R&D Investor Event Lead with innovation - June 23, 2020
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R&D Investor Event
Lead with innovation
June 23, 2020
Forward looking statements
This presentation contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, as amended. Forward-
looking statements are statements that are not historical facts. These statements include projections and estimates and their underlying assumptions,
statements regarding plans, objectives, intentions and expectations with respect to future financial results, events, operations, services, product
development and potential, and statements regarding future performance. Forward-looking statements are generally identified by the words “expects”,
“anticipates”, “believes”, “intends”, “estimates”, “plans” and similar expressions. Although Sanofi’s management believes that the expectations
reflected in such forward-looking statements are reasonable, investors are cautioned that forward-looking information and statements are subject to
various risks and uncertainties, many of which are difficult to predict and generally beyond the control of Sanofi, that could cause actual results and
developments to differ materially from those expressed in, or implied or projected by, the forward-looking information and statements. These risks and
uncertainties include among other things, the uncertainties inherent in research and development, future clinical data and analysis, including post
marketing, decisions by regulatory authorities, such as the FDA or the EMA, regarding whether and when to approve any drug, device or biological
application that may be filed for any such product candidates as well as their decisions regarding labelling and other matters that could affect the
availability or commercial potential of such product candidates, the fact that product candidates if approved may not be commercially successful, the
future approval and commercial success of therapeutic alternatives, Sanofi’s ability to benefit from external growth opportunities, to complete related
transactions and/or obtain regulatory clearances, risks associated with intellectual property and any related pending or future litigation and the ultimate
outcome of such litigation, trends in exchange rates and prevailing interest rates, volatile economic and market conditions, cost containment initiatives
and subsequent changes thereto, and the impact that COVID-19 will have on us, our customers, suppliers, vendors, and other business partners, and
the financial condition of any one of them, as well as on our employees and on the global economy as a whole. Any material effect of COVID-19 on
any of the foregoing could also adversely impact us. This situation is changing rapidly and additional impacts may arise of which we are not currently
aware and may exacerbate other previously identified risks. The risks and uncertainties also include the uncertainties discussed or identified in the
public filings with the SEC and the AMF made by Sanofi, including those listed under “Risk Factors” and “Cautionary Statement Regarding Forward-
Looking Statements” in Sanofi’s annual report on Form 20-F for the year ended December 31, 2019. Other than as required by applicable law, Sanofi
does not undertake any obligation to update or revise any forward-looking information or statements.
2
R&D Investor Event | Agenda
Paul Hudson Chief Executive Officer
Introduction
John Reed Global Head of Research & Development
Platforms Yong Jun Liu Global Head of Research
Synthorx Marcos Milla Chief Scientific Officer, Synthorx
John Reed Global Head of Research & Development
Pathways Karin Knobe TA Head, Rare Diseases and Rare Blood Disorders Development
Venglustat
Pablo Sardi TA Head, Rare and Neurologic Diseases Research
Q&A session 1 20'
Patients Vanessa Wolfeler Global Franchise Head, Rare Blood Disorders
Fitusiran & BIVV001 Dietmar Berger Global Head of Development, Chief Medical Officer
Capabilities Dietmar Berger Global Head of Development, Chief Medical Officer
COVID-19 John Shiver Global Head of Research & Development, Sanofi Pasteur
Conclusion John Reed Global Head of Research & Development
Q&A session 2 40'
TA: Therapeutic area 3
Introduction Paul Hudson Chief Executive Officer
Our approach to R&D Days
Today
Dec. 10, April 23, June 2, June 11, June 23, Coming
2019 2020 2020 2020 2020 soon
Capital BTKi '168 Oncology Dupixent® R&D Investor Nirsevimab
Markets Day • SERD '859 Event
• Next chapter for • Sarclisa® • Synthorx
Sanofi R&D • Anti- • Venglustat
• Priority assets CEACAM5 '701 • Fitusiran &
• Libtayo® BIVV001
• COVID-19
5
Continuing to deliver on our priority assets…
Asset Key progress in H1 2020 Planned initial submission(1)
Dupixent®(2) AD U.S. 6-11 years & China Adults approval; EoE pivotal results Launched
Fitusiran &
Fitusiran & BIVV001 Phase 3 enrollment ongoing 2021e/2022e
BIVV001(3)
SERD '859 ASCO 3 posters; 2/3L mBC Phase 3 enrollment ongoing 2021e
Venglustat ADPKD Part A of Phase 3 fully enrolled (TKV endpoint) 2022e
Nirsevimab(4) Phase 3 ongoing; investor event planned 2023e
BTKi '168(5) PoC in RMS; pivotal studies started 2024e
Breakthrough designation
PoC: Proof of concept, clinical and commercial evidence to initiate pivotal study; AD: Atopic dermatitis; EoE: Eosinophilic esophagitis; mBC: metastatic Breast cancer; ADPKD:
Autosomal dominant polycystic kidney disease; TKV: Total kidney volume; RMS: Relapsing multiple sclerosis
(1) First submission for assets with multiple potential indications (2) Breakthrough designation for AD 6-11 years. Dupixent® in collaboration with Regeneron (3) In collaboration 6
with Sobi (4) In collaboration with AstraZeneca (5) In collaboration with Principia
… and our other late-stage molecules
Asset Key progress in H1 2020 Planned initial submission(1)
Sarclisa® 2L RRMM positive pivotal results; 3L RRMM approval U.S. & EU(3) Launched
Libtayo®(2) 1L NSCLC and 2L BCC positive pivotal results Launched
MenQuadfi™ U.S. approval for ≥2 year-old age group Approved
Avalgluco-
LOPD positive pivotal trial results 2020e
sidase alfa
Sutimlimab Cold Agglutinin Disease Phase 3 priority review 2020e
Olipudase
ASMD positive pivotal trial results 2021e
alfa
Anti-CEACAM5
Phase 3 lung and Phase 2 in additional settings initiated 2022e
'701
Breakthrough designation
RRMM: Relapsed refractory multiple myeloma; NSCLC: Non-small-cell lung carcinoma; BCC: Basal cell carcinoma; LOPD: Late-onset Pompe disease; ASMD: Acid
sphingomyelinase deficiency. (1) First submission for products with multiple potential indications (2) Breakthrough designation for Cutaneous squamous cell carcinoma.
