Financial Results for FY02/2024
TSE Growth：4891

Disclaimer
This document has been translated from part of the Japanese original for reference purposes only. Please
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
construed as, an offer to sell or issue or the solicitation of an offer to buy or acquire securities of theCompany in Japan, the United States or any other jurisdictions.

 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
the forward-looking statements. Therefore, you may not rely entirely on forward-looking statements.

 Information about pharmaceutical products (including products in development) in this document is notintended to constitute solicitations or advertisements of the products or medical advice.

 Information on companies other than the Company and information provided from third parties are

based on public information or sources. The Company has not independently verified the accuracy andappropriateness of data and indicators used herein, which are provided from third parties and based on
public information or sources, nor assume any responsibility for the accuracy and appropriateness ofsuch data and indicators presented in this document.

 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Agenda1. Highlight
2. Summary of Financial results for FY02/2024
3. Pipeline
4. TMS-007
5. JX09
6. TMS-008 / 009
7. Expansion of Pipelines
8. Appendix

3

Highlight4

Highlight１

TMS-007 rights assigned from Biogen to Ji Xing Pharmaceuticals

Timeline June 5, 2018
 May 11, 2021
 Mar 10, 2023
 Apr 25, 2023
 Jan 11, 2024

TMS and Biogen signed the Option Agreement
Biogen exercised its option
TMS-007 Ph2b outline registered at ClinicalTrials.gov
Biogen announced pausing of TMS-007 Ph2b study
Biogen assigned the Option Agreement to Ji Xing
Pharmaceuticals１. BIIB131 is renamed JX10.

* TMS continues to use TMS-007 as its internal product code

Status JIXING is planning a new clinical trial

1.

The contract party is Ji Xing Pharmaceuticals Hong Kong Limited

5

Highlight2

Capital and business Alliance with JIXING/RTW
US-based global life sciences investor
RTW owns 9.99% of
TMS shares

Japan-based biotech
developing innovative
therapeutics for the patientsworldwide

Alliance on SMTP
compounds, including
TMS-007, and JX09

RTW founded JIXING in 2019
Owns ＞80% shares

China-based fast-growing
biotech aspiring to become a
global player• TMS-007 global development to be accelerated under the
Capital and Business Alliance with JIXING/RTW• TMS regained TMS-007 Japan rights• Newly acquired JX09 Japan rights

6

Highlight2

Capital and business Alliance with JIXING/RTW
JIXING shares $5m

Japan

Japan

TMS-007Japan rights (royalty-free)
Development milestone up to $12.5m
Commercial milestone up to $355m
Tiered royalties (high single digit to
low teen percentages)

JX09
 Japan rights (royalty-free)Worldwide
ex-JapanWorldwide
ex-Japan TMS plans to participate TMS-007 and JX09 global development through
JDCC (Joint Development and Commercialization Committee)
 TMS is entitled to receive 75% reimbursement of TMS-007 and JX09
development costs under certain conditions (maximum: TMS-007 $10m,
JX09 $5m)

7

Highlight３

Timeline : JX09 and TMS-008


TMS-008 : Ph1 CTN submitted in Feb 2024



JX09 : Ph1 study initiated in Feb 2024 by JIXING (Australia)
FY Feb 2024 (Mar 2023 – Feb 2024)
H1

FY Feb 2025 (Mar 2024 – Feb 2025)

H2
CTN
PMDA１ Discussion

TMS-008

DS Supply

DP Supply

IRB２

H1

H2

Dosing start

Last cohortcomplete

Ph1 Clinical Trial

GLP Study (Safety/Toxicity)３

JX09

Ph1 Clinical Trial (JIXING)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.

