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K I A D I S P H A R M A | C O M PA N Y P R E S E N TAT I O N | N O V E M B E R 2 0 1 9

Leveraging the natural strengths of humanity and our collective immune systems to source the best cells for life

Cell therapy to treat cancer, combining innate and adaptive immune system

Disclaimer

2

These slides and the accompanying oral presentation contain forward-looking statements and information. Forward-looking statements are subject to known and

unknown risks, uncertainties, and other factors that may cause our or our industry’s actual results, levels or activity, performance or achievements to be materially

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“estimate”, “project”, “intend”, “future”, “potential” or “continue”, and other similar expressions are intended to identify forward looking statements. For example, all

statements we make regarding (i) the initiation, timing, cost, progress and results of our preclinical and clinical studies and our research and development programs, (ii)

our ability to advance product candidates into, and successfully complete, clinical studies, (iii) the timing or likelihood of regulatory filings and approvals, (iv) our ability

to develop, manufacture and commercialize our product candidates and to improve the manufacturing process, (v) the rate and degree of market acceptance of our

product candidates, (vi) the size and growth potential of the markets for our product candidates and our ability to serve those markets, and (vii) our expectations

regarding our ability to obtain and maintain intellectual property protection for our product candidates, are forward looking . All forward-looking statements are based

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only as of the date on which it was made. We undertake no obligation to publicly update or revise any forward-looking statement, whether as a result of new

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KIADIS PHARMA | www.kiadis.com

Kiadis: Proprietary K-NK cell cancer immunotherapy

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K-NK cell therapy:

Clinical benefit across treatments modalities, combining innate and adaptive immune system

K-NK pipeline:

Blood cancer and solid tumor cell-therapy programs

K-NK platform:

Off-the-shelf potent, high dose and persistent NK cells based on universal donor

• Salvage therapy: stand alone• Front line therapy: adjunctive to

surgery, chemo, MAbs, PARP• Preventive therapy

• K-NK002: Phase 1/2 with haplo HSCT with PTCy (2020)

• K-NK003: phase 1/2a to treat AML R/R (2020)

• K-NK00X: preclinical solid tumor programs

• Off-the-shelf: mature universal donor optimal for all patients

• PM21 mbIL21 particle activation: hyperfunctional & persistent phenotype

• Industrial: >1000 doses/batch; tumor-cell free final product

HSCT: hematopoietic stem cell transplantation; Haplo: haploidentical (genetically half matched); allodepleted T-cells: T-cells without patient specific T-cells that could cause GVHD; GVHD: Graft versus Host disease; RMAT: Regenerative Medicine Advanced Therapy (‘breakthrough designation’); PTCy: post transplant cyclophosphamide


Kiadis K-NK Pipeline: Blood tumors and solid tumors, entering Phase 1/2 in 2020

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PROGRAM INDICATION SETTINGPRE-CLINICAL PoC

PHASE 1/2

CATALYSTS IN 2020

PROOF OF CONCEPT

K-NK002HSCT blood cancer

Adjunctive to standard of care HSCT-PTCy (chemo)

2020

Phase 1/2 (63 patients) start with US BMT-CTN

25 patients: reduction of relapse from 45% to 8%

K-NK003 AML R/RStand alone salvage therapy

2020 Phase 1/2a start13 patients: 69% complete remission

K-NK00X Solid tumorsCombo with front line therapy (Mabs, chemo)

Preclinical data; initiation new trials

Preclinical data and literature


NK-cell therapy:

Clinical benefit across all treatment modalities, combining strengths

of innate and adaptive immune system

NK cells naturally potent, safe and tumor specific; No need for CAR-engineering

7

Issue T-cells

HLA-1 down-regulation by tumor to escapeT-cells

Issues CAR engineering

Toxicity; limited to single target


GITRKIRXDSX

CD16

mAb

NK-cell

Multiple stress/viral ligands (HLA independent)‘Self protection’ by recognition of HLA-1

TCR

T-cell

CAR-T

Single antigen via HLA-1 or CAR-TCheckpoints (HLA-1 independent)

Activation

Inhibition

Clinical benefit of combining NK-cells with antibody (examples Herceptin and Erbitux)

KIADIS PHARMA | www.kiadis.com 10

Improved outcomes in patients that have high affinity NK-cell to antibody binding (CD16 polymorphism in 10-15% of population)

Clinical benefit of giving NK cells after chemo (examples HSCT, breast cancer and multiple myeloma)


Chemo inhibits NK-cell killing

Patient own NK cells important to fight disease,

yet not functional

Chemo sensitives

tumor to NK-cells

Adoptive infusion of new

NK cells afterchemo

• NK activity and numbers associated with low tumor burden4

• Lower numbers of NK cells in blood of patients1, 2

• Patient NK cells have low expression of activating receptors3,1

• Patients with advanced disease have increased proportion of immature and non-cytotoxic NK cells9,10

• Docetaxel and bortezomib upregulates activating ligands, MICA, PVR and ULBP1-3, on tumor cells1,6, 13

• Bortezomib and carfilzomib decrease inhibitory ligands, MHC, on tumor cells7,8

• Mature NK cells infused with graft lost upon PTCy administration, blunting NK cell alloreactivity in transplantation15

