2Q FY02/2024 Financial Results
TSE Growth：4891（Six months ended August 31,2023）

Disclaimer
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note that words are supplemented where they are difficult to understand in a literal English translation. In
the event of any discrepancy between this translated document and the Japanese original, the original shallprevail.
 This document has been prepared by TMS Co., Ltd. (herein after referred to as the Company) solely for

information purpose only. This document does not constitute or form part of and should not be
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 This document contains forward-looking statements include but not limited to expressions such as"believe", “expect", "plan", "strategic", "expect", "anticipate", "predict" and "possibility”, as well as othersimilar expressions to explain future business activities achievements, events and future conditions.
Forward-looking statements are predictions about the future that reflect management's judgment basedon currently available information. These forward-looking statements are subject to various risks anduncertainties that could cause actual results to differ materially from those expressed in or suggested by
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 The Company does not assume any obligation to change or correct any information or statements in thisdocument considering new information, future events or other findings.

1

Corporate Mission

Create impactful therapeutics by the power ofrelentless exploration and challenge

2Agenda
1. Topics
2. Summary of Financial results for 2Q FY02/2024(6M)
3. TMS-007
4. TMS-008 / 009
5. Expansion of Pipelines
6. Appendix

3

Topics4

Topics１

TMS-007 (BIIB131)

Timeline Mar 10, 23
 Apr 25, 23
 Apr 27, 23
 Jul 25, 23

 Jul 27, 23

Outline of Ph2b trial was registered at ClinicalTrials.gov (estimated startdate Apr 17)
Biogen announced it would pause and re-examine initiation of the Ph2b trial
Registered information at ClinicalTrials.gov was updated (estimated startdate updated to Aug 21)
Biogen’s 2Q financial results earnings call
BIIB131 continued to be listed on the pipeline table without a specificcomment
Registered information at ClinicalTrials.gov was updated (estimated startdate updated to Dec 1)

 TMS continues to collect information through various communication lines
 Preparing for three possible scenarios

1. Biogen moves forward to develop TMS-007/BIIB131

2. Biogen terminates development

3. Biogen to transfer/license/joint-develop the asset with a third party

 Contacted by several third parties, pending until Biogen’s decision5

Topics１

TMS-007 (BIIB131)

Recent development of Biogen with new CEONovember 2022

Mr. Chris Viehbacher appointed as new CEO

April 2023

BIIB093 (large hemispheric infarction) terminated
BIIB093 (brain contusion) terminated
BIIB132 (spinocerebellar ataxia) terminatedOphthalmology field withdrew
BIIB131 (acute ischemic stroke) pausedJuly 2023

LEQEMBI (Alzheimer’s disease) officially approved by FDA
BIIB122 (Parkinson’s disease) terminatedAnnounced headcount reduction of approximately 1,000
Announced acquisition of Reata Pharmaceuticals, Inc. ($7.3 billion)

October 2023

Jane Grogan, Ph.D. appointed as Head of Research

6Topics２

TMS-008


３

Making progress to initiate Ph1 clinical trial by the end of this fiscal year
・ Planned IND Application (PMDA) 4Q this fiscal year and completion of the Ph1trial during the next fiscal year

Pipeline expansion
Efforts to expand pipeline continue utilizing both internal and external sources. Internal
projects leverage our expertise combined with external chemical libraries.

Internal projects

・New indications
for TMS-008
・sEH inhibitors
・Natural productscreening

Exploring external
library Initiated evaluation of an external
compound library (October 2022)
 Entered joint research agreementwith the Microbial Chemistry
Research Foundation(June 2023)

External projects
Option agreements with
Hokkaido University

Project 1(July 2022)

Project 2(May 2023)

7

Summary of
Financial Results
FY02/2024.2Q(6M)

8Financial Results FY02/2024.2Q(6M)- Statement of Income
Although one-time non-operating expenses were recorded due to the preparation for the stocklisting in the same period of the previous fiscal year, no one-time expenses were recorded inthis Q2 FY02/2024, resulting in a smaller loss in both ordinary income and net income(million of yen)

Q2(YTD)
FY02/2023

Q2(YTD)
FY02/2024

Operating revenue

-

-

-

-

Operating expenses

268

345

76

28.5%

151

213

62

41.1%

(268)

(345)

(76)

-

Non-operating income

0

3

3

-

Non-operating expenses

200

0

(200)

(99.8%)

Ordinary income

(469)

(342)

126

-

Net income

(468)

(342)

125

-

Research anddevelopment expenses
Operating income

Change(YoY)

Expected expenses for FY02/2024(million of yen）

Research and Development expenses

500

-

800

Other selling, general and administrative expenses

350

-

450

YoY increased mainly due
to the recording ofexpenses for TMS-008
Ph1 trial
IPO-related expenses
were recorded in the Q2
FY02/2023
R&D expenses aremainly for;- Development of
TMS-008- Research activities
for pipeline
expansion- Introduction of
external assets
9Financial Results FY02/2024.2Q(6M)- Cash flows
Cash and cash equivalents at end of period increased 1,254 million yen from the same period of
the previous fiscal year due to the issuance of new shares with IPO in November 2022
(million of yen)