Libtayo® in collaboration with Regeneron (3) Sarclisa® approved for patients with≥2 prior therapies, including lenalidomide and a proteasome inhibitor. Approved in the U.S., EU, 7
Canada, Australia and Switzerland, indication in certain non-U.S. countries also includes disease progression on last therapy
Sanofi's approach to R&D
Platforms Pathways Patients
Expanded tools for Deep understanding Relentless
drug discovery of disease pathways patient focus
Expanding capabilities
8
Introduction
John Reed
Global Head of Research & Development
Sanofi R&D is transforming
Focus Lead with Accelerate Reinvent how
on priorities innovation efficiency we work
• Diabetes & • Building industry • Achieving top-tier • Faster and more
Cardiovascular exit leading platforms to performance rigorous decision
deliver practice- making
• Focus on priority • Digital R&D
changing medicines
assets, within 5 operations • Urgency of
therapeutic areas(1) execution
(1) Immunology and Inflammation, Oncology, Neurosciences, Rare Diseases and Vaccines 10Maximizing the potential of our priority assets
Fitusiran &
Dupixent®(1) SERD ‘859 Venglustat Nirsevimab(3) BTKi ‘168(4)
BIVV001(2)
• Leveraging • Comprehensive • Aiming to • Leveraging • Paradigm shift • Covering the
Type 2 biology program across become conserved aiming for full MS
to maximize 4 hemophilia backbone of disease biology universal spectrum
patient benefit segments for choice across to expand to passive supported by
across multiple fitusiran(5) lines of broader immunization centrally acting
indications therapies populations for all infants mechanism
• Fast roll-out of • Selected • Accelerating • Accelerated • Supported by • Smart
several new endpoints for pivotal studies development in large RSV investment
indications BIVV001 to in early BC GBA-PD and development allowed fastest
supported by capture impact supported by ADPKD program possible
Real World on daily cooperative informed by Phase 3 start
Evidence activities groups genetics
BC: Breast cancer; PD: Parkinson disease; ADPKD: Autosomal dominant polycystic kidney disease; RSV: Respiratory syncytial virus; MS: Multiple sclerosis
(1) In collaboration with Regeneron (2) In collaboration with Sobi (3) In collaboration with AstraZeneca (4) In collaboration with Principia (5) Hemophilia A, B, with and without 11
inhibitorsProgressing on our long-term promises
>75% Potential first- or best-in-class molecules within development pipeline (objective: >80%)
~65% Biologics in research pipeline (objective: ~70%)
~65% Internal(1) assets with no revenue sharing (objective: ~70%)
(1) This includes assets discovered internally or wholly owned through acquisition and assets in-licensed at an early stage and for which Sanofi retains the majority share of the 12
economicsConcrete illustrations of Sanofi's approach to R&D
Platforms Synthorx
Expanded tools for Boosting the impact of cancer immunotherapies
drug discovery by expanding the genetic alphabet
Pathways Venglustat
Deep understanding of Leveraging our knowledge of disease pathways
disease pathways to invent new medicines applicable to multiple disorders
Patients Fitusiran & BIVV001(1)
Relentless Turning cutting-edge protein engineering and new modalities
patient focus into innovative patient offerings
Capabilities COVID-19
Leveraging expanding Applying our scale and broad platforms
capabilities to battle a global health crisis
(1) In collaboration with Sobi 13Platforms
Synthorx
Yong-Jun Liu
Global Head of Research
Marcos Milla
Chief Scientific Officer, SynthorxSanofi platforms to expand the druggable universe
Gene mRNA(2) siRNA Gene Vaccine Vaccine Vaccine
Editing(1) Conjugates Therapy DNA/mRNA Monoclonal Subunit
Antibodies
85% of the proteome
remains undruggable
Antibody Multispecific Nanobodies Expanded Vaccine Vaccine
Conjugates Antibodies Genetic Inactivated Live
Multiple platforms (bi- & trispecific)
CH2
VHH VHH
Alphabet (killed) Attenuated
required to address CH3
difficult targets
Monoclonal Small Enzymes Fusion Vaccine Vaccine Vaccine
Antibodies Molecules Proteins Virus-like Glyco- Viral/Bacterial
Particles conjugate vector
Opportunity to create
new (“synthetic”) biology
for tackling disease
Focus of R&D Event Approved products Exploratory/in progress Vaccine platforms
(1) In collaboration with Sangamo (2) In collaboration with BioNtech 15Tri-specific T-cell activation: A novel platform for cancer
immunotherapy
Mechanism of action(1)
Optimized T-cell activation by stimulating T-cells Tumor Granzymes & T-cell
cell T-cell kills the perforin
through both TCR (CD3) and co-stimulatory receptor tumor cell
(CD28):
T-cell
• Conventional CD3-based T-cell engagers provide CD3
activation
only "signal 1": TCR Target
Cytokines
Cytokines
TCR
• In the absence of "signal 2" from co-stimulatory antigen
T-cell Amplifying immune
death
receptors, this promotes activation-induced T-cell Bcl-xl response by
cytokine release
death, limiting anti-tumor response CD28
• CD28 provides "signal 2" to promote survival of
activated T-cells and generation of "T-cell memory"
Trispecific
Improved targeting: Tri-specific antibody also has the antibody
potential to bind 2 targets on tumor cells: the
established target CD38 as well as CD28, which is
expressed on myeloma and other hematologic cancers
TCR: T-cell receptor
(1) Adapted from Garfall et al, Trispecific antibodies offer a third way forward for anticancer immunotherapy, Nature 575, 2019 ©2019, Springer Nature (under permission
requested). Article screenshot from Wu et al, Trispecific antibodies enhance the therapeutic efficacy of tumor-directed T cells through T cell receptor co-stimulation, Nat Cancer 16
2020 ©2020, Springer Nature (under permission requested)SAR442257: First-in-class next-gen T-cell immunotherapy,
now in the clinic
Trispecific CD38 antibody Trispecific CD38 antibody showed a 3- to 4-log higher killing potency
against human myeloma cell lines vs. daratumumab(1)
• T-cell engager aiming for enhanced
therapeutic efficacy vs conventional RPM I8226 U266 KMS-11
T-cell engagers CD38/cell 129,000 14,000 2,500
• Expect CAR-T cell-like efficacy with CD28/cell 84,000 170,000 35,000
an antibody 80
Dual function of targeting CD28 60
Lysis (%)
• Co-stimulation of T-cells by delivering
40
"signal 2" to promote T-cell survival
20
• Targeting CD28 (expressed on >95%
of MM cells) directs T-cells more 0
100
100
100
10
1
10
10
0
0
1
0
1
1000
10000
1000
10000
1000
10000
efficiently to myeloma cells (even at
low levels of CD38 expression)
[Protein] (pM) SAR442257 Daratumumab Control
First-in-human study in RRMM and RR-NHL initiated
