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
influence, only inform. We appreciate your suggestions and feedback. Write to us at
sr_inquiries@sharedresearch.jp.

Coverage initiated on: 2014-10-31
Last update: 2024-02-09

INDEX
Executive summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.
Key financial data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5.
Recent updates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6.
Trends and outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8.
Quarterly trends and results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8.
Full-year company forecast . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11.
Long-term outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11..
Business . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15..
Business description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15..
Business strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17..
Pipeline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20..
Earnings structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33..
Strengths and weaknesses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .34..
Market overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .35..
Historical performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .38..
Income statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .57..
Balance sheet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .58..
Cash flow statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .58..
Other information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .60..
News and topics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .65..
Company profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .69..

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

2

Executive summary
SymBio in-licenses drugs for development and sale
SymBio Pharmaceuticals Ltd. is a specialty pharmaceutical company that acquires development and marketing rights to drugcandidates for rare diseases. The main target areas are cancer, blood disorders, and multiple viral infections. The company
primarily acquires rights from European and US biotech and pharmaceutical companies. Once the company secures theserights, it conducts clinical trials to obtain manufacturing and sales rights, aiming to generate revenues from product sales.
The company does not conduct basic research but instead focuses on developing novel drug candidates that have alreadyundergone basic research in humans and have established proof of concept (POC). In addition to sourcing potential drugcandidates through independent information gathering conducted by internal experts, the company holds a Scientific
Advisory Board (SAB) meeting three times a year to evaluate and select candidates with a high probability of approval. The
company is also pursuing a lab-less strategy to increase cost efficiency, focusing on unmet medical needs to increase
profitability, and seeking to expand revenue opportunities through a global expansion strategy.
Normally, drug development takes 10–17 years from basic research to manufacturing and approval for sale. However, thecompany obtained domestic manufacturing and sales approval for its first development product, Treakisym®, within five
years of in-licensing, and gained a market share of over 50% three years after its launch.
The company had obtained approval for and launched Treakisym® (anticancer agent for hematologic malignancies) for theindications of relapsed or refractory low-grade non-Hodgkin’s lymphoma (NHL) and mantle cell lymphoma (MCL), untreated(first-line treatment) low-grade NHL and MCL, chronic lymphocytic leukemia (CLL), and relapsed or refractory diffuse large Bcell lymphoma (DLBCL). Treakisym® is listed in the Practical Guidelines for Hematological Malignancies 2018 edited andpublished 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. In February 2022, the company received approval for Treakisym® rapid infusion (RI) formulation. The RI
formulation reduces the administration time to just 10 minutes, versus 60 minutes for the lyophilized injection and RTD
formulation. This reduces the burden on patients and healthcare professionals. The re-examination term for the lyophilized
formulation of Treakisym® ended in 2020, but by launching and switching to the RTD formulation and RI formulation towhich SymBio has exclusive rights, the company believed it could extend the product life cycle of Treakisym® until 2031.
However, the situation changed significantly in 2022 when two companies ignored the patent infringement warnings andcommercialized generic Treakisym®.
Drugs in the development pipeline include rigosertib (anticancer agent for myelodysplastic syndromes) IV and oral
formulations, and antiviral drug brincidofovir (BCV). All planned development for Treakisym® has been completed andmanagement is shifting development resources to BCV, which has potential to treat various diseases. In May 2023, thecompany successfully established the human proof of concept (POC) in the Phase II clinical trial of BCV targeting adenovirus(AdV) infections.

Earnings
In FY12/23, SymBio reported sales of JPY5.6bn (-44.1% YoY), an operating loss of JPY812mn (compared to an operating profitof JPY2.0bn in the previous year), a recurring loss of JPY736mn (compared to a recurring profit of JPY2.0bn), and a net loss
attributable to owners of the parent of JPY2.0bn (compared to a net income of JPY1.2bn). Sales declined as the impact ofgeneric sales of Treakisym® (bendamustine) became apparent. In addition, the ongoing impact of the COVID-19 pandemic
in the oncology sector led to reduced overall use of bendamustine, including its generics.
The company's forecast for FY12/24 calls for sales of JPY3.6bn (-34.9% YoY), an operating loss of JPY2.8bn (compared to an
operating loss of JPY812mn in the previous year), a recurring loss of JPY2.9bn (compared to a recurring loss of JPY736mn),
and a net loss attributable to owners of the parent of JPY2.9bn (compared to a net loss of JPY2.0bn). SymBio expects sales todecline due to a substantial cut in the price of Treakisym® and the impact of sales of generic drugs. The company also
anticipates an increase in R&D expenses as it progresses with the global development of the antiviral drug BCV.

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

3

The medium-term plan unveiled in February 2020 forecasted FY12/23 sales to reach JPY12.4bn. However, actual results did
not meet these projections, primarily due to the commercialization of generic Treakisym® by two companies, which
occurred despite SymBio's patent infringement warnings. As of February 2024, the company has yet to announce a new
medium-term management plan.

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 of the company include its dependence on a single
individual and product (see Strengths and weaknesses).

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

4

Key financial data
(JPYmn)FY12/14

FY12/15

FY12/16

FY12/17

FY12/18

FY12/19

FY12/20

FY12/21

FY12/22

FY12/23

FY12/24

ParentParentParentParentParentParentParentParent

Cons.

Cons.

Company
forecast

Sales

1,955

1,933

2,368

3,444

3,836

2,838

2,987

8,257

10,008

5,590

3,641

YoY

27.6%

-1.1%

22.5%

45.4%

11.4%

-26.0%

5.3%

176.4%

21.2%-44.1%-34.9%

527

583

904

1,031

1,173

865

867

5,800

7,600

4,411

YoY

65.6%

10.7%

55.1%

14.1%

13.7%

-26.3%

0.2%

569.1%

31.0%-42.0%

Gross profit margin

26.9%

30.2%

38.2%

29.9%

30.6%

30.5%

29.0%

70.2%

75.9%

78.9%

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

1,016

1,964

-812

-2,837

YoY

-

-

-

-

-

-

-

-

93.3%

-

-

Operating profit margin

-

-

-

-

-

-

-

12.3%

19.6%

-

-

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

1,001

2,000

-736

-2,867Gross profit

Recurring profit
YoY

-

-

99.8%

-

-

-

-

-

-

-

12.1%

20.0%

-

-

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

2,032

1,179

-1,963-2,870

YoY

-

-

-

-

-

-

-

-

-42.0%--Net margin

-

-

-

-

-

-

-

24.6%

11.8%

-

-

Shares issued at year-end (000shares)30,63432,391

46,53154,04920,56026,43838,20338,45739,60442,278EPS (JPY)-145.0-325.0-235.3-319.1-165.5-189.0-124.1

53.0

30.2

-49.2

-71.9

EPS (fully diluted)

-

-

-

-

-

-

-

52.3

29.8

-

-

Dividend per share (JPY)

-

-

-

-

-

-

-

-

-

-

835.2

510.2

434.4

200.0

212.2

143.1

105.8

162.3

204.8

164.3

Recurring profit margin
Net income

-

-

-

-

-

-

-

Per-share data (split-adjusted;
JPY)

Book value per share (JPY)
Balance sheet (JPYmn)
Cash and cash equivalents

6,591

4,261

5,719

2,947

4,821

3,911

3,849

3,860

6,283

6,517

Total current assets

7,290

4,827

6,685

4,037

6,038

4,887

5,815

6,748

9,313

8,083

Tangible fixed assets

49

53

75

47

57

75

77

84

69

-

Investments and other assets

49

53

77

100

73

70

81

1,362

829

88

Intangible assets

66

52

42

69

71

241

302

259

222

-

7,454

4,984

6,878

4,252

6,239

5,274

6,275

8,453

10,4338,170

Accounts payable

306

320

322

604

726

121

665

70

47

-

Short-term debt

-

-

-

-

-

-

-

-

-

-

488

551

942

1,011

1,336

872

1,615

1,518

1,924

957

Total assets

Total current liabilities
Long-term debt

-

-

-

-

-

-

-

-

-

-

Total fixed liabilities

2

2

451

1

1

2

2

189

3

4

Total liabilities

490

552

1,394

1,013

1,338

874

1,617

1,707

1,927

960

6,964

4,432

5,485

3,239

4,902

4,400

4,657

6,746

8,506

7,210

-

-

-

-

-

-

-

-

-

-

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

140

1,614

-195

Cash flows from investing activities

314

1,489

-44

-78

-26

-216

-160

-71

-47

-377

Cash flows from financing activities

544

-3

3,658

1,164

4,272

3,740

4,222

-72

628

680

ROA (RP-based)-14.7%-42.3%-39.1%-71.5%-52.4%-76.0%-79.9%

13.6%

21.2%

-7.9%

ROE

-15.8%-48.3%-50.4%-102.6%-77.8%-107.4%-104.7%

39.6%

16.5%

-26.1%

Equity ratio

93.4%

88.9%

79.7%

76.2%

78.6%

83.4%

74.2%

79.8%

81.5%

88.2%

Net assets
Total interest-bearing debt
Cash flow statement (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.
Note: The company moved to consolidated reporting from FY12/22 as SymBio Pharma USA, Inc. started operations. Figures for FY12/22 are consolidated, and YoY figures areprovided for reference purposes only.

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

5

Recent updates
BCV selected for oral session at EBMT Annual Meeting2024-02-14

SymBio Pharmaceuticals Limited announced that an abstract demonstrating the anti-adenovirus (AdV) effects of brincidofovir(BCV) has been selected for an oral session at the Annual Meeting of the European Society for Blood and Marrow
Transplantation (EBMT).
The 50th Annual Meeting of the EBMT, where this presentation is scheduled, will be held in Glasgow, UK, in April 2024. This
marks the third oral presentation at a prominent conference about the antiviral activity of BCV against AdV infection.

Additional brincidofovir Phase IIa data to be presented at 2024
Tandem Meetings in US
2024-01-23

SymBio Pharmaceuticals Limited announced that its antiviral drug under development, brincidofovir (BCV), has been
selected as a presentation topic for the Pediatric Best Abstracts session at the 2024 Tandem Meetings in the US.
This event, jointly hosted by the American Society for Transplantation and Cellular Therapy (ASTCT) and the Center forInternational Blood and Marrow Transplant Research (CIBMTR), is scheduled for February 2024. The presentation will buildon the content shared at a previous academic conference in December 2023, introducing new findings on BCV's
effectiveness against adenovirus (AdV) in stool samples.
Because adenovirus (AdV) in stool samples often tests positive before the onset of AdV viremia in children, it is monitoredinternationally as an early indicator of the infection. The upcoming presentation will include the following new content:
A dose-dependent reduction of AdV in stool samples was observed, with levels falling below the detection thresholdin PCR tests.
Intravenous BCV demonstrated a dose-dependent effect in lowering AdV quantities in the blood. Short-term treatment
effectively cleared AdV from both blood and stool samples, indicating a prolonged anti-AdV effect.

SymBio granted patent in Japan for use of BCV to treat ADV
infections
2024-01-19

SymBio Pharmaceutical Limited announced that it has obtained a patent in Japan covering the use of brincidofovir (BCV)
injection as a treatment for adenovirus (AdV) infections.
The company has successfully registered a use patent for BCV injection as a treatment for AdV infections in Japan. The detailsof the patent are as follows:
Drug covered by the patent: BCV liquid formulation
Indication: Infectious diseases caused by AdV infection
Dosage and administration: Administer a fixed amount of BCV liquid formulation intravenously at regular intervals,
based on the patient's weight. Continue administration for a specified period and discontinue according to thediscontinuation criteria.
The company plans to proceed with filing patent applications for the same drug and indication in Europe, the US, and otherregions.

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

6

Results from a Phase II clinical trial of brincidofovir (BCV) for
adenovirus (AdV) infection
2023-12-11

SymBio Pharmaceuticals Limited announced results from a Phase II clinical trial of brincidofovir (BCV) for adenovirus (AdV)
infection.
The results of a Phase IIa clinical trial of BCV in patients with AdV infection were presented at the 65th American Society of
Hematology Annual Meeting and Exposition in San Diego, US, in December 2023.
In this study, 27 immunocompromised patients with AdV infection received intravenous (IV) BCV twice a week. In the group
receiving 0.4mg/kg IV BCV twice a week (Cohort 3), AdV clearance was confirmed in 100% of patients, and 90% of thesepatients achieved viral clearance within four weeks of treatment. No serious adverse events were observed.
Based on the data from this trial, the company plans to consider a Phase III trial for BCV.

Revision of FY12/23 earnings forecast
2023-11-14

SymBio Pharmaceuticals Limited announced a revision to its full-year earnings forecast for FY12/23.

Revision of full-year earnings forecast for FY12/23
In November 2023, the company announced a revision to its full-year company forecast for FY12/23. The revised company
forecast is as follows:
Sales: JPY5.6bn (previous forecast: JPY6.5bn)
Operating loss: JPY680mn (previous forecast: operating loss of JPY331mn)
Recurring loss: JPY549mn (previous forecast: recurring loss of JPY219mn)
Net loss attributable to owners of the parent: JPY1.3bn (previous forecast: net loss of JPY370mn)
Reasons for revision
In comparison to the previous forecast, the company has downwardly revised its sales forecast by JPY874mn to JPY5.6bn.
Although the impact of bendamustine generics generally met the company's expectations, the decline in drug usage percase of malignant lymphoma treatment, coupled with treatment delays, persisted due to the influence of seasonal flu and
COVID-19.
The company has revised its operating loss forecast to a loss of JPY680mn, a decrease of JPY349mn from the previous
forecast. While prioritizing R&D investments for the global development of brincidofovir (BCV), the company has beenreviewing expenses to reduce SG&A expenses. However, this was not sufficient to compensate for the decrease in sales.
The company has also revised its recurring loss forecast to JPY549mn, a decrease of JPY330mn from the previous
forecast, despite forex valuation gains on foreign currency-denominated assets.
As a result of evaluating the recoverability of deferred tax assets in the future, the company has decided to reverse
JPY642mn of deferred tax assets and record deferred income taxes at the end of FY12/23. As a result, the company has
reduced its forecast for net loss attributable to owners of the parent by JPY921mn from the previous forecast to JPY1.3bn.

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

7

Trends and outlook
Quarterly trends and results
Earnings (cumulative)(JPYmn)FY12/22

FY12/23

FY12/23

Q1

Q1-Q2

Q1-Q3

Q1-Q4

Q1

Q1-Q2

Q1-Q3

Q1-Q4

Sales

2,316

4,874

7,356

10,008

1,545

3,179

4,421

5,590

YoY

63.1%

54.9%

32.5%

21.2%

-33.3%-34.8%-39.9%-44.1%

Gross profit

1,898

4,010

5,467

7,600

1,243

2,473

3,476

4,411

YoY

87.9%

76.3%

35.1%

31.0%

-34.5%-38.3%-36.4%-42.0%
78.9%

Gross profit margin

82.0%

82.3%

74.3%

75.9%

80.5%

77.8%

78.6%

SG&A expenses

1,389

2,638

3,878

5,636

1,192

2,523

3,759

5,223

YoY

13.8%

6.8%

7.1%

17.8%

-14.2%

-4.4%

-3.1%

-7.3%

SG&A ratio

60.0%

54.1%

52.7%

56.3%

77.2%

79.4%

85.0%

93.4%

Operating profit

509

1,372

1,589

1,964

51

-50

-283

-812

-

-

274.5%

93.3%-89.9%

-

-

-

22.0%

28.2%

21.6%

19.6%

3.3%

-

-

-

479

1,447

1,843

2,000

48

67

-156

-736

YoY
Operating profit margin
Recurring profit
YoY
Recurring profit margin
Net income
YoY
Net margin-89.9%-95.4%

-

-

20.0%

3.1%

2.1%

-

-

163

1,108

1,556

1,179

4

-80

-789

-1,963--378.9%-42.0%-97.3%

-

-

-

-

7.0%

22.7%

21.2%

11.8%

0.3%

-

-

-

-

FY12/22
Q4

Q1

Q2

Q3

Q4

2,653

1,545

1,634

1,242

1,169
-55.9%

YoY

63.1%

48.2%

3.1%

-1.9%

-33.3%-36.1%-49.9%

Gross profit

1,898

2,112

1,456

2,133

1,243

1,230

1,003

935

YoY

87.9%

67.0%

-17.8%

21.6%-34.5%-41.8%-31.1%-56.2%

Gross profit margin

82.0%

82.6%

58.7%

80.4%

80.5%

75.3%

80.7%

80.0%

SG&A expenses

1,389

1,249

1,240

1,759

1,192

1,331

1,237

1,463

YoY

13.8%

0.0%

7.6%

51.3%

-14.2%

6.5%

-0.3%

-16.8%

SG&A ratio

60.0%

48.8%

50.0%

66.3%

77.2%

81.5%

99.5%

125.2%

Operating profit

509

863

216

375

51

-101

-233

-528

-

-

-65.0%-36.7%-89.9%

-

-

-

22.0%

33.8%

8.7%

14.1%

3.3%

-

-

-

479

969

396

156

48

19

-223

-580

-

-

-35.9%-73.3%-89.9%

-

-

-

20.7%

37.9%

16.0%

5.9%

3.1%

1.1%

-

-

163

945

448

-377

4

-84

-709

-1,174---15.6%--97.3%

-

-

-

7.0%

36.9%

18.0%

-

0.3%

-

-

-

Net margin--1,291

FY12/23
Q3

YoY

-549

99.8%

2,482

Net income

-

25.1%

Q2

Recurring profit margin-

344.8%

2,558

YoY

-680

-

Q1

Recurring profit

-

29.7%

2,316

Operating profit margin

5,603-44.0%

-

Sales

YoY

99.8%

20.7%

Earnings (quarterly)(JPYmn)% of forecast FY forecast

Source: Shared Research based on company data
Note: Figures may differ from company materials due to differences in rounding methods.
Note: “- ”denotes YoY change of over 1,000%.
Note: Starting from FY12/22, the company switched to preparing consolidated financial statements in connection with the commencement of full- fledged operations at SymBio
Pharma USA. As data for FY12/22 are on a consolidated basis, YoY comparisons are for reference only.

