Research Coverage Report by Shared Research Inc.

4582

SymBio Pharmaceuticals
Shared Research Inc. has produced this report by request from the company discussed in thereport. The aim is to provide 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 highlightany biases, we clearly attribute our data and findings. We will always present opinions fromcompany management as such. Our views are ours where stated. We do not try to convince or
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Coverage initiated on: 2014-10-31
Last update: 2021-12-03

INDEX
Executive summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.
Key financial data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5.
Recent updates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6.
Trends and outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8.
Business . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18..
Business description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18..
Business strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20..
Pipeline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23..
Earnings structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35..
Strengths and weaknesses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36..
Market overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .37..
Historical performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40...
Income statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .56..
Balance sheet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .57..
Cash flow statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .57..
Other information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .59..
News and topics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .64..
Company profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .71..

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2

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
typically seeks 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 forfurther assessment of the science behind each molecule, preclinical/clinical data, target market, and the feasibility ofreceiving 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 to which 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) administration of Treakisym®, rigosertib (anticancer agent for myelodysplastic
syndromes) IV and oral formulations, and the antiviral drug brincidofovir. With regard to Treakisym® indicated for refractoryor relapsed DLBCL, in March 2021 the company obtained approval for the combination therapies of Treakisym® withrituximab, 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 ofTreakisym® for relapsed or refractory DLBCL.

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3

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 andproduct (see Strengths and weaknesses).

SymBio Pharmaceuticals/ 4582
Research Coverage Report by Shared Research Inc. | https://sharedresearch.jp

4Key financial data
FY12/11

FY12/12FY12/13

FY12/14

FY12/15

FY12/16

FY12/17

FY12/18

FY12/19

FY12/20(JPYmn)

Par.

Par.

Par.

Par.

Par.

Par.

Par.

Par.

Par.

Par.

Est.

Sales

1,883

1,955

1,532

1,955

1,933

2,368

3,444

3,836

2,838

2,987

9,151

YoY

29.8%

3.9%

-21.6%

27.6%

-1.1%

22.5%

45.4%

11.4%

-26.0%

5.3%

206.4%

658

593

318

527

583

904

1,031

1,173

865

867

Gross profit
YoY-45.7%-9.9%-46.4%

65.6%

10.7%

55.1%

14.1%

13.7%

-26.3%

0.2%

Gross profit margin

35.0%

30.3%

20.8%

26.9%

30.2%

38.2%

29.9%

30.6%

30.5%

29.0%

Operating profit

FY12/21-2,067-1,700-1,681-1,303-2,552-2,127-3,947-2,656-4,302-4,506

YoY

-

-

-

-

-

-

-

-

-

-

-

Operating profit margin

-

-

-

-

-

-

-

-

-

-

14.9%
1,350

Recurring profit

1,361-2,095-1,729-1,601-1,110-2,630-2,317-3,977-2,749-4,377-4,616

YoY

-

-

-

-

-

-

-

-

-

-

-

Recurring profit margin

-

-

-

-

-

-

-

-

-

-

14.8%
1,149

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

-

-

-

-

-

-

-

-

-

-

12.6%

Shares issued (year-end; '000)

19,131

19,131

30,63430,63432,391

46,53154,04920,56026,43838,203EPS-574.4-362.4-277.2-145.0-325.0-235.3-319.1-165.5-189.0-124.1

EPS (fully diluted)

-

-

-

-

-

-

-

-

-

-

Dividend per share (JPY)

-

-

-

-

-

-

-

-

-

-

1,381.1

1,018.8

957.9

835.2

510.2

434.4

200.0

212.2

143.1

105.8

Per-share data (split-adjusted;
JPY)

Book value per share (JPY)30.1-

Balance sheet (JPYmn)
Cash and cash equivalents

6,511

4,840

7,264

6,591

4,261

5,719

2,947

4,821

3,911

3,849

Total current assets

7,178

5,421

7,634

7,290

4,827

6,685

4,037

6,038

4,887

5,815

Tangible fixed assets

17

14

9

49

53

75

47

57

75

77

Investments and other assets

48

57

37

49

53

77

100

73

70

Intangible assets

81

13

11

8

66

52

42

69

71

241

302

7,256

5,502

7,687

7,454

4,984

6,878

4,252

6,239

5,274

6,275

Accounts payable

309

330

-

306

320

322

604

726

121

665

Short-term debt

-

-

-

-

-

-

-

-

-

-

646

599

251

488

551

942

1,011

1,336

872

1,615

Total assets

Total current liabilities
Long-term debt

-

-

-

-

-

-

-

-

-

-

Total fixed liabilities

5

4

3

2

2

451

1

1

2

2

Total liabilities

651

602

254

490

552

1,394

1,013

1,338

874

1,617

6,606

4,900

7,433

6,964

4,432

5,485

3,239

4,902

4,400

4,657

-

-

-

-

-

-

-

-

-

-

Cash flows from operating activities-2,074-1,659-1,677-1,266-2,272-1,960-3,817-2,325-4,351-4,122

Cash flows from investing activities

-117

-411

-1,332

314

1,489

-44

-78

-26

-216

-160

Cash flows from financing activities

4,611

-1

4,057

544

-3

3,658

1,164

4,272

3,740

4,222

ROA (RP-based)-36.5%-27.2%-24.3%-14.7%-42.3%-39.0%-71.5%-52.5%-76.0%-70.8%

ROE-39.4%-30.2%-26.3%-15.8%-48.3%-50.4%-102.6%-77.8%-107.4%-104.7%

Equity ratio

91.0%

89.1%

96.7%

93.4%

88.9%

79.7%

76.2%

78.6%

83.4%

74.2%

Net assets
Total interest-bearing debt
Statement of cash flows (JPYmn)

Financial ratios

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.

SymBio Pharmaceuticals/ 4582
Research Coverage Report by Shared Research Inc. | https://sharedresearch.jp

5Recent updates
Obtained approval to extend the expiration date of Treakisym®
Injection (RTD formulation)
2021-11-24

On November 24, 2021, SymBio Pharmaceuticals Ltd. announced that it obtained approval to extend the expiration date ofTreakisym® Injection (RTD formulation).
The company obtained approval to make a partial change to the approved matters of Treakisym® Injection 100mg/4ml(ready-to-dilute [RTD] formulation), aimed at extending the expiration date of the drug to 30 months based on the results oflong-term stability tests.

SymBio announced final results of phase III trial in Japan for
Treakisym® used in combination with rituximab as treatment for
r/r DLBCL
2021-09-29

SymBio Pharmaceuticals Ltd. announced the final results of the phase III trial in Japan for Treakisym® used in combination
with rituximab (BR therapy) as treatment for relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL).

The company announced the final results of a phase III trial in Japan for its anticancer agent Treakisym® used in BR therapy totreat r/r DLBCL.
The company conducted the phase III trial and its long-term follow-up study to obtain approval for use of Treakisym® in BR
therapy for r/r DLBCL, and the final results were presented at the 83rd Annual Meeting of the Japanese Society of
Hematology in September 2021. The phase III trial confirmed the efficacy of BR therapy as demonstrated in the phase II trial(conducted in Japan and Korea), and the regulatory approval was granted in March 2021.
Final main efficacy evaluation results of phase III trial and long-term follow-up study (38 cases)
Response rate (complete or partial response [CR+PR]): 76.3%
Complete response (CR): 47.4%
Median overall survival: 29.2 months

Initiation of controls on shipments of Treakisym® lyophilized
injection formulation
2021-09-21

SymBio Pharmaceuticals Ltd. announced that it will initiate controls on shipments of Treakisym® lyophilized
injection formulation.
In January 2021, SymBio commenced manufacture and sale of a ready-to-dilute (RTD) formulation of Treakisym® intravenous
fluid in quantities of 100mg/4ml, as a successor to the lyophilized (freeze-dried [FD]) powder formulation of Treakisym®
100mg. Although the company is still manufacturing and selling both the RTD and FD formulations as of September 2021, itis actively converting the market from FD to RTD.
However, SymBio has announced that it will initiate controls on shipments of the FD formulation, to avoid a potential stockout
arising from delays in the migration from FD to RTD.
The company has sufficient inventory to ensure stable supply of RTD. In addition, in May 2021 SymBio submitted a partialchange application with respect to its marketing authorization for the RTD liquid formulation to add rapid infusion (RI)
administration.

SymBio Pharmaceuticals/ 4582
Research Coverage Report by Shared Research Inc. | https://sharedresearch.jp

6As of September 2021, there is no change to the company’s full-year FY12/21 earnings forecast in relation to the controls on
shipments.

UCSF Brain Tumor Center initiates studies to investigate new
indications for brincidofovir IV
2021-09-08

SymBio Pharmaceuticals Ltd. announced that the University of California San Francisco (UCSF) Brain Tumor Center initiatedstudies to investigate new indications for brincidofovir IV.
The company announced that the Brain Tumor Center, Department of Neurological Surgery, UCSF, initiated preclinicalstudies to investigate antitumor effects of brincidofovir IV against brain tumor.

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7

Trends and outlook
Quarterly trends and results
Earnings (cumulative)

FY12/20

FY12/21

FY12/21(JPYmn)

Q1

Q1–Q2

Q1–Q3

Q1–Q4

Q1

Q1–Q2

Q1–Q3

Sales

551

1,361

2,333

2,987

1,420

3,147

5,553

YoY

-65.8%-32.1%

16.2%

5.3%

157.6%

131.3%

138.1%

Gross profit

128

330

611

867

1,010

2,275

4,046

YoY

-79.0%-37.7%

8.5%

0.2%

690.9%

589.5%

562.4%

Gross profit margin

23.2%

24.2%

71.1%

72.3%

72.9%

Q1–Q4

% of Est.
60.7%

FY Est.
9,151
206.4%

26.2%

29.0%

SG&A expenses

1,090

2,170

3,753

5,373

1,221

2,470

3,622

YoY

-9.6%

-14.7%

-8.4%

4.0%

12.0%

13.8%

-3.5%

SG&A ratio

197.6%

159.5%

160.9%

179.9%

85.9%

78.5%

65.2%

Operating profit-962-1,840-3,142-4,506

-211

-195

424

YoY

-

-

-

-

-

-

-

-

Operating profit margin

-

-

-

-

-

-

7.6%

14.9%

Recurring profit

31.2%

-991

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

-209

-204

YoY

-

-

-

-

-

-

-

-

Recurring profit margin

-

-

-

-

-

-

7.5%

14.8%

-992

-1,885-2,694-4,090

-210

-206

325

YoY

-

-

-

-

-

-

-

-

Net margin

-

-

-

-

-

-

5.9%

12.6%

Net income

Quarterly

FY12/20

414

Q1

Q2

Q3

Q4

Q1

Q2

Q3

Sales

551

809

972

654

1,420

1,726

2,406

YoY

-65.8%

105.7%--21.1%

157.6%

113.3%

147.6%

128

202

281

256

1,010

1,265

1,771

YoY

-79.0%-

738.4%-15.2%

690.9%

525.5%

530.6%
73.6%

Gross profit margin

23.2%

25.0%

28.9%

39.1%

71.1%

73.3%

SG&A expenses

1,090

1,080

1,583

1,620

1,221

1,249

1,152

YoY

-9.6%

-19.4%

1.8%

51.8%

12.0%

15.6%

-27.2%

SG&A ratio

197.6%

133.5%

162.9%

247.5%

85.9%

72.4%

47.9%

Operating profit

-962

-878

-1,302-1,364

-211

16

YoY

-

-

-

-

-

-

-

Operating profit margin

-

-

-

-

-

0.9%

25.7%

-991

-892

-1,338-1,395

-209

5

618

YoY

-

-

-

-

-

-

-

Recurring profit margin

-

-

-

-

-

0.3%

25.7%
530

Recurring profit

Net income

28.3%

1,350

1,149

FY12/21(JPYmn)Gross profit

30.7%

1,361

Q4

619

-992

-893

-809

-1,396

-210

4

YoY

-

-

-

-

-

-

-

Net margin

-

-

-

-

-

0.2%

22.0%

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
Earnings (cumulative)(JPYmn)FY12/20