MM: Multiple myeloma; RRMM: Relapsed refractory multiple myeloma; RR-NHL: Relapsed refractory non-Hodgkin lymphoma
(1) Wu, L. et al Nature Cancer, 2019: mix peripheral blood mononuclear cells with myeloma cell lines and applied antibodies 17
SAR442257 is an asset under investigation and is not approved by any regulatorsNext-gen T-cell engagers based on Nanobody® platform
Advantages inherent to Nanobody® platform
Ability to tune PK profile through clinically validated half-life T-cell recruiting NAb Anti-tumor NAb
extension technology reduces dosing frequency a-HSA
Formatting flexibility
• Multiple options for optimizing a-antigen 2
• Multi-valent and multi-specific formats to increase efficacy,
selectivity and/or avoid escape Cancer
• Engineer high affinity on low-density tumor antigens
cell
Faster production cycle time at lower cost (expressed in yeast) T-cell
a-antigen 1
Excellent CMC characteristics, robust manufacturing
A leading IP position in the industry
T-cell engaging
Nanobody®
Multiple Nanobody® candidates entering the clinic next year
PK: Pharmacokinetics; CMC: Chemistry, manufacturing and control; IP: Intellectual property; NAb: Nanobody 18Synthorin platform: Expanding the genetic alphabet to
generate more diverse protein drugs
Amino
Nature DNA mRNA Proteins
Acids
G C
4 nucleotides 64 codons code for 20 Amino acids determine the shape
2 base pairs amino acids and function of proteins
X Y
Expanded Amino
eDNA eRNA More diverse proteins
alphabet Acids
A T
6 nucleotides 216 codons code for A greater variety of amino acids
3 base pairs up to 172 amino acids results in more diverse proteins
19Application of the X-Y genetic code for recombinant
production of therapeutic proteins: Synthorins
Production system for Synthorins in E. coli
X and YTPs enter nAA diffuses into cells; used
cell via transporter by aminoacyl tRNA synthetase
dXTP dYTP to charge X-Y tRNAs
Engineered E. coli to
install a novel amino
acid (nAA) utilizing
X-Y to produce
optimized biologics
Translation Machinery decodes X-Y codons introduce nAA
into "Synthorin" proteins
First application is multi-functional, site-specific pegylation
nAA: novel Amino Acid 20IL-2 has dual pharmacology explained by differential
engagement of IL-2 receptor subtypes
Immune cells
Receptor type activated Immune response
Suppression
Treg proliferation → suppression
αβγ of CD8 Teff and NK Cells
Treg
High affinity CD4+
(Kd ~ 10-11M) Side effects
ILC2 expansion → eosinophils
Primarily Treg (vascular leak syndrome)
βγ
Stimulation
Intermediate CD8 Teff Proliferation of CD8 Teff
affinity NK
(Kd ~ 10-9M) and NK Cells
Broadly expressed
Site-specific pegylation allows
fine-tuning receptor interactions
Treg: regulatory T cells; Teff: effector T cells; NK: Natural Killer; ILC2: Group 2 Innate Lymphoid Cells 21Site-specific pegylation to turn interleukins into precision
drugs for oncology and autoimmune disease indications
THOR-707 IL-2 THOR-809 IL-2
Synthorin for immuno-oncology Synthorin for autoimmune diseases
IL-2 Rα Unique properties IL-2 Rα Unique properties
Non-
• PEG blocks engagement Natural
• PEG blunts engagement
of IL-2R α chain Amino
IL-2 of IL-2R β chain, making
PEG
• Selectively expands anti-
Acid potency at IL-2R αβγ
tumor CD8+ T and NK cells contingent on α chain binding
IL-2 • Selectively expands CD4+
• No expansion of immune-
regulatory T cells
suppressive CD4+ regulatory
Non- T cells • No expansion of CD8+ T
Natural and NK Cells
Amino
• No activation of type 2 innate IL-2 Rβ
lymphoid cells and • Preclinical therapeutic
IL-2 Rβ Acid
IL-2 Rγ efficacy in delayed
eosinophils responsible for
vascular leak syndrome type hypersensitivity
IL-2 Rγ
“Not-alpha” “Reduced beta”
Shared pharmacological properties: pegylation increasing IL-2 half-life and reduced immunogenicity risk
NK: Natural killer 22Single THOR-707 dose induces lymphocyte expansion in
non-human primates without increasing eosinophils
Aldesleukin induced both lymphocyte THOR-707 single dose NHP leukocyte
and eosinophil expansion in humans(1) Subpopulations: High lymphocytes, no eosinophils
20 35
Lymphocytes White blood cells
30
Eosinophils Lymphocytes
25
Cell Counts x
Cell Counts x
Eosinophils
103/L
103/L
20
10
15
10
5
0 0
Pre treatment Post treatment -2 0 2 4 6 8 10 12 14 16 18 20 22
Dose Days
Aldesleukin dosing limited in people (37 µg/kg) No signs of VLS in NHP with THOR-707 up to
and NHP (25 µg/kg and higher) by VLS 1,000 µg/kg (highest dose level tested)
Compared to aldesleukin, THOR-707 shows a strong preference for expanding tumor-fighting lymphocytes
vs. eosinophils which are responsible for VLS
NHP: Non-human primates; VLS: Vascular leak syndrome
(1) Meyers FJ, et al Clin Pharmacol Ther. 1991 23
THOR-707 is an asset under investigation, not approved by any regulatorsHAMMER FIH study: Promising early biomarker data
Pharmacodynamics markers of surrogate Pharmacodynamics markers of selectivity
anti-tumor activity and surrogate safety
Peak peripheral expansion post initial THOR-707 dose(1) Peak peripheral expansion post initial THOR-707 dose(1)
Fold change in cell count(2) Fold change in cell count(2)
8 8
7.0
6 6
4 4
2.8
1.9 1.9
2 2
0 0
CD8+ Effector T-Cell NK Cell CD4+ Regulatory T-Cell(3) Eosinophil(4)
THOR-707 RG7461 NKTR-214
At 16 µg/kg, further dose escalation ongoing At RP2D (26 µg/kg)(5) At RP2D (6 µg/kg)(6)
FIH: First In Human; RP2D: Recommended Phase 2 Dose
(1) Mean across dose cohort of 4 patients, maximum fold expansion following one dose of THOR-707 (2) Normalized to pre-treatment count (3) Surrogate Marker of Potential
Tumor-Promoting Immunosuppression (4) Surrogate Marker of Potential Vascular Leak Syndrome (5) Estimated from Melero et al, ESMO 2018, 2-week expansion (6)
Estimated from Bentebibel et al, Cancer discovery, 2019, mean expansion between day 1 (before treatment) and day 8 (after treatment) 24
THOR-707 is an asset under investigation, not approved by any regulatorsLandscape of IL-2 compounds in development – THOR707
has best-in-class profile
No Yes, limited Yes
aldesleukin(1) ALKS 4320(2) NKTR-214(3) RG7461(4) THOR-707(5)
Fusion protein Random Lys pegylation with Fusion protein
Description Native IL2
IL-2 fused to IL-2Rα (on avg.) 6 cleavable PEGs IL-2v fused to FAP-mAb
Site-specific pegylation
Dose 37 µg/kg TID x 5 days 6 µg/kg/day 6 µg/kg Q3W
~26 µg/kg QW 16 µg/kg,
(IL-2 equivalent) equivalent dose escalation ongoing
Not Alpha
Exposure(6)
Q3W dosing
Expansion of CD8+T-cells n.a.
Significant fold increase above baseline(7)
Expansion of NK cells n.a.
Significant fold increase above baseline(8)
No expansion of CD4-Tregs n.a.
