in clinicalstudies from phase I through III. According to the company, the probability of a chemical compound having a signal withpharmacological activity in a particular disease being approved as a drug is 1/20,000 to 1/25,000, and only 15–20% of drugs thatmanage to enter the marketplace achieve profitability for the sponsor.
Given the high rate of attrition of drug candidates in clinical development, SymBio reduces development risk by only targeting
quality drug candidates undergoing clinical development with proof-of-concept (confirming efficacy and safety of a new drugcandidate through administration to animals or humans) established in human subjects and/or market sales. NDA filings that use
clinical data generated overseas can expedite product development in Japan and other parts of Asia, slashing development costs
and improving the overall success rate.
Post-proof-of-concept strategy

Source: Shared Research based on company data

Screening strategy: independent search network plus evaluation experience
The company identifies quality chemical compounds owned by pharmaceutical and biotech companies in the US or EU using aproprietary “search engine” and rigorous evaluation process. These candidates are first screened in-house by the search andevaluation team, whose members have extensive product development experience working at various pharmaceutical andbiotech companies.

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Onsite due diligence
After a select team visits the potential licensor to conduct due diligence, a decision is made regarding whether to pursue thein-licensing opportunity based on the results of onsite due diligence and input from the company’s SAB members.

Only a few new drug candidates have met the company’s stringent criteria since its foundation
The company has in-licensed only a few new drug candidates that have met its stringent criteria. The first was Treakisym®, which
the company currently sells in Japan (as of February 2021). Clinical trials for additional Treakisym® indications are underway, as
are preparations to file for approval of the RI formulation of the drug. The company is also developing intravenous and oral
formulations of rigosertib and antiviral drug brincidofovir.

Scientific Advisory Board
The Scientific Advisory Board is comprised of former directors of pharmaceutical companies, researchers, and doctors, and meets
three times a year. Typically, the SAB panel evaluates two to three drug candidates that have been selected via the company’s
in-house screening process. This in-house screening of only those drug candidates having proof-of-concept established in humansubjects with supportive efficacy and safety data followed by SAB assessment enables the company to reduce development risk
and to pursue only those opportunities having the best chance of reaching the marketplace.
Scientific Advisory Board members
NameProfilePresently Chairman GBS Venture Capital firm, Deputy Chairman Victorian Comprehensive Cancer Centre,

George Morstyn, M.D., Ph.D.

Director of Co-operative Research Centre for Cancer Therapeutics and Proacta.
Former Senior Vice-President of Development and CMO at Amgen Inc.
Former Senior Vice-President of US R&D, Aventis Pharmaceuticals;
Chief Scientific Officer, Cell Therapeutics; Head of Discovery Research,

Robert Lewis, M.D., Ph.D.

Syntex Pharmaceuticals; Associate Professor, Harvard Medical School
Currently serves as consultant in Immunology/Inflammation, Roche Palo Alto;
Adjunct Faculty Member, Rockefeller University, New YorkTomomitsu Hotta, M.D.
Makoto Ogawa, M.D., Ph.D.
Tatsutoshi Nakahata, M.D.,
Ph.D.

Toshio Suda, M.D., Ph.D.

Honorary President, National Cancer Center
Honorary Director, Nagoya Medical Center
Honorary President, Aichi Cancer Center
Advisor and Program-Specific Research Center Professor at Center for iPS Cell Research and Application(CiRA), and Head of Drug Discovery Technology Development Office, Kyoto University
Honorary member, The Japanese Society of Hematology
Distinguished Professor, International Research Center for Medical Sciences, Kumamoto University
Professor, Cancer Science Institute of Singapore, National University of Singapore
Vice President, The Japanese Society of Hematology in 2012

Tsutomu Takeuchi, M.D., Ph.D.

Professor of Medicine, Keio University, School of Medicine (Division of Rheumatology, Department ofInternal Medicine)
Professor, Kanazawa University College of Medical, Pharmaceutical and Health Sciences, Division of Cancer

Shinji Nakao, M.D., Ph.D.

Koichi Takahashi, M.D.

Medicine Cellular Transplantation Biology (Hematology/Respirology)
Executive Director, The Japanese Society of Hematology in 2012
Assistant Professor, Department of Leukemia, Division of Cancer Medicine, MD Anderson Cancer Center,
The University of Texas

Source: Shared Research based on company data

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Drug candidate selection process

Source: Shared Research based on company data
CDA = confidential disclosure agreement

Fabless strategy with a lean management team
SymBio seeks to reduce costs and raise profits by finding the right partner(s) to develop and commercialize drugs nimbly andefficiently through flawless execution. Specifically, the company designs clinical trial protocols and whenever possible, will
participate in global phase III studies being conducted by its partner(s) overseas with the aim of shortening development
timelines in Japan. It may be possible to file NDAs in Japan using foreign data to support or “bridge” data generated in Japaneseclinical trials, thereby avoiding the need to complete domestic phase II and/or phase III studies for marketing approval. The
company uses its well-established network for bendamustine to coordinate with medical professionals, outsourcing routine
development duties. Production is also outsourced either to the company that originally granted the product license, or to otherdomestic or foreign manufacturer(s). The company began in-house sales in Japan of Treakisym® on December 10, 2020, taking
over from Eisai, which marketed the product until December 9, 2020.

Niche markets: oncology, hematology, and rare diseases
SymBio focuses on drugs for underserved medical needs—even when the market may be as small as JPY10bn—rather thanfocusing on blockbuster drugs with sales in the hundreds of billions of yen. It aims to take advantage of therapeutic areas that
tend to be overlooked in the pharmaceutical industry and thus, lack effective drugs. Specifically, the company specializes intherapeutic areas with high barriers to entry, such as oncology, hematology, and rare diseases.
According to the company, globally Japan has the third largest oncology market after the US and EU, and the market is expected
to continue to expand due to Japan’s aging population. However, regarding the type of tumors that anticancer drugs caneffectively treat, there is a considerable range of indications with a limited number of patients who will benefit from approved
cancer treatments, particularly in the elderly population where the occurrence of serious adverse events can be prohibitive. As aresult, barriers to entry are high—developing cancer drugs for niche markets is especially difficult and requires a high level ofexpertise. Concerns about having sufficient profit margins from marketed drugs to fund large operations means that major
pharmaceutical companies may be reluctant to target indications with limited patient numbers for development, presenting an
opportunity with fewer competitors in the marketplace for smaller and more specialized pharmaceutical companies such as
SymBio. The company can also increase value added of niche disease areas by additional indications and putting new productson the market. For example, its first in-house proprietary drug Treakisym® has gained over 50% market share three years after
going on sale. In July 2018, Treakisym® was newly included as a standard option for first-line treatment of low-grade NHL andmantle cell lymphoma in the Guidelines for Hematological Malignancies 2018 issued by the Japan Society of Hematology in July
2018.

Strategy for global expansion
The company is seeking to develop new drugs that are complementary to Treakisym® and rigosertib to sell in China/Hong Kong,
Taiwan, South Korea, and Singapore, as well as in Japan. Also, it acquired exclusive worldwide rights to develop, manufacture,and market brincidofovir.

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Pipeline
Name/CodeTreakisym®
SyB L-0501(FD)

LicensedcountryJapan

Indications

Development stage

Sales partner

Relapsed or refractory
low-grade NHL and MCL

Approved (Oct. 2010)

In-house sales

Relapsed or refractory
DLBCL (aggressive NHL)Approval application in review

Untreated low-grade NHL and Approved
MCL(Dec. 2016)

Singapore

CLL

Approved(Aug. 2016)Low-grade B-cell NHL

Approved(Jan. 2010)

CLL
South Korea

rights granted to Eisai)

CLLMMApproved(May 2011)

Eisai Co., Ltd.
(Exclusive development and sales

Relapsed or refractory
low-grade NHL

Approved(Jun. 2014)

rights granted to Eisai)

China

Low-grade NHL

Clinical trials underway

Hong Kong

Low-grade NHL

Approved

Cephalon, Inc. (US)(Exclusive development and sales

CLL(Dec. 2009)

rights granted to Eisai)

Low-grade NHL

Approved

InnoPharmax, Inc. (Taiwan)

CLL(Oct. 2011)(Exclusive development and sales
rights granted to Eisai)

All indications

Approved

In-house sales

TaiwanTreakisym®
SyB L-1701

Eisai Co., Ltd.
(Exclusive development and sales

Japan(Sep 2020)

(RTD)
Japan

All indications

Clinical trials underway—

Rigosertib(IV)
SyB L-1101

Japan

Relapsed or refractory
higher-risk MDS

Global phase III clinical trials
Additional analysis underway—

Rigosertib(oral)SyB C-1101

Japan

Relapsed or refractory
higher-risk MDS

Phase I clinical trials underway —Treakisym®
SyB L-1702(RI)

Brincidofovir (IV)SyB V-1901(monotherapy)

Worldwide

Untreated higher-risk MDS

Global phase I/II clinical trials(with azacitidine)

completed

Adenovirus infection after
hematopoietic stem cell andPreparations for phase II
clinical trials underway——

kidney transplantation
Source: Shared Research based on the company website

As of February 2021, the main drugs for which SymBio was preparing to file for approval or in the development pipeline were as
follows:▷

Treakisym®, for the indication of relapsed or refractory DLBCL (aggressive NHL): Completed enrollment of patients for thephase III clinical trial (April 2019). Filed for approval in May2020. Expects to obtain approval and begin sales in FY12/21.

▷

Treakisym®, clinical trials of the RI formulation: Initiated clinical trials in November 2018. Plans to file for approval in FY12/21
and begin sales in FY12/22

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Rigosertib (intravenous formulation), for the indication of relapsed or refractory higher-risk MDS: Conducting additional
analysis of global phase III clinical trial results▷

Rigosertib (oral formulation), for the indication of higher-risk MDS: Completed patient enrollment for the phase I clinical trial inJune 2019, and completed global phase I/II clinical trials of the combination therapy with azacitidine. Preparing for phase I
clinical trial of the combination therapy with azacytidine.

▷

Antiviral drug brincidofovir: Preparing to begin phase II clinical trials of brincidofovir (liquid formulation) targeting adenovirus
infection in children

SyB L-0501 (generic name: bendamustine HCI, product name: Treakisym®)
SyB L-0501 (Treakisym®) or bendamustine hydrochloride is an anticancer agent. It is used as a treatment for low-grade NHL, MCL,
MM and CLL.
*Bendamustine was developed in 1971 by Jenapharm in former East Germany, where it was approved as a first-line treatment for low-grade NHL, MM,
and CLL. After the unification of Germany in 1990, bendamustine was again evaluated for its effectiveness against these indications. In 2005, Germany
approved the use of the drug for untreated low-grade NHL, MM and CLL. The drug was also approved in several other European countries in 2007. In
the US, Treanda (bendamustine) was approved in March 2008 for relapsed or refractory NHL and CLL, with sales in October the same year. A separate
application was filed in the US (2008) for the additional indication of previously untreated CLL.

According to the company, no cross-resistance (resistance to drugs with a similar structure or action as the study drug) has beenshown for this drug, which means it is safer and more efficacious than existing treatments for target indications. In October 2010,
SymBio received regulatory approval in Japan to market the drug for relapsed or refractory low-grade NHL and MCL. Eisai has
been selling the drug since its launch in December 2010. The company received permission to add CLL as an indication for
Treakisym® in August 2016, and first-line treatment of low-grade NHL and MCL in December 2016. As of February 2021, thecompany had filed for approval of Treakisym® for the additional indication of relapsed or refractory DLBCL (aggressive NHL; May2020).

Lymphatic cancer
Lymphatic cancer, a malignant growth of lymphocytes in white blood cells
Lymphatic cancer is a malignant growth of lymphocytes in white blood cells. It causes inflammation of the lymphatic nodes. The
most common symptom is a painless lump or swelling in one or more lymph nodes, usually in the neck, armpit or groin. In
lymphatic cancer, the lump or swelling grows persistently without decreasing in size, also spreading to other parts of the bodyand eventually presenting as generalized symptoms, including fever, weight loss, and night sweats. Other symptoms can include
widespread itching and skin rash, as well as airway obstruction, interrupted blood flow, and numbness arising from pressure ofswollen lymph nodes on the respiratory tract, blood vessels, and spinal cord.
Lymphatic cancer is divided into Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL). Among the Japanese
population, only 4% of lymphatic malignancies are HL. About 70–80% of NHL cases affect B-cells; the remaining 20–30% affect
T/NK cells. According to the Japanese Association of Clinical Cancer Centers (JACCC), the five-year relative survival rates for
lymphatic malignancies (among patients diagnosed between 2001 and 2005) are as outlined in the table below. In Hodgkin’s
lymphoma (all cases) the five-year relative survival rate was 76.0%, as compared with 68.3% for non-Hodgkin’s lymphoma (allcases).

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Lymphatic malignancy: frequency by type
Category

Frequency

Non-Hodgkin's lymphoma

94%

B lymphocytes

69%

T/NK lymphocytes

25%

Hodgkin's lymphoma

4%

Other

2%

Source: Japanese Society for Lymphoreticular Tissue Research (JSLTR)

Five-year relative survival rate for lymphatic malignancies (in patients diagnosed between 2001 and 2005)
Hodgkin’s lymphoma

Non-Hodgkin’s lymphoma

Number of cases

5-year relative
survival rate (%)

Number of cases

5-year relative
survival rate (%)

Ⅰ

19

91.4

462

86.7

Ⅱ

46

84.6

385

74.3

Ⅲ

22

65.3

319

64.0

Ⅳ

19

44.7

535

54.6

All cases

122

76.0

1,844

68.3

Stage

Source: Survival Statistics of Japanese Association of Clinical Cancer Centers (November 2015)
Note: Covers not just patients undergoing chemotherapy, but also those undergoing radiation therapy or some other form of cancer treatment.
Note: Cancer progression is categorized into stages; in lymphatic malignancies, these are Stage I, Stage II, Stage III, and Stage IV.

Method of treatment determined by grade; separate clinical trials required for each disease subtype
Physicians examine tissue and determine the method of treatment depending on the type of cancerous cells observed: they lookat the grade (high, intermediate, or low, depending on the aggressiveness of the disease) and clinical staging, which shows towhat extent the cancer has spread. To gain approval to manufacture and sell pharmaceuticals, companies must conduct separate
clinical trials for each disease subtype. Clinical trial subjects are categorized as either treatment-naïve, or relapsed/refractory(patients who have received treatment in the past, which has proven ineffective).

Treakisym® in-licensed from Astellas; developed jointly with Eisai in Japan; sold in-house from December
2020
In December 2005, SymBio signed a license agreement for the exclusive right to bendamustine in Japan with Astellas
Deutschland GmbH (“Astellas”), a subsidiary of Astellas Pharma Inc. The company entered into a second license agreement with
Astellas in March 2007 to extend its exclusive development and commercialization right for bendamustine to China/Hong Kong,
Taiwan, South Korea, and Singapore.
In August 2008, SymBio granted Eisai Co., Ltd. the co-development and exclusive marketing right for Treakisym® in Japan. Under
the agreement, SymBio receives one-time payments from Eisai as well as milestone payments based on the clinical trial stage for aparticular indication, plus revenues after supplying Treakisym® to Eisai. Eisai shoulders half of the development costs for
Treakisym®, including labor costs for researchers and outsourcing costs for clinical trials (see the Earnings structure section). The
marketing agreement with Eisai expired in December 2020, after which SymBio began to independently market Treakisym® inJapan.
SymBio has granted exclusive marketing rights for Treakisym® to InnoPharmax, Inc. in Taiwan, Cephalon, Inc. in China, and Eisai in
South Korea and Singapore. In return, SymBio receives one-time milestone payments, and books revenue from the sale of the
drug to these companies.

Approved for relapsed or refractory low-grade NHL, MCL in October 2010
In October 2010, five years after acquiring the right to Treakisym®, SymBio received marketing approval in Japan for relapsed or
refractory low-grade NHL and MCL. In FY12/16—six years after the domestic launch of the drug in December 2010—Treakisym®
sales reached JPY4.7bn on an NHI drug price basis.

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According to the company, Japan has about 4,700 patients who suffer from relapsed or refractory NHL and MCL. SymBio thinks
annual Treakisym® sales could reach JPY4.5–5.0bn.

Treakisym®: additional indications, RTD, RI, and oral formulations
Approval as the first-line treatment for untreated low-grade NHL, MCL in December 2016, and for additional
indication of CLL in August 2016
In December 2016, Treakisym® was approved in Japan as the first-line treatment for low-grade NHL/MCL. It was approved for CLL
in August 2016. The company filed for the approval of Treakisym® for the additional indication of relapsed or refractory DLBCL(aggressive NHL) in May 2020.
Market for Treakisym® and number of patients
Non-Hodgkin's Lymphoma
Low-grade B-cell

First-line

Chronic
Lymphatic
Leukemia

Moderate- tohigh-grade

Number of patients

6,967

Approval

Obtained

Obtained

Development status

Obtained approval(Aug. 2016)

Number of patients

Obtained approval(Dec. 2016)
9,336

Approval

Obtained

Completed patient
enrollment forphase III clinical
trials in Japan

Development status

Obtained approvalin Japan(Oct. 2010)

Applied approval(May 2020)

Relapsed andrefractory

656

18,672

Source: Shared Research based on company data

Treakisym® indicated for untreated low-grade NHL and MCL
According to the company, R-CHOP therapy—a combination of rituximab with CHOP chemotherapy drugs (cyclophosphamide,
doxorubicin (hydroxydaunomycin), vincristine (oncovin), and prednisolone)—was standard first-line treatment for low-grade
NHL and MCL in Japan prior to December 2016. In December 2016, Treakisym® won approval for the additional indication of
first-line treatment of low-grade NHL and MCL, and subsequently in July 2018, Treakisym® was newly included as a standard
option for first-line treatment of low-grade NHL and MCL in the Guidelines for Tumors of Hematopoietic and Lymphoid Tissues
2018 issued by the Japan Society of Hematology.
In Phase III clinical trials conducted overseas, rituximab in combination with Treakisym® (bendamustine hydrochloride; BRtherapy) demonstrated safety and efficacy superior to those of the standard R-CHOP therapy for previously untreated low-grade
B-cell NHL. These findings were presented at the American Society of Hematology Annual Meeting in December 2012. Based onthese results, the National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO)
guidelines recommend the use of BR therapy as first-line therapy for patients with untreated low-grade NHL.
These comparative studies were conducted at 81 facilities in Germany, in patients who were newly diagnosed between
September 2003 and August 2008 with stage III or IV low-grade NHL or MCL. The studies compared R-CHOP therapy with the
combination therapy of bendamustine-rituximab (BR) (bendamustine is marketed as Levact®, Ribomustin®, or Ribovact® in Europe).
A total of 275 patients underwent R-CHOP therapy, while 274 underwent the BR therapy. The median observation period was 45
months. Clinical results showed that the median progression-free survival was 69.5 months for the BR group and 31.2 months(p<0.0001) for the R-CHOP group, demonstrating greater statistical significance for the BR therapy. Comparison of overall
survival and safety between the two groups also showed superior results for the BR group.
p-value: In statistics, the p-value indicates the randomness of an observed result, or how trustworthy the sample is. A p-value of 0.01 indicates that an
observed result will occur randomly one out of 100 times. Generally, if the value is below 5%, the result is statistically significant.

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Results of comparative study of BR and R-CHOP therapies in patients with untreated low-grade NHL/MCL

Source: Company data

Treakisym® approved in December 2016 for untreated low-grade NHL and MCL
In December 2016, SymBio received marketing approval of Treakisym® in Japan, for untreated low-grade NHL and MCL. Shared
Research believes this shift will gain support from the aforementioned data demonstrating that BR therapy is more efficacious
than R-CHOP therapy, and inclusion of BR therapy as a standard treatment option in the Guidelines for Tumors of Hematopoietic
and Lymphoid Tissues 2018.

Untreated low-grade NHL and MCL: patient population and estimated sales
SymBio estimates that there are 6,967 first-line low-grade NHL and MCL patients in Japan. Although fewer than the number ofpatients with relapsed or refractory low-grade NHL and MCL, the company expects higher market penetration amid the trend of
switching from R-CHOP to BR therapy. Treakisym® sales could reach JPY5.0–7.0bn as the Japanese population continues to age.