PMDA refers to Pharmaceuticals and Medica Devices Agency
IRB refers to Institutional Review Board

3．GLP refers to Good Laboratory Practice8Summary of
Financial Resultsfor FY02/2024

9

Financial Results FY02/2024 - Statement of Income
Higher R&D expenses due to TMS-008 phase 1 implementation
In line with forecasts (ordinary income loss of ￥943m, net income loss of ￥960m)(million of yen)
ChangeFY02/2023

FY02/2024

Operating revenue

-

-

-

-

Operating expenses

520

943

423

81.3％

297

607

309

104.0％

Operating income(loss)

(520)

(943)

(423)

-

Non-operating income

0

3

3

-

Non-operating expenses

341

3

(337)

(99.0％)

Ordinary income (loss)

(861)

(943)

(81)

-

Extraordinary loss

-

15

15

-

Net income (loss)

(860)

(960)

(99)

-

Research andDevelopment expenses

Expected expenses for FY02/2025

Amount Percentage(million of yen)

Research and Development expenses

750- 1,100

Other selling, general and administrative expenses

300

- 400

Up on previous year
mainly due to recording ofdevelopment costs for
TMS-008 Ph1
implementation
IPO-related expenses
recorded in FY02/2023
Recorded impairment loss
on non-current assets
Mainly for development
costs for each pipeline at
the clinical stage, and useof external seeds andexploration for pipeline
10
expansion

Financial Results FY02/2024 - Cash Flows
While operating cash flow was negative due to R&D activities, cash / cash equivalents at theend of the period were roughly the same as the previous fiscal year due to proceeds from theissuance of shares through a capital and business alliance(million of yen)
FY02/2023
Cash flows from operating activities

FY02/2024

（688)

(822)

（861)

(959)

Cash flows from investing activities

（13)

(3)

Cash flows from financing activities

1,688

688

Income from issuance of shares

(420)

-

Proceeds from issuance of shares

2,109

688

Net increase and decrease in cash and cash
equivalents (indicates decrease)

986

(138)

Cash and cash equivalents at beginning of
period

2,598

3,584

Cash and cash equivalents at end of period

3,584

3,446

Net income before tax

Investment from RTW

11

Financial Results FY02/2024 - Balance sheet
Investment related to the capital and business alliance offset by R&D expenditures, mainly for
TMS-008(million of yen)
FY02/2023

FY02/2024

3,766

ChangeAmountPercentage

3,551

(215)

(5.7％)

3,584

3,446

(138)

(3.9％)

23

３

(20)

(86.5％)

3,790

3,554

(235)

(6.2％)

Current liabilities

76

97

21

28.3％

Total liabilities

76

97

21

28.3％

Subscription rights toshares

-

11

11

-

Total net assets

3,714

3,457

(256)

(6.9％)

Total liabilities and net
assets

3,790

3,554

(235)

(6.2％)

Current assets
Cash and deposits
Non-current assets
Total assets

Due to expenses related todevelopment of TMS-008
and decrease in advancepayments to development
subcontractor, etc.
Due to impairment of noncurrent assets

Due to granting of stock
options12

Pipeline

13

Pipeline
TMS-007 : Transferred from Biogen to JIXING; TMS regained development and marketing rights in Japan
JX09: Development and marketing rights in Japan acquired from JIXING (Ph1 in Australia)
TMS-008 : Clinical entry / Phase 1 CTN filing
Development
Code

TargetDisease

TMS-007（JX10）

Acute
Ischemic
Stroke

JX091

Resistant or
uncontrolled
hypertension

New

TMS-008２

TMS-009 ２
Pipelinecandidates<Internal>

Pipelinecandidates<External>

MoA
sEHInhibition

Plasminogen

Research

Preclinical

Ph1

TBD

Ph3

Development
andCommercialization

Japan: TMS
Outside Japan:
JIXING

Ph2a completed in Japan

ASI
Anticipated Next Steps

Acute Kidney
InjuryOther
indications

Ph2

Japan: TMS
Outside Japan:
JIXINGTMS

sEHInhibition

TMS
sEHInhibition

TMS

Search for novel sEH inhibitors and other compounds

TMS

Evaluating multiple programs

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.

Obtained free license for development and marketing rights in Japan from JIXING (January 2024).
TMS-008 and TMS-009, which were being developed under a free license from Biogen, continue to be developed under a free license from JIXING.
TMS-009 is a backup compound for TMS-008.

14

TMS-007
Potential Next Generation
Acute Ischemic Stroke
Treatment15

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

16

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

17

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) Stroke18

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

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 all

2

Slight disability; unable toperform all previous activities butable to look after own affairs
without assistance3

Moderate disability; requires
some help, but able to walk without
assistance1

TMS-007群
TMS-007(N=52)

59.6%

40.4%

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

usual duties and activities

6

Moderately 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 : Estimated Market Size
Estimated market size for TMS-007 with excellent efficacy and safety potential
Estimated TMS-007 Market Size

‘000m USD

250
200
150
100
50
0

t-PA Sales$21b1(2021)
t-PA

Estimate
Up to 12hr : 1.6X
Up to 24hr : 1.9X
1. Time window

Estimate
2.9X

普及率の拡大2. Penetration expansion

3. Price increase

expansion

1.
2.
3.
1.

