IR Session 2023

IVD Business
Progress of R&D Activities and CDMO Business(Neuro/Alzheimer and Ultrasensitive Detection Technology)
December 1st, 2023

Agenda(1) Progress of IVD Business Strategy(Overview)(2) R&D Activities and CDMO Businessin Neuro/Alzheimer field(3) Ultrasensitive Detection Technologyand CDMO Business

H.U. Group Holdings, Inc., Executive Officer (IVD)
Fujirebio Holdings, Inc., President and CEO
Goki Ishikawa
Fujirebio Holdings, Inc., Board Member (Neuro Business)
Fujirebio Europe NV, CEOChristiaan De Wilde
ADx NeuroSciences, CEOKoen Dewaele
Fujirebio Holdings, Inc., Board Member (R&D)
Katsumi Aoyagi Ph.D.
Fluxus Inc., CEOPeter Wagner Ph.D.
1

Progress of IVD Business Strategy(Overview)
H.U. Group Holdings, Inc., Executive Officer (IVD)
Fujirebio Holdings, Inc., President and CEO
Goki Ishikawa

2

Progress of Strategy (Overview)
CDMO agreements
for contract development
and manufacturingwith IVD players
having immunoassay
analyzer installed base• 7 Partners forcontract development
and manufacturing• Ab supply: Many

15% Base Revenue
spend on R&D activities• Focus on Immunoassay

Supply toDevelop
Global market
New Contentsthrough「ONLY ONE」
partnerships

Global R&D Team、
300+ members in JPN/EU/US• 20%+ of total employees
2 newly acquired companies
integrated fully into the group• Part of our growth strategy

Prove Value onOwn Platform

Develop and launch quickly• RUO to IVD approach3

ADx and Fluxus successfully integrated into the groupADx creates tailor-made antibodies and assays in the Neuro field.

Fluxus develops Ultrasensitive Detection Technology based platform.

•No employees left the company because of acquisition.

•R&D teams across entities are collaborating day-to-day in our Global R&D team.

•CDMO discussions ongoing based on “FUJIREBIO strategy” incorporating both companies.
Pursue Synergies in FUJIREBIO strategy while keeping both companies’ Entrepreneurial Culture4Our Approaches
Life Science / RUO market

In Vitro Diagnostics Market
Medical institutions etc.

Pharma and Research institutions etc.
LUMIPULSE

Speed-up the expansion of Neuromarkers line-up.

Regulatory applications for selected markers(e.g. FDA)•

Ultrasensitive
Detection

Identify areas where Ultrasensitive
Detection can add clinical values,
and accelerate reagent development

Subsidiaries experienced in regulatory affairs(Clinical trials, Regulatory registration)

Regulatory applications for selected markers
and the instrument (e.g. FDA)•Advance the development of improved
high-throughput versions

Aim to expand our business in two markets, “RUO” and “IVD”,
by leveraging CDMO business model5

Progress of KPI：Accumulated # of Markers (Reagent)
Global Partners# ofMarkers

In development

60504247

Regional Partners

Development completed
4930

10172530

3160

45171845402645

20
17Development completed

3028
17In development

5026402054# ofMarkers

1019002019
Actual

2020
Actual2021
Actual2022
Actual2023
Forecast

2019
Actual

2020
Actual2021
Actual2022
Actual2023
Forecast

A number of Neuro related markers are expected to be signed as new contract development projects in 2023
6Growth scenario Post-COVID“Base business” will continue to grow steadily

Revenue growth in IVD business■: Base business□: COVID

CAGRMSDCAGR+6.5%•“Base business” excluding COVID
has grown by +6.5%/year since FY2019•Aiming at continuous Mid-Single Digit growth

CDMO will lead our growth in mid and long term
based on our strategic and multitiered initiatives
1. Steady growth in Reagent manufacturing
and Raw material supply in “Oncology field”
2. Start of Reagent manufacturing of newdevelopment projects gained since 2020
3. New CDMO deals in Neuro field from 2023
(expected to complete development in 2025)

2018 2019 2020 2021 2022 2023 2024

2027

4. New CDMO deals for Ultrasensitive Detection

Growth image

Focus on Neuro field and Ultrasensitive Detection where our CDMO business is expected to grow7