Treakisym® indicated for chronic lymphocytic leukemia (CLL)
Additional indication of CLL approved in August 2016
In Japan, SymBio obtained approval for the additional indication of CLL for Treakisym® in August 2016.

Potential patient population, estimated sales
SymBio estimates that there are about 656 CLL patients in Japan. Shared Research estimates that sales could reach JPY300mn–
JPY350mn. This estimate is based on Treakisym® sales per patient with relapsed or refractory low-grade NHL or MCL.

Treakisym® indicated for relapsed or refractory DLBCL (aggressive NHL)
Diffuse large B-cell lymphoma (DLBCL), or aggressive NHL, progresses rapidly but recovery may be expected in patients forwhom anticancer drugs are effective. R-CHOP is the standard therapy for relapsed or refractory DLBCL, the most common type ofNHL.
But according to the company, 40% of untreated patients treated with R-CHOP relapse or become refractory, and only patients
who are 65 or younger can undergo chemotherapy at higher doses together with autologous stem cell transplants. Because themajority of relapsed or refractory DLBCL patients are elderly, physicians must consider potential side effects when selecting asuitable treatment. Weaker patients—due to age or other illnesses—have limited choices for treatment, and there is a need for asafer, more efficacious method of treatment such as Treakisym®.

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R&D status: approval application of Treakisym® for the indication of relapsed or refractory DLBCL
Results of phase III clinical trials in patients with relapsed or refractory DLBCL
Following consultations with the Pharmaceuticals and Medical Devices Agency (PMDA), the company commenced phase III
clinical trials of Treakisym® in combination with rituximab (BR therapy) for relapsed or refractory DLBCL. The objective of thestudy was to examine the efficacy and safety of BR therapy, with the overall response rate (ORR; antitumor effect) as the primary
endpoint. Enrollment of 60 patients was completed in April 2019.
The following results of the clinical trial (main efficacy evaluation results in 38 cases) were presented at the Japanese Society of
Medical Oncology Annual Meeting 2021 held in February 2021.

▷

Response rate (CR+PR): 76.3%▷

Complete response (CR): 47.4%▷

Median overall survival: 29.2 months* CR (complete response) = disappearance of all signs of cancer in response to treatment. Also known as complete remission.
* PR (partial response) = the cancer partly responded to treatment, but has not disappeared. Also known as partial remission.

Based on these results the company filed for approval of Treakisym® to make BR therapy possible for the treatment of relapsed or
refractory DLBCL. The company expects to obtain approval for this indication and begin sales in FY12/21.

Potential use of Treakisym® as pretreatment agent for CAR-T therapy
In April 2018, Novartis Pharma K.K. applied in Japan for approval of the chimeric antigen receptor T-cell (CAR-T) therapy CTL019(US product name: Kymriah®), for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) in patients
aged 25 years or younger and relapsed or refractory DLBCL. In May 2018, Novartis obtained approval in the US for use of CTL019
to treat adult patients with relapsed or refractory DLBCL after two or more lines of systemic therapy. Since the use of CTL019 islimited to adult patients for whom two or more lines of therapy have proved ineffective, Shared Research understands that
CTL019 is different from Treakisym® and that the two companies do not compete in this area. In September 2018, the company
applied for a partial change to the approved matters of Treakisym® to enable its use as a pretreatment agent for CTL019 targeting
relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) and relapsed or refractory diffuse large B-cell lymphoma (DLBCL)
in adults.

Patient population, estimated sales
According to SymBio, the number of relapsed or refractory diffuse large B-cell lymphoma (DLBCL; aggressive NHL) patients inJapan is approximately 18,672. We estimate annual peak sales for the indication (NHI drug reimbursement price basis) at JPY8.0–
10.0bn.

Concluded license agreement for RTD and RI formulations of bendamustine hydrochloride (marketed as
Treakisym® in Japan) in September 2017
In September 2017, Eagle Pharmaceuticals and SymBio concluded a license agreement that licenses to SymBio rights to develop,
market, and sell Eagle Pharmaceuticals’ bendamustine hydrochloride ready-to-dilute (RTD) and rapid infusion (RI) products(marketed in the US by Teva Pharmaceutical Industries as BENDEKA®) in Japan. Under the terms of this agreement, SymBio will
pay Eagle Pharmaceuticals a USD12.5mn upfront payment and a milestone payment upon approval. The company will also pay
additional milestone payments on the achievement of cumulative sales thresholds and royalties on future sales of licensed
bendamustine products.

RTD and RI products do not require reconstitution; RI product can be administered in one sixth of the time as FD product
The FD powder injection product currently available must be reconstituted manually before administration by intravenous
infusion. Since RTD and RI products are already liquidized, they do not require the time-consuming process of reconstitution andsubstantially reduce the workload of healthcare professionals. RI products also do not require reconstitution and can beadministered by intravenous infusion in 10 minutes instead of 60 minutes for FD powder injection and RTD products, which
reduces stress on patients.

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Comparison of RTD/RI formulations and current (freeze-dried) formulation

RTD products

RI products

Currently available products

Generic namebendamustine hydrochloride

Dosage form

LiquidReconstitution

Not required

Dilution

Dilute with 250ml physiologicalsalineDilute with 50ml physiologicalsalineDilute with 250ml physiologicalsalineAdministration time

60 minutes

10 minutes

60 minutes

Specifications

100mg/4mL

100mg/vial
25mg/vial

Storage

Refrigerated storage (2–8°C)

Room temperature

Freeze-dried powder injection
Required (manual reconstitution)

Life cycle of Treakisym® can be extended until 2031
The re-examination term for the FD formulation of Treakisym® ends in 2020, after which generics can be manufactured and sold.
SymBio believes that by selling the RTD and RI formulations of the product that offer the advantages of reducing healthcare
professionals’ workload and stress on patients after 2020, it can extend the exclusive sales period until 2031. This increases thepossibility of prolonging the life cycle of Treakisym® and limiting the spread of generics.

Profits of a company that develops a brand-name product are protected by patents and re-examination. After a drug is developed, other companies
cannot manufacture products using the same active ingredient until the patent expires (usually 20 years, up to a maximum of 25 years). Brand-nameproducts have a re-examination period, usually of six years up to a maximum of 10 years, and during this period, even if the patent has expired, othercompanies cannot apply to manufacture generic versions of the drug.

Bendamustine hydrochloride RTD and RI injection products are marketed in the US by Teva Pharmaceutical Industries as
BENDEKA®, which has 97% share of the US bendamustine market within two years after its sales.

R&D status: obtained approval in September 2020 for RTD formulation and preparing for approval application of RI formulation
The company obtained approval for the bendamustine hydrochloride RTD formulation in September 2020. As of February 2021,
it was preparing to file for approval of the RI formulation.
Clinical trials are required for the RI formulation because the administration time is different from the FD formulation. In
November 2018, the company began a clinical trial of Treakisym® RI formulation in 36 patients. It plans to launch the RI
formulation in 1H FY12/22.

Treakisym® as a pretreatment agent for a regenerative medicine product (CAR-T cell therapy)
In September 2018, the company applied for a partial change to the approved matters of anticancer drug Treakisym® to enable
its use as a pretreatment agent for regenerative medical products.
In April 2018, Novartis Pharma K.K. filed for manufacture and marketing approval for the first chimeric antigen receptor T-cell(CAR-T) therapy (CTL019) in Japan for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) inpatients aged 25 years or younger and relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in adult patients. If thetherapy is approved, Treakisym® can be used as a pretreatment agent for CAR-T therapy for the treatment of ALL and DLBCL.
Further, the approval would mark the addition of regenerative medicine as a new area of indication for Treakisym®.
CAR-T cell therapy genetically modifies T-cells collected from patients’ blood samples to express chimeric antigen receptors (CARs) on their surface at acell processing facility. Then, the genetically modified T-cells (CAR-T cells) are infused back into the patients where they assume the role of immune
system and specifically attack cells that express target proteins including cancer cells. CTL019 is an immune cell therapy that collects T-cells frompatients’ blood samples and genetically modifies them so that they specifically recognize CD19 proteins expressed on cancer cells among others andattack them. CTL019 therapy requires only a single administration.

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SyB L-1101 (injection)/ SyB C-1101 (oral) (generic name: rigosertib)
Rigosertib is an anti-cancer agent under development by Onconova Therapeutics, Inc. in the US and EU for the treatment of
myelodysplastic syndromes (MDS) and solid tumors. According to SymBio, rigosertib has high safety profile and can be used in
combination with other anticancer drugs. It is provided in injection and oral formulations.
Rigosertib inhibits the action of multiple kinases such as phosphatidyl inositol 3-kinase (PI3K) by blocking the action of the Ras gene, a cancer-related
gene product. It is a small molecule anticancer agent with a new mechanism of action that kills cells by suppressing transmission of intracellular signals
required for cancer survival and growth.
The PI3K pathway is activated by various gene mutations in cancer, and is thought to be deeply involved in cancer survival, differentiation, andproliferation.
Onconova: A US biopharmaceutical company. Established in 1998, Onconova focuses on discovering and developing small molecule drug candidates
to treat cancer.

Myelodysplastic Syndromes (MDS)
MDS is a refractory disease with a poor prognosis and progression to acute myeloid leukemia (AML) in approximately 30% ofcases. It leads to abnormalities in hematopoietic stem cells that produce blood cells, resulting in a lack of blood. Blood cells
produced this way are abnormally shaped. This change in the cells is called dysplasia. The disease typically leads to frequentanemia with some patients dying from infection or bleeding due to the reduction in blood cells. The average survival period isabout three to five years, with some patients surviving 10 years or longer. It is still not clear what environmental or genetic factors
are responsible for the occurrence of MDS, although those who have received radiation treatment or taken anticancer drugs may
have a higher risk of developing the disease (source: Japan Adult Leukemia Study Group: JALSG).
The seriousness of MDS is determined with the use of the International Prognostic Scoring System (IPSS). The IPSS score is
calculated based on the ratio of myeloblasts (immature blood cells) in the bone marrow, chromosome analysis, and the results ofa general laboratory blood test. The risk level is assessed based on the number of years that the patient is expected to live,
disease progression, and the probability that the disease may lead to acute myeloid leukemia. Risk categories: low,intermediate-1, intermediate-2, and high. Lower-risk MDS refers to low and intermediate-1 patients, while higher-risk MDS refers
to intermediate-1 and high in the IPSS risk categories.

Acquired rights from Onconova to develop and market rigosertib in Japan, South Korea
In July 2011 SymBio bought exclusive rights to develop and sell the intravenous (IV) and oral forms of rigosertib in Japan and
Korea following completion of Onconova’s phase II US clinical trial for the IV form (upfront payment of JPY800mn, Shared
Research estimate). In September 2012, Baxter International Inc. acquired exclusive rights to develop and sell rigosertib in Europe.
It paid an upfront payment of USD50mn, for a total licensing fee including milestone payments of USD565mn.

Development status of rigosertib
As of February 2021, SymBio was developing the IV form of rigosertib for the indication of relapsed or refractory higher-risk MDS,
and the oral form for higher-risk MDS.
Onconova has been conducting joint global phase III clinical trials in over 20 countries since August 2015 for the intravenous
form of rigosertib in higher-risk MDS patients who had failed to respond to or relapsed after prior therapy with hypomethylating
agents (HMAs). In the Japanese market, the company has been conducting the joint global phase III clinical trials in cooperation
with Onconova since December 2015. In August 2020, Onconova announced that the global phase III trial of rigosertib (IV) failed
to meet its primary endpoints. Onconova is performing additional analysis of the results. The company commented that it islooking to apply the knowledge gleaned from additional analysis of the study to rigosertib development going forward.
Onconova completed phase I/II clinical trials in the US for the oral form of rigosertib as first-line treatment for higher-risk MDS (incombination with azacitidine), which demonstrated safety and efficacy of the combination therapy. SymBio restarted phase I
clinical trials of the oral formulation of rigosertib monotherapy in Japan in June 2017 and completed patient enrollment in June

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2019, to verify the tolerability and safety of the study drug in Japanese patients. After establishing safety in phase I clinical trials,
the company plans to resume the trial of rigosertib in combination with azacitidine and participate in global clinical trials of the
combination therapy planned by Onconova in higher-risk MDS patients.
Market for rigosertib (oral form) and number of patients
Low-risk MDSHigh risk MDS

Number of patients

Relapsed andrefractory
3,200

Approval

TBC

Development status

Global phase III
trials underway

First-line

IntravenousFirst-line

Number of patients

7,800

3,200

Approval

TBC

TBC

Development status

Phase II trials
Global clinical trials
underway in the US being reviewed by
Onconova
Phase I clinical
trials underway in
Japan

Oral

Source: Shared Research based on company data

Rigosertib injection in patients with higher-risk refractory or relapsed MDS
Higher-risk MDS (patients in the Intermediate-2 risk and High-risk groups based on International Prognostic Scoring System) is
likely to cause a decline in blood cells or lead to leukemia. Treatment may involve stem cell transplants, depending on thepatient’s age, condition, and the compatibility of the donor. In the US and Europe, Vidaza (azacitidine) and Dacogen(decitabine) are standard drug therapies for this treatment. In Japan, Vidaza (being marketed by Nippon Shinyaku) is also
administered in cases where stem cell transplants are not used. (for Vidaza, see Market and value chain)
However, some cases of higher-risk MDS show resistance to standard treatment with hypomethylating agents (HMAs) such as
Vidaza and Dacogen, including relapse following treatment. The most advanced research being conducted for rigosertib was forthe treatment of patients with higher-risk MDS who had progressed on, failed or relapsed after prior therapy with HMAs.
According to the company, no drugs had been approved for the treatment of post-HMA higher-risk MDS patients as of February
2021.

R&D status: global phase III studies underway in patients with relapsed higher-risk MDS following HMA therapy
Phase III clinical trials in patients with relapsed or refractory higher-risk MDSIn February 2014, Onconova completed its phase III ONTIME clinical trial for the intravenous form of the drug in MDS patients in
the US who showed resistance to standard treatment with HMAs, or who experienced recurrence of the disease after treatment
with HMAs.
Of the 299 patients enrolled in the phase III clinical trial, 199 were administered rigosertib and 100 were placed in the control
group. The overall survival (OS) period for those who received rigosertib was 8.2 months, while OS for the control group (BSC)
was 5.8 months. However, with a p-value of 0.27, there was no statistically significant difference between the two groups.
Among patients whose condition had deteriorated or not responded to previous treatment using hypomethylating agents (184of 299 people, or 62%), the overall survival period for higher-risk MDS patients who received rigosertib was 8.5 months, while forthose in the control group (BSC) it was 4.7 months. The p-value was 0.022, showing a statistically significant difference. The
hematological toxicity of the conventional anticancer agent was approximately 60%. With rigosertib, toxicity of Grade 3 or above
did not exceed 7%, and non-hematological toxicity did not exceed 3%, confirming safety of the drug.

Phase III clinical trials in patients with higher-risk MDS for whom HMA therapy was ineffective or who relapsed after treatment
In August 2015, Onconova submitted plans to US Food and Drug Administration (FDA) and regulatory agencies in England,
Germany, and Australia for global phase III comparative trials of rigosertib for patients who did not see results from low

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methylation, or experienced higher-risk refractory or relapsed MDS following HMA treatment. These global trials are currently
ongoing.
In August 2020, Onconova announced that the primary endpoint (overall survival compared with physician’s choice [PC]treatment) was not met in the phase III clinical trial. More specifically, the primary endpoint of the trial was overall survival,
comparing IV rigosertib plus best supportive care to PC plus best supportive care. Onconova also analyzed a pre-specified
subgroup of very high risk (VHR-MDS) patients. Results of the trial demonstrated that in the intent-to-treat analysis patients given
IV rigosertib achieved overall survival of 6.4 months, versus 6.3 months for PC (p=0.33) in the overall HR-MDS population. There
was also no significant difference in overall survival between the two study arms in the VHR-MDS subgroup. Onconova isconducting further analysis.

SymBio responsible for operation of global phase III clinical trials in JapanThe company has been conducting the global phase III clinical trials in Japan since December 2015. The first patient was
registered in July 2016 and 48 patients had been registered as of end December 2019 versus the target of 50. Regarding
Onconova’s August 2020 announcement regarding not meeting primary endpoints of its phase III clinical trial, SymBio
commented that it is looking to apply the knowledge gleaned from additional analysis of the study to rigosertib development
going forward.

Oral rigosertib in patients with higher-risk MDS
R&D status: phase I/II clinical trials underway
Onconova, the anticancer drug rigosertib’s licensor, presented phase II clinical trial data on oral rigosertib for patients withhigher-risk myelodysplastic syndromes (MDS) at the 58th American Society of Hematology (ASH) Annual Meeting held in
December 2016.
The data on the efficacy and safety of oral rigosertib and azacitidine combination for 33 MDS patients (20 HMA naïve; 13 HMA
resistant) was presented at the poster presentation, “Combination of Oral Rigosertib and Injectable Azacitidine in Patients with
Myelodysplastic Syndromes (MDS): Results from a Phase II Study.” The complete remission (CR) rate among HMA-naïve patientswas higher (35%) and responses occurred more rapidly and durably with the oral rigosertib combination compared to thesingle-agent azacitidine. The median duration of CR was eight months, comparing very favorably to the historic duration of CR of
3.2 months with single-agent azacitidine.
As of February 2021, Onconova was making efforts toward finalizing the design for a pivotal phase III oral rigosertib/azacitidine
combination trial for the first-line treatment of higher-risk MDS.

Phase I clinical trials in JapanThe company began the domestic phase I clinical trial of oral rigosertib to confirm the safety of the drug at high doses (arequirement for phase II clinical trials conducted by Onconova in the US for the indication of first-line treatment for relapsed or
refractory higher-risk MDS). The patient enrollment for the study was completed in June 2019. After establishing safety in thephase I clinical trial, the company plans to resume the trial of the drug in combination with azacitidine and participate in global
clinical trials conducted by Onconova. In December 2019, Onconova issued a press release announcing it was considering aphase II/III adaptive trial for untreated high-risk MDS patients based on data presented at the 61st American Society of
Hematology Annual Meeting and Exposition held in December 2019.

Exploring new indications
In January 2021, the company entered into a joint research agreement with the Institute of Medical Science, the University ofTokyo (IMSUT) to explore potential new indications for bendamustine and rigosertib. Under this agreement, SymBio will
undertake joint research with Professor Toshio Kitamura, from the Division of Cellular Therapy within IMSUT’s Advanced ClinicalResearch Center, using bendamustine and rigosertib in combination or with other approved drugs to explore efficacy and new
indications. The joint research will analyze the epigenetic control of various tumor cells to explore as-yet-unknown

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pharmacological effects of bendamustine and rigosertib, analyzing their effects when used in combination and with otherapproved drugs.
Professor Kitamura is an accomplished researcher and has a large network of researchers and physicians in the areas ofhematopoietic stem cell differentiation and hematopoietic tumors such as leukemia. He is also studying molecular mechanisms inthe development of hematopoietic tumors caused by epigenetic abnormalities, looking to develop novel therapies using
hematopoietic tumor models. SymBio will leverage its experience in winning early approval for proprietary anticancer drugs incollaborating with IMSUT to search for new indications for bendamustine and rigosertib.

Patient population, estimated sales
According to SymBio estimates, patients with lower-risk MDS in Japan number about 7,800, with 3,200 MDS patients classified as
higher-risk.
Nippon Shinyaku Co., Ltd. (TSE1: 4516) has been selling azacitidine in Japan as first-line therapy for MDS under the productname Vidaza since March 2011. According to Nippon Shinyaku, sales of Vidaza were JPY15.7bn in FY03/20 (+8.3% YoY) andforecast to reach JPY16.0bn in FY03/21. Shared Research thinks that sales of the intravenous and oral forms of rigosertib could
match or exceed sales of Vidaza, used for patients who have not received treatment with Vidaza or in combination therapy withVidaza.

