bio-ce0 & investor, new york 13-14 february2017€¦ · the group does not undertake any...

©Hybrigenics – 2016 – Confidential

Bio-CE0 & Investor, New York

13-14 February 2017

©Hybrigenics – 2016 – Confidential 1

Disclaimer

This document contains forward-looking information and statements.

This information and these statements express targets established based on the currentassessments and estimates of the Group’s executive management. They remain subject to avariety of factors and uncertainties, which are difficult to predict and generally outside of theGroup’s control, and may cause actual results and developments to differ materially from thoseexpressed, implied or planned.

The Group does not undertake any obligation to update or revise the forward-looking statementscontained in this document to reflect new information, future events or other factors.


Hybrigenics Pharma: a Phase II clinical stage

R&D company focused against cancer

Inecalcitol , an orally active vitamin D receptor agonist

– is in clinical Phase II for Chronic Myeloid Leukemia in France

– is in clinical Phase II for Acute Myeloid Leukemia both in France and in the United States

– has received Orphan Drug designation for Acute Myeloid Leukemia both in Europe and the United States

Pioneering research on Ubiquitin-Specific Proteases– five patents granted worldwide on inhibitors pan-USPs or of USP7or USP8

– Succesful drug discovery collaboration with Servier

A public company listed on Alternext in Paris

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Pharma


Hybrigenics Pharma R&D Pipeline:

Development of inecalcitol in oncology &

Research on deubiquitinating enzymes inhibitors

Pharma

Oral inecalcitol in Chronic Lymphocytic Leukemia

in Chronic Myeloid Leukeumia

Other DUBs

OrphanAdult

Leukemias

ProstateCancer

DUBs inOncology

In Acute Myeloid Leukemia

One USP

Oral inecalcitol in Castrate-Resistant P.C.

DrugDiscovery

DrugDevelopment

Status

HitFinding

Lead Opt.

Preclin. Phase I Phase IIPhase

III

Phase II completed

Phase II launched

Phase II launched

Phase IIa completed

Early stage research


Development

of inecalcitol

Pharma


Inecalcitol(in green)

Vitamin D Receptor(in orange)

The VDR is a nuclear receptor regulating the expression of genes involved in calcium homeostasis and cell proliferation/differentiation

Inecalcitol binds to the VDR but in a different conformation than natural vitamin D, resulting in

– Stronger inhibition of cell proliferation

– Stronger induction of cell differentiation

– Less hypercalcemic toxicity

Inecalcitol can be given orally up to 4 mg per day(Medioni et al., 2014, Clin. Cancer Res.)

Inecalcitol has Orphan Drug designation for AML both in Europe (�) and in the United States (�)

Inecalcitol clinical Phase II study in AML launchedin France (IMPD�) and in the United States (IND�)

Inecalcitol, an orally active vitamin D receptor agonist

Pharma

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Mechanism of action of vitamin D in cells

Calcitriol (1,25(OH)2D3), the active form of vitamin D, circulates in the body bound to the vitamin D binding protein .

Calcitriol dissociates from the vitamin D binding protein and enters into the cell.

Calcitriol binds to the vitamin D receptor (VDR) and forms a heterodimer with the retinoid X receptor (RXR).

The calcitriol/VDR/RXR complex binds to specific DNA sequences called vitamin D response element s (VDRE) to induce or repress expression of target genes.

VDRE-regulated genes are involved in calcium homeostasis, cell proliferation or apoptosis, cell differentiation, inflammationand immuno-modulation . Reproduced from Davis and Milner: J Nutrigenet Nutrigenomics 2011;4:1–11

Pharma


Inhibition of clonogenic growth of HL-60 cells:

inecalcitol 3 times more potent than calcitriol

inec

alci

tol

calc

itrio

l

Conc. (M) 0 10 -11 10-10 3.10-10 10-9 3.10-9 10-8 10-7

Soft agar clonogenic assay:HL-60 ECACC cells were plated and treated in 6-well plates using a two-layer soft agar system. Treatment was renewed every 7 days. After 14-18 days of culture, colonies were stained and counted.

Nu

mb

er

of

co

lon

ies

(%

of

co

ntr

ol)

Pharma

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Induction of CD11b antigens on HL-60 cell surface:

inecalcitol 3.3 times more potent than calcitriol

FITC: CD11b signal

CD11b flow cytometry:HL-60 ECACC cells were treated for 72h with inecalcitolor calcitriol. CD11b was detected on the surface of native cells by fluorescence-labelled anti-CD11b antibodies.