R&D Activities and CDMO Businessin Neuro/Alzheimer fieldFujirebio Holdings, Inc., Board Member (Neuro Business)
Fujirebio Europe NV, CEO
Christiaan De Wilde
ADx NeuroSciences, CEOKoen Dewaele
8Presenters

Board Member, Fujirebio Holdings Inc.
Fujirebio Europe NV, CEO
Christiaan De Wilde••

15+yrs, J&J/Janssen Pharmaceuticals• CFO, Janssen-Cilag Belux
CEO, Innogenetics/Fujirebio Europe (2007~)ADx NeuroSciences, CEOKoen Dewaele•••

35+yrs, in In Vitro Diagnostic business10+yrs, Innogenetics• Various positions (Marketing etc.)
Founder & CEO, ADx NeuroSciences (2011~)

9Alzheimer’s Disease Pathology
Source:Le Bastard et al., 2009
CML-Neurology

Micro

A. Amyloid plaques identified in the hippocampus with 4G8 immunohistochemistry (40x)
B. Neurofibrillary tangles identified in the hippocampus with NFT200 immunohistochemistry (100x)

Macro

A. Normal brain
B. Atrophic brain

Source: http://journals.lww.com/neurotodayonline/blog/breakingnews/pages/post.aspx?PostID=363
10

History of Alzheimer’s Diagnosis

Innogenetics (Fujirebio Europe)
ADx NeuroSciences
Source: https://doi.org/10.1152/physrev.00015.2020
11

Biomarker changes during the disease processSource: https://doi.org/10.3390/biomedicines10040850
12

Trends in Neurobiomarker Testing
Early Detection

From CSF to Blood

Ultrasensitive13

Effective therapies will need specific biomarkers
Up to 20 years to clinical AD

Disease progression
Clinical AD

ClinicalStage

Asymptomatic
preclinical AD

Progressive
Brain Pathology

Therapy

Diagnostic tools
In Vivo /In Vitro

Prodromal
AD

MildAD

ModerateAD

SevereAD

Inflammation, protein abnormalities, neuronal loss, synapse loss
Future Therapy

Current Therapy

Disease modifying therapy
Combination therapy
Prevention therapy

Non-disease modifying therapy
Late intervention
Symptom relief

BLOOD

BLOOD + CSF
PET, MRIBLOOD + CSF
PET, MRI

Biomarkers are needed for pharma to select the right patients and the most effective therapy
14

Specific biomarkers for neurodegeneration
Up to 20 years to clinical AD

Disease progression
Clinical AD

ClinicalStage

Asymptomatic
preclinical AD

Progressive
Brain Pathology

Prodromal
AD

MildAD

ModerateAD

SevereAD

Inflammation, protein abnormalities, neuronal loss, synapse loss

Tau (total), BD Tau,
MTBR Tau
Neurofilament light,
VILIP-1, NSE, BDNF …

Neuronal
Loss

Other

Neurogranin,
Beta-synuclein,Pentraxin (NPTX2),
SNAP-25, VAMP2,
GLuR4 …

Synaptic
Loss

BDNF, ApoE, SMN,LRRK2, Rab10, Ataxin

Inflammation

ProteinAbnormalities

GFAP, sTREM2YKL-40Beta-Amyloid,
BACE1, pTau, DDC
α-Syn, pTDP-43

15

Neuro – Fujirebio Assay Development Road Map
FY
2021

RUO

IVD

RUO Launch• Plasma
Amyloid Beta 1-42
• Plasma
Amyloid Beta 1-40
• Plasma pTau181

FY
2022

FY
2023

FY
2024

RUO Launch
RUO Launch• CSF Neurofilament• PlasmaLight (NfL)
pTau217• Plasma NeurofilamentLight (NfL)• Plasma ApoE4• Plasma Pan ApoE
FDA Clearance• CSF
Amyloid Beta 1-42
• CSF
Amyloid Beta 1-40

Plasma
FDA Clearance
IVDR Registration
PMDA submission

16

Publications - Broad International Scientific Coverage> 25

Posters on
international
conferences> 15

Peer reviewed
scientificarticles> 10

Oral presentations
on international
conferences
Period Jul 2022- Nov 2023

17

LUMIPULSE Assay PerformanceSant Pau, Barcelona, Spain (pTau 217, pTau181, Aβ1-42 and Aβ1-40)
Study principle

