ANALYST NET Company Report

SymBio Pharmaceuticals Ltd.
Issued: December 6, 2021

（4582 JASDAQ）

SymBio’s JPY1.3 Billion Operating Profits Target Achievable
2021 operating profit in the JPY1.3 billion range within reachDue to inventory consolidation following the switch to in-house sales and as a resultof the COVID-19 pandemic, cumulative sales of Treakisym®, the company’s key
product, were somewhat lacklustre in the first three quarters, reaching only 60.7%
of full-year expectations. However, with the approval of the r/r DLBC indication in
March 2021, there has been steady progress in the expansion of indications, and thecompany’s new in-house sales structure has made a good start. On the other hand,the switch to an RTD formulation has not been as rapid as the company had planned
and the effect this would have had on reducing unit costs has been delayed
somewhat. For this reason, third quarter unit costs stood at 26.4%, only 0.3 points
below the second quarter level. Even so, the operating margin rose to 25.7% in thethird quarter, and cumulative operating profits for quarters 1-3 were positive,
totaling JPY424 million. SymBio Pharmaceuticals estimates the RTD switch isaround 3 months behind the original schedule, which means fourth quarter unit costs
could fall to 22-24%, and next year to around 20%. Even assuming annual sales
come in at JPY8.35 billion, missing the company’s target of JPY9.15 billion, if
fourth quarter unit costs fall to 24% and SG&A remains at the level of the third
quarter, it is quite possible that the company will secure annual operating profits of
JPY1.3 billion or above, in line with its forecast. A further decline in unit costs andannual sales close to the company forecast of JPY9.1 billion would make it likely
for operating profits to exceed the company’s expectations.
New therapies will not alter Treakisym’s status for the time being
The main areas in which Treakisym® is competing are malignant lymphomas andr/r DLBCL, areas for which a lot of antibody and immunotherapies are being
developed. Antibody drug conjugates (ADC’s) such as Polivy® have appeared, as
has the high-response rate CAR-T therapy, in addition to which there is thepromising area of Bi-specific T-cell engagers (BiTEs). Some of these can be usedin combination with Treakisym® (the Pola-BR therapy) or Treakisym® can be used
in a pretreatment (CAR-T). In the case of BiTEs, there have not yet been any trials
of Treakisym® in combination mode, but the possibility is there. In any case, since
there are not yet enough results available for r/r DLBCL therapies, it is quitepossible that various combinations of treatments will be considered using the
combined therapies and usages that have been overviewed so far. We think
Treakisym’s position is assured for the interim unless a therapy is developed thatchallenges the B-R therapy’s established position and effectiveness.
Development of rigosertib and brincidofovir
SymBio has now begun a review of its pipeline strategy. That is, while rigosertib
was originally developed to treat myelodysplastic syndromes, at present the focus
is on its function as a RAS inhibitor. Its development as a cancer drug is ongoing at
Onconova Therapeutics, which was the original licensor. SymBio is now seeking toelucidate other modes of action in collaboration with academia. As for brincidofovir(BCV), focusing on viral infections contracted after hematopoietic stem celltransplantation in blood cancer patients, Phase-2 trials on children with adenovirus
infections are now underway, and it is likely that in the second half of 2022 a plan
to extend trials to global Pivotal will evolve. Further, development is underway touse BCV to treat viral infections following kidney transplantations and, further
down the line, plans are in hand to develop a treatment for malignant brain tumours.
Results

Revenues
JPY mil.

2018/12 Actual
2019/12 Actual

Follow-Up Report
Fair Research Inc
Tsuyoshi Suzuki

Company Outline
LocationTokyo

President

Fuminori Yoshida

EstablishedMarch 2005

Capital

JPY17,152 mil

ListedOctober 2011

URL

www.
symbiopharma.com

Industry

PharmaEmployees

144 (non-consol)

Key Indicators (Dec. 3, 2021)
Stock Price

JPY1,236

52-week high

JPY2,423

52-week low
Sharesoutstanding
Trading Unit

JPY38738,449thousand100 shares

Market Cap

JPY47,523 mil

Dividend (est)0.0

Forecast EPS

JPY 30.0

Forecast PER

41.19X

Actual BPS

JPY117.60

Actual PBR

10.51X

Note: EPS, PER, BPS、and PBR calculatedon the basis of shares outstanding excl.
treasury shares
。

YoY
％

EPS
JPY

Stock Price
High
Low

-2,752NA-165.5335

196-4,376

NA-189.0

275

150

NA

-4,090NA-124.1653

243-3,220NA-2,694

NA

-84.6

644

264

NA

414

NA

324

NA

8.48

2,423

387

NA

1,350

NA

1,149

NA

30.0

YoY
％

Op. Income

JPY mil

YoY％

Rec. Profit
JPY milYoY％

Net Income
JPY mil

3,835

11.4

-2,656NA-2,748

NA

2,837

-26.0

-4,301NA-4,376NA

2020/12 Actual

2,987

5.3

-4,506NA-4,6152020/1Q-3Q Actual

2,332

16.2

-3,142NA

2021/1Q-3Q Actual

5,553

138.1

424

2021/12 Forecast

9,151

206.4

1,361

1/17
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals （4582 JASDAQ）

Issued: December 6, 2021

会社概要・経営理念＜Business Model＞
The company is a specialty
pharma engaged in drug
discovery without the riskspresented by laboratories or
manufacturing, employing aniche strategy to secure highreturns