-11 -10 -9 -8 -7 -60

25

50

75

100

inecalcitol: EC50 = 1.8 0.8 nM (n = 4)

calcitriol: EC50 = 5.9 1.4 nM (n = 4)

log (concentration [M])

Pharma

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Inecalcitol: low in vivo calcemic activity and toxicity

inecalcitol

calcitriol

10

11

12

13

Tota

l pla

sma

calc

ium

on d

ay 8

(m

g/dl

)

Dose (µg/kg/day)0.1 0.3 1 3 10 30 100 300

Plasma calcium

Control level

Inecalcitol is 70 times less hypercalcemic than calcitriol

Inecalcitol is 125 times less toxic than calcitriol

Dose (µg/kg/day)

Bod

y w

eigh

tgai

n in

7 d

ays

(% o

f pre

trea

tmen

tval

ue)

Untreated controls

10

0

-10

-20

-30

20

30.1 0.3 1 10 30 100 300

Body weight gain or loss

inecalcitol

calcitriol

Study design:Inecalcitol or calcitriol s.c. injections for 7 days to male rats

Pharma

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Inecalcitol Summary Product Profile

New Chemical Entity

Unique pro-differentiation properties on hematological cells

General anti-proliferative activity on cancer cells

Safe: only blood calcium levels to monitor

Convenient oral tablet administration

Patent protection worldwide until 2031

Orphan Drug for Acute Myeloid Leukemia in Europe and the

United States

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Pharma


The four major types of leukemias:

acute or chronic and lymphoid or myeloid

Type of Leukemia

Lymphoid Myeloid

Chronic

Chronic Lymphocytic Leukemia32% annual incidence

19% deaths from leukemiaMost frequent > 50 years5-year survival rate = 85%

Chronic Myeloid Leukemia14% annual incidence

4% deaths from leukemiaMost frequent > 65 years5-year survival rate = 63%

Acute

Acute Lymphoblastic Leukemia11% annual incidence

6% deaths from leukemiaMost frequent < 20 years5-year survival rate = 70%

Acute Myeloid Leukemia33% annual incidence

43% deaths from leukemiaMost frequent > 50 years

5-year survival rate = 26%

Total estimated new leukemia cases in the US: 60,140 in 2016

Total estimated new AML cases in the US: 19,950 in 2016

(Source: Cancer Facts & Figures, American Cancer Society, 2016)

Pharma


Cancer Facts & Figures, American Cancer Society, 2007 - 2016

Pharma

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

An

nu

al

inc

ide

nc

e i

n t

h U

nit

ed

Sta

tes

Nu

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of

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wly

dia

gn

os

ed

pa

tie

nts


Inecalcitol-treated mice showed an improved survival (50% at day 60),as compared to vehicle-treated mice (100% mortality at day 30)

(12th International Congress on Targeted Anticancer Therapies, Washington DC, March 2014)

Inecalcitol improves survival in a mouse model of

AML triggered by NPM1c and FLT3-ITD mutations

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Mice were injected with NPM1c and FLT3-ITD mutated AML cells and treated by IPinjections of vehicle alone or of inecalcitol

(20 µg/mouse, 3 days per week)

0 20 40 60 800

20

40

60

80

100 vehicle

logrank= 0.0092

inecalcitol

daysP

erce

nt s

urvi

val

Pharma


Inecalcitol improves survival in a mouse model of

AML triggered by NPM1c and FLT3-ITD mutations

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Pharma

spleen weight

contr

ol

vehic

le

inec

alcito

l

0

200

400

600 *

mg

Inecalcitol treatment totally prevented the increase in spleen size and weight (splenomegaly ) induced by AML



Combination of inecalcitol and decitabine improves

survival in a mouse model of AML (NPM1c/FLT3-ITD)

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Pharma

The combination of inecalcitol with decitabine further improves survival as compared to treatment by decitabine alone


Mice were injected with NPM1c and FLT3-ITD mutated AML cells and treated by IPinjections of decitabine (DAC, 0.5 mg/kg/dayfor 5 days) alone or in combination with IPinjections of inecalcitol (20 µg/mouse, 3days per week)


Focus on Acute Myeloid Leukemia

The highest unmet medical need

The shortest development time

The highest benefit/price expectations

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Pharma


Pharma

Clinical Advisory Board

Prof. Michael MauroLeader, Myeloproliferative

Neoplasms Program, Memorial Sloan Kettering Cancer Center, New York

Prof. Jorge CortesDeputy Chair,

Department of Leukemia,MD Anderson Cancer

Center, Houston, Texas

Prof. Olivier Hermine Head, Hematology

Department, Necker University Hospital and Imagine Institute, Paris

Prof. Ali TurhanHead, HematologyDepartment and Inserm Research Unit 935, South Paris University Hospitals,