Breakdown of SG&A expenses
Earnings (cumulative)(JPYmn)FY12/22

FY12/23

Q1

Q1-Q2

Q1-Q3

Q1-Q4

Q1

Q1-Q2

Q1-Q3

SG&A expenses

1,389

2,638

3,878

5,636

1,192

2,523

3,759

5,223

YoY

13.8%

6.8%

7.1%

17.8%

-14.2%

-4.4%

-3.1%

-7.3%
2,638

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

496

1,009

1,564

2,555

550

1,204

1,824

4.8%

10.6%

21.6%

47.2%

10.8%

19.3%

16.6%

893

1,629

2,314

3,081

642

1,319

1,936

2,584

19.5%

4.6%

-0.9%

1.1%

-28.1%-19.0%-16.4%-16.1%

Earnings (quarterly)(JPYmn)

Q1-Q4

FY12/223.3%

FY12/23

Q1

Q2

Q3

Q4

Q1

Q2

Q3

Q4

SG&A expenses

1,389

1,249

1,240

1,759

1,192

1,331

1,237

1,463

YoY

13.8%

0.0%

7.6%

51.3%

-14.2%

6.5%

-0.3%

-16.8%

496

513

554

991

550

654

620

815

4.8%

16.9%

48.2%

120.3%

10.8%

27.4%

11.8%

-17.8%

893

736

686

767

642

677

617

649

19.5%

-9.2%

-11.9%

7.7%-28.1%-8.0%-10.0%-15.5%

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

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

Full-year FY12/23 results (out February 8, 2024)
Sales: JPY5.6bn (-44.1% YoY)
Operating loss: JPY812mn (compared to an operating profit of JPY2.0bn in the previous year)
Recurring loss: JPY736mn (compared to a recurring profit of JPY2.0bn)
Net loss attributable to owners of the parent: JPY2.0bn (compared to a net income of JPY1.2bn)
In February 2022, SymBio obtained approval for a partial change to the marketing authorization for the ready-to-dilute (RTD)
intravenous formulation of TREAKISYM® 100mg/4ml, which was launched in January 2021, to add rapid infusion (RI)
administration. Compared to the freeze-dried (FD) formulation, the RTD formulation reduces the time required for the

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

8

complicated dissolution process. RI administration further benefits both patients and healthcare providers by reducing theinfusion time from the 60 minutes required by the RTD formulation. In addition, the RI administration uses less saline
solution and accordingly less salt (sodium chloride).
The switch from the FD to RTD formulation is almost complete. With over 90% of medical institutions administering the RI
formulation to patients as of end-December 2023, progress was made in the switch to the RI formulation. On the quality
assurance front, SymBio also has taken steps to ensure the stable supply of the RTD formulation of TREAKISYM®.
Sales decreased by 44.1% YoY to JPY5.6bn. This decline can be attributed to several factors: first, the reduced usage of drugs
per patient due to COVID-19's impact; second, the introduction of generic drugs in June 2022, affecting SymBio's productsales. Additionally, a temporary sales spike occurred in the previous year due to the transition from the FD formulation to the
RTD formulation, impacting this year's sales. Concerns over the increased risk of infection for patients with blood cancers,
especially those with malignant lymphoma, and the possibility of prolonged or severe infections during or after treatment
with bendamustine have led to a decrease in bendamustine prescriptions, including generics.
Gross profit was JPY4.4bn (-42.0% YoY), and the gross profit margin reached 78.9% (+3.0pp YoY). SG&A expenses were
JPY5.2bn (-7.3% YoY), of which R&D expenses amounted to JPY2.6bn (+3.3% YoY). As a result, the operating loss was
JPY812mn (compared to an operating profit of JPY2.0bn in the previous year).
Establishment of an in-house sales organization
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®.
In conducting in-house sales, SymBio established a sales organization that can cultivate needs, provide information on thecompany products, and plan seminars. In addition to medical representatives, the company deployed hematology experts
with extensive knowledge of the field throughout Japan. Further, the company concluded basic agreements with Suzuken
Co., Ltd and Toho Pharmaceutical Co., Ltd for the procurement and sale of pharmaceuticals to build a nationwide distribution
network. The company has established two distribution centers, one in Eastern Japan and the other in Western Japan, undermanagement by S.D. Collabo Co., Ltd.
Anticancer agent 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®
In March 2021, SymBio obtained approval for the use of the FD formulation of TREAKISYM® in BR therapy to treat r/r DLBCLas an additional indication. In February 2022, the company secured approval for a partial amendment to the marketing
authorization for the ready-to-dilute (RTD) formulation of TREAKISYM® (in-licensed from US-based Eagle Pharmaceuticals,Inc.), enabling the use of RI administration for all approved indications of the RTD formulation.
SymBio will continue to explore new potential applications of TREAKISYM®, including via joint research with the Universityof Tokyo and Kyoto University.
Anticancer agent SyB L-1101 (IV)/SyB C-1101 (oral); generic name: rigosertib sodium
For rigosertib and TREAKISYM®, the company is searching for new indications as well as new applications for the drugs usedin combination with each other or with other existing drugs, through joint research and the offering of academia-industry
collaborative courses with the University of Tokyo.
Antiviral drug SyB V-1901 (generic name: brincidofovir)
In development of the intravenous and oral formulations of the antiviral drug brincidofovir (SyB V-1901; BCV IV and BCVOral), the company is conducting joint research with top research institutions specialized in each field in Japan and overseas
in light of the broad spectrum of the drug's effectiveness against dsDNA virus infections. It will consider conducting
additional global clinical trials based on the scientific findings of the research.
Earlier clinical trials in the US and Europe conducted by US-based Chimerix Inc. have demonstrated that BCV Oral has
broad-spectrum antiviral effects against a variety of dsDNA viruses. BCV IV is expected to be effective and safe for theprevention and treatment of many dsDNA virus infections, including adenovirus (AdV) infections after hematopoietic stem
cell transplantation. In June 2021, Chimerix announced that the US FDA had granted BCV Oral approval for the treatment ofsmallpox.

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

9

In September 2022, Chimerix announced that it had completed procedures to transfer the rights to brincidofovir to
Emergent BioSolutions Inc. (headquarters: Maryland, US). The agreement, however, has no impact on the company's
exclusive rights to develop, manufacture, and sell brincidofovir globally for all indications except orthopoxvirus diseases
including smallpox and monkeypox.
Based on a global advisory board review held in February 2020, the company has decided to prioritize the global
development of BCV IV primarily in Japan, the US, and Europe, targeting disseminated AdV infections occurring after
hematopoietic stem cell transplantation, a niche area with a high unmet medical need. In March 2021, the company filed an
IND application with the US Food and Drug Administration (FDA) to conduct a Phase II clinical trial primarily in pediatricpatients suffering from AdV infections (also including adults). This development program was granted fast-track designationby the FDA in April 2021, and the investigational drug was administered to the first patient in August 2021. In May 2023,
BCV has demonstrated proof of concept in humans in the same study. Positive data demonstrating efficacy from the study
were presented orally at the 65th Annual Meeting of the American Society of Hematology in December 2023. In January2024, a use patent for BCV related to the treatment of AdV infections and infectious diseases was established and registeredin Japan.
BK virus nephropathy after kidney transplantation is considered a disease with serious consequences for the recipient,the donor, the medical practitioner, and society, as it may result in serious conditions such as decreased renal function andgraft loss. In order to find an early solution to this problem, SymBio submitted a clinical trial notification for a global Phase II
study in patients infected with BK virus after receiving kidney transplant to the Pharmaceuticals and Medical Devices Agency(PMDA) of Japan in May 2022 and to the Therapeutic Goods Administration (TGA) of Australia in August 2022. The
investigational drug was administered to the first patient in Australia in August 2022. While the trial was initially planned forcompletion in 2025, delays in the accumulation of cases have led to a review of the protocol.
SymBio has been preparing for clinical development of brincidofovir for multiple sclerosis, a rare disease related to EB virus.
In August 2022, the company signed a collaboration agreement for the transfer of human materials with the National
Institute of Neurological Disorders and Stroke (NINDS) of the US National Institute of Health (NIH). In March 2023, SymBio
signed a cooperative research and development agreement (CRADA) with NINDS to obtain information necessary to
conduct future clinical trials. In October 2023, the results of the research were presented at the 9th Joint ECTRIMS-ACTRIMS
Meeting in Milan, Italy.
In April 2023, SymBio also signed a CRADA with the National Institute of Allergy and Infectious Diseases (NIAID), part of theNIH, to evaluate the efficacy of BCV in EB virus-related lymphoproliferative disorders.
In November 2022, the company concluded a material transfer agreement (MTA) with US-based Penn State College ofMedicine, and initiated a non-clinical study evaluating the efficacy of BCV in a mouse model of polyomavirus infection.
In December 2022, the company concluded a sponsored research agreement with US-based Tufts University, and began ajoint research study evaluating the efficacy of BCV in a herpes simplex virus infection model. This study aims to explore
BCV's potential to treat neurological diseases, including Alzheimer's disease.
In addition to antiviral activity, the company expects brincidofovir to have antitumor effects. Through joint research with the
National Cancer Centre Singapore and University of California San Francisco Brain Tumor Center, SymBio is investigating
new indications for the drug in oncology, including rare brain tumors and EB virus-positive lymphoma. In March 2022, thecompany commenced joint research with Brown University of the US to investigate the antitumor effects of brincidofovir on
glioblastoma (GBM) caused by cytomegalovirus (CMV) infection.
In December 2022, the results of collaborative research with the National Cancer Centre Singapore (NCCS) on thetherapeutic efficacy of BCV in the treatment of rapidly progressing NK/T-cell lymphoma were presented at the 64th
American Society of Hematology (ASH) Annual Meeting.
At the 17th International Conference on Malignant Lymphoma (ICML) in June 2023, research into biomarkers that predict
the anti-tumor effect of BCV was presented.
Overseas (SymBio Pharma USA)In August 2023, the company appointed Dr. Stephane Berthier as CEO and President of its wholly-owned subsidiary SymBio
Pharma USA, Inc. In September 2023, SymBio added Nkechi Azie, MD, as Global Chief Medical Officer (CMO) to further
reinforce its global development structure. SymBio Pharma USA plans to accelerate global development of the antiviral drug
brincidofovir.

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

10

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
FY12/23 company forecast (revised in November 2023)
FY12/22(JPYmn)FY12/23

FY12/24

1H results

2H results

FY results

1H results

2H results

FY results

FY forecast

YoY

Sales

4,874

5,135

10,008

3,179

2,411

5,590

3,641

-34.9%

R&D expenses

1,009

1,545

2,555

1,204

1,434

2,638

3,207

21.6%

SG&A expenses excl.
R&D

1,629

1,453

3,081

1,319

1,266

2,584

-

-

Operating profit

1,372

591

1,964

-50

-762

-812

-2,837-

Operating profit margin

28.2%

11.5%

19.6%

-

-

-

-

Recurring profit

1,447

553

2,000

67

-803

-736

-2,867

Recurring profit margin

29.7%

10.8%

20.0%

2.1%

-

-

-

Net income

1,108

71

1,179

-80

-1,883-1,963-2,870Net margin

22.7%

1.4%

11.8%

-

-

-

-

-

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

FY12/24 company forecast (announced in February 2024)
The company's full-year forecast for FY12/24 calls for sales of JPY3.6bn (-34.9% YoY), an operating loss of JPY2.9bn (compared
to an operating loss of JPY812mn in the previous year), a recurring loss of JPY2.9bn (compared to a recurring loss of
JPY736mn), and a net loss of JPY2.9bn (compared to a net loss of JPY2.0bn).
The company expects a significant reduction in the drug price for Treakisym® in FY12/24 due to its removal from the scopeof price maintenance premiums given to certain new drugs. It also factored in the impact of generic drug sales. The
company has filed patent infringement litigation regarding the generic versions of Treakisym® asking for an injunction
against their manufacture and sale, but has not included any impact on sales due to the time required to reach a decision.
The company forecasts R&D spending of JPY3.2bn (+21.6% YoY), including the following items.
Global development of antiviral drug BCV IV for adenovirus infection and other infectious diseases
Development of new indications and evaluation of new drug development candidates through joint research withacademia

Long-term outlook
Sales projections from 2023 to 2030 (as of February 2023)

Source: Shared Research based on company information.
*Company projections as of the FY12/22 earnings results briefing (February 2023)**Unit value for figures in the vertical axis is JPY100mn

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

11

In the medium-term plan to FY12/23 (announced February 2020), SymBio forecasted Treakisym® sales would continue togrow YoY in FY12/23. This was based on the expectations that although the re-examination period for Treakisym® would end
in 2020, SymBio could potentially extend the product life to 2031 through commercialization and switching to Treakisym®
RTD and Treakisym® RI, formulations for which SymBio retains exclusive marketing rights. However, following the launch ofgeneric Treakisym® by two companies in June 2022 and December 2022, the company revised its medium-term plan
forecasts and now expects FY12/23 Treakisym® sales to decline 30.1% YoY.
At the FY12/22 earnings results briefing held in February 2023, the company explained the rationale for the revised
medium-term plan forecasts and presented an overall image of sales from 2023 through 2030. As of February 2023, SymBio
has not yet issued a new medium-term plan, including new earnings forecasts.

Treakisym® sales projection in 2030
The reason for management's revision of the medium-term guidance is that the MHLW approved generic Treakisym® andtwo companies commercialized their versions despite SymBio's patent infringement warnings. Management noted thatmarket share erosion to generic competition in public and quasi-public medical institutions is inevitable given government
policies promoting the use of generic drugs. Accordingly, SymBio has reduced its 2030 forecast for Treakisym® to half ofthe estimated peak sales level of JPY10bn (i.e., approximately JPY5bn). This halving of the Treakisym® sales forecast stillaccounts for market expansion due to the aging population and the increasing share of Treakisym®. The company still
expects Treakisym® to have a 50% share of the prescription market in 2030.

Business development and new in-licensing opportunities
The company is considering multiple licensing opportunities and conducting exploratory assessments to acquire licensing
rights to new development candidates. Management indicated that sales contributions from these new acquisitions could
generate sales of JPY3bn by 2030.

Business development and BCV global partnering
The company has decided against independent large-scale development of BCV in areas such as multiple sclerosis andAlzheimer's disease, but is considering transfer of rights, including joint development with a large pharmaceutical company
capable of global development (i.e., global partnering). Compensation for the transfer of rights for the last five years to 2030
is expected to reach JPY10bn, or an average of JPY2bn per year during this period.

Development of BCV
The company aims to obtain approval for two to three indications for BCV currently under development and generate
JPY10.0bn in sales from BCV by 2030, equivalent to the peak annual sales of Treakisym®.

R&D development from 2023 to 2030 (as of February 2023)
Management provided a rough roadmap of its R&D plan through 2030 at the FY12/22 earnings results briefing held in
February 2023. Development of Treakisym® has been completed and development from 2023 will focus on BCV. As BCV
has potential in multiple therapeutic categories, prioritization of development will be important. The development of BCV
will focus on three therapeutic categories: hematopoietic stem cell and organ transplantation, hematologicalmalignancies/oncology, and neurodegenerative diseases (NDD). Management explained the development prioritization andthe timeline of the development plan, noting that clinical development for hematopoietic stem cell and organtransplantation will be prioritized as approval is the most likely.
Hematopoietic stem cell and organ transplantation
Adenovirus trials, BKVN trials, CMV trials
Hematological malignancies and oncology
CMV (+) brain tumor, NK/T lymphoma
Neurodegenerative diseases
EBV multiple sclerosis, HSV-1 Alzheimer's type dementia

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

12

Initial clinical development for hematopoietic stem cell and organ transplantation
Initial clinical development in hematopoietic stem cell and organ transplantation will focus on two indications: adenovirus
infection and BK virus infection. In the development plan to 2030, management believes that approval for these indications
is most likely.
Adenovirus trial (post-hematopoietic stem cell transplantation adenovirus infection)
Phase IIa escalating-dose confirmatory study on safety and tolerability underway. Slated for completion in Q4 2023
BKVN trial (post-kidney transplantation BK viral infection)
Phase II underway. Slated for completion in Q2 2025
Announces full-scale development of CMV therapeutics in the transplantation field
CMV trial (post-hematopoietic stem cell cytomegalovirus infection)
Preparation for Phase Ib (Slated to start in Q4 2023 and be completed in Q1 2025)
At the FY12/22 earnings results information briefing held in February 2023, management explained the company's policy
for full-scale development of BCV for cytomegalovirus (CMV) infection in transplant recipients and its significance. Although
CMV is a strong development candidate, SymBio had put development in this indication on hold pending clarification of thetherapeutic effect of Takeda's competitor maribavir (approved in November 2021).
After evaluating the therapeutic efficacy of maribavir, management identified an unmet therapeutic need for CMV in thetransplantation field and announced the full-scale development of BCV for this indication. SymBio's determination that there
is an unmet therapeutic need, even after maribavir has been marketed, is based on the following three points.
Resistance to maribavir is 44.3% and no effective therapy is available for these resistant patients
Even after the virus is no longer detectable following maribavir treatment, relapse and resistance occurred in 23% of
patients at six weeks and 30% at 12 weeks.
Maribavir failed to demonstrate equivalence to the original drug (valganciclovir) in a non-inferiority trial
The number of transplant recipients treated for CMV is exceptionally high for a rare disease (25,000, of which 10,000 are
resistant or refractory). One reason that megapharma Takeda decided to develop maribarivir independently was likely thatthe large potential patient base made it look more lucrative. The company noted that the large patient base made patient
enrollment for clinical trials much easier. The Phase Ib clinical trial is being prepared to start with dose selection. The trial is
expected to begin in Q4 2023 and be completed by Q1 2025.
Hematological malignancies and oncology
CMV (+) brain tumors (collaboration with Brown University in the US; glioblastoma [GBM])
Phase I clinical trial / Slated to start in Q2 FY12/24 and be completed in 1Q FY12/26
The only pipeline in the hematological malignancies and oncology field for which a development timeline has been
proposed is glioblastoma, a type of CMV (+) brain tumor. In March 2022, the company launched a joint non-clinical study
with Brown University of the US to investigate the antitumor effect on cytomegalovirus positive infection and glioblastoma(GBM). This non-clinical study is expected to be completed in Q3 2023 with the goal of establishing PoC in animals. The
Phase I clinical trial is expected to begin in Q2 2024 and be completed in Q1 2026.
NK/T lymphoma (joint research with National Cancer Centre Singapore)
BCV demonstrated anticancer activity against NK/T cell lymphoma in the non-clinical study regardless of EB viral infection.
No clinical trial timeline was disclosed for NK/T lymphoma.
Neurodegenerative diseases (NDD)
SymBio announced that it will not independently develop BVC for neurodegenerative diseases (NDD) such as multiple
sclerosis and Alzheimer's disease. Rather, SymBio seeks to partner with a large pharmaceutical company capable of global
development (global partnering) and receive compensation through the transfer of rights. The company aims to establish
early proof-of-concept in animals through collaborations with world-renowned academic institutions. For the multiple
sclerosis indication, SymBio is advancing a Phase I study with the US NIH. For the Alzheimer's disease indication,
management is planning a co-development with a partner starting with Phase I.

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

13

EBV multiple sclerosis (joint research with US NIH)
Basic study (NIH/SymBio) started from Q3 2022
Animal model (NIH/SymBio) plans to start from Q3 2023
Phase I clinical trial (NIH/SymBio) plans to start from Q2 2024 with completion projected for Q2 2025
HSV-1 Alzheimer's type dementia (under joint research with Tufts University of the US)
3-D brain modeling (Tufts University) started from Q4 2022
Animal modeling (SymBio) plans to start from Q4 2023
Phase I clinical trial (partner/SymBio) plans to start from Q1 2025 with completion projected after end-2026

Therapeutic categories under consideration for development
Not specified, but the following therapeutic categories are potentially under consideration for development (as of February2023).
Post-transplantation infection
Post-hematopoietic stem cell transplantation adenovirus/BK viral hemorrhagic cystitis (VHC) and HHV-6 encephalitis,
EBV infectious mononucleosis
Hematological malignancies/oncology
EBV (+) lymphoma
Neurological
EBV sequelae
Ophthalmological
Adenovirus epidemic keratoconjunctivitis

Unexplored development possibilities
Additional potential therapeutic categories that have not been explored for development are listed below (as of February2023).
Post-transplantation infections
Prevention of post-hematopoietic stem cell transplantation CMV infection, multiviral agent for post-hematopoietic
stem cell transplantation use
Hematological malignancies/oncology
HPV (+) head and neck cancer, HPV (+) endometrial cancer
Dermatological
Varicella-zoster virus (VZV)/Herpes virus (HPV)

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

14

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%.

Products under development: Treakisym® (RTD formulation and
RI formulation), brincidofovir, and rigosertib (injection and oral)
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, mantle cell lymphoma, and relapsed or refractory diffuse large B-cell lymphoma (DLBCL).
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.

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

15

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.
Relapsed or refractory diffuse large B-cell lymphoma (DLBCL): Approved as additional indication in March 2021.

Treakisym® (RTD formulation and RI formulation)
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 freeze-dried (FD) product (whose exclusive sales rights inJapan expired 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. The company obtained approval for the RI formulation in
February 2022.
With this, it aims to promote a switch in clinical settings from lyophilized powder formulation to RTD and RI formulations thatlighten the workload for medical professionals, at the same time curtailing uptake of Treakisym® generics. 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.

