ANALYST NET Company Report

SymBio Pharmaceuticals Ltd.
Issued: January 16, 2023

（4582 Growth）

New Business Development: Advances Made in BCV
Still room for Treakisym® to grow despite emergence of generics
SymBio Pharmaceuticals was the first company to receive approval in Japan for Treakisym®
as a treatment for malignant lymphomas and subsequent formulations. Generics began toappear in February 2022. In that month four companies received approval to manufactureand sell generic RTD Treakisym®. After SymBio notified these companies of possible patent
infringement, Towa Pharmaceutical initiated sales (the other three put off commencing sales).
In addition, the generic versions were initially indicated only for indolent B-NHL and MCL,
but in June approval was given for the additional indication of r/r DLBCL (B-R therapy). The
CLL and r/r DLBCL P-BR therapy remained un-indicated. Given this situation, SymBio
accelerated a switch to RI administrations. According to SymBio, some 20 institutions werereceiving deliveries of the generic formulation by mid-October, indicating a cautious stanceon the part of medical facilities. As a result, the company’s July-September sales weretrending around the level SymBio had forecast in August. However, in November 2022, theRI-type generic from Towa and Pfizer (Japan) received approval. SymBio believes that there
is a possibility of patent infringement regarding RI administration On December 16, it filed
a patent infringement lawsuit against Towa Pharmaceuticals, and on December 26, filed asimilar lawsuit against Pfizer. In the fields of hematology and oncology, a relatively cautious
attitude toward generic products with slight differences from Treakisym® in terms of
constituents still persists. Further, since the use of the B-R therapy and the P-BR therapy inthe treatment of r/r DLBCL is less than 50%, it is believed that there is still room for
Treakisym® to penetrate.

Despite the emergence of BiTEs, the position of Treakisym® remains solid
SymBio’s mainstay product, Treakisym®, is mainly aimed at malignant lymphomas,
particularly r/r DLBCL, an area in which work on antibody therapy and immunotherapy
development is very active. Hence the appearance of ADC’s (antibody drug conjugates) suchas Polivy and a number of highly effective CAR-T therapies. There is also much hope placedin the development of BiTEs (bispecific T cell inducer antibodies). Polivy® has achieved
significant market penetration in a combination therapy with Treakisym®. The CAR-T
therapy is currently restricted to third-line treatment and also faces major barriers in terms of
cost and availability. BiTEs is making progress and there have been several examples ofoverseas approvals, but these have been more late-line therapy approvals. The sort ofindications for which BiTEs will be approved is still unclear. Unless a therapy clearly more
effective than the familiar B-R therapy is developed there is for the time being no threat toTreakisym’s position.

Progress in development of brincidofovir (BCV)
SymBio first developed BCV in the area of haematology: ① to treat viral infections
following stem cell transplants; and further, ② expanded development to viral infections at
the time of organ transplant. As for ①, Phase-2 international collaborative clinical trials are
currently underway and are due for completion in the first half of 2023. As for ②, Phase-2
international collaborative clinical trials just started and, following establishment of POC,
the plan is to launch corporate tie-up activities. Further, SymBio is considering developing
BCV for "therapeutic voids" where no existing antiviral agents have been approved. Actual
developments under consideration include ③ glioblastoma (GBM), a malignant brain
tumour, and ④ multiple sclerosis (MS). SymBio is undertaking a variety of joint research
projects with multiple US universities. In addition, it is also promoting a joint research
provision agreement with the National Institute of Neurological Disorders and Stroke, which
belongs to the National Institutes of Health, to evaluate the antiviral effect of BCV against
the EB virus. The first results of collaboration are already apparent, and the expectation isthat major pharmas will show an interest.

Follow-Up Report
Fair Research
Tsuyoshi Suzuki

Company Outline
LocationTokyo

President

Fuminori Yoshida

EstablishedMarch 2005
JPY17,152
mil.
October 2011

CapitalListedwww.
symbiopharma.com

URL
Industry

PharmaEmployees

125 (consol.)

Key Indicators (Jan. 12, 2023)
Share Price

640

52-week high1,284

52-week low
SharesOutstanding
Trading Unit

610
39,585,406

Market Cap

JPY25,335 mil.

Dividend (est.)

0.0

Forecast EPS

JPY42.4

Forecast PER

15．09X

Actual BPS

JPY213.9

Actual PBR

2.99X

100 shares(Note: EPS 、 PER 、 BPS 、 PBR based onshares outstanding (excl. treasury shares)

Results

Revenues
JPY milYoY％

Op. Income

JPY mil

YoY％

Rec. Profit
JPY milYoY％

Net Income
JPY mil

YoY
％

EPS
JPY

Stock Price
High
Low

2019/12 Actual
2020/12 Actual

2,837
2,987

-26.0
5.3

-4,301-4,506NANA-4,376-4,615NANA-4,376-4,090NA
NA-189.0-124.1

275
653

150
243

2021/12 Actual

8,256

176.4

1,016

NA

1,001

NA

2,032

NA

53.0

2,423

387

2021/1Q-3Q Actual2022/1Q-3Q Actual

5,553
7,355

138.1
NM

424
1,588

NA
NA

414
1,843

NA
NA

324
1,555

NA
NA

8.4
40.0

2,423
1,284

387
610

2022/12 Forecast

10,003

NM

2,000

NA

2,300

NA

1,650

NA

42.4

1/23
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals Ltd. （4582 Growth）

Issued: Jan. 16, 2023

Company overview and management philosophy
SymBio Pharmaceuticals Ltd. is a global specialty pharma with a focus on rare
conditions with strong unmet medical need in the areas of cancer and haematology,
in which the major pharmaceutical companies have little involvement. The
The
companyisa company’s activities extend from clinical trials, rather than from the high-risk area
pharmaceuticals
venture of drug discovery, through to sales activity undertaken by the company itself. The
business aiming for high company’s business model has three characteristics:
returns using a niche
strategy, operating withoutlaboratories
or ① Post-POC strategy
manufacturing facilities to
The company does not itself undertake drug discovery research but investigates
reduce much of the risk
new drug candidates developed by drug discovery ventures and pharmaceuticals
inherent in new drug
companies around the world. Usually, proof of concept has already been
discovery
established. By insisting on prior evidence of efficacy and safety in humansubjects the company reduces the development risks of new drug candidates.
＜BUSINESS MODEL＞② SymBio is a specialty pharma using a high return, high share niche strategy
The company focuses its efforts on drugs for relatively rare conditions in, forexample, cancer and haematology, where the need is high, but where the major
pharmaceuticals companies are relatively unrepresented. Using this niche
strategy, the company seeks high market share and high returns. Until 2020, thecompany’s business model involved entering into licensing agreements
covering new drug candidates it had selected, developing them in Japan andthen licensing out to other pharmaceuticals companies. Since 2021, however, it
has set up its own sales function in Japan and has established itself as a pharma
specialising mainly in haematology.