No significant fold increase above baseline(9)
No Vascular Leak Syndrome
Tolerability
No anti-drug antibodies
TID: three times a day; QD: every day; QW: every week; Q3W: every three weeks; NK: Natural killer; n.a.: non available (1) Lotze M T et al, J Immunol 1985; Meyers FJ, et al
Clin Pharmacol Ther. 1991; Foureau et al Cancer Immunol Immunother 2014; Schantz et al, Arch Otolaryngol Head Neck Surg 1990 (2) Lopes et al, Journal for
ImmunoTherapy of Cancer 2020; medication package insert (3) Bentebibel et al, Cancer discovery, 2019; Charych et al, PLOS One 2017 (4) Melero et al, ESMO 2018. IL-2
equivalent dose assessed based on recommended dose (20 mg), avg. weight (70 kg) and relative size (RG7461 11x larger than IL-2 as the cytokine is fused to 150,000 daltons
IgG) (5) Synthorx data (6) Only THOR-707 has shown sustained exposure: RG7461 exposure is reduced with repeat dosing, all other compounds have low exposure (7) Yes:
>2x; Yes, limited: 1.5-2x; No: 2x; Yes, limited: 1.5-2x; No:Beyond interleukins, the X-Y genetic code technology
enables diverse applications using nAA chemistry
Multispecific biologics
Tailoring nucleophile/electrophile chemistry
Bioconjugation
Peptide drug conjugates
Novel binding surfaces
Hydrolysable linkers/protection
Macro-cyclization
nAA: novel Amino Acid 26Conclusions
Expanded Genetic Alphabet has the potential to turn interleukins into precision drugs for oncology and
✔ autoimmune diseases
✔ THOR-707 and THOR-809 harness dual IL-2 biology:
• “Not-alpha” THOR-707 selectively upregulates CD8+ T and NK cells to eliminate tumors without increasing
CD4+ regulatory T cells (Tregs) and eosinophils
• “Decreased beta” THOR-809 selectively upregulates Tregs to suppress autoimmunity without upregulating CD8+
T and NK cells
Initial biomarker data from human studies increases our confidence in THOR-707 potential to become partner of
✔ choice for checkpoint inhibitors (no ADA issues; well tolerated; target pathway engagement)
THOR-707 dose-finding Phase 1b combinations with anti-PD-1 (T-cell) and anti-CD38 (NK cell), final Phase 1 results and
✔ RP2D expected in 2021
Wide applicability of Synthorx platform expected to yield multiple clinical candidates in coming years, with further
✔ precision interleukins to enter the clinic in 2021-2023
NK : Natural Killer; IL: Interleukin; ADA: Anti-drug antibody; RP2D: Recommended Phase 2 dose 27Pathways
Introduction
John Reed
Global Head of Research & DevelopmentTwo areas where Sanofi science stands out specifically
Human immunology Monogenic disorders
IO Vx I&I Neurology Hematology Gaucher Pompe Fabry Hemophilia Others(2)
Marketed(1)
THOR-707 Nirsevimab Anti CD40L BTKi '168 Sutimlimab Venglustat Aval- Venglustat Fitusiran Olipudase alfa
development(1)
glucosidase
… … … … …
Clinical
Anti TGFb Next gen. RIPK1i alfa BIVV001
PCV
SHP2i Anti-IL33 … …
Shan 6
… …
…
IO: Immuno-oncology; Vx: Vaccines; I&I: Immunology and Inflammation
(1) Selection of assets (2) Including Hunter disease, Hurler disease, Niemann-Pick 29
Note: Includes Sanofi wholly-owned and assets developed in collaborationHuman immunology: A view into our immunomodulatory
pipeline and products
TH 1 TH 17 TH 2
Mf
B TH T Reg
PC TCTL NK
Tumor
Inhibition Activation
Mf: Macrophages; PC: Plasma cells; TH: T helper cells; TCTL: Cytotoxic T lymphocytes; NK: Natural killer cells; TReg: Regulatory T cells 30Human immunology: A view into our immunomodulatory
pipeline and products
Bispecific NAb SM candidate
Dupixent®(1)
RIPK1i(5) TH 1 TH 17 TH 2 a-IL-33(1)
Mf EOS
BTKi(4) Bispecific NAb
Kevzara®(1)
a-CD40L(6)
a-TGFβ
B TH T Reg
BTKi(4) THOR-809 IL-2
Libtayo®(1)
Sarclisa® THOR-707 (IL-2)
PC a-CD38-CD28-CD3 TCTL NK
a-CD38-Fc SHP2i(2)
Cytokine mRNA(3)
a-CD123-CD3 Tumor
Inhibition Activation IO I&I a-TAA-CD28-CD3
Mf: Macrophages; PC: Plasma cells; TH: T helper cells; TCTL: Cytotoxic T lymphocytes; NK: Natural killer cells; TReg: Regulatory T cells; EOS: Eosinophils; SM: Small
molecule; NAb: Nanobody; IO: Immuno-oncology; I&I: Immunology and Inflammation. (1) In collaboration with Regeneron (2) In collaboration with Revolution Medicines (3) In 31
collaboration with BioNTech (4) In collaboration with Principia (5) In collaboration with Denali Therapeutics (6) In collaboration with ImmuNextSanofi's pioneering history in Monogenic disorders
1994 2003 2006 2014 Next
Cerezyme® Aldurazyme® Myozyme® Cerdelga® Olipudase alfa
Gaucher Hurler Pompe Gaucher Niemann-Pick
3.6k 0.4k 2k 3.6k 1k
Avalglucosidase alfa(2)
Pompe
2k
Alprolix®
Fabrazyme® Elaprase® Eloctate® Venglustat
Launch date Fabry Hunter Hemophilia A/B GD3, Fabry, GM2
Investigational 3k 0.6k 16k 3.2k
U.S. diagnosed patients(1)
Life-threatening and life-altering indications, still highly under-diagnosed
(1) DRG, 2018, number of patients diagnosed in the U.S., thousands (2) Press release on Phase 2 results published of June 16, 2020 32Pathways
Venglustat
Karin Knobe
TA Head, Rare Diseases & Rare Blood
Disorders Development
Pablo Sardi
TA Head, Rare and Neurologic
Diseases ResearchLeveraging Sanofi’s heritage in LSD and GSL metabolism
Sanofi
Genzyme
LSD heritage
Making a difference in Expanding the reach in
patients with LSDs more common disorders
with large unmet need
LSD: Lysosomal storage disease; GSL: Glycosphingolipid 34Broad role of glycosphingolipids in cellular functions
Plasma membrane
microdomains
Cell signaling
Receptor localization
and function
• GSLs are components of many
cellular membranes Primary cilia
Extracellular sensing
• GSLs can interact with adjacent Intracellular signaling
proteins within the membrane
to modulate protein function
• Plasma membrane GSLs Endo-lysosomal System
& Vesicular Transport
provide surface features that Autophagy
provide cell recognition signals
• GSLs modulate many cellular
processes required for normal
function
: GSL
GSL: Glycosphingolipid 35
Source: Natoli et al; Cellular Signalling 69, 2020GCS-inhibition as central regulator of GSL metabolism
Ceramide
GCase, GBA GCS, UGTG Venglustat (SRT)
Gaucher disease
• GBA mutation and lysosomal GL1
accumulation in the spleen liver, GlcCer (GL1) ADPKD
bone marrow, lungs and brain • Inhibition of GCS in
genetic models reduces
kidney cyst growth and
GB3 synthase preserves kidney function
GBA-Parkinson’s disease LacCer GL3
• Mutant GBA highest risk factor for
Parkinson's disease a-galactosidase
• Inhibition of GCS in PD models
arrests disease progression b-hexosaminidase Fabry disease
• a-galactosidase
GM2 mutations and lysosomal
GL3 accumulation
GM2 gangliosidosis
• b-hexosaminidase mutations and
lysosomal GM2 accumulation
GSL: Glycosphingolipid; GCS: Glucosylceramide synthase, coded by gene UGTG; Gcase: Glucocerebrosidase, coded by gene GBA; GlcCer (GL1): Glucosylceramide; LacCer:
Lactosylceramide; GL-3: Globotriaosylceramide; ADPKD: Autosomal dominant polycystic kidney disease; PD: Parkinson's disease; GM2 gangliosidoses: rare autosomal
recessive genetic disorders including Tay-Sachs and Sandhoff disease; SRT: Substrate-reduction therapy 36
Venglustat is an asset under investigation and is not approved by any regulatorsTreatment dimensions give venglustat potential to be
best-in-class oral GCS-inhibitor
1st gen GCS-inhibitors(1) Venglustat target profile
Treatment burden Oral; twice-daily ✔ Oral; once-daily
Potency/selectivity Medium ✔ High
Brain penetrance Very limited ✔ Yes
Multiple LSDs & other
Applicability Multiple LSDs ✔ GSL pathologies
GCS: Glucosylceramide synthase; LSD: Lysosomal storage disease; GSL: Glycosphingolipid
(1) Examples include miglustat, eliglustat, lucerastat
No head-to-head studies comparing above products have been conducted. Venglustat target profile is aspirational and comparisons with other therapies cannot be made at this 37
time. Venglustat is an asset under investigation and is not approved by any regulatorsVenglustat: Leveraging GCS biology in CNS & key organs
LSDs Beyond LSD
Central Manifestations of LSDs: PD with GBA mutations and potentially
GD3 & GM2 idiopathic PD with GSL pathologies
Brain
U.S. diagnosed GD3 patients: ~75
U.S. GBA-PD population: ~78,000
U.S. diagnosed GM2 patients: ~100
Potential new treatment option ADPKD with PKD1 or PKD2 mutations
for Fabry patients with lower disease affecting GSL signaling in cilia
Kidney/ burden (~40% of diagnosed)
heart
U.S. diagnosed Fabry patients: ~3,000 U.S. ADPKD population: ~140,000
GCS: Glucosylceramide synthase; CNS: Central nervous system; LSD: Lysosomal storage disease; GSL: Glycosphingolipid; GD3: Type 3 Gaucher Disease; GM2
gangliosidoses: rare autosomal recessive genetic disorders including Tay-Sachs and Sandhoff disease; PD: Parkinson's disease; ADPKD: Autosomal dominant polycystic 38
kidney disease. Venglustat is an asset under investigation and is not approved by any regulatorsVenglustat's activity validated in GD3 and in Fabry
Gaucher Type 3 Fabry
Phase 2 data at 1 year Phase 2 data at 3 years
Paired t-test between seed-based connectivity maps
0.40
Increase in BOLD signal over baseline
0.35
0.30
Vv (Inc/Endo)
0.25
0.20
0.15
0.10
Baseline 3 months 6 months 3 years
Study Visit
Enhanced occipito-parietal connectivity Reduction in lysosomal GL3 storage
is the most prominent feature
GD3: Type 3 Gaucher Disease 39
Venglustat is an asset under investigation and is not approved by any regulatorsVenglustat: Transformative potential in ADPKD
GCS inhibition restores differentiation Robust preclinical data in validated animal
signaling in ADPKD model(1)
Human Mouse Kidney volume (MRI, live animals)
GlcCer GlcCer 1,600
Normal ADPKD GSL reduction (GL-1) (GL-1)
5 4.0
Primary cilium 1,200
Mutation
Kidney GlcCer (AU x 107)
Kidney GlcCer (AU x 104)
GSL GSL GSL 3.5 Treatment start
Volume (mm2)
4
3.0 Control
Growth signal Reset 2.5 800
Differentiation 3
differentiation
signal 2.0
signal 2
Nucleus Nucleus Nucleus 1.5
400 Treated
1.0
1
Differentiated Loss of differentiation Restores 0.5
cell differentiation 0 0.0 0
Cyst formation Norm PKD ctr cKO 4 5 6 7 8 9
Pkd1
Age (weeks)
↑ glycosphingolipid levels GCS inhibition slows cyst growth
in cystic kidneys
Phase 3 STAGED-PKD: Stage 2 initiated at high dose based on tolerability profile
GCS: Glucosylceramide synthase; ADPKD: Autosomal dominant polycystic kidney disease; GSL: Glycosphingolipid; GlcCer: Glucosylceramide; MRI: Magnetic resonance
imaging. (1) Natoli et al, Nat Med. 2010 40
Venglustat is an asset under investigation and is not approved by any regulatorsVenglustat: Potentially first DMT in GBA-PD
GBA mutations associated Venglustat: potential to be MOVES-PD: first industry
with higher PD incidence the first disease modifying sponsored clinical trial in a
and greater disease severity therapy in PD via GBA-PD genetic form of PD
Progression to dementia Mean % change in CSF GL-1
Cumulative incidence (%) at week 4 across doses(1)
100% GSL accumulation 10 6.9
GBA carriers GCS inhibition
(lysosome dysfunction) 0
HR: 3.16
75% (pPreclinical evidence for therapeutic benefit of venglustat
in sporadic PD population
Loss of GCase activity in sporadic GCS inhibition reduces toxic GCS inhibition improves cognitive
PD and Lewy bodies dementia(1) α-Synuclein conversion(2) function in mouse model(3,4)
Substantia nigra
Gcase activity (pmol/min/mg)
900 1.2 50
800 1.0
40
α – Syn (Fold)
700 0.8
Recall (%)
30
600 0.6
20
500 0.4
400 0.2 10
0.0 0
Control Parkinson Lewy Bodies Control GCSi (LD)* GCSi (HD)* WT** Control Venglustat
Disease* Dementia* analogue*
A 53T-SNCA
FDA recommendation to include idiopathic PD patients in Phase 3
*p-value vs. ControlLysosome pathway defects are central to most PD
Gene mutations associated to PD affect Phosphorylated
lysosomal function, GCase activity and GSL flux P
LRRK2
• Synuclein overexpression and aggregation SNCA overexpression (or
LRRK2
reduce GCase activity(1) α-Synuclein aggregation)
mutations
• SNCA and LRRK2 mutations reduce vesicular ↓ Vesicular
trafficking and lysosomal activity(1,2) trafficking
• LRRK2 and GBA mutations reduce GCase
activity and affect GSLs levels(2,3) Aggregated
↓ GCase α-synuclein
• Excessive burden of LSD gene variants in PD(4)
activity
Modulation of GSLs levels by GCS inhibition GBA mutations
improves lysosomal and neuronal function, and
reduces alpha-synuclein toxicity ↓ Lysosomal LSD gene mutations
function
GSLs regulate cellular processes driving Parkinson's disease progression(5)
GCase: Glucocerebrosidase; GCS: Glucosylceramide synthase; PD: Parkinson's disease; GSL: Glycosphingolipid; LSD: Lysosomal storage disease
(1) Mazzulli et al, Cell 2011 (2) Ysselstein et al, Nature Comm 2019 (3) Gegg et al, Ann Neurol 2012 (4) Robak et al, Brain 2017 (5) Sardi et al, PNAS 2017; Zunke et al, 43
Neuron 2018PD-FIDI: Potentially first validated digital endpoint in PD
ePRO & App Wrist-worn device
assessments assessments
Part I Part II Part III Part IV
Motor impacts Dyskinesia impacts(1) Functional motor Continuously monitored
impacts functional impacts
• 13 items adapted from • 2 items adapted from • Gait and balance including • Gait and balance
MDS-UPDRS Part II MDS-UDyRS Part Ib stride length • Physical activity and
• Postural tremor of hands general mobility
• Pronation/supination
of hands Measured passively and
• Finger tapping continuously
Exploratory Sleep • 4 original ePRO items assessing sleep duration and quality
• Sleep duration and quality actigraphy measures (measured passively and continuously)
Assessments
Additional data could mean lower variability, so fewer subjects needed to achieve statistical power
PD: Parkinson's disease; FIDI: Functional impacts digital instrument; MDS-UPDRS: Movement Disorder Society Unified Parkinson's Disease Rating Scale; MDS-UDyRS:
Movement Disorder Society Unified Dyskinesia Rating Scale; PRO: Patient reported outcomes 44
(1) Only included for patients taking PD medicationsVenglustat: Leveraging GCS biology in CNS & key organs
LSDs Beyond LSD
GD3: LEAP Phase 2/3 ongoing(1) Parkinson (MOVES-PD)
• Submission expected by H1 2023 • Phase 2 PoC expected by H1 2021
Brain GM2: Phase 3 started • Submission expected by 2025
• Submission expected by H2 2023
Fabry: Phase 3 in preparation ADPKD (STAGED-PKD)
• Submission expected by H2 2023 • Part A fully enrolled (TKV)
Kidney/ • Part A (TKV) pivotal results expected by
heart Q4 2021
• Submission expected by 2022
GCS: Glucosylceramide synthase; CNS: Central nervous system; LSD: Lysosomal storage disease; PoC: Proof of concept, clinical and commercial evidence to initiate pivotal
study; ADPKD: Autosomal dominant polycystic kidney disease; GD3: Type 3 Gaucher Disease; GM2 gangliosidoses: rare autosomal recessive genetic disorders including Tay-
Sachs and Sandhoff disease; TKV: Total Kidney Volume; GFR: Glomerular Filtration Rate. Venglustat is an asset under investigation and is not approved by any regulators 45
(1) Current LEAP Phase 2 study to be expanded to Phase 3 by end of yearQ&A session 1
Paul Hudson Dietmar Berger
Chief Executive Officer Global Head of Development
John Reed Marcos Milla
Global Head of R&D Chief Scientific Officer, Synthorx
Jean-Baptiste de Chatillon Karin Knobe
Chief Financial Officer TA Head, RD and RBD Development
Bill Sibold Pablo Sardi
Global Head of Sanofi Genzyme TA Head, RND Research
Yong-Jun Liu Shannon Resetich
Global Head of Research Global Franchise Head, RD
RD: Rare Diseases; RBD: Rare Blood Disorders; RND: Rare and Neurologic Diseases; TA: Therapeutic area 46Patients
Fitusiran & BIVV001(1)
Vanessa Wolfeler
Global Franchise Head,
Rare Blood Disorders
Dietmar Berger
Global Head of Development,
Chief Medical Officer
(1) In collaboration with SobiLimitations of current Hemophilia treatments
Treatment burden Activity restrictions
• Monotherapy • Active control on protection
Factors • IV infusion • Proven safe and effective
• Frequent dosing • “Peak and trough” dependent protection
• SQ injection • Steady state efficacy
Non-factor • Weekly / every other week dosing usually(1) • “Normal” levels of protection out of reach(2)
(emicizumab)
• On-demand IV Factor needed (dual therapy) • Difficult to measure protection level
Future treatments aim to minimize treatment burden and remove activity restrictions
IV: intravenous; SQ: subcutaneous
(1) 7% of emicizumab patients on monthly dosing – 2019 Specialty Pharmacy data obtained through Specialty Pharmacy Distributors, Hemophilia Alliance HTCs & Direct HTCs 48
(2)Patients’ daily activities are defined by protection levels
Risk with Need for supple-
Daily activities surgery/trauma mental Factor Impact
Factor VIII level (%, Log scale)
High impact activity possible Major surgery/
100 with no pain (sports, physical trauma possible without None None
jobs, active days) Factor requirement
Normal
40 Intense activity possible with
Minor invasive
Strenuous no pain (most sports, play with Minor
procedures possible Rare
friends, travel, physical jobs) – adjustments
without Factor requirement
15 low bleed risk
Mild Limited activity with some pain
Invasive procedures
(desk job, careful with active Significant
5 require supplemental Regular
kids) – risk of spontaneous or adjustments
Factor
micro bleeds
Sedentary
High risk of spontaneous Invasive procedures
bleeds with low activity and require supplemental Frequent Vulnerable
pain with target joints Factor
Source : Iorio et al, Hemophilia. 2017 49Current treatments require trade-off between treatment
burden and protection levels
x/x Dose frequency Advate(2) Eloctate®(3) Emicizumab(4) Factors
Factor VIII level(1) (%, Log scale) High protection, high dose frequency
• Short-period: 2-3 infusions per week required
100 • Patients at risk when at trough
• Patients at risk when missing infusion
40
Non-Factor (emicizumab)
Reduced dose frequency, lower protection
15 • ~9% FVIII equivalent level(4)
• 90% patients experiencing acute bleeds
1x/week
require additional Factor(5)
5 • 7% patients on monthly regimen(6)
3-4x/week 1x/4 days
Patients achieve protection permitting
strenuous activityOur ambition: Pushing patients protection beyond current
limitations
x/x Dose frequency Advate(2) Eloctate®(3) Emicizumab(4) BIVV001 target profile
Factor VIII level(1) (%, Log scale) Higher for longer
• One week of protection, including ~3.5 days
100 at normal activity level and ~6 days at
1x/week BIVV001(5) strenuous activity level
• Increased joint protection
40
Fitusiran(4)
1x/month Fitusiran target profile
15 High-efficacy monthly therapy
1x/week • Aiming for 15-20% FVIII equivalent level(4),
allowing strenuous activity level
5 • First real once-monthly Hemophilia treatment
3-4x/week 1x/4 days
Aiming to get more patients above
strenuous level for >80% of their time(6)
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0
Days post dose
(1) Illustration of Factor VIII levels of Hemophilia A patients, or equivalent for non-Factor (2) Advate 50 IU/Kg (Phase 3) (3) Eloctate® 50 IU/Kg (Phase 3). Source: Mahlangu,
J., et al, Blood (4) Equivalent FVIII level, based on Lenting P et al, ISTH 2019, Lenting P et al, Blood Adv. 2020 (5) BIVV001 50 IU/Kg (Phase 1) – Day 22 (6) Assuming FVIII
level >15% all the time for fitusiran and 6 days a week for BIVV001. Fitusiran and BIVV001 are assets under investigation and are not approved by any regulators – BIVV001 in 51
collaboration with Sobi. No head-to-head studies comparing the above products have been conductedBIVV001: New class of factor therapy engineered to
achieve higher factor levels, for longer
Effects of activated thrombin
(1)
rFVIIIFc VWF XTEN
A2 XTEN® insertions(3)
• Hydrophilic sequences
comprising natural amino acids
• Decrease degradation,
A3 increase half-life
A1
Thrombin-cleavable linker(2)
• Enables release of D′D3
FcFc Fc domain(4,5)
upon FVIII activation
• Extends half-life
C1
C1 C2
C2 Fc through FcRn-mediated
Covalent linkage to the D′D3 domain of VWF(2) recycling pathway
• Prevents binding to endogenous VWF, decoupling from VWF-
mediated clearance D’D3
• Partial protection from degradation normally afforded by VWF D’D3
Scissors represent thrombin activity. rFVIIIFc: recombinant factor VIII Fc fusion protein; VWF: von Willebrand factor. aXTEN® is a registered trademark of Amunix
Pharmaceuticals, Inc. (1) Julie Rayes et al, A molecular jewel for hemophilia A treatment, Blood, 2020 ©2020, Blood Journal (under permission requested); Ekta Seth Chhabra
et al, BIVV001, a new class of factor VIII replacement for hemophilia A that is independent of von Willebrand factor in primates and mice, Blood, 2020 ©2020, Blood Journal