SymBio Pharmaceuticals Ltd. is a global specialty pharma with a focus on rare
conditions with high medical need in the areas of cancer and hematology, to which
the major pharmaceutical companies have paid little attention. Its involvement
extends from clinical trials, rather than the high-risk area of drug discovery, throughto sales activity. The company’s business model has three characteristics:① Post-POC strategy
The company does not itself undertake drug discovery research but investigatescandidates developed by drug discovery ventures and pharmaceuticals
companies around the world. Usually, proof of concept has already been
established. By insisting on prior evidence of efficacy and safety in humansubjects the company reduces the development risks of new drug candidates.
② SymBio is a specialty pharma operating a high return, high market share niche
strategy.
The company focuses its efforts on drugs for relatively rare indications in, forexample, cancer and hematology, where the need is high, but where the major
pharmaceuticals companies are relatively unrepresented. Using this niche
strategy, the company seeks high market share and high returns. Until 2020, The
company’s business model involved entering into licensing agreements
covering new drug candidates it has selected, developing them in Japan and thenlicensing out to other pharmaceuticals companies. However, it has now set up
its own sales function in Japan and has established itself as a pharma
specialising in hematology.
③ Global licensor
Further, in September 2019, SymBio acquired exclusive rights (development,
production and sales) to brincidofovir (BCV), a product with global
applications. SymBio has thus evolved from a company seeking licenses inJapan to one providing licenses around the world, firstly in Asia, including
China, and also the US and Europe.

The key to returns is thecompany’s network of drug
discovery companies and its
own expertise

SymBio is an unusual bioventure in that it already has
a product on the market,
which took only five years
from inception to regulatory
approval
Treakisym® selected as astandard therapy in 2018
Successful expansion of
approved indications

The success or failure of this business model is dependent on the company’s networkof pharma-collaborators around the world and the company’s own expertise. Hence,the company’s track record. Normally, it takes some 10-20 years to bring a drug
from basic research to the market. In terms of the probability of success, someestimates suggest that, counting from the chemical compound stage, it is less than
1/30,000, and even from the POC stage, only around 7-8%.
In the case of SymBio’s first product, Treakisym® (generic name: bendamustine) it
took only five years or so to go from licensing-in (in 2005) to manufacturing andsales approval (in 2010). The first approved indications were relapsed/refractory
low-grade non-Hodgkin's lymphoma and mantle cell lymphoma. Additional
indications then came one after the other. In August 2016, chronic lymphocytic
leukemia (CLL) became an additional approved indication, as did untreated lowgrade NHL/MCL in December of the same year. Additionally, in July 2018,with respect to all approved indications, Treakisym® was newly listed in
the Guidelines for Clinical Practice in Hematopoietic Tumours for 2018
(edited by the Japanese Society of Hematology) as a standard treatment
option. In March 2021, the company succeeded in acquiring
authorisation for relapsed/refractory diffuse large B-cell lymphoma (r/r
DLBCL).
2/17

This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals （4582 JASDAQ）

Issued: December 6, 2021

Note: malignant lymphoma types
Lymphoma is a blood disease caused by the cancerisation of immunity cells called
lymphocytes (a type of leukocyte). Ｔhere are two major types: Hodgkin’s lymphoma(HL) and non-Hodgkin’s lymphoma (NHL). Most Japanese cases of malignant
lymphoma are NHL, which can be classified into three types depending on speed of
disease progression (Treakisym® is indicated for the NHL type). The most frequently
occurring medium-grade malignant NHL in Japan is diffuse large B-cell lymphoma(DLBCL).

Types of malignant lymphoma (Japan)(%)
Non-Hodgkin Lymphoma

DLBCL

45.3

Focular Lymphoma

13.5

MZBCL

7.2

CLL/SLL

3.2

MCL

2.0

Burkitt Lymphoma

1.3

T/NK Cell Lymphoma

18.1

Hodgkin Lymphoma

5.9

Others

3.8
Low gradeMedium-high grade

Source: Chihara D et al “Differences in incidence and trends of haematologicalmalignancies in Japan and the United States”, British Journal of Haematology, 2014

Progress in life-cycle
management throughformulation changes

Additionally, the company has been working on managing the product’s life cycleby making changes to the formulation. To this end it has promoted thedevelopment of a liquid formulation, which is easier to use than the existing freezedried formulation, and in September 2020 it acquired authorisation for an RTD
formulation. In May 2021 the company additionally submitted an application for
approval of an even more convenient RI formulation, which it expects to receive inthe first half of 2022. This should extend product life-cycle to the end of 2031.
Comparison of the FD, RTD and RI formulations

Source: SymBio results meeting

3/17
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals （4582 JASDAQ）

Issued: December 6, 2021

Reference: Having launched a freeze-dried formulation in 2014, the US company,
Teva Pharmaceuticals Industries, in January 2016 launched an RI preparation(product name: Bendeka®, licensed in from Eagle Pharmaceuticals) which is moreeasily administered). In only two years Bendeka® came to account for 97% of the
Treakisym® market.