SyB V-1901 (antiviral drug, brincidofovir)
In September 2019, SymBio concluded an exclusive global license agreement with Chimerix Inc. for the antiviral drug
brincidofovir (SyB V-1901). The company acquired exclusive global rights to develop, manufacture, and market brincidofovir for
all diseases except smallpox. Under the terms of the agreement, the company will pay Chimerix an upfront payment of USD5mn,
milestone payments on future developments of USD180mn, and royalties on the product sales. Brincidofovir differs from othercandidates in SymBio’s pipeline in that it targets the global market and that the company had acquired not only development
and marketing rights but also manufacturing rights to the drug.
According to the company, Chimerix had been developing oral formulation of brincidofovir, but suspended development due tothe failure of the phase III clinical trial. SymBio determined that the failure of the oral formulation was due to its low intestinal
absorption rate and side effects arising from toxicity, and thought that it could circumvent such problems if it worked on
developing brincidofovir as an intravenous formulation. The company commented that one of the reasons it entered the license
agreement with Chimerix was the latter’s policy of focusing on cancer.

Mechanism of action and target indications of brincidofovir
Brincidofovir is an antiviral drug formed by conjugating a lipid chain (hexadecyloxypropyl, or HDP) of specified length tocidofovir (antiviral drug already approved and marketed in the EU and the US, but not approved in Japan). As a lipid conjugate, it
has a novel mechanism of action and can be taken up by cells at enhanced efficiency compared to cidofovir (i.e., brincidofovir
has higher cell membrane permeability). Once inside a cell, brincidofovir transforms into a direct-acting agent and inhibits viral
replication, demonstrating high antiviral efficacy. It is also easy to use as it has a low risk of nephrotoxicity, which is a side effect of
cidofovir, hence making it a novel, highly active anti-multiviral drug. It is expected to become an effective treatment against awide array of infectious diseases caused by DNA viruses, including cytomegalovirus (CMV) and other herpes viruses,
adenoviruses, BK virus, papillomaviruses, and smallpox virus.

Cidofovir (CDV): Approved by FDA in 1996 for the treatment of cytomegalovirus retinitis in AIDS patients. It inhibits replication of multiple families of
DNA viruses other than herpes viruses, including adenoviruses, papillomaviruses, and polyomaviruses.
CDV is taken up by renal tubular epithelial cells through organic anion transporter 1 (OAT1), and its accumulation in the cells cause nephrotoxicity.
brincidofovir is expected to have a low risk of nephrotoxicity as its lipid chain prevents it from being taken up by OAT1 and accumulating in renal
tubular epithelial cells.

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Development status: preparing to begin phase II clinical trials in the US and Europe
The US-based phase I clinical trial of intravenous formulation of brincidofovir was completed. No serious side effects wereobserved in the study.
After a review at the global advisory board held in February 2020, the company concluded that it would prioritize global
development of brincidofovir (mainly in Japan, the US, and Europe) to treat adenovirus (AdV) infections in patients receiving
hematopoietic stem cell transplantation to address an unmet medical need. Based on safety and efficacy data acquired from its
study, the company plans to review the drug’s efficacy against dsDNA viral infections in patients receiving hematopoietic stem
cell transplantation and extend its target indications to include multiviral infections. By exploring the potential for expanding
target disease areas to viral infections related to organ transplants (including kidney transplants), the company aims to grow themarket for and maximize the business value of brincidofovir. As of February 2021, the company was in preparation to initiate adose-finding study of the liquid formulation of brincidofovir in pediatric patients.
Clinical trials by Chimerix have demonstrated superior, broad-spectrum antivirus activity of the oral formulation of brincidofovir,
raising expectations for the potential of the liquid formulation as a safe and effective therapy to prevent and treat a range of viral
infections in patients receiving hematopoietic stem cell transplantation.
Hematopoietic stem cell transplantation is one of the therapies aimed at completely curing diseases such as blood cancer andimmunodeficiency disorders that are difficult to treat with conventional chemotherapy. In Japan, there are about 4,000 patients
who have undergone allogeneic hematopoietic stem cell transplantation, and about 60% of them have contacted viralhemorrhagic cystitis (vHC) or HHV-6 encephalitis. For vHC, cidofovir is used as first-line treatment in the EU and US. For
encephalitis, foscavir and denocin are designated as the first-line drugs, and cidofovir as the second-line drug.

dsDNA viruses: Includes families of herpesviridae, adenoviridae, polyomaviridae, papillomaviridae, and poxviridae, such as cytomegaloviruses (CMV),
adenoviruses (AdV), human herpesvirus 6 (HHV-6), BK virus, herpes simplex virus HSV-1 and -2, varicella-zoster virus (VZV), human papillovirus (HPV),JC virus (JCV), and smallpox (variola virus).
Viral hemorrhagic cystitis (vHC): Among viral infections that frequently occur following hematopoietic stem cell transplantation, adenovirus infections
causing hemorrhagic cystitis are particularly refractory in nature. When severe, they can cause disseminated infection and become fatal. Cases of
adenovirus spreading to the kidney and causing kidney failure and ultimately death have been reported. These infections are especially likely to occur in
unrelated donor transplantation and in umbilical cord blood transplantation, which are relatively common in Japan. The infections are likely to be
refractory, as they are further complicated by the length of time required for reconstruction of the immune system. Drugs currently used in treatment,
including cidofovir (CDV), are either unapproved or off-label in Japan.
HHV-6 encephalitis: HHV-6 (Human Herpesvirus 6) is the sixth human herpesvirus to be discovered. It reactivates in 30–70% of patients after allogenic
hematopoietic stem cell transplantation and can cause HHV-6 encephalitis. Most cases of HHV-6 encephalitis develop within 2–6 weeks after
transplantation, most frequently in the third week after transplantation. It is characterized by the three major symptoms of impaired memory,disordered consciousness, and convulsions, which in typical cases gradually appear in the same order (convulsions occur in 30–70% of patients). In
rapidly progressing cases, which are not uncommon, neurological symptoms worsen by the hour, often requiring respirator management for repeatedconvulsions and respiratory depression. The conditions of HHV-6 encephalitis patients often deteriorate rapidly over a short period of time, making
early treatment important. According to guidelines edited and issued by the Japan Society for Hematopoietic Cell Transplantation (February 2018), thefirst-line drugs are foscarnet (FOS) and ganciclovir (GCV), followed by the second-line drug cidofovir (CDV). CDV is not the preferred first-line drug
due to nephrotoxicity and because it transfers poorly into cerebrospinal fluid (CSF). All three of these drugs have been found to be effective in vitro, but
no trials have been conducted yet to confirm their clinical efficacy in patients with HHV-6 encephalitis.

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Earnings structure(JPYmn)FY12/11

FY12/12FY12/13

FY12/14

FY12/15

FY12/16

FY12/17

FY12/18

FY12/19

FY12/20

Sales

1,883

1,955

1,532

1,955

1,933

2,368

3,444

3,836

2,838

2,987

YoY

29.8%

3.9%

-21.6%

27.6%

-1.1%

22.5%

45.4%

11.4%

-26.0%

5.3%

Product sales

1,632

1,955

1,432

1,940

1,933

2,137

3,444

3,810

2,811

2,977

YoY

401.3%

19.8%-26.8%

35.5%

-0.3%

10.6%

61.1%

10.6%

-26.2%

5.9%

Treakisym sales (NHI price basis; reference)

3,390

3,940

4,230

4,320

4,760

4,720

7,600

8,500

-

-

Product sales / Sales (NHI price basis)

48.2%

49.6%

33.9%

44.9%

40.6%

45.3%

45.3%

44.8%

-

-

250

-

100

15

-

231

-

26

26

10

1,872

1,930

1,486

1,908

1,852

2,265

3,382

3,648

2,831

2,546

29.5%

3.1%

-23.0%

28.4%

-2.9%

22.3%

49.4%

7.9%

-22.4%-10.1%

Royalty revenue
Sales to Eisai
YoY

Sales to other partners

10

26

46

47

81

104

62

187

6

441

1,224

1,362

1,214

1,428

1,350

1,464

2,413

2,663

1,973

2,120

CoGS / Product sales

75.0%

69.7%

84.8%

73.6%

69.8%

68.5%

70.1%

69.9%

70.2%

71.2%

CoGS / Sales (NHI price basis)

36.1%

34.6%

28.7%

33.1%

28.4%

31.0%

31.7%

31.3%

-

Product procurement

1,434

1,322

1,175

1,550

1,242

1,606

2,589

2,969

1,684

3,163

658

593

318

527

583

904

1,031

1,173

865

867

Product gross profit

408

593

218

512

583

673

1,031

1,147

838

857

Gross profit margin

25.0%

30.3%

15.2%

26.4%

30.2%

31.5%

29.9%

30.1%

29.8%

28.8%

CoGS

Gross profit

Royalty revenue
SG&A expenses
Personnel expenses
R&D expenses
Other
Operating profit

250

-

100

15

-

231

-

26

26

10

2,725

2,293

1,999

1,830

3,135

3,031

4,978

3,829

5,166

5,373

365

413

441

479

488

541

554

504

506

530

1,945

1,438

1,053

774

2,035

1,667

3,018

1,833

2,442

2,267

415

442

505

577

612

823

1,406

1,492

2,219

2,576

-2,067-1,700-1,681-1,303-2,552-2,127-3,947-2,656-4,302-4,506

Source: Shared Research based on company data

Sales
The company’s sales are made up of product sales and royalty revenue. Per the above table, most of the sales through FY12/19
have originated from Eisai. The company began own sales of Treakisym® from December 10, 2020 and recorded sales to non-Eisai
partners of JPY441mn in FY12/20.

Product sales
Product sales are revenue from selling Treakisym®. The company began booking product sales in FY12/10, when it obtained
approval for Treakisym® and started selling the anticancer agent in December 2010. ThroughFY12/16, the company booked salesof Treakisym® indicated for relapsed or refractory low-grade NHL and MCL.
In FY12/17, the company booked sales of additional indications of untreated low-grade NHL and MCL, resulting in a strong sales
YoY.
FY12/19 product sales declined YoY. A lyophilized injection formulation of Treakisym® imported from Astellas Deutschland GmbH,a consolidated subsidiary of Astellas Pharma, was found to contain impurities and appearance defects, and as a result, shipmentsof Treakisym® 100mg to Japan distributor Eisai were postponed. Consequently, booking of some product sales was delayed until
the following fiscal year, resulting in a YoY decline in sales.

Royalty revenue
Royalty revenue includes one-time contract payments and milestone payments.

CoGS
Cost of goods sold refers to procurement costs for drugs. SymBio purchases lyophilized Treakisym® from Astellas DeutschlandGmbH. Before December 2019, Astellas supplied Treakisym® to the company for about 70% of SymBio’s wholesale price to Eisai.
As noted above, the company began own sales of Treakisym® on December 10, 2020. This allows the company to receive not
only the gross profit it received previously, but also the gross profit earned by Eisai through December 9, 2020 (i.e., thedifference between the shipment price from Eisai to pharmaceutical wholesalers and the price Eisai paid the company to source
the product). Shared Research understands that this is a factor that contributes to higher GPM.

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SymBio sources the RTD formulation of Treakisym® from US company Eagle Pharmaceuticals. According to the company, its GPM
on the RTD formulation is higher than for lyophilized Treakisym®.

SG&A expenses
Personnel and R&D are the main SG&A expenses.

Personnel expenses
Personnel expenses consist of directors’ remuneration as well as expenses for personnel involved in such tasks as marketing,searching for in-licensing candidates and general administration. Personnel expenses have been trending upward in line withadditions to the pipeline and business expansion.

R&D expenses
R&D expenses include personnel expenses for R&D staff as well as clinical trial outsourcing expenses and upfront payments
accompanying product in-licensing. R&D expenses fluctuate depending on the progress of clinical trials and new license
agreements from in-licensing activities. According to the company, in-licensing expenses are between JPY500mn and JPY1bn perdrug, and domestic clinical trials cost between JPY1bn and JPY2bn.
Eisai paid half of the development costs for the Treakisym® freeze-dried (FD) formulation in Japan.

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Strengths and weaknesses
Strengths◤ Unique candidate selection process: SymBio makes decisions on in-licensing new drug candidates based on an initialassessment and screening process by its in-house search and evaluation team. The final decision is made by the company after
evaluation by a team of medical experts—the Scientific Advisory Board (SAB). President Yoshida’s extensive range of contacts
in the pharmaceutical industry built during his tenure at Amgen Japan and Amgen Inc. is a significant hurdle for competitors
attempting to emulate the quality of the company’s search and evaluation team, SAB panel and selection process.
◤ Strong product development: Treakisym® (bendamustine hydrochloride)—the first drug the company developed—received

marketing approval in Japan just five years after the license agreement was signed with Astellas. Treakisym®, launched by thecompany in December 2010, is being used by a number of Japanese physicians and is considered to be an essential drug forthe treatment of relapsed or refractory low-grade NHL and MCL. The company’s success with Treakisym® demonstrates its
strong product development capabilities and nimbleness.
◤ Strong share in niche markets: SymBio focuses on niche markets for rare oncologic and hematologic diseases and rarediseases. The company takes advantage of a less competitive environment by developing drugs for indications that serve a
limited number of patients and require a high degree of in-house expertise. Thus, the company has succeeded in securing
more than 50% of the target market for Treakisym® in relapsed or refractory low-grade NHL and MCL in the third year after
launch.

Weaknesses◤ Dependence on a single individual: Founding President and CEO, Fuminori Yoshida, has played a central role in all aspectsof SymBio’s management since its foundation. If for any reason Mr. Yoshida is unable to perform his duties, this could have an
impact on company operations.
◤ Dependence on a single product: As of February 2021, Treakisym® accounted for all product sales of the company. SymBio

is a biotech startup whose strength lies in having brought a pharmaceutical product to market, but its dependence on a single
product raises the risk of earnings volatility. Sales and gross profit declined in FY12/19 and FY12/20 due to contamination andirregular appearance of lyophilized Treakisym® imported from Astellas Deutschland GmbH, which led to a temporary slump in
product sales.

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Coverage

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Market and value chain
Market overview
Lymphatic cancer: patient population, market size, treatment drugs
Morbidity of lymphatic cancer
In 2017, the number of people diagnosed with lymphatic cancer in Japan was 34,571 (+1.0% YoY; average annual increase inpast 10 years is 6.3%), according to “Cancer statistics and cancer registration in Japan” complied by the Center for Cancer
Control and Information Services. Of these, 27,887 (+1.3% YoY), or 80.7% (80.4% in the previous year), were 60 years or older.
Of the 977,393 (-1.8% YoY) people diagnosed with cancer, those diagnosed with lymphatic cancer accounted for only 3.5%
(3.4% in the previous year), but their number increased 84.1% between 2007 and 2017 versus a 38.8% increase in the numberof people newly diagnosed with cancer.
Morbidity of lymphatic malignancy
40,00035,00030,00025,00020,00015,00010,000
5,000
0
1975

1980

Number of patients
Incidence rate (per 100,000)

1985

1990

1995

2000

2005

2010

2015

1975

1980

1985

1990

1995

2000

2005

2010

2015

4,013

4,741

6,635

9,297

11,195

13,307

16,991

23,91930,103

3.6

4.1

5.5

7.5

8.9

10.5

13.3

18.7

23.7

Source: Shared Research based on data from Center for Cancer Control and Information Services, National Cancer Center

Treakisym® market potential and patient population
The company estimates that the number of patients being treated for relapsed or refractory low-grade NHL and MCL in Japan is9,336 and the number of patients with untreated low-grade NHL and MCL is 6,967. On an NHI drug reimbursement price basis,
Treakisym® sales reached JPY8.5bn in FY12/18 (JPY7.6bn in FY12/17).
The company estimates that the number of Japanese patients with relapsed or refractory DLBCL for which the company isconsidering application for approval of an additional indication is 18,672.
Treakisym® indications and number of patients
Indications

Patients

Progress

Relapsed or refractory low-grade NHL and relapsed or
refractory MCL

9,336 Approved

Untreated low-grade NHL, and untreated MCL

6,967 Approved

CLL
Relapsed or refractory NHL

Notes
Sales: JPY8.5bn (FY12/18)

656 Approved
18,672 Clinical trials underway

Source: Shared Research based on company data
*Sales based on NHI prices.

Drugs competing with Treakisym®
As of February 2015, these include rituximab and ibritumomab tiuxetan.

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Rituximab (product name: Rituxan)
The drug, co-developed by the US companies IDEC Pharmaceuticals and Genentech, Inc. received US approval in November
1997 as the world’s first monoclonal antibody.
Rituxan consists of a portion of both mouse antibody and IgG, a human antibody. It attaches itself to the CD20 antigen thatappears on B cells in the body and fights tumors through complement-dependent cytotoxicity and antibody‐dependent cell‐
mediated cytotoxicity effects (source: Chugai, Zenyaku Kogyo).
In Japan, Zenyaku Kogyo and Chugai have been jointly selling the drug since September 2001. Chugai’s Rituxan sales were
JPY7.2bn (-39.5% YoY) in FY12/20.

Ibritumomab tiuxetan (product name: Zevalin)
Like Rituxan, the antibody drug Zevalin targets CD20 antigen on B cells. It combines the antibody with a radioactive substanceand attacks B cells with radiation. The treatment is only available at medical institutions authorized to handle radioactive
elements.
Zevalin was approved in January 2008 as a treatment for refractory lymphatic cancer (low-grade B-cell NHL). It is sold by Fujifilm
RI Pharma Co., Ltd., a subsidiary of Fujifilm Holdings Corporation.

Patient population, treatment drugs for MDS
MDS patient population estimated at 11,000
A high proportion of people aged 60 or older suffer from MDS. The number of patients totaled 9,000 in 2008, with 2,781 deaths
from the disease according to Japan’s Ministry of Health, Labour and Welfare (MHLW). SymBio estimates that there are currently
about 11,000 MDS patients in Japan amid a larger elderly population. Even though the number of patients continues to rise,
there is a high unmet medical need in Japan with no efficacious treatment available.
Rigosertib indications and number of patients
Condition

Patients

Low-risk MDS

7,800

High-risk MDS

3,200

Source: Shared Research based on company data

Drugs competing with rigosertib
According to the company, as of February 2021, Nippon Shinyaku Co., Ltd.’s Vidaza was the only IV drug approved in Japan forthe main indication of MDS.

Azacitidine (product name: Vidaza)
Vidaza, developed by Pharmion Corporation (now Celgene Corporation) in the US, is a treatment for first-line intermediate andhigher-risk MDS. Nippon Shinyaku Co., Ltd. signed a license agreement with Pharmion in 2006 to sell this drug in Japan,
obtaining marketing approval in January 2011 following the completion of domestic clinical trials.
In addition to killing cancerous cells, azacitidine inhibits DNA methylation. It becomes efficacious after use for three to six months,
with bone marrow suppression as the main side effect (a decline in white blood cells and platelets). However, while the use of
hypomethylating agents such as azacitidine and decitabine (Dacogen) in the treatment of MDS has improved the outcome ofpatients who tend to have very poor survival, about half of MDS patients do not respond, progress, or relapse at different times
after their response on these HMAs, followed by an extremely poor prognosis.

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According to Nippon Shinyaku, Vidaza is the only approved drug in Japan for the first-line treatment of higher-risk MDS, with noefficacious treatment available once patients treated with Vidaza relapse. Nippon Shinyaku booked Vidaza sales of JPY15.7bn(+8.3% YoY) in FY03/20 and expects sales of JPY16.0bn in FY03/21.

