ANALYST NET Company Report

SymBio Pharmaceuticals Limited
Issued: Nov. 7, 2019（4582 JASDAQ）

Transformation to a Global Licensor
Specialty pharma with multiple promising new drugs

Follow-Up Report

SymBio does not itself undertake drug discovery research but rather uses its insights and its links
with drug discovery companies around the world to license in and develop promising new drugs.
In particular, it focuses its development efforts on drugs for less common conditions in oncology
and hematology, in which areas, despite a definite medical need, the major pharmaceuticalcompanies show little interest. In these niche areas, the company seeks to maximise market shareand revenues. In most cases, new drug candidates so selected have a proven track record of efficacy
and safety, and therefore entail limited business risk. Thus, the company’s first product success
was Treakisym®, which went from licensing-in by the company through regulatory approval andmarket launch in a mere five years, and more recently achieved standard therapy status. The
company is now pursuing the development of further applications and changes in formulation as
steps in product life cycle management. At the same time, it is making preparations to have its own
in-house sales force by 2020 and to evolve as a pharma specializing in blood conditions. Phase 3
clinical trials of rigosertib, the company’s second product, targeting the blood disease
myelodysplastic syndrome, seem to be going well. Further, in October 2019 the company
announced it had acquired exclusive global rights to the drug Brincidofovir. This gives thecompany a foothold outside of Japan in China and other Asian countries and allows it to develop
in the West, evolving as a licensor of pharmaceuticals.

Fair Research Inc.
Tsuyoshi Suzuki

Company Outline

Acquisition of exclusive global license for brincidofovir
Brincidofovir is an antiviral drug developed by Chimerix, Inc. in the United States, and targets
viral infections following hematopoietic stem cell transplantation and organ transplantation, an
area of high unmet medical needs. In hematopoietic stem cell transplantation and organtransplantation, an immunosuppressive agent is used to suppress rejection, thus facilitating
infection. An estimated 20% of patients who undergo hematopoietic stem cell transplantation aresaid to develop viral cystitis. In addition, HHV-6 encephalitis can develop after hematopoietic stem
cell transplantation. This can be fatal once it develops, and serious sequelae remain while thepatient survives, so preventive measures are important. Brincidofovir is less toxic and more
effective than other antiviral drugs that have been used in the past. For the time being, it is likelythat in Japan Brincidofovir will first be developed as a treatment for viral cystitis after
hematopoietic stem cell transplantation, then developed as a treatment for HHV-6 encephalitis after
hematopoietic stem cell transplantation, followed by the expansion of sales in other Asian
countries. Also, in Europe and the United States, where organ transplants are more common, there
is a high possibility that it will be deployed via partnership arrangements.

LocationTokyo

President

Fuminori Yoshida

EstablishedMarch 2005

Capital

JPY12,972 mil.

ListedOctober 2011

URL

www.
symbiopharma.com

Industry

Pharmaceuticals

Employees

102 (non-consol.)

Key Indicators (at Nov. 6, 2019)
Share price765

52-week high1,088

52-week low

542

Shares outstanding

24,363thousand

Brincidofovir potential extremely highTrading unit

100 shares

The milestones to be paid by SymBio to Chimerix for licensing-in come to a total of $180 million(including a lump-sum $5 million contractual payment), and the royalties rate after launch isthought to be in the double digit range. It is estimated that in Japan the number of viral infections(viral cystitis + HHV-6 encephalitis) after hematopoietic stem cell transplantation is about 2,600
per year, and the market size is around JPY7-8 billion. In Europe and the US, there are some 14,000
cases annually. In developing regions, including Asia, the population-adjusted number ofhematopoietic stem cell transplantations per year is still approximately 1/20 that of Japan, the US
and Europe, and is expected to expand in the future. The number of cases of viral infection after
kidney transplantation, which is expected to be the next application, is around 500 annually inJapan. However, the scale of organ transplantation overseas is extensive, amounting to some
15,000 cases annually in the US and Europe. We have conducted a trial calculation based on fairly
challenging hypothetical conditions and posit pipeline value at JPY24-44 billion yen just forhematopoietic stem cell transplantation targets in Japan, the US and Europe. If we include thedevelopment of additional viral infections and organ transplants the figure could rise to JPY50
billion. The company’s three main products could bring in a total of JPY90 billion.

Market cap

JPY18,637 mil.

Results

Revenues
JPY milYoY%

Op Income
JPY mil

YoY%

2014/12 Actual

1,955

27.6

-1,303

2015/12 Actual
2016/12 Actual

1,933
2,368

-1.1
22.5

-2,551-2,1272017/12 Actual

3,444

45.4

2018/12 Actual

3,835

11.4

2019/12Comp.Forecast

3,092

-19.4

Dividend (est.)
EPS (company est.)

0-167.66 yen

Forecast PER

NA

Actual BPS

198.87 yen

Actual BPR

3.85ｘ

Note: EPS, PER, BPS and PBR based onshares outstanding excl. treasury shares.