We believe SymBio’s track record has been made possible by the expertise of thecompany’s staff and by the way the company is organised. SymBio has a staff of155, of whom 55 are involved in R&D (figures as of end of 2020). The drug searchfunction is supported by a Scientific Advisory Board (SAB) of experts (including
Nobel Prize candidates). Needless to say, a major role has been played by thecompany founder and CEO, Fuminori Yoshida, who developed the network andcontributes his expertise.
SymBio’s network andexpertise are enhanced by an
outstanding workforce andcompany organisation

In the 15 years since the company was founded, it has introduced six products. It iscurrently promoting the development of three drugs, the first of which isTreakisym®, whose various modes of action it is elucidating to further expand the
product’s area of utility. The second is rigosertib, a RAS pathway inhibitor licensed
in from the US firm, Onconova Therapeutics. And the third is brincidofovir (BCV),a highly active multiviral drug for treating infections, licensed in from the US firm,
Chimerix. It can be used to fight various infections contracted by blood cancer
patients after hematopoietic stem cell transplantation in the interval until thepatient’s own immunity recovers. It can also be used to fight viral infections in organtransplant patients.

4/17
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals （4582 JASDAQ）

Issued: December 6, 2021

Reference: SymBio’s product pipelines

Note: The company is now studying multiple modes of action prior to deciding future
strategy direction

Source: SymBio Pharmaceuticals web site

*1: NDA: Filing for New Drug Approval*2: MA: Approval

5/17
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals （4582 JASDAQ）

Issued: December 6, 2021

Insights from the company’s Q3/2021 results
Operating revenues finallyachieve profitability in thethird quarter

SymBio Pharmaceuticals released its third-quarter results on November 11, 2021.
The company has at last achieved a cumulative profit surplus for the three quarters
January-September, recording JPY424 million on an operating basis. Looking at
individual quarters, the April-June second quarter had already produced a small
positive result.

Preparations for the in-house sales structure continued until the middle of last year
Sales are on a recovery track and became operational in December. However, there was an adverse impact frombutarelagging
the the inventory adjustments necessitated by the switch from Eisai to doing its own
company’s full-year forecast sales, and also from the effect on sales activities of COVID-19. These factors led toa slightly sluggish start, with sales in the first quarter coming to JPY1.42 billion andin the second quarter JPY1.726 billion. However, due to the addition of r/r DLBCL
However, unit costs areas an approved indication in March 2021, sales recovered to JPY2.4 billion in thedown significantly, andthird quarter. Elsewhere, because of the change to in-house sales and the switch toprofitability up, due to thean RTD formulation, unit costs fell sharply from 71% in 2020 to 28.9% in the firstin-house sales change andquarter of 2021 and 26.7% in the second quarter, leading to a profit surplus.
the switch to a liquid
formulation
Nevertheless, the switch to the RTD formulation is proceeding less smoothly thanoriginally expected (around 20% in the first quarter and 91% by the end of 2021)
But the introduction of aand consequently the decline in unit costs is lagging expectations, by 0.3 points toliquid formulation is behind
26.4% in the third quarter. All the same, third quarter operating revenues reached
schedule
25.7% in the third quarter.
The switch to a liquid
The reason why the switch to an RTD formulation has not proceeded as planned isformulation is running somethat, while the conventional freeze-dried formulation comes in lots of 100mg and3 months behind the
25mg, the RTD formulation is 100mg only. This caused problems at medical
company’s schedule
facilities which had become accustomed to using the 25mg lots. In addition, it has
taken some time to make improvements to the device used for extracting the drug
Unit costs expected to fall to solution from the vials. SymBio believes it is about 3 months behind schedule in the
22-24% in the fourth quarter switching process, meaning that fourth quarter unit costs should come in at about
22-24%, and fall next year to around 20%.
It therefore seems likely thatwhile sales may not meet thecompany’s
projections,operating profits should

In the fourth quarter, the effect of adding r/r DLBCL to approved indications is
expected to keep sales on a growth trend. However, even if sales in the fourth quarter
were to stall at JPY2.8 billion yen and annual sales came to JPY8.353 billion, shortof the company's forecast of JPY9.151 billion, the unit cost rate in the fourth quarter
would drop to 24%. Thus, if SG&A expenses remain at the same level as in the third
quarter, it is quite possible that annual operating income will reach the mid-JPY1.3
billion level, on a par with the company's forecast (JPY1.361 billion). If the unit cost
rate drops further and sales approach the company's forecast of JPY9.1 billion yen,then operating profit is likely to exceed the company expectations. (It should be
noted that Eagle Industries, the source of the liquid formulation, does not receive
milestone payments from SymBio in 2021.)