Study set-up•Plasma samples selection from the clinic
20 A-T- cognitively healthy
30 A+T+ prodromal AD(Mild Cognitive Impairment)
20 A-T- non-neurodegenerative MCI(MCI not linked to AD or other degenerativediseases)
31 A+T- symptomatic individuals(heterogenous group of clinical diagnosis)•
Study coordinators
Dr. Alberto Lleo & Dr. Daniel Alcolea
Hospital Sant-Pau, Barcelona, Spain

Assays included
Lumipulse G pTau 217 Plasma
Lumipulse G pTau 181 Plasma
Lumipulse G Amyloid Beta 1-42 Plasma
Lumipulse G Amyloid Beta 1-40 Plasma

18

LUMIPULSE Assay PerformanceSant Pau, Barcelona, Spain (pTau 217, pTau181, Aβ1-42 and Aβ1-40)
Ability LMP assays to categorize samples correctly
by Area Under the Curve (AUC)→

Amyloid positive (A+) from Amyloid negative (A-)→

Amyloid positive/Tau positive (A+T+) fromAmyloid negative/Tau negative (A-T-)

AssayAUC(A+/A-)AUC(A+T+/A-T-)

Lumipulse G pTau 217 Plasma

0,95

0,99

Lumipulse G pTau 181 Plasma

0,84

0,86

Lumipulse G AB42/40 Plasma

0,90

0,90

A+: n = 55
A-: n = 40

Clinical performance LMP assays by AUC(A+ vs A- samples)

A+T-: n = 31
A-T-: n = 30

19

Fujirebio’s Value Story
PharmaProcess
What’snecessary

Fujirebio’ssolution

Clinical

Pre-Clinical•

NovelDrug Modifying
Therapy (DMT)
Candidates•

Novel biomarkers•

New biomarker
discovery

Phase I / II / III•

Exploratorybiomarker trials•

Develop and supply reagentson robust Lumipulse platform•

Gain regulatory registration(FDA/IVD-R/PMDA)

FDA

Drug Launch••

Biomarkers forClinical use

Develop and supply reagentsthrough CDMO partners•

Global installed base ofCDMO partner’s instrument•

Beckman Coulter•

Sysmex•Major diagnostics
companies in China/India20

SUMMARY•

There is huge portfolio of neurodegenerative disease biomarkers• We will expand our biomarker portfolio from Amyloid Beta, pTau, NfL etc.

•Fujirebio aims to develop novel biomarkers on a robust system, LUMIPULSE
Since 2021, we are successful in developing and registering new markers•

Fujirebio’s reagents show highest level of performance compared to other players in market•

Fujirebio can support the community through broad range of solutions• With ADx NeuroSciences joining Fujirebio, we can provide comprehensive solutions topharmaceutical companies who need biomarkers for their drug development•LUMIPULSE & CDMO strategy can contribute to preparing necessary testing capacity globally• Our Neuro CDMO partners have strong footprint on a global scale; Beckman Coulter, Sysmex
and major diagnostics companies in China and India•

Our global team is committed to grow the diagnostic market for neurodegenerative disease21

Ultrasensitive Detection Technologyand CDMO BusinessFujirebio Holdings, Inc., Board Member (R&D)
Katsumi Aoyagi Ph.D.
Fluxus Inc., CEOPeter Wagner Ph.D.

22

Presenters

Board Member, Fujirebio Holdings Inc.
Managing Director, Fujirebio, Inc.
Katsumi Aoyagi Ph.D.
•••

Ph.D.（Tohoku University）
CEO, Advanced Life Science Institute, Inc. (2017~)
Board member (R&D), Fujirebio, Inc.(2016~)

Fluxus Inc., CEOPeter Wagner Ph.D.
•••

26+yrs experience in Life Science tools and IVD
Founder and CEO, Zyomyx Inc. (15+yrs)
Founder and CEO, Fluxus Inc. (2016~)
23

Fluxus Ultrasensitive Detection Technology• Fluxus, located in Silicon Valley, California, codeveloped Ultrasensitive Detection technologies
with Fujirebio for the past 6 years.
• Fluxus was acquired by Fujirebio HD in July 2022.
• At IR Day 2022, Fluxus was announced with thepromise of launching an ultrasensitive analyzer inearly 2024.
• As promised, I would like to introduce to you thenew Fujirebio ultrasensitive analyzer system
which will be launched in early 2024.