Source: SymBio Pharmaceuticals: “Matters pertaining to the management plan andcompany growth potential”, April 2022

③ Global licensor
Further, in September 2019, SymBio acquired exclusive rights (development,
production and sales) to brincidofovir (BCV), a product with global
2 / 23This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals Ltd. （4582 Growth）

Issued: Jan. 16, 2023

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 performance isthe company’s network of
drug discovery companies
and its own expertise

The success of this business model owes much to the company’s network of pharmacollaborators around the world and the company’s own expertise. Hence, thecompany’s track record. Normally, it takes some 10-20 years to bring a drug frombasic research to the market. In terms of the probability of success, some estimatessuggest that, counting from the chemical compound stage, it is less than 1/30,000,
and even from the POC stage, it is only around 7-8%. In the case of SymBio’s first
product, Treakisym® (generic name: bendamustine), it took only five years or so togo from licensing-in (in 2005) to manufacturing and sales approval (in 2010). In
July 2018 it became the preferred drug for the treatment of malignant lymphomas.
SymBio is a rare bio-venture
In the 17 years since the company was founded SymBio has introduced 6 products,
in that it already has a
3 of which are now under development or at the development planning stage.
product on the market,
which took only five years
from inception to regulatory Members of the SAB （Scientific Advisory Board）
approval

Source: SymBio Pharmaceuticals

This product was selected in2018 as the standard therapy
The company has also
succeeded in expanding
indications

Current SymBio sales come from the company’s first product, Treakisym® (genericname: bendamustine). Treakisym® took only around five years to go from licensingin in 2005 to receiving manufacturing and sales approval in 2010 (the first approved
indications were relapsed/refractory low-grade non-Hodgkin’s lymphoma andmantle cell lymphoma). This was followed by a series of additional approvals: forchronic lymphocytic leukemia (CLL) in August 2016, and untreated low-grade
NHL/MCL in December of the same year. Further, in July 2018 Treakisym® for all
approved indications was for the first time listed as a standard therapy option in the
Hematopoietic Tumor Clinical Practice Guidelines 2018 Edition (edited by: Japan
Society of Hematology), and the B-R therapy combining Treakisym®
(bendamustine) with Rituxan® (rituximab) became the standard therapy. Then, in
March 2021, there was success in acquiring approval for a further indication,
relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). At the same time,
the P-BR therapy combining Roche’s Polivy® and Treakisym® (bendamustine) and
Rituxan® (rituximab) received approval for all previously authorised indications.

3 / 23This 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.

Issued: Jan. 16, 2023

SymBio Pharmaceuticals Ltd. （4582 Growth）

Reference: Types of malignant lymphoma
Lymphoma is a blood disease caused by the cancerization of lymphocytes (a type ofwhite blood cell) that act as immunity cells. There are two major types: Hodgkin’s
lymphoma (HL) and non-Hodgkin’s lymphoma (NHL), with Japanese patients mostlyof the NHL type. NHL, which is the target of Treakisym®, can be divided into three
Focus on human capital and types depending on speed of disease progression. Further, the most common form ofcompany organisation to medium-grade NHL in Japan is diffuse large B-cell lymphoma (DLBCL).

support networking
expertiseandDistribution of malignant lymphoma by type (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 grade lymphoma
Medium-High grade lymphoma

Source: Compiled from Chihara et al, “Differences in incidence and trends ofhaematological malignancies in Japan and the United States”, British Journal of
Haematology, 2014

The company has also developed new formulations and administration modes.
Hence, in addition to the existing freeze-dried formulation it is also promoting a very
convenient liquid formulation, and in September 2020 received approval for an RTD
formulation, which has now been supplied to most medical facilities in Japan.
Additionally, approval was given for the highly convenient (10-minuteadministration) RI formulation in February 2022. As of September 2022, more than
94% of medical facilities have confirmed their intention to use RI administrations,demonstrating a smooth crossover.
Comparison of the FD, RTD and RI (10-minute administration) formulations

Source: SymBio Pharmaceuticals results meeting4 / 23This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals Ltd. （4582 Growth）

Issued: Jan. 16, 2023

1.The impact of generics

In 2022 RTD generics
entered the market

SymBio was the first company in Japan to develop and receive approval for
Treakisym® and a number of new formulations, for the treatment of malignant
lymphomas. From February 2022, however, generics began entering the market.
In 2022, Pfizer (Japan), Meiji Seika Pharma, Koaisei, and Towa Pharmaceuticalreceived approval for the manufacture and sale of generic versions of Treakisym®
intravenous infusion (RTD formulation). In Japan, under the government’s policy of
promoting the use of generics, it seems that a generic is likely to be approved as an
improved product if it includes constituents different from the original product, butthere remains the problem of patent infringement.

On February 25 2022, SymBio notified the four companies of concerns about patent
infringement. The patent in question, which has also been recognized in Japan, isthe property of Eagle Pharmaceuticals Inc., a US company, which is the original
licensor of the RTD formulation and RI administration. There was a previous
instance in the US of patent infringement involving the Treakisym Bendeka® RIadministration. The court in that case found for Eagle Pharmaceuticals (the licensor
was Teva) and enjoined the generics makers from selling the product for a prescribedperiod. On February 28 2022 approval was given for the RI formulation, which iseven more convenient to administer than the RTD formulation, and SymBio began
One of the companies encouraging a switch. On May 11, Meiji Seika Pharma announced it was putting off
SymBio notified of patent the posting of drug prices scheduled for June. With this the risk posed by generics
infringement
concerns receded somewhat and, in fact only one company, Towa, got as far as posting prices
started sales
and starting sales.

CLL and P-BR therapy are
not indicated for generics

The indications approved for the four generics makers in February covered indolent
B-NHL and MCL, but not r/r DLBCL. In June, Towa received approval for the
additional indication of r/r DLBCL. Meanwhile, CLL is covered by exclusive
protection during the reexamination period (until 2026) and cannot be included in
the indications for generic products. Additionally, not approved for the P-BR therapy
to treat r/r DLBCL.