(under permission requested) (2) Konkle BA et al, Haemophilia. 2019 (3) Podust VN, et al, J Control Release. 2016 (4) Roopenian DC, Akilesh S. Nat Rev Immunol. 2007 (5) 52
Shapiro A. Expert Opin Biol Ther. 2013. BIVV001 is an asset under investigation and is not approved by any regulators – in collaboration with SobiNo bleed events in BIVV001 Phase 1 repeat dose study
Analysis of bleeding events (n=24) 4 weekly doses well tolerated
48
✔ No inhibitor development to Factor VIII detected
✔ No treatment-related adverse events reported
No adverse events of allergic reaction or
0 ✔
anaphylaxis reported
Bleed events Bleed events in 4-week
in 12-month prophylactic BIVV001
pre-study (median)(1) treatment period(2)
No bleeds reported during treatment period and for at least 10 days after last dose of BIVV001
(1) Pre-study treatment regimen: 21 patients treated with on-demand regimen and 3 with prophylactic regimen (2) Once-weekly BIVV001 dose of 50 IU/kg (n=10) or 65 IU/kg
(n=14). Source: World Federation of Hemophilia Virtual Summit (June 2020). Exploratory results, BIVV001 is an asset under investigation and is not approved by any regulators 53
– in collaboration with SobiFitusiran: Aiming to be the only therapy designed to bring
high protection in a subcutaneous monthly therapy
Unique approach to rebalance the deficient coagulation cascade by reducing antithrombin
Hemophilia A and B are caused by an imbalance
FVIII
FIX ANTITHROMBIN in hemostasis due to Factor deficiency, resulting
in insufficient thrombin generation
Fitusiran is designed to improve thrombin
generation by lowering antithrombin
250+ patients enrolled in clinical trials, with 4+
years of clinical data
Fitusiran is an asset under investigation and is not approved by any regulators 54Fitusiran target profile confirmed in Phase 2 OLE trial
Safety and tolerability
Efficacy: median ABR
(n=34)
Subjects without inhibitors Subjects with inhibitors
12.0 42.0
✔ No thrombotic events in any
subjects who remained compliant
with the bleed management
2.0 guidelines since their
1.0
0.4 implementation in December 2017
Prophylaxis On demand Observation Pre-study Observation
(n=7) (n=12) period (n=14) period ✔ No cases of anti-drug antibody
(n=19) (n=14) formation
Pre-study
Median duration in observation period: Median duration in observation period:
36 months (range: 5-45 months) 28 months (range: 7-36 months)
0.84 overall median ABR during observation period & median 2.6 yrs of fitusiran dosing (max. 4.7 yrs)
OLE: Open-label extension; ABR: Annualized bleed rate
Data cutoff: March 10, 2020. ABR and duration represent pooled data from Phase 1 and Phase 2 OLE studies. Phase 1 data are included if gap between studies was ≤56 days.
Only subjects with 28 days of follow-up during the observation period are included in this analysis. Clinical hold period (last dose before hold + 29 days, first dose after hold + 28 55
days) is excluded. Source: Fitusiran Phase 2 OLE Interim Results, WFH (June 2020). Fitusiran is an asset under investigation and is not approved by any regulatorsFitusiran: Potential best-in-class non-Factor therapy for all
Hemophilia patients
Fitusiran Emicizumab(2)
(target profile)
ABR 2 for Q4W(2) for Hem A
First SQ for all Hem B ✔
1 prefilled syringe(1) ✔ Up to 4 injections(3)
Low-volume fixed dose ✔ Weight-based dose; up to 4 mL(3)
Room temperature stable ✔ Refrigeration & cold chain storage required
Reversal agent available ✔
ABR: annual bleed rate; Hem: Hemophilia; Q4W: once every four weeks; SQ: subcutaneous
(1) Fitusiran prefilled syringe, room temperature stable: planned for launch (2) Hemlibra® U.S. Prescribing Information (3) Hemlibra® U.S. Prescribing Information, assuming 56
some patients may be over 75kg. Fitusiran is an asset under investigation and is not approved by any regulatorsWrap-up: Sanofi portfolio addresses white space of
current patients needs
Expected submissions
Treatment burden
(frequency & number of needles) H2 2021(8) – Fitusiran
1/month Fitusiran
Q4W target profile(4) • Three ATLAS studies (>12 years old)
(3)
• Two of three Phase 3 studies fully enrolled;
emicizumab(1) BIVV001
(~25% patients(2)) near completion of 3rd
Q2W target profile(5)
On-demand factor • Pediatric Phase 3 study enrolling
required to manage bleed
1/week
Q1W
H1 2022(8) – BIVV001
FVIII(6) • Phase 3 study in previously treated patients
(~75% patients(2))
initiated (>12 years), n=150
1/day
• Study initiated in Q4 2019
High Activity restrictions(7) Limited • Endpoints to capture impact on restrictions in
(ABR, All bleeds) daily activities
Q4W: once every four weeks; Q2W: once every two weeks; Q1W: once per week; ABR: annualized bleed rate
(1) emicizumab: 2.1 ABR with Q4W; 1.6 ABR with Q2W; 0.6 ABR with Q1W (U.S. prescribing information; median ABR (HAVEN-3 for Q1W & Q2W, HAVEN-4 for Q4W)
(2) Based on Evaluate Pharma 2020, U.S. patients (3) 7% of emicizumab patients on monthly dosing – 2019 Specialty Pharmacy data obtained through Specialty Pharmacy
Distributors, Hemophilia Alliance HTCs & Direct HTCs (4) fitusiran: 0.84 ABR with Q4W (Phase 2 OLE Interim Results) (5) BIVV001: Target Product Profile aiming for weekly
dose, no bleed reported in Phase 1 repeat dose study (6) Individualized prophylaxis varies from daily to every 4 days and between 1 ABR (7) No head-to-head studies
comparing the efficacy of emicizumab and fitusiran or BIVV001 have been conducted (8) Expected submission in the U.S. Fitusiran and BIVV001 are assets under investigation 57
and are not approved by any regulators – BIVV001 in collaboration with SobiAiming for first “true” cure in Hemophilia with LVV GT
AAV limitations for LVV target profile for
Hemophilia patients Hemophilia patients
• DNA insert size limitations: challenging to • Larger DNA insert size permits BDD Factor
package BDD Factor VIII cDNA into AAV VIII cDNA and additional control elements
• Limitations on target population • Aiming to address all patients
• 21-74% of patients have pre-existing • No pre-existing antibodies to VSVG
antibodies to AAV(1) pseudotyped LVV
• Episomal AAV cargo gets diluted when liver • Treat in pediatrics: LVV cargo integrates into
grows – expression lost if treated too early, the host genome, growing with the patient
cannot treat pediatric patients • Expected to be durable (integrative nature), as
• FVIII levels continuously declining over time demonstrated in preclinical models
(long-term Hemophilia A data)
Sanofi/SR-TIGET to develop first-ever in vivo lenti application – expected to enter clinic by 2022
LVV: Lentiviral vector; GT: Gene Therapy; AAV: Adeno-associated virus; BDD: B-domain deleted; cDNA: complementary DNA; VSVG: Vesicular stomatitis virus glycoprotein;