Q2(YTD)
FY02/2023

Q2(YTD)
FY02/2024

Cash flows from operating activities

(364)

(336)

Income before income taxes

(469)

(342)

Cash flows from investing activities

(6)

(1)

Cash flows from financing activities

(233)

1

(233)

-

Net (decrease) increase in cash andcash equivalents

(604)

(336)

Cash and cash equivalents at beginningof period

2,598

3,584

Cash and cash equivalents at end of
period

1,993

3,248

Income from the issuance of shares

10Financial Results FY02/2024.2Q(as of Aug. 31)- Balance sheet
No operating revenue was recorded in Q2 FY02/2024, resulting in decreases in both total assets
and total net assets(million of yen )FY02/2023(as of Feb. 28)

Q2 FY02/2024(as of Aug. 31)

3,766

3,415

（350)

（9.3%)

3,584

3,248

（336)

（9.4%)

23

21

(1)

(7.7%)

3,790

3,437

(352)

(9.3%)

Current liabilities

76

61

(14)

(19.6%)

Non-current liabilities

-

-

-

-

Total liabilities

76

61

(14)

(19.6%)

Total net assets

3,714

3,376

(337)

(9.1%)

Total liabilities andnet assets

3,790

3,437

(352)

(9.3%)

Current assets
Cash and deposits
Non-current assets
Total assets

Change(YTD)

11

Growing and Differentiated Drug Pipeline
TMS-007 Ph2a completed: TMS-007 (BIIB131) is the lead pipeline which was acquired by Biogen
TMS-008 Preclinical stage: Being developed by TMS under grant-back license from Biogen
Development
Code

TMS-007（BIIB131）

TargetDisease

Acute
Ischemic
StrokeMoA
sEH
Inhibition
Plasminogen

Acute
KidneyInjuryTMS-0083

CancerCachexia

Research

Preclinical

Ph1

Ph2

Ph3

Acquired by Biogen
Ph2b1

Ph2a completed in Japan

Pipelinecandidates<Internal>

Pipelinecandidates<External>

TBD

BiogenPh2b clinical trial to be initiated by Biogen 1,2
Planned to initiate Ph1 in FY02/2024

sEH
Inhibition

Anticipated Next Steps

Other
indications
TMS-0093

Development
andCommercialization

TMS
TMS
TMS

sEH
Inhibition

TMS
Search for novel sEH inhibitors and other compounds

TMS

Evaluating multiple programs
Two option agreements

TMS

The above information contains forward-looking statements based on our judgement in light of the information currently available to us. Therefore, please
be aware that the above information is subject to various risks and uncertainties, and actual development may differ significantly from these projections.
1.
2.

Biogen has registered and published detailed clinical trial information in ClinicalTrials.gov on March 10, 2023. ： https://www.clinicaltrials.gov/study/NCT05764122?cond=BIIB131&checkSpell=false&rank=1
Biogen has announced to pause initiation of Phase 2b clinical trial and reassess whether to initiate the trial at its Q1 2023 Earnings Presentation on April 25, 2023.
Our development rights for TMS-008 and TMS-009, which are being developed under a free license from Biogen, are limited to certain indications, and TMS-009 is a backup compound for TMS-008.

12

TMS-007
Potential Next Generation
Acute Ischemic Stroke
Treatment13

Lecture requests on SMTP focusing on TMS-007
 The 38th Interactive Seminar for Novel Medicinal Sciences at The Pharmaceutical Society ofJapan
Lecture dateJuly 14, 2023

Lecturer

Keiji Hasumi, Ph.D., Chief Scientific Officer, Board Member

Lecture title“Discovery and development of prothrombotic compound SMTP”

Lecture outline

Introduced stages from discovery of SMTP compound family to mechanism of action,
pharmacological activity and drug development

 The 75th Symposium at The Society for Biotechnology, Japan
Lecture date

September 4, 2023

Symposium name“Synthetic Biology-Facilitated Next Generation Drug Discovery of Engineered
Natural Products”

Lecturer

Keiji Hasumi, Ph.D., Chief Scientific Officer, Board Member

Lecturer title“Discovery of the prothrombotic compound SMTP and its development as a drugfor treatment of ischemic stroke”

Lecture outline

Introduced discovery history, mechanism of action and pharmacological activity of
SMTP compound including TMS-007 and TMS-008 as well as overview ofdevelopment of TMS-007 as a drug for treatment of ischemic stroke. Alsopresented significance of SMTP biosynthetic pathway and biosynthesis, andfurther to attractivity and possibility of natural product as a drug.
14

Acute Ischemic Stroke - Important Unmet Medical Needs
Acute Ischemic Stroke (AIS) Overview


RuptureBlockage

AIS is caused by blockages of blood supply to thebrain
Potentially leads to permanent brain damage :hemiplegia, memory loss, speech problems, reading andcomprehension difficulties and other complications



The number of patients with Ischemic Stroke:
approx. 1.3 million/year (total of 7 major countries)
and it is expected to increase

Patient Population with AIS 1(million)

1.57

1.29

0.60

0.51

0.27

0.23

1.84
0.69
0.28

0.55

0.71

0.86

2018
Actual2028
Eestimate

2038
Estimate

US

Japan

5 European countries 2

Important Unmet Medical Needs
Cause of death in the US (2019) 3#

DiseaseRatio

1

Heart Disease

23.1%

:

:

:

4

CLRD

5.5%

5

Stroke5.3%

6Alzheimer

4.3%

1.
2.
3.
4.