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Historical performance
Full-year FY12/20 results▷

Sales:▷

Operating loss: JPY4.5bn (loss of JPY4.3bn in FY12/19)▷

Recurring loss:

JPY4.6bn (loss of JPY4.4bn in FY12/19)▷

Net loss:

JPY4.1bn (loss of JPY4.4bn in FY12/19)

JPY3.0bn (+5.3% YoY)

Sales increased YoY, as the company booked sales of Treakisym®. Sales declined 32.1% YoY to JPY1.4bn in 1H (January–June2020), but were up 95.3% YoY to JPY1.6bn in 2H (July–December 2020). Through 1H, there was a high defect rate andunreliable delivery of multiple batches of lyophilized formulations of Treakisym® (supplied by Astellas Deutschland), reflected in
the YoY sales decline. Sales recovered sharply YoY in 2H, because the defect rate improved and the company sold inspected
products.
The business alliance agreement with Eisai for Treakisym® expired on December 9, 2020, and SymBio began independently
marketing Treakisym® in Japan on December 10. Sales broke down by customer were as follows: Eisai, JPY2.5bn (-10.1% YoY);
Suzuken Group, JPY126mn (JPY0mn in FY12/19); and Toho Pharmaceutical JPY120mn (JPY0mn in FY12/19).
Based on Treakisym® sales data from Eisai, which marketed the product until December 9, 2020, revenue from Treakisym® was
JPY7.7bn (+6.3% YoY) in FY03/20. Total sales from Q4 FY03/20 through Q3 FY03/21 (January–December 2020) came to JPY6.9bn(JPY7.5bn for the same period a year earlier).
Gross profit was JPY867mn (+0.2% YoY) and GPM on product sales was 28.8% (-1.0pp YoY). The CoGS ratio rose in 1H due tostrengthened inspection procedures for lyophilized formulation of Treakisym® (two visual inspections), valuation loss oninventories (JPY69mn versus JPY188mn a year earlier), and higher transportation costs. The inventory valuation loss was related toquality defects of Treakisym®.
The GPM improved from 24.2% in 1H to 33.0% in 2H. The company booked a valuation loss on inventories in 1H, but none in 2H.
Shared Research understands that beginning its own marketing of Treakisym® in Q4 also contributed to the GPM improvement.
Reasons why in-house marketing of Treakisym® contributed to GPM improvement: Switching from marketing through Eisai (based the marketing
agreement with Eisai) to doing its own marketing meant that products are shipped to pharmaceutical wholesalers instead of to Eisai starting from
December 10, 2020. This allows the company to receive not only the gross profit it received previously (the company’s sales to Eisai minus cost of
sales), but also the gross profit earned by Eisai through December 9, 2020 (i.e., the difference between the shipment price from Eisai to pharmaceuticalwholesalers and the price Eisai paid the company to source the product).

SG&A expenses increased 4.0% YoY to JPY5.4bn. Although the company reduced R&D and administrative expenses by JPY900mn,
SG&A expenses increased overall due to upfront spending to establish its own sales structure.
▷

R&D expenses declined 7.2% YoY to JPY2.3bn. This included expenses for conducting clinical trials of intravenous
formulations of Treakisym® and rigosertib. The company also recorded a milestone payment of roughly JPY500mn on
obtaining marketing approval for the RTD formulation of Treakisym®.

▷

Excluding R&D expenses, SG&A expenses rose 14.0% YoY to JPY3.1bn. The company incurred upfront expenses toestablish its own sales organization.

Losses expanded across the board despite higher sales due to an increase in SG&A expenses. The difference between recurring
loss and net loss is attributable to a JPY525mn settlement payment booked as extraordinary gains.

Business progress updates
Major business developments in FY12/20 were as follows.

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The business alliance agreement with Eisai for Treakisym® expired on December 9, 2020, and SymBio began independently
marketing Treakisym® in Japan on December 10.

▷

In September 2020, the company obtained approval for the RTD formulation of Treakisym®. It began sales in January 2021.

▷

Also in September 2020, the company completed observation of all patients enrolled in a clinical trial of the RI formulation ofTreakisym®. The company plans to apply for approval on completion of the clinical trial, targeting approval in 2H FY12/22.

▷

In August 2020, Onconova, the licensor of anticancer drug rigosertib, announced that its global phase III trial (INSPIRE study)
addressing higher-risk myelodysplastic syndromes (higher-risk MDS) intolerant of treatment using hypomethylating agents
failed to meet its primary endpoints. SymBio engages in clinical development of rigosertib in Japan, and plans to use theknowledge obtained from genomic analysis of the INSPIRE study in future development of rigosertib.

▷

In August 2020, the company decided to develop intravenous formulation of antiviral drug brincidofovir (SyB V-1901, BCV IV)
globally (mainly in Japan, the US, and Europe) for adenovirus (AdV) infections occurring after hematopoietic stem celltransplantation. Shared Research understands this is the first time the company has conducted global new drug development
independently.

▷

In July 2020, the Court of Arbitration delivered a ruling in The Medicines Company (MDCO) arbitration case. The court did notgrant damage claims made against MDCO but ordered MDCO to pay 50% of costs incurred by SymBio (USD4.95mn) in thearbitration proceedings, including attorney fees.

▷

In July 2020, the company applied for a partial change to the approved matters of Treakisym® for use in combination with
polatuzumab vedotin and rituximab targeting patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL).

▷In May 2020, the company submitted an application for partial change to the approved matters of BR therapy (combination of
anticancer agents Treakisym® and rituximab) to enable its use for r/r DLBCL.

Domestic
Preparations for in-house sales organization begin
The business alliance agreement between SymBio and Eisai Co., Ltd. under which Eisai acts as a sales agent expired in December
2020. The company therefore began preparations to build an in-house sales organization for domestic sales of Treakisym®.
In FY12/21, the company has deployed a nationwide network of 53 marketing representatives as well as nine hematology experts
to cover each region to establish a highly productive internal sales organization capable of making proposals that fit the needs ofeach region.
To establish a nationwide distribution structure, in September 2020, the company concluded a basic agreement with Suzuken
Co., Ltd (Suzuken Group) and Toho Pharmaceutical Co., Ltd (a consolidated subsidiary of Toho Holdings Co., Ltd.; Kyoso Mirai
Group) for the procurement and sale of pharmaceuticals. SymBio is using Suzuken Group and Kyoso Mirai Group as its sole
distributors after the marketing agreement with Eisai expired. The company has established two distribution centers, one in
Eastern Japan and the other in Western Japan, under management by S.D. Collabo Co., Ltd.
SymBio has thus completed building its in-house sales organization, and transitioned to in-house sales of Treakisym® in December
2020 after expiry of the business alliance agreement with Eisai.

Stable product supply
SymBio imports lyophilized Treakisym® for injection from Astellas Deutschland (consolidated subsidiary of Astellas Pharma).
Treakisym® inventories were substantially depleted in 1H relative to year-ago levels, but inventory levels recovered in 2H assecondary packaging and quality tests were applied to some batches of Treakisym® 100mg vials imported from Astellas
Deutschland.

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In September 2020, the company obtained manufacturing and marketing approval for liquid formulations of Treakisym® (RTD
formulation) under license from Eagle Pharmaceuticals with plans to begin sales in January 2021. Import and shipments to thesole distributors of the Treakisym® (RTD formulation) began in Q4 FY12/20 (October–December 2020).

Anticancer agents: SyB L-0501[lyophilized injection]/SyB L-1701 [RTD]/SyB L-1702 [RI] (generic name: bendamustine hydrochloride,
product name: Treakisym®)
The anticancer agent Treakisym® is used to treat malignant lymphomas, indicated for untreated low-grade non-Hodgkin’s
lymphoma and mantle cell lymphoma (marketing approval obtained in December 2016), refractory or relapsed low-grade NHL
and MCL (October 2010), and chronic lymphocytic leukemia (August 2016).
The combination therapy of Treakisym® and rituximab (BR therapy) was newly included in the Practical Guidelines for
Hematological Malignancies 2018 published by Japanese Society of Hematology as a standard treatment option, which applies toall of the approved indications. This has seen Treakisym® establish its position as a standard treatment for lymphatic cancer.
Also, SymBio obtained approval for the partial change to the approved matters of Treakisym® in July 2018. Treakisym® can now be
used in combination with new anti-CD20 antibodies and not just rituximab for the treatment of CD20-positive follicularlymphoma, the most common histological type of low-grade NHL. This allows the company to provide patients a new treatment
option: combination therapy with obinutuzumab. In March 2019, SymBio obtained approval for the partial change to theapproved matters of Treakisym® to enable its use as a pretreatment agent in tumor-specific T cell infusion therapy. This allows
Treakisym® to be used as a pretreatment agent for Kymriah® intravenous infusion, which was the first chimeric antigen receptor
T-cell (CAR-T) therapy approved in Japan and on the NHI drug price list from May 2019. Growing use of Treakisym® as apretreatment agent in regenerative medicine has solidified its positioning as standard therapy for malignant lymphomas.
In the phase III clinical study of Treakisym® in BR therapy conducted in patients with relapsed or refractory diffuse large B-cell
lymphoma (r/r DLBCL), an additional indication following the above approved ones, results showed that the response rate
(primary endpoint) was better than expected. Based on this, the company submitted an application for partial change toapproved matters in May 2020. It is currently conducting a follow-up study with overall survival as the primary endpoint, because
evaluating the survival data (e.g., overall survival and progression-free survival) for Treakisym® administered in combination withrituximab is crucial for establishing Treakisym® as a treatment for DLBCL. Also, after Chugai Pharmaceutical Co., Ltd. applied for
manufacture and marketing approval for polatuzumab vedotin in combination with BR therapy to treat r/r DLBCL in June 2020,
the company submitted an application for partial change to the approved matters of Treakisym® for use in combination with
polatuzumab vedotin and rituximab. If the new drug applications by Chugai and SymBio are approved and polatuzumab vedotin
is added to the NHI drug price list, Treakisym® can be used with polatuzumab vedotin in combination with BR therapy. At present
there are no effective treatments for the additional indication of r/r DLBCL, which is usually treated by a combination of
anticancer agents as salvage chemotherapy, so development of a highly effective but safe new drug would be ideal. Since BR
therapy is already being used in the West to treat r/r DLBCL, patient organizations and related academic societies have petitioned
MHLW so that it can be used in Japan as soon as possible.
The company concluded an exclusive licensing agreement in Japan with Eagle Pharmaceuticals (based in New Jersey, US) in
September 2017 for the RTD and RI formulations of Treakisym®. Manufacturing and marketing approval of the RTD formulation
was obtained in September 2020, and the company plans to launch it in January 2021. The company is conducting clinical trials
to confirm safety of the RI formulation and plans to apply for approval in FY12/21. Unlike the current lyophilized powder
formulation, the RTD formulation reduces the workload of medical professionals, because it eliminates the need for troublesome
manual dissolution. The RI formulation can be administered in just 10 minutes versus 60 minutes for the current lyophilized
injection and RTD formulation. This reduces the burden on patients and healthcare professionals, providing significant value
added. Multiple patent protections in the form of a liquid product license will enable the extension of the product life ofTreakisym® to 2031.

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Anticancer agents: SyB L-1101 [injection]/SyB C-1101 [oral] (generic name: rigosertib sodium)
Onconova Therapeutics, Inc., the licensor, conducted a global phase III trial (INSPIRE study) across more than 20 countries
addressing higher-risk myelodysplastic syndromes (higher-risk MDS) with overall survival as the primary endpoint. The target ispatients who do not respond to the current standard treatment with hypomethylating agents, relapse after treatment under thecurrent standard of care, or are intolerant to hypomethylating agents. In August 2020, Onconova announced a comparator trial
to physicians’ choice of treatment failed to achieve the primary endpoint. The company leads clinical trials conducted in Japanand is looking to apply the knowledge gleaned from additional analysis of the INSPIRE study to rigosertib development going
forward.
Regarding the oral formulation of rigosertib, Onconova completed a phase I/II clinical trial for the drug used in combination withazacitidine, whose results suggested the efficacy and safety of the combination therapy. To verify the tolerability and safety of thehigh-dose oral formulation of rigosertib as an initial treatment for higher-risk MDS among Japanese patients, SymBio began aphase I clinical trial in Japan in June 2017 and completed patient enrollment in June 2019.

Antiviral drug, SyB V-1901 (generic name: brincidofovir）
In September 2019, SymBio concluded an exclusive global license agreement with Chimerix Inc. (hereafter Chimerix) for
brincidofovir (SyB V-1901), an antiviral drug in intravenous and oral forms). The company acquired exclusive global rights todevelop, manufacture, and market brincidofovir for all diseases except smallpox.
After a review at the global advisory board held in February 2020, the company concluded that it would prioritize global
development of brincidofovir IV (mainly in Japan, the US, and Europe) to treat adenovirus (AdV) infections in patients receiving
hematopoietic stem cell transplantation to address an unmet medical need. Based on safety and efficacy data acquired from its
study, the company plans to review the drug’s efficacy against dsDNA viral infections in patients receiving hematopoietic stem
cell transplantation and extend its target indications to include multiviral infections. By exploring the potential for expanding
target disease areas to viral infections related to organ transplants (including kidney transplants), the company aims to grow themarket for and maximize the business value of brincidofovir. The company is presently in preparation to initiate a dose-finding
study of the liquid formulation of brincidofovir in pediatric patients slated to begin in December 2021.
Clinical trials by Chimerix have demonstrated superior, broad-spectrum antivirus activity of brincidofovir oral against dsDNA
viruses. Brincidofovir IV is also expected to become a safe and effective therapy to prevent and treat a range of viral infections inpatients receiving hematopoietic stem cell transplantation.
Chimerix announced in December 2020 that the FDA had accepted its new drug application (NDA) for brincidofovir as a medical
defense against smallpox. The FDA has approved priority review for BCV under the Prescription Drug User Fee Act (PDUFA) andset the date for completing the review (PDUFA date) at April 7, 2021.

SyB P-1501, transdermal pain management system
Regarding SyB P-1501 licensed by The Medicines Company (marketed as IONSYS in the US), the company initiated an arbitration
against The Medicines Company (MDCO), under the rules of the International Chamber of Commerce, seeking damages of
USD82mn arising from MDCO’s repudiation of the license agreement. SymBio argued that MDCO’s failure to provide sufficientassurance to the company regarding the performance of obligations under the license agreement in light of its decision towithdraw from business activities relating to SyB P-1501 in the European and US markets was a material breach of the license
agreement. In September 2020, SymBio announced it had received the arbitration judgment and although the Court of
Arbitration did not award damages sought by the company, it did order MDCO to pay 50% of legal costs (about USD5mn)
sought by the company.

Overseas
The company marketed SyB L-0501 in South Korea, Taiwan, and Singapore, and product sales were in line with the company’splans.

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In-licensing of drug candidates
The company is currently focusing on unrolling global development plans for antiviral drug brincidofovir it in-licensed in
September 2019. It is constantly looking into multiple licensing deals and looking for and evaluating promising in-licensing drugcandidates.

Cumulative Q3 FY12/20 results▷

Sales:▷

Operating loss: JPY3.1bn (loss of JPY3.5bn in Q3 FY12/19)▷

Recurring loss:

JPY3.2bn (loss of JPY3.6bn in Q3 FY12/19)▷

Net loss:

JPY2.7bn (loss of JPY3.6bn in Q3 FY12/19)

JPY2.3bn (+16.2% YoY)

Overview
In cumulative Q3 FY12/20, sales increased YoY, as the company booked sales of Treakisym®. Sales were JPY1.4bn (-32.1% YoY) in
1H and JPY972mn in Q3 (versus sales of JPY3mn in Q3 FY12/19), representing YoY growth on a cumulative Q3 basis. A large
defect ratio in multiple batches of lyophilized Treakisym® formulations imported from Astellas Deutschland and unstabledeliveries continued in 1H, resulting in lower YoY sales. The defect ratio improved and selling inspected products led to higher
YoY sales in Q3.
Based on data supplied by Treakisym® distributor Eisai, sales of Treakisym® were JPY7.7bn (+6.3% YoY) in FY03/20. Sales were
solid on a quarterly basis at JPY1.6bn in Q4 FY03/20 (January–March 2020) versus JPY1.4bn in Q4 FY03/19, JPY1.9bn in Q1
FY03/21 (April–June 2020) versus JPY2.0bn in Q1 FY03/20, and JPY1.7bn in Q2 FY03/21 (July–September 2020) versus JPY2.1bn
in Q2 FY03/20.
Gross profit was JPY611mn (+8.5% YoY) and the GPM on product sales was 26.2% (-1.8pp YoY). The cost ratio increased due tostrengthened inspection procedures for lyophilized formulation of Treakisym® (two visual inspections), valuation loss oninventories (JPY69mn versus JPY188mn a year earlier), and higher transportation costs. The inventory valuation loss was related toquality defects of Treakisym®. However, GPM was 28.9% in Q3, an improvement over 24.2% in 1H. Although the company
booked an inventory valuation loss in 1H, it did not book a loss in Q3, leading to an improved cost ratio.
SG&A expenses declined 8.4% YoY to JPY3.8bn.

▷

R&D expenses declined 11.5% YoY to JPY1.7bn. This included expenses for conducting clinical trials of intravenous
formulations of Treakisym® and rigosertib.

▷

Excluding R&D expenses, SG&A expenses fell by 5.6% YoY to JPY2.0bn. The company incurred development costs for its
in-house sales organization.

Losses narrowed across the board on higher sales and lower SG&A expenses. The difference between recurring and net losses is
attributable to a JPY525mn settlement payment booked as extraordinary gains.

Business progress updates
Major business developments in cumulative Q3 FY12/20 were as follows.

▷

In September 2020, the company obtained approval for the RTD formulation of Treakisym®. It plans to begin sales in January
2021.

▷

Also in September 2020, the company completed observation of all patients enrolled in a clinical trial of the RI formulation ofTreakisym®. The company plans to apply for approval on completion of the clinical trial, targeting approval in 2H FY12/22.

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In August 2020, Onconova, the licensor of anticancer drug rigosertib, announced that its global phase III trial (INSPIRE study)
addressing higher-risk myelodysplastic syndromes (higher-risk MDS) intolerant of treatment using hypomethylating agents
failed to meet its primary endpoints. SymBio engages in clinical development of rigosertib in Japan, and plans to use theknowledge obtained from genomic analysis of the INSPIRE study in future development of rigosertib.

▷

In August 2020, the company decided to develop intravenous formulation of antiviral drug brincidofovir (SyB V-1901, BCV IV)
globally (mainly in Japan, the US, and Europe) for adenovirus (AdV) infections occurring after hematopoietic stem celltransplantation. Shared Research understands this is the first time the company has conducted global new drug development
independently.

▷

In July 2020, the Court of Arbitration delivered a ruling in The Medicines Company (MDCO) arbitration case. The court did notgrant damage claims made against MDCO but ordered MDCO to pay 50% of costs incurred by SymBio (USD4.95mn) in thearbitration proceedings, including attorney fees.

▷

In July 2020, the company applied for a partial change to the approved matters of Treakisym® for use in combination with
polatuzumab vedotin and rituximab targeting patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL).

▷In May 2020, the company applied for a partial change to the approved matters of BR therapy (combination of anticancer
agents Treakisym® and rituximab) to enable its use for r/r DLBCL.

▷In May 2020, an abstract on analysis of phase III BR therapy (combination of anticancer agents Treakisym® and rituximab)
results for treatment of relapsed or refractory diffuse large B-cell lymphoma was adopted for the 25th Congress of theEuropean Hematology Association scheduled to be held in June 2020.

Domestic
Preparations for in-house sales organization begin
The business alliance agreement between SymBio and Eisai Co., Ltd. under which Eisai acts as a sales agent expires in December
2020. The company plans to transition to its in-house sales organization for domestic sales of Treakisym® in January 2021. Thisshould facilitate a move into the black from FY12/21 and ongoing profit growth thereafter and lay the groundwork for futurebusiness development.
In Q3, the company has started work on transferring marketing operations from Eisai, and as planned, has deployed a nationwide
network of 51 marketing representatives as well as six hematology experts to cover each region.
In September 2020, the company concluded a basic agreement with Suzuken Co., Ltd (hereafter, Suzuken Group) and Toho
Pharmaceutical Co., Ltd (a consolidated subsidiary of Toho Holdings Co., Ltd., hereafter Kyoso Mirai Group) for the procurement
and sale of pharmaceuticals. SymBio will use Suzuken Group and Kyoso Mirai Group as its sole distributors once the marketing
agreement with Eisai expires. The company will have two distribution centers, one in Eastern Japan and the other in WesternJapan, under management by S.D. Collabo Co., Ltd.

Stable product supply
SymBio imports lyophilized Treakisym® for injection from Astellas Deutschland (consolidated subsidiary of Astellas Pharma), which
is marketed in Japan by sales agent Eisai. Treakisym® inventories were substantially depleted in 1H relative to year-ago levels, butinventory levels were recovering as of Q3 as secondary packaging and quality tests were applied to some batches of Treakisym®
100mg vials imported from Astellas Deutschland while shipments to Eisai were on track with plan.