However, on November 9 2022 Towa Pharmaceuticals and Pfizer (Japan) received
regulatory approval for an RI generic, and Pfizer (Japan) began sales on December
In November 2022, two 16. The indications approved for Pfizer included P-BR for r/r DLBCL. SymBio
companies
received also believes this RI generic could be in breach of its patent. On December 16 2022,
approval for their RI SymBio filed a lawsuit against Towa Pharmaceuticals seeking an injunction against
the manufacture and sale of generic products and compensation for damages on thegenerics
grounds of patent infringement. Then, on December 26, SymBio also initiated asimilar legal action against Pfizer (Japan).
Lawsuit filed for patent
infringement

In August the impact ofgenerics was estimated at
JPY200 million (second halfof 2022)
Sales in the July-September
period approximately in linewith expectations

In August 2022 SymBio reduced its forecast for sales by around JPY992 million
from an initial JPY10,992 million to JPY10,003 million. The reasons given for the
downward revision were the continued effects of COVID-19 and the entry ofgenerics, with the latter accounting for an estimated JPY200 million. The estimate
was arrived at by a quantified consideration of the proportion of generics adopted
by each facility, the recent status of anti-cancer drug use by each facility, theproportion of in-patients to out-patients, the ownership of each facility (public
hospitals are under pressure to use generics), and whether or not the facility hasreceived guidance on the freeze-dried formulation. Precise predictions are obtainedby distributors/agents drug expertise, familiarity of MR’s (Treakisym Managers –TM’s) with medical facilities, the status of RI use and the timing of any switch to
RTD. The forecast third quarter sales was JPY2,476 million and for the fourth
quarter JPY2,654 million. Since actual third quarter sales came in at a close
JPY2,481 million the accuracy of the estimation is evident. There were 20 facilities
5 / 23This 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.

Issued: Jan. 16, 2023

SymBio Pharmaceuticals Ltd. （4582 Growth）

As of mid-October, it was receiving deliveries of generics in mid-October, so the concern about generic use isconfirmed that 20 facilities well founded.
had received delivery ofgenerics
SymBio plans to announce new forecasts, including the impact of the emergence ofgenerics for RI administration, at a briefing in February 2023. However, a major
The impact of the RI consideration is that haematological oncology departments are relatively cautious
generics will now be closely about generics since they differ slightly from Treakisym® in terms of constituents.
scrutinised
In addition, prescriptions are still expected to increase due to market share expansion
because the share of the B-R and P-BR therapies in treating r/r DLBCL is still lessthan 50%. Put more accurately, the B-R and P-BR therapies in the treatment of r/r
Medical facilities relatively
DLBCL started as late-line intervention (third-line or fourth-line) but interventions
cautious about generics
at earlier stages have increased. This could significantly boost sales and explains theefforts being put by the sales department into expanding use in the area of r/r
Still room for the BR and P- DLBCL.
BR therapies to increase
market penetration
Treakisym® sales trend

3000

2704
2557
2406

2500

（mi l lion yen）
2649
2481

1500

1600

2316

1900

1900

2000

（2654）（2476）

1726

1700
1420

1000

r/rDLCBL
Adaptation Expansion

500
02020 2020 2020 2020 2021 2021 2021 2021 2022 2022 2022 2022
1Q
2Q
3Q
4Q
1Q
2Q
3Q
4Q
1Q
2Q
3Q
4Q

Note: Values in parentheses are forecasts as of August
Source: SymBio Pharmaceuticals

6 / 23This 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.

Issued: Jan. 16, 2023

SymBio Pharmaceuticals Ltd. （4582 Growth）

Reference: 3rd quarter (July-Sept) 2022 results and full-year 2022 revised forecast
Sales in the July-September quarter came in at JPY2,482 million, below the level ofthe previous period, mainly because of the continued effects of COVID-19, but thiswas still in line with the predicted JPY2,476 million. There was not much of an
impact from generics since, as noted above, generic RI administration had not yet
been approved, and the scope of indications was limited.
Gross profit from sales came in at JPY146 million, making it look as though the grossprofit rate had fallen sharply, but this was in fact due to the payment of a JPY550
million sales milestone to Eagle Pharmaceuticals. This needs to be excluded, leaving
a gross profit margin of 80.8%. In the October-December quarter a gross profit of
79.3% is expected but yen depreciation means the trend is slightly more sluggish thanin the first half.
R&D outlays in the July-September quarter totaled JPY554 million but are likely torise to JPY920 million as BCV-related R&D accelerates in the October-December
quarter. As a result, the plan is for total SG&A to go from JPY1,204 million in the
July-September quarter to JPY1,689 million in the October-December quarter.
However, compared with the revised management plan in August, because of
downward pressure on SG&A, operating revenues for the full 2022 year have beenrevised up by JPY230 million to JPY2 billion. In addition, full-year recurring profit
in 2022 has been revised up by JPY550 million to JPY2.3 billion due to currency gains
on foreign currency assets, and net earnings has been revised up by JPY170 million
to JPY1.65 billion.

Results – quarterly trend and 2022 full year
（JPY-mil）

Jan-March
Sales

2,315

April-June
2,558(forecast as at August)Gross Profits

Jly-Sept

Oct-Dec

2022

(Est)

(Rev. plan) (Aug plan）

2,482

2,648

(2,476)(2,654)10,003

10,003

7,567

8,106

1,898

2,112

1,456

2,101

82.0%

82.6%

58.7%

79.3%

SG&A

1,388

1,285

1,204

1,689

5,566

6,336

R&D

469

540

554

920

2,483

2,524

Op. income

509

863

216

412

2,000

1,770

Rec. profit

478

969

396

457

2,300

1,750

Net profit

163

945

447

95

1,650

1,480

Source: Compiled by Fair Research Inc, using short-form earnings reports

7 / 23This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals Ltd. （4582 Growth）
2.
The B-R therapy has
becomethestandard
treatment for DLBCL, theprevalent type of malignant
lymphoma

Issued: Jan. 16, 2023

Trends in DLBCL therapy development and Treakisym®

Looking back briefly at the history of DLBCL therapies, this condition, particularly
r/r DLBCL, had no effective treatment until the development of multi-drugchemotherapy (such as the CHOP therapy). While CHOP was developed in the
1970’s and DLBCL ceased to be incurable, its effectiveness left much to be desired.
In 1997, the R-CHOP therapy using Rituxan® (generic name: rituximab) wasapproved, providing a much better OS than CHOP. Nevertheless, one-third ofpatients failed to recover or suffered a relapse, making this an area of high unmet
medical need. Additionally, malignant lymphomas are particularly prevalent in theelderly, who are susceptible to the side-effects of the multi-drug chemotherapy usedin R-CHOP. In contrast, the B-R therapy (P-BR therapy) has fewer side-effects anda high response rate, thus allowing it to make rapid inroads in the area of r/r DLBCL.
Despite being launched only in the second half of 2021 it has already captured
around 45% of the market and looks set for 60%.
Reference
Results of the Phase-3 trials of the B-R therapy targeting r/r DLBCL wereannounced at the European Hematology Association conference (EHA) in June
2020. The overall response rate (ORR) reported was a high 76.3%, and thecomplete response rate (CR) was 47.4%. An important finding was the efficacy inelderly patients (age 65 and over) for whom HSC transplantation was not thestandard therapy. In addition, it was reported that the complete response rate for
non-GCB DLBCL’s, which have a poor prognosis, was 39%.