Stroke causes significant economic loss 5
Breakdown of Stroke 4
Others13%

US$73.7bn (2010)

Japan
AIS
87％

Datamonitor Healthcare, ”Stroke Epidemiology”, Ref Code:DMKC0201444, Published on 07 January 2019
5 European countries are composed of five major countries: Germany, France, Italy, Spain, and United
KingdomCenters for Disease Control and Prevention, “National Vital Statistics Reports volume 70”
Tsao et al. (2022) Heart Disease and Stroke Statistics—2022 Update: A Report From the American
Heart Association

UK
5.
6.

$59.9bn (2016) 6$33.3bn (2015)
National Stroke Association, Explaining stroke 101, 2011; Current, future and avoidable cost of
stroke in the UK, 2017; Yamaga et al. (2016), “Cost of illness in cerebrovascular disease”
Calculation based on exchange rates; USD/JPY=110, USD/GBP=1.3
Estimated COI based on direct and indirect costs related to stroke for 1 year until November
2015

15

t-PA - The only FDA-approved drug for AIS
No drug has been approved since 1996 in the US
Market size 1 of the existing drug

Challenges of the existing drug

Sales of t-PA is estimated to be approx. $2.1bn in 2021

Incidence rate of fatal intracranial hemorrhage 3,5(USD million)
2,500
2,095
2,000

1,842

2,161

2,217

2,260

2,295

2,324

1,908

t-PA
Placebo2.7%
0.4%

Mortality 4,5
t-PA

1,500

Placebo
1,000

2019

2020 2 2021

2022

2023

2024

2025

17.9%
16.5%

2026 (year)(estimated)
 t-PA (tissue Plasminogen Activator): the only FDA-approved drug for AIS (thrombolytic agent) t-PA generally needs to be administered within 4.5 hours from symptom onset and is used for <10% of patients 6

1.
2.
3.
4.
5.
6.

Informa; estimated as the sum of sales of Activase® and Actilyse® for each year
As Actilyse® sales in 2020 is not available, Actilyse® sales in 2019 is used for estimation for 2020
Incidence rate at 7 days
Mortality at 90 days
Emberson et al. (2014), “Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis ofindividual patient data from randomised trials”
Audebert et al. Nat. Rev. Neurol. 10.675-676, 2014 ‘Time is brain’ after stroke, regardless of age and severity

16

TMS-007: Mechanism of Action
Dual mechanism – “Anti-inflammatory” and “Thrombolytic” activities

TMS-007
sEH
Inhibition

Plasminogen

Inhibition of Soluble Epoxide Hydrolase1

Promotion of Plasminogen Activation4

Anti-inflammatory 1,2,3
Inhibition of Phos activity

Promotion of Endogenous thrombolysis 4,5,6

Inhibition of EH activity

Our SMTP-based small molecule analogues with unique therapeutic properties
Anti-inflammatory and thrombolytic activities
Ideal profile for acute ischemic stroke treatment
1.
2.
3.
4.
5.
6.

Matsumoto et al. (2014) J Biol Chem
Shibata et al. (2011) N-S Arch Pharmacol
Ito et al. (2014) Brain Res
Hasumi et al. (2010) FEBS J
Hu et al. (2012) Thrombosis J
Miyazaki et al. (2011) Stroke17

TMS-007 (BIIB131): Acquired by Biogen, the U.S. Biotech Company
Biogen exercised its option to acquire all IP and assets related to TMS-007 and SMTP compound in May 2021 1
Oct, 2015

Nov, 2017

Jun, 2018

May, 2021

Aug, 2021

TMS completed
Ph1 Clinical Trial

TMS started
Ph2a Clinical
Trial

OptionAgreement with
Biogen Signed

Biogen Exercises
Option Rights

TMS Completed
Ph2a Clinical
Trial

Received

Upfront Payment

Upfront Payment

$4mn

$18mn

Milestone Revenues ~$335mn + Royalties
Next Step 2

Biogen initiates
Ph2b
Clinical Trial 3

Biogen initiates
Ph3
Clinical Trial

Biogencompletes Ph3
Clinical Trial

Potential Receipt

Potential Receipt

Development Milestone

Development Milestone$60mn~$105mnCompletion of the first dosing of the fifth patientin Ph3 Clinical Trial in US

Biogen MA Inc.
Parent Company (Biogen Inc.) is listed on NASDAQ (BIIB)
with a market capitalization of approx. $37bn 4
 One of the first global biotech companies in the world
 Primary targets are neurological diseases
・Submit Application
for New Drug Approval・New Drug Approval＋Insurance Coverage

1.
2.
3.

4.
5.