Net Income
JPY mil

YoY
%

EPS
Yen

Share Price (yen)
High
Low

NA

-1,115NA-145.0

1,572

784

NA
NA

-2,632-2,313NANA-325.0-235.3

1,532
2,036

708
692

-3,976NA-3,977NA-319.1

1,244

800-2,748NA-2,752NA-165.5

1,052

464-3,856NA-3,859NA-167.66

RP
JPY mil

YoY％

NA-1,110NANA-2,630-2,316-3,947NA-2,656NA-3,780NA

1/14This report is prepared by Fair Research Inc. (Fair Research) for the purpose of providing information to investors and not for the solicitation of securities trading. Although it is based on informationand materials Fair Research judges reliable there is no guarantee of accuracy, credibility, completeness or timeliness. Fair Research shall not take any responsibility whatsoever for any outcome,including direct or indirect damages arising from the use of, or reliance on, this report. Investors should take responsibility for securities and other transactions. The intellectual property rights of thisrepot belong to Fair Research, and any copy, transmission or quotation of any contents is legally prohibited.

SymBio Pharmaceuticals Ltd. （4582 JASDAQ）

Issued: November 7 2019

Company outline and management philosophy＜Business Model＞

SymBio Pharmaceuticals Ltd. has the following special characteristics

Operatingwithout ① “Labless” to reduce business risklaboratories, and thereby
Operates without laboratories, thereby controlling the risk of its operations. In
reducing the risks in new drug
terms of business model, the company itself does not conduct drug discovery
discovery, SymBio operates a
research. Rather, it seeks out and carefully investigates new drug candidates
niche strategy, evolving fromdeveloped by drug discovery ventures and pharmaceutical companies around thea pharmaceuticals venture toworld. A new drug candidate selected as a result of this process can become thea pharma company
subject of a licensing agreement and, following development in Japan, can belicensed out to another company for commercialization, or can be commercialized
by SymBio itself. Since the company undertakes development in Japan, it should
be recognized as not simply a technology trader but as a bio-pharmaceuticalcompany.
② High market share and strong earnings from a niche business strategy
The company focuses its development efforts on drugs for relatively rare
conditions in, for example, oncology and hematology which, despite strong
medical needs, the major pharma companies have mostly steered clear of. Using
this niche strategy, it aims for high market share and strong revenues.
③ Post-POC strategy
In most cases Proof of Concept has already been established. By insisting on priorevidence of efficacy and safety in human subjects, the company reduces the
The determinants of successdevelopment risks of new drug candidates.
are interactions with a
network of drug discovery This business model, then, is one which seeks to control the risks inherent in drug
companies and the ability to discovery while at the same time securing good returns.
discern, judge and evaluate

The success of this business model is dependent, obviously, on having a network of
SymBio is one of those rare drug discovery companies worldwide, but also a keenly discerning eye for what isbio-ventures with a product likely to succeed.
on the market took five years
to develop from licensing-in
That the company has what is needed is demonstrated by its track record. Normally, ittakes some 10-20 years to bring a drug from basic research to the market. In terms of
the probability of success, some estimates suggest that, counting from the chemicalcompound stage, it is less than 1/30,000, and even from the POC stage, around 7-8%.
Special attention to the But SymBio managed to get its first product, Treakisym®, from licensing-in to
support provided by the manufacturing and commercial approval in a mere five years, and in July 2018 itcompany’s human resources became the recommended standard therapy. To date, the company has licensed-in 6
and organization
products, of which 3 are currently slated for development.
We believe this track record has been made possible by the expertise of the company’s
staff and by the way the company is organised. SymBio has a workforce of 90, ofwhom 40 are involved in research & development. The drug search function is
supported by a Scientific Advisory Board (SAB) of specialists (including Nobel Prizecandidates) who review drug candidates.
In 2018 the company’s leading product, Treakisym®, achieved standard therapy status.
Smooth progress is being made on expanding indications and adding formulations
which, together with the decision to build its own sales structure, means the company
is making the leap from the bio-venture stage to full-fledged pharmaceuticals company.

2/14
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 based on information andmaterials that Fair Research judges reliable, there is no guarantee of accuracy, credibility, completeness, suitability or timeliness. Fair Research shall not take any responsibility whatsoever for any
results, including direct or indirect damages arising form the use of, or reliance on, this report. Investors shall be responsible for securities and other transactions. The intellectual property rights of thisreport belong to Fair Research, and any copy, transmission or quotation from this report without permission is legally prohibited.