6/17
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals （4582 JASDAQ）

Issued: December 6, 2021

SymBio quarterly results and simulated forecast
１Q

２Q(JPY-mil)４Q（results)

３Q

1Q-2Q

１Q

1Q-3Q

(JPY-mil)
1Q-4Q（results)

Sales

1,420

1,726

2,407

2,800 ～

3,600

Sales

1,420

3,146

5,553

8,353 ～

9,153

CoGS

410

461

636

672 ～

864

CoGS

410

871

1,507

2,179 ～

2,371

Gross profit

1,009

1,265

1,771

2,128 ～

2,736

Gross profit

1,009

2,274

4,045

6,173 ～

6,781

SG&A

SG&A

1,220

1,249

1,152

1,200 ～

1,200

1,220

2,469

3,621

4,821 ～

4,821

R&D

473

439

374

400 ～

400

R&D

473

912

1,286

1,686 ～

1,686

Excl R&D

747

810

778

800 ～

800

Excl R&D

747

1,557

2,335

3,135 ～

3,135

Op. profit

-210

16

618

928 ～

1,536

Op. profit

-210

-194

424

1,352 ～

1,960

Rec. profit

-208

5

617

928 ～

1,536

Rec. profit

-208

-203

414

1,342 ～

1,950

Net profit

-209

4

529

Net profit

-209

-205

324

1,149

Cost rate
Op. profit rate

28.9%
-14.8%

26.7%
0.9%

26.4%
25.7%

(Difference）

１Q

２Q

３Q

Cash
Accounts receivable
Finished goods
Semi-finished goods
Pre-paid costs

-915
455
83
-63
48

-607
199
177
156
53

24.0%
33.1%

24.0%
42.7%
(Balance）

287
777
-30
-299
-42

Cash
Accounts receivable
Finished goods
Semi-finished goods
Pre-paid costs

2020Dec

2021 March

3,848
406
271
672
80

2,933
861
354
609
128

June
2,326
1,060
531
765
181

September
2,613
1,837
501
466
139

Provisional

Source: Fair Research Inc. using short-form results

Reference: SymBio’s 2021 annual plan and medium-term plan
(JPYmil）

2020(actual）

Sales

2021
9,151

866

6,957

GP margin ratio

29.0%

76.0%

SG&A

5,373

5,596

2,266

2,019

of which, R&D
Operating profit-4,506OP margin ratio

2023(forecast） （med. term plan） （med.term plan）

2,987

Gross profit

2022
10,985

12,369

1,361

1,738

2,099

14.9%

15.8%

17.0%

Recurring Profit-4,615

1,350

1,727

2,088

Net profit-4,090

1,149

1,470

1,778

Source: Fair Research Inc. using SymBio’s Medium Term Corporate Plan andsecurities report filings

7/17
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals （4582 JASDAQ）

Issued: December 6, 2021

Treakisym® in the context of new drug developments to treat DLBCLThe B-R therapy is now thestandard therapy in thetreatment of DLBCL, whichis the main type of malignant
lymphoma

Looking back briefly at the history of DLBCL therapies, until the development ofmulti-drug chemotherapies (e.g. the CHOP therapy) there was no effective
treatment, especially for r/r DLBCL. The CHOP therapy was developed in the
1970’s but, while DCBCL was thereby no longer incurable, CHOP’s effectivenessfell short. However, in 1997 the use of Rituxan® (generic name: rituximab) in RCHOP therapy was authorised and this produced a much better rate of overall
survival than the CHOP therapy. Nevertheless, about one-third of patients failed torespond or suffered a recurrence, rendering them the subject of high unmet medical
needs. In addition, many patients with malignant lymphoma tend to be of advanced
years, for whom the there was always a risk of side-effects from the multi-drug RCHOP therapy. In response to this, the B-R therapy was developed. This consists ofTreakisym® (generic name: bendamustine) together with Rituxan® (generic name:rituximab), providing greater efficacy with fewer side-effects. It has since
established itself as a standard treatment of choice.
Comparative study of the R-CHOP and B-R therapies

Source: SymBio company briefing (showing better results for the B-R therapy)
Note: R-CHOP therapy

In recent years, in the area ofmalignant lymphoma, muchprogress has been made in
developing new antibody
andimmunotherapy
modalities

Chemotherapy that combines the molecular targeted drug rituximab with theanticancer drugs cyclophosphamide, doxorubicin hydrochloride, vincristine
sulfate, and the steroid prednisolone.

Currently, in the field of malignant lymphoma, antibody/immunotherapy has
progressed and is being developed as a primary therapy. It is often the case thatmalignant lymphoma is caused by an abnormality in the B-cells. Malignant B-cells
express CD19, CD20, CD22, CD30, CD79a and CD79b on the B-cell surface, andresearch is progressing to develop therapies which target these.