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Anticancer agents: SyB L-0501[lyophilized injection]/SyB L-1701 [RTD]/SyB L-1702 [RI] (generic name: bendamustine hydrochloride,
product name: Treakisym®)
Approved indications
The anticancer agent Treakisym® is used for the indications of untreated low-grade non-Hodgkin’s lymphoma and mantle cell
lymphoma (marketing approval obtained in December 2016), refractory or relapsed low-grade NHL and MCL (October 2010),
and chronic lymphocytic leukemia (August 2016).
The combination therapy of Treakisym® and rituximab (BR therapy) was newly included in the Practical Guidelines for
Hematological Malignancies 2018 edited and published by Japanese Society of Hematology as a standard treatment option,
which applies to all of the approved indications. This has seen Treakisym® establish its position as a standard treatment for
lymphatic cancer.
Also, SymBio obtained approval for the partial change to the approved matters of Treakisym® in July 2018. Treakisym® can now be
used in combination with new anti-CD20 antibodies and not just rituximab for the treatment of CD20-positive follicularlymphoma, the most common histological type of low-grade NHL. This allows the company to provide patients a new treatment
option: combination therapy with obinutuzumab. In March 2019, SymBio obtained approval for the partial change to theapproved matters of Treakisym® to enable its use as a pretreatment agent in tumor-specific T cell infusion therapy. This allows
Treakisym® to be used as a pretreatment agent for Kymriah® intravenous infusion, which was the first chimeric antigen receptor
T-cell (CAR-T) therapy approved in Japan and on the NHI drug price list from May 2019.

Relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL)
In the phase III clinical study of Treakisym® administered in combination with rituximab (BR therapy) targeting relapsed or
refractory diffuse large B-cell lymphoma (r/r DLBCL), an additional indication following the above approved ones, results showedthat the response rate (primary endpoint) was better than expected. Based on this, the company applied for a partial change toapproved matters in May 2020. It is currently conducting a follow-up study with overall survival as the primary endpoint, because
evaluating the survival data (e.g., overall survival and progression-free survival) for Treakisym® administered in combination withrituximab is crucial for establishing Treakisym® as a treatment for DLBCL.
In May 2020, an abstract on analysis of phase III BR therapy (combination of anticancer agents Treakisym® and rituximab) results
for treatment of relapsed or refractory diffuse large B-cell lymphoma was adopted for the 25th Congress of the European
Hematology Association scheduled to be held in June 2020. The company noted the main results of the phase III (38 patients)
trial analysis were as follows:
Overall response rate (ORR) was 76% and complete response (CR) rate was 47%.
<By gene activity pattern>▷

GCB type: ORR of 83%, CR rate of 67%▷

Non-GCB type: ORR of 78%, CR rate of 39%

Divided into GCB or non-GCB type DLBCLGCB type: Geminal center B-cell type
Non-GCB type: non Geminal center B-cell type

<By age group>▷

Under 65 years of age: ORR of 86%, CR rate of 71%▷

65 to 75 years old: ORR of 75%, CR rate of 45%▷

Over 75 years of age: ORR of 73%, CR rate of 36%

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As reference for the anticipated impact of adding the indication of r/r DLBCL, the company estimates that the number of patients
being treated for relapsed or refractory low-grade NHL and MCL in Japan is 9,336 and the number of patients with untreatedlow-grade NHL and MCL is 6,967, for a total of 16,303. For these indications, distributor Eisai booked sales of JPY8.0bn in FY03/20.
By comparison, the company estimates that the number of Japanese patients with r/r DLBCL is 18,672.
Also, after Chugai Pharmaceutical Co., Ltd. applied for manufacture and marketing approval for polatuzumab vedotin in
combination with BR therapy to treat r/r DLBCL in June 2020, the company applied for a partial change to the approved mattersof Treakisym® for use in combination with polatuzumab vedotin and rituximab. If the new drug applications by Chugai and
SymBio are approved and polatuzumab vedotin is added to the NHI drug price list, Treakisym® can be used with polatuzumab
vedotin in combination with BR therapy. At present there are no effective treatments for the additional indication of r/r DLBCL,
which is usually treated by a combination of anticancer agents as salvage chemotherapy, so development of a highly effective but
safe new drug would be ideal. Since BR therapy is already being used in the West to treat r/r DLBCL, patient organizations andrelated academic societies have petitioned MHLW so that it can be used in Japan as soon as possible.

Treakisym® liquid formulations (RTD/RI)
The company concluded an exclusive licensing agreement in Japan with Eagle Pharmaceuticals (based in New Jersey, US) in
September 2017 for the RTD and RI formulations of Treakisym®. Manufacturing and marketing approval of the RTD formulation
was obtained in September 2020, and the company plans to launch it in Q1 FY12/21. SymBio commenced a clinical trial for the RI
formulation in November 2018 primarily to confirm safety, and the follow-up period for all patients enrolled in the trial wascompleted in September 2020 (LPLV: Last Patient Last Visit). The company will apply for approval without delay after the end of
the clinical trial of the RI formulation and aims to begin sales in 2H FY12/22. The RI formulation can be administered in just 10
minutes versus 60 minutes for the current lyophilized injection and RTD formulation. This reduces the burden on patients andhealthcare professionals, providing significant value added.
Multiple patent protections in the form of a liquid product license (for RTD and RI formulations) will enable the extension of the
product life of Treakisym® to 2031. The RTD and RI formulations were launched in the US market from January 2016 and had
captured a 40% share of the bendamustine market within four months of commercialization, rising to over 90% within 12 months.
The company looks for an even more rapid switch from the lyophilized powder to liquid formulations in Japan.

Treakisym® lifecycle management strategy
As noted above, SymBio anticipates Treakisym® sales will expand on the back of increased sales for already approved indications
and contributions from the new indication of r/r DLBCL. Treakisym® is designated as a treatment for rare diseases and there-examination period ends in 2020, so the launch of liquid Treakisym® (RTD and RI formulations) will extend the product life
until 2031.
In addition, SymBio is slated to take over domestic marketing of Treakisym® in January 2021. Shared Research thinks this could
lead to higher profit margins for SymBio as it may be able to pocket gross profits booked by Eisai (difference between Eisai’s
procurement price and delivery price to drug wholesalers). We further believe gross profit margins could rise following transition
to liquid Treakisym® owing to a change in suppliers. The lyophilized powder formulation of Treakisym® is supplied by Astellas
Deutschland whereas the RTD and RI formulations are supplied by Eagle Pharmaceuticals. The company is also consideringin-house production of liquid Treakisym® as a future possibility.

Anticancer agents: SyB L-1101 [IV]/SyB C-1101 [oral] (generic name: rigosertib Sodium)
Rigosertib injection
Onconova Therapeutics, Inc., the licensor, conducted a global phase III trial (INSPIRE study) across more than 20 countries
addressing higher-risk myelodysplastic syndromes (higher-risk MDS) with overall survival as the primary endpoint. The target ispatients who do not respond to the current standard treatment with hypomethylating agents, relapse after treatment under thecurrent standard of care, or are intolerant to hypomethylating agents. In August 2020, Onconova announced a comparator trial
to physicians’ choice of treatment failed to achieve the primary endpoint. The company leads clinical trials conducted in Japan

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and is looking to apply the knowledge gleaned from genomic analysis of the INSPIRE study to rigosertib development going
forward.

Oral rigosertib
Regarding the oral formulation of rigosertib, Onconova completed a phase I/II clinical trial for the drug used in combination withazacitidine, whose results suggested the efficacy and safety of the combination therapy. To verify the tolerability and safety of thehigh-dose oral formulation of rigosertib as an initial treatment for higher-risk MDS among Japanese patients, SymBio began aphase I clinical trial in Japan in June 2017 and completed patient enrollment in June 2019.

Antiviral drug to treat infections: SyB V-1901 (generic name: brincidofovir)
In September 2019, SymBio concluded an exclusive global license agreement with Chimerix Inc. (hereafter Chimerix) for
brincidofovir (SyB V-1901, hereafter BCV IV and BCV Oral), an antiviral drug for the treatment of infections in intravenous and oral
forms). The company acquired exclusive global rights to develop, manufacture, and market BCV for all diseases except smallpox.
After a review at the global advisory board held in February 2020, the company concluded that it would prioritize global
development of BCV IV (mainly in Japan, the US, and Europe) to treat adenovirus (AdV) infections in patients receiving
hematopoietic stem cell transplantation to address an unmet medical need. Based on safety and efficacy data acquired from its
study, the company plans to review the drug’s efficacy against dsDNA viral infections in patients receiving hematopoietic stem
cell transplantation and extend its target indications to include multiviral infections. By exploring the potential for expanding
target disease areas to viral infections related to organ transplants (including kidney transplants), the company aims to grow themarket for and maximize the business value of BCV. The company is presently in preparation to initiate a dose-finding study ofthe liquid formulation of BCV in pediatric patients slated to begin in December 2021.
Clinical trials by Chimerix have demonstrated superior, broad-spectrum antivirus activity of BCV Oral against dsDNA viruses,
raising expectations for its potential as a safe and effective therapy to prevent and treat a range of viral infections in patients
receiving hematopoietic stem cell transplantation.

SyB P-1501, transdermal pain management system
Regarding SyB P-1501 licensed by The Medicines Company, the company initiated an arbitration against The Medicines
Company (MDCO), under the rules of the International Chamber of Commerce, seeking damages of USD82mn arising from
MDCO’s repudiation of the license agreement. SymBio argued that MDCO’s failure to provide sufficient assurance to thecompany regarding the performance of obligations under the license agreement in light of its decision to withdraw from businessactivities relating to SyB P-1501 in the European and US markets was a material breach of the license agreement. In September
2020, SymBio announced it had received the arbitration judgment and although the Court of Arbitration did not award damages
sought by the company, it did order MDCO to pay 50% of legal costs (USD4.95mn) sought by the company.

Overseas
The company marketed SyB L-0501 in South Korea, Taiwan, and Singapore, and product sales were in line with the company’splans.

In-licensing of drug candidates
The company is currently focusing on unrolling global development plans for antiviral drug brincidofovir it in-licensed in
September 2019. It is constantly looking into multiple licensing deals and looking for and evaluating promising in-licensing drugcandidates.

1H FY12/20 results▷

Sales:▷

Operating loss: JPY1.8bn (loss of JPY2.0bn in 1H FY12/19)▷

Recurring loss:

JPY1.4bn (-32.1% YoY)

JPY1.9bn (loss of JPY2.1bn in 1H FY12/19)

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Net loss:

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JPY1.9bn (loss of JPY2.1bn in 1H FY12/19)

Earnings summary
Sales fell YoY. The company booked sales of Treakisym®. As discussed later, lyophilized Treakisym® for injection imported from
Astellas Deutschland continued to have high defect ratios and deliveries were irregular in 1H FY12/20. Consequently, supply
problems persisted, and sales declined YoY.
According to materials disclosed by Treakisym® distributor Eisai, FY03/20 product sales increased 6.3% YoY to JPY7.7bn. Even on
a quarterly basis, Treakisym® sales were flat YoY, at JPY1.6bn in Q4 FY03/20 (JPY1.4bn in Q4 FY03/19) and JPY1.9bn in Q1 FY03/21(JPY2.0bn in Q1 FY03/20).
Gross profit totaled JPY330mn (-37.7% YoY) while GPM dropped 2.2pp YoY to 24.2%. The cost ratio increased due tostrengthened inspection procedures for lyophilized formulation of Treakisym® (two visual inspections), valuation losses oninventories, and higher transportation costs. Valuation losses on inventories was JPY69mn in 1H (versus JPY188mn in 1H FY12/19)
and attributable to quality defects of Treakisym® products.
SG&A expenses fell 14.7% YoY to JPY2.2bn.

▷

R&D expenses declined 13.4% YoY to JPY834mn. This included expenses for conducting clinical trials of intravenous and oral
formulations of Treakisym® and rigosertib.

▷

Excluding R&D expenses, SG&A expenses fell by 15.5% YoY to JPY1.3bn. The company incurred development expenses for its
in-house sales organization. Among expense items, salaries and promotion expenses increased YoY while fee expenses
declined from JPY542mn in 1H FY12/19 to JPY35mn.

As a result, operating loss, recurring loss, and net loss narrowed YoY.

Progress versus company full-year forecast
SymBio left its FY12/20 full-year forecast unchanged even though 1H sales reached only 40.0% of target. Heading into 2H, thecompany looks for sales of Treakisym® to increase on higher overseas sales and a boost from its nationwide marketing operation.
On the supply side, the company aims to alleviate the Treakisym® substandard problems by maintaining high inventories andthus make up for the 1H shortfall in 2H.
Also, as discussed later, the Court of Arbitration in August 2020 ordered The Medicines Company (MDCO) to pay SymBio 50% of
costs incurred in the arbitration proceedings, including attorney fees. The company plans to thoroughly review the related costs
and later estimate the impact on FY12/20 earnings forecast.

Business progress updates
New major business developments in 1H FY12/20 were as follows.

▷

In August 2020, the company decided to develop intravenous formation of antiviral drug brincidofovir (SyB V-1901, BCV IV)
globally (mainly in Japan, the US, and Europe) for adenovirus (AdV) infections occurring after hematopoietic stem celltransplantation. Shared Research understands this is the first time the company has conducted global new drug development
independently.

▷

In July 2020, the Court of Arbitration delivered a ruling in The Medicines Company (MDCO) arbitration case. The court did notgrant damage claims made against MDCO but ordered MDCO to pay 50% of costs incurred by SymBio in the arbitration
proceedings, including attorney fees.

▷

In July 2020, the company applied for a partial change to the approved matters of Treakisym® for use with polatuzumab
vedotin and rituximab targeting patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL).

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In May 2020, the company applied for a partial change to the approved matters of BR therapy (combination of anticancer
agents Treakisym® and rituximab) to enable its use for r/r DLBCL.

▷In May 2020, an abstract on analysis of phase III BR therapy (combination of anticancer agents Treakisym® and rituximab)
results for treatment of relapsed or refractory diffuse large B-cell lymphoma was adopted for the 25th Congress of theEuropean Hematology Association scheduled to be held in June 2020.

▷

In March 2020, Onconova, the licensor of anticancer drug rigosertib, announced it had completed enrollment of the target
360 patients for the international joint phase III (INSPIRE) study, 48 of whom were enrolled in Japan.

▷

In March 2020, enrollment of trial subjects for the study to confirm safety of Treakisym® liquid formulation (rapid infusion, RI)
was completed.

Domestic
Preparations for in-house sales organization begin
The business alliance agreement between SymBio and Eisai Co., Ltd. under which Eisai acts as a sales agent expires in December
2020. The company plans to transition to its in-house sales organization for domestic sales of Treakisym® in January 2021. Thisshould facilitate a move into the black from FY12/21 and ongoing profit growth thereafter and lay the groundwork for futurebusiness development.
In Q2, the company completed setting up its nationwide internal sales organization as planned, hiring and training additional
Treakisym® medical representatives (MRs) and regional sales managers. The nationwide in-house marketing team consists of 51
MRs, six regional managers, one key account manager (KAM) of key opinion leaders, and four hematology experts, for a total of
62. In addition, SymBio continued building its distribution and logistics capabilities with logistics centers in East and West Japanand in-house infrastructure including a new IT system with ERP, which is also now in the final stages.

Substandard products
SymBio imports lyophilized Treakisym® for injection from Astellas Deutschland (consolidated subsidiary of Astellas Pharma). Some
batches of Treakisym® 100mg vials imported from Astellas Deutschland for domestic sales in FY12/19 had impurities andappearance defects in a significantly higher percentage than stipulated in the supply agreement. In order to prevent a recurrenceof such product quality issues, the company objected to Astellas Deutschland, and demanded steps such as corrective andpreventive action (CAPA) processes to fulfil its responsibilities as the supplier.
Nonetheless, there was no improvement in 1H, with persistent supply issues. Several batches from Astellas Deutschland had highdefect ratios and deliveries were irregular. Q2 sales fell YoY as Treakisym® inventory levels were low compared with Q2 FY12/19.
In Q3, the company is persisting with its efforts to restore Treakisym® inventory levels by continuing discussions with Astellas
Deutschland to reduce defect rates, and stabilize supply.

Anticancer agents: SyB L-0501[lyophilized injection]/SyB L-1701 [RTD]/SyB L-1702 [RI]/SyB C-0501 [oral] (generic name:bendamustine hydrochloride, product name: Treakisym®)
Approved indications
The anticancer agent Treakisym® is used for the indications of untreated low-grade non-Hodgkin’s lymphoma and mantle cell
lymphoma (marketing approval obtained in December 2016), refractory or relapsed low-grade non-Hodgkin’s lymphoma andmantle cell lymphoma (October 2010), and chronic lymphocytic leukemia (August 2016).
The combination therapy of Treakisym® and rituximab (BR therapy) was newly included in the Practical Guidelines for
Hematological Malignancies 2018 edited and published by Japanese Society of Hematology as a standard treatment option,
which applies to all of the approved indications. This has seen Treakisym® establish its position as a standard treatment for
lymphatic cancer.

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Also, SymBio obtained approval for the partial change to the approved matters of Treakisym® in July 2018. Treakisym® can now be
used in combination with new anti-CD20 antibodies and not just rituximab for the treatment of CD20-positive follicularlymphoma, the most common histological type of low-grade NHL. This allows the company to provide patients a new treatment
option: combination therapy with obinutuzumab (launched in August 2018). In March 2019, SymBio obtained approval for thepartial change to the approved matters of Treakisym® to enable its use as a pretreatment agent in tumor-specific T cell infusion
therapy. This allows Treakisym® to be used as a pretreatment agent for Kymriah® intravenous infusion, which was the firstchimeric antigen receptor T-cell (CAR-T) therapy approved in Japan and on the NHI drug price list from May 2019.

Relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL)
Following on from the above approved indications, the company conducted a phase III clinical study for the fourth indication of
relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL), with Treakisym® administered in combination with rituximab (BRtherapy). The response rate (primary endpoint) in the test results released in November 2019 was better than expected. In May
2020, the company applied for a partial change to approved matters.
In May 2020, an abstract on analysis of phase III BR therapy (combination of anticancer agents Treakisym® and rituximab) results
for treatment of relapsed or refractory diffuse large B-cell lymphoma was adopted for the 25th Congress of the European
Hematology Association scheduled to be held in June 2020. The company noted the main results of the phase III (38 patients)
trial analysis were as follows:
Overall response rate (ORR) was 76% and complete response (CR) rate was 47%.
<By gene activity pattern>▷

GCB type: ORR of 83%, CR rate of 67%▷

Non-GCB type: ORR of 78%, CR rate of 39%

Divided into GCB or non-GCB type DLBCLGCB type: Geminal center B-cell type
Non-GCB type: non Geminal center B-cell type

<By age group>▷

Under 65 years of age: ORR of 86%, CR rate of 71%▷

65 to 75 years old: ORR of 75%, CR rate of 45%▷

Over 75 years of age: ORR of 73%, CR rate of 36%

As reference for the anticipated impact of adding the indication of r/r DLBCL, the company estimates that the number of patients
being treated for relapsed or refractory low-grade NHL and MCL in Japan is 9,336 and the number of patients with untreatedlow-grade NHL and MCL is 6,967, for a total of 16,303. For these indications, distributor Eisai booked sales of JPY8.0bn in FY03/20.
By comparison, the company estimates that the number of Japanese patients with r/r DLBCL is 18,672.
After Chugai Pharmaceutical Co., Ltd. applied for manufacture and marketing approval of polatuzumab vedotin in combination
with BR therapy to treat r/r DLBCL in June 2020, the company applied for a partial change to the approved matters of Treakisym®
for use in combination with polatuzumab vedotin and rituximab therapy. If the new drug applications by Chugai and SymBio areapproved and polatuzumab vedotin is added to the NHI drug price list, Treakisym® can be used with polatuzumab vedotin in
combination with BR therapy. At present there are no effective treatments for the additional indication of r/r DLBCL, which isusually treated by a combination of anticancer agents as salvage chemotherapy. An effective new drug with few side effects issought, however, because salvage chemotherapy produces severe adverse effects. Since BR therapy is already being used in theWest to treat r/r DLBCL, patient organizations and related academic societies have petitioned MHLW so that it can be used inJapan as soon as possible.

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Treakisym® liquid formulations (RTD and RI)
The company concluded an exclusive licensing agreement in Japan with Eagle Pharmaceuticals (based in New Jersey, US) in
September 2017 for the RTD and RI formulations of Treakisym®.

▷

The company applied for approval of the RTD formulation in September 2019, and plans to launch it in Q1 FY12/21.