FY12/21

Q1

Q1–Q2

Q1–Q3

Q1–Q4

Q1

Q1–Q2

Q1–Q3

SG&A expenses

1,090

2,170

3,753

5,373

1,221

2,470

3,622

YoY

-9.6%

-14.7%

-8.4%

4.0%

12.0%

13.8%

-3.5%

438

834

1,745

2,267

473

912

1,286

-7.1%

-13.4%-11.5%

-7.2%

8.0%

9.4%

-26.3%

R&D expenses
YoY
SG&A expenses excl. R&D
YoY

651

1,336

2,008

3,107

747

1,557

2,335

-11.1%-15.5%

-5.6%

14.0%

14.7%

16.6%

16.3%

Quarterly

FY12/20(JPYmn)FY12/21

Q1

Q2

Q3

Q4

Q1

Q2

Q3

SG&A expenses

1,090

1,080

1,583

1,620

1,221

1,249

1,152

YoY

-9.6%

-19.4%

1.8%

51.8%

12.0%

15.6%

-27.2%

438

396

911

522

473

439

374

-7.1%

-19.4%

-9.7%

11.0%

8.0%

11.0%

-59.0%

R&D expenses
YoY
SG&A expenses excl. R&D
YoY

Q1–Q4

651

685

672

1,098

747

810

778

-11.1%-19.3%

23.2%

83.9%

14.7%

18.3%

15.7%

Q4

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

Cumulative Q3 FY12/21 results
Sales: JPY5.6bn (+138.1% YoY)
Operating profit: JPY424mn (loss of JPY3.1bn in cumulative Q3 FY12/20)
Recurring profit: JPY414mn (loss of JPY3.2bn in cumulative Q3 FY12/20)
Net income: JPY325mn (loss of JPY2.7bn in cumulative Q3 FY12/20)
Sales increased YoY in cumulative Q3 (January–September) FY12/21, largely due to the transfer of sales from Eisai Co., Ltd.
to the company’s own sales force. The business alliance agreement with Eisai for Treakisym® expired on December 9, 2020,and SymBio began independently marketing Treakisym® in Japan on December 10. 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

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8

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).
However, there were headwinds such as the clearance of market inventory of the FD formulation sold by Eisai prior to theswitch to the company’s own sales force in December 2020, delays in medical care due to the COVID-19 outbreak from late2020, and constraints on sales activities due to tighter restrictions on facilities visits.
In Q3, sales of Treakisym® for the indication of relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) accelerated.
This was partially because the backlog of delayed medical treatments cleared on COVID-19 measures, including vaccinations
for the elderly. Other factors included the March 2021 approval of BR-therapy and P-BR therapy to treat r/r DLBCL, andChugai Pharmaceutical's polatuzumab vedotin being added to the NHI drug list in May 2021.
Gross profit was JPY4.0bn (+562.4% YoY), and GPM was 72.9% (+46.7pp YoY). The company attributes the GPM rise to theshift to its own marketing system and the launch of Treakisym® Ready-to-dilute (RTD) formulation in January 2021. In
cumulative Q3, sales of Treakisym® lyophilized formulations surpassed those of Treakisym® RTD formulations.
Reasons why in-house marketing of Treakisym® contributed to GPM improvement: Switching from marketing throughEisai (based the marketing agreement with Eisai) to doing its own marketing meant that products are shipped topharmaceutical 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 topharmaceutical wholesalers 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 of Treakisym® from Astellas Deutschland, but the liquid formulations (RTD and RI
formulations) are supplied by Eagle Pharmaceuticals. The company says that the GPM on liquid formulations ofTreakisym® is higher than the GPM on the lyophilized formulation.

Profits at the operating profit level down grew on reduced SG&A expenses and sales growth, and the company achieved
profitability in cumulative Q3. SG&A expenses decreased 3.5% YoY to JPY3.6bn
R&D expenses decreased 26.3% YoY to JPY1.3bn. This included expenses for conducting clinical trials of intravenous
formulations of Treakisym® and brincidofovir.
Excluding R&D expenses, SG&A expenses rose 16.3% YoY to JPY2.3bn. The switch to in-house sales drove up the cost of
sales.
Q3 FY12/21 (July–September 2021) results
In Q3 FY12/21 (July–September 2021), sales were JPY2.4bn (+147.6% YoY), gross profit was JPY1.8bn (+530.6% YoY), theGPM was 73.6% (+44.7pp YoY), and operating profit was JPY619mn (JPY1.3bn loss in Q3 FY12/20). The company turned
profitable at OP level in Q2 and further increased OP in Q3.
Versus Q2 FY12/21, sales were up JPY680mn, gross profit up JPY506mn, the GPM up 0.3pp, and operating profit up
JPY603mn.
Factors that contributed to sales growth were as follows. In Q2, sales were impacted by clearance of unsold inventory oflyophilized formulations sold by Eisai prior to December 2020, but this was no longer a factor in Q3. In March 2021, BR
therapy was approved for r/r DLBCL while Chugai Pharmaceutical received approval for the combination of polatuzumab
vedotin + BR therapy (P-BR therapy). In Q3, sales of Treakisym® used in BR and P-BR therapies for the for the r/r DLBCL
treatment increased.
The GPM rose QoQ, because the switch from the lyophilized formulation to the RTD formulation of Treakisym® progressed
faster in Q3 than in Q2.

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9Progress in cumulative Q3 versus full-year FY12/21 company forecast
When reporting Q2 FY12/21 results, 1H sales fell short of the company forecast, but the company left its full-year forecast
unchanged, because it expects higher sales in 2H than in 1H, and thinks the full-year forecast is achievable. Reasons for thecompany's expectation of profit growth in 2H versus 1H are as follows.
In 1H FY12/21, the impact of the clearance of unsold inventory of the lyophilized formulation of Treakisym® sold by Eisai
totaled around JPY400mn. The clearance was completed in 1H and will have no impact on 2H results.
Patients cut back on hospital visits in 1H because of COVID-19, but the company expects this pattern to change in 2H as
more seniors are vaccinated and likely to resume hospital visits.
The company received approval for BR therapy indicated for r/r DLBCL in March 2021, while Chugai Pharmaceuticalreceived approval for polatuzumab vedotin + BR therapy indicated for r/r DLBCL. These approvals were granted about
three months earlier than the company expected at the beginning of FY12/21. The company targets JPY2.6bn in sales ofTreakisym® indicated for r/r DLBCL on a NHI drug reimbursement price basis, but Shared Research understands thatsales may exceed this target because of the earlier-than-expected approval timing. The company recorded sales ofTreakisym® indicated for r/r DLBCL in the second half of Q2 and expects this sales to increase in 2H.
The company forecasts a higher GPM in 2H as the switch from the lyophilized formulation to the RTD formulation ofTreakisym® progresses.
Cumulative Q3 sales were 60.7% of full-year FY12/21 company forecasts while operating profit came in at 31.2%. It is ourunderstanding that Q3 earnings are in line with company expectations for 2H. Q4 sales and operating profit are projected to
exceed Q3 levels as higher vaccination rates help reduce patient hesitancy for doctor consultations, progress is madeswitching to the higher-margin RTD formulation, and increases in SG&A expenses are curbed.
Overview of business progress
In FY12/21, progress in main businesses are as follows:
In October 2021, Dr. Carolyn Yanavich was appointed Vice President, and Head of Project Management and Clinical
Operations of SymBio Pharma USA.
In September 2021, results of the domestic phase III trial evaluating TREAKISYM in combination with Rituximab fortreatment of relapsed and refractory diffuse large B-cell lymphoma were disclosed. The phase III and follow-up studies
demonstrated a response rate (complete response and partial response [CR+PR]) of 76.3%, complete response rate (CR)of 47.4%, and median overall survival of 29.2 months.
In September 2021, the company announced plans to adjust shipments of lyophilized TREAKISYM. As of September
2021, SymBio manufactures and markets both the RTD and FD formulations while it looks to switch FD to RTD.
Adjustments to FD shipments are being made because of potential stockout.
In September 2021, the company initiated a pre-clinical study to investigate the anti-tumor effect of brincidofovir IV onbrain tumors at the Brain Tumor Center, Department Neurological Surgery, University of California, San Francisco.
In September 2021, the company concluded a joint research agreement with the National Cancer Centre Singapore to
explore the anti-tumor effects of brincidofovir IV in Epstein-Barr (EB) virus positive lymphoma and its mechanism ofaction.
In August 2021, the company announced it had started administration to the first patient enrolled (FPI) in the Phase II
clinical trial of antiviral drug brincidofovir (IV forumulation).
Also in August 2021, the company concluded a joint research agreement with Kyoto University regarding the mechanismof effect of bendamustine, under development as an anticancer agent indicated for DLBCL.
In July 2021, the company concluded a joint research agreement with the General Surgical Science Department, Gunma
University Graduate School of Medicine regarding the exploration of new indications for bendamustine and rigosertib,
which are under development as anticancer agents.

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10

In June 2021, Chimerix, Inc. (licensor of brincidofovir) obtained FDA approval of brincidofovir tablets and oralsuspensions 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 incombination 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
with rituximab and polatuzumab vedotin for the treatment of r/r DLBCL.
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 tocover each region to establish a highly productive internal sales organization capable of making proposals that fit the needsof each region. With the termination of its alliance agreement with Eisai, in September 2020, the company concluded abasic agreement with Suzuken Co., Ltd and Toho Pharmaceutical Co., Ltd for the procurement and sale of pharmaceuticals toachieve nationwide distribution. The company has established two distribution centers, one in Eastern Japan and the other inWestern Japan, under management by S.D. Collabo Co., Ltd.
During cumulative Q3, 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 manufacturing and marketing authorization
for bendamustine-rituximab combination therapy (BR therapy) and bendamustine-rituximab-polatuzumab vedotin combination
therapy (P-BR therapy) to treat r/r DLBCL patients. This enabled conventional lyophilized (freeze-dried [FD]) powder
formulation of Treakisym® to be used in BR therapy right away. In April 2021, the company obtained approval of Treakisym®
ready-to-dilute (RTD) liquid formulation for use in BR therapy and P-BR therapy for the treatment of r/r DLBCL. In May 2021,
Chugai Pharmaceutical's polatuzumab vedotin was added to the NHI drug price list, enabling Treakisym® to be used in P-BR
therapy.
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 FD formulation.
SymBio imports FD formulation Treakisym® for injection from Astellas Deutschland (consolidated subsidiary of Astellas
Pharma) and Treakisym® RTD formulation from Eagle Pharmaceuticals Inc.
On the quality control front, the company conducts secondary packaging and quality screening on imported batches of both
the FD and RTD formulations of TREAKISYM® to maintain stable quality.
On the supply front, the company is striving to replace the FD formulation of TREAKISYM® with RTD formulation in themarket, but the current conversion rate is behind plan. Due to the possibility of the FD formulation being out of stock,
SymBio began controlling shipments of FD from September 21, 2021. The company has secured sufficient quantities of the
RTD formulation to ensure stable supply.
Treakisym® (SyB L-0501[FD formulation]/SyB L-1701 [RTD formulation]/SyB L-1702 [RI administration]; genericname: bendamustine hydrochloride or bendamustine hydrochloride hydrate, 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).