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

Source: SymBio company briefing

As noted above, Treakisym® has secured its position as a core therapy in thetreatment of blood cancers. However, in recent years a number of new therapies inthe blood cancer area targeted by Treakisym® have emerged, requiring a reexamination of the competitive landscape.

In recent years, in the area ofmalignantlymphomatreatment there has been a
lot of development work
being doneon newmodalities using antibody
therapy and immunotherapy① Indolent-B-NHL (low grade B-cell non-Hodgkin’s lymphoma)
For indolent-B-NHL, the combination therapies (BR therapy and B-G therapy) of
Treakisym® and an anti-CD20 antibody (rituximab, trade name Rituxan) or
obinutuzumab (trade name: Gazyva) are the standard and recommended treatment
options in the main clinical practice guidelines for hematopoiesis. In January 2020,a therapy combining lenalidomide (trade name: Revlimid®) and rituximab (R-R
therapy) was approved for relapsed /refractory indolent-B-NHL. Revlimid® is athalidomide derivative and may be teratogenic, so appropriate control procedures
have been established. Treatment should be selected based on the individual patient's
condition and the drug’s characteristics, but the B-R therapy is still considered oneof the standard therapies.
8 / 23This 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.

Issued: Jan. 16, 2023

SymBio Pharmaceuticals Ltd. （4582 Growth）

Reference: In the AUGMENT study, which underpinned approval of the R-R therapy,
the median progression-free survival (PFS) for R-R was 39.4 months, well above the14.1 months of rituximab alone. While no direct comparison can be made, in thecomparative tests of the CHOP-R therapy and B-R therapy mentioned earlier, the BR therapy registered a median PFS of 69.5 months.

While an R-R therapy to
treat
relapsed/refractoryindolent B-NHL has been
approved, there has been nochange in the standard ② Relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL)
therapy status of the B-R＜P-BR therapy and B-R therapy＞
therapy
In June 2019 the FDA announced the expedited approval of a three-drug therapy (PBR) for the treatment of transplant-ineligible relapsed or refractory diffuse large Bcell lymphoma (r/r DLBCL). This therapy consists of the B-R therapy of
bendamustine (Treakisym®) + rituximab (Rituxan®) together with the anti-CD79b
antibody drug-conjugate polatuzumab vedotin (product name: Polivy®, developedby Genentech and Roche). In Japan, an application for approval of the combined BR and Polivy® therapy was submitted by Chugai in July 2020, and approved in
March 2021. While the amount of Treakisym® required for the B-R therapy alone
is 120mg per dose, for the three-drug therapy it is 90mg.
Polivy® was the first Reference: P-BR therapy vs B-R therapy (r/r DLBCL)
antibody drug conjugate
Data shows that the complete response (CR) rate for P-BR is 40% (GO29365(ADC) worldwide to receive
study; Phase-1b/2. Source: Sehn LH e al., J Clin Oncol, 2019). In addition, Phaseapproval
2 trials in Japan (P-DRIVE trials) produced a CR rate of 34.3%. The CR rate for
Polivy® is not used alone
but in combination with
Treakisym® and Rituxan®
(Pola+BR therapy)

the B-R therapy, whose cohort was included in the GO29365 study, was 17.5%.
Elsewhere, the Phase-3 results for the B-R therapy on r/rDLBCL and released by
SymBio, produced a 47.4% CR rate, a 76.3% overall response rate (ORR), and amedian overall survival rate (mOS) of 29.2 months. (Note: 70% of the patients onwhom genetic analysis was conducted were of the non-GCB type; 57.5% of thepatients in the B-R therapy GO29365 study cohort were non-GCB).
GO29365 Trial
Pola-BR

SymbioB-R

B-R(90mg/㎡）(120mg/㎡）

ORR(％）

70.0

32.5

76.3

CR(％）

57.5

20.0

47.4

ｍOS

12.4

4.7

29.2

(month)( ) dose of Treakisym

Source:Compiled from Sehn LH et. al, J Clin Oncol 2019, and SymBio IR materials
Since the two patient cohorts have different backgrounds we cannot make asimple comparison. Also, in the GO29365 B-R trials the Treakisym® dose
administered was 90mg/m2, while the Treakisym® dose administered in the
Phase-3 B-R trials released by SymBio was 120mg/m2. This means that thedifference in response, for the same B-R therapy, could be due to the difference indosage. It is not at present possible to say one is superior to the other.
In any event, P-BR and B-R will remain the main therapies for r/r DLBCL.

Pola-BR and B-R are both
becoming mainstream in the
In December 2021, Chugai Pharmaceutical submitted an application for the P-RCHP
treatment of r/r DLBCL
therapy targeting first-line DLBCL (Treakisym® non-indicative). However,clinicians are divided on how to evaluate the clinical test results since there was onlya small difference from R-CHOP in OS terms. It is unclear at the present time
whether or not disease recurrence is reduced using P-RCHP. If recurrence is lower,
then the r/r DLBCL market could shrink and the proportion of refractory patients
resistant to treatment would rise. In addition, if P-RCHP therapy is selected for the
9 / 23This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals Ltd. （4582 Growth）

Issued: Jan. 16, 2023

1st-line, it is currently unknown whether P-BR therapy will be effective in refractory
cases and recurrent cases from the 2nd-line onwards.
＜The CAR-T therapy＞
In the area of r/r DLBCL treatment CAR-T therapies are becoming more widely
accepted, with such CAR-T therapies as Kymriah®, Yescarta® and Breyanzi®
having already received approval. CAR-T is a T cell with a CAR (chimeric antigen
receptor) that specifically binds to the cancer antigen CD19 on the surface oftumorised B cells. T cells specifically attack cancerous B cells, and the response rateis thought to be in the area of 70-90%.
Previously, it was thought that bendamustine (Treakisym®) could be used as apretreatment for the CAR-T therapy. Today, however, various guidelines andreviews have recommended that the use of Treakisym® be avoided in pre-treatment,such that there are now almost no cases of the P-BR and BR therapies being usedprior to CAR-T.
However, the target patients for CAR-T therapy are currently limited mostly to those
The CAR-T therapy faces who are not indicated for transplantation (mainly third-line). In addition, the use ofmany challenges before it autologous cells in CAR-T therapy requires sophisticated technology andcan be widely adopted
equipment, and is time-consuming. It is also extremely costly (said to be in excessof JPY30 million per procedure) and can only be carried out at facilities that canhandle adverse events, such as cytokine release syndrome. The use of CAR-T
therapy is thus, in any case, likely to be extremely limited.