Possibility to expand time window after onset (12hr or 24hr)
Possibility to expand penetration due to excellent safety

Possibility to claim higher pricing if higher efficacy and safety than t-PA are achieved

Data for 2021 from Informa
Calculated as the sum of estimated 2021 sales of Activase® and Actilyse®. Actual market size may differ from estimate due to the limitations peculiar to such statistical data andpublications in terms of their accuracy

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

JX09
Resistant or uncontrolled
hypertension

26

JX09
JX09 has a potential of best-in-class therapeutics for the rHTN indication


Therapeutic candidate for “resistant/uncontrolled hypertension”, potentiallylarge unmet medical needs

10-20% of treated hypertension patients are believed to be resistant1.

Oral, small molecule aldosterone synthesis inhibitor (ASI)Highly selective inhibition of aldosterone synthase (CYP11B2) overstructurally similar CYP11B1 is crucial for effective ASI. JX09 has very highselectivity.





1.
2.

> 300 fold selectivity for CYP11B2 over CYP11B1 (in vitro), suggesting selectivity
higher than baxdrostat (<100 fold) ２
Achieved >90% aldosterone lowering with no increase in CYP11B1 precursor
steroids (in vivo, non-human primates) ２

Phase I clinical trial started in Feb 2024 by Ji Xing.
Dudenbostel et al (2017): Resistant hypertension (rHTN) is relatively common with an estimated prevalence of 10-20% of treated hypertensive patients
Source JIXING website March 2023 "JIXING Presents the Latest Research Data of Cardiovascular Asset JX09 at the American College of Cardiology Annual Congress 2023"

27

JX09
Highly selective inhibition: Inhibits aldosterone synthase (CYP11b2) 1 more selectively than
the structurally similar CYP11b1
Angiotensinogen
CYP11B1

Renin
Angiotensin I

Existing
inhibitor

Insufficient selectivity
ASI

JX09

ACE
Aldosterone
Synthetase(CYP11B2)

Angiotensin II

Cortisol

ASI with high selectivity towards
aldosterone synthase

Aldosterone: Angiotensin converting enzyme: Aldosterone synthase inhibitor: Mineralocorticoid receptors

Off-target
inhibitionMR
antagonist

Aldosterone breakthrough in
rHTNS
ACE
ASI
MR

Side
effectsblood
pressure

Position of aldosterone synthesis inhibitors among hypertension drugs
1. Lee J, et al, Abstract 121: The Selective Aldosterone Synthase Inhibitor PB6440 Normalizes Blood Pressure In A Human Aldosterone Synthase-Transgenic
Mouse Model Of Hypertension, Hypertension 2022; 79:A121

28

JX09: Japan Market
JX09 targets treatment-resistant hypertension, which is expected to affect 1.3 to 2.6 million
patients in Japan alone
Prevalent HTN
32M

25% of total population or
30% of >20 yo polulation1

Diagnosed HTN
19M

60% of prevalent HTN cases2

Treated HTN
17M

90% of diagnosed HTN cases3

rHTN
1.7-3.5M
Compliant rHTN
1.3-2.6M

10-20% of all treated HTN
cases are resistant4

75% of treated rHTN5

1：Estimated with data from Health Service Bureau, MHLW "National Health and Nutrition Survey 2019“: https://www.mhlw.go.jp/english/database/compendia.html
2：Saito et al. (2015): We find that there are much higher rates of undiagnosed hypertension in Japan (44.3%) than in the U.S. (11.9%)
3：Used the same treatment rate as in China, as per Zhang (2022): diagnosed but untreated ~10% in 2018
4：Dudenbostel et al (2017): Resistant hypertension (RHTN) is relatively common with an estimated prevalence of 10-20% of treated hypertensive patients
5：Siddiqui et al (2019): Among patients with RHTN, multiple studies have reported high rates of poor medication adherence. Strauch et al (2013): Our main finding is a surprisingly low
compliance with drug treatment in out-patients with resistant hypertension (23% partially noncompliant and 24% totally noncompliant – in total, 47% prevalence of noncompliance).