Brincidofovir
Brincidofovir is an antiviral drug formed by conjugating a lipid chain (hexadecyloxypropyl, or HDP) of specified length tocidofovir (an antiviral drug already approved and marketed in the EU and the US, but not approved in Japan). It has a novel
mechanism of action, which is attributed to its being a lipid conjugate, and can be taken up into cells with enhanced
efficiency compared to cidofovir (i.e., brincidofovir has higher cell membrane permeability). Once inside a cell,brincidofovir transforms into a direct-acting agent and inhibits viral replication, demonstrating high antiviral effect. It is 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. In August 2021, the company launched phase II clinical trials in the US targeting adenovirus infection inchildren.

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

16

Revenue source: Treakisym® sales
Revenue mainly comes from product sales of Treakisym®. Operating losses had persisted since the company’s founding withthe exception of FY12/08 when the company booked operating profit due to a one-time contract payment from Eisai for an
exclusive domestic right to sell Treakisym®.
In FY12/21, the company turned profitable from the operating profit line down. SymBio began in-house sales of Treakisym®
in December 2020 and sales of the RTD formulation in January 2021, and in March 2021 it obtained approval for the
additional indication of relapsed or refractory DLBCL in FY12/21, which all contributed to sales growth and GPM
improvement.
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. It can obtain approval 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 beapproved in the future through an effective in-house screening 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
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.

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

17

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 2022). 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.

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

18

Scientific Advisory Board members
Name
George Morstyn,M.D., Ph.D.

ProfilePresently 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 YorkTomomitsu Hotta,
Honorary President, National Cancer Center
M.D.
Honorary Director, Nagoya Medical Center
Makoto Ogawa,
M.D., Ph.D.
Tatsutoshi
Nakahata, M.D.,
Ph.D.

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,
Professor of Medicine, Keio University, School of Medicine (Division of Rheumatology, Department of Internal Medicine)
M.D., Ph.D.
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.
SymBio Pharmaceuticals 4582
Research Coverage Report by Shared Research Inc. | https://sharedresearch.jp | Subscribe for FREE

19

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

Treakisym®
SyB L-0501(FD)

Singapore

South Korea
China
Hong Kong
TaiwanTreakisym®
SyB L-1701(RTD)

Indications
Relapsed or refractory
low-grade NHL and MCL
Relapsed or refractory
DLBCL (aggressive NHL)Development stage

Sales partner

Approved (Oct. 2010)
Approved (Mar. 2021)

Untreated low-grade NHL and MCL

Approved(Dec. 2016)

CLL

Approved(Aug. 2016)

In-house sales

CLL

Approved(Jan. 2010)

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

CLL
MM
Relapsed or refractory low-grade
NHL

Approved(May 2011)
Approved(Jun. 2014)

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

Low-grade NHL
Low-grade NHL
CLL

Clinical trials underway

Low-grade NHL

Approved(Oct. 2011)

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

Low-grade B-cell NHL

CLL

Approved(Dec. 2009)

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

All indications

Approved(Sep 2020)

In-house sales

Japan

All indications

Approved(Feb. 2022)

In-house sales

Japan

Relapsed or refractory
higher-risk MDS

Global phase III clinical trials
Additional analysis underway—

Rigosertib(oral)SyB C-1101

Relapsed or refractory higher-risk
MDS(monotherapy)
Untreated higher-risk MDS (withazacitidine)

Phase I clinical trials underway

—

Japan

Global phase I/II clinical trials
completed—

Brincidofovir (IV)SyB V-1901

Worldwide

Phase II clinical trials underway—

Treakisym®
SyB L-1702(RI)
Rigosertib(IV)
SyB L-1101

Adenovirus infection after
hematopoietic stem cell and kidneytransplantation

Source: Shared Research based on the company website

As of February 2023, the main drugs for which SymBio was preparing to file for approval or in the development pipeline
were as follows:

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

20

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: Under development for multiple indications. Refer to the "R&D development from 2023 to2030" for details.

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. In
March 2021, the company gained approval of Treakisym® for the additional indication of relapsed or refractory DLBCL(aggressive NHL).

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).

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: Shared Research based on materials from Japanese Society for Lymphoreticular Tissue Research (JSLTR)

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

21

Five-year relative survival rate for lymphatic malignancies (in patients diagnosed between
2001 and 2005)
Hodgkin’s lymphoma
Stage
Ⅰ
Ⅱ
Ⅲ
Ⅳ
All cases

Non-Hodgkin’s lymphoma

Number of cases

5-year relative survival rate(%)

Number of cases

5-year relative survival rate
(%)

19
46
22
19
122

91.4
84.6
65.3
44.7
76.0

462
385
319
535
1,844

86.7
74.3
64.0
54.6
68.3

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, a subsidiary of Astellas Pharma Inc (TSE Prime: 4503). The company entered into a second license
agreement with Astellas in March 2007 to extend its exclusive development and commercialization right for bendamustine
to China/Hong Kong, Taiwan, South Korea, and Singapore.
In August 2008, SymBio granted Eisai Co., Ltd. the co-development and exclusive marketing right for Treakisym® in Japan.
Under the agreement, SymBio receives one-time payments from Eisai as well as milestone payments based on the clinical
trial stage for 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. The domestic launch of the drug was in December 2010.
According to the company, Japan has about 4,700 patients who suffer from relapsed or refractory NHL and MCL. SymBio
thinks annual Treakisym® sales could reach JPY4.5–5.0bn.

Treakisym®: additional indications, RTD and RI
formulations
Approval as the first-line treatment for untreated low-grade NHL,MCL in December 2016, and for additional indication of CLL in
SymBio Pharmaceuticals 4582
Research Coverage Report by Shared Research Inc. | https://sharedresearch.jp | Subscribe for FREE

22

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 received approval of Treakisym® for the additional indication of relapsed or refractory DLBCL (aggressiveNHL) in March 2021.

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

Approval

Obtained

Development status

Obtained approval (Dec. 2016)

Number of patients
Relapsed andrefractory

Chronic Lymphatic Leukemia

Moderate- to high-grade
6,967

-

656

- Obtained- Obtained approval (Aug. 2016)
9,336

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.

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

23

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

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

24

when selecting a suitable treatment. Weaker patients—due to age or other illnesses—have limited choices for treatment, andthere was a need for a safer, more efficacious method of treatment such as Treakisym®.
In March 2021, the company obtained approval for a partial change to the marketing authorization of Treakisym® for use inbendamustine-rituximab combination therapy to treat r/r DLBCL. In April 2021, it obtained approval for a partial change tothe marketing authorization of Treakisym® RTD formulation for use in BR and P-BR therapy as a treatment for r/r 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.

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.
The treatment for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) involves administering 120mg once
daily for two consecutive days (one cycle), repeated over a maximum of six cycles. A 100mg vial of Treakisym® forintravenous infusion costs JPY95,764 (NHI drug price).

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)
formulations (marketed in the US by Teva Pharmaceutical Industries as BENDEKA®) in Japan. Under the terms of thisagreement, SymBio will pay Eagle Pharmaceuticals a USD12.5mn upfront payment and a milestone payment upon approval.
The company will also pay additional milestone payments on the achievement of cumulative sales thresholds and royalties on
future sales of licensed bendamustine products.

RTD and RI products do not require reconstitution; RI formulation 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 reduce the workload of healthcare professionals. RI formulation also does 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. The volume of diluted saline solution is one-fifth that of the RTD formulation, with the lower saltcontent making it suitable for elderly patients.

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

25

Comparison of RTD/RI formulations and freeze-dried formulation
Generic name
Dosage form
Reconstitution
Dilution

RTD formulation
bendamustine hydrochloride
LiquidNot required
Dilute with 250ml physiological saline

Administration time

60 minutes

Specifications

100mg/4mL

Storage

Refrigerated storage (2–8°C)

RI formulation

FD powder injection product

Dilute with 50ml physiological saline

Freeze-dried powder injection
Required (manual reconstitution)
Dilute with 250ml physiological saline

10 minutes

60 minutes
100mg/vial
25mg/vial
Room temperature

Scenario of extending life cycle of Treakisym® until 2031
The re-examination term for the FD formulation of Treakisym® ended in 2020, after which generics can be manufactured
and sold. SymBio believes that by selling the RTD and RI formulations of the product that offer the advantages of reducing
healthcare professionals’ workload and stress on patients after 2020, it can extend the exclusive sales period until 2031 if
these penetrate the market. The company aimed to prolong the life cycle of Treakisym® and limit 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 Eagle Pharmaceuticals as BENDEKA®,
which captured a 97% share of the US bendamustine market within two years after its launch. According to the company,
some companies in the US have attempted to launch generic versions of Treakisym® liquid formulations, but they all
infringed on Eagle Pharmaceuticals’ patents, and Eagle prevailed in lawsuits. The company did not think generic versions ofTreakisym® liquid formulations would be marketed in Japan.
However, the situation changed with the commercialization of generic Treakisym by Towa Pharmaceutical in June 2022,
followed by Pfizer Japan in December 2022. SymBio filed patent infringement lawsuits against both companies in December
2022, and the litigation is ongoing.

R&D status: obtained approval in September 2020 for RTD formulation and RI
formulation in February 2022
The company obtained approval for the bendamustine hydrochloride RTD formulation in September 2020 and rapid infusion(RI) administration in February 2022.

Treakisym® as a pretreatment agent for a regenerative medicine
product (CAR-T cell therapy)
In March 2019, Novartis Pharma K.K. received approval in Japan for 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. Shared Research understands that Novartis Pharma’s
CTL019 is limited to adult patients for whom two or more lines of therapy have proved ineffective, and is thus different from
SymBio's Treakisym® used to treat DLBCL, so the two do not compete.
In March 2019, the company obtained approval for a partial change to the marketing authorization for Treakisym® as apretreatment agent prior to CTL019 for relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) and relapsed or
refractory DLBCL in adults.

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

26

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.

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

27

Development status of rigosertib
Licensor Onconova conducted joint global phase III clinical trials in over 20 countries starting in August 2015 for the
intravenous form of rigosertib in higher-risk MDS patients who had failed to respond to or relapsed after therapy withhypomethylating agents (HMAs). In the Japanese market, the company conducted joint global phase III clinical trials startingin December 2015. As a result, in August 2020, Onconova announced that the global phase III trial of rigosertib (IV) failed
to meet its primary endpoints. Onconova is performing additional analysis of the results. The company commented that it islooking to apply the knowledge gleaned from additional analysis of the study to rigosertib development going forward.
Onconova completed phase I/II clinical trials in the US for the oral form of rigosertib as first-line treatment for higher-risk
MDS (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.

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 advanced research being conducted for rigosertib was forthe treatment of patients with higher-risk MDS who had progressed on, failed or relapsed after prior therapy with HMAs.

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.
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.

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

28

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 and launched global phase III comparative trials of rigosertib for patients who did not see resultsfrom low methylation, or experienced higher-risk refractory or relapsed MDS following HMA treatment.
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.

SymBio responsible for operation of global phase III clinical trials in JapanThe company conducted global phase III clinical trials in Japan from 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 August2020 announcement regarding not meeting primary endpoints of its phase III clinical trial, SymBio commented that it islooking 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.

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.

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

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

29

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. (TSE Prime: 4516) has been selling azacitidine in Japan as first-line therapy for MDS under the
product name Vidaza since March 2011. According to Nippon Shinyaku, sales of Vidaza were JPY15.4bn in FY03/21 (-1.9%
YoY) and forecast to reach JPY18.0bn in FY03/22.

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.
In June 2021, Chimerix received FDA approval for the use of the oral BCV formulation as a medical defense against
smallpox.

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 highantiviral efficacy. It is also easy to use as it has a low risk of nephrotoxicity, which is a side effect of cidofovir, hence making it
a novel, highly active anti-multiviral drug. It is expected to become an effective treatment against a wide array of infectious
diseases caused by DNA viruses, including cytomegalovirus (CMV) and other herpes viruses, adenoviruses, BK virus,
papillomaviruses, and smallpox virus.
Cidofovir (CDV): Approved by FDA in 1996 for the treatment of cytomegalovirus retinitis in AIDS patients. It inhibits
replication of multiple families of DNA viruses other than herpes viruses, including adenoviruses, papillomaviruses, 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.

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

30

Comparison of brincidofovir (BCV) antiviral activity versus other agents

Source: Company data
Note: Table shows IC50 (μM) values (concentration at which 50% of viruses targeted by pharmaceutical agent can be inhibited). The lower the IC50 value, the greater theantiviral activity.
Note: Cidofovir, Maribavir, Letemovir, Ganciclovir, Foscarnet, and Acyclovir are antiviral agents.

Development status of IV formulation of brincidofovir
The US-based phase I clinical trial of intravenous formulation of brincidofovir was completed. No serious side effects wereobserved in the study.

Phase II clinical trials targeting adenovirus diseases in children
In March 2021, the company filed an indicative new drug (IND) application with the US FDA, so it could start a phase II
clinical trial for the indication of adenovirus diseases in children (including adults). The development program received fasttrack designation from the FDA in April 2021, and the investigational drug was administered to the first patient enrolled in
the clinical trial in August 2021. In January 2022, the company submitted a Clinical Trial Application (CTA) to the Medicinesand Healthcare products Regulatory Agency (MHRA) of the UK, which was accepted.

The company is preparing to investigate the development of the intravenous formulation of brincidofovir in other transplant
areas, cancer, and neuro-infectious diseases.

Transplants
Proceeding with development targeting AdV infections following hematopoietic stem cell transplants
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. In Q1 2022, the company started the global
phase II study targeting ADV infections following hematopoietic stem cell transplants and completion is projected for Q4
2023. 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 toinclude multiviral infections.
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.

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

31

Expanding target disease areas to cover organ transplants
In a bid to grow the market for brincidofovir and maximize its business value, the company is exploring the potential for
expanding target disease areas to viral infections related to kidney and other organ transplants, in addition to ADV infections
following hematopoietic stem cell transplants. In Q3 2022, the Phase III clinical trial targeting BK virus infections following
kidney transplants was started and the completion is projected for Q2 2025.
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. When severe, they cancause disseminated infection and become fatal. Cases of adenovirus spreading to the kidney and causing kidney failure
and ultimately death have been reported. These infections are especially likely to occur after unrelated donor andumbilical cord blood transplants, which are relatively common in Japan. The infections are likely to be refractory, as they
are further complicated by the length of time required for reconstruction of the immune system. Drugs currently usedin treatment, including cidofovir (CDV), are either unapproved or off-label in Japan.
HHV-6 encephalitis: HHV-6 (Human Herpesvirus 6) is the sixth human herpesvirus to be discovered. It reactivates in
30–70% of patients after allogenic hematopoietic stem cell transplantation and can cause HHV-6 encephalitis. Most
cases of HHV-6 encephalitis develop within 2–6 weeks of transplantation, most frequently in the third week. It ischaracterized by the three major symptoms of impaired memory, disordered consciousness, and convulsions, which intypical cases gradually appear in the same order (convulsions occur in 30–70% of patients). In rapidly progressing
cases, which are common, neurological symptoms worsen by the hour, often requiring ventilator management for
repeated convulsions and respiratory depression.
The condition of HHV-6 encephalitis patients frequently deteriorates rapidly, making early treatment important.
According to guidelines from the Japan Society for Hematopoietic Cell Transplantation (February 2018), the first-line
drugs are foscarnet (FOS) or ganciclovir (GCV), followed by the second-line drug cidofovir (CDV). CDV is not thepreferred first-line drug due to nephrotoxicity and because it transfers poorly into cerebrospinal fluid (CSF). All threedrugs 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.

CancerIn addition to antiviral activity, the company thinks BCV may have antitumor effects. 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 in oncology, including refractory brain tumors and EB virus-positive lymphoma.
As of February 2023, the company was conducting a nonclinical study targeting glioblastoma multiforme (GBM), brain
tumors associated with cytomegalovirus infection. According to the company, roughly 50% of GBM patients havecytomegalovirus infections, and it is possible that cytomegalovirus promotes tumorigenesis. Further, while many GBM
therapies are being developed, none of them target cytomegalovirus and GBM (other than brincidofovir). In March 2022,
the company launched a joint nonclinical study with Brown University of the US to investigate the antitumor effect of BCV IV
on brain tumors associated with cytomegalovirus infection.
Glioblastoma multiforme: A malignant brain tumor of the glial cells that support the brain’s nerve cells. Survival is 15–
20 months, with a five-year survival rate of under 5%.

Neuro-infectious diseases
According to Science magazine (January 2022), a Harvard University team found that Epstein-Barr virus(EBV) infections are a major pathogenic factor in multiple sclerosis (MS). Analysis of a sample of over 10mn US military
personnel showed that a history of EBV infection increased the risk of MS by 32 times. A January 2022 story in Nature
magazine said that a research team from Stanford University elucidated the mechanism of action whereby the EBV causes

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

32

MS. The magazine says that this suggests eradication of the EBV from the body after the onset of MS could hinder its
progression.
BCV has strong antiviral activity on the EBV, so the company plans to investigate whether it could be an effective treatment
for MS.
Multiple sclerosis (MS): A disease in which lesions form throughout the brain, spinal cord, and optic nerves, causing avariety of symptoms. MS often features repeated relapses of symptoms and remissions (symptoms subside). Symptoms
vary widely depending on the location of the lesions, and include loss of vision, double vision, and motor paralysis.
There are roughly 3mn MS patients worldwide, and treatment sales were over JPY1.5tn (2020).

Earnings structure
FY12/19

FY12/20

FY12/21

FY12/22

Sales(JPYmn)

1,532

1,955

1,933

2,368

3,444

3,836

2,838

2,987

8,257

10,008YoY

FY12/13-21.6%

FY12/1427.6%

FY12/15-1.1%

FY12/1622.5%

FY12/1745.4%

FY12/18
11.4%-26.0%

5.3%

176.4%

Product sales

1,432

1,940

1,933

2,137

3,444

3,810

2,811

2,977

8,257

10,008

YoY-26.8%

35.5%

-0.3%

10.6%

61.1%

10.6%

-26.2%

5.9%

177.4%

21.2%

Treakisym sales (NHI price basis;
reference)( )

4,230

4,320

4,760

4,720

7,600

8,500

-

-

-

-

Product sales/Sales (NHI price basis)

33.9%

44.9%

40.6%

45.3%

45.3%

44.8%

-

-

-

-

Royalty revenue

100

15

-

231

-

26

26

10

-

-

Sales to Eisai

1,486

1,908

1,852

2,265

3,382

3,648

2,831

2,546

-

-

YoY

-23.0%

28.4%

-2.9%

22.3%

49.4%

7.9%

-22.4%-10.1%

-

-

46

47

81

104

62

187

6

441

8,257

10,008

Sales to other partners
CoGS

1,214

1,428

1,350

1,464

2,413

2,663

1,973

2,120

2,452

2,408

COGS / Product sales

84.8%

73.6%

69.8%

68.5%

70.1%

69.9%

70.2%

71.2%

29.7%

24.1%

Cost ratio(CoGS/Sales (NHI price basis))

28.7%

33.1%

28.4%

31.0%

31.7%

31.3%

-

-

-

-

Product procurement

1,175

1,550

1,242

1,606

2,589

2,969

1,684

3,163

2,145

Gross profit

318

527

583

904

1,031

1,173

865

867

5,800

Product gross profit

218

512

583

673

1,031

1,147

838

857

5,800

7,600

Gross profit margin

15.2%

26.4%

30.2%

31.5%

29.9%

30.1%

29.8%

28.8%

70.2%

75.9%

7,600

Royalty revenue

100

15

-

231

-

26

26

10

-

-

SG&A expenses

1,999

1,830

3,135

3,031

4,978

3,829

5,166

5,373

4,784

5,636

441

479

488

541

554

504

506

530

574

1,053

774

2,035

1,667

3,018

1,833

2,442

2,267

1,736

505

577

612

823

1,406

1,492

2,219

2,576

2,474

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

1,016

Personnel expenses
R&D expenses
Other
Operating profit

2,555
1,964

Source: Shared Research based on company data
*SymBio Pharma USA, Inc was consolidated from FY12/22 in line with the start of operation. Note that FY12/22 results are consolidated figures and the year-on-year changes
are for reference.