SymBio Pharmaceuticals Ltd. （4582 JASDAQ）＜The third pillar＞
Company acquires global
license for BrincidofovirCompared to other antiviraldrugs BCV is highly activewith low toxicity

Issued: November 7 2019

On October 1, 2019 SymBio announced its acquisition of the exclusive global licensing
rights (development, manufacture and commercialization) to Brincidofovir (BCV).
The acquisition, from the US company, Chimerix Inc., covers all applicable humanindications excluding smallpox. This represents a major change for SymBio, which has
until now licensed in from overseas and undertaken development mainly for theJapanese market. The contract arrangements on this occasion allow SymBio to licenseout on a global basis. BCV is to be the company’s third strategic product, following
Treakisym® and rigosertib.
BCV’s distinctive characteristics
There are other antiviral drugs such as cidofovir (CDV) and foscarnet (FOS), but
compared to these, BCV is a highly active multi-viral drug.
BCV demonstrates high activity versus various viruses

Note: The EC50 (effective concentration of a drug or antibody evincing the maximum
response 50% from the lowest value) in which lower values indicate higher activity. In
the above figure, at a minimum EC50 value the level of activity is color-coded, so thatgreen has high activity and red has low. BCV on the left is green against various viruses.
Source: Chimerix Inc.
Note: Cidofovir (CDV) (extract from SymBio IR materials)
In 1996 the FDA approved the use of cidofovir (CDV) for the treatment ofcytomegaloviral retinitis in AIDS patients. CDV is a cytosine nucleotide analog that
inhibits replication of DNA viruses such as adenovirus, papillomavirus, polyomavirus
as well as herpesvirus. CDV is also effective against ganciclovir (GCV) resistance (UL97
gene mutation) and is considered useful when foscarnet (FOS) cannot be used when
GCV resistance appears. In Japan, it is an unapproved drug that has not beendeveloped.

In addition, Chimerix develops pharmaceuticals that behave like natural phospholipids,
providing additional effectiveness by improving the metabolic distribution of drugs,
and lower toxicity. Cidofovir (CDV) is a typical example of such a recognised antiviraldrug (although not approved in Japan and limited to private import). However, BCV
has a very different metabolic distribution from cidofovir, allowing the avoidance ofnephrotoxicity. Further, while foscarnet (FOS), which is approved for HIV-6
encephalitis, is nephrotoxic, such toxicity can be avoided with Brincidofovir.
3/14This 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 based on information andmaterials that Fair Research judges reliable, there is no guarantee of accuracy, credibility, completeness, suitability or timeliness. Fair Research shall not take any responsibility whatsoever for any
results, including direct or indirect damages arising form the use of, or reliance on, this report. Investors shall be responsible for securities and other transactions. The intellectual property rights of thisreport belong to Fair Research, and any copy, transmission or quotation from this report without permission is legally prohibited.

SymBio Pharmaceuticals Ltd. （4582 JASDAQ）

Issued: November 7 2019

Reference: BCV’s mechanism of action
BCV is a lipid conjugate of CDV with hexadecyloxypropyl (HDP), evincing a rapid
incorporation to the plasma membrane with efficient cellular uptake due to the lipid
conjugate. Once uptaken inside target cells, the lipid chain is cleaved by action of
intracellular phospholipases releasing CDV, which is then converted to the active form,
CDV-PP-CDV diophosphate. As a result of this being retained in the cell for an extended
period, the antiviral activity of the drug is dramatically improved. Furthermore, BCV
can greatly reduce the risk of nephrotoxicity associated with CDV because HDP
conjugation brings no accumulation of CDV in renal tubular epithelial cells through the
OAT-1 transporter, and low plasma exposure of CDV.

Source: SymBio IR materials

Targeted diseases
Symbio has announced that it will focus BCV development initially on viral infections
following hematopoietic stem cell transplantation and kidney transplantation, which
BCV targets viral infections are characterized by poor prognosis and high lethality, and which constitute a strong
after hematopoietic stem cell unmet medical need. Generally, in hematopoietic stem cell transplantation and organtransplantation and organ transplantation, radiation or an immuno-suppressive agent is used to suppress rejection,
but this increases the likelihood of viral infection. Normally, other antiviral agents,
transplantationsuch as CDV and FOS, have been used but there is a concern about the nephrotoxicity
side effect. BCV is a key product in SymBio’s ambition of becoming a specialist
pharma in the area of renal medicine.
This product will give support
to the company becoming a
specialty pharma in the areaof hematology

The first targeted disease areas will be:① Viral hemorrhagic cystitis after hematopoietic stem cell transplantation② Encephalitis due to HHV-6 infection after hematopoietic stem celltransplantation③ Virus infection after kidney transplantation
Note: Hematopoietic stem cell transplantation（HCT）
Treatment that aims at complete cure for blood diseases (mainly blood cancers such as leukemia) thatare difficult to treat with anticancer drug treatment (chemotherapy) or radiation therapy alone.
Note: Viral hemorrhagic cystitis (extract from SymBio IR materials)
Among viral infections that frequently occur after hematopoietic stem cell transplantation, adenoviral
infections that causes hemorrhagic cystitis are generally refractory, and cause severe symptoms forpatients, such as frequent urination, abdominal pain, and micturition pain. In serious cases it can befatal. In addition, there have also been reports of cases where adenovirus is transferred to the kidney,causing renal failure and resulting in death. It tends to occur especially in the case of unrelated donors

4/14
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 based on information andmaterials that Fair Research judges reliable, there is no guarantee of accuracy, credibility, completeness, suitability or timeliness. Fair Research shall not take any responsibility whatsoever for any
results, including direct or indirect damages arising form the use of, or reliance on, this report. Investors shall be responsible for securities and other transactions. The intellectual property rights of thisreport belong to Fair Research, and any copy, transmission or quotation from this report without permission is legally prohibited.