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11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, whichapplies 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 revision to the marketing authorization 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 follicular lymphoma, the most common histological type of low-grade NHL. This allows the company toprovide patients a new treatment option: combination therapy with obinutuzumab. In March 2019, SymBio obtained approval
for the partial revision to its application to use Treakisym® 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 chimericantigen receptor T-cell (CAR-T) therapy approved in Japan. Growing use of Treakisym® as a pretreatment agent inregenerative medicine has solidified its positioning as standard therapy for malignant lymphomas.
In the phase III clinical study of Treakisym® administered in BR therapy targeting r/r DLBCL, the company filed for approval
for partial revision to manufacturing and marketing authorization in May 2020 and obtained that approval in March 2021. In
April 2021, it obtained approval for partial revision to manufacturing and marketing authorization of Treakisym® RTD liquid
formulation for use in BR and P-BR therapy as treatment for r/r DLBCL. The company has conducted a follow-up study withoverall survival as the primary endpoint, because evaluating the survival data (e.g., overall survival and progression-freesurvival) 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.
In response to Chugai's June 2020 filing for manufacturing and marketing approval of combination therapy of polatuzumab
vedotin + BR therapy (P-BR therapy) to treat r/r DLBCL, SymBio submitted a filing for Treakisym® + polatuzumab vedotin +rituximab in July 2020 and received approval in March 2021. Polatuzumab vedotin was included in the NHI price list fromMay 2021, at which time it became possible to use Treakisym® in P-BR therapy. Prior to this, there were no effective
treatments for this indication so multi-drug regimens comprised of different anticancer agents were used as rescue
chemotherapy. Accordingly, there was strong demand for development of an effective and safe treatment option. As BR
therapy was already used to treat r/r DLBCL in Europe and the US, patient groups and related academic societies submitted arequest to MHLW for an accelerated approval in Japan.
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 administrationtime). Manufacturing and marketing approval of the RTD formulation was obtained in September 2020, and the company
launched it in January 2021. The company has concluded clinical trials to confirm safety of the RI formulation and applied forapproval in May 2021. Unlike the current FD 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 injust 10 minutes, versus 60 minutes for the current FD and RTD formulation. This reduces the burden on patients andhealthcare professionals, providing significant value added.
Rigosertib Sodium (SyB L-1101 [IV]/SyB C-1101 [oral]; anticancer agent; 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
is patients who do not respond to the current standard treatment with hypomethylating agents, relapse after treatment under
the current standard of care, or are intolerant to hypomethylating agents. In August 2020, Onconova announced acomparator trial to physicians’ choice of treatment failed to achieve the primary endpoint. The company leads clinical trials
conducted in Japan and 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
with azacytidine, whose results suggested the efficacy and safety of the combination therapy. To verify the tolerability andsafety among Japanese patients, SymBio began a phase I clinical trial in Japan in June 2017 and completed patient
enrollment in June 2019.
The company said it would conduct joint research into Treakisym® and rigosertib with the University of Tokyo's Institute ofMedical Science and Gunma University regarding efficacy of using the two compounds in combination or with existing drugs
and also explore new indications.

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12）

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) totreat 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 as a 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 and on August 16, 2021, the investigational
drug was administered to the first patient enrolled (first patient in [FPI]) in the clinical trial.
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 December 2020 that the FDA had accepted its new drug application (NDA) for BCV as a medical
defense against smallpox and that it had received FDA approval in June 2021. Further, through joint research with the
National Cancer Centre Singapore and University of California San Francisco Brain Tumor Center, SymBio is investigating
new indications for BCV.

Overseas
The company’s US-based wholly-owned subsidiary SymBio Pharma USA, Inc. appointed Dr. Carolyn Yanavich as its Vice
President, and Head of Project Management and Clinical Operations on October 11, 2021, and launched full-scale
operations aimed at accelerating global development of antiviral drug brincidofovir toward commercialization.

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

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

FY12/21

1H Act.

2H Act.

FY Act.

1H Act.

2H Est.

FY Est.

1,361

1,626

2,987

3,147

6,004

9,151

330

537

867

2,275

4,682

6,957

24.2%

33.0%

29.0%

72.3%

78.0%

76.0%

SG&A expenses

2,170

3,203

5,373

2,470

3,126

5,596

SG&A ratio

159.5%

197.0%

179.9%

78.5%

52.1%

61.2%
2,019

2,267

912

1,107

SG&A expenses excl. R&D

1,336

1,770

3,107

1,557

2,020

Operating profit

R&D expenses-1,840834-2,666-4,506

-195

1,556

1,361

-

-

-

-

25.9%

14.9%

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

-204

1,554

1,350

-

-

-

-

25.9%

14.8%

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

-206

1,355

1,149

Net margin

-

-

-

-

22.6%

12.6%

Operating profit margin
Recurring profit
Recurring profit margin

1,433

3,577

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).

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13

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 meant that 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 thegross profit earned by Eisai through December 9, 2020 (i.e., the difference between the shipment price from Eisai topharmaceutical 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® indicatedfor 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
to higher sales and GPM. The GPM rise is due to starting in-house sales of Treakisym® and switching to the RTD
formulation of the product. 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 to higher sales and GPM. The GPM rise is due to starting in-house sales of Treakisym® andswitching 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 (basedon 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.,the difference between the shipment price from Eisai to pharmaceutical wholesalers and the price Eisai paid thecompany to source the product). Before December 9, 2020, the company was selling the lyophilized formulation ofTreakisym® 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
formulation and RI administration) are supplied by Eagle Pharmaceuticals. The company commented that the GPM on
liquid formulations of Treakisym® will 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 andsustain 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.

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14

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 endof 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 fordose determination in children.

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.

Targets

Targets

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

-

-

27.7%

20.8%

15.8%

17.0%

Operating profit
YoY
Operating profit margin

-

14.9%

-4,616

1,350

1,727

2,088

YoY

-

-

27.9%

20.9%

Recurring profit margin

-

14.8%

15.7%

16.9%

Recurring profit

Net income-4,090

1,149

1,470

1,778

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-housesales organization.
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.

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15

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 bearound 50% of the NHI drug price. With the transition to an in-house sales structure in FY12/21, though, Shared Researchthinks the price that 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 productsales 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 infer that Eisai’s gross profit is roughly Eisai’s sales minus SymBio’s sales, so once SymBio begins its own sales ofTreakisym®, it is our understanding 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 of Treakisym® based on an NHI drug price should remain solid, reflecting actual market demand, but SymBio plans tostop shipping to Eisai with a target date of end-1H FY12/20. It expects FY12/20 sales to decline by a commensurate amount.
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 tocommence 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 ofpatients being treated for relapsed or refractory low-grade NHL and MCL in Japan is 9,336 and the number of patients withuntreated low-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
to wholesalers). 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.

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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
and FY12/23. It also expects an increase in clinical trial expenses for brincidofovir in FY12/22 onward.
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, businessdevelopment, and management related costs. From FY12/21, SymBio assumes costs associated with operating its own
sales organization for sales of Treakisym®. It forecasts an increase primarily in personnel expenses due to a higher
medical representative headcount and 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 effectaccounting. Heeding the advice 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 bareminimum of 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 thisin personnel expenses.

Funding plans
Regarding funding plans, the company will work toward strengthening its financial base so that it can respond in a flexible
and nimble 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 needto 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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Research Coverage Report by Shared Research Inc. | https://sharedresearch.jp17Business
Business description
SymBio obtains rights to develop and market new drugcandidates from biotech companies in the US and EU
President and CEO, Fuminori Yoshida, established SymBio in March 2005 to address underserved medical needs in Japanand the Asia Pacific region, with main focus on oncologic, hematologic and autoimmune diseases. The company aspires tobe a leading specialty pharmaceutical company in the Asia Pacific region. Its strategic approach to drug development
negates the need for costly and time-consuming investment in earlier-stage R&D activities with an in-house search andevaluation team to identify and assess 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 undergoingclinical development 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 ahigh unmet medical in Japan and other Asia Pacific markets with the potential to secure marketing approval in a shorter
clinical development 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 alonger marketing exclusivity period due to high unmet medical needs—including oncology, hematology, and rarediseases—and smaller patient populations. Larger pharmaceutical companies may be reluctant to develop drugs in nichemarkets due to limited sales potential—SymBio sees an opportunity to avoid intense competition in the marketplace byfocusing on the development of orphan or ‘orphan-like’ drugs.
Global expansion: The company identifies and capitalizes on opportunities to grow sales by acquiring the right todevelop 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 amarket share of over 50%.
An example of the company’s ability to identify and pursue quality in-licensing opportunities with proof-of-concept
established is the license agreement signed for the development and commercialization right to rigosertib—currently injoint 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 sevenmonths from the initial meeting between the two companies. The following year, Baxter International Inc. entered into anagreement with Onconova for the 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.

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Products under development: Treakisym® (FD), Treakisym® (RTD
formulation and RI administration), rigosertib (injection and oral),and brincidofovir
Additional indications for Treakisym®
For patients that have developed resistance to other drugs, Treakisym® is safer and more efficacious than existingtreatments. As outlined below, the company has gained approval in Japan for the indications of refractory or relapsed lowgrade non-Hodgkin’s lymphoma and mantle cell lymphoma, chronic lymphocytic leukemia, and first-line treatment of lowgrade 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 the trial 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 approvalin 1H FY12/21.

Treakisym® (RTD formulation and RI administration)
In September 2017, Eagle Pharmaceuticals and SymBio concluded a license agreement that licenses to SymBio rights todevelop, market, and sell Eagle’s bendamustine hydrochloride ready-to-dilute (RTD) formulation and rapid infusion (RI)
administration products in Japan. Securing products to replace existing freeze-dried (FD) product (whose exclusive sales
rights in Japan expire in 2H 2020) had been a priority for the company. SymBio obtained approval for the RTD formulation in
September 2020, and launched the product in January 2021. For the RI administration, the company concluded clinical
trials aimed at confirming the drug’s safety and in May 2021, submitted an approval application.
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(filing for 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 respondto the standard therapy with hypomethylating agents (HMAs) or relapsed in more than 20 countries, and announced inAugust 2020 that they had failed to meet the primary endpoints in comparison with physician’s choice. In Japan, thecompany 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,
which suggested efficacy and safety of rigosertib-azacitidine combination therapy. SymBio initiated the phase I clinical trial ofrigosertib monotherapy for higher-risk MDS in Japan in June 2017 and completed patient enrollments in June 2019.
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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 alsoeasy to use as it has a low risk of 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, andsmallpox virus.
In September 2019, SymBio entered an exclusive global license agreement with Chimerix Inc. for brincidofovir. As a result,the company 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 foran 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
and expects to continue posting operating profit over the medium term thereafter.

Business strategy
Unlike conventional pharmaceutical companies, SymBio does not conduct basic research or develop its own drug candidates
in labs 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
to develop new drugs more likely to succeed and secure regulatory approval with the use of bridging data wheneverpossible to shorten development timelines. Because the company does not conduct basic research, the company can obtainapproval and start 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-housescreening process and rigorous 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 anestablished 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 inclinical studies from phase I through III. According to the company, the probability of a chemical compound having a signal
with pharmacological activity in a particular disease being approved as a drug is 1/20,000 to 1/25,000, and only 15–20%
of drugs that manage 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

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new drug candidate 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, slashingdevelopment 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
Identify candidate drugs by utilizing independent search network and evaluation
experience
The company identifies quality chemical compounds owned by pharmaceutical and biotech companies in the US or EU using
a proprietary “search engine” and rigorous evaluation process. These candidates are first screened in-house by the searchand evaluation team, whose members have extensive product development experience working at various pharmaceuticaland biotech companies.

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.

Evaluation by a panel of pharmaceutical experts
The final in-licensing candidate will be determined by the Scientific Advisory Board after rigorous evaluation by external
experts involved in therapeutic research in related fields.

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 areunderway, 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, andmeets three times a year. Typically, the SAB panel evaluates two to three drug candidates that have been selected via thecompany’s in-house screening process. This in-house screening of only those drug candidates having proof-of-concept
established in human subjects with supportive efficacy and safety data followed by SAB assessment enables the company toreduce development risk and to pursue only those opportunities having the best chance of reaching the marketplace.

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Scientific Advisory Board members
NameProfilePresently Chairman GBS Venture Capital firm, Deputy Chairman Victorian Comprehensive Cancer Centre, Director of Co-operative ResearchCentre 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.,
Syntex Pharmaceuticals; Associate Professor, Harvard Medical School
Ph.D.
Currently serves as consultant in Immunology/Inflammation, Roche Palo Alto;
Adjunct Faculty Member, Rockefeller University, New York
George Morstyn,M.D., Ph.D.