24

Fujirebio Ultrasensitive Analyzer powered by Fluxus Technology• Fully Automated:
Walk-away sample-to-answer processing• Ultrasensitive:
Integrated UDM detection system forsingle-molecule counting• Efficient:
Up to 48 assays per batch run, multiple
formats in parallel• Flexible:
Accommodates a wide variety of assay
conditions and analytes

25

Why Ultrasensitivity?
• Conventional immunoassay methods have reached their limits of sensitivity and dynamicrange.
• Market demand for ultrasensitive technologies is increasing - particularly in neurology
infectious disease, and oncology testing.
• Higher sensitivity enables:• New clinical utility• Discovery of new markers at lower levels in all fields• Earlier detection and diagnosis• Infectious disease, oncology• Use of less invasive sample types• Infectious disease marker in urine, saliva, etc.
• Lower volume consumption = more tests per sample

26

Fluxus Technology – Key Components• Universal Detection Module (UDM)• Optofluidic Cartridges• High Performance Reagents & Assays• Data Analysis Algorithms• Ultrasensitive Analyzer (RUO)
27

Universal Detection Module (UDM)• Single molecule detection• Incorporates replaceable optofluidic UDM
Cartridge• Sample injection with automated pipettor• Small footprint for integration into any system• Stackable to accommodate any throughput:

1x ~ 60 tests/hour
2x ~ 120 tests/hour
3x ~ 180 tests/hour
4x ~ 240 tests/hour

28

Assays Incorporate Fluxus and Fujirebio Components

Fujirebio Reagents• Industry leader in theidentification and supply ofnovel antibodies

Fluxus Reporter• Proprietary fluorescent dyecarrier construct

Single Test Cartridges• Same concept as LUMIPULSE
G1200• Conjugated to detection
antibody• High precision, reproducibility• Fujirebio manufacturingexpertise29

Easy Adaptation of Pre-Existing Assays

Existing
Immunoassay+

Fluxus Reporter+UDM

Single Molecule
Detection30

Typical Analytical Performance Data
Detection Sensitivity and Dynamic Range

1 nM• Linearity: 100 aM ~ 1 nM

Measurement value

100 pM
10 pM• Sensitivity: < 100 aM

Digital detection

1 pM

Analog detection

100 fM
10 fM
1 fM• Dynamic range : > 7 Logs
Potentially > 9 Logs
< 100 aM - 100 nM

100 aM

100 aM

1 fM

10 fM

100 fM

1 pM

10 pM

100 pM

1 nM

Theoretical concentration

31Performance Comparison Alpha-Version of New Analyzer vs LUMIPULSE
Typical example: IL-6 Assay

Detector performance using only measurement ofdiluted reporter conjugate (no immunoassay)

Approx.
128folds
Approx.
125-folds>1,000folds

The new platform detector demonstrated thepotential for more than 1,000 times moresensitivity than the LUMIPULSE G1200.
32

Future Roadmap
Launch RUO Analyzer and expand menu line-up (Neuro, Infectious diseases, Oncology etc.)

Bring to IVD (Analyzer and selected markers)

Licensing-out technology to be used for CDMO partner’s next-generation
immunoassay platform++33

SUMMARY•

Fujirebio believes Ultrasensitive Detection will add huge clinical benefit for selected markers
in immunoassay field.

•Fluxus has been developing the Ultrasensitive Detection system since 2017, through partnershipwith Fujirebio, with the intent to include in Fujirebio’s future immunoassay platform.

•With the acquisition of Fluxus by Fujirebio HD in 2022, development of benchtop RUO analyzer
and reagents has been accelerated, currently scheduled for launch in early 2024.

•Initial data shows high performance as expected. For selected markers, Fluxus RUO analyzer
shows over 100 times higher sensitivity compared to LUMIPULSE.

•First wave of assays to be launched on RUO analyzer will be neuro biomarkers. Fujirebio willwork on menu expansion beyond neuro into infectious disease and oncology, and also bring to IVD.

•This Ultrasensitive Detection technology will also be offered to our CDMO partners. Fujirebio isin discussion with multiple companies on licensing-out this technology and components.
34

QUESTIONS?

35