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 (i.e., wholesalers) of JPY441mn in FY12/20. From FY12/21, all sales were to non-Eisai partners.

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. Through FY12/16, the company
booked sales of Treakisym® indicated for relapsed or refractory low-grade NHL and MCL.
In FY12/17, the company booked sales of additional indications of untreated low-grade NHL and MCL, resulting in sales
growth 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.
Sales increased YoY in FY12/21, largely due to the transfer of sales from Eisai to the company’s own sales force. The businessalliance agreement with Eisai for Treakisym® expired on December 9, 2020, and SymBio began independently marketing
Treakisym® in Japan on December 10. This enabled the company to earn not only its previous gross profit (sales to Eisai
minus cost of sales), but also the gross profit earned by Eisai through December 9, 2020 (the difference between the
shipment price from Eisai to pharmaceutical wholesalers and the price Eisai paid SymBio to supply Treakisym®).

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

33

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

CoGS
CoGS 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 allowed 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), boosting GPM.
SymBio sources the liquid (RTD and RI) formulations of Treakisym® from US company Eagle Pharmaceuticals. According to
the company, its GPM on the liquid formulations 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.
Strong share in niche markets: SymBio focuses on niche markets for rare oncologic, hematologic, and multiviral infectious
diseases and rare diseases. The company takes advantage of a less competitive environment by developing drugs forindications 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.

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

34

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 2023, 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 2018, the number of people diagnosed with lymphatic cancer in Japan was 35,782 (+3.5% YoY; average annual increase inpast 10 years is 4.9%), according to “Cancer statistics and cancer registration in Japan” complied by the Center for Cancer
Control and Information Services. Of these, 29,156 (+4.6% YoY), or 81.5% (80.7% in the previous year), were 60 years orolder.
Of the 980,856 (+0.4% YoY) people diagnosed with cancer, those diagnosed with lymphatic cancer accounted for only 3.6%
(3.5% in the previous year), but their number increased 62.1% between 2008 and 2018, versus a 30.8% 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).
The company estimates that the number of Japanese patients with relapsed or refractory DLBCL is 18,672.

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

35

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

6,967

Approved

CLL
Relapsed or refractory NHL

656
18,672

Approved
Clinical trials underway

Notes

Sales: JPY8.5bn (FY12/18)

Drugs competing with Treakisym®
Drugs that compete with Treakisym® include rituximab and ibritumomab tiuxetan. SymBio has successfully pursued adevelopment policy aimed at demonstrating that the co-administration of Treakisym® improves the efficacy of these drugs.

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.

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 Toyama Chemical Co., Ltd., a subsidiary of Fujifilm Holdings Corporation (TSE Prime: 4901).

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
High-risk MDS

Number of patients
7,800
3,200

Source: Shared Research based on company data

Drugs competing with rigosertib
Nippon Shinyaku Co., Ltd.’s Vidaza is an IV drug approved in Japan for the main indication of MDS.

Azacitidine (product name: Vidaza)
Vidaza, developed by Pharmion Corporation (now Celgene Corporation) in the US, is a treatment for first-line intermediateand higher-risk MDS. Nippon Shinyaku Co., Ltd. (TSE Prime: 4516) signed a license agreement with Pharmion in 2006 tosell this drug in Japan, obtaining marketing approval in January 2011 following the completion of domestic clinical trials.

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

36

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
JPY15.4bn (-1.9% YoY) in FY03/21 and expects sales of JPY18.0bn in FY03/22.

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

37

Historical performance
Cumulative Q3 FY12/23 results
Sales: JPY4.4bn (-39.9% YoY)
Operating loss: JPY283mn (versus an operating profit of JPY1.6bn in cumulative Q3 FY12/22)
Recurring loss: JPY156mn (versus a recurring profit of JPY1.8bn in cumulative Q3 FY12/22)
Net loss attributable to owners of the parent: JPY789mn (versus a net income of JPY1.6bn in cumulative Q3 FY12/22)
In February 2022, SymBio obtained approval for a partial change to the marketing authorization for the ready-to-dilute (RTD)
intravenous formulation of Treakisym® 100mg/4ml, which was launched in January 2021, to add rapid infusion (RI)
administration. Compared to the freeze-dried (FD) formulation, the RTD formulation reduces the time required for thecomplicated dissolution process. RI administration further benefits both patients and healthcare providers by reducing theinfusion time from the 60 minutes required by the RTD formulation. In addition, the RI administration uses less saline
solution and accordingly less salt (sodium chloride).
The switch from the FD to RTD formulation is almost complete. With over 90% of medical institutions administering the RI
formulation to patients as of end-June 2023, progress was made in the switch to the RI formulation. On the quality assurance
front, SymBio also has taken steps to ensure the stable supply of the RTD formulation of Treakisym®.
Sales decreased by 39.9% YoY to JPY4.4bn. This decline can be attributed to several factors: firstly, the reduced amount ofdrugs used per patient due to the impact of COVID-19 and seasonal flu; secondly, the launch of generic drugs in June 2022,
which affected SymBio's product sales. Additionally, there was a temporary sales spike in the same period last year resulting
from the switch from the FD formulation to the RTD formulation, which impacted this year's sales.
The 39.9% YoY drop in cumulative Q3 sales outpaced the decline projected in the company's previous forecast. As aresult, the company further downgraded its sales forecast from JPY6.5bn (-35.3% YoY) to JPY5.6bn (-44.0% YoY). The
company had expected the sales volume of the RTD formulation of Treakisym® to return to pre-pandemic levels, but therecovery of usage in the treatment of malignant lymphoma fell short of expectations.
The decline in Treakisym® RTD sales was primarily due to generic competition, the impact of the pandemic, and theseasonal influenza outbreak. As a result, drug usage per malignant lymphoma case continued to decline and treatment
delays persisted, leading to a contraction of the overall bendamustine market (which include both Treakisym® andgeneric products).
The company expects a decision from the Tokyo District Court in early 2024 on its patent infringement lawsuit against thegeneric version of Treakisym® RTD. The company is seeking an injunction to stop sales of the generic products anddamages for patent infringement.
Gross profit totaled JPY3.5bn (-36.4% YoY) and the gross profit margin was 78.6% (+4.3pp YoY). SG&A expenses came to
JPY3.8bn (-3.1% YoY), including R&D expenses of JPY1.8bn (+16.6% YoY). As a result, the company recorded an operating lossof JPY283mn (versus an operating profit of JPY1.6bn in cumulative Q3 FY12/22).
SG&A expenses, excluding R&D expenses, were JPY1.9bn (-16.4% YoY). In FY12/22, the company reduced its employee
count by 19 compared to the end of the previous fiscal year. SymBio has continued downsizing in FY12/23, and theassociated reduction in personnel costs also contributed to the lower SG&A expenses.
GPM was 78.6% (+4.3pp YoY) in cumulative Q3. This improvement was due to the absence of a one-time milestone
payment of JPY550mn recorded in Q3 of the previous year.
Progress versus full-year FY12/23 company forecast (revised on August 2023)
In November 2023, SymBio announced a second revision to its full-year forecast for FY12/23, lowering projections for bothsales and operating profit (refer to the Full-year company forecast section for details). Cumulative Q3 sales of JPY4.4bn,compared to the revised full-year forecast of JPY5.6bn, represent a progress rate of 78.9%. The company's sales are normallyweighted toward 2H, but the revised forecast takes into account the latest sales trend.
Against the full-year company forecast of an operating loss of JPY680mn, the operating loss for cumulative Q3 was
JPY283mn. This implies that the projected operating loss for Q4 is JPY397mn. The larger projected loss in Q4 is partly due to

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

38

R&D expenses, which are typically higher in 2H for SymBio, particularly in Q4.

Business progress
As of November 2023, the year-to-date progress in the company's key businesses was as follows.
In November 2023, SymBio announced the results of Phase II clinical trials for BCV targeting adenovirus infections.
These results will be presented at the 65th American Society of Hematology Annual Meeting in December 2023.
In October 2023, US licensor Onconova the released data related to rigosertib in treating squamous cell carcinoma.
In October 2023, SymBio published the results of a collaborative study on the treatment of multiple sclerosis with BCV.
In October 2023, the company announced the conclusion of STraight-Equity Issue Program (STEP) and the issuance of
new shares through third-party allotment.
In August 2023, SymBio announced a change in the global chief medical officer.
In August 2023, SymBio announced changes to the clinical development plan for the injectable drug brincidofovir (BCV)
for the treatment of BK virus infections.
In July 2023, the company's US subsidiary, Symbio Pharma USA, appointed Dr. Stephane Berthier, PharmD, as CEO andpresident to expand its global development structure.
In June 2023, research findings related to a biomarker (TLE1/transcription factor) predicting the anti-tumor effect of BCV
were published.
In May 2023, the proof of concept (POC) was established in the Phase II clinical trial of BCV for the treatment of
adenovirus infection.
In April 2023, the company entered into a CRADA with the National Institute of Allergy and Infectious Diseases (NIAID),
part of the NIH, to evaluate the therapeutic effects of BCV in diseases caused by the EBV.
In March 2023, the company entered into a cooperative research and development agreement (CRADA) with the
National Institute of Neurological Disorders and Stroke (NINDS), part of the US National Institutes of Health (NIH), todevelop brincidofovir (BCV) as a treatment for multiple sclerosis. Since August 2022, the company and NINDS havebeen collaborating on evaluating the antiviral effects of BCV against the Epstein-Barr virus (EBV).

Establishment of an in-house sales organization
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®.
In conducting in-house sales, SymBio established a sales organization that can cultivate needs, provide information on thecompany products, and plan seminars. In addition to medical representatives, the company deployed hematology experts
with extensive knowledge of the field throughout Japan. Further, the company concluded basic agreements with Suzuken
Co., Ltd and Toho Pharmaceutical Co., Ltd for the procurement and sale of pharmaceuticals to build a nationwide distribution
network. The company has established two distribution centers, one in Eastern Japan and the other in Western Japan, undermanagement by S.D. Collabo Co., Ltd.

Anticancer agent SyB L-0501 (FD formulation)/SyB L-1701 (RTD formulation)/SyB L-1702(RI administration); generic name: bendamustine hydrochloride or bendamustinehydrochloride hydrate, product name: Treakisym®
In March 2021, SymBio obtained approval for the use of the FD formulation of TREAKISYM® in BR therapy to treat r/r DLBCLas an additional indication. In February 2022, the company secured approval for a partial amendment to the marketing
authorization for the ready-to-dilute (RTD) formulation of TREAKISYM® (in-licensed from US-based Eagle Pharmaceuticals,Inc.), enabling the use of RI administration for all approved indications of the RTD formulation.

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

39

SymBio will continue to explore new potential applications of TREAKISYM® through joint research with Kyoto University.

Anticancer agent SyB L-1101 (IV)/SyB C-1101 (oral); generic name: rigosertib sodium
Onconova Therapeutics, Inc., the drug's licensor, announced in August 2020 that INSPIRE, the pivotal Phase III study inhigher-risk myelodysplastic syndromes (HR-MDS) patients comparing IV rigosertib to physicians' choice of treatment, did notmeet its primary endpoint. SymBio is in charge of clinical development in Japan and is collaborating with Onconova
regarding the future development of rigosertib.
For rigosertib and TREAKISYM®, the company is searching for new indications as well as new applications for the drugs usedin combination with each other or with other existing drugs, through joint research and the offering of academia-industry
collaborative courses with the University of Tokyo.

Antiviral drug SyB V-1901 (generic name: brincidofovir, hereafter BCV)In development of the intravenous and oral formulations of the antiviral drug brincidofovir (SyB V-1901; BCV IV and BCVOral), the company is conducting joint research with top research institutions specialized in each field in Japan and overseas
in light of the broad spectrum of the drug's effectiveness against dsDNA virus infections. It will consider conducting
additional global clinical trials based on the scientific findings of the research.
Broad potential of BCV and rights relative to Chimerix
Earlier clinical trials in the US and Europe conducted by US-based Chimerix Inc. have demonstrated that BCV Oral has
broad-spectrum antiviral effects against a variety of dsDNA viruses. BCV IV is expected to be effective and safe for theprevention and treatment of many dsDNA virus infections, including adenovirus (AdV) infections after hematopoietic stem
cell transplantation. In June 2021, Chimerix announced that the US FDA had granted BCV Oral approval for the treatment ofsmallpox.
In September 2022, Chimerix announced that it had completed procedures to transfer the rights to brincidofovir to
Emergent BioSolutions Inc. (headquarters: Maryland, US). The agreement, however, has no impact on the company's
exclusive rights to develop, manufacture, and sell brincidofovir globally for all indications except orthopoxvirus diseases
including smallpox and monkeypox.
BCV clinical development: disseminated AdV infections following hematopoietic stem cell transplantation
Based on a global advisory board review held in February 2020, the company has decided to prioritize the global
development of BCV IV primarily in Japan, the US, and Europe, targeting disseminated AdV infections occurring after
hematopoietic stem cell transplantation, a niche area with a high unmet medical need.
In March 2021, the company filed an IND application with the US Food and Drug Administration (FDA) to conduct a Phase II
clinical trial primarily in pediatric patients suffering from AdV infections (also including adults). This development program
was granted fast-track designation by the FDA in April 2021, and the investigational drug was administered to the first patientin August 2021. In January 2022, a clinical trial application (CTA) was submitted to the UK's Medicines and Healthcare
products Regulatory Agency (MHRA). In May 2023, the same study demonstrated proof of concept (POC) for BCV in humanpatients. Positive trial data demonstrating the BCV's effectiveness will be orally presented at the 65th American Society of
Hematology Annual Meeting in December 2023.
The Data Safety Monitoring Board (DSMB) and the FDA confirmed the POC in terms of both safety and efficacy. While the
POC has been confirmed in trials up to cohort 3, the company is continuing to verify the POC with cohort 4 at therequest of the FDA. The dosage regimens for cohorts 1 through 4 are as follows.
For cohorts 1 to 3, BCV was administered twice weekly, at doses of 0.2mg/kg for cohort 1, 0.3mg/kg for cohort 2, and
0.4mg/kg for cohort 3. In cohort 3 (0.4mg/kg, twice weekly via IV), the disappearance of AdV in the blood wasconfirmed in 100% of patients (n=10). Of these, 90% of patients (n=9) achieved viral clearance within four weeks oftreatment.
BCV clinical development: BK virus infection following kidney transplantation
BK virus nephropathy after kidney transplantation is considered a disease with serious consequences for the recipient,the donor, the medical practitioner, and society, as it may result in serious conditions such as decreased renal function andgraft loss. In order to find an early solution to this problem, SymBio submitted a clinical trial notification for a global Phase II
study in patients infected with BK virus after receiving kidney transplant to the Pharmaceuticals and Medical Devices Agency
SymBio Pharmaceuticals 4582
Research Coverage Report by Shared Research Inc. | https://sharedresearch.jp | Subscribe for FREE

40

(PMDA) of Japan in May 2022 and to the Therapeutic Goods Administration (TGA) of Australia in August 2022. The
investigational drug was administered to the first patient in Australia in August 2022. The trial was originally planned toconclude in 2025, but progress has been slower than expected due to delays in patient enrollment. SymBio announced achange to its clinical development plan in August 2023, stating that it will consider a protocol amendment.
The company has decided to prioritize two clinical trials: a Phase Ib clinical trial for cytomegalovirus infection following
hematopoietic stem cell transplantation and another Phase Ib clinical trial for brain tumors. Typically, it is easier toaccumulate cases in trials targeting larger markets.
BCV non-clinical studies: EB virus, multiple sclerosis, lymphoproliferative disorders
SymBio has been preparing for clinical development of brincidofovir for multiple sclerosis, a rare disease related to EB virus.
In August 2022, the company signed a collaboration agreement for the transfer of human materials with the National
Institute of Neurological Disorders and Stroke (NINDS) of the US National Institute of Health (NIH). In March 2023, SymBio
signed a cooperative research and development agreement (CRADA) with NINDS to obtain information necessary to
conduct future clinical trials. In October 2023, the research results were presented at the 9th Joint ECTRIMS-ACTRIMS
Meeting in Milan, Italy.
CRADA: Refers to a contract on collaborative R&D between a US government organization and entities such as a privatesector company. The private-sector company may be able to obtain licensing of patent rights regarding inventions
developed under the CRADA. Because a company may receive patent rights from a project using government funds,
the barriers to being selected for a CRADA are significant (SymBio is the second Japanese company to be selected).

In April 2023, SymBio also signed a CRADA with the National Institute of Allergy and Infectious Diseases (NIAID), part of theNIH, to evaluate the efficacy of BCV in EB virus-related lymphoproliferative* disorders.
*Refers to a wide range of diseases related to the EB virus: Cancers such as T-cell lymphoma, Burkitt lymphoma,
Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, NK T-cell lymphoma, and post-transplant lymphoproliferative disease, Xlinked lymphoproliferative syndrome, and AIDS-related lymphoproliferative disease. (Source: Materials for company’s
18th ordinary general meeting of shareholders.)

BCV non-clinical study: polyomavirus
In November 2022, the company concluded a material transfer agreement (MTA) with US-based Penn State College ofMedicine, and initiated a non-clinical study evaluating the efficacy of BCV in a mouse model of polyomavirus infection.
BCV non-clinical joint research: herpes simplex virus, Alzheimer's type dementia
In December 2022, the company concluded a sponsored research agreement with US-based Tufts University, and began ajoint research study evaluating the efficacy of BCV in a herpes simplex virus infection model. This study aims to explore
BCV's potential to treat neurological diseases, including Alzheimer's disease.
BCV non-clinical joint research: applications for hematological malignancies/oncology
In addition to antiviral activity, the company expects brincidofovir to have antitumor effects. Through joint research with the
National Cancer Centre Singapore and University of California San Francisco Brain Tumor Center, SymBio is investigating
new indications for the drug in oncology, including rare brain tumors and EB virus-positive lymphoma. In March 2022, thecompany commenced joint research with Brown University of the US to investigate the antitumor effects of brincidofovir on
glioblastoma (GBM) caused by cytomegalovirus (CMV) infection.
In December 2022, the results of collaborative research with the National Cancer Centre Singapore (NCCS) on thetherapeutic efficacy of BCV in the treatment of rapidly progressing NK/T-cell lymphoma were presented at the 64th
American Society of Hematology (ASH) Annual Meeting.
At the 17th International Conference on Malignant Lymphoma (ICML) in June 2023, research into a biomarker*(TLE1/transcription factor) that predicts the anti-tumor effect of BCV was presented.

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

41

*The use of biomarkers allows for the selection of patients who are likely to respond well to treatment, which increases
the probability of successful clinical trials.