▷

SymBio started clinical trials for the RI formulation in November 2018 with the main objective of confirming safety andcompleted patient enrollment in March 2020. The company will apply for approval without delay upon completion of theclinical trials of the RI formulation and aims to begin sales in 2H FY12/22. The RI formulation can be administered in just 10
minutes versus 60 minutes for the current lyophilized injection and RTD formulation. This reduces the burden on patients andhealthcare professionals, providing significant value added.

Multiple patent protections of the product in liquid formulations (RTD and RI) with product licenses will enable the extension of
the product life of Treakisym® to 2031. The RTD and RI formulations were launched in the US market from January 2016 and had
captured a 40% share of the bendamustine market within four months of commercialization, rising to over 90% within 12 months.
The company looks for an even more rapid switch from the lyophilized powder to liquid formulations in Japan.

Treakisym® lifecycle management strategy
As noted above, SymBio anticipates Treakisym® sales will expand on the back of increased sales for already approved indications
and contributions from the new indication of r/r DLBCL. Treakisym® is designated as a treatment for rare diseases and there-examination period ends in 2020, so the launch of liquid Treakisym® (RTD and RI formulations) will extend the product life
until 2031.
In addition, SymBio is slated to take over domestic marketing of Treakisym® in January 2021. Shared Research thinks this could
lead to higher profit margins for SymBio as it may be able to pocket gross profits booked by Eisai (difference between Eisai’s
procurement price and delivery price to drug wholesalers). We further believe gross profit margins could rise following transition
to liquid Treakisym® owing to a change in suppliers. The lyophilized powder formulation of Treakisym® is supplied by Astellas
Deutschland whereas the RTD and RI formulations are supplied by Eagle Pharmaceuticals. The company is also consideringin-house production of liquid Treakisym® as a future possibility.

Anticancer agents: SyB L-1101 [IV]/SyB C-1101 [oral] (generic name: rigosertib sodium)
Rigosertib injection
Onconova Therapeutics, Inc., the licensor, is currently conducting a global phase III trial (INSPIRE trial), with SymBio performing
the Japan trial. The global phase III trial addresses higher-risk myelodysplastic syndromes (higher-risk MDS), which do notrespond to the current standard treatment with hypomethylating agents, which relapse after treatment under the current
standard of care, or which are intolerant to hypomethylating agents, and is under way at clinical trial sites in more than 20
countries worldwide. Onconova announced that it had reached its target of enrolling 360 patients worldwide as of March 2020
and achieved the required number of survival events in July 2020. Onconova said the primary endpoint results would become
clear in Q3 2020, and that it planned to announce trial results at an academic conference by the end of the year. Based on thesetrial results, the company plans to apply for approval in Japan at the same time as in the US and Europe.

Oral rigosertib
Regarding the oral formulation of rigosertib, Onconova completed phase I/II clinical trials for the drug used in combination withazacitidine, whose results suggested the efficacy and safety of the combination therapy. To verify the tolerability and safety of theoral formulation of rigosertib among Japanese patients, SymBio began phase I clinical trials in Japan in June 2017 and completed
patient enrollment in June 2019. After completing the phase I trials, the company will participate in global clinical trials of the
drug used in combination with azacitidine as first-line treatment for higher-risk MDS currently planned by Onconova. In
December 2019, Onconova announced that it was considering the design of a Phase II/III adaptive trial with untreated higher- risk

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MDS patients based on the data presented at the 61st American Society of Hematology (ASH) Annual Meeting in December
2019.

Antiviral drug to treat infections SyB V-1901 (generic name: brincidofovir)
In September 2019, SymBio concluded an exclusive global license agreement with Chimerix Inc. (hereafter Chimerix) for
brincidofovir (SyB V-1901, hereafter BCV IV and BCV Oral), an antiviral drug for the treatment of infections in intravenous and oral
forms). The company acquired exclusive global rights to develop, manufacture, and market BCV for all diseases except smallpox.
After concluding the exclusive global license agreement, SymBio held discussions with Japanese and overseas infectious disease
experts to examine the scientific and medical validity of BCV and progress its feasibility study. The company concluded in August2020 that it would prioritize global development of BCV IV (mainly in Japan, the US, and Europe) to treat adenovirus (AdV)
infections in patients receiving hematopoietic stem cell transplantation to address an unmet medical need. Based on safety andefficacy data acquired from its study, the company plans to extend its target disease area to multiviral infections in patients
receiving hematopoietic stem cell transplantation. By exploring the potential for expanding target disease areas to organtransplants (including kidney transplants) to grow the market for, and maximize the business value of BCV, the company aims totransform itself into a global specialty pharmaceutical company with an integrated structure to supply quality pharmaceuticalproducts.
Clinical trials by Chimerix have demonstrated superior, broad-spectrum antivirus activity of BCV Oral against dsDNA viruses,
raising expectations for its potential as a safe and effective therapy to prevent and treat a range of viral infections in patients
receiving hematopoietic stem cell transplantation.

SyB P-1501, transdermal pain management system
Regarding SyB P-1501 licensed by The Medicines Company, the company initiated an arbitration against The Medicines
Company (MDCO), under the rules of the International Chamber of Commerce, seeking damages of USD82mn (approximately
JPY9.0bn) arising from MDCO’s repudiation of the license agreement. SymBio argued that MDCO’s failure to provide sufficientassurance to the company regarding the performance of obligations under on the license agreement in light of its decision tosuspend and withdraw from business activities relating to SyB P-1501in the European and US markets was a material breach of thelicense agreement. In August 2020, SymBio announced that it had received the arbitration judgment. The Court of Arbitration
did not award damages sought by the company, but ordered MDCO to pay 50% of all arbitration costs as sought by thecompany. Counterclaims and claims for costs by MDCO were rejected. The above costs are under close examination and
expected to take several weeks to finalize. The company commented that it would examine the arbitration judgment in detail toassess carefully its impact on FY12/20 earnings forecast.
For reference, Shared Research understands expenses associated with the arbitration proceeding, including attorney fees, werebooked as fee expenses under SG&A expenses. The arbitration petition against MDCO was initiated in December 2017, and thecompany booked fee expenses of JPY137mn in FY12/16, JPY567mn in FY12/17, JPY444mn in FY12/18, and JPY712mn in FY12/19.
Shared Research believes expenses associated with the arbitration were a major factor boosting fee expenses from FY12/17.

Overseas
The company marketed SyB L-0501 in South Korea, Taiwan, and Singapore, and product sales were in line with the company’splans.

In-licensing of drug candidates
The company is currently focusing on producing and unrolling development plans for antiviral drug brincidofovir it in-licensed in
September 2019. It is constantly looking into multiple licensing deals and looking for and evaluating promising in-licensing drugcandidates.

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Q1 FY12/20 results▷

Sales:JPY551mn (-65.8% YoY)▷

Operating loss:

JPY962mn (loss of JPY596mn in Q1 FY12/19)▷

Recurring loss:

JPY991mn (loss of JPY616mn in Q1 FY12/19)▷

Net loss:

JPY992mn (loss of JPY617mn in Q1 FY12/19)

Sales fell YoY. The company booked sales of Treakisym®. As will be described later, high product defect rates and unstabledeliveries persisted in Q1 for multiple batches of Treakisym® lyophilized injections supplied by Astellas Deutschland so sales
declined YoY due to continued supply problems.
According to disclosure by Eisai, the sales agent for Treakisym®, FY03/20 sales of the product increased 6.2% YoY to JPY8.0bn. On
a quarterly basis, Q4 (January–March 2020) Treakisym® sales were JPY1.6bn, up from JPY1.5bn in Q1 FY12/19.
Gross profit totaled JPY128mn (-79.0% YoY) while GPM was 23.2% (-14.6pp YoY). Increased inspections boosted the cost ratio
for Treakisym® lyophilized injection.
SG&A expenses fell 9.6% YoY to JPY1.1bn and R&D expenses declined 7.1% YoY to JPY438mn. This included expenses for
conducting clinical trials of intravenous and oral formulations of Treakisym® and rigosertib. Excluding R&D expenses, SG&A
expenses declined 11.1% YoY to JPY651mn. The company incurred development expenses building its in-house sales structure,but it seems fee and other expenses declined YoY.
As a result, operating loss, recurring loss, and net loss widened YoY. The difference between operating loss and recurring loss was
accounted for largely by JPY30mn in non-operating expenses: mainly JPY16mn in forex losses and JPY13mn in stock issuancecosts.
Although Q1 sales reached only 16.2% of the company’s full-year target, SymBio left full-year forecast unchanged, likely because
it anticipates the supply issues concerning Treakisym® lyophilized injection formulation to be resolved in 2H.
Major pipeline progress in Q1 FY12/20 is shown below.

▷

May 2020: submitted an application for partial change to the approved matters of BR therapy (combination use of anticancer
agents Treakisym® and rituximab) to enable its use for relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

▷

May 2020: an abstract on analysis of phase III BR therapy (combination of anticancer agents Treakisym® and rituximab) results
for treatment of relapsed or refractory diffuse large B-cell lymphoma was adopted for the 25th Congress of the European
Hematology Association scheduled to be held in June 2020.

▷

March 2020: Onconova, the licensor of anticancer drug rigosertib, announced it had completed enrollment of the target 360
patients for the international joint phase III (INSPIRE) study, 48 of whom were enrolled in Japan.

▷

March 2020: Enrollment of trial subjects for the study to confirm safety of Treakisym® liquid formulation (rapid infusion, RI) wascompleted.

Domestic
Preparations for in-house sales organization begin
The business alliance agreement between SymBio and Eisai Co., Ltd. under which Eisai acts as a sales agent expires in December
2020. The company plans to transition to its in-house sales organization in January 2021. This should facilitate a move into theblack from FY12/21 and ongoing profit growth thereafter and lay the groundwork for future business development.

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In Q1, the company hired and trained additional Treakisym® sales representatives and regional sales managers who will form thecore of its in-house marketing network. This set the stage to complete the nationwide sales structure in 1H FY12/20. SymBio
continued building its distribution and logistics capabilities with logistics centers in East and West Japan and in-houseinfrastructure including a new IT system with ERP.

Substandard products
SymBio imports lyophilized Treakisym® for injection from Astellas Deutschland (consolidated subsidiary of Astellas Pharma). Some
batches of Treakisym® 100mg vials imported from Astellas Deutschland for domestic sales in FY12/19 had impurities andappearance defects in a significantly higher percentage than stipulated in the supply agreement. In order to prevent a recurrenceof such product quality issues, the company objected to Astellas Deutschland, and demanded steps such as corrective andpreventive action (CAPA) processes to fulfil its responsibilities as the supplier. Nonetheless, there was no improvement in Q1,
with persistent supply issues. Several batches from Astellas Deutschland had high defect ratios and deliveries were irregular. Sales
fell YoY as Treakisym® inventory levels were low compared with Q1 FY12/19.
The problems with defective products and irregular deliveries are likely to persist through the rest of 1H, and SymBio expects
sales from shipments to its Treakisym® sales agent, Eisai, to be down YoY. The company is persisting with its efforts to restore
Treakisym® inventory levels, reduce defect rates, and stabilize supply through discussions with its supplier.

Anticancer agents: SyB L-0501[lyophilized injection]/SyB L-1701 [RTD]/SyB L-1702 [RI]/SyB C-0501 [oral] (generic name: bendamustinehydrochloride, product name: Treakisym®)
The anticancer agent Treakisym® is used for the indications of untreated low-grade non-Hodgkin’s lymphoma and mantle cell
lymphoma (marketing approval obtained in December 2016), refractory or relapsed low-grade non-Hodgkin’s lymphoma andmantle cell lymphoma (October 2010), and chronic lymphocytic leukemia (August 2016).
The combination therapy of Treakisym® and rituximab (BR therapy) was newly included in the Practical Guidelines for
Hematological Malignancies 2018 edited and published by Japanese Society of Hematology as a standard treatment option,
which applies to all of the approved indications. This has seen Treakisym® establish its position as a standard treatment for
lymphatic cancer.
Also, SymBio obtained approval for the partial change to the approved matters of Treakisym® in July 2018. Treakisym® can now be
used in combination with new anti-CD20 antibodies and not just rituximab for the treatment of CD20-positive follicularlymphoma, the most common histological type of low-grade NHL. This allows the company to provide patients a new treatment
option: combination therapy with obinutuzumab (launched in August 2018). In March 2019, SymBio obtained approval for thepartial change to the approved matters of Treakisym® to enable its use as a pretreatment agent in tumor-specific T cell infusion
therapy. This allows Treakisym® to be used as a pretreatment agent for Kymriah® intravenous infusion, which was the firstchimeric antigen receptor T-cell (CAR-T) therapy approved in Japan and on the NHI drug price list from May 2019.
Following on from the above approved indications, the company conducted a phase III clinical study for the fourth indication of
relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL), with Treakisym® administered in combination with rituximab (BRtherapy). The response rate (primary endpoint) in the test results released in November 2019 was better than expected. In May
2020, the company applied for a partial change to approved matters.
In May 2020, an abstract on analysis of phase III BR therapy (combination of anticancer agents Treakisym® and rituximab) results
for treatment of relapsed or refractory diffuse large B-cell lymphoma was adopted for the 25th Congress of the European
Hematology Association scheduled to be held in June 2020. The company noted the main results of the phase III (38 patients)
trial analysis were as follows:<By gene activity pattern>▷

GCB type: Overall response rate (ORR) of 83%, complete response (CR) rate of 67%

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Non-GCB type: ORR of 78%, CR rate of 39%

Divided into GCB or non-GCB type DLBCLGCB type: Geminal center B-cell type
Non-GCB type: non Geminal center B-cell type

<By age group>▷

Under 65 years of age: ORR of 86%, CR rate of 71%▷

65 to 75 years old: ORR of 75%, CR rate of 45%▷

Over 75 years of age: ORR of 73%, CR rate of 36%

The company concluded an exclusive licensing agreement in Japan with Eagle Pharmaceuticals (based in New Jersey, US) in
September 2017. Following consultations with the PMDA, the company filed for approval of the RTD formulation in September
2019, and plans to launch it in Q1 FY12/21. SymBio launched clinical trials for the RI formulation in November 2018 primarily toconfirm safety and completed patient enrollment in March 2020. The company will apply for approval without delay after theend of the clinical trials of the RI formulation and aims to begin sales in 2H FY12/22. The RI formulation can be administered in just
10 minutes versus 60 minutes for the current lyophilized injection and RTD formulation. This reduces the burden on patients andhealthcare professionals, providing significant value added. Multiple patent protections in the form of a liquid product license
extended the product life of Treakisym® to 2031.

Anticancer agents: rigosertib sodium (SyB L-1101 [IV]/SyB C-1101 [oral] (generic name: rigosertib sodium)
Onconova Therapeutics, Inc., the licensor, is currently conducting a global phase III trial and SymBio Pharmaceuticals started theJapan trial in December 2015 (50 patients enrolled as of April 2020). The global phase III trial addresses higher-risk
myelodysplastic syndromes (higher-risk MDS), which do not respond to the current standard treatment with hypomethylating
agents, which relapse after treatment under the current standard of care, or which are intolerant to hypomethylating agents, andis under way at clinical trial sites in more than 20 countries worldwide. Onconova announced that it had reached its target ofenrolling 360 patients worldwide as of March 2020. Onconova said the primary endpoint results would become clear in 2H 2020,
and that it planned to announce trial results at an academic conference by the end of the year. Based on these trial results, thecompany plans to apply for approval in Japan at the same time as in the US and Europe.
Regarding the oral formulation of rigosertib, Onconova completed phase I/II clinical trials for the drug used in combination withazacitidine, whose results suggested the efficacy and safety of the combination therapy. To verify the tolerability and safety of theoral formulation of rigosertib among Japanese patients, SymBio began phase I clinical trials in Japan in June 2017 and completed
patient enrollment in June 2019. After completing the phase I trials, the company will participate in global phase III clinical trialsof the drug used in combination with azacitidine as first-line treatment for higher-risk MDS currently planned by Onconova. In
December 2019, Onconova announced that it was considering the design of a Phase II/III adaptive trial with untreated higher risk
MDS patients based on the data presented at the 61st American Society of Hematology (ASH) Annual Meeting in December
2019.

Antiviral drug to treat infections SyB V-1901 (generic name: brincidofovir)
In September 2019, SymBio concluded an exclusive global license agreement with Chimerix Inc. (hereafter Chimerix) for
brincidofovir (SyB V-1901, hereafter BCV IV and BCV Oral), an antiviral drug for the treatment of infections in intravenous and oral
forms). The company acquired exclusive global rights to develop, manufacture, and market BCV for all diseases except smallpox.
BCV Oral has demonstrated a strong, broad-spectrum antiviral effect in clinical trials in Europe and the US by Chimerix. The
company will design a global clinical trial based on these findings.

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The company will initially develop BCV-IV for treatment of viral hemorrhagic cystitis (vHC) occurring after hematopoietic stem
cell transplantation for the domestic market, which has high unmet medical needs. It plans to conduct clinical studies and gain
approval in Japan first so it can offer it to patients there. It also plans to market BCV IV globally after conducting international joint
clinical trials in countries including the US and Europe. As well, the company plans clinical development of BCV IV as an antiviraltreatment of infections after kidney transplants, because it is likely to be effective for transplants other than hematopoietic stem
cell transplants, including organ transplants. The company looks to expand its business in Europe, the US and Asia (including
China), where organ transplant markets are larger than Japan’s. It is also looking for partnerships that take advantage of regional
characteristics of these target diseases.

SyB P-1501, transdermal pain management system
Regarding SyB P-1501 licensed by The Medicines Company, the company initiated an arbitration against The Medicines
Company, under the rules of the International Chamber of Commerce, seeking damages of USD82mn (approximately JPY9.0bn)
arising from The Medicines Company’s repudiation of the license agreement. SymBio argued that The Medicine Company’s
failure to provide sufficient assurance to the company regarding the performance of obligations under on the license agreement
in light of its decision to suspend and withdraw from business activities relating to SyB P-1501in the European and US markets
was a material breach of the license agreement. On November 30, 2017, the license agreement was terminated as the breach
was not corrected within the contract period and development of the product ceased in February 2018. Arbitration proceedings
against The Medicines Company are still ongoing. In January 2020, Swiss company Novartis AG announced that it had acquired
The Medicines Company. SymBio expects an arbitration judgment in 1H 2020.

Overseas
The company marketed SyB L-0501 in South Korea, Taiwan, and Singapore, and product sales were in line with the company’splans.

In-licensing of drug candidates
The company is currently focusing on producing and unrolling development plans for antiviral drug brincidofovir it in-licensed in
September 2019. It is constantly looking into multiple licensing deals and looking for and evaluating promising in-licensing drugcandidates.

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Income statement
FY12/11

FY12/12FY12/13

FY12/14

FY12/15

FY12/16

FY12/17

FY12/18

FY12/19

FY12/20(JPYmn)Sales

Income statement

Par.
1,883

Par.
1,955

Par.
1,532

Par.
1,955

Par.
1,933

Par.
2,368

Par.
3,444

Par.
3,836

Par.
2,838

Par.
2,987

YoY

29.8%

3.9%

-21.6%

27.6%

-1.1%

22.5%

45.4%

11.4%

-26.0%

5.3%

CoGS
Gross profit

1,224
658

1,362
593

1,214
318

1,428
527

1,350
583

1,464
904

2,413
1,031

2,663
1,173

1,973
865

2,120
867
29.0%

35.0%

30.3%

20.8%

26.9%

30.2%

38.2%

29.9%

30.6%

30.5%

SG&A expenses

Gross profit margin

2,725

2,293

1,999

1,830

3,135

3,031

4,978

3,829

5,166

5,373

SG&A ratio

144.8%

117.3%

130.4%

93.6%

162.1%

128.0%

144.5%

99.8%

182.1%

179.9%

Operating profit-2,067-1,700-1,681-1,303-2,552-2,127-3,947-2,656-4,302-4,506

-

-

-

-

-

-

-

-

-

-

Non-operating income
Non-operating expenses
Recurring profit

56
85-2,0957
37-1,729114
35-1,601215
22-1,11017
96-2,6307
196-2,3175
34-3,9772
95-2,7494
79-4,3773
112-4,616

YoY
Recurring profit margin

-

-

-

-

-

-

-

-

-

-

5
4

0
4

4

2
3
4

3
1
4

9
1
4

17
15
4

10
10
4

4
4

529
4

YoY
Operating profit margin

Extraordinary gains
Extraordinary losses
Income taxes
Implied tax rate

Net income

-

-

-

-

-

-

-

-

-

-

-2,105-1,733-1,605-1,116-2,632-2,313-3,978-2,753-4,376-4,090

-

-

-

-

-

-

-

-

-

-

YoY
Net margin

Source: Shared Research based on company data
Note: Figures may differ from company materials due to differences in rounding methods.