Polivy® was the first① Antibody drug conjugates (ADC’s)
antibody drug conjugate(ADC) worldwide to receive Authorised for the treatment of r/r DLBCL, Polivy® (polatuzumab vedotin) is anauthorisation
antibody drug conjugate (ADC) of MMAE, a mitotic inhibitor that inhibits
8/17This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals （4582 JASDAQ）

Issued: December 6, 2021

microtubule polymerization and binds to CD79b. The mechanism at work inhibits
cell division and induces apoptosis.
The structure of Polivy®

Source: Chugai Pharmaceutical, Polivy intravenous drip information meeting
materials, June 2021

Polivy® is not used alone
but in combination with Polivy® is not used alone but in combination with Treakisym® and Rituxan®
Treakisym® and Rituxan® (Pola+BR therapy)(Pola+BR therapy)
Reference: Pola+BR therapy vs B-R therapy (r/r DLBCL)
There is data showing that the complete response (CR) rate for Pola+BR is 40%(GO29365 study; Phase-1b/2. Source: Sehn LH e al., J Clin Oncol, 2019). In addition,
Phase-2 trials in Japan (P-DRIVE trials) produced a CR rate of 34.3%. The CR rate
for the B-R therapy, whose cohort was included in the GO29365 study, was 17.5%.
Elsewhere, the SymBio’s Phase-3 results targeting the B-R therapy on r/rDLBCL
produced a 47.4% CR rate, a 76.3% overall response rate (ORR), and a median overall
survival rate (mOS) of 29.2 months. (Note: In SymBio’s Phase-3, 70% of the patientson whom genetic analysis was conducted were of the non-GCB type; In the B-R
therapy GO29365 study cohort, 57.5% of the patients were non-GCB).
GO29365 Trial
Pola-BR

SymbioB-R

B-R(90mg/㎡）(120mg/㎡）

ORR(％）

70.0

32.5

76.3

CR(％）

57.5

20.0

47.4

ｍOS (month)

12.4

4.7

29.2

( ) dose of Treakisym

Source: Sehn LH et al, J Clin Oncol 2019, and SymBio IR materials
Since the two cohorts have different backgrounds, we cannot simply compare them.
Also, in the GO29365 B-R therapy trials, the Treakisym® dose administered was
90mg/m2, while the Treakisym® dose administered in SymBio’s Phase-3 B-R trials
was 120mg/m2. This means that the difference in response, for the same B-R therapy,
could be due to the difference in dosage. It is not at present possible to say one issuperior to the other.

Pola-BR and B-R could both
become the main therapies It is thought that Pola-BR and B-R will become the mainstream therapies for r/r
for r/r DLBCLDLBCL, but whatever happens, Treakisym® (bendamustine) will be used.
For first-line DLBCL, a Pola+RCHP study is now underway, with the possibility
that this could become a treatment option. However, even if Pola-RCHP is approved
9/17
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals （4582 JASDAQ）

Issued: December 6, 2021

for first-line DLBCL, it is thought that the size of the r/r DLBCL market for which
Treakisym® is indicated will not change much in the short term. Pola-RCHP may
achieve a longer progression-free survival (PFS), but it is unclear at the present time
whether recurrence is reduced or not. If the rate of recurrence is reduced, then it ispossible that the r/r DLBCL market will contract but the proportion of refractorypatients resistant to treatment will increase. It is not thought there will a significant
effect on f Treakisym® sales in first-line (off-label) treatment.
Another ADC is Zynlonta® (generic name: loncastuximab), which was authorisedin the US in April 2021for the treatment of third-line DLBCL. Since this ADC is a
CD19 targeting antibody and alkylating agent it is unlikely to be used in combination
with Treakisym®, which also has an alkylation action, thus leaving room forcompetition. However, as it is a third-line therapy, this competition will be limited.
Also, brentuximab vedotin (target:CD30) is now undergoing trials for thetreatment of DLBCL in combination with Rituxan® (rituximab) and lenalidomide,and combined use with Treakisym® for the treatment of Hodgkin’s lymphoma is
being studied (however, this indication not authorised in Japan). A monotherapy
using coltuximab ravtansine(target: CD19) is undergoing Phase-2 trials for
DLBCL. While both could be competitive in the distant future, neither offers
immense competition for the time being.

There are many problems
facing broader use of the
CAR-T cell therapy

In the CAR-T therapy
Treakisym® is used as pretreatment② The CAR-T cell therapy
In addition to antibody drug conjugates, another therapy receiving attention is the
CAR-T cell therapy. Kymriah®, Yescarta® and Breyanzi® have already been
approved for use in CAR-T therapy. CAR-T is a T cell with a CAR (chimeric antigen
receptor) that specifically binds to the cancer antigen CD19 on the surface oftumorised B cells. The T-cell only targets cancerous B-cells and is said to have a
response rate of 70-90%. The CAR-T cell therapy is currently limited to transplant
non-adaptive (mostly third-line) cases. The intention is to expand the scope tosecond-line cases and development is underway with the aim of achieving a higher
response than autologous transplantation. However, because CAR-T cell therapy
requires advanced technology, equipment, and considerable labor to create the CART cells using autologous cells, it is very costly (around JPY30 million per patient)and can only be administered at medical facilities with the ability to respond toadverse events, such as cytokine release syndrome. The use of the CAR-T celltherapy is therefore extremely limited. Treakisym® is used as a pretreatment with
Kymriah®, Yescarta® and Breyanzi®.
Conceptual depiction of CAR-T and BiTEs

Source: Batlevi CL et al “Novel immunotherapies in lymphoid malignancies”, Nat
Rev Clin Oncol, 2016