Sales
Potential Receipt

Commercial Milestone~$170mnPhased Royalties on TMS-007
Drug sales 5

TMS and Biogen joint press release (May 12, 2021)
All future development, manufacturing andcommercialization costs and expenses will be borne
by Biogen.
Biogen has announced to pause initiation of Phase
2b clinical trial and reassess whether to initiate thetrial at its Q1 2023 Earnings Presentation on April
25, 2023.
Biogen Inc (BIIB) market capitalization as of September 30, 2023
A percentage of worldwide annual sales of TMS-007 (under certain circumstances, payment may
decrease due to changes in the cap)

High single-digit ~low-teens percentages

18

TMS-007: Ph2a clinical trial showed good results
TMS-007 has the potential to become the first line AIS treatment 1

Time Window

Efficacy

SafetyTherapeutic time windowmRS 2 0-1 ratio at 90 days
Gold-standard Endpoint

Symptomatic Intracerebral
hemorrhage risk 3,4

Odds ratio 5 :<12.0

TMS-007(hour)



1.
2.
3.

0

5

Adjusted odds
ratio 5 :3.34

TMS-007

Pla
ceb
Placebo 18.4
%
o

<4.5

t-PA

3.00

TM
TMS-007
S40.4%
007

10

プラセボ
Placebo

3.0%
3％
0%

15

Clinical trials indicate that TMS-007
may work in potentially longer time
window (within 12h).

0％
0.0%



mRS score 0-1 indicates recovery toa level that does not interfere withdaily life, and “Gold-standard”
endpoint with statistical significance(P value＜0.05）was achieved.

The data comparisons above are not based on head-to-head clinical studies.
Number of patients(N)=52 for TMS-007, N=3,391 and N=2,488 for t-PA
mRS indicates modified Rankin Scale, and it refers to degree of independence in daily life
Biogen, Investor Day Material (September 21, 2021), Q4 and Full Year 2021: Financial Results
and Business Update

4.
5.



5%

10%

TMS-007 showed the potential to
overcome the biggest problem oft-PA.

Wardlaw et al. (2012), “Recombinant tissue plasminogen activator for acute ischaemic
stroke: an updated systematic review and meta-analysis”, N=2,488
Calculation of each odds ratio;
TMS-007: odds ratio 3.0=(40.4%/59.6%)/(18.4%/81.6%),
adjusted odds ratio 3.34, (statistically adjusted to control for otherpredictor variables; Source: ISC2022 Poster)19

TMS-007: Ph2a clinical results Achieved the “Gold-standard” Endpoint
TMS-007 achieved statistically significant improvement on mRS 0-1 ratio at 90 days,
one of the most important indicators
Placebo

TMS-007

Number of patients (N)3852

Number of patients scored mRS 0-1

7

21

18.4%

40.4%

mRS 0-1 ratio Odds ratio 3.00, Adjusted odds ratio 3.34
 P value ＜0.05
mRS 0-1 ratio at 90 daysmRS (modified Rankin Scale)0

No symptoms

1

No significant disability, despite
symptoms; able to perform all1

TMS-007群
TMS-007(N=52)

2

59.6%

40.4%

3

4
Placebo群
Placebo(N=38)

18.4%

0%
1.

81.6%

20%

40%
0-1
2-6

60%

5
80%

100%

Biogen, Investor Day Material (September 21, 2021), Q4 and Full Year 2021: Financial Results and Business Update

6

usual duties and activities

Slight disability; unable toperform all previous activities butable to look after own affairs
without assistanceModerate disability; requires
some help, but able to walk without
assistanceModerately severe disability;

unable to walk without assistanceand unable to attend to own bodily
needs without assistanceSevere disability; bedridden,

incontinent and requires constantnursing care and attention

Death
20

TMS-007: Ph2a clinical results Efficacy - Vessel Recanalization
TMS-007’s promising efficacy is potentially backed by good recanalization outcome 1
Effect of vessel recanalization confirmed for patients with full or partial vascular occlusion - MRA image
Full or Partial Recanalization

the percentage of subjects receiving TMS-007 achieving recanalization was
greater than those treated with placebo

1.

Placebo Pooled

TMS-007 Pooled

Number of patients (N)

15 (100)

24 (100)

Number of patients with recanalization

4 (26.7)

14 (58.3)

Estimate of odds ratio (TMS-007 vs placebo)

-

4.23

95% CI for the odds ratio-

0.99, 18.07

Biogen, Investor Day Material (September 21, 2021), Q4 and Full Year 2021: Financial Results and Business Update

21

TMS-007: Ph2a clinical results Safety
In terms of safety, the biggest concern of t-PA, TMS-007 demonstrated reduced risk of
the incidence of symptomatic Intracerebral Hemorrhage (sICH) 1
Incidence rate of sICH1
TMS-007 vs Placebo 2
TMS-007

Ph2a

t-PA vs Placebo 3

Placebo

t-PA

8%

8%

6%

6%

4%

7.8%

1.7%

2%

0.0%

0%

1

2

N

52

38

N

Prehospital
time

9.5h
(Average)

9.3h(Average)

Prehospital
time

1.
2.
3.