Development of γ δ CAR-T
therapy is still in progress

Recently, a lot of interest has been shown in the development of γ δ CAR-T therapies
that can be used off the shelf without autologous cells. However, there is as always
a number of problems about safety, and in the case of research on the more advanced
AD-001 there is a problem with sustaining effectiveness (after 6 months following
the start the response rate falls to 20%). It therefore seems that it will not becompetitive for some time.
CAR-T and BiTEs - image

Source: Batlevi CL et al. 「Novel immunotherapies in lymphoid malignancies」
Nat Rev Clin Oncol 201610 / 23
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whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

Issued: Jan. 16, 2023

SymBio Pharmaceuticals Ltd. （4582 Growth）＜BiTEs （Bispecific T cell engagers）＞
A lot of interest is now being A promising therapy now being developed which has fewer barriers to overcome
shown in the development of than CAR-T is bispecific T-cell engagers (BiTEs). This involves a cancer
BiTEs （ bispecific T cell immunotherapy that induces a complex containing a portion that binds to CD19 andCD20 appearing on the surface of tumorigenic B cells and a portion that binds toengagers）
CD3 appearing on the surface of T cells, and transforms T cells, which are immune
cells, into tumors.
In October 2022, AbbVie Inc. applied for approval of Epcortimab for the third-line
A number of late-line treatment of NHL. Of particular note is that, even cases which were nontherapies
havebeen responsive to CAR-T have evidenced a 54% ORR.
approved
Roche is developing two bispecific T cell engagers. Glofitamab is one, which has
undergone Phase-2 trials and for which interim results show a 52% ORR and a 39%
CR . The other is Mosunetuzumab, which has already been approved in Europe andtheUS for the treatment of relapsed/refractory follicular lymphoma. Its brand nameis Lunsumio and Phase-2 SUNMO trials in combination with Glofitamab to treat r/r
DLBCL are now being undertaken.

Blinatumomab

Glofitamab

r/r aNHLr/r DLBCL(2L+)

r/r aNHL

Targeting
Cases

25

Phase

Ph2

Ph2

（NP30179）

Ph1

155

129

Ph2

NCT02500407

68

19

90

of which, pre-CAR treatment

ORR

43%

CR

19%

CRS

13％＞G3

Roche GROUP

Product name: BLINCYTO

Amgen/Astellas

Developer

FDA in Sept. 2016 and PMDA in Aug.

Notes

2018 approved all

Roche GROUP

Regeneron

AbbVie/Genmab

Now at Phase2 for r/rDLBCL (2L+)（STARGLO studies、SUNMO trials）(SUNMO trial of Glofitamab combination)

Approved in Europe and US for r/r FL

Now at Phase2 for FL(2L+)

19%1% of NHL totalNow at Phase2 for DLBCL (2L+)＞G3

3.9%>G3

26%

39%

49%

52%

35%

60%

（CELESTIMO study）

37%

Trade name: Lunsumio

Now re-doing Phase2 (NCT03888105)

Suspended due to treatment-related

deathsPhase3 targeting DLBCL(NCT04628494)

Xencor

66%7%>G3

2.5%＞G3

Phase2 trials on r/r NHL withtafasitamab and lenalidomide

Adicet

ASH reports ORR and CR for 24 2022 cases
AffimedRecurrence 6 months later

80%

24%

r/r iNHL

39%

Ph1

33%

34%

GO029781（ELM-1）

63%

136

21

54%

Regeneron

Ph2

2022Oct 3-L NHL application

IGM

157

r/r FLr/r NHLof which, DLBCL(>80mg)

of which, pre-CAR treatment

r/r DLBCL（3L＋）（ENCORE NHL-1）

Odronextamab combination

18%

71%

In 2021 ASH reported unsurprising results

47%

97%

（Ph1） （Ph1）

22%

Ph1

ATHENA-1

260 Ph1/2（IGM-2323）

Ph1/2

240 Ph2

9 Ph1

BiTEs and relapsed/refractory B-cell non-Hodgkin lymphomaTypeCD19/CD3

CD20×2/CD3

CD20/CD3

Mosunetuzumab CD20/CD3

Odronextamab

CD20/CD3

r/rDLBCL

Epcortimab

NHL,CLL

r/rNHL

CD22/CD28

r/rNHL

CD20/CD3

CD20/CD3

REGN5837

CD30/NK

Imvotamab

Plamotamab

γδCAR-T(CD20) NHL

AFM13

Others

ADI-001

Source: Fair Research Inc. using various resources

At present, it is unclear what indications bispecific T cell inducer antibodies will beapproved for. In addition to which, the response rate of the familiar B-R therapy isby no means low (while a simple comparison cannot be made, it has an ORR of 76%
and a CR of 47% against r/r DLBCL.) Unless a therapy emerges which is clearlysuperior to the B-R therapy in terms of responsiveness, it is likely that the positionof Treakisym® is assured for the time being. One long term side effect ofIn the absence of a treatment Treakisym® is that it inhibits the activity of T cells and since the bispecific antibody
which clearly exceeds the exerts its effect by engaging T cells, the possibility of combined use is thought to be
response rate of the more low.
familiar B-R therapy the
position of Treakisym isassured11 / 23
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals Ltd. （4582 Growth）

By acquiring BCV SymBio
has become a global pharma
specialising in haematology
and is expanding into
oncology and cranial nerve
diseasesIssued: Jan. 16, 2023

3. Brincidofovir (BCV) development
SymBio is now a global pharmaceuticals company specializing in haematology, andis beginning to expand its foothold in the oncology and neurological disease fields.
On October 1 2019 SymBio announced that, as a strategic product successor to
Treakisym®, it had acquired from Chimerix Inc. exclusive global license rights(development, manufacturing and sales) to brincidofovir (BCV) for all diseases
except smallpox. Developed by Chimerix, BCV is highly active and effective
against multiple infectious diseases.
Heretofore, SymBio has acquired licenses overseas and developed them in theJapanese market, but with this agreement it has evolved into a licensor of developed
products which it licenses out globally (parenthetically, in September 2022 Chimerix
announced it had transferred the BCV license to Emergent BioSolutions Inc., but
this has no effect on the rights acquired by SymBio).
SymBio first started development of BCV in haematology targeting viral infections
after hematopoietic stem cell transplantation. It then expanded development to viral
infections during organ transplantation. The strategy now is to develop BCV totarget "therapeutic voids" for which existing antiviral agents have not been
approved. As noted below, in addition to transplantation-related fields, the company
is also looking at a wide range of fields related to viral infections, cancer, nervous
system diseases, ophthalmology, and dermatology.