10/17
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals （4582 JASDAQ）

Issued: December 6, 2021

A promising approach is③ BiTEｓ（Bispecific T-cell engagers）
currently being developed:
A promising therapy now being developed which has lower barriers to adoption thanthe bispecific T-cell engager
CAR-T is bispecific T-cell engagers (BiTEs). In this therapy, a complex of which(BiTEs)one part binds to CD19 or CD20 that present on the surface of tumorised B cells,
and one part binds to CD3 that presents on the surface of T cells. The T cells are
induced to tumorise the B cells, providing cancer immunotherapy. Currently, Phase2
trials are underway involving the administration of blinatumomab (CD19 / CD3
BiTEs) to first-line DLBCL patients after rituximab-based immuno-chemotherapy,
and good results have been reported. Also, trials are underway of glofitamab(CD20/CD3 BiTEs) combined with R-CHOP, G-CHOP targeting first-line DLBCL,
as are trials of mosunetuzumab (CD20/CD3 BiTEs) targeting r/r DLBCL. None ofthese have been trialed in combination with Treakisym® and it is unlikely that any
combination therapy would be with Rituxan®, which targets CD20. A Treakisym®
combination would be possible.
Treakisym’s position will
not be threatened unless a
It is apparent that the results of various r/r DLBCL therapies are still insufficient. It
therapy producing a muchseems likely that the different therapies discussed above, individually and insuperior response rate to the
combination, will be the subject of consideration going forward. But the position of
widely used B-R therapy is
Treakisym® will not be challenged for the time being unless a therapy producing adeveloped
much superior response rate to the widely used B-R therapy is developed.

11/17
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals （4582 JASDAQ）

Issued: December 6, 2021

Rigosertib and Brincidofovir (BCV) – development going forward

Onconva Therapeutics, theoriginal
licensorofrigosertib,changes
its
purpose to RAS pathway
inhibitor① Rigosertib (intravenous injection and oral formulations)
The development of rigosertib was originally directed at the treatment of
myelodysplastic syndromes (MDS). However, in joint international Phase3 trials(INPIRE trials) it failed to achieve the primary endpoint (August 2020). Currently,
however, the focus is on its function as a RAS inhibitor, and the original licensor,
Onconova Therapeutics, is pressing ahead with its development as a cancer drug.
Rigosertib action mechanism

Source: Daniel A. Ritt et al, “Inhibition of Ras/Raf/ MEK/ERK Pathway
Signalng by a Stress-induced Phospho-regulatory Circuit” Mol Cell 2016 Dec
It is thought that rigosertib’s microtubule inhibition action activates JNK and acts on the
Ras/Raf/MEK/ERK pathway

Confirmed response incombination
with
OPDIVO®
(anti-PD-1
antibody) targeting NSCLC
with KRAS mutations
Since OPDIVO® does notalways evoke a response,even in some patients with a
high
PD-L1
rate
of
expression, drug companies
are concentrating on thedevelopment of combinationdrugs

In September 2021, Onconova Therapeutics disclosed interim partial results for
Phase-1/2a trials combining rigosertib (oral formulation) and the anti-PD-1
antibody nivolumab (OPDIVO®), targeting KRAS-mutated non-small cell lungcancer (NSCLC).
The target patients in these trials were KRAS-mutation NSCLC patients who had atleast one treatment with anti-PD-1 antibodies. In the case of NSCLC patients, antiPD-1 antibodies such as OPDIVO® are targeted at patients with a PD-L1 expression
rate of 50% or higher, but among patients with a PD-L1 expression rate of 50% or
higher, the response rate of anti-PD-1 antibodies is only about 45%. In other words,
even if genetic testing indicates treatment with the anti-PD-1 antibody (OPDIVO®),
it is ineffective in 55% of patients at the initial treatment stage. There is thus anunmet medical need here, and drug companies are competing vigorously with eachother to fill the need.
In terms of the interim results, two of the 12 subjects had not yet reached theevaluation stage and 3 withdrew due to side-effects. Of the seven patients who were
eligible for evaluation, 2 registered a partial response (PR), 1 recorded disease
12/17

This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals （4582 JASDAQ）

Issued: December 6, 2021

stabilisation (SD) and the disease control rate was 43%. Partial response wasobserved in patients with G12C mutations as well as G12V mutations. No
unexpected serious side effects were observed.

Other KRAS inhibitors binddirectly to the mutation
location, acting on specificmutations

Rigosertib elicits a response
notwithstanding differencesin mutation

Among NSCLC patients, around 20% have KRAS mutations, the most common(13%) of which are G12C mutations. The first KRAS inhibitor worldwide to receive
authorisation was LUMAKRAS® (generic name sotorasib; Amgen Inc. received
accelerated approval in May 2021), a G12C inhibitor. The US firm, Mirati
Therapeutics, is developing adagrasib, a KRAS (G12C) inhibitor targeting NSCLC,
and also a KRAS (G12D) inhibitor targeting pancreatic and other cancers. However,both the Amgen and Mirati drugs bind with specific KRAS mutation and are only
effective against those mutations. On the other hand, rigosertib has several potential
action mechanisms, including RAS signaling inhibition and microtubule
destabilisation, so can elicit responses despite the differences in KRAS mutations
noted above, making it more widely applicable.