Development potential for BCV in other areas
Joint research with the National Institute of Infectious Diseases has found BCV to have potent antiviral activity against viralhemorrhagic cystitis (VHC) after hematopoietic stem cell transplantation, a disease associated with adenovirus type B11, andepidemic keratoconjunctivitis, a disease associated with adenovirus type D54. Of these, epidemic keratoconjunctivitis in theophthalmic area is a non-core area. Herpes virus development in the dermatological space is also outside of the company's
core competency. Shared Research believes development of non-core areas is a low priority.
BCV development policy
SymBio aims to maximize the business value of BCV by examining the efficacy of the drug in dsDNA virus infections,
expanding target indications to include multiviral infections, and striving to meet the underserved medical needs fortreatments of viral diseases and accompanying complications.
SymBio explained its BCV development policy to 2030 at the FY12/22 earnings results information briefing. In addition to
the core areas of hematological cancer/oncology, the company is entering the neurodegenerative diseases (NDD) space,such as multiple sclerosis and Alzheimer's type dementia. SymBio will not develop BCV independently forneurodegenerative diseases but looks to partner with a major pharmaceutical company capable of global development (seedetails in the Long-term outlook section, R&D image to 2030). The company expects to receive about JPY10bn incompensation for transferring rights to the joint development over five years (2025–2030).
SymBio aims for approval and commercialization of two or three indications for BCV by 2030. The indication with thehighest potential for approval is viral infection following hematopoietic stem cell and kidney transplantation, two areas ofclinical development prioritization.

Overseas development bases (SPU/SymBio Pharma USA)In August 2023, the company’s US-based wholly-owned subsidiary SymBio Pharma USA, Inc. appointed Dr. Stephane
Berthier as CEO and President to further reinforce its global development structure. SymBio Pharma USA plans to accelerate
global development of the antiviral drug brincidofovir.

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.

Topics: Drug Discovery AI
The company has been pursuing a lab-less and fab-less strategy, without owning any research institutes or manufacturing
sites. During its earnings announcement in August 2023, the company announced the establishment of the Institute of AI
Biosciences (IOAB). At this institute, the company has built its own AI drug discovery system and implemented the Global
Medical & Science Information collection system, a system on par with those of the world's most advanced research institutes,
into its proprietary platform.

Fundraising
In October 2023, SymBio announced it will enter into an agreement with EVO FUND to set up a STraight-Equity Issue
Program (STEP) and issue new shares through third-party allotment under this program. The total number of shares that may
be issued under the program is 6,000,000, and the dilution rate, based on the total number of issued shares of 39,841,000
at end-June 2023, is 15.06% (15.25% based on voting rights). The estimated net proceeds are JPY2.2bn. (See the Recent
update section for details.)

1H FY12/23 results
Sales: JPY3.2bn (-34.8% YoY)
Operating loss: JPY50mn (operating profit of JPY1.4bn in 1H FY12/22)
SymBio Pharmaceuticals 4582
Research Coverage Report by Shared Research Inc. | https://sharedresearch.jp | Subscribe for FREE

42

Recurring profit: JPY67mn (-95.4% YoY)
Net loss attributable to owners of the parent: JPY80mn (net income of JPY1.1bn in FY12/22)
In February 2022, SymBio obtained approval for a partial change to the marketing authorization for the ready-to-dilute (RTD)
intravenous formulation of Treakisym® 100mg/4ml, which was launched in January 2021, to add rapid infusion (RI)
administration. Compared to the freeze-dried (FD) formulation, the RTD formulation reduces the time required for thecomplicated dissolution process. RI administration further benefits both patients and healthcare providers by reducing theinfusion time from the 60 minutes required by the RTD formulation. In addition, the RI administration uses less saline
solution and accordingly less salt (sodium chloride).
The switch from the FD to RTD formulation is almost complete. With over 90% of medical institutions administering the RI
formulation to patients as of end-June 2023, progress was made in the switch to the RI formulation. On the quality assurance
front, SymBio also has taken steps to ensure the stable supply of the RTD formulation of Treakisym®.
Sales decreased 34.8% YoY to JPY3.2bn. The decline was due to the following factors: 1) medical institutions were reluctant topurchase drugs due to price revisions; 2) the amount of drugs used per patient decreased during the COVID-19 pandemic;
and 3) the launch of generic drugs in June 2022 affected SymBio's product sales. In addition, there was a temporary sales
spike last year due to the switch from the FD formulation to the RTD formulation, which impacted this year's sales.
The 34.8% YoY decline in 1H sales exceeded the company's initial forecast of a 30.1% YoY decrease for the full year. As aresult, the company has downgraded its full-year sales forecast from JPY7.0bn to JPY6.5bn (-35.3% YoY). The company had
expected the sales volume of the RTD formulation of Treakisym® to return to pre-pandemic levels, but the recovery ofusage in the treatment of malignant lymphoma fell short of expectations.
The price reduction for Treakisym® RTD in the April 2023 NHI price revision was relatively small at around 3.5%. The
drop in sales is therefore mainly due to generic penetration and the impact of the pandemic. Although the rate of market
share loss for Treakisym® is relatively slow compared to other anticancer drugs for which generics have been introduced,
the company noted that incentives for hospitals to use generics (reimbursement premium) are impacting sales of its
branded drug.
The company expects a decision from the Tokyo District Court in early 2024 on its patent infringement lawsuit against thegeneric version of Treakisym® RTD. The company is seeking an injunction to stop sales of the generic products anddamages for patent infringement.
Gross profit totaled JPY2.5bn (-38.3% YoY) and the gross profit margin was 77.8% (-4.5pp YoY). SG&A expenses came to
JPY2.5bn (-4.4% YoY), including R&D expenses of JPY1.2bn (+19.3% YoY). As a result, the company recorded an operating lossof JPY50mn (vs. operating profit of JPY1.4bn in 1H FY12/22).
SG&A expenses excluding R&D expenses were JPY1.3bn (-19.0% YoY). In FY12/22, the company reduced its employee
count by 19 compared to the previous fiscal year (as of December 2022). The company said it further downsized its
workforce in 1H, and the associated reduction in personnel costs also contributed to the lower SG&A expenses.
The gross profit margin was 80.4% in Q4 FY12/22, 80.5% in Q1 FY12/23, and 75.3% in Q2 FY12/23. The decrease in
GPM in Q2 was due to the drug price revision in April 2023, which reduced the price of Treakisym® by approximately
3.5%.
Progress versus full-year FY12/23 company forecast (revised on August 2023)
In August 2023, SymBio announced a revision to its full-year forecast for FY12/23. While the sales forecast was lowered, theoperating profit forecast remained unchanged (see the Full-year company forecast section for details). The 1H sales of
JPY3.2bn represent a progress rate of 49.1% against the revised full-year forecast of JPY6.5bn. The company's sales arenormally skewed towards 2H due to seasonal factors.
The company reported an operating loss of JPY50mn in 1H, compared with a full-year operating loss forecast of JPY331mn.
The relatively smaller loss was partly due to the fact that SG&A expenses in 1H were only 46.9% of the full-year budget of
JPY5.4bn (of which, R&D expenses were 41.8% of the budget). Typically, the company's R&D expenses are more heavily
burdened in 2H.

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

43

Business progress
As of August 2023, the year-to-date progress in the company's key businesses was as follows.
In August 2023, SymBio announced changes to the clinical development plan for the injectable drug brincidofovir (BCV)
for the treatment of BK virus infections.
In July 2023, the company's US subsidiary, Symbio Pharma USA, appointed Dr. Stephane Berthier, PharmD, as CEO andpresident to expand its global development structure.
In June 2023, research findings related to a biomarker (TLE1/transcription factor) predicting the anti-tumor effect of BCV
were published.
In May 2023, the proof of concept (POC) was established in the Phase II clinical trial of BCV for the treatment of
adenovirus infection.
In April 2023, the company entered into a CRADA with the National Institute of Allergy and Infectious Diseases (NIAID),
part of the NIH, to evaluate the therapeutic effects of BCV in diseases caused by the EBV.
In March 2023, the company entered into a cooperative research and development agreement (CRADA) with the
National Institute of Neurological Disorders and Stroke (NINDS), part of the US National Institutes of Health (NIH), todevelop brincidofovir (BCV) as a treatment for multiple sclerosis. Since August 2022, the company and NINDS havebeen collaborating on evaluating the antiviral effects of BCV against the Epstein-Barr virus (EBV).

Establishment of an in-house sales organization
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®.
In conducting in-house sales, SymBio established a sales organization that can cultivate needs, provide information on thecompany products, and plan seminars. In addition to medical representatives, the company deployed hematology experts
with extensive knowledge of the field throughout Japan. Further, the company concluded basic agreements with Suzuken
Co., Ltd and Toho Pharmaceutical Co., Ltd for the procurement and sale of pharmaceuticals to build a nationwide distribution
network. The company has established two distribution centers, one in Eastern Japan and the other in Western Japan, undermanagement by S.D. Collabo Co., Ltd.

Anticancer agent SyB L-0501 (FD formulation)/SyB L-1701 (RTD formulation)/SyB L-1702(RI administration); generic name: bendamustine hydrochloride or bendamustinehydrochloride hydrate, product name: Treakisym®
In March 2021, SymBio obtained approval for the use of the FD formulation of TREAKISYM® in BR therapy to treat r/r DLBCLas an additional indication. In February 2022, the company secured approval for a partial amendment to the marketing
authorization for the ready-to-dilute (RTD) formulation of TREAKISYM® (in-licensed from US-based Eagle Pharmaceuticals,Inc.), enabling the use of RI administration for all approved indications of the RTD formulation.
SymBio will continue to explore new potential applications of TREAKISYM® through joint research with Kyoto University.

Anticancer agent SyB L-1101 (IV)/SyB C-1101 (oral); generic name: rigosertib sodium
Onconova Therapeutics, Inc., the drug's licensor, announced in August 2020 that INSPIRE, the pivotal Phase III study inhigher-risk myelodysplastic syndromes (HR-MDS) patients comparing IV rigosertib to physicians' choice of treatment, did notmeet its primary endpoint. SymBio is in charge of clinical development in Japan and is collaborating with Onconova
regarding the future development of rigosertib.
For rigosertib and TREAKISYM®, the company is searching for new indications as well as new applications for the drugs usedin combination with each other or with other existing drugs, through joint research and the offering of academia-industry
collaborative courses with the University of Tokyo.

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

44

Antiviral drug SyB V-1901 (generic name: brincidofovir, hereafter BCV)In development of the intravenous and oral formulations of the antiviral drug brincidofovir (SyB V-1901; BCV IV and BCVOral), the company is conducting joint research with top research institutions specialized in each field in Japan and overseas
in light of the broad spectrum of the drug's effectiveness against dsDNA virus infections. It will consider conducting
additional global clinical trials based on the scientific findings of the research.
Broad potential of BCV and rights relative to Chimerix
Earlier clinical trials in the US and Europe conducted by US-based Chimerix Inc. have demonstrated that BCV Oral has
broad-spectrum antiviral effects against a variety of dsDNA viruses. BCV IV is expected to be effective and safe for theprevention and treatment of many dsDNA virus infections, including adenovirus (AdV) infections after hematopoietic stem
cell transplantation. In June 2021, Chimerix announced that the US FDA had granted BCV Oral approval for the treatment ofsmallpox.
In September 2022, Chimerix announced that it had completed procedures to transfer the rights to brincidofovir to
Emergent BioSolutions Inc. (headquarters: Maryland, US). The agreement, however, has no impact on the company's
exclusive rights to develop, manufacture, and sell brincidofovir globally for all indications except orthopoxvirus diseases
including smallpox and monkeypox.
BCV clinical development: disseminated AdV infections following hematopoietic stem cell transplantation
Based on a global advisory board review held in February 2020, the company has decided to prioritize the global
development of BCV IV primarily in Japan, the US, and Europe, targeting disseminated AdV infections occurring after
hematopoietic stem cell transplantation, a niche area with a high unmet medical need.
In March 2021, the company filed an IND application with the US Food and Drug Administration (FDA) to conduct a Phase II
clinical trial primarily in pediatric patients suffering from AdV infections (also including adults). This development program
was granted fast-track designation by the FDA in April 2021, and the investigational drug was administered to the first patientin August 2021. In January 2022, a clinical trial application (CTA) was submitted to the UK's Medicines and Healthcare
products Regulatory Agency (MHRA). In May 2023, the same study demonstrated proof of concept (POC) for BCV in humanpatients. As of end-June 2023, a total of 27 cases have been enrolled and patient enrollment is ongoing.
The Data Safety Monitoring Board (DSMB) and the FDA confirmed the POC in terms of both safety and efficacy. While the
POC has been confirmed in trials up to cohort 3, the company is continuing to verify the POC with cohort 4 at therequest of the FDA. The dosage regimens for cohorts 1 through 4 are as follows.
In cohorts 1 to 3, BCV was administered twice a week for four weeks, with dosages of 0.2mg/kg for cohort 1, 0.3mg/kg
for cohort 2, and 0.4mg/kg for cohort 3. The dosage for cohort 4 (0.4mg/kg) is the same as that for cohort 3, but the
number of doses is reduced to once weekly for four weeks.
BCV clinical development: BK virus infection following kidney transplantation
BK virus nephropathy after kidney transplantation is considered a disease with serious consequences for the recipient,the donor, the medical practitioner, and society, as it may result in serious conditions such as decreased renal function andgraft loss. In order to find an early solution to this problem, SymBio submitted a clinical trial notification for a global Phase II
study in patients infected with BK virus after receiving kidney transplant to the Pharmaceuticals and Medical Devices Agency(PMDA) of Japan in May 2022 and to the Therapeutic Goods Administration (TGA) of Australia in August 2022. The
investigational drug was administered to the first patient in Australia in August 2022. The trial was originally planned toconclude in 2025, but progress has been slower than expected due to delays in patient enrollment. SymBio announced achange to its clinical development plan in August 2023, stating that it will consider a protocol amendment.
The company has decided to prioritize two clinical trials: a Phase Ib clinical trial for cytomegalovirus infection following
hematopoietic stem cell transplantation and another Phase Ib clinical trial for brain tumors. Typically, it is easier toaccumulate cases in trials targeting larger markets.
BCV non-clinical studies: EB virus, multiple sclerosis, lymphoproliferative disorders
SymBio has been preparing for clinical development of brincidofovir for multiple sclerosis, a rare disease related to EB virus.
In August 2022, the company signed a collaboration agreement for the transfer of human materials with the National
Institute of Neurological Disorders and Stroke (NINDS) of the US National Institute of Health (NIH). In March 2023, SymBio

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

45

signed a cooperative research and development agreement (CRADA) with NINDS to obtain information necessary to
conduct future clinical trials.
CRADA: Refers to a contract on collaborative R&D between a US government organization and entities such as a privatesector company. The private-sector company may be able to obtain licensing of patent rights regarding inventions
developed under the CRADA. Because a company may receive patent rights from a project using government funds,
the barriers to being selected for a CRADA are significant (SymBio is the second Japanese company to be selected).

In April 2023, SymBio also signed a CRADA with the National Institute of Allergy and Infectious Diseases (NIAID), part of theNIH, to evaluate the efficacy of BCV in EB virus-related lymphoproliferative* disorders.
*Refers to a wide range of diseases related to the EB virus: Cancers such as T-cell lymphoma, Burkitt lymphoma,
Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, NK T-cell lymphoma, and post-transplant lymphoproliferative disease, Xlinked lymphoproliferative syndrome, and AIDS-related lymphoproliferative disease. (Source: Materials for company’s
18th ordinary general meeting of shareholders.)

BCV non-clinical study: polyomavirus
In November 2022, the company concluded a material transfer agreement (MTA) with US-based Penn State College ofMedicine, and initiated a non-clinical study evaluating the efficacy of BCV in a mouse model of polyomavirus infection.
BCV non-clinical joint research: herpes simplex virus, Alzheimer's type dementia
In December 2022, the company concluded a sponsored research agreement with US-based Tufts University, and began ajoint research study evaluating the efficacy of BCV in a herpes simplex virus infection model. In the future, the company islooking for applications to use BCV to treat Alzheimer's type dementia as a target treatment for HSV.
BCV non-clinical joint research: applications for hematological malignancies/oncology
In addition to antiviral activity, the company expects brincidofovir to have antitumor effects. Through joint research with the
National Cancer Centre Singapore and University of California San Francisco Brain Tumor Center, SymBio is investigating
new indications for the drug in oncology, including rare brain tumors and EB virus-positive lymphoma. In March 2022, thecompany commenced joint research with Brown University of the US to investigate the antitumor effects of brincidofovir on
glioblastoma (GBM) caused by cytomegalovirus (CMV) infection.
In December 2022, the results of collaborative research with the National Cancer Centre Singapore (NCCS) on thetherapeutic efficacy of BCV in the treatment of rapidly progressing NK/T-cell lymphoma were presented at the 64th
American Society of Hematology (ASH) Annual Meeting.
At the 17th International Conference on Malignant Lymphoma (ICML) in June 2023, research into a biomarker*(TLE1/transcription factor) that predicts the anti-tumor effect of BCV was presented.
*The use of biomarkers allows for the selection of patients who are likely to respond well to treatment, which increases
the probability of successful clinical trials.

Development potential for BCV in other areas
Joint research with the National Institute of Infectious Diseases has found BCV to have potent antiviral activity against viralhemorrhagic cystitis (VHC) after hematopoietic stem cell transplantation, a disease associated with adenovirus type B11, andepidemic keratoconjunctivitis, a disease associated with adenovirus type D54. Of these, epidemic keratoconjunctivitis in theophthalmic area is a non-core area. Herpes virus development in the dermatological space is also outside of the company's
core competency. Shared Research believes development of non-core areas is a low priority.
BCV development policy
SymBio aims to maximize the business value of BCV by examining the efficacy of the drug in dsDNA virus infections,
expanding target indications to include multiviral infections, and striving to meet the underserved medical needs for

SymBio Pharmaceuticals 4582
Research Coverage Report by Shared Research Inc. | https://sharedresearch.jp | Subscribe for FREE46

treatments of viral diseases and accompanying complications.
SymBio explained its BCV development policy to 2030 at the FY12/22 earnings results information briefing. In addition to
the core areas of hematological cancer/oncology, the company is entering the neurodegenerative diseases (NDD) space,such as multiple sclerosis and Alzheimer's type dementia. SymBio will not develop BCV independently forneurodegenerative diseases but looks to partner with a major pharmaceutical company capable of global development (seedetails in the Long-term outlook section, R&D image to 2030). The company expects to receive about JPY10bn incompensation for transferring rights to the joint development over five years (2025–2030).
SymBio aims for approval and commercialization of two or three indications for BCV by 2030. The indication with thehighest potential for approval is viral infection following hematopoietic stem cell and kidney transplantation, two areas ofclinical development prioritization.

Overseas development bases (SPU/SymBio Pharma USA)In August 2023, the company’s US-based wholly-owned subsidiary SymBio Pharma USA, Inc. appointed Dr. Stephane
Berthier as CEO and President to further reinforce its global development structure. SymBio Pharma USA plans to accelerate
global development of the antiviral drug brincidofovir.

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.

Topics: Drug Discovery AI
The company has been pursuing a lab-less and fab-less strategy, without owning any research institutes or manufacturing
sites. During its earnings announcement in August 2023, the company announced the establishment of the Institute of AI
Biosciences (IOAB). At this institute, the company has built its own AI drug discovery system and implemented the Global
Medical & Science Information collection system, a system on par with those of the world's most advanced research institutes,
into its proprietary platform.