Source: SymBio Pharmaceuticals company briefing

After development of the transplantation-related area the company plans to work on
GBM (glioblastoma, a malignant brain tumor) and MS (multiple sclerosis).

AdV
infection
after
hematopoietic stem celltransplantationinhematological cancer is thefirst target
Source: SymBio Pharmaceuticals company briefing
12 / 23
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whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

Issued: Jan. 16, 2023

SymBio Pharmaceuticals Ltd. （4582 Growth）① Disseminated adenoviral infections after hematopoietic stem celltransplantation
In general, in the case of hematopoietic stem cell (HSC) transplantations and organtransplantations (SOT), irradiation and immuno-suppressants are used to suppress
rejection, thus rendering the patient vulnerable to infection. It used to be that CDV,FOS or some other anti-viral drug was used to offset this, but with the attendant riskof nephrotoxic side-effects. Hence, the importance of BCV, which has low risk ofnephrotoxicity, to SymBio's goal of becoming a specialty pharmaceuticals company
in the field of haematology.
SymBio originally planned to develop BCV to target viral infections after HSC
International joint Phase-2 transplantations, an area with poor prognosis, high lethality, and of strong unmet
trials on AdV virus medical needs. After a meeting of the company’s Global Advisory Board in February
infections in children – FPI 2020 it was decided that the first development target would be adenovirus infections
contracted after HSC transplantation, and that tests on children would be given
achieved in August 2021
particular priority. Since Chimerix data had already confirmed safety, the first stepwould be Phase-2 dosing tests, after which, when POC was confirmed in trials onchildren, development directed at adults would start.
SymBio submitted an application to conduct Phase-2 joint international trials of
BCV for adenovirus infections in children on March 10, 2021 (registration number
NCT04706923). On April 26, the FDA gave fast track examination status to
Development moving ahead development programs for pediatric adenovirus infections. On August 16, 2021,
to global Pivotal trials when SymBio registered its first patient (FPI). In January 2022, an application to conduct
joint international trials are clinical trials was submitted in the UK.
completed in the first half ofFirstly, in Phase-2a ATHENA trials, four groups of six patients each are to receive
2023
stepped increases in doses to test safety and tolerance. At the present time,registrations have been completed up to and including two cases in the third group(depending on the results of the third group the FDA may permit registration to close
early). Phase-2 is scheduled for completion in the first half of 2023.
First cohort:

BCV 0.2mg per1kg body weight.
Two administrations per week for more than 4 weeks

Second cohort: BCV 0.3mg per 1kg body weight.
Two administrations per week for more than 4 weeks
Third cohort:

BCV 0.4mg per 1kg body weight.
Two administrations per week for more than 4 weeks

Fourth cohort:

BCV 0.4mg per1kg body weight.
two administrations per week for more than 4 weeks

If all goes according to plan, Phase-3 (several hundred cases) will start in the firsthalf of 2024 and an NDA to the FDA will be submitted in 2026-2027 prior to a
Development work to treat market launch in 2027-2028.
viral infections after kidneytransplantations is viewed Phase-2 trials for adult cases are expected to begin in around 2027, when approval
for children is scheduled.
with promise

13 / 23
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whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals Ltd. （4582 Growth）

Start
of
patient
administrationsforinternational joint tests(Phase-2)

Phase-2 completion set for
first half of 2025

POC could be the trigger
for a corporate tie-up

Issued: Jan. 16, 2023

② Kidney transplantations – BK virus infections
SymBio plans to move development beyond viral infections following
haematopoietic stem cell transplantation to viral infections at the time of organtransplantations. Organ transplants are more common in the West than in Japan. For
example, while some 1,600 kidney transplantations are carried out annually inJapan, 20,000 are carried out in the US and around the same number in the five
major European countries. Of these, an estimated one-third contract the BK virus
and the CMV (cytomegalovirus). While the number of infections is a quite low 560
in Japan, in the US + 5 main countries of Europe the total is around 15,000 cases
annually.
SymBio is scheduled to begin development in Australia, Japan and one other country
and on June 14 2022 submitted to the PMDA an application to conduct Phase-2 joint
international clinical trials of BCV on BK viral infections after kidneytransplantations. Additionally, on August 22 2022 the company submitted a clinical
trials plan to the Australian Therapeutic Goods Administration (TGA). In these joint
international trials, dose-setting tests are first carried out, and the plan is to have 3
groups of 12 cases each. The beginning of administrations in Australia wasannounced on December 13 2022. Phase-2 is scheduled for completion in the firsthalf of 2025.
Cohort 1 BCV 0.3mg per 1kg body weight
Two administrations per week for 8-14 weeks
Cohort 2 BCV 0.4mg per 1kg body weight
Two administrations per week for 8-14 weeks
Cohort 3 (expanded cohort) BCV recommended dose
Two administrations per week for 8-14 weeks

The company plans to undertake its own trials, but the organ transplantations areoutside its area of expertise, and there are not enough cases in Japan. For those
The company plans to move reasons it is thinking of partnering with a European or US company to promotealso into the area of development and sales in the area of organ transplantations. The same goes foradenovirus development, and the establishment of POC (at Phase-2 completion)
oncology
could be key to setting up collaborative partnerships.
Additionally, the company in November 2022 entered a research sharing agreementwith the Pennsylvania State University, and started non-clinical tests evaluating theefficacy of BCV using the polyomavirus infection model. Polyomavirus is a doublestranded DNA virus that causes serious disease and existing antiviral agents havevirtually no effect. The BK virus and JC virus are both types of polyomavirus.

14 / 23
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whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals Ltd. （4582 Growth）

Issued: Jan. 16, 2023

③ Development targeting glioblastoma (GBM)
There is a connection Glioblastoma (GBM) is the most common malignant brain tumor and is an area of
betweenthe extremely high unmet needs, with a survival rate of only 15 to 20 months and a 5cytomegalovirus
and year survival rate of 5% or less. It is known that about 50% of GBM patients aremalignant brain tumours
CMV (cytomegalovirus) positive. Various drug therapies are these days being
developed for various conditions but there is no drug development candidate
targeting CMV.