Placebo

4%

3.0%

2%
0%

Meta-analysis

1

2

3,384

3,330
Within 6h

The data comparisons below are not based on head-to-head clinical studies. N=52 for TMS-007, N=3,384 for t-PA
Biogen, Investor Day Material (September 21, 2021), Q4 and Full Year 2021: Financial Results and Business Update
Wardlaw et al. (2012), “Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis”

22Potential of TMS-007: Potential Market Size
Potential Market Size for TMS-007 with possible outstanding Efficacy and Safety(Drug price)

TMS-007

TMS-007t-PA
US drug price$8,800t-PATime Window
approx. $2.1bn
Expansionin 20211

Penetration Expansion(For illustrative purpose only)(Share of AIS treatment by number of patients)

 TMS-007 has potential to realize the expansion of time window⇒ Total addressable patients of TMS-007 may expand significantly

 If TMS-007 can achieve higher efficacy and safety than t-PA, higher drug price could be expected(sales of t-PA estimated to be approx. $2.1bn in 2021 1)


1.
2.

In clinical trial TIMELESS to test the use of tenecteplase, a potential alternative to t-PA, for ischemic stroke patients
within 4.5 to 24 hours from symptom onset, there was no significant difference between tenecteplase and theplacebo group on a measure of autonomy at 90 days which is a primary efficacy endpoint ２
For 2021, Informa; calculated as the sum of estimated sales of Activase® and Actilyse® in 2021. Actual market size may differ from the estimate due to the limitations peculiar to suchstatistical data and publications in terms of their accuracy
Source:： "ESOC 2023: Large Clinical Trials Session", American Heart Association Blogs, June 5, 2023, DOI: 10.1161/blog.20230605.574378, Ana Ponciano, MD MSc

23

Potential of TMS-007: Expanding Time Window
Relationship between Prehospital Time and treatment 1
 Number of t-PA treated patients is only a part of entire patient population arriving at a hospital Time window expansion for TMS-007 could expand the target patient population 2(Percentage of patients 1)

100.0%

32.5%

80.0%
60.0%
40.0%
20.0%
0.0%
1.

t-PA Applicable time<3.5h 3

21.1%

34.7%

34.7%

0 < 3.5h

3.5 < 11h

TMS assumption using average breakdown of patients by prehospital time based on the following papers.
Please note that the company’s estimate above is based on various assumptions and beliefs stated herein,
including the available dose window, disregard certain significant conditions such as the eligibility of thepatients and may not be supported by any clinical data;
Tong et al. (2012), “Times From Symptom Onset to Hospital Arrival in the Get With The Guidelines–Stroke
Program 2002 to 2009”
Harraf (2002), “A multicenter observational study of presentation and early assessment of acute stroke”
Kim (2011), “Stroke awareness decreases prehospital delay after acute ischemic stroke in Korea”
Matsuo (2017), “Association Between Onset-to-Door Time and Clinical Outcomes After Ischemic Stroke”

11.7%

11.7%

21.1%

21.1%

※Assuming
34.7% 1 hour needed to decide
34.7%atreatment option after arriving at a hospital

11 < 23h

2.
3.

23h <

(Prehospital Time)

Expantion of time window over 12 hours (maximum 24 hours) isbased on the registered and pubished information by Biogen on
ClinicalTrials.gov on March 10, 2023.
Assuming 1 hour needed to decide a treatment option after arriving
at a hospital24

Potential of TMS-007: Expanding Penetration
How t-PA is treated for patients arriving within 2 hours from symptom onset 1
 Due to its high safety profile, TMS-007 has a potential to expand its penetration

 It is estimated that TMS-007 may be used for up to 75% of patients, within the dosing window

TMS-007 potential eligibility: 75%
t-PA Non-eligible: 65%

t-PA Eligible: 35%

t-PA treated
26%

Rapid Improvement or
Mild Stroke 33%
Patients with the following

No t-PA
9%
1.

Others16%

Messe (2016), “Why are acute ischemic stroke patients not receiving IV t-PA”

Current severity of
disease is not consistent
with risk-benefit of t-PA
administration
Patients whose disease isso mild that they may notbenefit from treatment
with t-PA

AdvancedAge
5%

Patient orfamilyrefusal 4%
Bleeding
4%

Blee
ding
Risk
3%

25

TMS-008/009
Acute Kidney Injury
and other indications

26

Progress of TMS-008/TMS-009
TMS-008：IND (PMDA1) filing in H2 FY02/2024 and Ph1 completion during FY02/2025 planned
TMS-009：GMP manufacturing process development and preliminary PK/PD/TOX studies ongoing
FY02/2024 (March 2023 to February 2024)
H1

FY02/2025 (March 2024 to February 2025)

H2

H1

H2

IND Application
PMDA１ consultation
TMS-008

Drug substancemanufacturing

Drug productmanufacturing

Ph1 clinical trial

GLP2 studies
safety pharmacology/toxicology

TMS-009DS
production
processdevelopmentDS
purification
processdevelopment
Preliminary PK/PD and toxicology studies
DP development / pharmacological studies

The above information contains forward-looking statements based on our judgement in light of the information currently available to us. Therefore, please
be aware that the above information is subject to various risks and uncertainties, and actual development may differ significantly from these projections.
1.