Q1 FY12/23 results
Sales: JPY1.5bn (-33.3% YoY)
Operating profit: JPY51mn (-89.9% YoY)
Recurring profit: JPY48mn (-89.9% YoY)
Net income attributable to owners of the parent for the quarter: JPY4mn (-97.3% YoY)
In February 2022, SymBio obtained approval for a partial change to the marketing authorization for the ready-to-dilute (RTD)
intravenous formulation of TREAKISYM® 100mg/4ml, which was launched in January 2021, to add rapid infusion (RI)
administration. Compared to the freeze-dried (FD) formulation, the RTD formulation reduces the time required for thecomplicated dissolution process. RI administration further benefits both patients and healthcare providers by reducing theinfusion time from the 60 minutes required by the RTD formulation. In addition, the RI administration uses lesssaline solution and accordingly less salt (sodium chloride).
The switch from the FD to RTD formulation is almost complete. With over 80% of medical institutions administering the RI
formulation to patients as of end-March 2023, progress was made in the switch to the RI formulation. On the quality
assurance front, SymBio also has taken steps to ensure the stable supply of the RTD formulation of TREAKISYM®.
Sales decreased 33.3% YoY to JPY1.5bn. The decline was due to the following factors: 1) medical institutions were reluctant topurchase drugs due to price revisions; 2) the amount of drugs used per patient decreased during the COVID-19 pandemic;
and 3) the launch of generic drugs in June 2022 affected SymBio's product sales. In addition, there was a temporary sales
spike last year due to the switch from the FD formulation to the RTD formulation, which impacted this year's sales.
According to the company, the biggest factor in the steeper 33.1% YoY fall in Q1 versus its forecast of a 30.1% YoY decline
in sales in FY12/23 was a fallback from the temporary spike in sales the previous year. It explains that sales of JPY2.3bn(+63.1% YoY) in Q1 FY12/22 were significantly boosted by a temporary sales spike accompanying the switch to the RTD
formulation. It thinks the penetration of generic drugs will have an increasingly large impact from Q2 onward.

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

47

Gross profit totaled JPY1.2bn (-34.5% YoY) and the gross profit margin was 80.5% (-1.5pp YoY). SG&A expenses came to
JPY1.2bn (-14.2% YoY), including R&D expenses of JPY550mn (+10.8% YoY). As a result, operating profit was JPY51mn (-89.9%
from operating profit of JPY509mn in FY12/22).
GPM was 80.5% (-1.5pp YoY) and up 0.1pp from 80.4% in Q4 FY12/22.
SG&A expenses excluding R&D expenses were JPY642mn (-28.1% YoY). The company explained that at end-December
2022, the number of employees decreased by 19 YoY, resulting in a decline in personnel expenses.
April 2023 NHI drug price revisions
In the April 2023 drug price revisions, the new price for the intravenous formulation of TREAKISYM® 100mg/4ml was
JPY92,175, a cut of just 3.5% from the previous JPY95,515. TREAKISYM® had benefited from the price maintenanceincentive system for newly discovered drugs, but the impact of losing this incentive was minor (Shared Research previously
assumed a price cut of at least 10%).
Progress in Q1 versus full-year FY12/23 company forecast
Sales progress versus the full-year FY12/23 company forecast was 22.1%, versus 23.1% of full-year sales in Q1 FY12/22.
However, Shared Research understands that progress was in line with company expectations given that sales in FY12/22 got
a temporary boost with the switchover to the RTD formulation, and that in Q1 FY12/23, some customers were putting off
purchases ahead of the NHI drug price revisions.
The company booked operating profit of JPY51mn in Q1 FY12/23, versus a full-year forecast operating loss of JPY331mn.
One reason was that SG&A expenses were just 20.4% of the full-year budget of JPY5.9bn. Shared Research understands that
progress at the profit line was also in line with company expectations, as the company made progress in using up R&D
expenses in Q4 FY12/22.

Business progress
In Q1 FY12/23, progress in the company’s main businesses was as follows:
In March 2023, the company entered into a cooperative research and development agreement (CRADA) with the
National Institute of Neurological Disorders and Stroke (NINDS), part of the US National Institutes of Health (NIH), todevelop brincidofovir (BCV) as a treatment for multiple sclerosis. Since August 2022, the company and NINDS havebeen collaborating on evaluating the antiviral effects of BCV against the Epstein-Barr virus (EBV).
In April 2023, the company entered into a CRADA with the National Institute of Allergy and Infectious Diseases (NIAID),
part of the NIH, to evaluate the therapeutic effects of BCV in diseases caused by the EBV.

Establishment of an in-house sales organization
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®.
In conducting in-house sales, SymBio established a sales organization that can cultivate needs, provide information on thecompany products, and plan seminars. In addition to medical representatives, the company deployed hematology experts
with extensive knowledge of the field throughout Japan. Further, the company concluded basic agreements with Suzuken
Co., Ltd and Toho Pharmaceutical Co., Ltd for the procurement and sale of pharmaceuticals to build a nationwide distribution
network. The company has established two distribution centers, one in Eastern Japan and the other in Western Japan, undermanagement by S.D. Collabo Co., Ltd.

Anticancer agent SyB L-0501 (FD formulation)/SyB L-1701 (RTD formulation)/SyB L-1702(RI administration); generic name: bendamustine hydrochloride or bendamustinehydrochloride hydrate, product name: Treakisym®
In March 2021, SymBio obtained approval for the use of the FD formulation of TREAKISYM® in BR therapy to treat r/r DLBCLas an additional indication. In February 2022, the company secured approval for a partial amendment to the marketing
authorization for the ready-to-dilute (RTD) formulation of TREAKISYM® (in-licensed from US-based Eagle Pharmaceuticals,Inc.), enabling the use of RI administration for all approved indications of the RTD formulation.

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

48

SymBio will continue to explore new potential applications of TREAKISYM®, including via specified clinical research with
Saitama Medical University and joint research with Kyoto University.

Anticancer agent SyB L-1101 (IV)/SyB C-1101 (oral); generic name: rigosertib sodium
Onconova Therapeutics, Inc., the drug's licensor, announced in August 2020 that INSPIRE, the pivotal Phase III study inhigher-risk myelodysplastic syndromes (HR-MDS) patients comparing IV rigosertib to physicians' choice of treatment, did notmeet its primary endpoint. SymBio is in charge of clinical development in Japan and is collaborating with Onconova
regarding the future development of rigosertib.
For rigosertib and TREAKISYM®, the company is searching for new indications as well as new applications for the drugs usedin combination with each other or with other existing drugs, through joint research and the offering of academia-industry
collaborative courses with the University of Tokyo.

Antiviral drug SyB V-1901 (generic name: brincidofovir, hereafter BCV)In development of the intravenous and oral formulations of the antiviral drug brincidofovir (SyB V-1901; BCV IV and BCVOral), the company is conducting joint research with top research institutions specialized in each field in Japan and overseas
in light of the broad spectrum of the drug's effectiveness against dsDNA virus infections. It will consider conducting
additional global clinical trials based on the scientific findings of the research.
Broad potential of BCV and rights relative to Chimerix
Earlier clinical trials in the US and Europe conducted by US-based Chimerix Inc. have demonstrated that BCV Oral has
broad-spectrum antiviral effects against a variety of dsDNA viruses. BCV IV is expected to be effective and safe for theprevention and treatment of many dsDNA virus infections, including adenovirus (AdV) infections after hematopoietic stem
cell transplantation. In June 2021, Chimerix announced that the US FDA had granted BCV Oral approval for the treatment ofsmallpox.
In September 2022, Chimerix announced that it had completed procedures to transfer the rights to brincidofovir to
Emergent BioSolutions Inc. (headquarters: Maryland, US). The agreement, however, has no impact on the company's
exclusive rights to develop, manufacture, and sell brincidofovir globally for all indications except orthopoxvirus diseases
including smallpox and monkeypox.
BCV clinical development: disseminated AdV infections following hematopoietic stem cell transplantation
Based on a global advisory board review held in February 2020, the company has decided to prioritize the global
development of BCV IV primarily in Japan, the US, and Europe, targeting disseminated AdV infections occurring after
hematopoietic stem cell transplantation, a niche area with a high unmet medical need.
In March 2021, the company filed an IND application with the US Food and Drug Administration (FDA) to conduct a Phase II
clinical trial primarily in pediatric patients suffering from AdV infections (also including adults). This development program
was granted fast-track designation by the FDA in April 2021, and the investigational drug was administered to the first patientin August 2021. In January 2022, a clinical trial application (CTA) was submitted to the UK's Medicines and Healthcare
products Regulatory Agency (MHRA). Completion of the study is projected for Q2 FY12/23. As of end-March 2023,
cumulative patient enrollment came to 22.
BCV clinical development: BK virus infection following kidney transplantation
BK virus nephropathy after kidney transplantation is considered a disease with serious consequences for the recipient,the donor, the medical practitioner, and society, as it may result in serious conditions such as decreased renal function andgraft loss. In order to find an early solution to this problem, SymBio submitted a clinical trial notification for a global Phase II
study in patients infected with BK virus after receiving kidney transplant to the Pharmaceuticals and Medical Devices Agency(PMDA) of Japan in May 2022 and to the Therapeutic Goods Administration (TGA) of Australia in August 2022. The
investigational drug was administered to the first patient in Australia in August 2022.
BCV non-clinical studies: EB virus, multiple sclerosis, lymphoproliferative disorders
SymBio has been preparing for clinical development of brincidofovir for multiple sclerosis, a rare disease related to EB virus.
In August 2022, the company signed a collaboration agreement for the transfer of human materials with the National
Institute of Neurological Disorders and Stroke (NINDS) of the US National Institute of Health (NIH). In March 2023, SymBio

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

49

signed a cooperative research and development agreement (CRADA) with NINDS to obtain information necessary to
conduct future clinical trials.
CRADA: Refers to a contract on collaborative R&D between a US government organization and entities such as a privatesector company. The private-sector company may be able to obtain licensing of patent rights regarding inventions
developed under the CRADA. Because a company may receive patent rights from a project using government funds,
the barriers to being selected for a CRADA are significant.

In April 2023, SymBio also signed a CRADA with the National Institute of Allergy and Infectious Diseases (NIAID), part of theNIH, to evaluate the efficacy of BCV in EB virus-related lymphoproliferative* disorders.
*Refers to a wide range of diseases related to the EB virus: Cancers such as T-cell lymphoma, Burkitt lymphoma,
Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, NK T-cell lymphoma, and post-transplant lymphoproliferative disease, Xlinked lymphoproliferative syndrome, and AIDS-related lymphoproliferative disease. (Source: Materials for company’s
18th ordinary general meeting of shareholders.)

BCV non-clinical study: polyomavirus
In November 2022, the company concluded a material transfer agreement (MTA) with US-based Penn State College ofMedicine, and initiated a non-clinical study evaluating the efficacy of BCV in a mouse model of polyomavirus infection.
BCV non-clinical joint research: herpes simplex virus, Alzheimer's type dementia
In December 2022, the company concluded a sponsored research agreement with US-based Tufts University, and began ajoint research study evaluating the efficacy of BCV in a herpes simplex virus infection model. In the future, the company islooking for applications to use BCV to treat Alzheimer's type dementia as a target treatment for HSV.
BCV non-clinical joint research: applications for hematological malignancies/oncology
In addition to antiviral activity, the company expects brincidofovir to have antitumor effects. Through joint research with the
National Cancer Centre Singapore and University of California San Francisco Brain Tumor Center, SymBio is investigating
new indications for the drug in oncology, including rare brain tumors and EB virus-positive lymphoma. In March 2022, thecompany commenced joint research with Brown University of the US to investigate the antitumor effects of brincidofovir on
glioblastoma (GBM) caused by cytomegalovirus (CMV) infection.
In December 2022, the results of collaborative research with the National Cancer Centre Singapore (NCCS) on thetherapeutic efficacy of BCV in the treatment of rapidly progressing NK/T-cell lymphoma were presented at the 64th
American Society of Hematology (ASH) Annual Meeting.
Development potential for BCV in other areas
Joint research with the National Institute of Infectious Diseases has found BCV to have potent antiviral activity against viralhemorrhagic cystitis (VHC) after hematopoietic stem cell transplantation, a disease associated with adenovirus type B11, andepidemic keratoconjunctivitis, a disease associated with adenovirus type D54. Of these, epidemic keratoconjunctivitis in theophthalmic area is a non-core area. Herpes virus development in the dermatological space is also outside of the company's
core competency. Shared Research believes development of non-core areas is a low priority.
BCV development policy
SymBio aims to maximize the business value of BCV by examining the efficacy of the drug in dsDNA virus infections,
expanding target indications to include multiviral infections, and striving to meet the underserved medical needs fortreatments of viral diseases and accompanying complications.
SymBio explained its BCV development policy to 2030 at the FY12/22 earnings results information briefing. In addition to
the core areas of hematological cancer/oncology, the company is entering the neurodegenerative diseases (NDD) space,such as multiple sclerosis and Alzheimer's type dementia. SymBio will not develop BCV independently forneurodegenerative diseases but looks to partner with a major pharmaceutical company capable of global development (seedetails in the Long-term outlook section, R&D image to 2030). The company expects to receive about JPY10bn incompensation for transferring rights to the joint development over five years (2025–2030).

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

50

SymBio aims for approval and commercialization of two or three indications for BCV by 2030. The indication with thehighest potential for approval is viral infection following hematopoietic stem cell and kidney transplantation, two areas ofclinical development prioritization.

Overseas development bases (SPU/SymBio Pharma USA)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 in October 2021. In April 2022, SymBio Pharma USA
appointed Dr. Yanavich as President, Chief Operating Officer, and Chief Development Officer. SymBio Pharma USA plans toaccelerate global development of the antiviral drug brincidofovir.

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 FY12/22 results
Sales: JPY10.0bn (+21.2% YoY)
Operating profit: JPY2.0bn (+93.3%YoY)
Recurring profit: JPY2.0bn (+99.8% YoY)
Net income attributable to owners of the parent: JPY1.2bn (-42.0% YoY)
SymBio has applied the Accounting Standard for Revenue Recognition (ASBJ Statement No. 29) from Q1 FY12/22. Under
the previous accounting standard, the company recorded allowance for sales returns in the amount equivalent to gross profit.
However, in accordance with the new accounting standard regarding variable consideration, the company nolonger recognizes revenue at the time of sale and records refund liabilities as “other” under the current liabilities section of
the balance sheet.
As a result of adopting the Accounting Standard for Revenue Recognition, full-year sales, operating profit, and recurring
profit each increased by JPY63mn.
In February 2022, SymBio obtained approval for a partial change to the marketing authorization for the ready-to-dilute (RTD)
intravenous formulation of TREAKISYM® 100mg/4ml, which was launched in January 2021, to add rapid infusion (RI)
administration. Compared to the freeze-dried (FD) formulation, the RTD formulation reduces the time required for thecomplicated dissolution process. RI administration further benefits both patients and healthcare providers by reducing theinfusion time from the 60 minutes required by the RTD formulation. In addition, the RI administration uses lesssaline solution and accordingly less salt (sodium chloride).
The RI formulation reduces burden on patients and healthcare providers by shortening the infusion time compared withthat required for the FD and RTD formulations. Further, RI formulation is diluted using only one-fifth of the amount ofsaline solution required for the RTD formulation, reducing the amount of salt used and hence rendering it appropriate
for elderly patients.

The switch from the FD to RTD formulation is almost complete. With over 80% of medical institutions administering the RI
formulation to patients as of end-December 2022, progress was made in the switch to the RI formulation. On the quality
assurance front, SymBio also has taken steps to ensure the stable supply of the RTD formulation of TREAKISYM®.
Despite sales activities being constrained by factors including delays in treatment and restrictions on medical facility visits
due to the COVID-19 pandemic, sales rose 21.2% YoY to JPY10.0bn. The increase was largely due to the approval in March
2021 of TREAKISYM® for the additional indication of combination use in bendamustine-rituximab (BR) therapy and inpolatuzumab vedotin plus bendamustine-rituximab (Pola-BR) therapy to treat recurrent/refractory diffuse large B-cell
lymphoma (r/r DLBCL). The May 2021 NHI price listing of Chugai Pharmaceutical’s antibody drug conjugate polatuzumab
vedotin contributed to an increase in sales for the indication of r/r DLBCL.
Gross profit grew YoY on the back of higher sales and GPM. The increase in gross profit exceeded the rise in SG&A
expenses, leading to YoY growth in all profit categories from the operating profit line down.

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

51

Gross profit was JPY7.6bn (+31.0% YoY), and GPM was 75.9% (+5.7pp YoY). The rise in GPM was mainly attributable to theabovementioned switch to the liquid (RTD and RI) formulations of Treakisym®.
GPM rises due to switching from the lyophilized formulation to the liquid (RTD and RI) formulations of Treakisym®: The
company sourced the lyophilized formulation of Treakisym® from Astellas Deutschland, but the liquid formulations aresupplied by Eagle Pharmaceuticals. The company says that the GPM on liquid formulations of Treakisym® is higher thanthe GPM on the lyophilized formulation.

SG&A expenses were JPY5.6bn (+17.8% YoY).
R&D expenses rose 47.2% YoY to JPY2.6bn. This included expenses for conducting clinical trials for the intravenous
formulation of brincidofovir.
Excluding R&D expenses, SG&A expenses increased 1.1% YoY to JPY3.1bn.
As a result of the above, operating profit expanded 93.3% YoY, from JPY1.0bn to JPY2.0bn.

Q4 FY12/22 (October-December 2022) results
In Q4 FY12/22, sales were JPY2.7bn (-1.9% YoY), gross profit was JPY2.1bn (+21.6% YoY), GPM was 80.4% (+15.5pp YoY), andoperating profit was JPY375mn (-36.7% YoY).
Factors that contributed to sales growth were the March 2021 approval of bendamustine-rituximab (BR) therapy andbendamustine-rituximab plus genetically engineered polatuzumab vedotin (Pola-BR) therapy for treatment of r/r DLBCL andthe May 2021 NHI price listing of Chugai's polatuzumab vedotin (genetically engineered), which boosted sales for the r/r
DLBCL indication. However, Q4 sales declined 1.9% YoY due to market share losses to generic competition.
The increase in GPM was driven by progress in the switch to the RTD and RI formulations of Treakisym®. Although themilestone payment* booked in Q3 was not repeated, GPM did not recover to the 82.3% level of the first half. The company
cited a change in the royalty rate as a factor.
*In Q3 FY12/22, the company booked as cost of sales JPY550mn in a sales milestone payment paid to Eagle
Pharmaceuticals, triggered by cumulative sales of the Treakisym® RTD formulation reaching JPY11.0bn. This was a onetime payment, and was the last such milestone payment the company expects to pay.

Sales increased JPY171mn QoQ while gross profit was up JPY677mn, GPM increased 21.7pp, and operating profit rose
JPY158mn. This was largely attributable to the JPY550mn milestone payment in Q3 and higher SG&A expenses in Q4.

Full-year FY12/22 results versus company forecasts
The progress rate versus full-year FY12/22 company forecasts was 100.1% for sales (JPY5mn above forecast) and 98.2% foroperating profit (JPY36mn below forecast).
When SymBio reported Q3 results (November 2022), it raised its guidance for all profit categories below the operating line,
citing lower SG&A expenses. Overall, FY12/22 results were in line with the company's guidance.

Overview of business progress
FY12/22 progress in main businesses was as follows:
In December 2022, the company concluded a sponsored research agreement with US-based Tufts University, and began ajoint research study evaluating the efficacy of BCV in treating herpes simplex virus (HSV) infection. In this joint research,
the company will conduct a nonclinical study evaluating the efficacy of BCV in a herpes simplex virus infection modelwith a three-dimensional brain model established by Tufts University.
In December 2022, SymBio and Eagle initiated a lawsuit against Pfizer Japan and Towa Pharmaceutical Co., Ltd (TSE
Prime: 4553) seeking injunction against the manufacture and sale of generic drugs arising from patent infringement as

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

52

well as compensation for damages.
In December 2022, SymBio commenced a global Phase II study of BCV for kidney transplant recipients with BK virus
infection in Australia. This is the second indication being developed for BCV, following a global Phase II study for patients
infected with adenovirus after hematopoietic stem cell transplantation.
In December 2022, the results of collaborative research with the National Cancer Centre Singapore (NCCS) on thetherapeutic efficacy of BCV in the treatment of rapidly progressing NK/T-cell lymphoma were presented at the 64th
American Society of Hematology (ASH) Annual Meeting.
In November 2022, the company concluded a material transfer agreement (MTA) with US-based Penn State College ofMedicine, and initiated a non-clinical study evaluating the efficacy of BCV in a mouse model of polyomavirus infection.
In August 2022, SymBio concluded a contract to supply the US National Institute of Neurological Disorders and Stroke(NINDS; a part of the National Institutes of Health) with brincidofovir intravenous injections for use in joint research toevaluate antiviral activity against the Epstein-Barr (EB) virus. Under the agreement, the company will supply BCV so that
NINDS can conduct non-clinical studies to evaluate the potential effects of BCV on diseases caused by EB virus.