While the CMV-brain tumour mechanism is certainly not fully understood, researchusing a mouse model conducted at Brown University shows that CMV infection
enhances the NF-κB signal, leading to increased expression of PDGF-D, anangiogenetic factor, which promotes the growth of GBM cancer cells. It has also
been found that the antiviral agent cidofovir (CDV) inhibits CMV reactivation in
CMV-infected mice and improves survival rates. (The Journal of Clinical
Investigation, 2019, Sean E Lawler et al.)
SymBio is now considering whether or not to develop BCV as a treatment for GBM
based on this and other research. The mechanism of action of BCV against GBM
consists of BCV converting to CDV-PP in the cell, inhibiting the replication cycleof tumor cells and inducing apoptosis. BCV inhibits reactivation of CMV and isthought to have an inhibitory effect on tumor growth.
SymBio is now doing joint research with the University of California on evaluating
the anti-tumour potential of BCV. It is also working with Brown University to
When data from the joint evaluate BCV’s anti-tumour effectiveness and its tumour malignancy suppression
researchwith
US effect. As soon as the data from this research is available a decision will be made on
universities
becomes what the next stage should be.
available a decision will bemade on the next step
④ Expansion into the field of neurovirology (multiple sclerosis)
The EC50 value of BCV against the Epstein-Barr virus (EB virus) is significantly
lower than that of other antiviral agents, and BCV is known to have extremely highantiviral activity against the EB virus. The EB virus is also known as humanherpesvirus 4, and 95% of adults are infected. It is almost entirely symptom free andis inactive in lymphocyte B cells in a latent state. However, in some people it isAttention
focusedon thought to cause blood cancers and other intractable diseases (such as autoimmune
antiviral effect of BCV on diseases).
EB virus
SymBio in February 2022 announced it was considering making multiple sclerosis(MS), one type of autoimmune disease, a new target indication of BCV. In addition,
in August 2022, the company concluded a joint research exchange agreement with
the National Institute of Neurological Disorders and Stroke (NINDS), within the
National Institutes of Health (NIH), to evaluate BCV’s antiviral effect on the EB
Thought is being given to virus. Under this agreement, SymBio provides NINDS with BCV for non-clinicalmultiple sclerosis as an tests to evaluate the potential effect on diseases thought by NINDS to be caused by
the EB virus. It is possible that in late 2023 the collaboration will be strengthened.
additional indication
If that comes about the major pharmaceutical companies are bound to take aninterest.
Concluded a joint researchexchange agreement with15 / 23
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals Ltd. （4582 Growth）
the National Institute of
Neurological Disorders andStroke (NINDS), within the
National Institutes of Health(NIH)

Issued: Jan. 16, 2023

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

Source: Multiple Sclerosis.jp

The mechanism by which the EB virus causes MS is not fully understood, but
epidemiological surveys have supported the association. A Harvard research teamanalyzed a sample of around 10 million serving U.S. military personnel, and foundthat 955 cases were diagnosed with MS during military service. Analysis of these955 cases found that the risk of contracting MS after being infected with the EB
virus was 32 times higher than that from other viral infections.（Science, January13
2022, “Longitudinal analysis reveals high prevalence of Epstein-Barr virus
associated with multiple sclerosis”）
A research team at Stanford University has recently put forward a powerful new
hypothesis explaining the mechanism of MS onset by EB virus (Nature, January 24
2022: “Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and Glial
CAM”) According to this hypothesis, the EB virus transcription factor, EBNA1, andthe glial cell adhesion molecule, GlialCAM, in the brain are structurally similar,
leading the lymphocytes that produce autoantibodies which recognize both tomigrate to the center, accidentally damaging their own myelin, leading to the onsetof multiple sclerosis (MS). This hypothesis is supported by the effectiveness ofblocking the transfer of lymphocytes into the central nervous system (sphingosin 1phosphate receptor agonist) or blocking the migration of lymphocytes from thelymph nodes (anti-α4 integrin antibody) and the effectiveness of molecular-targeteddrugs such as the anti-CD20 antibody (ocrevus) in targeting B-cells. SymBio
believes that if our understanding of this mechanism is correct, the progression of
MS can be inhibited by the prompt elimination of the EB virus using BCV after the
onset of MS.

16 / 23
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whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals Ltd. （4582 Growth）

Issued: Jan. 16, 2023

⑤ Applications in the area of haematological malignancies (NK/T cell
lymphoma applications)Applications of BCV are
also being studied in thefield of haematological The EB virus was the first human cancer virus, an oncovirus isolated from Burkitt's
lymphoma, a type of blood tumor (1964), and is known to be associated with various
tumours
cancers. Involvement in nasopharyngeal cancer, Hodgkin’s lymphoma, NK/T cell
lymphoma, and others has been clarified. However, infection is not necessarily thesame as cancer onset. Rather, genetic changes in infected cells contribute tocarcinogenesis by the EB virus.
In December 2022 the American Society of Hematologists (ASH) reported that
results of joint research by SymBio and the National Cancer Centre of Singapore,
had demonstrated BCV was effective in non-clinical trials on rapid onset NK/T cell
lymphoma, for which to date there has been no effective therapy.

Occurrencesof
NK/T
lymphoma are particularly
frequent in Asia (most NK/T cell lymphomas are malignant lymphomas originating in NK cells or T cells,
patients are infected with the occurring mainly in the perinasal and cutaneous areas, primarily as extranodal
NK/T-cell lymphomas. This disease is more common in East Asia and SouthEB virus)
America than in the US or Europe. While it accounts for less than 1% of nonHodgkin’s lymphoma in Europe and the US, in East Asia (China) it accounts foraround 10%. In addition, most patients test positive for the EB virus.
Distribution of NK/T lymphomas

Source: ASH, December 2022

The causes underlying carcinogenesis are no means well understood but thefollowing mechanism is a possibility. The EB virus exists in a dormant state but
expressing various EB virus genes is in the cancer cells within the NK/T lymphoma.
For example, EBNA-1, EBNA-2, LMP-1, LMP-2, and so on. When EBNA-1 isexpressed, p53 is suppressed and cancer cell apoptosis controlled. In the case of
LMP-1, the activation of NF-κB suppresses apoptosis. LMP-2 is thought to promote
BCV
suppresses
the carcinogenesis via the P13K and MAPK pathways.
expression of genes that
promote tumor malignancy,andalso
induces Genes promoting EBV tumor malignancy
immunogenic cell death
EBNA-1＝P53 instability＝＞apoptosis suppression
EBNA-2=>MYC, LMP1/2 expedited expression=>immortality
LMP-1==＞NF-κB activation＝＞apoptosis suppression

LMP-2 ＝PI3K pathway /MAPK pathway activation=>involvement in carcinogenesis
In the area of cranial nerve This research confirmed that BCV not only suppresses the expression of genes
diseases, there is also the which promote the EB-virus induced tumour malignancy, but destroys tumour cells
possibility of application to and induces immunogenic cell death that activates cancer immunity. As a result, it
17 / 23
This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors, and not for solicitation of securities trading. Although this is basedon the information and materials that Fair Research judged reliable, there is no guarantee of accuracy, credibility, completeness, suitability and timeliness. Fair Research shall not take any responsibility
whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals Ltd. （4582 Growth）

Issued: Jan. 16, 2023

treat the after effects of is expected to be effective in combination with the immunotherapy provided by, for
COVID-19, and Alzheimer's example, anti-PD-1 inhibitors.
disease.
Note: Immunogenic cell death
When cancer cells die, intracellular matter is expelled from the destroyed cells anddendritic cells, a type of immune cell, receive a signal that cancer cells have been
destroyed. Effector memory cells are taught how to recognise cancer cells, bringing
the immune system into play. This type of cell death is called immunogenic cell death.