PMDA refers to Pharmaceuticals and Medica Devices Agency

2．GLP refers to Good Laboratory Practice27

TMS-008 Indication: Anti-inflammatory activities with potential for broad indications
Potent sEH inhibitor with high anti-inflammatory and antioxidant activity
Inflammation-related parameter using AIS model mouse 1

Antioxidant activity test 1,2

One hour after the start of ischemia, 10 mg/kg wasadministered continuously intravenously for 30 minutes.
Brain slices at 24 hours were evaluated by RT-PCR method.



H-ORAC： hydrophilic oxygen
radical absorbance capacity method
Mean±SE（N=3)

Mean±SE（N=6)

TNF-α

0.18

0.7

0.16

0.12

0.5

0.10

0.4

0.08

0.3

0.06

0.15
0.10

＊＊

0.1

0.02

Control

TMS-008

0.0

5.0

0.20

0.2

0.04

6.0

0.25

0.6

0.14

0.00

IL-6

mol TE/mol

IL-1β

Control

TMS-008** P<0.01、＊P＜0.05 （vs. control)

3.0
2.0

0.05
0.00

4.0

1.0

Control

TMS-008

0.0

α-Tocopherol

TMS-008

1. SourceEuropean Journal of Pharmacology Volume 818, 5 January 2018, “Evaluation of the effects of a new series of SMTPs in the acetic acid-induced embolic cerebral infarct mouse model”
Publication number：WO 2011/004620
2. Results are shown in Trolox equivalents (TE). α-Tocopherol ORAC Values are for reference (Huang et al., J. Agric. Food Chem., 50, 1815-1821 (2002)).

28

TMS-008 Indication: Acute Kidney Injury (AKI) 1,2,3,4
TMS-008 development is directed to take advantage of its strong anti-inflammatory properties
Decreased renal function
adversely affects heart andother organs

No protein leakage
Appropriate toxin
excretion

Indication

Patient population of AKI is projected to reach
11.1mn by 2030
Total Incident Population of AKI in Hospitalized Patients 6

Acute(million)

Overview

Number ofpatients

Treatment
method

1.
2.
3.
4.

Acute Kidney Injury (AKI) is a rapid decline in renal function
over a period of hours to days
20-25% mortality rate in hospitalized AKI patients
AKI causes chronic kidney disease (CKD) and end-stage
renal disease (ESRD)

5 European countries: ~5,080,000
 United States: ~3,800,000 Japan: ~2,300,000(Patients assumptions for year 2030 as of 2020) No approved therapeutic drug 5

Nature Reviews Nephrology volume 16, pages747–764 (2020)
Adv Chronic Kidney Dis. 2017;24(4):194-204
Nephron. 2017 ; 137(4):297–301
Delveinsight, “Acute Kidney Injury - Market Insights, Epidemiology, and Market
Forecast—2030”

5.
6.
7.

US

Japan

5 European Countries 7

10.9

10.9

11.0

11.1

5.0

5.0

5.0

5.1

2.2

2.2

2.2

2.3

3.7

3.7

3.8

3.8

2020
Actual2021
Estimated

2026
Estimated

2030
Estimated

Perioperative renal protection, Current Opinion in Critical Care December 2021 - Volume 27 - Issue
6 pages 676-685
Delveinsight, “Acute Kidney Injury - Market Insights, Epidemiology, and Market Forecast—2030”
5 European countries includes Germany, France, Italy, Spain, and the UK

29

TMS-008 Indication: Acute Kidney Injury (AKI)
Preclinical studies in collaboration with Japanese university using AKI mouse models
confirmed its potential as a new treatment for AKI
Preclinical studies confirmed efficacy in two animal models, indicating the feasibility of TMS-008 for practical use Improvement on Scr (serum creatine) and BUN (blood urea nitrogen), which are parameters of

renal function, has been observed

AKI model mouse experiment at Showa University 1
Scr (mg/dL)

3.0

BUN(mg/dL)

250
200

2.0

150
100

1.0

0.0

1.

**

sham

Control

TMS-008

**

50
0

sham

Mean ± SE (n = 6), *p value < 0.05 and **p value < 0.01 as compared with control groups by using ANOVA with Bonferroni correction

Control

TMS-008
30

TMS-009: Backup for TMS-008
TMS-009 showed compelling potential as an anti-inflammatory agent with strong sEH 1 inhibition
observed
TMS-009 is protective of renal function in a mouse model of AKI
 Demonstrated equivalent pharmacological activity as TMS-008 in vitro 2 and in vivo 3 studies

 Designated as a backup clinical candidate by taking advantage of dissimilar chemical structureand safety profile to TMS-008

AKI model mouse experiment at Showa Univ
Scr (mg/dL)
2.5

250

2

200

1.5

150

1

100

**

0.5
0

1.
2.
3.