SymBio Pharmaceuticals Ltd. （4582 JASDAQ）

Issued: November 7 2019and umbilical cord blood transplants, which have a high ratio in Japan. It is often extremely refractory
due to the time required to reconstruct the immune system.
Note: HHV-6 encephalitis (extract from SymBio IR materials)
HHV-6 (human herpesvirus 6) is the sixth human herpes virus to be discovered. In allogeneic
hematopoietic stem cell transplantation, reactivation of HHV-6 occurs in 30-70% of patients, causing
HHV-6 encephalitis. This mostly happens in the second to sixth week, with the peak being in the third
week following transplantation. Memory impairment, consciousness disorder, and convulsions are
the three major symptoms. In typical cases, symptoms progress gradually from memory impairment
to consciousness disorder and convulsions, with the reported incidence of convulsions being 30-70%.
In fast-growing cases, neurological symptoms worsen over time, and many cases require ventilator
management for repeated convulsions and respiratory depression. Early treatment is very importantfor patients with HHV-encephalitis as the patient's condition often deteriorates rapidly in a short time.
According to clinical guidelines*, the first drug is foscarnet (FOS) or ganciclovir (GCV), and thesecond drug is cidofovir (CDV). CDV is the second-line drug because of strong nephrotoxicity andpoor transfer of the drug into the cerebrospinal fluid (CSF). However, while the effects of these drugs
have been confirmed in vitro, no tests to date have been conducted to confirm the clinical effects ofthese drugs on HHV-6 encephalitis cases.
* Guidelines for hematopoietic cell transplantation: Prevention and treatment of viral infections
HHV-6 (Japan Society for Hematopoietic Cell Transplantation: February 2018 edition)

Potential market size and development strategy
The number of hematopoietic stem cell transplants is estimated to be around 78,000
annually worldwide, of which about 43,000 are autologous and have a low rejection
risk. To reduce the risk of rejection it is necessary to suppress immune responses. There
are about 35,000 allogeneic allografts that have a high risk of viral infection.
BCV is used to treat the estimated 8.6%-24% of the latter who contract viralhemorrhagic cystitis, and the 30-70% who contract HHV-6 encephalitis. The
probability of contracting encephalitis in Japan is high due to the high proportion of
unrelated donor transplants.
SymBio estimates that 50-60% of allogeneic transplantations in Europe and the US,
and around 70% in Japan can be targeted. As a result, the annual number of cases inJapan comes to around 2,600, and in the West (US plus the five major countries in theEU) comes to around 14,000 cases. In the developing world, the incidence of
population-adjusted stem cell transplants is still around one-twentieth of thosecountries, but the trend is likely to grow.
Number of stem cell transplantations (HCT) and organ transplantations (SOT)and use of BCV

Source: SymBio based on Chimerix data

Assuming a drug cost per case of JPY3 million to treat viral infections following stem
cell transplantations yields a market value in Japan of approximately JPY8 billion, and
5/14This 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 based on information andmaterials that Fair Research judges reliable, there is no guarantee of accuracy, credibility, completeness, suitability or timeliness. Fair Research shall not take any responsibility whatsoever for any
results, including direct or indirect damages arising form the use of, or reliance on, this report. Investors shall be responsible for securities and other transactions. The intellectual property rights of thisreport belong to Fair Research, and any copy, transmission or quotation from this report without permission is legally prohibited.

SymBio Pharmaceuticals Ltd. （4582 JASDAQ）

Potential market scale given
incidence of stem celltransplants is JPY8 billion forJapan, and JPY42 billion for
the US and Europe. The Asianmarket (including China) also
has big potential
The company willl develop
targeting of stem celltransplantations in Japan, andwill then give consideration to
expansion
into
Asia,
including China
Initial viral hemorrhagic
cystitis targeted development
will be in 2020, with pivotal
tests starting in the second
half,
and
development
targeting HHV-6 encephalitis
expected to folllow a year
later

Issued: November 7 2019

in the US plus the five major EU countries in excess of JPY42 billion. We believe theincidence of stem cell transplantations is growing in Asia, but assuming the populationadjusted rate is the same as Japan, we estimate the potential size of the China market(population 1.4 billion) could be in excess of JPY83 billion. However, looking only at
the coastal region, where most of the medical infrastructure is, the actual figure could
be half of this.
SymBio is likely to initially concentrate development in Japan on viral hemorrhagic
cystitis beginning in early 2020, using already existing data collated overseas to help
advance the schedule. Pivotal studies in Japan are expected to begin in late 2020 on
about 50 subjects. It will take around 18 months to complete the roster of cases, and in
the second half of 2023 pivotal studies will be completed. It is thought that an
application for approval will be made in 2024 and marketing will begin in 2025. Tests
targeting HHV-6 encephalitis and hemorrhagic cystitis of around the same scale will
follow with a delay of around one year. Overseas, development is likely to follow
receipt of approval in Japan, with the initial emphasis on Asia including China.