Tomomitsu Hotta,
M.D.
Makoto Ogawa,
M.D., Ph.D.
Tatsutoshi
Nakahata, 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
Toshio Suda, M.D.,
Professor, Cancer Science Institute of Singapore, National University of Singapore
Ph.D.
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 of Internal Medicine)

Professor, Kanazawa University College of Medical, Pharmaceutical and Health Sciences, Division of Cancer Medicine Cellular
Shinji Nakao, M.D.,
Transplantation Biology (Hematology/Respirology)
Ph.D.
Executive Director, The Japanese Society of Hematology in 2012
Koichi Takahashi,
Assistant Professor, Department of Leukemia, Division of Cancer Medicine, MD Anderson Cancer Center, The University of Texas
M.D.

Source: Shared Research based on company data

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 Japanese clinical 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 other domestic
or foreign manufacturer(s). The company began in-house sales in Japan of Treakisym® on December 10, 2020, taking overfrom 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.
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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 can effectively 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 canbe prohibitive. As a result, barriers to entry are high—developing cancer drugs for niche markets is especially difficult andrequires a high level of expertise.
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 suchas SymBio. The company can also increase value added of niche disease areas by additional indications and putting new
products on 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 lowgrade NHL and mantle cell lymphoma in the Guidelines for Hematological Malignancies 2018 issued by the Japan Societyof 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/HongKong, Taiwan, South Korea, and Singapore, as well as in Japan. Also, it acquired exclusive worldwide rights to develop,
manufacture, and market brincidofovir.

Pipeline
Pipeline
Name/CodeLicensedcountryJapan

Indications

Development stage

Relapsed or refractory
low-grade NHL and MCL

Approved (Oct. 2010)

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

Untreated low-grade NHL and MCL
CLLTreakisym®
SyB L-0501(FD)

Singapore

South Korea
China
Hong Kong
TaiwanTreakisym®
SyB L-1701(RTD)
Treakisym®
SyB L-1702(RI)
Rigosertib(IV)
SyB L-1101

Low-grade B-cell NHL
CLL

Approved(Dec. 2016)
Approved(Aug. 2016)
Approved(Jan. 2010)

Sales partner

In-house sales

Eisai Co., Ltd.
(Exclusive development and sales
rights granted to Eisai)

CLL
MM
Relapsed or refractory low-gradeNHL
Low-grade NHL
Low-grade NHL
CLL

Approved(May 2011)
Approved(Jun. 2014)
Clinical trials underway

Low-grade NHL

Approved(Oct. 2011)

InnoPharmax, Inc. (Taiwan)(Exclusive development and sales
rights granted to Eisai)

CLL

Approved(Dec. 2009)

Eisai Co., Ltd.
(Exclusive development and sales
rights granted to Eisai)
Cephalon, Inc. (US)(Exclusive development and sales
rights granted to Eisai)Japan

All indications

Approved(Sep 2020)

In-house sales

Japan

All indications

Clinical trials underway

—

Japan

Relapsed or refractory
higher-risk MDS

Global phase III clinical trials
Additional analysis underway—

Phase I clinical trials underway—

Global phase I/II clinical trials
completed—

Preparations for phase II clinical
trials underway—

Rigosertib(oral)SyB C-1101

Japan

Brincidofovir (IV)SyB V-1901

Worldwide

Relapsed or refractory higher-risk
MDS(monotherapy)
Untreated higher-risk MDS (withazacitidine)
Adenovirus infection after
hematopoietic stem cell and kidneytransplantation

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:

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Treakisym®, for the indication of relapsed or refractory DLBCL (aggressive NHL): Completed enrollment of patients forthe phase 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
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 in June 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, productname: 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 untreatedlow-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 thesame 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
been shown 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, the company had filed for approval of Treakisym® for the additional indication of relapsed or refractory
DLBCL (aggressive NHL; May 2020).

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
body and 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 arisingfrom pressure of swollen 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 (all cases).

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Lymphatic malignancy: frequency by typeClassification

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
Stage

Non-Hodgkin’s lymphoma

Ⅰ
Ⅱ
Ⅲ
Ⅳ

19
46
22
19

5-year relative survival rate
(%)
91.4
84.6
65.3
44.7

All cases

122

76.0

Number of cases

462
385
319
535

5-year relative survival rate
(%)
86.7
74.3
64.0
54.6

1,844

68.3

Number of cases

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 eachdisease subtype
Physicians examine tissue and determine the method of treatment depending on the type of cancerous cells observed: theylook at the grade (high, intermediate, or low, depending on the aggressiveness of the disease) and clinical staging, whichshows to what 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 agreementwith 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 a particular indication, plus revenues after supplying Treakisym® to Eisai. Eisai shoulders half of thedevelopment costs for Treakisym®, including labor costs for researchers and outsourcing costs for clinical trials (see theEarnings structure section). The marketing agreement with Eisai expired in December 2020, after which SymBio began toindependently market Treakisym® in Japan.
SymBio has granted exclusive marketing rights for Treakisym® to InnoPharmax, Inc. in Taiwan, Cephalon, Inc. in China, andEisai in South Korea and Singapore. In return, SymBio receives one-time milestone payments, and books revenue from thesale 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 forrelapsed 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.
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.
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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 (aggressiveNHL) in May 2020.

Market for Treakisym® and number of patients
Non-Hodgkin's lymphoma
Low-grade B-cell
Number of patientsFirst-line-

Approval

Obtained- Obtained

Development status

Obtained approval (Dec. 2016)- Obtained approval (Aug. 2016)

Number of patients
Relapsed andrefractory

Chronic Lymphatic Leukemia

Moderate- to high-grade
6,967

9,336

656

18,672

Approval

Obtained

Completed patient enrollment for phase III clinical
trials in Japan

Development status

Obtained approval in Japan (Oct. 2010)

Applied approval (May 2020)

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 forthe additional indication of first-line treatment of low-grade NHL and MCL, and subsequently in July 2018, Treakisym® wasnewly 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 lowgrade B-cell NHL. These findings were presented at the American Society of Hematology Annual Meeting in December
2012. Based on these 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 withthe 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 groupand 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 pvalue of 0.01 indicates that an observed result will occur randomly one out of 100 times. Generally, if the value isbelow 5%, the result is statistically significant.

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26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 numberof patients with relapsed or refractory low-grade NHL and MCL, the company expects higher market penetration amid thetrend 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 of NHL.
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 the majority of relapsed or refractory DLBCL patients are elderly, physicians must consider potential side effects

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when selecting a suitable treatment. Weaker patients—due to age or other illnesses—have limited choices for treatment, andthere is a need for a safer, more efficacious method of treatment such as Treakisym®.

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 theprimary endpoint. Enrollment of 60 patients was completed in April 2019. The following results of the clinical trial (mainefficacy 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 ofrelapsed 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 is limited 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 apretreatment 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) patientsin Japan 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 ofbendamustine 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 todevelop, 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.

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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
and substantially 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.

Comparison of RTD/RI formulations and current (freeze-dried) formulation
Generic name
Dosage form

RTD products
bendamustine hydrochloride
LiquidReconstitution
Dilution
Administration time

Not required
Dilute with 250ml physiological saline
60 minutes

Specifications

100mg/4mL

Storage

Refrigerated storage (2–8°C)

RI products

Currently available products
Freeze-dried powder injection

Dilute with 50ml physiological saline
10 minutes

Required (manual reconstitution)
Dilute with 250ml physiological saline
60 minutes
100mg/vial
25mg/vial
Room temperature

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 andsold. 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 the possibility 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 isdeveloped, 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-name products 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, other companies 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® toenable 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 Tcell (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®.

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CAR-T cell therapy genetically modifies T-cells collected from patients’ blood samples to express chimeric antigen
receptors (CARs) on their surface at a cell processing facility. Then, the genetically modified T-cells (CAR-T cells) areinfused 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 from patients’ blood
samples and genetically modifies them so that they specifically recognize CD19 proteins expressed on cancer cells
among others and attack them. CTL019 therapy requires only a single administration.

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 usedin 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 thatkills 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, and proliferation.
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 frequent anemia with some patients dying from infection or bleeding due to the reduction inblood cells. The average survival period is about 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 havereceived 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 theresults of a 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.

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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 withhypomethylating 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 is looking 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 (in combination 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 2019, to verify the tolerability and safety of the study drug in Japanese patients. After establishing safetyin phase I clinical trials, the company plans to resume the trial of rigosertib in combination with azacitidine and participate inglobal 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 MDSFirst-line
Intravenous

Oral

First-line

Relapsed and refractory

Number of patients--

Approval-- TBD

Development status-

Number of patients

7,800

3,200

- Global phase III trials underway
3,200

-

Approval

TBD

TBD

-

Development status

Phase II trials underway in the US

Global clinical trials being reviewed by Onconova-

Phase I clinical trials underway in Japan

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 wasfor the 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 ofFebruary 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 thecontrol 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 twogroups.

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Among patients whose condition had deteriorated or not responded to previous treatment using hypomethylating agents(184 of 299 people, or 62%), the overall survival period for higher-risk MDS patients who received rigosertib was 8.5 months,
while for those 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, toxicityof 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
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 is conducting 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 inPatients with Myelodysplastic Syndromes (MDS): Results from a Phase II Study.” The complete remission (CR) rate among
HMA-naïve patients was higher (35%) and responses occurred more rapidly and durably with the oral rigosertib combinationcompared to the single-agent azacitidine. The median duration of CR was eight months, comparing very favorably to thehistoric 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 inthe phase I clinical trial, the company plans to resume the trial of the drug in combination with azacitidine and participate inglobal clinical trials conducted by Onconova. In December 2019, Onconova issued a press release announcing it wasconsidering a phase 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.

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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 Clinical Research Center, using bendamustine and rigosertib in combination or with otherapproved 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 of bendamustine and rigosertib, analyzing their effects whenused 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 in the 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 in collaborating with IMSUT to search for new indications for bendamustine andrigosertib.

Patient population, estimated sales
According to SymBio estimates, patients with lower-risk MDS in Japan number about 7,800, with 3,200 MDS patientsclassified 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 with Vidaza.

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 other candidates 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 to the 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 ofnephrotoxicity, 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 a wide array 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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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, andpolyomaviruses.
CDV is taken up by renal tubular epithelial cells through organic anion transporter 1 (OAT1), and its accumulation in thecells cause nephrotoxicity. brincidofovir is expected to have a low risk of nephrotoxicity as its lipid chain prevents it frombeing taken up by OAT1 and accumulating in renal tubular epithelial cells.

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 fromits 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 brincidofovir. As of February 2021, the company was inpreparation to initiate a dose-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 andtreat 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
and immunodeficiency 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
viral hemorrhagic 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.

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dsDNA viruses: Includes families of herpesviridae, adenoviridae, polyomaviridae, papillomaviridae, and poxviridae, suchas 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 celltransplantation, 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 causingkidney failure and ultimately death have been reported. These infections are especially likely to occur in unrelateddonor 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 theimmune system. Drugs currently used in treatment, including cidofovir (CDV), are either unapproved or off-label inJapan.
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, andconvulsions, 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 repeated convulsions 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), the first-line drugs arefoscarnet (FOS) and ganciclovir (GCV), followed by the second-line drug cidofovir (CDV). CDV is not the preferred firstline 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 inpatients with HHV-6 encephalitis.

Earnings structure(JPYmn)FY12/11

FY12/12FY12/13

FY12/14

FY12/15

FY12/16

FY12/17

FY12/18

FY12/19

FY12/20

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

Sales

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%

-

-

Royalty revenue

250

-

100

15

-

231

-

26

26

10

Sales to Eisai

1,872

1,930

1,486

1,908

1,852

2,265

3,382

3,648

2,831

2,546

YoY

29.5%

3.1%

-23.0%

28.4%

-2.9%

22.3%

49.4%

7.9%

-22.4%-10.1%

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

Sales to other partners
CoGS

Gross profit

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%

Royalty revenue
SG&A expenses
Personnel expenses
R&D expenses

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

Other

415

442

505

577

612

823

1,406

1,492

2,219

2,576

Operating profit-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 throughFY12/19 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
sales of Treakisym® indicated for relapsed or refractory low-grade NHL and MCL.