BUN (mg/dL)

sham

Control

TMS-009

**

50
0

sham

ControlsEH refers to soluble epoxide hydrolase
in vitro refers to a medical experiment which uses human or animal tissue to detect drug responses within the confines of a test tube or laboratory dishin vivo refers to a medical experiment that detects drug responses in living organisms or cells, such as a laboratory animal or human

TMS-00931

Expansion of
Pipelines

32

Pipeline expansion efforts both internally and externally
Pursue internal and external paths for pipeline expansion, leveraging knowledge andexperience through SMTP compounds development

R&D and business development capabilities
cultivated through SMTP compounds
Internal programsNovel small moleculecompounds

・New indications for TMS-008
・sEH inhibitors
・Natural product screening



Brought TMS-007 all
the way fromresearch to clinicaldevelopment

Programacquisition

External programs(Academia and others)

Collaborative
researchPartneringexperience with a
global biopharmacompany

Global Market

DeployHuman sEH

Licensing, etc.
* Global market is >10 times larger thanJapanese market

Bridging innovation in Japanese academia to global market
Value creation on academic innovations by leveraging our unique capability as aJapanese biotechPositions well to bring academic innovation to market based on TMS-007 experience
Global experience: global partnering and global IPO

Pursuing business opportunities through bridging local innovation to global market

Global IPO
Partnering with
global pharmacompanies

Japanese biotech companies:
Several hundreds

Innovations from Japanese academia

Global innovations
from Japan

 Statin Opdivo

 Actemra Fingolimod
 Ivermectin
 Crizotinib

etc.
34

Appendix

35

Corporate ProfileName

TMS Co., Ltd.
(Stock Code: 4891)

EstablishedFebruary 17, 2005

Closing month

February

Representative
Directors

Takuro Wakabayashi
Chief Executive Officer

Address

Headquarters:
1-9-11F, Fuchu-cho, Fuchu-shi, Tokyo
JAPAN

Business Field

Research and development of drug
products

Management

Board Member: 6
Audit & Supervisory Board Member: 4

Number of
employee

14 (as of February 28, 2023)

History
Feb. 2005

TMS Co., Ltd. founded2005 - 2011

Demonstrated thrombolytic and antiinflammatory activities of SMTP ameliorate
ischemic stroke in pharmacological studies of
SMTP

Nov. 2011

Started IND-enabling study of TMS-007

Oct. 2014

Started Phase I clinical trial of TMS-007

Oct. 2015

Completed Phase I clinical trial of TMS-007

Feb. 2018

Started phase IIa clinical trial of TMS-007 forischemic stroke patientsJun. 2018

Option agreement with Biogen on TMS-007

May. 2021

Biogen exercised an option to acquire TMS-007

Aug. 2021

Completed phase IIa clinical trial of TMS-007

Nov. 2022

Listing on the Tokyo Stock Exchange GrowthMarket (Stock code: 4891)

Business Model
ResearchResearch
Institutes

Preclinical Studies

Approval /LaunchClinical Trials

Collaborative
Research

LicenseIntellectual
properties

Development rights
Market rights

Royalties

Upfront / Milestones
Royalties

Pharmaceutical
Companies

DS/DP manufacturing
In vitro / in vivo Testing
Support for clinical trials

Fees

Contracted Service ProvidersThe basic model is that TMS Co., Ltd. conduct drug development from the discovery and research stage
to the early clinical stage in collaboration with research institutions and contracted service providers,and partner with pharmaceutical companies from late development stage to commercialization.
Depending on the disease area, TMS Co., Ltd. may execute late-stage clinical development, obtaining
regulatory approval, and even marketing.

37

History of TMS Co., Ltd.
SMTP

Stachybotrys
Microspora
Triprenyl
Phenol

1990s

2005

2011

TMS-007

TMS Co., Ltd. Founded(February 17, 2005)

Spinoff from Tokyo University ofAgriculture and Technology
1.

The contract party is Biogen MA Inc.

Started Ph2a clinical
trial for acute ischemic
stroke patients

Completed Ph1
Clinical Trial

2014

TMS-007

TMS-007

Launched Ph1
clinical trial in Japan

Started IND-enabling
study

Invention of the hyperlipidemia drug
statin (HMG-CoA reductase
inhibitor), one of the best-sellingcategory of drugs in history.

Worked alongside Dr. Akira Endo for
17 years
Succeeded Dr. Endo’s lab in 1997

TMS-007

TMS-007

Distinguished Professor Emeritus
of Tokyo University of Agriculture
and Technology

Ph.D.
Founder
Chief Scientific Officer

A small molecule compound
produced by Stachybotrys
microspore, a type of fungus

Identification of SMTP
compounds as modulators ofplasminogen

Dr. Akira Endo

Keiji Hasumi

2015

Completed Ph2aClinical Trial

TMS-008

Listing on the Tokyo
Stock Exchange
Growth Market

Started IND-enabling
study

2017

2018

2020

2021

2022

Option Agreement with Biogen 1

Biogen 1 exercises Option Right

Rights Covered: TMS-007 and all IP and
asset rights for the SMTP compound family

Transfered all IP and assets related to TMS007 and SMTP to Biogen.

38

TMS-007 Mechanism of Action: Mechanism of thrombolysis1 (1)Plasminogen changes toplasmin by binding
to blood clots

Generalt-PA
t-PA

Plasminogen
Plasminogen

Thrombolysis

PlasminPlasminFibrinPromotes binding ofplasminogen toblood clots

TMS-007

TMS-007

Plasminogen

Rapid thrombolysis

PlasminFibrin1.