See the Earnings Structure section for more information about specific items (from total sales to recurring profit) on thecompany’s income statement. Regarding non-operating profit/loss, extraordinary gain/loss, corporate income tax, etc.,
extraordinary gain of JPY529mn in FY12/20 mainly comes from the booking of JPY525mn in settlement payment.

Historical forecast accuracy
Results vs. Initial Est.
(JPYmn)Sales (Initial Est.)
Sales (Results)
Results vs. Initial Est.
Operating profit (Initial Est.)
Operating profit (Results)
Results vs. Initial Est.
Recurring profit (Initial Est.)
Recurring profit (Results)
Results vs. Initial Est.
Net income (Initial Est.)
Net income (Results)
Results vs. Initial Est.

FY12/11
Par.
1,933
1,883
-2.6%
-2,351-2,067-2,398-2,095-2,407-2,105-

FY12/12
Par.
2,338
1,955
-16.4%-1,625-1,700-1,652-1,729-1,656-1,733-

FY12/13
Par.
1,927
1,532
-20.5%-1,889-1,681-1,922-1,601-1,926-1,605-

FY12/14
Par.
1,785
1,955
9.5%
-1,654-1,303-1,650-1,110-1,654-1,116-

FY12/15
Par.
1,785
1,933
8.3%
-1,654-2,552-1,650-2,630-1,654-2,632-

FY12/16
Par.
2,339
2,368
1.2%
-2,778-2,127-2,811-2,317-2,815-2,313-

FY12/17
Par.
2,903
3,444
18.6%
-3,238-3,947-3,303-3,977-3,306-3,978-

FY12/18
Par.
4,201
3,836
-8.7%
-2,981-2,656-3,044-2,749-3,056-2,753-

FY12/19
Par.
4,465
2,838
-36.4%-3,587-4,302-3,612-4,377-3,612-4,376-

FY12/20
Par.
3,404
2,987
-12.2%-5,090-4,506-5,134-4,616-4,803-4,090-Source: Shared Research based on company data
Note: Figures may differ from company materials due to differences in rounding methods.

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Balance sheet
Balance sheet(JPYmn)ASSETSCash and deposits
Marketable securities
Accounts receivable
Inventories
Other current assets
Total current assets
Buildings (net)
Tools, furniture, and fixtures (net)Total tangible fixed assets
Total other fixed assets
Software
Other
Total intangible fixed assets
Total fixed assets
Total assets

FY12/11

FY12/12FY12/13

FY12/14

FY12/15

FY12/16

FY12/17

FY12/18

FY12/19

FY12/20

Par.

Par.

Par.

Par.

Par.

Par.

Par.

Par.

Par.

Par.

4,559
1,953
162
207
297
7,178
2
15
17
48
10
3
13
78
7,256

4,540
300
148
165
268
5,421
3
11
14
57
8
3
11
82
5,502

6,163
1,100
125
245
7,634
2
6
9
37
6
2
8
53
7,687

5,692
899
273
245
181
7,290
22
27
49
49
62
4
66
164
7,454

4,261
301
133
131
4,827
22
31
53
53
51
1
52
158
4,984

5,719
487
273
205
6,685
31
43
75
77
42
42
193
6,878

2,947
490
363
237
4,037
28
18
47
100
66
3
69
216
4,252

4,821
412
534
271
6,038
37
20
57
73
51
20
71
201
6,239

3,911
549
1
427
4,887
47
19
75
70
95
146
241
386
5,274

3,849
407
945
615
5,815
43
34
77
81
296
6
302
459
6,275

309
278
59
646
-

330
196
73
599
-

207
44
251
-

306
143
39
488
-

322
553
68
942
450
1
451
1,394

604
331
76
1,011
1
1
1,013

726
504
107
1,336
1
1
1,338

121
639
112
872
2
2
874

665
193
646
111
1,615
2
2
1,617

LIABILITIES
Accounts payable
Unearned revenue
Accounts payable–other
Short-term debt
Other
Total current liabilities
Long-term debt
Corporate bonds
Other fixed liabilities
Total fixed liabilities
Total interest-bearing debt
Total liabilities
NET ASSETS
Capital stock
Capital surplus
Retained earnings
Treasury stock
Share subscription rights
Total net assets

5
5
651

4
4
602

3
3
254

2
2
490

320
184
47
551
2
2
552

6,025
5,995
-5,413
-0
6,606

6,025
5,995
-7,146
-0
27
4,900

8,059
8,029
-8,752
-0
97
7,433

8,331
8,301
-9,868
-0
200
6,964

8,331
8,301
-12,500
-0
300
4,432

9,948
9,918
-14,813
-0
431
5,485

10,762
10,732-18,791
-0
537
3,239

12,973
12,943-21,543
-0
530
4,902

14,871
14,841-25,919
-15
621
4,400

17,04517,019-30,010
-18
620
4,657

Working capital
Total interest-bearing debt
Net debt

61-4,559-17-4,540125-6,163212-5,692

114-4,261439-5,719249-2,947220-4,821429-3,911686-3,849Source: Shared Research based on company data
Note: Figures may differ from company materials due to differences in rounding methods.

Assets
SymBio outsources manufacturing and clinical development. Therefore, most of the company’s assets are cash and deposits.
Within current assets, inventory assets consist mostly of Treakisym® merchandise inventory.

Liabilities
As of FY12/20, the company did not have interest-bearing liabilities. Booked liabilities are accounts payable and arrears.

Net assets
Capital stock and capital surplus are increasing as a result of fundraising efforts. However, the deficit in retained earnings is
expanding as the company continued to post losses.

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Cash flow statement
Cash flow statement(JPYmn)Cash flows from operating activities (1)Cash flows from investing activities (2)Free cash flow (1+2)
Cash flows from financing activities

FY12/11Par.
-2,074-117-2,1914,611

FY12/12Par.
-1,659-411-2,069-1

FY12/13
Par.
-1,677-1,332-3,0104,057

FY12/14Par.
-1,266
314
-952
544

FY12/15
Par.
-2,272
1,489
-783
-3

FY12/16Par.
-1,960-44-2,004
3,658

FY12/17Par.
-3,817-78-3,8941,164

FY12/18
Par.
-2,325-26-2,3514,272

FY12/19
Par.
-4,351-216-4,5673,740

FY12/20
Par.
-4,122-160-4,283
4,222

Depreciation and good will amortization (A)Capital expenditures (B)Change in working capital (C)Simple FCF (NI + A + B - C)

8
-12
56
-2,1659-3-78-1,6508
142-1,73913-109
86-1,29824-24-98-2,53426-28
325-2,64030-57-190-3,81535-40-29-2,72938-217
209-4,76464-149
257-4,433

Cash and cash equivalents (year-end)

6,311

4,240

5,294

5,092

4,261

5,719

2,947

4,821

3,911

3,849

Source: Shared Research based on company data
Note: Figures may differ from company materials due to differences in rounding methods.

Cash flows from operating activities
Cash flows from operating activities almost matches the company’s current net loss before tax.

Cash flows from investing activities
Outlays on the purchase of tangible fixed assets and intangible assets are limited as SymBio outsources clinical trials andmanufacturing. But investment in time deposits and securities meant outflow from investing activities widened in FY12/12 andFY12/13. SymBio booked an inflow of JPY1.5bn in FY12/15 due to payments from time deposits and the redemption of securities.

Cash flows from financing activities
The company has reported a series of inflows from financing activities.
Main sources of funding
Date

Change inshares issued

Total sharesissuedChange in capitalstock and capital

Capital stock andcapital surplus

surplus (JPYmn)(JPYmn)Feb. 2011

11,032

122,769772

8,164 Paid-in private placement

Feb. 2011

17,368140,137

1,216

9,380 Paid-in private placement

Oct. 2011

5,100,000

19,130,900

2,628

12,019 Paid-in public offering (price determinedby the book building process)Jan. to Dec. 2013

3,921,257

23,052,157

1,244

13,263 Exercise of stock options attached toconvertible corporate bonds and otherstock options

Dec. 2013

6,720,200

29,772,357

2,504

15,767 Paid-in public offering (price determinedby the book building process)Dec. 2014

1,756,666

32,390,923

544

16,632 Exercise of stock options attached toconvertible corporate bonds and otherstock options

Jan. to Dec. 2016

14,139,901

46,530,824

3,235

19,867 Exercise of stock options attached toconvertible corporate bonds and otherstock options

Jan. to Dec. 2017

7,518,400

54,049,224

1,627

21,493 Exercise of stock options attached toconvertible corporate bonds and otherstock options

Apr. to Dec. 2018

28,349,700

82,398,924

4,422

25,915 Exercise of stock options

Jan. to Dec. 2019

1,726,800

26,437,681

3,796

29,711 Exercise of stock options

Jan. to Dec. 2020

11,765,275

38,202,956

4,349

34,064 Exercise of stock options

Source: Shared Research based on company data
Note: In July 2019, the company conducted a 4:1 reverse stock split, reducing the number of shares outstanding by 73,088,043.

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Other information
History
SymBio was established in March 2005 by Fuminori Yoshida, former Corporate Vice President of Amgen Inc., and founding
President and CEO of the Japanese subsidiary, Amgen Japan. Mr. Yoshida’s desire to address the unmet medical needs of patientsin underserved markets often overlooked by the pharmaceutical industry due to limited patient numbers inspired him to create
SymBio Pharmaceuticals.
In 2013, Amgen Inc. was the largest biopharmaceutical company in the world by revenue. It was established in 1980 in Thousand Oaks, California as
Applied Molecular Genetics. Mr. Yoshida established Amgen Japan in May 1993, serving as President and CEO for 12 years prior to founding SymBio
Pharmaceuticals in March 2005. In February 2008, Takeda Pharmaceutical Co. Ltd. acquired Amgen Japan.

After its establishment, SymBio obtained financing totaling JPY1bn from Daiichi Pharmaceutical Co., Ltd. (now Daiichi Sankyo,
Inc.; TSE1: 4568), Medical & Biological Laboratories Co., Ltd. (JASDAQ: 4557), EPS Corporation (TSE1: 4282), and SBI Holdings,
Inc. (TSE1: 8473). The company used the cash raised to in-license its first drug candidate, bendamustine hydrochloride, from
Astellas Pharma GmbH in December 2005 with the exclusive right to develop and commercialize the drug in Japan.
After the global financial crisis of September 2008, the company experienced a shortage of capital as Treakisym® was advancing in
the clinic. Mr. Yoshida visited more than 50 venture capital firms in Japan and elsewhere in December 2008, eventually raising
JPY1.5bn in capital from Cephalon, Inc. (acquired by Teva Pharmaceutical Industries Ltd. (NASDAQ: TEVA) in October 2011).
SymBio obtained Japanese marketing and manufacture approval for Treakisym® in October 2010 and began domestic sales in
December of that year.
As of February 2021, Treakisym® for relapsed or refractory low-grade NHL and MCL is the company’s mainstay product. Clinical
trials are also in preparation or under way toward attaining domestic approval for additional Treakisym® indications, RI
formulation of Treakisym®, and anticancer drug rigosertib for myelodysplastic syndromes. In addition, after acquiring exclusive
worldwide rights from Chimerix in September 2019 to develop, manufacture, and market brincidofovir for all indications except
smallpox, SymBio looks to commercialize it by the mid-2020s.

March 2005

SymBio Pharmaceuticals Limited established with JPY30mn in capital.

December 2005

License Agreement finalized with Astellas Pharma GmbH for SyB L-0501 (bendamustine) development andcommercialization rights in Japan.

March 2006

Manufacturer’s License (packaging, labeling and storage) obtained from Tokyo Metropolitan Government (License#13AZ200010).

March 2007

Abeille Pharmaceuticals licensed SyB D-0701 (granisetron patch) to SymBio Pharmaceuticals for development &commercialization in Japan, China (HK), Taiwan, South Korea and Singapore.

March 2007

License Agreement finalized with Astellas Deutschland GmbH for SyB L-0501 (bendamustine) development &commercialization rights in China (HK), Taiwan, South Korea and Singapore.

August 2008

License Agreement finalized with Eisai Co., Ltd. for co-development and commercialization rights of SyB L-0501(bendamustine) in Japan.

March 2009

SymBio Pharmaceuticals concluded Sublicense Agreement with Cephalon, Inc. for development and commercializationrights of bendamustine hydrochloride in China (HK).

May 2009

License Agreement finalized with Eisai Co., Ltd. for co-development and commercialization rights of SyB L-0501(bendamustine) in South Korea and Singapore.

September 2010

SymBio Pharmaceuticals and Eisai launch SYMBENDA® (bendamustine) in Singapore for the treatment of Low-grade
Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia.

October 2010

Announced NDA Approval of Treakisym® (bendamustine) in Japan.

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December 2010

Launched Treakisym® in Japan.

July 2011

Onconova and SymBio Pharmaceuticals concluded License Agreement for SyB L-1101/SyB C-1101 (rigosertib, a phaseⅢ stage multi-kinase inhibitor for Myelodysplastic Syndromes).

October 2011
October 2011
February 2012

Launched Symbenda® (bendamustine hydrochloride) in South Korea for the treatment of Chronic Lymphocytic
Leukemia and multiple myeloma.
Listed on Osaka Securities Exchange JASDAQ Growth Market.
Launched Innomustine® (bendamustine hydrochloride) in Taiwan for the treatment of Low-grade Non-Hodgkin’s
Lymphoma and Chronic Lymphocytic Leukemia.

October 2015

Concluded a license agreement with The Medicines Company (US) on exclusive development and marketing rights to
Ionsys (transdermal pain management system) in Japan.

August 2016

Received approval for the additional indication of chronic lymphocytic leukemia for Treakisym®.

December 2016

Obtained approval for the additional indication of untreated low-grade non-Hodgkin’s lymphoma and mantle cell
lymphoma for the anticancer drug Treakisym®

September 2017Concluded an exclusive license agreement with Eagle Pharmaceuticals, Inc. (US) on rights to develop, market, and sell
Eagle’s bendamustine hydrochloride RTD and RI formulations in Japan.

September 2019Concluded an exclusive global license agreement with Chimerix Inc. (US) on rights to develop, manufacture, and market
antiviral brincidofovir for all indications except smallpox.

December 2020

Began in-house sales of anticancer drug Treakisym®

January 2021

Launched Treakisym® liquid formulation (RTD)

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News and topics
February 2021
On February 22, 2021, the company announced the results of phase III clinical trial for Treakisym® as a treatment for relapsed or
refractory diffuse large B-cell lymphoma.
At the 2021 Annual Meeting of the Japanese Society of Medical Oncology held on February 20, 2021, the company announced
results of phase III clinical trial of anticancer agent Treakisym® (generic name: bendamustine hydrochloride) administered in
combination with rituximab (BR therapy) in patients with relapsed or refractory diffuse large B-cell lymphoma.

Primary phase III clinical trial results concerning efficacy (38 patients)▷

Response rate (complete and partial response): 76.3%▷

Complete response rate: 47.4%▷

Median overall survival (29.2 months)

On February 4, 2021, the company announced a three-year medium-term plan covering FY12/21–FY12/23.
Medium-term plan targets
FY12/21

FY12/22

FY12/23(JPYmn)Est.

TargetTarget

Sales

9,151

10,985

12,369YoY

206.4%

20.0%

12.6%

1,361

1,738

2,099

-

27.7%

20.8%

14.9%

15.8%

17.0%

1,350

1,727

2,088

-

27.9%

20.9%

14.8%

15.7%

16.9%

1,149

1,470

1,778

-

27.9%

21.0%

12.6%

13.4%

14.4%

Operating profit
YoY
Operating profit margin

Recurring profit
YoY
Recurring profit margin

Net income
YoY
Net margin

Source: Shared Research based on company data

Targets in medium-term plan (FY12/21–FY12/23)
Sales
SymBio expects product sales of Treakisym® to account for the bulk of sales. Product sales targets reflect the recent pace of market
penetration and sales trends, which feed into the company’s revised sales growth rates calculated over the medium-term plan
period. Sales through FY12/20 were booked based on product shipment sales to the sales distributor, Eisai. From FY12/21 onward,
sales will be booked on product shipment sales to pharmaceutical wholesalers from the company’s own in-house salesorganization.
In estimating sales from FY12/21 onward, SymBio disclosed targets assuming increased product sales of Treakisym® as it expects
to gain approval of the drug as a treatment for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in Q2 FY12/21.

SG&A expenses
The company has broken down SG&A expenses into primarily R&D spending and other SG&A expenses.

▷

The company calculated R&D expenses based on the latest development plans for its existing pipeline comprising Treakisym®,
rigosertib, and brincidofovir, an antiviral drug.

▷

The company does not assume any upfront payments for in-licensing drug candidates outside its existing pipeline after
brincidofovir, an antiviral drug, although it will continue to evaluate and investigate them.

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Other SG&A expenses comprise primarily Treakisym® sales and marketing, production and distribution, business development,
and management related costs. From FY12/21, SymBio assumes costs associated with operating its own sales organization forsales of Treakisym®. It forecasts an increase primarily in personnel costs due to a higher medical representative headcount andhigher costs due to more activities.

Net income
In the previous medium-term plan announced in February 2020, the company forecast net income exceeding recurring profit in
FY12/21 and FY20/22 to reflect the reduction in loss carried forward from FY12/21 onward on tax effect accounting. Heeding theadvice of accounting auditors, the new medium-term plan was formulated by removing income taxes adjustment factors for
FY12/21 onward.

Personnel plans
SymBio completed the formation of its 62-member nationwide sales structure in FY12/20. It plans to allocate the bare minimumof necessary personnel in other parts of the organization and is budgeting for personnel expenses accordingly. The company
plans to increase personnel expenses for global expansion of brincidofovir, an antiviral drug, and reflected this in personnel
expenses.

Funding plans
Regarding funding plans, the company will work toward strengthening its financial base so that it can respond in a flexible andnimble way to the need for funds according to business developments.

January 2021
On January 28, 2021, the company announced that it had entered into a joint research agreement with the University of Tokyo’s
Institute of Medical Science to explore potential new indications for bendamustine and rigosertib.
The company has entered into a joint research agreement with the Institute of Medical Science, the University of Tokyo (IMSUT),
to explore potential new indications for two anticancer agents it has in development: bendamustine and rigosertib.
Under this agreement, SymBio will undertake joint research with Professor Toshio Kitamura, from the Division of Cellular Therapy
within IMSUT’s Advanced Clinical Research Center, using bendamustine and rigosertib in combination or with other approved
drugs to explore efficacy and new indications.
The joint research will analyze the epigenetic control of various tumor cells to explore as-yet-unknown pharmacological effects ofbendamustine and rigosertib, analyzing their effects when used in combination and with other approved drugs.
Professor Kitamura is an accomplished researcher and has a large network of researchers and physicians in the areas ofhematopoietic stem cell differentiation and hematopoietic tumors such as leukemia. He is also studying molecular mechanisms inthe development of hematopoietic tumors caused by epigenetic abnormalities, looking to develop novel therapies using
hematopoietic tumor models. SymBio will leverage its experience in winning early approval for proprietary anticancer drugs incollaborating with IMSUT to search for new indications for bendamustine and rigosertib.
On January 12, 2021, the company announced the sales launch of the ready-to-dilute (RTD) liquid formulation of Treakisym®.
On the same day, the company began selling its ready-to-dilute (RTD) formulation of Treakisym® intravenous fluid in quantities of100mg/4mL.
In September 2017, the company concluded an exclusive license agreement with Eagle Pharmaceuticals, Inc. covering both the
RTD and rapid infusion (RI) liquid formulations of Treakisym® in Japan. With multiple patent protections obtained using

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pharmaceutical licenses for both of these formulations of Treakisym®, the company will be able to extend the life of the productthrough 2031.
Unlike the lyophilized formulation of Treakisym® that is currently on the market, the RTD formulation eliminates the need fortroublesome manual dissolution, reducing the required dissolving time. This advantage provides value-added by reducing
burdens placed on medical personnel. Meanwhile, the RI formulation of Treakisym® is currently undergoing clinical trials todetermine its safety, and the company plans to apply for its approval in FY12/21.
In the US market, the company has received FDA approval for the RI formulation of its Bendeka® intravenous fluid and ismarketing it through Teva Pharmaceutical Industries Ltd. This formulation reduces the required administration time to 10 minutes,
lightening burdens placed on patients and medical personnel.