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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 DeutschlandGmbH, a consolidated subsidiary of Astellas Pharma, was found to contain impurities and appearance defects, and as a result,shipments of 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
old refers to procurement costs for drugs. SymBio purchases lyophilized Treakisym® from Astellas Deutschland GmbH.
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 tosource the product). Shared Research understands that this is a factor that contributes to higher GPM.
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 linewith additions 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
per drug, 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.

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 ofcontacts in the pharmaceutical industry built during his tenure at Amgen Japan and Amgen Inc. is a significant hurdle forcompetitors 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.
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36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 asingle product raises the risk of earnings volatility. Sales and gross profit declined in FY12/19 and FY12/20 due tocontamination and irregular appearance of lyophilized Treakisym® imported from Astellas Deutschland GmbH, which led toa temporary slump in product sales.

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 orolder.
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 thenumber of people newly diagnosed with cancer.

Morbidity of lymphatic malignancy

Number of patients
Incidence rate (per 100,000)

1,975

1,980

1,985

1,990

1,995

2,000

2,005

2,010

2,015

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 Japanis 9,336 and the number of patients with untreated low-grade NHL and MCL is 6,967. On an NHI drug reimbursement pricebasis, Treakisym® sales reached JPY8.5bn in FY12/18 (JPY7.6bn in FY12/17).

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

Patients

Progress

9,336

Approved

Untreated low-grade NHL, and untreated MCL
CLL
Relapsed or refractory NHL

6,967
656
18,672

Approved
Approved
Clinical trials underway

Notes

Sales: JPY8.5bn (FY12/18)

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

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
substance and 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
Low-risk MDS

Number of patients
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 Japanfor the main indication of MDS.

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Azacitidine (product name: Vidaza)
Vidaza, developed by Pharmion Corporation (now Celgene Corporation) in the US, is a treatment for first-line intermediateand higher-risk MDS. Nippon Shinyaku Co., Ltd. signed a license agreement with Pharmion in 2006 to sell this drug inJapan, 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 theoutcome of patients who tend to have very poor survival, about half of MDS patients do not respond, progress, or relapse atdifferent times after their response on these HMAs, followed by an extremely poor prognosis.
According to Nippon Shinyaku, Vidaza is the only approved drug in Japan for the first-line treatment of higher-risk MDS, withno efficacious 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
1H FY12/21 results
Sales: JPY3.1bn (+131.3% YoY)
Operating loss: JPY195mn (loss of JPY1.8bn in 1H FY12/20)
Recurring loss: JPY204mn (loss of JPY1.9bn in 1H FY12/20)
Net loss: JPY206mn (loss of JPY1.9bn in 1H FY12/20)
Sales increased YoY in 1H, largely due to the transfer of sales from Eisai Co., Ltd. to the company’s own sales force. The
business alliance agreement with Eisai concerning the marketing of Treakisym® expired on December 9, 2021, and thecompany began its own marketing in Japan on December 10, 2021, starting shipments to pharmaceutical wholesalers insteadof Eisai. This allowed 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).
However, there were negative factors for Treakisym® sales, such as the impact of clearance of unsold inventory oflyophilized formulations sold by Eisai prior to December 2020, delays in treating patients after the COVID-19 outbreakstarting in late 2020, and tightened restrictions on visiting facilities limiting sales activities.
From Q3 onward, the company says that it expects sales of drugs targeting relapsed or refractory diffuse large B-cell
lymphoma (r/r DLBCL) to accelerate. The backlog of delayed medical treatments should clear as measures to combat COVID19, including vaccinations for the elderly, progress. Other factors include the March 2021 approval of BR-therapy and Pola-BRtherapy to treat r/r DLBCL, and Chugai Pharmaceutical's polatuzumab vedotin being added to the NHI drug list in May
2021.
Gross profit was JPY2.3bn (+589.5% YoY), and GPM was 72.3% (+48.0pp YoY). The company attributes the GPM rise to theshift to its own marketing system and the launch of Treakisym® Ready-to-dilute (RTD) formulation in January 2021. In 1H, salesof Treakisym® lyophilized formulations surpassed those of Treakisym® RTD formulations.
Reasons why in-house marketing of Treakisym® contributed to GPM improvement: Switching from marketing throughEisai 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 pharmaceutical wholesalers and the price Eisai paid thecompany 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 of Treakisym® from Astellas Deutschland, but the liquid formulations (RTD and RI
formulations) are supplied by Eagle Pharmaceuticals. The company says that the GPM on liquid formulations ofTreakisym® is higher than the GPM on the lyophilized formulation.

Although SG&A expenses increased in 1H, losses at the operating profit/losses level down narrowed thanks to the effect ofsales growth, and the company recorded operating profit in Q2 (April–June 2021). SG&A expenses increased 13.8% YoY to
JPY2.5bn and R&D expenses increased 9.4% YoY to JPY912mn.
R&D expenses were JPY912mn (+9.4% YoY). The company incurred clinical trial expenses for the IV formulations ofTreakisym® and brincidofovir.
SG&A expenses other than R&D expenses were JPY1.6bn (+16.6% YoY). Sales expenses associated with the transition to its
own sales system increased.
Q2 FY12/21 (April-June 2021) results
In Q2 FY12/21, sales were JPY1.7bn (+113/3% YoY), gross profit was JPY1.3bn (+525.5% YoY), the GPM was 73.3% (+48.3pp
YoY), and operating profit was JPY16mn (JPY878mn loss in Q2 FY12/20). The company turned profitable at OP level.
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Versus Q1 FY12/21, sales were up JPY306mn, gross profit up JPY255mn, the GPM up 2.2pp, and operating profit up
JPY226mn.
Factors that contributed to sales growth were as follows. In Q1, sales were impacted by clearance of unsold inventory oflyophilized formulations sold by Eisai prior to December 2020, but this effect faded in Q2. In March 2021, approval was
granted for Treakisym® in combination with rituximab for the indication of r/r DLBCL (BR therapy). In Q2, the company
recorded sales of Treakisym® for the indication of r/r DLBCL.
The GPM rose QoQ, because the switch from the lyophilized formulation to the RTD formulation of Treakisym® progressed
faster in Q2 than in Q1.
June 2021 results
The company commented that it turned profitable on a monthly basis in June 2021. Sales were JPY706mn (+298.3% YoY),
gross profit was JPY523mn (+881.6% YoY), the GPM was 74.1% (+44.1pp YoY), and operating profit was JPY85mn (JPY324mn
loss in June 2020).
Sales in June 2021 surpassed the average monthly sales in Q2 FY12/21 and the GPM was also higher than the monthly
average in Q2. Sales were higher in June than in April and May, because the company recorded sales of Treakisym®
targeting r/r DLBCL. GPM rose especially in the latter half of Q2 thanks to the switch to the RTD formulation.
Progress in 1H versus full-year FY12/21 company forecast
In 1H FY12/21, sales were 34.4% of the full-year forecast, while the company posted a JPY195mn operating loss versus thefull-year forecast of JPY1.4bn profit. Although 1H sales fell short of the company forecast, the company left its full-year
forecast unchanged, because it expects higher sales in 2H than in 1H, and thinks the full-year forecast is achievable. Reasonsfor the company's expectation of profit growth in 2H versus 1H are as follows.
In 1H FY12/21, the impact of the clearance of unsold inventory of the lyophilized formulation of Treakisym® sold by Eisai
totaled around JPY400mn. The clearance was completed in 1H and will have no impact on 2H results.
Patients cut back on hospital visits in 1H because of COVID-19, but the company expects this pattern to change in 2H as
more seniors are vaccinated and likely to resume hospital visits.
The company received approval for BR therapy indicated for r/r DLBCL in March 2021, while Chugai Pharmaceuticalreceived approval for polatuzumab vedotin + BR therapy indicated for r/r DLBCL. These approvals were granted about
three months earlier than the company expected at the beginning of FY12/21. The company targets JPY2.6bn in sales ofTreakisym® indicated for r/r DLBCL on a NHI drug reimbursement price basis, but Shared Research understands thatsales may exceed this target because of the earlier-than-expected approval timing. The company recorded sales ofTreakisym® indicated for r/r DLBCL in the second half of Q2 and expects this sales to increase in 2H.
The company forecasts a higher GPM in 2H as the switch from the lyophilized formulation to the RTD formulation ofTreakisym® progresses.
Business progress
In August 2021, the company announced it had started administration to the first patient enrolled (FPI) in the Phase II
clinical trial of antiviral drug brincidofovir (IV forumulation).
Also in August 2021, the company concluded a joint research agreement with Kyoto University regarding the mechanismof effect of bendamustine, under development as an anticancer agent indicated for DLBCL.
In July 2021, the company concluded a joint research agreement with the General Surgical Science Department, Gunma
University Graduate School of Medicine regarding the exploration of new indications for bendamustine and rigosertib,
which are under development as anticancer agents.
Chimerix Inc., the licensor of antiviral drug brincidofovir, obtained approval from the US Food and Drug Administration(FDA) in June 2021 for antiviral drug brincidofovir tablets and oral formulation as a treatment for smallpox.
In May 2021, the company filed for approval of of Treakisym® Rapid Infusion (RI) formulation.

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41

In April 2021, the company received approval for the RTD formulation of Treakisym® in combination with rituximab, andfor the RTD formulation of Treakisym® in combination with rituximab and polatuzumab vedotin for the indication of r/r
DLBCL.
In March 2021, the company received approval for Treakisym® in combination with rituximab, and for Treakisym® incombination with rituximab and polatuzumab vedotin for the indication of r/r DLBCL.
In March 2021, the company filed an Investigational New Drug (IND) application of brincidofovir IV formulation for a
Phase II clinical trial targeting adenovirus infection in children.
In January 2021, the company began sales of the read-to-dilute (RTD) liquid formulation of Treakisym®.

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 tocover each region to establish a highly productive internal sales organization capable of making proposals that fit the needsof each region. With the termination of its alliance agreement with Eisai, in September 2020, the company concluded abasic agreement with Suzuken Co., Ltd and Toho Pharmaceutical Co., Ltd for the procurement and sale of pharmaceuticals toachieve nationwide distribution. The company has established two distribution centers, one in Eastern Japan and the other inWestern Japan, under management by S.D. Collabo Co., Ltd.
During 1H, 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 manufacturing and marketing authorization
for bendamustine-rituximab combination therapy (BR therapy) and bendamustine-rituximab-polatuzumab vedotin combination
therapy (Pola-BR therapy) to treat r/r DLBCL patients. This enabled conventional lyophilized (freeze-dried [FD]) powder
formulation of Treakisym® to be used in BR therapy right away. In April 2021, the company obtained approval of Treakisym®
ready-to-dilute (RTD) liquid formulation for use in BR therapy and Pola-BR therapy for the treatment of r/r DLBCL. In May
2021, Chugai Pharmaceutical's polatuzumab vedotin was added to the NHI drug price list, enabling Treakisym® to be usedin Pola-BR therapy.
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 FD formulation.
SymBio imports FD formulation Treakisym® for injection from Astellas Deutschland (consolidated subsidiary of Astellas
Pharma) and Treakisym® RTD formulation from Eagle Pharmaceuticals Inc. In 1H, secondary packaging and quality tests wereapplied to imported batches, resulting in stable quality, and as of May 2021, inventories had maintained proper levels toenable stable product supply.
On the supply front, the company is aiming for 91% completion of the switchover from the FD formulation to the RTD
formulation of Treakisym®.
Treakisym® (SyB L-0501[FD formulation]/SyB L-1701 [RTD formulation]/SyB L-1702 [RI formulation]; generic name:bendamustine hydrochloride or bendamustine hydrochloride hydrate, 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, whichapplies to all of the approved indications. This has seen Treakisym® establish its position as a standard treatment for
lymphatic cancer.