SymBio Pharmaceuticals is now collaborating on research with academia (Tokyo
University’s Institute of Medical Science and Gunma University) to elucidate novel
SymBio Pharmaceuticals is mechanisms of rigosertib and Treakisym® (bendamustine). The future strategy for
now considering the way rigosertib should become apparent in mid-2022.
forward for rigosertib
Potential combinations for rigosertib and Treakisym® (bendamustine)

Source: SymBio Pharmaceuticals company briefing② Brincidofovir new developments
The primary target is AdV
infections
following
hematopoietic stem celltransplantation for bloodcancer treatment
The first patient for joint
international Phase-2 trials
targeting AdV infections inchildren was registered inAugust 2021
The schedule is for joint

On August 16, 2021, SymBio succeeded in registering its first patient (FPI) for
Phase-2 joint international trials of the anti-viral brincidofovir intravenous
preparation (BCV IV) for treatment of child adenovirus infections (AdV
infections). These trials are directed at an area of extreme medical needs for which
there is currently no effective treatment, i.e. disseminated AdV infections and AdV
infections from immunodeficiency in children (infections acquired following
hematopoietic stem cell transplantation as part of blood cancer therapy). The object
is to evaluate safety, tolerability and effectiveness and to decide on recommended
dose volumes for subsequent trials. Looking ahead, with more medical facilities
contributing in the US, we believe the brincidofovir trials will steadily move ahead,and medical facilities in the UK are scheduled to participate in trials in 2022. The
plan is to complete the joint international trials in the second half of 2022 and moveahead to global Pivotal trials. Further, planning is in hand to direct development of
brincidofovir at AdV infections of immuno-deficient adults. In addition, a joint
13/17

This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals （4582 JASDAQ）
international trials to becompleted,andglobalPivotal trials to begin, in thesecond half of 2022
There is also promisingtreatment development in
the areas of viral infections
following kidney transplants

There are also plans to go
beyond viral diseases into
the area of oncology
Cytomegalovirus is related
to malignant brain tumours
In order to expedite thedevelopment
andcommercialisationofbrincidofovir,
thecompany’s US subsidiaryhas brought a key person on
board

Issued: December 6, 2021

research agreement has been signed with the National Cancer Center of Singapore
to search for antitumor effects and their mechanisms against Epstein-Barr viruspositive lymphoma.
Consideration is also being given to other indications for brincidofovir. Particularly
promising is development targeting BK viral infections which are a frequent
occurrence worldwide following kidney transplants. There could be anannouncement of a new development plan in the first half of 2022.
SymBio Pharmaceuticals also plans to expand beyond viral diseases into the areaof oncology. In September 2021, the company began pre-clinical studies of theantitumor effect on brain tumors at the Brain Tumor Center in the Department of
Neurological Surgery at the University of California in San Francisco. BCV cancross the blood-brain barrier (BBB). In almost all cases of malignant brain
tumours a large amount of cytomegalovirus (CMV) is present (Nikkei Sciencemagazine, March 2009). It has been established that CMV creates the protein
which turns off the genetic switch preventing defective cell growth, which isnecessary for tumor growth.
In October 2021, the company’s wholly-owned subsidiary, SymBio Pharma USA,appointed Dr. Carolyn Yanavich as Deputy CEO and Head of Clinical Operations
to start operations in earnest. Looking ahead, using this as the strategy base for
global specialty pharma operations, the company plans to accelerate thedevelopment of the brincidofovir injection formulation in Europe and the UnitedStates and realise commercialization.

14/17
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals （4582 JASDAQ）

Issued: December 6, 2021

Conclusions
The operational plan isbeing implemented with aview to achieving a positive
profit figure

SymBio Pharmaceuticals has set up is own in-house sales structure and acquired a
new drug, brincidofovir, for which it has a global license. In so doing it has laid thegroundwork for growth as a haematology specialist pharma and embarked on a newcorporate life. While sales of its main product, Treakisym®, have been slightly
lacklustre as a result of inventory adjustments in the switch to in-house sales, andbecause of the COVID-19 pandemic, there has been progress in expanding
indications and changing formulations, and in preparing for the introduction of a
The company could achieve new sales structure. In the company’s 3Q2021 results released in November 2021 it
an operating surplus of was reported that cumulative operating profits for the three quarters to date were at
JPY1.3-1.4 billion in the full last showing a surplus. In results for the full year 2021 there may be a shortfall inyear 2021
sales compared to the company’s projections but expectations for operating profit
should be amply met.
The main challenge for the company’s key product, Treakisym®, is in the area of
Various new modalities inmalignant lymphomas, notably r/r DLBCL, where antibody therapies andthe key r/r DLBCL area
immunotherapies have made advances. Polivy® and other ADCs (antibody drug
conjugates) have arrived, as has the high-response CAR-T therapy. There is also
optimism for the development of bispecific T-cell engagers (BiTEs). However, manyof these are used in combination with Treakisym®, such as in the POLA-BR therapy,
or as preliminary treatment in CAR-T. No trials have been conducted withBiTEs but
The established status of the possibility is there. Whatever the case, it is apparent that the results of various
Treakism® is assured unless r/r DLBCL therapies are still insufficient. It seems likely that the different therapies
a therapy with a superior discussed above, individually and in combination, will be the subject of
response rate to the B-R consideration going forward. But Treakisym’s position will not be threatened for thetherapy appears
time being unless a therapy producing a much superior response rate to the widelyused B-R therapy is developed.
New
developmentsof As SymBio is now entering its second corporate existence it will pause to review its
rigosertib and brincidofovir pipeline strategy. That is to say, while rigosertib has opened the way as a RAS
inhibitor there are now other mechanisms of action whose elucidation is under study.
also emerging
Similarly, Phase-2 trials have started on BCV for pediatric adenovirus subjects as aprelude to viral infections in blood cancer patients following hematopoietic stem
cell transplantation. It is expected that global Pivotal trials will take place in thesecond half of 2022. Finally, researchers are now looking at developing therapies
for infections following liver transplants for treating malignant brain tumours.
SymBio advancing to its second stage
2021～2025
Maximise value of current
products/prospective pipelines