Transplantation surgery is carried out more actively overseas than in Japan. For
example, there are around 1,600 kidney transplantations per year in Japan, comparedto some 20,000 in the US and the same in Europe (five main EU countries). An
estimated one-third of these are infected with either the BK virus or the CMV(cytomegalovirus). Japan therefore has only about 560 cases, compared to some 15,000
cases in the US and the five main countries of the EU. Organ transplantation is notwithin SymBio’s area of expertise, and Japan has relatively little exposure, which could
lead SymBio to tie up with a US or European pharmaceutical company. The partner
As for the development ofwould probably handle development and merchandising of post-organ transplantation
BCV for viral infections
product strategies.
following organ transplantant,the company’s strategy is totie up with US and European Reference: Modelling the BCV pipeline value
Under the agreement SymBio is to pay Chimerix a total of USD180 million in milestone payments
pharma partners(including a licensing-in sum of USD5 million), and royalties (said to be a fixed double-digit
percentage based on sales). We assume this to be in the lower 10% range and have set it at 12% for
the purposes of our modelling. Further, for the same purpose we have limited applications to thoserelated to stem cell transplantations. As for markets, we have assumed Japan and Asia (including
China) will be central to development. We have assumed a market size of JPY8 billion for Japan, andfor the overseas markets a fairly conservative figure of 4 times that amount, or JPY32 billion. As fordevelopment costs, as noted earlier, this will depend on each condition, with an assumed 50 subjects
undergoing pivotal tests at a cost of around JPY500 million per year. We further assume a grossproduct margin of 80% on the product in Japan. In overseas markets, it is possible that SymBio willconduct the sales function, but we assume for our calculations that there will be a licensing out, with
SymBio receiving a gross profit margin of 50%. Milestone revenues associated with the licensingout are assumed to total one-third of peak sales, or JPY10 billion. In addition, we assume probabilityof success is 80% since POC has been established for human subjects. Given these rather challenging
assumptions we posit pipeline value at around JPY24-44billion. On the assumption that progress ismade with other viral infections and organ transplantations we imagine there is a possibility that theBCV pipeline value could exceed JPY50 billion.
Modeling the BCV pipeline value（Pretax; only for HCT）
(100mil Yen)

Success Rate80%
DCF discount rate

100%

8%

328

436

10%

241

325

Source: Calculated by Fair Research

In any case, with a pipeline value of at least JPY50 billion, and milestones amounting to USD180
million (JPY19 billion) and double-digit royalties, this acquisition looks like an extremely good deal
for SymBio.

6/14
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 based on information andmaterials that Fair Research judges reliable, there is no guarantee of accuracy, credibility, completeness, suitability or timeliness. Fair Research shall not take any responsibility whatsoever for any
results, including direct or indirect damages arising form the use of, or reliance on, this report. Investors shall be responsible for securities and other transactions. The intellectual property rights of thisreport belong to Fair Research, and any copy, transmission or quotation from this report without permission is legally prohibited.

SymBio Pharmaceuticals Ltd. （4582 JASDAQ）

Issued: November 7 2019

Chimerix’s situation
Chimerix had been concentrating on the development of Brincidofovir (BCV), an antiviral drug, but has importantly changed its product strategy to concentrate mainly on
the oncology area. In July 2019 it licensed in “CX-01” from Cantex Pharmaceuticals,Inc. CX-01 is now preparing for Phase 3 for acute myeloid leukemia (AML). In
September 2019 Brincidofovir was licensed out on a global basis to SymBio
Pharmaceuticals for all indications excluding smallpox.
Chimerix will focus on thedevelopment of drugs for
acute myeloid leukemia andBCV for smallpox

When Chimerix was concentrating on the development of Brincidofovir, hopes werehigh for the company’s share price in the stock market. In December 2015, however,expectations were greatly diminished when, in Phase 3 trials on magalovirus infection
after hematopoietic stem cell transplantation, it was announced that no significant
reduction in infection was achieved. This is thought to be because of the need toadminister high dose steroids in order to suppress GvHD, or graft versus host disease,in which donor leukocytes contaminated with transplanted hematopoietic stem cells
attack the patient’s cells. This can lead to reinfection. Chimerix
continued
thedevelopment after amending the trial design. Antiviral efficacy was demonstrated but
a problematic side effect was noted with diarrhea. This caused patient registrations forthe trials to dry up and development fell behind schedule. Chimerix developed bothoral (100 mg) and intravenous (10 mg) versions, with the emphasis being on the highdose oral drugs. However, SymBio is considering the development of an intravenous
injection that is effective even when the dose is small and does not consider side effects
such as diarrhea as problematic.

7/14
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 based on information andmaterials that Fair Research judges reliable, there is no guarantee of accuracy, credibility, completeness, suitability or timeliness. Fair Research shall not take any responsibility whatsoever for any
results, including direct or indirect damages arising form the use of, or reliance on, this report. Investors shall be responsible for securities and other transactions. The intellectual property rights of thisreport belong to Fair Research, and any copy, transmission or quotation from this report without permission is legally prohibited.