SR-TIGET: San Raffaele-Telethon Institute for Gene Therapy 58
(1) Steven W. Pipe, John Wiley & Sons Ltd. 2020Expanding capabilities
COVID-19
Dietmar Berger
Global Head of Development,
Chief Medical Officer
John Shiver
Global Head of R&D,
Sanofi PasteurExpanding R&D capabilities, focusing on Specialty Care
and Vaccines
News ways of
Enhanced patient Digital R&D & Real Focused, simplified
working &
centricity World Evidence footprint
engagement models
• Patient-related insights • DARWIN platform for • Simplifying R&D • Integrated Development
(PROs, tolerability, Real World Evidence footprint, focusing organization
health value, etc.) clinical operations where
• Digital transformation of • Fast, rigorous decision-
it matters
• Patient-centric trial Clinical Operations making – taking 'smart'
conduct (leverage • Global hubs for priority risks
• Optimization of
telehealth, home Therapeutic Areas
development candidates • Early engagement of
delivery, digital tools through artificial • Investments in leading- investigators to optimize
when possible) intelligence, indication edge capabilities: study design (#1 Sponsor
• E-consent and patient selection, trial biomanufacturing, Gene of Global Clinical Trials)(1)
portal improving patient optimization, etc. Therapy CMC, evolutive • Multiple collaborations
experience vaccines facility
• Digital in CMC and (e.g. BARDA, GSK)
Regulatory Affairs
PRO: Patient reported outcomes; CMC: Chemistry, manufacturing and control; BARDA: Biomedical Advanced Research and Development Authority 60
(1) Center Watch survey 2019Ambitious digital transformation across Sanofi R&D
Real World Evidence
• Commercial value increase of marketed products
• Clinical trial hypotheses support, virtual control arms
• Disease models, biomarker-driven population enrichment
• Search of new indications for development compounds
• Pharmacovigilance
Digital Research Digital in CMC
• In-silico screening • Paperless CMC labs
• AI-driven compound optimization • One data platform
• De-novo antibody design • Digitized workflows across all
• ML-driven developability CMC, including external partners
• Process modeling simulation
Key digital
assessment
Digital Clinical Operations programs
• Innovative, evidence-based design
• Digital biomarkers, sensors & tools Digital in Regulatory Affairs
• Patient engagement platform • Automated document generation
• Investigator & site platform • Language translation
• Real-time data management • Cloud-based AI to support
• Digital control room document management
AI: Artificial intelligence; ML: Machine learning; CMC: Chemistry, manufacturing and control 61Improved capabilities and fast execution
Illustration with BTKi ('168)(1)
Phase 1 and 2 conducted Phase 3 studies being launched across
1 year faster than benchmarks the full MS spectrum(2)
• Data exchange platform (Patient – Site – Sponsor) • Planning Phase 3 studies at risk to start as fast as
enabling continuous data exchange possible (sites pre-identified and on-boarded)
• Home delivery of study drug; leverage of • Control arm size in PPMS reduced to accelerate study
telehealth when possible (visits, performance completion while maintaining acceptable statistical power
outcomes, etc.)
• Optimized study design through early patient and
• Remote site visits enabling business continuity investigator engagement
Trials maintained during COVID-19 First patient enrolled in RMS trial on June 11,
97% of patients are on long-term extension study despite pandemic
BTKi: Bruton's tyrosine kinase inhibitor; RMS; Relapsing multiple sclerosis; PPMS: Primary progressive multiple sclerosis; NR-SPMS: Non relapsing secondary progressive 62
multiple sclerosis. (1) Not yet approved by regulators – in collaboration with Principia (2) RMS, PPMS and NR-SPMS160+ COVID-19 vaccine candidates in development
based on multiple technologies
As of June 19, 2020
Proven
technologies 3 9 Live virus
Virus-based
Whole inactivated virus
35 Vector vaccines(1)
66
Gene delivery-based DNA vaccines
mRNA vaccines
13 Recombinant protein-based(2)
Exploratory Unknown / not disclosed
20 23
platforms
Half of clinical candidates are based on exploratory vaccine platforms
(1) Includes replicating and non replicating (2) Includes viral proteins, subunits, virus-like particles 63
Source: Milken InstitutesVaccine platforms: Different safety and efficacy profiles
Established large
Clinical Efficacy / manufacturing
Technology candidates immune response Duration of protection Safety capacity & process
Recombinant Requires adjuvant
Long-lasting immunity
protein- 2 ✔ and potentially ✔ ✔ Limited concerns ✔ Yes
(if adjuvanted)
based(1) booster dose
Unknown, may Limited candidates(4)
mRNA Unknown (limited
3 ? require several ? Unknown ? database)
? (exception:
vaccines doses Translate Bio)
Unknown, may Potential integration
DNA No existing
1 ? require several ? Unknown ? into DNA; requires ? product
vaccines doses electrical stimulation
10-50% of Unknown, booster not History of enhanced
Vector population have possible (due to infections rates with No existing
2 ✔ ? ? ?
vaccines(2) pre-existing immunity against vector selected product
antibodies to vector after first vaccination) adenovaccines
Whole Requires adjuvant,
Long-lasting immunity
inactivated 4 ✔ and potentially ✔ Risk of VAERD ✔ Yes
(if adjuvanted)
virus several doses
Complex biosafety
Live Induces strong
measures(3);
attenuated 0 ✔ response with ✔ Long-lasting immunity ✔ Yes
immuno-depressed
virus single dose
patients ineligible
VAERD: Vaccine-associated enhanced respiratory disease
(1) Includes viral proteins, subunits, virus-like particles (2) Includes replicating and non replicating (3) Risks: contamination, reversion to virulence, stability (4) In collaboration 64
with GSK and Translate BioSanofi is developing two complementary vaccines – each
with differentiated profile
1 2
Recombinant protein- mRNA
based vaccine vaccine
Platform (Baculovirus) (natural)
Protein antigen Adjuvant mRNA Lipid nanoparticle
• Licensed recombinant platform(1) • Innovative approach(2) – natural mRNA
• Existing large-scale capacity • Potential for accelerated development
Description • BARDA collaboration • Significant existing investment in mRNA
• Collaboration with gsk for proven AS03 adjuvant capacity to be applied towards vaccine
• Unknown safety risks (potentially differentiated
Unknowns • May require booster dose(s)
safety profile vs. modified mRNA)
• Most de-risked technology • Promising technology
Strengths • Existing capacities to leverage • Only established large scale mRNA
manufacturing capacity (Translate Bio)
BARDA: Biomedical Advanced Research and Development Authority 65
(1) Flublok® is manufactured with this platform and licensed in the U.S. (2) In collaboration with Translate BioYou can also read