SymBio Pharmaceuticals/ 4582
Research Coverage Report by Shared Research Inc. | https://sharedresearch.jp42

Also, SymBio obtained approval for the partial revision to the marketing authorization 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 follicular lymphoma, the most common histological type of low-grade NHL. This allows the company toprovide patients a new treatment option: combination therapy with obinutuzumab. In March 2019, SymBio obtained approval
for the partial revision to its application to use Treakisym® 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 chimericantigen receptor T-cell (CAR-T) therapy approved in Japan. Growing use of Treakisym® as a pretreatment agent inregenerative medicine has solidified its positioning as standard therapy for malignant lymphomas.
In the phase III clinical study of Treakisym® administered in BR therapy targeting r/r DLBCL, the company filed for approval
for partial revision to manufacturing and marketing authorization in May 2020 and obtained that approval in March 2021. In
April 2021, it obtained approval for partial revision to manufacturing and marketing authorization of Treakisym® RTD liquid
formulation for use in BR and Pola-BR therapy as treatment for r/r DLBCL. The company has conducted a follow-up study withoverall survival as the primary endpoint, because evaluating the survival data (e.g., overall survival and progression-freesurvival) 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, thecompany applied for approval for partial revision to manufacturing and marketing authorization for Treakisym® in Pola-BRtherapy and obtained approval in March 2021. Polatuzumab vedotin was added to the NHI drug price list in May 2021, andnow Treakisym® may be used in Pola-BR therapy. Previously there were no effective treatments for the additional indicationof r/r DLBCL, which was usually treated by a combination of anticancer agents as salvage chemotherapy, so development of ahighly effective but safe new drug was sought after. Since BR therapy is already being used in the West to treat r/r DLBCL,
patient organizations and related academic societies petitioned MHLW so that it could 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 administrationtime). Manufacturing and marketing approval of the RTD formulation was obtained in September 2020, and the company
launched it in January 2021. The company has concluded clinical trials to confirm safety of the RI formulation and applied forapproval in May 2021. Unlike the current FD 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 injust 10 minutes, versus 60 minutes for the current FD and RTD formulation. This reduces the burden on patients andhealthcare professionals, providing significant value added. Multiple patent protections in the form of a liquid productlicense will enable the extension of the product life of Treakisym® to 2031.
Rigosertib Sodium (SyB L-1101 [IV]/SyB C-1101 [oral]; anticancer agent; 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
is patients who do not respond to the current standard treatment with hypomethylating agents, relapse after treatment under
the current standard of care, or are intolerant to hypomethylating agents. In August 2020, Onconova announced acomparator trial to physicians’ choice of treatment failed to achieve the primary endpoint. The company leads clinical trials
conducted in Japan and 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
with azacytidine, whose results suggested the efficacy and safety of the combination therapy. To verify the tolerability andsafety among Japanese patients, SymBio began a phase I clinical trial in Japan in June 2017 and completed patient
enrollment in June 2019.
The company said it would conduct joint research into Treakisym® and rigosertib with the University of Tokyo's Institute ofMedical Science regarding efficacy of using the two compounds in combination or with existing drugs and also explore new
indications.

）

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) totreat adenovirus (AdV) infections in patients receiving hematopoietic stem cell transplantation to address an unmet medical

SymBio Pharmaceuticals/ 4582
Research Coverage Report by Shared Research Inc. | https://sharedresearch.jp43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 as a 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 December 2020 that the FDA had accepted its new drug application (NDA) for BCV as a medical
defense against smallpox and that it had received FDA approval in June 2021.

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
drug candidates.

Q1 FY12/21 results
Sales: JPY1.4bn (+157.6% YoY)
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)
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., the difference between the shipment price from Eisai to pharmaceutical wholesalers and the price Eisai paid thecompany to source the product).
Earnings were partially hindered by medical care delays due to the COVID-19 outbreak since late 2020 and constraints onsales activities due to tighter restrictions on facilities visitations, but considering the clearance of market inventory of thelyophilized (freeze-dried [FD]) powder formulation of Treakisym® sold by Eisai prior to the switch to the company’s own sales
force in December 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 thecompany’ own sales force, there will be minimal impact on sales overall, and the company says that it anticipates sales growthon 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 theshift to its own marketing system and the launch of Treakisym® Ready-To-Dilute (RTD) formulation in January 2021. In Q1,sales of Treakisym® lyophilized formulations surpassed those of Treakisym® RTD formulations

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Reasons why in-house marketing of Treakisym® contributed to GPM improvement: Switching from marketing throughEisai (based the marketing agreement with Eisai) to doing its own marketing meant that products are shipped topharmaceutical 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 topharmaceutical wholesalers 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 of Treakisym® from Astellas Deutschland, but the liquid formulations (RTD and RI
formulations) are supplied by Eagle Pharmaceuticals. The company says that the GPM on liquid formulations ofTreakisym® 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:
In June 2021, Chimerix, Inc. (licensor of brincidofovir) obtained FDA approval of brincidofovir tablets and oralsuspensions 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 incombination 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
with rituximab 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 tocover each region to establish a highly productive internal sales organization capable of making proposals that fit the needsof each region. With the termination of its alliance agreement with Eisai, in September 2020, the company concluded abasic agreement with Suzuken Co., Ltd and Toho Pharmaceutical Co., Ltd for the procurement and sale of pharmaceuticals toachieve nationwide distribution. The company has established two distribution centers, one in Eastern Japan and the other inWestern Japan, under management by S.D. Collabo Co., Ltd.

SymBio Pharmaceuticals/ 4582
Research Coverage Report by Shared Research Inc. | https://sharedresearch.jp45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 (freezedried) 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)
and Treakisym® RTD formulation from Eagle Pharmaceuticals Inc. In Q1, secondary packaging and quality tests were applied
to imported batches, resulting in stable quality, and as of May 2021, inventories had maintained proper levels to enablestable product 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®.
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, whichapplies 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 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 newtreatment option: combination therapy with obinutuzumab. In March 2019, SymBio obtained approval for partial change tothe 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 first chimericantigen receptor T-cell (CAR-T) therapy approved in Japan. Growing use of Treakisym® as a pretreatment agent inregenerative 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 as treatment for r/r DLBCL. The company has conducted a follow-up study with overall survival as theprimary 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 topublicize 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 forapproval for a partial change to the approved 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 pricelist, Treakisym® will be able to be used in Pola-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, sodevelopment of a highly effective but safe new drug would be ideal. Since BR therapy is already being used in the West to

SymBio Pharmaceuticals/ 4582
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46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 administrationtime). Manufacturing and marketing approval of the RTD formulation was obtained in September 2020, and the company
launched it in January 2021. The company has concluded clinical trials to confirm safety of the RI formulation and applies forapproval 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 beadministered 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 theform 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
is patients who do not respond to the current standard treatment with hypomethylating agents, relapse after treatment under
the current standard of care, or are intolerant to hypomethylating agents. In August 2020, Onconova announced acomparator trial to physicians’ choice of treatment failed to achieve the primary endpoint. The company leads clinical trials
conducted in Japan and 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
with azacytidine, whose results suggested the efficacy and safety of the combination therapy. To verify the tolerability andsafety of the high-dose oral formulation of rigosertib as an initial treatment for higher-risk MDS among Japanese patients,
SymBio began a phase 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) totreat 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 as a 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.

Overseascompany 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
drug candidates.

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47

Full-year FY12/20 results
Sales: JPY3.0bn (+5.3% YoY)
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)
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) cameto 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 to quality 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 nonein 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 throughEisai (based the marketing agreement with Eisai) to doing its own marketing meant that products are shipped topharmaceutical 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 topharmaceutical wholesalers 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.
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.
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Also in September 2020, the company completed observation of all patients enrolled in a clinical trial of the RI
formulation of Treakisym®. The company plans to apply for approval on completion of the clinical trial, targeting approvalin 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 the knowledge 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 cell transplantation. 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 not grant damage claims made against MDCO but ordered MDCO to pay 50% of costs incurred by SymBio(USD4.95mn) 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 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 ofTreakisym®.
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 of each 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.
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 the sole distributors of the Treakisym® (RTD formulation) began in Q4 FY12/20 (October–December 2020).

SymBio Pharmaceuticals/ 4582
Research Coverage Report by Shared Research Inc. | https://sharedresearch.jp49Anticancer agents: SyB L-0501[lyophilized injection]/SyB L-1701 [RTD]/SyB L-1702 [RI] (generic name: bendamustinehydrochloride, 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, whichapplies 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
follicular lymphoma, 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 partialchange 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. Growing
use of Treakisym® as a pretreatment agent in regenerative medicine has solidified its positioning as standard therapy formalignant lymphomas.
In the phase III clinical study of Treakisym® in BR therapy conducted in patients with relapsed or refractory diffuse large Bcell 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 with rituximab 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 ofTreakisym® 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, sodevelopment of a highly effective but safe new drug would be ideal. Since BR therapy is already being used in the West totreat 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 isconducting clinical trials to confirm safety of the RI formulation and plans to apply for approval in FY12/21. Unlike thecurrent lyophilized powder formulation, the RTD formulation reduces the workload of medical professionals, because iteliminates 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 [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
is patients who do not respond to the current standard treatment with hypomethylating agents, relapse after treatment under
the current standard of care, or are intolerant to hypomethylating agents. In August 2020, Onconova announced acomparator trial to physicians’ choice of treatment failed to achieve the primary endpoint. The company leads clinical trials
conducted in Japan and 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
with azacitidine, whose results suggested the efficacy and safety of the combination therapy. To verify the tolerability and

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50

safety of the high-dose oral formulation of rigosertib as an initial treatment for higher-risk MDS among Japanese patients,
SymBio began a phase 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 dataacquired 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 thepotential for expanding target disease areas to viral infections related to organ transplants (including kidney transplants), thecompany aims to grow the market 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 in patients 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) and set 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 anarbitration 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 toprovide sufficient assurance to the company regarding the performance of obligations under the license agreement in lightof its decision to withdraw 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 andalthough 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.

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
drug candidates.

Cumulative Q3 FY12/20 results
Sales: JPY2.3bn (+16.2% YoY)
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)
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

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unstable deliveries 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 to quality defects of Treakisym®. However, GPM was 28.9% in Q3, an improvement over 24.2% in 1H. Although thecompany 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 inJanuary 2021.
Also in September 2020, the company completed observation of all patients enrolled in a clinical trial of the RI
formulation of Treakisym®. The company plans to apply for approval on completion of the clinical trial, targeting approvalin 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 the knowledge 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 cell transplantation. 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 not grant damage claims made against MDCO but ordered MDCO to pay 50% of costs incurred by SymBio(USD4.95mn) 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 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.

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52

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® inJanuary 2021. This should facilitate a move into the black from FY12/21 and ongoing profit growth thereafter and lay thegroundwork for future business development.
In Q3, the company has started work on transferring marketing operations from Eisai, and as planned, has deployed anationwide 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 andthe other in Western Japan, 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, but inventory levels were recovering as of Q3 as secondary packaging and quality tests were applied to some batchesof Treakisym® 100mg vials imported from Astellas Deutschland while shipments to Eisai were on track with plan.

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 (October2010), 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
follicular lymphoma, 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 partialchange 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)
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
showed that the response rate (primary endpoint) was better than expected. Based on this, the company applied for a partialchange to approved 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 with rituximab 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 theEuropean 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:

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53

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 ofpatients being treated for relapsed or refractory low-grade NHL and MCL in Japan is 9,336 and the number of patients withuntreated low-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
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, sodevelopment of a highly effective but safe new drug would be ideal. Since BR therapy is already being used in the West totreat r/r DLBCL, patient organizations and related 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 followup period for all patients enrolled in the trial was completed 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 and healthcare 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 andhad 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 the re-examination period ends in 2020, so the launch of liquid Treakisym® (RTD and RI formulations) will extend the
product life until 2031.

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54

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 considering in-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
is patients who do not respond to the current standard treatment with hypomethylating agents, relapse after treatment under
the current standard of care, or are intolerant to hypomethylating agents. In August 2020, Onconova announced acomparator trial to physicians’ choice of treatment failed to achieve the primary endpoint. The company leads clinical trials
conducted in Japan 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
with azacitidine, whose results suggested the efficacy and safety of the combination therapy. To verify the tolerability andsafety of the high-dose oral formulation of rigosertib as an initial treatment for higher-risk MDS among Japanese patients,
SymBio began a phase 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 fromits 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. The company is presently in preparation to initiate adose-finding study of the 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 frombusiness 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 notaward 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.