For illustrative purposes only

39

TMS-007 Mechanism of Action: Mechanism of thrombolysis (2)TMS-007 promotes binding of fibrin to blood clots1
Native plasminogen

Relaxed plasminogen

E1

K5

PAN

PAN

SMTP

K1

K2

P

SMTP

K4

Fibrin

K1

PAN

K5
t-PA

SMTP

K4

K3

Enhanced fibrin-binding of
open-conformation plasminogen
1.

Activation toplasmint-PA

Fibrin
K1

PAN

E1
K5
SMTP
K4

K2

K2
P

K3

SMTP-7 stabilizes the open
conformation of plasminogen

FibrinE1

K1
K2

Closed, spiralconformation

K5

K4

Conformational change

K3

P

K5

SMTP

K4

E1

P

K3

Fibrin-bound t-PA attacks the“activation cleavage site” (red circle)
for activation to plasmin

thrombolysis

P

K2

K1

PA
N

E1

K3

The resulting plasmin cleaves fibrin.
SMTP can thus enhance regulated
Endogenous fibrinolysis

Hasumi & Suzuki (2021), “Impact of SMTP Targeting Plasminogen and Soluble Epoxide Hydrolase on Thrombolysis, Inflammation, and Ischemic Stroke” Diagrams shown above havebeen modified by the Company from the original versions. For illustrative purposes only40

TMS-007 (BIIB131): Outline of Ph2b Clinical Trial (DAISY) 1
Summarized information, based on the publicly available information registered by Biogen 2

Outline Multicenter, operationally seamless, double-blind, dose-ranging, placebo-controlled, randomized,
parallel-group Estimated enrollment: 760 participants
 Estimated duration: Dec. 2023 – July 2025

Key Inclusion Criteria

 “Patients with thrombus site confirmed by imaging” 3 or “Patients with an estimation of penumbra 4
volume to be ≧10ml” 5 Presentation and treatment start are within 4.5 - 24 hours of LKW 6
 No statement regarding limitations with or without endovascular therapy
 Age 18 – 85 years

Part 14 groups: Low, Medium and High dose, andPlaceboPrimary Outcome Measures Arterial revascularization 7
 Reduction of at least 90% of the area
presumed to be penumbra for patients inwhom the occlusion cannot be located8

1.
2.
3.
4.
5.
6.
7.
8.

Part 2

2 groups: a single dose specified in Part1 andPlaceboPrimary Outcome Measures modified Rankin Scale (mRS) score at
90 days

Biogen has announced to pause initiation of Phase 2b clinical trial and reassess whether to initiate the trial at its Q1 2023 Earnings Presentation on April 25, 2023. As of October 18, 2023, it is not clear if the Phase 2b clinical trial will resume.
The above information are summarized by TMS Co., Ltd., based on the information registered and published in ClinicalTrials.gov (https://www.clinicaltrials.gov/study/NCT05764122?cond=BIIB131&checkSpell=false&rank=1) by Biogen.
Therefore, the accuracy of the information cannot be assured.
Patients with CTA or MRA showing symptomatic intracranial occlusion, at one of the following locations: intracranial internal carotid, M1, M2 or distal branches of the middle cerebral artery (MCA), anterior cerebral artery (ACA), or posterior cerebral artery.
Penumbra is an area of brain, in the early (hyperacute) phase of cerebral infarction, where blood flow is reduced but cells have not yet become necrotic, and rapid vascular recanalization is expected to prevent the area from transition to infarction.
Patients with the volume of Tmax>6s to be ≥10 mL on perfusion imaging.
LKW: Last Know Well, meaning the last time patient was confirmed to be normal before symptoms started.
Patients with an AOL score of 2 or 3 at 4 ± 2 hours post-treatment (or at the time of the first angiogram for patients undergoing endovascular therapy).
For patients with no visible occlusion at baseline, >90% reduction of Tmax > 6s at 4 ± 2 hours after treatment completion.

41

TMS-007 (BIIB131): Ph2b (DAISY) 1 / Ph2a comparison
Summarized information, based on the publicly available information registered by Biogen 2
Ph2a

Ph2b

Basic design

1 stage

2 stages (Part 1、Part 2)

Enrollment

90

760 (Estimated）

Primary efficacy endpoint

mRS 0-1 ratio

Part 1・Arterial revascularization
・Reduction of at least 90% of
penumbra
Part 2・mRS score

Ages eligible for trial

Male: 20 - 88 years
Female: 60 - 88 years

18 - 85 years

Time window

Within 12 hours after on set

Within 4.5 - 24 hours of LKWEndovascular therapy (EVT)

Only for patients without EVT

May include patients undergoing
EVT

Pre-treatment score of NIHSS

6 - 23(Patients with moderate symptoms)≧5(Severe patients are also eligible)

1.
2.

Biogen has announced to pause initiation of Phase 2b clinical trial and reassess whether to initiate the trial at its Q1 2023 Earnings Presentation on April 25, 2023. As of October 18,
2023, it is not clear if the Phase 2b clinical trial will resume.
The above information are summarized by TMS Co., Ltd., based on the information registered and published in ClinicalTrials.gov(https://www.clinicaltrials.gov/study/NCT05764122?cond=BIIB131&checkSpell=false&rank=1) by Biogen. Therefore, the accuracy of the information cannot be assured.

42

www.tms-japan.co.jp

43