SymBio Pharmaceuticals Ltd. （4582 JASDAQ）
Update on the status ofother product pipelines

Issued: November 7 2019

As of October 2019, SymBio’s main development drugs excluding Brincidofovir
include Treakisym® for relapsed/refractory diffuse large B-cell lymphoma(r/rDLBCL), and the introduction of a number of RTD and RI formulations to help
with Treakisym® life cycle management. In addition, there is an oral and injection
formulation for rigosertib for the treatment of myelodysplastic syndrome (for details
see our Basic Report issued on April 16, 2019). Below we present an update ofdevelopments since the issue of our last report.
（１）Treakisym®

Source: SymBio home page

Exceeded expected response
rate in Phase 3 trials on
recurrent refractory DLBCL.
Development is proceedingsmoothly◎ Relapsed/refractory diffuse large B-cell lymphoma (r/rDLBCL)As also noted in our previous report, it was announced on April 8, 2019 that the caseregistration for Phase 3 clinical trials on a fourth indication, relapsed / refractory
diffuse large B cell lymphoma (r/r DLBCL), has been completed. The observation
period for all patients was completed on September 18, and on November 5 it wasannounced that overall response rates had exceeded expectations, thus demonstratingsmooth progress in development. There is no change in plans to submit an applicationin the second quarter of 2020 and to begin marketing in the third quarter of 2021.
◎ RTD formulation
Announced on September 26 that an application had been submitted for an RTD
formulation (Ready-to-Dilute; dilution without need for dissolution). Plan is still torelease in the first quarter of 2021.
◎RI formulation
On April 10th 2019, the company announced it had administered its RI formulation(rapid intravenous formulation) to the first batch of 36 patients in clinical trials.
Smooth progress reported in patient registration. No change in plan to release in firsthalf of 2020.
◎ Oral formulation
Sixteen patients completed registration for Phase 1 clinical trials of the oral
formulation in July 2019.

8/14
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 based on information andmaterials that Fair Research judges reliable, there is no guarantee of accuracy, credibility, completeness, suitability or timeliness. Fair Research shall not take any responsibility whatsoever for any
results, including direct or indirect damages arising form the use of, or reliance on, this report. Investors shall be responsible for securities and other transactions. The intellectual property rights of thisreport belong to Fair Research, and any copy, transmission or quotation from this report without permission is legally prohibited.

SymBio Pharmaceuticals Ltd. （4582 JASDAQ）

Issued: November 7 2019

◎ Possibility of using in CAR-T therapy
On May 22 2019 Novartis Pharma KK announced that the Kymriah® antigen receptor
T-cell (CAR-T cell) therapy, or Kymriah® Intravenous Infusion (generic name:
Tisagenelcleucal), had been listed in the official drug prices for relapsed or refractory
CD-19 positive B-cell acute lymphoblastic leukemia (B-ALL) and relapsed or
refractory CD19- positive diffuse large B cell lymphoma (r/r DLBCL). Already inMarch 2019, partial changes in Treakisym® were approved for the pre-treatment oftumor-specific T-cell infusion therapy, allowing it to be used also for pre-treatment ofKymriah® intravenous infusion.
◎ Combined use with Polivy® approved by FDA
In June 2019, the FDA announced the rapid approval of a three-drug therapy consistingof bendamustine (Treakisym®) + rituximab (Rituxan®) (BR therapy) and the antiCD79b antibody-drug complex polatuzumab vedotin (trade name Polivy, developed by
Genentech and Roche) for non-transplantable, relapsed/refractory diffuse large B-cell
lymphoma (r/r DLBCL). It is expected that an application for approval will be
submitted in Japan in 2021. In B-R therapy, the amount of Treakisym® used is 120mg
per dose but will be 90mg in the case of this three-way therapy. B-R therapy isthought to be supplementary and Treakisym® will have a relatively subsidiary effect.
◎ Status of competing products
It was announced on May 28 2019 that the FDA had approved a therapy combining
Revlimid® (commercial name: Lenalidomide) and Rituxan for the treatment offollicular lymphoma and marginal zone lymphoma. Revlimid® is an oral immunomodulator developed by Celgene which has already been approved for multiple
myeloma (MM) and myelodysplastic syndrome with chromosome 5 long arm deletion(5q-MSD). On May 22 2019, Celgene announced it had applied for approval of atherapy combining rituximab and Revlimid® in patients with relapsed/refractory lowgrade diffuse large B-cell lymphoma. However, most of the DLBCL cases were GCBtype and in tests evinced little effect. ROBUST study of non-GCB type is now ongoing.
Provisional interim results did not show the expected promising results for ABC-type
DLBCL’s, which constitute most of the non-GCB type.