SymBio Pharmaceuticals/ 4582
Research Coverage Report by Shared Research Inc. | https://sharedresearch.jp55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
drug candidates.

Income statement
Income statement

FY12/11

FY12/12FY12/13

FY12/14

FY12/15

FY12/16

FY12/17

FY12/18

FY12/19(JPYmn)

Par.

Par.

Par.

Par.

Par.

Par.

Par.

Par.

Par.

Par.

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%

CoGS

1,224

1,362

1,214

1,428

1,350

1,464

2,413

2,663

1,973

2,120

Gross profit

FY12/20

658

593

318

527

583

904

1,031

1,173

865

867

Gross profit margin

35.0%

30.3%

20.8%

26.9%

30.2%

38.2%

29.9%

30.6%

30.5%

29.0%

SG&A expenses

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

YoY

-

-

-

-

-

-

-

-

-

-

Operating profit margin

-

-

-

-

-

-

-

-

-

-

Non-operating income

56

7

114

215

17

7

5

2

4

3

Non-operating expenses

85

37

35

22

96

196

34

95

79

112

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

YoY

-

-

-

-

-

-

-

-

-

-

Recurring profit margin

-

-

-

-

-

-

-

-

-

-

Extraordinary gains

-

-

-

2

3

9

17

10

4

529

Extraordinary losses

5

0

-

3

1

1

15

10

-

-

Income taxes

4

4

4

4

4

4

4

4

4

4

Recurring profit

Implied tax rate

-

-

-

-

-

-

-

-

-

-

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

YoY

-

-

-

-

-

-

-

-

-

-

Net margin

-

-

-

-

-

-

-

-

-

-

Net income

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.

FY12/11

FY12/12FY12/13

FY12/14

FY12/15

FY12/16

FY12/17

FY12/18

FY12/19(JPYmn)

Par.

Par.

Par.

Par.

Par.

Par.

Par.

Par.

Par.

Par.

Sales (Initial Est.)

1,933

2,338

1,927

1,785

1,785

2,339

2,903

4,201

4,465

3,404

Sales (Results)

1,883

1,955

1,532

2,368

3,444

3,836

2,838

2,987

Results vs. Initial Est.

-2.6%

-16.4%-20.5%

9.5%

8.3%

1.2%

18.6%

-8.7%

-36.4%-12.2%

Operating profit (Initial Est.)-2,351-1,625-1,889-1,654-1,654-2,778-3,238-2,981-3,587-5,090Operating profit (Results)-2,067-1,700-1,681-1,303-2,552-2,127-3,947-2,656-4,302-4,506

-

-

-

-

-

-

-

-

-

-

Recurring profit (Initial Est.)-2,398-1,652-1,922-1,650-1,650-2,811-3,303-3,044-3,612-5,134

Recurring profit (Results)-4,616

Results vs. Initial Est.

1,955

1,933

FY12/20-2,095-1,729-1,601-1,110-2,630-2,317-3,977-2,749-4,377

Results vs. Initial Est.

-

-

-

-

-

-

-

-

-

-

Net income (Initial Est.)-2,407-1,656-1,926-1,654-1,654-2,815-3,306-3,056-3,612-4,803

Net income (Results)-2,105-1,733-1,605-1,116-2,632-2,313-3,978-2,753-4,376-4,090

-

-

-

-

-

-

-

-

-

-

Results vs. Initial Est.

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

SymBio Pharmaceuticals/ 4582
Research Coverage Report by Shared Research Inc. | https://sharedresearch.jp56Balance sheet
Balance sheet (JPYmn)

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.

Cash and deposits

4,559

4,540

6,163

5,692

4,261

5,719

2,947

4,821

3,911

3,849

Marketable securities

1,953

300

1,100

899

-

-

-

-

-

-

Accounts receivable

162

148

-

273

301

487

490

412

549

407

ASSETS

Inventories

207

165

125

245

133

273

363

534

1

945

Other current assets

297

268

245

181

131

205

237

271

427

615

Total current assets

7,178

5,421

7,634

7,290

4,827

6,685

4,037

6,038

4,887

5,815

Buildings (net)

2

3

2

22

22

31

28

37

47

43

Tools, furniture, and fixtures (net)

15

11

6

27

31

43

18

20

19

34

Total tangible assets

17

14

9

49

53

75

47

57

75

77

Investments and other assets

48

57

37

49

53

77

100

73

70

81

Software

10

8

6

62

51

42

66

51

95

296

Other

3

20

146

6

Total intangible assets

13

11

8

66

52

42

69

71

241

302

Total fixed assets

78

82

53

164

158

193

216

201

386

459

7,256

5,502

7,687

7,454

4,984

6,878

4,252

6,239

5,274

6,275

Accounts payable

309

330

-

306

320

322

604

726

121

665

Unearned revenue

-

-

-

-

-

-

-

-

-

193

278

196

207

143

184

553

331

504

639

646

-

-

-

-

-

-

-

-

-

-

Other

59

73

44

39

47

68

76

107

112

111

Total current liabilities

646

599

251

488

551

942

1,011

1,336

872

1,615

-

-

-

-

-

-

-

-

-

-

450

-

-

-

-

Total assets

3

2

4

1

-

3

LIABILITIES

Accounts payable–other
Short-term debt

Long-term debt
Corporate bonds-

Other fixed liabilities

5

4

3

2

2

1

1

1

2

2

Total fixed liabilities

5

4

3

2

2

451

1

1

2

2

Total interest-bearing debt

-

-

-

-

-

-

-

-

-

-

651

602

254

490

552

1,394

1,013

1,338

874

1,617

Total liabilities
NET ASSETS
Capital stock

6,025

6,025

8,059

8,331

8,331

9,948

10,762

12,973

14,871

17,045

Capital surplus

5,995

5,995

8,029

8,301

8,301

9,918

10,732

12,943

14,841

17,019Retained earnings-5,413-7,146-8,752-9,868-12,500-14,813-18,791-21,543-25,919-30,010

Treasury stock

-0

-0

-0

-0

-0

-0

-0

-0

-15

-18

Share subscription rights

-

27

97

200

300

431

537

530

621

620

6,606

4,900

7,433

6,964

4,432

5,485

3,239

4,902

4,400

4,657

61

-17

125

212

114

439

249

220

429

686

-

-

-

-

-

-

-

-

-

-

-4,559-4,540-6,163-5,692-4,261-5,719-2,947-4,821-3,911-3,849Net assets
Working capital
Total interest-bearing debt
Net debt

Source: 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.

Cash flow statement
Cash flow statement(JPYmn)Cash flows from operating activities (1)Cash flows from investing activities (2)FY12/11

FY12/12FY12/13

FY12/14

FY12/15

FY12/16

FY12/17

FY12/18

FY12/19

Par.

Par.

Par.

Par.

Par.

Par.

Par.

Par.

Par.

FY12/20
Par.

-2,074-1,659-1,677-1,266-2,272-1,960-3,817-2,325-4,351-4,122-117-411-1,332

314

1,489

-44

-78

-26

-216

-160

Free cash flow (1+2)-2,191-2,069-3,010-952-783-2,004-3,894-2,351-4,567-4,283

Cash flows from financing activities

4,611

-1

4,057

544

-3

3,658

1,164

4,272

3,740

4,222

8

9

8

13

24

26

30

35

38

64

-12

-3

-

-109

-24

-28

-57

-40

-217

-149

Depreciation and good will amortization(A)
Capital expenditures (B)Change in working capital (C)

56

-78

142

86

-98

325

-190

-29

209

257

Simple FCF (NI + A + B - C)

-2,165-1,650-1,739-1,298-2,534-2,640-3,815-2,729-4,764-4,433

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.

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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
and FY12/13. 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

122,769

Change in capitalstock and capitalsurplus (JPYmn)
772

Capital stock andcapital surplus(JPYmn)8,164

Paid-in private placement

140,137

1,216

9,380

Paid-in private placement

5,100,000

19,130,900

2,628

12,019Jan. to Dec. 2013

3,921,257

23,052,157

1,244

13,263

Dec. 2013

6,720,200

29,772,357

2,504

15,767

Dec. 2014

1,756,666

32,390,923

544

16,632

Jan. to Dec. 2016

14,139,901

46,530,824

3,235

19,867Jan. to Dec. 2017

7,518,400

54,049,224

1,627

21,493Apr. to Dec. 2018

28,349,700

82,398,924

4,422

25,915

Exercise of stock options attached to convertible
corporate bonds and other stock options
Exercise of stock options

Jan. to Dec. 2019
Jan. to Dec. 2020

1,726,800
11,765,275

26,437,681
38,202,956

3,796
4,349

29,711
34,064

Exercise of stock options
Exercise of stock options

Date

Change inshares issued

Total sharesissuedFeb. 2011

11,032Feb. 2011

17,368Oct. 2011

Paid-in public offering (price determined by the bookbuilding process)Exercise of stock options attached to convertible
corporate bonds and other stock options
Paid-in public offering (price determined by the bookbuilding process)Exercise of stock options attached to convertible
corporate bonds and other stock options
Exercise of stock options attached to convertible
corporate bonds and other 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 ofpatients in 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 inThousand 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, bendamustinehydrochloride, from Astellas Pharma GmbH in December 2005 with the exclusive right to develop and commercialize thedrug in Japan.
After the global financial crisis of September 2008, the company experienced a shortage of capital as Treakisym® wasadvancing 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, andmarket brincidofovir for all indications except smallpox, SymBio looks to commercialize it by the mid-2020s.

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59March 2005
December 2005
March 2006
March 2007
August 2008
March 2009
May 2009

SymBio Pharmaceuticals Limited established with JPY30mn in capital.
License Agreement finalized with Astellas Pharma GmbH for SyB L-0501 (bendamustine) development and commercialization rights
in Japan.
Manufacturer’s License (packaging, labeling and storage) obtained from Tokyo Metropolitan Government (License #13AZ200010).
License Agreement finalized with Astellas Deutschland GmbH for SyB L-0501 (bendamustine) development & commercializationrights in China (HK), Taiwan, South Korea and Singapore.
License Agreement finalized with Eisai Co., Ltd. for co-development and commercialization rights of SyB L-0501 (bendamustine) inJapan.
SymBio Pharmaceuticals concluded Sublicense Agreement with Cephalon, Inc. for development and commercialization rights ofbendamustine hydrochloride in China (HK).
License Agreement finalized with Eisai Co., Ltd. for co-development and commercialization rights of SyB L-0501 (bendamustine) inSouth Korea and Singapore.

October 2010

SymBio Pharmaceuticals and Eisai launch SYMBENDA® (bendamustine) in Singapore for the treatment of Low-grade NonHodgkin’s Lymphoma and Chronic Lymphocytic Leukemia.
Announced NDA Approval of Treakisym® (bendamustine) in Japan.

December 2010

Launched Treakisym® in Japan.

September 2010

July 2011
October 2011
October 2011
February 2012
October 2015
August 2016
December 2016
September 2017

Onconova and SymBio Pharmaceuticals concluded License Agreement for SyB L-1101/SyB C-1101 (rigosertib, a phase Ⅲ stage
multi-kinase inhibitor for Myelodysplastic Syndromes).
Launched Symbenda® (bendamustine hydrochloride) in South Korea for the treatment of Chronic Lymphocytic Leukemia andmultiple 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 andChronic Lymphocytic Leukemia.
Concluded a license agreement with The Medicines Company (US) on exclusive development and marketing rights to Ionsys(transdermal pain management system) in Japan.
Received approval for the additional indication of chronic lymphocytic leukemia for Treakisym®.
Obtained approval for the additional indication of untreated low-grade non-Hodgkin’s lymphoma and mantle cell lymphoma for the
anticancer drug Treakisym®
Concluded 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.

December 2020

Concluded an exclusive global license agreement with Chimerix Inc. (US) on rights to develop, manufacture, and market antiviralbrincidofovir for all indications except smallpox.
Began in-house sales of anticancer drug Treakisym®

January 2021

Launched Treakisym® liquid formulation (RTD)

September 2019

Major shareholders
Top shareholders

Shares held

Shareholding ratio

Kyoichi Kageyama

1,020,000

2.7%

Fuminori Yoshida

900,000

2.4%

SBI Securities Co., Ltd.