December 2020
On December 22, 2020, the company announced the conclusion of a syndicated loan agreement.
The company entered into a syndicated loan (committed credit line) agreement with a view to building a stable and agile
fundraising structure to undergird business expansion.

Overview of the syndicated loan agreement▷

Credit line amount:

JPY3.0bn▷

Date of agreement:

December 22, 2020▷

Commitment period: December 25, 2020 to June 24, 2022▷

Use of funds:

Working capital▷Interest rate:

Base rate + spread▷

Security:

Unsecured▷

Arranger and agent:

MUFG Bank, Ltd.

▷

Participating financial institutions: MUFG Bank, Ltd., The Bank of Yokohama, Ltd.

On December 10, 2020, the company announced that it began in-house sales of the anticancer drug Treakisym®.
With the expiration of its business alliance agreement with Eisai Co., Ltd. regarding the anticancer drug Treakisym® on December
9, 2020, the company began selling the drug in Japan through its own sales organization from December 10.
SymBio allocated a total of 62 medical representatives and others with expert knowledge and extensive sales experience inhematology to major regions nationwide, and established the Regulatory Affairs & Quality Assurance Division to enhance stablesupply of the product and quality assurance. Further, the company built a nationwide distribution system with Suzuken Groupand Kyoso Mirai Group as its sole distributors. It has two logistics centers, one in Eastern and the other in Western Japan, and incollaboration with S.D. Collabo Co., Ltd., the company said it has established an optimal nationwide distribution and logistics
system.

September 2020
On September 23, 2020, the company announced the acquisition of approval for the RTD formulation of Treakisym®.
The company has obtained approval for manufacturing and marketing the ready-to-dilute (RTD) liquid formulation of Treakisym®.
In September 2017, the company entered into an exclusive licensing agreement in Japan with Eagle Pharmaceuticals, Inc. for
Treakisym® liquid formulations (RTD and RI formulations), extending the product life of Treakisym® under patent protection to2031. Compared to lyophilized Treakisym® (FD formulation), liquid Treakisym® (RTD and RI formulations) does not require any

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complex and time-consuming manual reconstitution. This substantially reduces the burden on patients and healthcare
professionals, providing significant value added. The company plans to start selling the RTD formulation in January 2021.
On September 17, 2020, the company announced revisions to its earnings forecast and medium-term plan.

Revisions to earnings forecast
Revised full-year FY12/20 forecast▷

Sales:▷

Operating loss: JPY4.6bn (JPY5.1bn)▷

Recurring loss:

JPY4.7bn (JPY5.1bn)▷

Net loss:

JPY3.8bn (JPY4.8bn)▷

Loss per share:

JPY116.16 (JPY146.98)

JPY3.0bn (previous forecast: JPY3.4bn)

Reasoning behind revisions
With regard to sales in FY12/20, the outlook for the business environment is becoming more uncertain due to the impact fromthe novel coronavirus pandemic, and while the company forecasts sales to grow YoY over the full-year, it has downgraded its
initial forecast in consideration of 1H results (sales fell 32.1% YoY to JPY1.4bn). In 2H, SymBio forecasts sales to increase from
JPY1.4bn in 1H to JPY1.7bn, mainly because demand tends to be stronger in 2H than in 1H in the domestic market for Treakisym®,and because planned overseas sales in 2H are expected to push up sales.
SymBio is prioritizing necessary investments for the planned FY12/20 launch of its in-house sales structure, for achieving
profitability in FY12/21, and for making preparations for the planned launch of global phase II trials of brincidofovir in 1H FY12/21.
Otherwise, it plans to rein in spending by reviewing all other expenses. In this way, it plans to significantly reduce SG&A
expenses so as to minimize the impact from lower sales, and it has revised its forecast for operating profit (loss) in order to reflect
this.
SymBio has also revised its net income (loss) forecast to reflect the arbitration judgment announced in September 2020 for The
Medicines Company to pay SymBio USD5.0bn.

Revisions to the medium-term plan
SymBio has also revised its FY12/20 targets in its medium-term plan for the three years from FY12/20 to FY12/22 in accordancewith the above revisions to its earnings forecast. It is currently assessing the impact on FY12/21 and FY12/22.
On September 9, 2020, the company announced progress (LPLV) in clinical study of Treakisym® rapid infusion (RI) liquid
formulation.
In the clinical trial of Treakisym® RI liquid formulation (infusion time: 10 minutes) with the primary endpoint of confirming safety,
the company completed observation periods for all patients (last patient last visit, or LPLV) after it enrolled the target number ofpatients.
The company completed filing for approval of the ready-to-dilute (RTD) formulation of the drug in Q3 FY12/19, and is making
preparations with the aim of launching the product in Q1 FY12/21. For the RI formulation, the company plans to apply for
approval upon completion of the clinical trial, with the approval expected to be granted in 2H FY12/22.
On September 7, 2020, the company announced the transfer of the sale of Treakisym® to an in-house organization.
The business alliance agreement that the company entered into in August 2008 with Eisai Co., Ltd., granting the latter exclusive
marketing rights to bendamustine (Treakisym® 100mg and 25mg vials for intravenous infusion), will expire on December 9, 2020.

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As part of its preparations for transfer of the sales of anticancer drug Treakisym® in Japan to its in-house organization, the company
has begun preparations with Eisai for the inheritance of this business.
In addition, the company has entered into agreements in regard to the sale and purchase of Treakisym® with Suzuken Co., Ltd.
(hereafter “Suzuken Group”), and Toho Pharmaceutical Co., Ltd. (a consolidated subsidiary of Toho Holdings Co., Ltd., hereafter“Kyoso Mirai Group”) as part of the preparations to build its own distribution and logistics system.

Establishment of the sales organization
The company has already completed the assignment of 51 sales representatives across Japan, and will begin to distribute relevant
information from this point onward, in cooperation with Eisai. At the same time, the company will newly designate highly
specialized hematology experts responsible for the development and implementation of plans meeting the needs of each region.

Establishment of the distribution and logistics system
The two aforementioned companies (Suzuken Group and Kyoso Mirai Group) will serve as the sole nationwide agents. Two
distribution centers, located in Eastern and Western Japan, will commence operations under the management of Suzuken Groupsubsidiary S.D. Collabo Co., Ltd.
On September 1, 2020, the company announced that a resolution had been reached in its arbitration against The Medicines
Company, from which the company had in-licensed the patient-controlled pain management drug SyB P-1501.
The arbitral tribunal constituted under the rules of the International Chamber of Commerce (ICC) reached a final decision withrespect to the company’s arbitration against The Medicines Company (MDCO).
The arbitral tribunal dismissed the company’s claim for damages, dismissing the company’s claim that MDCO had failed toprovide adequate assurances of its performance under the license agreement. However, the arbitral tribunal determined that
MDCO is to pay the company USD4.95mn corresponding to 50% of the company’s legal fees and expenses. The arbitral tribunal
also dismissed MDCO’s counterclaim.
In terms of future outlook, the company states that it will undertake a thorough examination of the impact of the final decision of
the arbitration on FY12/20 company forecasts.

August 2020
On August 25, 2020, the company announced that Onconova Therapeutics, Inc. had released topline results of its phase III
INSPIRE trial targeting patients with higher-risk myelodysplastic syndromes (HR-MDS).
On August 24, 2020, Onconova, the licensor for rigosertib, an anticancer agent the company is developing, announced theresults of its phase III (INSPIRE) trial assessing the safety and efficacy of intravenous injection of rigosertib in patients withhigher-risk myelodysplastic syndromes (HR-MDS). Compared with physician’s choice (PC) treatment, it did not meet its primary
endpoint.
The primary endpoint of the trial was overall survival, comparing IV rigosertib plus best supportive care to PC plus best
supportive care. Onconova also analyzed a pre-specified subgroup of very high risk (VHR-MDS) patients.
Results of INSPIRE demonstrated that in the intent-to-treat analysis patients given IV rigosertib achieved overall survival of 6.4
months, versus 6.3 months for PC (p=0.33) in the overall HR-MDS population. There was also no significant difference in overall
survival between the two study arms in the VHR-MDS subgroup. Onconova is conducting further analysis.
Safety analysis indicates that IV rigosertib was generally well tolerated, with reported adverse events similar to those observed inprevious clinical studies with IV rigosertib in MDS patients. Serious adverse events were relatively uncommon, with a similar
profile of SAEs in both study arms.

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On August 5, 2020, the company announced the arbitration judgment in proceedings against The Medicines Company, thelicensor of SyB P-1501, a patient-controlled post-operative analgesia.
The company received the arbitration judgment against The Medicines Company (MDCO) on July 23, 2020. On October 11,
2017, the company initiated arbitration against MDCO, under the rules of the International Chamber of Commerce, seeking
damages of USD82mn arising from a material breach of the license agreement by MDCO. A judgment was issued on July 21 andreceived by the company through lawyers on July 23.

Summary of arbitration judgment
The Court of Arbitration did not award damages sought by the company, but ordered MDCO to pay 50% of all arbitration costs
as sought by the company. Counterclaims and claims for costs by MDCO were rejected. The above costs are under close
examination and expected to take several weeks to finalize.

July 2020
On July 13, 2020, the company announced that it had applied for a partial change to the approved matters of Treakisym® for use
in combination with polatuzumab vedotin and rituximab to treat relapsed or refractory diffuse large B-cell lymphoma.
The company applied for a partial change to the approved matters of its anticancer drug Treakisym® (generic name:bendamustine hydrochloride) for use in combination with polatuzumab vedotin and rituximab to treat relapsed or refractory
diffuse large B-cell lymphoma (r/r DLBCL).

Major shareholders
Top shareholders
Kyoichi Kageyama
Fuminori Yoshida
SBI Securities Co., Ltd.
Cephalon, Inc.
Arata Takahashi
Norihiro Kuroda
Matsui Securities Co., Ltd.
Fumishige Ehira
Hitochi Imamura
Eisai Co., Ltd.
SUM

Shares held
1,020,000
900,000
744,310647,250534,000
447,500
310,600
270,200
239,300
208,350
5,321,510

Shareholding
ratio
2.7%
2.4%
1.9%
1.7%
1.4%
1.2%
0.8%
0.7%
0.6%
0.5%
13.9%

Source: Shared Research based on company data
As of December 31, 2020
Note: Shareholding ratio calculated excluding treasury shares from shares issued.

Top management
Representative Director, President and CEO, Fuminori Yoshida established SymBio Pharmaceuticals Limited, his third company, in
March of 2005. As founding president of two other major healthcare companies, Nippon BioRad Laboratories (1980) and Amgen
Japan (1993), he has earned high visibility and credibility within Japan’s healthcare and academic communities. Following his
graduation from Gakushuin University in 1971 with a B.S. in Organic Chemistry, he went on to receive an M.S. in Molecular
Biology from MIT (1973) and M.S. in Health Policy and Management from Harvard University Graduate School (1975). He
possesses dual experience and expertise in the management of major Japanese and American corporations due to his prior work
experience at various companies, including Mitsubishi Corporation and AHS Japan, Syntex Japan (1993) as President and CEO,and Amgen Inc. where he served concurrently as Corporate Vice-President, President and CEO of Amgen Japan, for 12 years.

Employees
SymBio had a total of 127 employees as of December 31, 2020.

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Employees
No. of employees

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FY12/11Par.
71

FY12/12Par.
76

FY12/13Par.
72

FY12/14
Par.
69

FY12/15Par.
74

FY12/16
Par.
77

FY12/17Par.
78

FY12/18
Par.
90

FY12/19
Par.
107

FY12/20
Par.
127

15

5

-4

-3

5

3

1

12

17

20

YoY change

Source: Shared Research based on company data

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Other
Overview of clinical trials
Development of a new drug takes between 10 and 17 years
The development process of a new drug follows the four stages described below. It usually takes 10 to 17 years for a new drug to
win regulatory approval, according to the company.
Ordinary process and periods of developing new drugs
Process

PeriodWhat is done

Basic research

2-3 years

Creation of new substances and decision on candidates for drugs

Preclinical test

3-5 years

Confirmation of efficacy and safety through experiments on animals

Clinical trials

3-7 years

Phase I: Confirmation of safety and pharmacokinetics with a small number of healthy people
Phase II: Confirmation of efficacy and safety with a small number of patients
Phase III: Confirmation of efficacy and safety with many patients in comparison to existing drugs

Application and approval 1-2 years

Examination by the Ministry of Health, Labour and Welfare

Source: Shared Research based on company data

Probability of a compound receiving drug approval is 1/100,000
The probability of a chemical compound receiving regulatory approval is said to be 1/100,000, according to the company.
According to the 2013 edition of the Thomson Reuters Pharmaceutical R&D Factbook, the success rate of pharmaceuticalcompanies around the globe from 2006 to 2009 at various stages in the development process was:▷Preclinical: 67%▷

Phase I clinical trials: 46%▷

Phase II clinical trials: 19%▷

Phase III clinical trials: 77%▷

Regulatory approval: 90%.

The success rate of cancer drugs tends to be lower than that of other drugs. The success rate of cancer drugs that went throughclinical trials in the US between 2004 and 2011 was only 6.7%, compared with 12.1% for other drugs, according to BIOtechNow.
The success rate of cancer drugs that went through phase III clinical trials was 45%, while other drugs had a 64% success rate.

Ethnic factors in the acceptability of foreign clinical data
Japan’s Ministry of Health, Labour, and Welfare (MHLW) in 1998 released a report entitled Ethnic Factors in the Acceptability ofForeign Clinical Data (ICH-E5 Guideline) to spell out the government’s stance on the use of data on clinical trials conducted
outside Japan. The report discusses whether the use of such extrapolated data is acceptable.
Applications for drug approval in Japan normally require pharmacokinetic data, dose-responsive data, and clinical trial data on
efficacy for Japanese people. However, data from overseas clinical trials are acceptable if a bridging study demonstrates that suchdata can be used for Japanese people.
Pharmacokinetic data: Data concerning the fate of substances administered externally to a living organism: absorption, distribution, metabolization,and excretion (ADME).

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Glossary
AntigenNormally, a protein or other substance carrying bacteria and viruses that the body rejects as foreign, causing an antigen-antibody
reaction (AAR). When antigens enter the body, they either stimulate the production of antibodies or combine with them.

Bridging Data
Data generated from overseas clinical trials that can be applied to Japanese patients and used in Japan regulatory filings formarketing approval. The goal is to shorten the number of preclinical/clinical studies required for marketing approval in Japan by
avoiding the need to repeat the same studies that have already been carried out overseas (e.g., dispense with the need to do aphase II and/or III clinical trial in Japan).

Chronic Lymphocytic Leukemia (CLL)
A disease in which white blood cells, called lymphatic corpuscles, become cancerous.

Contract Research Organization (CRO)
Pharmaceutical companies often outsource some of their work to contract research organizations so they can focus on core
operations. Outsourced work may include monitoring of clinical trials to ensure that they are proceeding according to plan, andthe management of clinical trial data.

Dose-Responsiveness
Does-responsiveness shows the relationship between the dosage and efficacy of a drug. It is used to determine the method anddosage. Under normal circumstances, the effectiveness of a drug corresponds to its dosage.

First-line Drug
The first drug given to a patient for a disease that is typically part of a standard set of treatments such as surgery followed bychemotherapy and radiation. When used by itself, first-line therapy is the one accepted as the best treatment. If it doesn’t curethe disease (the patient has a relapse) or causes severe side effects, other treatments (second-line, third-line etc.) may be addedor used instead.

Immunoglobulin G (IgG)
The main antibody isotype found in blood and extracellular fluid which protects the body from infection by binding to manykinds of pathogens such as viruses, bacteria, and fungi —it does this via several immune mechanisms: IgG-mediated binding ofpathogens causes their immobilization and binding together.

Mantle-Cell Lymphoma (MCL)
A type of fast-growing B-cell non-Hodgkin’s lymphoma that normally affects people over a certain age. It is characterized by small
and medium-sized cancer cells that appear in lymphatic nodes, the spleen, bone marrow, blood, and the digestive system.

Monoclonal Antibody
A single antibody molecule taken from a single cell. It is possible to produce large amounts of these special antibodies and use
them in the development of antibody drugs.

Multikinase Inhibitor
Multikinase inhibitor blocks tyrosine kinases, which play an important role in transmitting signals involving the multiplication anddivision of cells. Tyrosine kinases can be energized due to genetic mutations. If this happens, the number of cells rapidly increases,
causing cancer or other illnesses.

Myelodysplastic Syndromes
Myelodysplastic Syndrome leads to abnormalities in hematopoietic stem cells that produce blood cells, resulting in a lack ofblood. Blood cells produced this way are abnormally shaped. This change in the cells is called dysplasia. The disease typically

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leads to frequent anemia with some patients dying from infection or bleeding due to the reduction in blood cells. The disease ismost common among the elderly. 10 to 20% of MDS patients progress to acute leukemia.

Non-Hodgkin’s Lymphoma (NHL)A group of ailments associated with all types of malignant tumors other than Hodgkin’s lymphoma.
In Japan, many of these diseases are diffuse large cell lymphomas.

Overall Survival (OS)Overall survival refers to the duration between the initiation of treatment and a patient’s death.

Progression-Free Survival (PFS)
Progression-free survival refers to the duration between the initiation of treatment, and either death or disease progression.

Proof-of-Concept (POC)
A proof-of-concept, when applied to drug development, is the concept that the efficacy and safety of a new drug candidate must
be validated through data generated in clinical trials.

Rare Disorders
Rare disorders are illnesses that affect few people, although they may be serious and/or life-threatening. Drugs designed to treat
rare medical conditions are called ‘orphan drugs’, and pharmaceutical companies often receive government incentives for thedevelopment of these drugs.
In Japan, the Ministry of Health, Labour and Welfare seeks to promote the development of orphan drugs by offering subsidies.
When a drug is designated as an orphan, it is placed on a fast track for approval (the time between the application and approval isreduced). The period of market exclusivity can also be extended to 10 years, and a system is in place to keep the NHI price oforphan drugs above a certain level.

R-CHOP therapy
A combination of rituximab with chemotherapy drugs cyclophosphamide, doxorubicin (hydroxydaunomycin), vincristine(Oncovin®), and prednisolone. R-CHOP is an acronym derived from the names of the drugs used. It is the standard initial
treatment for low-grade non-Hodgkin’s lymphoma (NHL) and mantle-cell lymphoma (MCL).

Special Protocol Assessment (SPA)
A system under which the US Food and Drug Administration (FDA) approves the protocol or design of a planned phase III clinical
trial, such as target illness, purpose, primary and secondary endpoints, and method of data analysis – the protocol may be revised
following FDA consultation prior to the start of the study. The SPA is intended to shorten the review period of new drug
applications (NDAs) by the FDA.

Standard Therapy
Standard therapy refers to treatment that is considered to be the best therapy currently available. It is a treatment widely
recommended to patients by physicians.

Company name
SymBio is derived from the words “symbiosis” and “biotechnology.” The company’s corporate philosophy emphasizes the
symbiotic or mutually supportive relationship that exists among major players in the healthcare industry, and is reflected in thecompany’s logo which symbolizes physicians, scientists, regulators, and investors, with patients at its center. The color of thelogo represents the evergreen tree—the company’s endeavor to create and sustain a life-giving force.

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Company profile
Company nameHead office
Toranomon 30 Mori Building

SymBio Pharmaceuticals Limited

3-2-2 Toranomon, Minato-ku
Tokyo, JAPAN 105-0001

Phone

Exchange listing+81-3-5472-1125

TSE JASDAQ GrowthEstablished

Listed on

March 25, 2005

October 20, 2011

WebsiteFiscal year-end

http://www.symbiopharma.com/index_e.html

December

IR webhttp://www.symbiopharma.com/ir_e/01.html

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