（２）Rigosertib

Source: SymBio home page

Progress made in registrateionof patients for Phase 3
injection
formualtion.
Development
proceedingsmoothly◎ International phase III clinical trial of injections
As of August 2, 2019, the number of cases in Japan came to 44, approaching the targetof 50 cases. According to a release by Onconova Therapeutics, Inc., the licensor, on
October 24 2019, the enrollment of all patients (360 cases) will be close to 90%
complete in the first half of 2020 and they will be ready to report on top-line (major
endpoint) results. Development therefore seems to be progressing smoothly.

9/14
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 based on information andmaterials that Fair Research judges reliable, there is no guarantee of accuracy, credibility, completeness, suitability or timeliness. Fair Research shall not take any responsibility whatsoever for any
results, including direct or indirect damages arising form the use of, or reliance on, this report. Investors shall be responsible for securities and other transactions. The intellectual property rights of thisreport belong to Fair Research, and any copy, transmission or quotation from this report without permission is legally prohibited.

SymBio Pharmaceuticals Ltd. （4582 JASDAQ）

Issued: November 7 2019◎ Oral formulation (targeting untreated high-risk MDS)
On October 24, 2019 Onconova Therapeutics announced that, following discussions
with the FDA on a Special Protocol Assessment it applied for in January 2019, it would
study Phase 2 clinical trial design (mainly to compare rigosertib/azacitidine
combination and azacitidine mono-theraphy) targeting untreated high-risk MDS.
◎ Development status of competing drugs (target: untreated high-risk MDS)
Drugs under development for high-risk myelodysplastic syndrome (MDS) include
guadecitabine, a methylation inhibitor similar to azacitidine (being developed by
Otsuka Pharmaceutical's US subsidiary, Astex Pharmaceuticals) and the moleculartarget drug Pevonedistat (under development in the U.S. by Millennium
Pharmaceutical, and in Japan by Takeda Pharmaceutical), but all remain at Phase 3. In
addition, US-based Karyopharm Therapeutics' XPOT1 inhibitor Selinexor® (rights
held by Ono Pharmaceutical in Japan), which is approved for multi-drug resistantmultiple myeloma, is also under development for myelodysplastic syndrome (MDS).
It is still in Phase 2 clinical trials. Also, SY-1425 (oral) from Syros Pharmaceuticals
seems to be prioritizing AML (acute myeloid leukemia) with RARα mutation overmyelodysplastic syndrome (MDS) as the object of development.

Company likely to complete
its hiring of 30 Treakisym
managers by early 2020, andhas already started work on acountrywide sales structure

SymBio’s in-house sales structure
As early as 2018 SymBio had secured a team of 10 very specialized individuals as
Treakisym Managers (TM’s) to undertake Treakisym® sales activities. The number
was brought to 17 in July 2019, and sales activities across the country began. The
company is planning to eventually have 30 TM’s and to add secondment Medical
Representatives (25-30). The hiring plan is going well at present so that by early 2020
it should have an in-house head count of 30 MR’s (TM’s).

10/14
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 based on information andmaterials that Fair Research judges reliable, there is no guarantee of accuracy, credibility, completeness, suitability or timeliness. Fair Research shall not take any responsibility whatsoever for any
results, including direct or indirect damages arising form the use of, or reliance on, this report. Investors shall be responsible for securities and other transactions. The intellectual property rights of thisreport belong to Fair Research, and any copy, transmission or quotation from this report without permission is legally prohibited.

SymBio Pharmaceuticals Ltd. （4582 JASDAQ）

Issued: November 7 2019

Supplement: Revisions to 2019 results

In the October-December
period of 2018 and the firsthalf of 2019, there were
product quality problems
which necessitated downward
revisions to corporate results

To make up loss in profits by
reducing all unnecessary
expenses

Because of a delay to Treakisym® shipments in August 2019 SymBio revised down its
12/2019 results. Sales were revised down by JPY1.372 billion from JPY4.465 billion
to JPY3.092 billion. The cause of the revision was a problem with the quality of thelyophilized Treakisym® imported from the manufacturer, Astellas Deutschland
GmBH. In the fourth quarter of 2018, too, there was a quality problem with the 25mg
formulations, so that from the first quarter of 2019 the company switched to 100mg
imports. In the second quarter, however, the 100mg formulations were found to contain
impurities and numerous imperfections in appearance. This meant that almost all
shipments planned in 2019 from the second quarter onwards could not be completed
until the early part of 2020. The present situation is that the cause of the problem has
been found, remedial measures are being put in place and the problem is being
resolved.
The downward revision in operating income is less than the downward revision insales. The reduced amount of operating income has been kept to JPY193 million bysavings, relative to the initial budget, of JPY500 million on R&D expenses and JPY300
million on SG&A. The reduction in R&D is mainly in basic research, so that thedevelopment work necessary for profitability after 2021 has not been affected. SG &A expenses other than R&D expenses are higher than initially expected, probably due
to front-loading the in-house sales structure.
Changes in P&L expectations for 12/2019(M illion Yen）