Ｂ

In June 2022, Symbio announced the submission of a clinical trial notification to the PMDA for a global Phase II trial of
BCV IV as a treatment for BK virus infection in kidney transplant recipients. The company aims to evaluate the safety,
tolerability, and efficacy of BCV in kidney transplant recipients with BK virus infections. In August 2022, the company
submitted another clinical trial notification to the Therapeutic Goods Administration (TGA) of the Australian Department
of Health.
In May 2022, Chimerix agreed to transfer its rights to anti-viral drug brincidofovir to Emergent BioSolutions Inc. In
September 2019, SymBio acquired from Chimerix exclusive worldwide rights to develop, manufacture, and market
brincidofovir for all indications except for prevention and treatment of smallpox. The transfer of rights to Emergent
BioSolutions will have no impact on the company's rights to brincidofovir. Procedures for the transfer were completed in
September 2022.
In May 2022, the company announced the issuance of new shares and the 58th series of share subscription rights througha third-party allotment. Net proceeds to be raised from the issuance are JPY2.2bn, and the dilution ratio is 7.80%. The
new shares and share subscription rights will be allotted to CVI Investments, Inc. operated by Heights CapitalManagement, Inc. According to the company, Heights Capital Management is a member of Susquehanna International
Group, a major global financial conglomerate, and has a track record of investing in over 100 biotech companies. The
company intends to allocate the funds raised to development of brincidofovir.
In February 2022, SymBio received approval for its for Treakisym® rapid infusion (RI) administration.
In February 2022, the Ministry of Health, Labour and Welfare approved manufacture and marketing of generic drugs ofthe company's Treakisym® intravenous infusion (RTD formulation). As this could possibly infringe the company's exclusive
rights to develop and commercialize the patent-protected product in Japan, the company consulted with the licensor
Eagle Pharmaceuticals, and notified the four companies that had obtained the approval for generic drugs of thepossibility of patent infringement, demanding they take appropriate actions. Among the four companies, only Towa
Pharmaceutical had its drug listed in the NHI drug price list, and then Pfizer Japan also had a version price-listed in
December 2022. SymBio initiated a patent infringement lawsuit against Towa Pharmaceutical and Pfizer in December
2022 seeking an injunction to halt the manufacture and sale of generic Treakisym.
Advantages of Symbio's Treakisym® Intravenous Infusion over generic competition have included: 1) availability of RI
formulation, 2) approved for more indications, and 3) established safety profile. However, additional approvals for thegeneric versions is gradually eroding these advantages.
RI formulation available: The company obtained approval for the rapid infusion (RI) administration ofTreakisym®, which reduces the administration time to only 10 minutes. SymBio has licensed exclusive rights in Japanto the RI formulation from patent holder Eagle Pharmaceuticals, so Shared Research's understanding was that genericcompanies could not use this administration method. However, in November 2022, generic drugs also received
approval for the RI administration, which can reduce the administration time to 10 minutes, diminishing the advantage
of Treakisym®.

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

53

Approved for more indications than generic competition: Approved indications for SymBio's Treakisym® include usewith Pola-BR therapy for relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) and chronic lymphocytic
leukemia. Generic drugs were approved for r/r DLBCL in June 2022, thereby further eroding advantages of theoriginal drug.
Established safety profile: A clinical trial with 38 Japanese patients was conducted evaluating SymBio's Treakisym®.
The data from this trial, coupled with safety data from US clinical trials conducted by Eagle Pharmaceuticals, were usedin the approval filing. In contrast, the generic versions have only been proven safe through physico-chemical
equivalence.
In September 2017, the company entered into a license agreement with Eagle Pharmaceuticals, Inc., based on which
Eagle granted the company exclusive rights to develop and commercialize bendamustine liquid formulation
BENDEKA® (RTD and RI formulations of Treakisym®) in Japan. According to the company, some companies in the US
have attempted to launch generic versions of Treakisym® liquid formulations, but they all infringed on Eagle’s patents,
and Eagle prevailed in lawsuits. In February 2022, four companies obtained marketing approval for generic versions ofTreakisym®, and in June 2022, only one (Towa Pharmaceutical) had its drug listed in the NHI drug price list andcommercialized it. Then in December 2022, Pfizer Japan also marketed a generic version. In December 2022, Symbio
and Eagle jointly filed a patent infringement lawsuit against Pfizer and Towa Pharmaceutical seeking an injunction to halt
the manufacture and sales of their generic versions and compensation for damages, but a final ruling will likely taketime.

Establishment of an in-house sales organization
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®.
In conducting in-house sales, SymBio established a sales organization that can cultivate needs, provide information on thecompany products, and plan seminars. In addition to medical representatives, the company deployed hematology experts
with extensive knowledge of the field throughout Japan. Further, the company concluded basic agreements with Suzuken
Co., Ltd and Toho Pharmaceutical Co., Ltd for the procurement and sale of pharmaceuticals to build a nationwide distribution
network. The company has established two distribution centers, one in Eastern Japan and the other in Western Japan, undermanagement by S.D. Collabo Co., Ltd.

Anticancer agent SyB L-0501 (FD formulation)/SyB L-1701 (RTD formulation)/SyB L-1702(RI administration); generic name: bendamustine hydrochloride or bendamustinehydrochloride hydrate, product name: Treakisym®
In March 2021, SymBio obtained approval for the use of the FD formulation of TREAKISYM® in BR therapy to treat r/r DLBCLas an additional indication. In January 2021, the company commenced sales of the ready-to-dilute (or RTD) formulation ofTreakysym® in-licensed from US-based Eagle Pharmaceuticals, Inc., having obtained marketing approval in September 2020.
In April 2021, the company obtained approval for a partial change to the marketing approval of the RTD formulation for its
use in BR and Pola-BR therapy for the treatment of r/r DLBCL. For the RI administration, the company completed clinicalstudies on safety and filed a partial change application in May 2021. This application was approved in February 2022,
enabling the use of RI administration for all approved indications of the RTD formulation.
SymBio will continue to explore new potential applications of TREAKISYM®, including via specified clinical research with
Saitama Medical University and joint research with Kyoto University.

Anticancer agent SyB L-1101 (IV)/SyB C-1101 (oral); generic name: rigosertib sodium
Onconova Therapeutics, Inc., the drug's licensor, announced in August 2020 that INSPIRE, the pivotal Phase III study inhigher-risk myelodysplastic syndromes (HR-MDS) patients comparing IV rigosertib to physicians' choice of treatment, did notmeet its primary endpoint. SymBio is in charge of clinical development in Japan and is collaborating with Onconova
regarding the future development of rigosertib.
For rigosertib and TREAKISYM®, the company is searching for new indications as well as new applications for the drugs usedin combination with each other or with other existing drugs, through joint research and the offering of academia-industry
collaborative courses with the University of Tokyo.

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

54

Antiviral drug SyB V-1901 (generic name: brincidofovir, hereafter BCV)In development of the intravenous and oral formulations of the antiviral drug brincidofovir (SyB V-1901; BCV IV and BCVOral), the company is conducting joint research with top research institutions specialized in each field in Japan and overseas
in light of the broad spectrum of the drug's effectiveness against dsDNA virus infections. It will consider conducting
additional global clinical trials based on the scientific findings of the research.
Broad potential of BCV and rights relative to Chimerix
Earlier clinical trials in the US and Europe conducted by US-based Chimerix Inc. have demonstrated that BCV Oral has
broad-spectrum antiviral effects against a variety of dsDNA viruses. BCV IV is expected to be effective and safe for theprevention and treatment of many dsDNA virus infections, including adenovirus (AdV) infections after hematopoietic stem
cell transplantation. In June 2021, Chimerix announced that the US FDA had granted BCV Oral approval for the treatment ofsmallpox.
In September 2022, Chimerix announced that it had completed procedures to transfer the rights to brincidofovir to
Emergent BioSolutions Inc. (headquarters: Maryland, US). The agreement, however, has no impact on the company's
exclusive rights to develop, manufacture, and sell brincidofovir globally for all indications except orthopoxvirus diseases
including smallpox and monkeypox.
BCV clinical development: disseminated AdV infections following hematopoietic stem cell transplantation
Based on a global advisory board review held in February 2020, the company has decided to prioritize the global
development of BCV IV primarily in Japan, the US, and Europe, targeting disseminated AdV infections occurring after
hematopoietic stem cell transplantation, a niche area with a high unmet medical need.
In March 2021, the company filed an IND application with the US Food and Drug Administration (FDA) to conduct a Phase II
clinical trial primarily in pediatric patients suffering from AdV infections (also including adults). This development program
was granted fast-track designation by the FDA in April 2021, and the investigational drug was administered to the first patientin August 2021. In January 2022, a clinical trial application (CTA) was submitted to the UK's Medicines and Healthcare
products Regulatory Agency (MHRA). Completion of the study is projected for Q2 FY12/23. As of end-December 2022,
cumulative patient enrollment came to 20.
BCV clinical development: BK virus infection following kidney transplantation
BK virus nephropathy after kidney transplantation is considered a disease with serious consequences for the recipient,the donor, the medical practitioner, and society, as it may result in serious conditions such as decreased renal function andgraft loss. In order to find an early solution to this problem, SymBio submitted a clinical trial notification for a global Phase II
study in patients infected with BK virus after receiving kidney transplant to the Pharmaceuticals and Medical Devices Agency(PMDA) of Japan in May 2022 and to the Therapeutic Goods Administration (TGA) of Australia in August 2022. The
investigational drug was administered to the first patient in Australia in August 2022. The company is also preparing toconduct clinical trials in South Korea.
BCV non-clinical studies: EB virus, multiple sclerosis
SymBio has been preparing for clinical development of brincidofovir for multiple sclerosis, a rare disease related to EB virus.
In August 2022, the company signed a collaboration agreement for the transfer of human materials with the National
Institute of Neurological Disorders and Stroke (NINDS) of the US National Institute of Health (NIH).
BCV non-clinical study: polyomavirus
In November 2022, the company concluded a material transfer agreement (MTA) with US-based Penn State College ofMedicine, and initiated a non-clinical study evaluating the efficacy of BCV in a mouse model of polyomavirus infection.
BCV non-clinical joint research: herpes simplex virus, Alzheimer's type dementia
In December 2022, the company concluded a sponsored research agreement with US-based Tufts University, and began ajoint research study evaluating the efficacy of BCV in a herpes simplex virus infection model. In the future, the company islooking for applications to use BCV to treat Alzheimer's type dementia as a target treatment for HSV.
BCV non-clinical joint research: applications for hematological malignancies/oncology
In addition to antiviral activity, the company expects brincidofovir to have antitumor effects. Through joint research with the
National Cancer Centre Singapore and University of California San Francisco Brain Tumor Center, SymBio is investigating
SymBio Pharmaceuticals 4582
Research Coverage Report by Shared Research Inc. | https://sharedresearch.jp | Subscribe for FREE

55

new indications for the drug in oncology, including rare brain tumors and EB virus-positive lymphoma. In March 2022, thecompany commenced joint research with Brown University of the US to investigate the antitumor effects of brincidofovir on
glioblastoma (GBM) caused by cytomegalovirus (CMV) infection.
In December 2022, the results of collaborative research with the National Cancer Centre Singapore (NCCS) on thetherapeutic efficacy of BCV in the treatment of rapidly progressing NK/T-cell lymphoma were presented at the 64th
American Society of Hematology (ASH) Annual Meeting.
Development potential for BCV in other areas
Joint research with the National Institute of Infectious Diseases has found BCV to have potent antiviral activity against viralhemorrhagic cystitis (VHC) after hematopoietic stem cell transplantation, a disease associated with adenovirus type B11, andepidemic keratoconjunctivitis, a disease associated with adenovirus type D54. Of these, epidemic keratoconjunctivitis in theophthalmic area is a non-core area. Herpes virus development in the dermatological space is also outside of the company's
core competency. Shared Research believes development of non-core areas is a low priority.
BCV development policy
SymBio aims to maximize the business value of BCV by examining the efficacy of the drug in dsDNA virus infections,
expanding target indications to include multiviral infections, and striving to meet the underserved medical needs fortreatments of viral diseases and accompanying complications.
SymBio explained its BCV development policy to 2030 at the FY12/22 earnings results information briefing. In addition to
the core areas of hematological cancer/oncology, the company is entering the neurodegenerative diseases (NDD) space,such as multiple sclerosis and Alzheimer's type dementia. SymBio will not develop BCV independently forneurodegenerative diseases but looks to partner with a major pharmaceutical company capable of global development (seedetails in the Long-term outlook section, R&D image to 2030). The company expects to receive about JPY10bn incompensation for transferring rights to the joint development over five years (2025–2030).
SymBio aims for approval and commercialization of two or three indications for BCV by 2030. The indication with thehighest potential for approval is viral infection following hematopoietic stem cell and kidney transplantation, two areas ofclinical development prioritization.

Overseas development bases (SPU/SymBio Pharma USA)
With a view to accelerating global development of the antiviral drug brincidofovir, 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 in October 2021. In April 2022, SymBio Pharma USA appointed Dr. Yanavich as President, Chief
Operating Officer, and Chief Development Officer.

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.

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

56

Income statement
Income statement

FY12/14

FY12/15

FY12/16

FY12/17

FY12/18

FY12/19

FY12/20

FY12/21

FY12/22

FY12/23(JPYmn)ParentParentParentParentParentParentParentParent

Cons.

Cons.

Sales

1,955

1,933

2,368

3,444

3,836

2,838

2,987

8,257

10,008

5,590

YoY

27.6%

-1.1%

22.5%

45.4%

11.4%

-26.0%

5.3%

176.4%

21.2%-44.1%

CoGS

1,428

1,350

1,464

2,413

2,663

1,973

2,120

2,452

2,408

1,179

527

583

904

1,031

1,173

865

867

5,800

7,600

4,411

Gross profit
Gross profit margin

26.9%

30.2%

38.2%

29.9%

30.6%

30.5%

29.0%

70.2%

75.9%

78.9%

SG&A expenses

1,830

3,135

3,031

4,978

3,829

5,166

5,373

4,784

5,636

5,223

SG&A ratio

93.6%

162.1%

128.0%

144.5%

99.8%

182.1%

179.9%

57.9%

56.3%

93.4%

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

1,016

1,964

-812

YoY

-

-

-

-

-

-

-

-

93.3%

-

Operating profit margin

-

-

-

-

-

-

-

12.3%

19.6%

-

215

17

7

5

2

4

3

17

139

133

Non-operating income
Non-operating expenses

22

96

196

34

95

79

112

32

103

57

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

1,001

2,000

-736

YoY

-

-

-

-

-

-

-

-

99.8%

-

Recurring profit margin

-

-

-

-

-

-

-

12.1%

20.0%

-

Extraordinary gains

2

3

9

17

10

4

529

0

106

101

Extraordinary losses

3

1

1

15

10

-

-

-

-

561

Income taxes

4

4

4

4

4

4

4

-1,031

927

767

Implied tax rate

-

-

-

-

-

-

-

-

-

-

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

2,032

1,179

-1,963

YoY

-

-

-

-

-

-

-

-

-42.0%-Net margin

-

-

-

-

-

-

-

24.6%

11.8%

-

Recurring profit

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. Income
taxes of -JPY1.0bn in FY12/21 were due to the booking of JPY1.3bn in deferred tax assets.

Historical forecast accuracy
Results vs. initial forecast

FY12/13

FY12/14

FY12/15

FY12/16

FY12/17

FY12/18

FY12/19

FY12/20

FY12/21(JPYmn)ParentParentParentParentParentParentParentParentParentCons.

Sales (initial forecast)

1,927

1,785

1,785

2,339

2,903

4,201

4,465

3,404

9,151

10,992

Sales (Results)

1,532

1,955

1,933

2,368

3,444

3,836

2,838

2,987

8,257

10,008Results vs. initial forecast-20.5%

9.5%

8.3%

1.2%

18.6%

-8.7%

-36.4%-12.2%

-9.8%

-8.9%

Operating profit (initial forecast)-1,889-1,654-1,654-2,778-3,238-2,981-3,587-5,0901,361

Operating profit (Results)-1,681-1,303-2,552-2,127-3,947-2,656-4,302-4,506

1,016

1,964

-

-

-

-

-

-

-

-

-25.3%

10.9%

Recurring profit (initial forecast)-1,922-1,650-1,650-2,811-3,303-3,044-3,612-5,134

1,350

1,750

Recurring profit (Results)-1,601-1,110-2,630-2,317-3,977-2,749-4,377-4,616

1,001

2,000

Results vs. initial forecast

-

-

-

-

-

-

-

-

-25.8%

14.3%

Net income (initial forecast)-1,926-1,654-1,654-2,815-3,306-3,056-3,612-4,803

1,149

1,480

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

2,032

1,179

-

-

-

-

-

-

-

-

76.9%

-20.3%

Results vs. initial forecast

Results vs. initial forecast

FY12/22

1,770

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.jp | Subscribe for FREE

57

Balance sheet
Balance sheet (JPYmn)

FY12/14

FY12/15

FY12/16

FY12/17

FY12/18

FY12/19

FY12/20

FY12/21

FY12/22

FY12/23

ParentParentParentParentParentParentParentParent

Cons.

Cons.

Cash and deposits

5,692

4,261

5,719

2,947

4,821

3,911

3,849

3,860

6,283

6,517

Marketable securities

899

-

-

-

-

-

-

-

-

-

Accounts receivable

273

301

487

490

412

549

407

2,148

2,085

913

AssetsInventories

245

133

273

363

534

1

945

386

469

232

Other current assets

181

131

205

237

271

427

615

355

476

420

Total current assets

7,290

4,827

6,685

4,037

6,038

4,887

5,815

6,748

9,313

8,083

Buildings (net)

22

22

31

28

37

47

43

45

41

-

Tools, furniture, and fixtures (net)

27

31

43

18

20

19

34

39

28

-

Total tangible assets

49

53

75

47

57

75

77

84

69

-

Investments and other assets

49

53

77

100

73

70

81

1,362

829

88

Software

62

51

42

296

255

222

-

66

51

95

Other

4

1

-

3

20

146

6

4

-

Total intangible assets

66

52

42

69

71

241

302

259

222

-

Total fixed assets

164

158

193

216

201

386

459

1,705

1,121

88

7,454

4,984

6,878

4,252

6,239

5,274

6,275

8,453

10,4338,170

Accounts payable

306

320

322

604

726

121

665

70

47

-

Unearned revenue

-

-

-

-

-

-

193

-

-

-

143

184

553

331

504

639

646

515

1,164

854

Total assets-

Liabilities

Accounts payable–other
Short-term debt

-

-

-

-

-

-

-

-

-

-

Other

39

47

68

76

107

112

111

933

697

103

Total current liabilities

488

551

942

1,011

1,336

872

1,615

1,518

1,924

957

-

-

-

-

-

-

-

-

-

-

450

-

-

-

-

-

-

Long-term debt
Corporate bonds
Other fixed liabilities

2

2

1

1

1

2

2

189

20

4

Total fixed liabilities

2

2

451

1

1

2

2

189

3

4

Total interest-bearing debt

-

-

-

-

-

-

-

-

-

-

490

552

1,394

1,013

1,338

874

1,617

1,707

1,927

960

Total liabilities
Net assets
Capital stock

8,331

8,331

9,948

10,762

12,973

14,871

17,045

17,15817,548

17,953

Capital surplus

8,301

8,301

9,918

10,732

12,943

14,841

17,01917,133

17,523

17,928Retained earnings-9,868-12,500-14,813-18,791-21,543-25,919-30,010-27,978-26,889-28,852

Treasury stock
Share subscription rights
Net assets
Working capital
Total interest-bearing debt
Net debt

-0

-0

-0

-0

-0

-15

-18

-86

-88

-89

200

300

431

537

530

621

620

519

412

277

6,964

4,432

5,485

3,239

4,902

4,400

4,657

6,746

8,506

7,210

212

114

439

249

220

429

686

2,464

2,508

1,145

-

-

-

-

-

-

-

-

-

-

-5,692-4,261-5,719-2,947-4,821-3,911-3,849-3,860-6,283-6,517

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 FY12/21, 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, there is a deficit in retained
earnings as the company continued to post losses.