⑥ Possible therapy for Alzheimer’s
Furthermore, there is increasing evidence that the herpes simplex type-1 virus (HSV1) is a contributing factor in the occurrence of Alzheimer’s disease (Nikkei-FT
Infectious Diseases Conference, October 24, 2022, as reported in the Nikkei
newspaper). According to the article, research at Tufts University has raised thepossibility that the VSV (varicella-zoster virus) activates HSV-1 and leads the tau
protein and amyloid β to accumulate, reducing the functioning of nerve cells. In
particular, it has been pointed out that carriers of the APOE4 gene are receptive.
Research at Oxford University has also shown that when HSV1 is present in thebrain the combination with APOE4 increases susceptibility to Alzheimer’s.
On December 19 2022 SymBio concluded a Sponsored Research Agreement with
Tufts University, using the 3-D brain infection model established by Tufts to conduct
non-clinical tests to evaluate the efficacy of BCV in a herpes simplex virus (HSV).
Longer term, this may lead to the development of an anti-virus to treat Alzheimer’s.
Note: HSV infection model using 3-D brain model
An experimental system in which human neural stem cells are cultured using
collagen-filled porous silk protein sponge as a base material, and then proliferated
and differentiated into a functional network of neurons and glial cells that are also
susceptible to virus infection. In this experimental system, electrophysiological
functions, amyloid-β fibril formation due to HSV infection, neuroinflammation, etc.
can be evaluated under conditions excluding other factors.

⑦ After effects of COVID-19
SymBio is now considering the possibility that the after-effects of COVID-19 (long
COVID symptoms: fatigue, brain fog, rash, etc.) may be caused by the reactivationof the EB virus by an inflammatory reaction after COVID-19 infection. In July 2021,
Professor Gold of the World Health Organization noted in The Journal of Pathogens
that most patients with long COVID symptoms have registered positive for EB virus
reactivation, versus only 10% in the control group.

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SymBio Pharmaceuticals Ltd. （4582 Growth）

Issued: Jan. 16, 2023

Reference 1: Principal features of brincidofovirCompared to other anti-viral drugs such as cidofovir (CDV) and Foscarnet (FOS),BCV is highly active and effective against multiple infectious diseases.

Brincidofovir (BCV) is highly active across a broad spectrum

Source: SymBio Pharmaceuticals company briefing
Note1: The figure above shows antiviral IC50 activity data; lower readings indicate
higher activity
Note 2: Cidofovir (CDV):
Was approved by the FDA in 1996 for the treatment of cytomegalovirus retinitis in
AIDS patients. CDV is a cytosine nucleotide analog which inhibits the replication of
DNA viruses such as adenovirus, papillomavirus, and polyomavirus as well as theherpesvirus family. CDV is also effective against ganciclovir (GCV) resistance (UL97
gene mutation) and is thought to be of use when foscarnet (FOS) cannot be
administered due to the development of GCV resistance. It is not approved for use inJapan.
As can be discerned from the previous table, cidofovir (CDV) has a similar level ofactivity across as broad a spectrum as BCV. However, while CDV is nephrotoxic anddifficult to handle, BCV has low toxicity and is very safe despite being highly active.
Reference 2: BCV action mechanism

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

Source: SymBio Pharmaceuticals IR materials

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SymBio Pharmaceuticals Ltd. （4582 Growth）

Issued: Jan. 16, 2023

Reference 3: Possibility of using rigosertib and Treakisym® (bendamustine) in
combination
Analysis is now being conducted of joint research undertaken with Kyoto University
on how bendamustine (Treakisym®) affects the LUBAC anti-tumour mechanism. By
verifying the effects on other pathways involved in this mechanism, the aim is todevelop new treatment methods. At the same time, joint research is being
undertaken with Tokyo University and Gunma University on the efficacy of
combining Treakisym® with other drugs, including rigosertib. The direction of future
development could possibly emerge in the middle of next year.

Source: SymBio Pharmaceuticals company briefing

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whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
intellectual property right of this report belongs to Fair Research, and any copy, transmission or quote of any contents without permission is legally prohibited.

SymBio Pharmaceuticals Ltd. （4582 Growth）

Issued: Jan. 16, 2023

＜Conclusions＞
SymBio in 2020 built an in-house sales structure and acquired brincidofovir, thereby
laying the groundwork for the company’s growth as a haematology-specialised
The effect of generics
pharma with a global license. Then, in 2021 it expanded the diseases for which its
constrained at the present
main product, Treakisym®, was indicated to r/r DLBCL, since which time its
time
finances have moved firmly into the black. While Treakisym® generics began
emerging in the second half of 2021, the impact is so far limited because of caution
on the part of haematology departments towards generics and differences inapproved indications. Additionally, SymBio is taking Towa Pharmaceuticals and
Now taking legal action
againsttwo
generics Pfizer（Japan） to court over patent infringement and is seeking an injunction on the
manufacture and sale of generic products and the payment of damages.
manufacturers
It looks as though SymBio will for the time being seek to maintain sales growth byincreasing the use of the B-R therapy and P-BR therapy in the treatment of r/r
DLBCL. Given its high marginal profit ratio, earnings growth momentum is
Treakisym® sales could probably inherent.
grow if the penetration rateof the B-R and P-BR If Treakisym sales do peak out, new growth drivers will emerge from the expansion
therapies risesof licensed-in products in the company’s specialist field of haematology, and fromcollaboration on developing and launching of brincidofovir (BCV) for viral
Expansion of indications infections after hematopoietic stem cell transplantation and viral infections after
now in sight for BCV, the kidney transplantation.
next growth driver

SymBio’s business development strategy

Source: SymBio Pharmaceuticals company briefing

21 / 23
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whatsoever for any results including direct or indirect damage arising from the use of, or reliance to, this report. Investors should take their own responsibility for securities and other transactions. The
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SymBio Pharmaceuticals Ltd. （4582 Growth）

Issued: Jan. 16, 2023

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SymBio Pharmaceuticals Ltd. （4582 Growth）

Issued: Jan. 16, 2023

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