Sales

Initial Plan
(February)
4,465

Revised Plan
Jan-Jun
Jul-Dec Plan
(August)Result(August)
3,092
2,005
1,087

Gross Profits

1,497

979

529

450

SG&A Cost
R&D Cost
Excl. R&D Cost

5,053
2,508
2,545

4,759
2,029
2,730

2,544
962
1,582

2,214
1,067
1,148

Operating Profit-3,780-3,780-2,015-1,765Recurring Profit-3,856-3,856-2,069-1,787Net Income-3,859-3,859-2,070-1,789Source: Fair Research, Inc. using results filings

However, absence of costs
for licensing-in BCV fromthe August 2019 plan makes
a further revised outlook
likelyHowever, the one-off payment for the licensing-in of Brincidofovir (BCV) is notincluded in the August revisions. In the final analysis, it is likely that operating
revenues will be revised down by JPY500 million to a loss of JPY4.3 billion, and at
the net level earnings will come in with a loss of around JPY4.4 billion. In the second
half of 2019 both operating and net earnings will chalk up losses of around JPY2.3
billion.

On the other hand, cash on the balance sheet totaled around JPY6 billion at the end ofJune 2019, and the final tranche (around JPY3 billion) in the multi-year capital
Despite this, no concern for procurement program is expected at the end of 2020. There is no fear, therefore, of thethe time being that cash may company depleting its cash holdings for the next 1-2 years, despite costs arising frombe insufficientthe establishment of an in-house marketing function and continued development of thecompany’s three main products

11/14This 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 based on information andmaterials that Fair Research judges reliable, there is no guarantee of accuracy, credibility, completeness, suitability or timeliness. Fair Research shall not take any responsibility whatsoever for any
results, including direct or indirect damages arising form the use of, or reliance on, this report. Investors shall be responsible for securities and other transactions. The intellectual property rights of thisreport belong to Fair Research, and any copy, transmission or quotation from this report without permission is legally prohibited.

SymBio Pharmaceuticals Ltd. （4582 JASDAQ）

Issued: November 7 2019

Elsewhere, some progress has been made in the arbitration proceedings filed with theInternational Chamber of Commerce against The Medicines Company, and some sortof conclusion is expected at the end of this year or early next year (SymBio is seeking
The company plans to amend an amount equivalent to about JPY9 billion). This sum would further enhance the cash
its medium-term management position.
plan. The 2021 target for
turning
profitableisunchanged, but earnings
growth post-2022 will be
more subdued due to BCV
development costs

The revised plan currently being formulated will reflect the 2019 results forecast aftereffects and the effect of licensing in BCV. It is possible that part of the Treakisym®
shipments that could not be completed in 2019 will be deferred until 2020. It should
also be noted that the 2021 date for turning profitable is unchanged. Rather, there may
be a change in attitude to earnings in and after 2022 given the weight of BCV
development costs. Needless to say, this was a necessary investment for a company
seeking additional growth and global specialty pharma status.
Previous medium-term earnings plan （as of Feb 2019）

Note: Sales during the period of the medium-term plan are for Treakisym® since salesof rigosertib, etc. not scheduled. Until 2020 wholesale deliveries to Eisai, and thencompany’s own sales
Source: SymBio Medium Term Management Plan, February 2019Conclusion
By developing an in-house sales capability and acquiring BCV, SymBio has built thefoundations for growth as a global renal specialty pharma. We estimate its three main
Total value for three productpipelines exceeds JPY90 pipelines (Treakisym®, rigosertib and Brincidofovir) have a combined value (pretax) of over JPY90 billion (refer to our basic report dated April 16 2019 for details on
billion(pretax)
the value of Treakisym® and rigosertib).
Opportunity for re-evaluationof SymBio

Symbio has recently been forced to make downward revisions due to quality issues
arising at another company. On the plus side, the multi-year funding program will becompleted soon, and we are optimistic the company will be re-evaluated by investors
as it becomes profitable in 2021.
Note: Please note differences between pipeline value and corporate value

12/14This 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 based on information andmaterials that Fair Research judges reliable, there is no guarantee of accuracy, credibility, completeness, suitability or timeliness. Fair Research shall not take any responsibility whatsoever for any
results, including direct or indirect damages arising form the use of, or reliance on, this report. Investors shall be responsible for securities and other transactions. The intellectual property rights of thisreport belong to Fair Research, and any copy, transmission or quotation from this report without permission is legally prohibited.

SymBio Pharmaceuticals Ltd. （4582 JASDAQ）

Issued: November 7 2019

Fair Research Inc.
Contact Details
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Tel: 03-6403-9217
Email: info@fair-research-inst.jp

13/14This 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 based on information andmaterials that Fair Research judges reliable, there is no guarantee of accuracy, credibility, completeness, suitability or timeliness. Fair Research shall not take any responsibility whatsoever for any
results, including direct or indirect damages arising form the use of, or reliance on, this report. Investors shall be responsible for securities and other transactions. The intellectual property rights of thisreport belong to Fair Research, and any copy, transmission or quotation from this report without permission is legally prohibited.

SymBio Pharmaceuticals Ltd. （4582 JASDAQ）

Issued: November 7 2019

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