Cash flow statement
Cash flow statement

FY12/14

FY12/15

FY12/16

FY12/17

FY12/18

FY12/19

FY12/20

FY12/21

FY12/22

FY12/23(JPYmn)ParentParentParentParentParentParentParentParent

Cons.

Cons.

Cash flows from operating activities (1)-1,266-2,272-1,960-3,817-2,325-4,351-4,122

140

1,614

-195

Cash flows from investing activities (2)

314

1,489

-44

-78

-26

-216

-160

-71

-47

-377

Free cash flow (1+2)

-952

-783

-2,004-3,894-2,351-4,567-4,283

69

1,567

-571

Cash flows from financing activities

544

-3

3,658

1,164

4,272

3,740

4,222

-72

628

680

Depreciation and good will amortization
(A)

13

24

26

30

35

38

64

94

98

96

-109

-24

-28

-57

-40

-217

-149

-64

-52

-233
-1,363

Capital expenditures (B)Change in working capital (C)

86

-98

325

-190

-29

209

257

1,777

44

Simple FCF (NI + A + B - C)

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

285

1,182

-737

Cash and cash equivalents (year-end)

5,092

4,261

5,719

2,947

4,821

3,911

3,849

3,860

6,283

6,517

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.jp | Subscribe for FREE

58

Cash flows from operating activities
Cash flows from operating activities almost matches the company’s net income before income tax.
In FY12/21, accounts receivable increased as the company started in-house sales, giving rise to a gap between cash flows
from operating activities and net income before income 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 historically often reported inflows from financing activities.

Main sources of funding
Date

Change inshares issued

Total sharesissuedChange in capitalstock and capitalsurplus (JPYmn)

Capital stock andcapital surplus(JPYmn)Feb. 2011
Feb. 2011

11,032
17,368

122,769
140,137

772
1,216

8,164
9,380

Oct. 2011

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

1,726,800

26,437,681

3,796

29,711

Exercise of stock options

Jan. to Dec. 2020

11,765,275

38,202,956

4,349

34,064

Exercise of stock options

Paid-in private placement
Paid-in private placement
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.

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

59

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.; TSE Prime: 4568), Medical & Biological Laboratories Co., Ltd., EPS Corporation, and SBI Holdings, Inc. (TSE Prime:8473). The company used the cash raised to in-license its first drug candidate, bendamustine hydrochloride, from Astellas
Pharma GmbH in December 2005 with the exclusive right to develop and commercialize the drug in Japan.
After the global financial crisis of September 2008, the company experienced a shortage of capital as Treakisym® 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.
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 ofTreakisym®, 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.

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

60

March 2005

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).

December 2005
March 2006

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

March 2007

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).

August 2008
March 2009

License Agreement finalized with Eisai Co., Ltd. for co-development and commercialization rights of SyB L-0501 (bendamustine) inSouth Korea and Singapore.
SymBio Pharmaceuticals and Eisai launch SYMBENDA® (bendamustine) in Singapore for the treatment of Low-grade NonHodgkin’s Lymphoma and Chronic Lymphocytic Leukemia.

May 2009
September 2010
October 2010

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

December 2010

Launched Treakisym® in Japan.
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).

July 2011

Launched Symbenda® (bendamustine hydrochloride) in South Korea for the treatment of Chronic Lymphocytic Leukemia andmultiple myeloma.
Listed on Osaka Securities Exchange JASDAQ Growth Market.

October 2011
October 2011

Launched Innomustine® (bendamustine hydrochloride) in Taiwan for the treatment of Low-grade Non-Hodgkin’s Lymphoma andChronic Lymphocytic Leukemia.

February 2012
August 2016

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®

December 2016

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.

September 2017

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
March 2021

Launched Treakisym® liquid formulation (RTD)
Obtained approval for use of Treakisym® in bendamustine-rituximab combination therapy to treat r/r DLBCL

February 2022

Received approval for Treakisym® rapid infusion (RI) administration

September 2019

Major shareholders
Shares held

Top shareholders

Shareholding ratio(shares)

Fuminori Yoshida

1,109,700

2.8%

ML PRO SEGREGATION ACCOUNT

1,001,000

2.5%

Sukenori Ito

430,000

1.1%

Daisuke Gomi

300,000

0.8%

Matsui Securities Co., Ltd.

250,200

0.6%

SMBC Nikko Securities Inc.

221,700

0.6%

Toshitaka Kashiwabara

220,025

0.6%

Nomura Securities Co., Ltd.

178,600

0.5%

Daiwa Securities Co. Ltd.

155,250

0.4%

JPMorgan Securities Japan Co., Ltd.

136,193

0.3%

4,002,668

10.1%

Total

Source: Shared Research based on company data
As of December 31, 2022
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 122 employees as of December 31, 2022.
Number of employees
Number of employees
ChangeFY12/13

FY12/14

FY12/15

FY12/16

FY12/17

FY12/18

FY12/19

FY12/20

FY12/21

FY12/22

ParentParentParentParentParentParentParentParentParent

Cons.

72

69

74

77

78

90

107

127

141

122

-4

-3

5

3

1

12

17

20

14

-19

Source: Shared Research based on company data

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

61

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 researchPreclinical test

2-3 years
3-5 years

Creation of new substances and decision on candidates for drugs
Confirmation of efficacy and safety through experiments on animals

Clinical trials

3-7 years

Phase I: Confirmation of safety and pharmacokinetics with a small number of healthy people
Phase II: Confirmation of efficacy and safety with a small number of patients

Application and approval

1-2 years

Phase III: Confirmation of efficacy and safety with many patients in comparison to existing drugs
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%, and 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
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.

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

62

Medical Representative (MR)A medical information specialist is responsible for providing, collecting, and transmitting information on the quality, efficacy,
safety, and other aspects of pharmaceuticals by visiting medical institutions and holding discussions with healthcare
professionals. The specialist is an expert on the company's pharmaceutical products.

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

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

63

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).

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.

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

64

News and topics
Announcement of results from Phase II clinical trial of BCV for
AdV infection
2023-11-06

SymBio Pharmaceuticals Limited announced results from a Phase II clinical trial of brincidofovir (BCV) for adenovirus (AdV)
infection.
The results of a Phase IIa clinical trial of BCV in patients with AdV infection will be presented at the 65th American Society of
Hematology Annual Meeting and Exposition scheduled to be held in San Diego, US, in December 2023.
In this study, 27 immunocompromised patients with AdV infection received intravenous (IV) BCV twice-weekly. In the group
receiving 0.4mg/kg IV BCV twice-weekly (Cohort 3), AdV clearance was confirmed in 100% of patients, and 90% of thesepatients achieved viral clearance within four weeks of treatment. No serious adverse events were observed.
Based on the data from this trial, the company plans to consider a Phase III trial for BCV.

US licensor Onconova releases rigosertib data for squamous cell
carcinoma2023-10-16

SymBio Pharmaceuticals Ltd. has announced that Onconova Therapeutics, Inc., the US licensor of the anticancer drug
rigosertib, has revealed research findings on this drug.
Onconova presented the research data on rigosertib for the treatment of recessive dystrophic epidermolysis bullosa at theEuropean Academy of Dermatology and Venereology Congress held in Berlin, Germany, on October 12, 2023.

Announcement of research results on multiple sclerosis
treatment with BCV
2023-10-12

SymBio Pharmaceuticals Limited announced the results of the collaborative research on the use of brincidofovir (BCV) for
the treatment of multiple sclerosis.
The company has been collaborating with the National Institute of Neurological Disorders and Stroke (NINDS), a part of the
National Institutes of Health (NIH) in the US, on research into the treatment of multiple sclerosis. The following results were
presented at the 9th Joint ECTRIMS-ACTRIMS Meeting in Milan, Italy.
In Epstein-Barr virus (EBV)-immortalized lymphoblastoid cell lines (EBV-positive B-cell lines) derived from both
multiple sclerosis patients and healthy individuals, BCV inhibited viral replication.
In EBV-negative B-cell lines used as controls, no effects of BCV, including growth suppression, were observed.
These data suggest the potential utility of BCV in anti-EBV therapy for patients with multiple sclerosis.
The company stated that these results indicate the potential for using BCV in the treatment of multiple sclerosis by directly
targeting EBV.

Conclusion of an equity issue program and issuance of newshares through third-party allotment
2023-10-06

SymBio Pharmaceuticals Limited announced it will enter into an agreement with EVO FUND to set up a STraight-Equity Issue
Program (STEP). Under this program, the company will issue new shares through third-party allotment.

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

65

Under STEP, the allotment can be made up to five times, in the 1st through 5th allotment. The total number of shares that
may be issued under the program is 6,000,000, and the dilution rate, based on the total number of issued shares of 39,841
thousand at end-June 2023, is 15.06% (15.25% based on voting rights).
Funds to be raised
Expected total payment for new shares under STEP: JPY2.2bn
Estimated amount of issuance costs: JPY24mn
Estimated net proceeds: JPY2.2bn
Specific use of funds to be raised
The specific use and planned expenditure period of the funds to be raised (JPY2.2bn) through the issuance of the shares are
as follows.
Development funds for antiviral drug brincidofovir (direct expenses): JPY658mn (to be expended from October 2023 toJune 2024)
Indirect expenses related to brincidofovir development: JPY742mn (to be expended from October 2023 to June 2024)
Investment funds for new in-licensing, M&A, etc.: JPY783mn (to be expended from October 2023 to June 2024)
Summary of offer

Overview of the 1st to 5th allotment
Due date of payment
Number of shares to be issued
Issue priceAmount of funding
Method for subscription or allotment
AllotteeNovember 10, 2023, December 20, 2023, February 7,2024, March 18, 2024, April 19, 2024 (5 times in total)
1.2mn common shares each time, a total of five times
To be determined
To be determined
Third-party allotment
EVO FUND

Source: Shared Research based on company data

Announcement of change in Global CMO
2023-08-29

SymBio Pharmaceuticals Ltd. has announced a change in its Global Chief Medical Officer (CMO).
The company announced that Dr. Nkechi E. Mbanefo-Azie will assume the position of Global CMO in September 2023. Dr.
Mbanefo-Azie is a fellow of the Infectious Diseases Society of America and will also serve as Senior Vice President and Headof R&D of SymBio Pharma USA, a US subsidiary.
The company is working to expand SymBio Pharma USA, the development site for the injectable drug brincidofovir.

Changes to BCV IV clinical development plan for BK virus
infections
2023-08-14

SymBio Pharmaceuticals Ltd. has announced changes to the clinical development plan for its intravenous formulation of
brincidofovir (BCV IV) for the treatment of BK virus infections.
The company has decided to revise the clinical development plan for the Phase II clinical trial of BCV IV in patients with postkidney transplant BK virus infections. The Phase II trial, which was originally planned to be completed in 2025, is
experiencing delays in patient enrollment, and as a result the company is considering protocol amendments.
In addition, the company will prioritize two clinical trials for BCV IV that were planned to start in FY12/24. These trials are a
Phase Ib trial in patients with cytomegalovirus (CMV) infection following hematopoietic stem cell transplantation and a Phase
Ib trial in patients with brain tumors.
SymBio Pharmaceuticals 4582
Research Coverage Report by Shared Research Inc. | https://sharedresearch.jp | Subscribe for FREE

66

According to the company, these changes will have no impact on the financial results for FY12/23.

Revision to full-year earnings forecast for FY12/23
2023-08-03

SymBio Pharmaceuticals Limited announced a revision to its full-year earnings forecast for FY12/23.

Revision to full-year earnings forecast for FY12/23
Sales: JPY6.5bn (vs. the previous forecast of JPY7.0bn)
Operating loss: JPY331mn (unchanged from the previous forecast)
Recurring loss: JPY219mn (vs. previous forecast loss of JPY351mn)
Net loss attributable to owners of the parent: JPY370mn (unchanged from the previous forecast)Reasons for revision
The company downgraded its sales forecast to JPY6.5bn, a decrease of JPY523mn from the previous forecast. While theimpact of bendamustine generic drugs was largely within the company's expectations, delays in the treatment ofmalignant lymphoma due to the impact of COVID-19 continued, despite the disease being reclassified as a Class 5
infection.
The company maintained its operating loss outlook. While prioritizing R&D investments for the global development of
brincidofovir (BCV), the company reviewed expenses to reduce SG&A spending and limit the impact of lower sales. The
recurring loss forecast was revised upwards to JPY219mn due to foreign exchange gains on foreign currencydenominated assets. The net loss forecast remained unchanged, with the impact of the foreign exchange gain offset by anincrease in deferred income taxes.

Change of CEO at US subsidiary2023-07-20

SymBio Pharmaceuticals Ltd. has announced a change of CEO at its US subsidiary.
SymBio Pharma USA, Inc., a wholly owned subsidiary of SymBio Pharmaceuticals, has announced that its current CEO,Fuminori Yoshida, will be succeeded by Stephane Berthier. Mr. Yoshida will continue to serve as chairman of the Board of
Directors of Symbio Pharma USA. The US subsidiary is becoming increasingly important as a development base forbrincidofovir injection.

Joint research finds biomarker to predict efficacy of BCV
2023-06-12

SymBio Pharmaceuticals Limited announced that it has identified a biomarker that predicts the anti-tumor effect of theantiviral drug brincidofovir (BCV) in a joint study with the National Cancer Centre Singapore (NCCS).
The joint research by the two organizations found that BCV is highly sensitive to NK/T cell lymphoma when the cell lines
have low expression of a transcriptional repressor called TLE1. NCCS will present these findings at the 17th International
Conference on Malignant Lymphoma.
SymBio noted the possibility that TLE1 could be used as a biomarker to predict the efficacy of BCV in advance.

POC established for BCV IV in patients with adenovirus
infections in Phase II study
2023-05-29

SymBio Pharmaceuticals Limited announced that it has established proof of concept (POC) for the antiviral effects ofbrincidofovir injection (BCV IV) in patients with adenovirus infections in a Phase II clinical trial.
The company is conducting a Phase II clinical trial for BCV IV in the US in patients with adenovirus infection following
hematopoietic stem cell transplantation. In this trial, the company established POC for the antiviral effects of BCV IV.
SymBio Pharmaceuticals 4582
Research Coverage Report by Shared Research Inc. | https://sharedresearch.jp | Subscribe for FREE

67

Following the independent Data and Safety Monitoring Board's review of the 24-case clinical data from the Phase II trial, thecompany submitted the data to the FDA, which confirmed POC in humans.
The company plans to review the dose regimen for Cohort 4 (with increased dosage) while continuing discussions with the
FDA to initiate a Phase III trial.

Onconova provides update on clinical study evaluating rigosertib
monotherapy in squamous cell carcinoma
2023-05-10

SymBio Pharmaceuticals Limited announced that Onconova Therapeutics, Inc. (Pennsylvania, US), the licensor of rigosertib,presented at the International Society of Investigative Dermatology (ISID)'s International Epidermolysis Bullosa Symposium
held in Osaka. Onconova provided an overview of its investigator-sponsored clinical trial evaluating rigosertib monotherapy
in squamous cell carcinoma associated with recessive dystrophic epidermolysis bullosa (RDEB-associated SCC).
In July 2011, SymBio entered into a license agreement with Onconova for exclusive rights to develop and commercialize
rigosertib in Japan and South Korea. Onconova plans to submit study results to regulatory authorities to seek approval for
rigosertib in RDEB-associated SCC.
(Click here for details on the Onconova’s announcement)

Announcement of cooperative research and development
agreement with the US National Institute of Allergy and
Infectious Diseases to evaluate brincidofovir
2023-04-24

SymBio Pharmaceuticals announced that it has entered into a cooperative research and development agreement (CRADA)
with the National Institute of Allergy and Infectious Diseases (NIAID), part of the US National Institutes of Health (NIH), toevaluate the therapeutic effects of brincidofovir (BCV) in diseases caused by Epstein-Barr virus (EBV).
The company has already signed a material transfer agreement with the National Institute of Neurological Disorders andStroke (NINDS), also part of the NIH, to evaluate the antiviral effect of BCV against EBV. The new CRADA with NIAID will
evaluate the potential of BCV as a targeted therapy for EBV-related diseases using a translational platform (which serves as abridge to clinical research) that can reproduce EBV infections and related diseases in cell and animal models.

Announcement regarding joint development of brincidofovir for
multiple sclerosis2023-03-22

SymBio Pharmaceuticals Limited announced the joint development of brincidofovir (BCV) for the treatment of multiple
sclerosis.
The company has entered into a cooperative research and development agreement with the National Institute of
Neurological Disorders and Stroke (NINDS), part of the US National Institutes of Health (NIH), to develop BCV for thetreatment of multiple sclerosis. SymBio and NINDS have previously collaborated to evaluate the antiviral effects of BCVagainst the EB virus.
This joint development will accumulate information for clinical trials through in vitro testing and animal model testing ofcells derived from multiple sclerosis patients infected with EB virus infections.

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

68

Profile
Company Name

Head Office

SymBio Pharmaceuticals Limited

7F TORANOMON TOWERS OFFICE, 4-1-28 Toranomon, Minatoku, Tokyo 105-0001, Japan

Phone
Listed On

03-5472-1125

Tokyo Stock Exchange, Growth Market
EstablishedExchange Listing

2005-03-25

2011-10-20
Fiscal Year-End
Dec

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

69

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.

Contact Details
Company namePhone

Shared Research Inc.

+81 (0)3 5834-8787

AddressEmail2-6-10 Kanda-Sarugakucho Chiyoda-ku Tokyo, Japan

info@sharedresearch.jp

Websitehttps://sharedresearch.jp

Disclaimer
This document is provided for informational purposes only. No investment opinion or advice is provided, intended, or solicited. Shared
Research Inc. offers no warranty, either expressed or implied, regarding the veracity of data or interpretations of data included in this report.
We shall not be held responsible for any damage caused by the use of this report. The copyright of this report and the rights regarding thecreation and exploitation of the derivative work of this and other Shared Research Reports belong to Shared Research. This report may be
reproduced or modified for personal use; distribution, transfer, or other uses of this report are strictly prohibited and a violation of the copyrightof this report. Our officers and employees may currently, or in the future, have a position in securities of the companies mentioned in thisreport, which may affect this report’s objectivity.
Japanese Financial Instruments and Exchange Law (FIEL) Disclaimer: The report has been prepared by Shared Research under a contract with thecompany described in this report (“the company”). Opinions and views presented are ours where so stated. Such opinions and views attributed
to the company are interpretations made by Shared Research. We represent that if this report is deemed to include an opinion from us that
could influence investment decisions in the company, such an opinion may be in exchange for consideration or promise of consideration fromthe company to Shared Research.

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

70