Enterprise Value = EPS ×

Pipeline Value
2021~

Treakisym®
Extend indications
Switch to RTD
Switch to RI
Combine with new compounds

Rigosertib
Combination therapy with
Treakisym® and/or others
New disease targets

Treakisym® - New modes of action
and new disease targets
License in new pipelines
BCV - global business expansion

Sustained sales andprofit expansion

Pipelines' underlying
enterprise value

BCV - global business expansion
Applied research with academia

BCV

New insights from AI discoveries

Recycling profits into maximising enterprise value

Source: SymBio results meeting materials

15/17
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals （4582 JASDAQ）

Issued: December 6, 2021

Note: Please see our Basic Report, released on June 1st, 2021, for details on pipeline values

Fair Research Inc.
BIZ SMART Kayabacho, 4th Floor
Shinkawa 1-3-21
Chuo-ku
Tokyo 104-0033
E-mail: info@fair-research-inst.jp

16/17This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals （4582 JASDAQ）

Issued: December 6, 2021

Disclaimers□ This report is prepared by Fair Research Inc. ("Fair Research") for the purpose of providing information toinvestors for fees under a contract with the covered company, and not for solicitation of securities trading.

□ Although, in preparing the report, Fair Research has obtained information through interviews with the covered
company, assumptions and views set forth in the report are not of the said company but are in principle based on
analysis and evaluation by Fair Research.

□ Although the report is written based on the information and materials that Fair Research judges reliable, there
is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Also, views and forecasts set forthin the report represent judgment by Fair Research at the time of issue of the report and may be changed without
notice.

□ Fair Research shall not take any responsibility whatsoever for any results including direct or indirect damages
arising from the use of, or reliance on, this report. Investors should take full responsibility for securities and othertransactions.

□ The intellectual property rights of this report belong to Fair Research, and any copy, transmission or quotation of
any contents without permission is legally prohibited
About “ANALYST NET”

□ ANALYST NET is the name of report services issued and distributed by Toward the Infinite World, Inc.
(hereinafter "TIW"). TIW serves as a delivery platform for providing information and a secretariat function.

□ Reports issued in the "ANALYST NET" brand name are intended to provide introductions to and descriptions ofindustries and companies by the different approach from the existing analyst reports, and mainly prepared byanalysts outside of "TIW" and business partners (hereinafter "authors").

□ TIW shall not review nor approve contents of the reports in principle (provided, however, that only in the case ofclear mistakes or inadequate expressions, they are pointed to authors).

□ TIW may directly or indirectly receive fees from the company covered by the report in compensation for planningand proposal for issuing the report and provision of the delivery platform function.

□ Authors may directly or indirectly receive fees from the covered company other than for preparation of the report.
Authors are also likely to hold securities issued by the covered company. TIW shall not manage these in principle,
nor take responsibility. Please review separate disclaimer by authors.

□ The report is prepared only for the purpose of providing information relevant to the investment decisions,andis not intended for solicitation of securities and other transactions. Investors should make final decision on securities
and other transactions in their own judgment and responsibilities.

□ Although, in preparing the report, authors have obtained information through interviews with the covered
company, assumptions and views set forth in the report are not of the said company but are in principle based on
analysis and evaluation by authors.

□ Although the report is written based on the information and materials that authors judged reliable, there is no
guarantee of accuracy, credibility, completeness, suitability and timeliness. Also, views and forecasts set forth in thereport represent judgment by authors at the time of issue of the report, and may be changed without notice.

□ TIW and authors shall take no responsibility for direct, indirect, incidental or special damage that may be incurredby investors as a result of reliance on the information or analysis set forth in the report.

□ The copyright of the report belongs to TIW or authors in principle. With respect to the information provided in thereport, copy, sale, indication, delivery, publication, amendment, dissemination or commercial use of such information
without approval of TIW are against the law.

□ "ANALYST NET" is a registered trademark owned by TIW.

17/17
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.