29

TMS-008/009
Acute Kidney Injury
and other indications

30

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)).

31

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
No protein leakage
Appropriate toxin
excretion

Indication

Decreased renal function
adversely affects heart andother organs

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

32

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
33

TMS-0008: Overview of Ph1 Clinical Trials
Ph1 Clinical Trial Design Objective： To confirm pharmacokinetics, tolerability, and safety of a single dose of TMS-008
administered to a healthy adult male as a First-In-Human study Design： Randomized, placebo-controlled, double-blind, dose-escalation, single-dose study

Number of subjects: 8 at each stage, 40 in total over 5 stages

Dose 5
Dose 4
Healthy
adult
males

Dose 3
Dose 2
Dose 1
A single dose of TMS-008 or the placebo is given at every dosestage. The dose is increased in stages while confirming
pharmacokinetics and safety.
34

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-00935

Expansion of
Pipelines

36

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 than
37
Japanese market

R&D Status of New Seeds
We are developing internal projects by actively utilizing external libraries, as well as exploring
seeds held by academic research institutions and conducting joint researchInternal projects

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

Exploring external
library Initiated evaluation of an external
compound library Entered joint research agreementwith the Microbial Chemistry
Research Foundation

External projects
Option agreementswith academia

Project 1

Project 238

External Program Approach
Leveraging TMS's track record to globally expand the discoveries from Japanese academia

Pursuing business opportunities by connecting outstanding life science innovations fromthe local to global markets
Continued assessment of numerous seeds

Global IPO
Partnering with
global pharmacompanies
Japanese biotech companies:
Several hundreds

Global innovations
from Japan

 Statin Opdivo

 Actemra Fingolimod

Innovations from Japanese academia

 Ivermectin
 Crizotinib

etc.
39

Appendix

40

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 29, 2024)

History
Feb. 2005

TMS Co., Ltd. founded2005 - 2011

Demonstrated thrombolytic and anti-inflammatory
activities of SMTP ameliorate ischemic stroke inpharmacological 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)

Jan. 2024

Biogen transferred TMS-007 rights to JIXING
Acquired development and marketing rights for
TMS-007 and JX09 in Japan

41

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.

42

History of SMTP Compounds
SMTP

Stachybotrys
Microspora
Triprenyl
PhenolPh.D.
Founder
Chief Scientific Officer

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

Launched Ph1
clinical trial in Japan

TMS-007

Started CTN-enabling
study

1990s

2005

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

TMS-007

Identification of SMTP
compounds as modulators ofplasminogen

FY 2011

FY 2014

Dr. Akira Endo

Keiji Hasumi

TMS-007

Distinguished Professor Emeritus
of Tokyo University of Agriculture
and Technology

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

TMS-007

TMS-007

Started Ph2a clinical
trial for acute ischemic
stroke patients

TMS-008

Started CTN -enabling
study

Completed Ph1
Clinical Trial

FY 2015

Completed Ph2aClinical Trial

FY 2017

FY 2018

FY 2020

Option Agreement with Biogen 1

Biogen 1 exercises Option Right

Spinoff from Tokyo University ofAgriculture and Technology

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

Transfered all IP and assets related
to TMS-007 and SMTP to Biogen.

1.
2.

The contract party is Biogen MA Inc.
JIXING：Ji Xing Pharmaceuticals Hong Kong Limited

CTN-Submission

FY 2021 FY 2022 FY 2023

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

TMS-008

Rights transfered from
Biogen1 to JIXING2
TMS reacquires development
and marketing rights for TMS007 in Japan43

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

44

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

K2
P

K3

Enhanced fibrin-binding of
open-conformation plasminogen
1.

K3

SMTP-7 stabilizes the open
conformation of plasminogen

FibrinE1

K1
K2

Closed, spiralconformation

K5

K4

Conformational change

K3

P

K5

SMTP

K4

E1

K5
t-PA

Activation toplasmin

SMTP

K4

t-PA

Fibrin
K1

PAN

E1
K5
SMTP
K4

K2
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 only45

www.tms-japan.co.jp

46