744,310

1.9%

Cephalon, Inc.

647,250

1.7%

Arata Takahashi

534,000

1.4%

Norihiro Kuroda

447,500

1.2%

Matsui Securities Co., Ltd.

310,600

0.8%

Fumishige Ehira

270,200

0.7%

Hitochi Imamura

239,300

0.6%

Eisai Co., Ltd.

208,350

0.5%

5,321,510

13.9%

SUM

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 toreceive 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.
Number of employees

FY12/11

FY12/12FY12/13

FY12/14

FY12/15

FY12/16

FY12/17

FY12/18

FY12/19

FY12/20

No. of employees

Par.

Par.

Par.

Par.

Par.

Par.

Par.

Par.

Par.

Par.

Number of employees

71

76

72

69

74

77

78

90

107

127

15

5

-4

-3

5

3

1

12

17

20

ChangeSource: Shared Research based on company data

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60

OtherOverview 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
Clinical trials

3-5 years
3-7 years

Confirmation of efficacy and safety through experiments on animals
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
through clinical 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 Acceptabilityof Foreign 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 dataon efficacy for Japanese people. However, data from overseas clinical trials are acceptable if a bridging study demonstrates
that such data can be used for Japanese people.

Glossary
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 bindingof pathogens causes their immobilization and binding together.

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

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61

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.

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

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

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

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

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,and the management of clinical trial data.

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
cure the disease (the patient has a relapse) or causes severe side effects, other treatments (second-line, third-line etc.) may be
added or used instead.

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.

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.

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 theneed to do a phase II and/or III clinical trial in Japan).

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62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.

Multikinase Inhibitor
Multikinase inhibitor blocks tyrosine kinases, which play an important role in transmitting signals involving the multiplicationand division 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.

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

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 bysmall and medium-sized cancer cells that appear in lymphatic nodes, the spleen, bone marrow, blood, and the digestivesystem.

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

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

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
the company’s logo which symbolizes physicians, scientists, regulators, and investors, with patients at its center. The color of
the logo represents the evergreen tree—the company’s endeavor to create and sustain a life-giving force.

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63News and topics
Collaborative research agreement with the National Cancer
Centre Singapore (NCCS) concerning the injectable formulationof antiviral drug brincidofovir
2021-09-01

SymBio Pharmaceuticals Limited announced that it has concluded a collaborative research agreement with the National
Cancer Centre Singapore (NCCS) concerning the injectable formulation of antiviral drug brincidofovir.
The company has entered a collaborative research agreement with the National Cancer Centre Singapore (NCCS) underwhich both parties will explore anti-tumor effects produced by brincidofovir IV in cases of Epstein-Barr (EB) virus positive
lymphoma and the mechanism of action.
Epstein-Barr (EB) virus: The EB virus is a tumor-causing virus that belongs to the Herpesviridae family of DNA viruses. It
was first discovered during 1964 in Burkitt lymphoma, a type of pediatric tumor primarily seen in Africa. Many infants
who contract the virus often display no symptoms. However, patients who contract the virus during puberty or later
exhibit temporary symptoms such as glandular fever (infectious mononucleosis), sore throat, and swollen lymph nodes.
This virus is also linked with the development of some types of malignant lymphoma and epipharyngeal cancer.

First patient dosed in Phase II clinical trial for antiviral agent
brincidofovir IV formulation (FPI milestone)
2021-08-17

SymBio Pharmaceuticals Limited announced dose administration for the first patient in the Phase II clinical trial for the
intravenous formulation of antiviral agent brincidofovir (First-Patient-In [FPI] milestone).
The company made progress in connection with the ongoing international joint Phase II clinical trial for the intravenous
formulation of antiviral agent brincidofovir as a treatment for adenovirus infections in children, achieving the First-Patient-In(FPI) milestone on August 16, 2021 (United States Pacific Daylight Time).

Conclusion of an agreement with Gunma University concerning
joint research into possible new indications for bendamustineand rigosertib
2021-07-15

SymBio Pharmaceuticals Ltd. announced the conclusion of an agreement with Gunma University concerning joint research
into possible new indications for bendamustine and rigosertib.
The company has concluded an agreement with the General Surgical Science Department of the Graduate School of
Medicine at Gunma University concerning joint research into possible new indications for pipeline anticancer agents
bendamustine and rigosertib.

Chimerix, Inc. obtained FDA approval of brincidofovir as a
medical countermeasure2021-06-07

SymBio Pharmaceuticals Ltd. announced that Chimerix, Inc. obtained FDA approval of brincidofovir as a medical
countermeasure for the treatment of smallpox.

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64Chimerix announced in its press release dated June 4, 2021 that FDA approved brincidofovir (generic name; BCV) tablets
and oral suspensions, 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 proceed with 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
injection is underway in patients with adenovirus (AdV) infections developed after hematopoietic stem cell transplantation.

Polatuzumab vedotin has been added to the NHI drug price list
2021-05-19

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 treatmentof relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) has been added to the NHI drug price list and that it
began selling 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 10, 2021, the company announced that it has filed for approval of the rapid infusion (RI)
method for Treakisym® intravenous formulation.

Filed for approval of the rapid infusion (RI) method forTreakisym® intravenous formulation
2021-05-10

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.

Obtained approval for Treakisym® RTD liquid formulation withrituximab and polatuzumab vedotin as treatment, and for the useof RTD liquid formulation
2021-04-28

On April 28, 2021, SymBio Pharmaceuticals Ltd. 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-todilute (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 incombination 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”).
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-todilute (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.

SymBio Pharmaceuticals/ 4582
Research Coverage Report by Shared Research Inc. | https://sharedresearch.jp65The US Food and Drug Administration granted fast track
designation to intravenous formulation and Onconova
Therapeutics, Inc. has dosed the first patient
2021-04-26

On April 26, 2021, SymBio Pharmaceuticals Ltd. 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 effectivein treating 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 investigatorinitiated 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
and safety of rigosertib in patients with recessive dystrophic epidermolysis bullosa (RDEB)-associated locallyadvanced/metastatic squamous cell carcinoma (SCC).

Applied for approval to extend the shelf life of Treakisym® RTD
liquid formulation
2021-03-29

On March 29, 2021, SymBio Pharmaceuticals Ltd. announced that it has applied for approval to extend the shelf life ofTreakisym® RTD liquid formulation.
The company submitted an application for partial change to the approved matters of the RTD formulation (ready-to diluteformulation; only requires diluting the drug before use, no dissolution required) of Treakisym® intravenous fluid with theaim of extending its shelf life.

Filed for approval of the RTD liquid formulation of Treakisym®
used in combination with rituximab and with rituximab andpolatuzumab vedotin
2021-03-25

On March 25, 2021, SymBio Pharmaceuticals Ltd. announced that it has filed for approval of the RTD liquid formulation ofTreakisym® used in combination with rituximab and with rituximab and polatuzumab vedotin, for the treatment of relapsed
or refractory diffuse large B-cell lymphoma.
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 injectionused in bendamustine-rituximab combination therapy (BR therapy) in patients with relapsed or refractory diffuse large B-cell

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66

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.

Obtained approval for Treakisym® used in combination withrituximab and polatuzumab vedotin and Treakisym® used in
combination with rituximab
2021-03-23

On March 23, 2021, SymBio Pharmaceuticals Ltd. 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 and100mg vials (lyophilized powder for intravenous infusion; generic name: bendamustine hydrochloride) for use incombination with rituximab 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 beused 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 toapply 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
to treat patients with r/r DLBCL.
The company obtained approval of a partial change to the approved matters of anticancer agent Treakisym® 25mg and100mg vials (lyophilized powder for intravenous infusion; generic name: bendamustine hydrochloride) for use incombination with rituximab (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
in primary 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
to the approved matters of the RTD formulation of Treakisym® for r/r DLBCL by March 27, 2021.

Submission of an investigational new drug (IND) application of
the injectable antiviral agent brincidofovir
2021-03-11

On March 11, 2021, SymBio Pharmaceuticals Ltd. 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.

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67Results of phase III clinical trial for Treakisym® as a treatment
2021-02-22

On February 22, 2021, SymBio Pharmaceuticals Ltd. announced the results of phase III clinical trial for Treakisym® as atreatment 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)

Three-year medium-term plan covering FY12/21–FY12/23
2021-02-04

On February 4, 2021, SymBio Pharmaceuticals Ltd. announced a three-year medium-term plan covering FY12/21–FY12/23.

Medium-term plan targets
FY12/21

FY12/22

FY12/23(JPYmn)Est.

Targets

Targets

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%

Operating profit
YoY
Operating profit margin
Recurring profit

1,350

1,727

2,088

-

27.9%

20.9%

14.8%

15.7%

16.9%

YoY
Recurring profit margin
Net income

1,149

1,470

1,778

-

27.9%

21.0%

12.6%

13.4%

14.4%

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 ofmarket penetration and sales trends, which feed into the company’s revised sales growth rates calculated over the mediumterm 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 inhouse sales organization.
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.
Other SG&A expenses comprise primarily Treakisym® sales and marketing, production and distribution, businessdevelopment, and management related costs. From FY12/21, SymBio assumes costs associated with operating its own

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68sales organization for sales of Treakisym®. It forecasts an increase primarily in personnel costs due to a higher medical
representative headcount and higher 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 effectaccounting. Heeding the advice 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 bareminimum of 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 thisin personnel expenses.
Funding plans
Regarding funding plans, the company will work toward strengthening its financial base so that it can respond in a flexible
and nimble way to the need for funds according to business developments.

Entered into a joint research agreement with the University ofTokyo’s Institute of Medical Science to explore potential new
indications for bendamustine and rigosertib
2021-01-28

On January 28, 2021, SymBio Pharmaceuticals Ltd. 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 otherapproved drugs to explore efficacy and new indications.
The joint research will analyze the epigenetic control of various tumor cells to explore as-yet-unknown pharmacologicaleffects of bendamustine 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 molecularmechanisms in the 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 in collaborating with IMSUT to search for new indications for bendamustine and rigosertib.

Sales launch of the ready-to-dilute (RTD) liquid formulation ofTreakisym®
2021-01-12

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 inquantities of 100mg/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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69pharmaceutical licenses for both of these formulations of Treakisym®, the company will be able to extend the life of the
product through 2031.
Unlike the lyophilized formulation of Treakisym® that is currently on the market, the RTD formulation eliminates the needfor troublesome 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.

Conclusion of a syndicated loan agreement
2020-12-22

On December 22, 2020, SymBio Pharmaceuticals Ltd. 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 capitalInterest rate: Base rate + spread
Security: Unsecured
Arranger and agent: MUFG Bank, Ltd.
Participating financial institutions: MUFG Bank, Ltd., The Bank of Yokohama, Ltd.

Begin in-house sales of the anticancer drug Treakisym®
2020-12-10

On December 10, 2020, SymBio Pharmaceuticals Ltd. 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 enhancestable supply of the product and quality assurance. Further, the company built a nationwide distribution system with Suzuken
Group and Kyoso Mirai Group as its sole distributors. It has two logistics centers, one in Eastern and the other in WesternJapan, and in collaboration with S.D. Collabo Co., Ltd., the company said it has established an optimal nationwide distribution
and logistics system.

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Profile
Company Name

Head Office

SymBio Pharmaceuticals Limited

Toranomon 30 Mori Building 3-2-2 Toranomon, Minato-ku Tokyo,
JAPAN 105-0001

Phone
Listed On

03-5472-1125

TSE JASDAQ GrowthEstablishedExchange Listing

2005-03-25

2011-10-20
Websitehttp://www.symbiopharma.com/index.html

Fiscal Year-End
Dec

IR Contact
IR Web-http://www.symbiopharma.com/ir_e/01.html
IR Phone
IR Email--

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71About Shared Research Inc.
We offer corporate clients comprehensive report coverage, a service that allows them to better inform investors and other stakeholders by
presenting a continuously updated third-party view of business fundamentals, independent of investment biases. Shared Research can be foundon the web at https://sharedresearch.jp.

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