Crude AML incidence rates per 100,000 (excluding Acute Promyelocytic Leukemia)– US = 5.8; EU = 4.5; Japan = 5.5

Total newly diagnosed AML cases per year in major markets: 44,400– US = 18,800; EU15 = 18,600; Japan = 7,000

Median age at diagnosis: 67 years in the US; 71 (France) or 72 (UK) years in EuropePercentage of diagnosed patients > 60 years: 66% in the US; 71% (France) or 75% (UK) in Europe

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(American Cancer Facts & Figures 2016; Francim, 2013; Cancer Research UK report 2016;Decision Ressources report 2015; GlobalData reports 2015 & 2016)

Standard or intensive chemotherapy

Hypomethylating agents* (HMA*)

<20 years 60 years 75 years

Best supportive care

Before 60-year old: chemotherapy for all AML patients− 6,400 patients in the US− 5,000 patients in EU15

After 60-year old:− Only 20% of patients fit for chemotherapy− 5% receive low dose cytarabine− HMA*, the only option for ~40% of patients

• 5,000 in the US• 5,400 in EU15

*decitabine or azacytidine

Pharma

Epidemiology and first line treatment options


Efficacy Phase II study of inecalcitol in combination with decitabinein frail or elderly AML patients unfit for standard chemotherapy

Primary endpoint: overall survival

Principal investigators:

- Prof. J. Cortes , MD Anderson Cancer Center, Houston, Texas

- Prof. O. Hermine , Necker Hospital, Paris, France

Timelines: launched in 2H16, results expected in 1H19

Randomization

110 elderlyAML patients

Decitabine intravenous cycles+INECALCITOL, daily by oral route, continuously unti l progression

Decitabine intravenous cycles+PLACEBO daily by oral route, continuously until pro gression

Pharma


Research on

De-Ubiquitinating Enzymes

Pharma


The Ubiquitin-Proteasome System

E3 Ligase Ub

USP

Protein Protein

(USP : ubiquitin-specific protease)

Ubiquitination

De-ubiquitination Degradationby the proteasome

The natural mechanism for selective sorting and recycling of proteins

Pharma


Rationale for using USP inhibitors

against oncoproteins involved in cancer

Onco-protein

Ub

Onco-protein

E3 Ligase

USP

USP inhibitors : potential for innovative anticancer drugs– Upstream specific targeting of the Ubiquitin-Proteasome system– Impairing the recycling of onco-proteins– Forcing their degradation by the proteasome

Pharma


Hybrigenics’ pioneer research position on DUBs

Focus on the role of Ubiquitin-Specific Proteases (USPs) in oncology

– 6 original articles and 5 reviews published by Hybrigenics’ research team

Estate of worldwide granted patents of inhibitors of USPs

– Three granted patents on pan-USPs inhibitors : Colland et al., 2009, Mol Cancer Ther, 8: 2286-95

– One granted patent on irreversible specific inhibitors of USP7 until 2031 in Europe, the US, Japan and China among others: Reverdy et al., 2012, Chem Biol, 19: 467-77

– One granted patent on reversible specific inhibitors of USP7 until 2032 in Europe, the US and Japan; examination pending in the rest of the world

Successful partnership with Servier for validation of one USP in oncology, screening of its lead inhibitors and profiling of development candidates

– Upfront and four years of research funding (€4.7m)

– Two objectives of the research collaboration have been reached (€2m)

– Potential further milestones until drug registration for a total amount of €12m

23

Pharma


Molecular modelling of a proprietary inhibitor

docked in the catalytic domain of USP7

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HGX 28,358 (in yellow) docked in the catalyticdomain of USP7 in blue (left) or grey (right)

Pharma


Inecalcitol Summary Product Profile

New Chemical Entity

Unique pro-differentiation properties on hematological cells

General anti-proliferative activity on cancer cells

Safe: only blood calcium levels to monitor

Convenient oral tablet administration

Patent protection worldwide until 2031

Orphan Drug for Acute Myeloid Leukemia in Europe and the

United States

25

Pharma


Hybrigenics’ Pharma R&D prospects in oncology

Further own drug discovery achievements in USP research

Next R&D milestone of the USP inhibitor developed by Servier

Results of Phase II clinical study of inecalcitol in combination withimatinib in Chronic Myeloid Leukemia expected in 2H2018

Results of Phase II clinical study of inecalcitol in combination withdecitabine in Acute Myeloid Leukemia expected in 1H2019

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Pharma

bio-ce0 & investor, new york 13-14 february2017€¦ · the group does not undertake any...

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