• Paclitaxel, docetaxel and bortezomib inhibit NK cell killing 5

• Dexamethasone, suppresses NK cell activity14

1. Mohyuddin et al, 2018 Advances in Cell and Gene Therapy; 2. Famularo et al, 1992 Journal of Clinical and Laboratory Immunology; 3. Fauriat et al, 2006 Leukemia; 4. Osterborg et al, 1996 European Journal of Hematology; 5. Markasz et al, 2007 Molecular Cancer Therapeutics; 6.Sorani et al, 2009 Immunobiology; 7. Shi et a l, 2008 Immunobiology; 8. Zang et al, 2015 Oncotarget; 9. Verma et al, 2015 Journal of Translational Medicine; 10.Mamessier et al, 2013 Journal of Immunology; 11.Chagollan-Garcia et al, 2018 Technology in Cancer Research and Treatment; 12. Zingoni et al, 2018 Frontiers in Immunology; 13. Acebes-Huerta et al, 2016 Oncoimmunology; 14. Chen et al, 2018 Inflammapharmacology; 15. Russo et al, 2018 Blood

K-NK pipeline:

Blood cancer and solid tumor NK-cell therapy programs

K-NK002: Clinical Proof-of-concept as adjunct to haplo HSCT with PTCy (MD Anderson Cancer Center*)

1313

*NK-cells from haplo donor produced with feeder cells expressing mbIL21 and 41bbl, not with PM21 particlesn=13 Phase 1 dose finding (published in Blood), n=12 Phase 2 at highest dose (presented at ASCO and Haplo2018); Ciurea SO, et. al. Blood 2017, (link to paper); Ciurea SO EMBT Mar2018; Ciurea SO, Haplo2018, Nov2018; Russo et al, Blood 2018

45%

SIZE DOSING SCHEDULEFOLLOW UP OUTCOMES

n=25 104 to 108

cells/kgDay -2 (after conditioning)Day +7 (after cyclo)Day +28 (booster)

28 months(0.9-48)

• Improved OS, PFS, relapse• Reduced reactivation of CMV/BKV

8%

Phase 1 clinical trial using mbIL21 ex vivo-expanded donor derived NK cells after haploidentical transplantation

Ciurea et all, Blood 2017

‘Infusion of high doses of ex vivo–expanded NK cells after haploidentical HSCT associated with significantly improved NK-cell number and function, lower viral infections, and low relapse rate posttransplant’


74%

45%

https://doi.org/10.1182/blood-2017-05-785659

K-NK002: Phase 1/2 NK-REALM with Blood and Marrow Transplant Clinical Trials Network (BMT CTN)

Study designed and conducted with US BMT-CTN (established to conduct large multi-institutional HSCT trials):

• Single arm, open label multicenter trial

• Patients undergoing a haploidentical HSCT using PTCy protocol

• 63 patients

• High-risk AML or MDS

• First cohort to be evaluated during safety lead-in phase

• Primary endpoint: cumulative incidence of relapse at 1-year post transplant

• Haplo donor

• K-NK002 dosing: 1 x 108 NK cells per kg on days -2, +7 and +28 after transplant graft infusion


HAPLO-IDENTICAL NK-CELLS TO

PREVENT POST-TRANSPLANT

RELAPSE IN AML AND MDS (NK-REALM)

K-NK003: Clinical proof-of-concept* for treatment of AML R/R 2nd line salvage

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SIZE PATIENTS DOSINGFOLLOW

UPOUTCOMES

MD Anderson Cancer Center

n=8 • 4 median prior treatments

• 3/8 prior HSCT• 43% median BM

blasts

6 doses (11 days) of

106 cells/kg

329 days(71-730)

• CR/CRi: 75% (day 30)• Negative MRD: 37,5%

(PCR/flow)• HSCT: 50%• Survival: 37,5% (1

year)

MD Anderson Cancer CenterAnd HCPA, Porto Alegre, Brazil

N= 13 • 4 median prior treatments

• 7/13 prior HSCT • 45% median BM

blasts

5-6 doses (11 days) of 106

to 107

cells/kg

202 days (39-590)

• CR/CRi: 69%

*NK-cells from haplo donor produced with feeder cells expressing mbIL21 and 41bbl, not with membrane particles; Ciurea SO, et. al. ASCO June2018; Ciurea SO Haplo2018. Nov2018

15KIADIS PHARMA | www.kiadis.com

K-NK003: Treatment of AML R/R 2nd line salvage – examples

1616

AML, MALE, 25 YRS (MDACC)

• 8 lines of prior treatment, incl prior failed HSCT• Active disease, 90% BM blasts• Treated with NK cells plus one course of FLAG,

no subsequent HSCT• Complete response• Ongoing Minimum Residual Disease (MRD)

decrease at 120 days• Relapsed/death at two years

AML, MALE, 22 YRS (HCPA; Brazil)

• Diagnosed at age 15• 3rd relapse; 2nd CNS relapse• Refractory to CNS-directed therapy• Treated with NK cells plus one course of FLAG• Complete response• Continued remission at 5 months • Relapsed/death at two years

1 week pre-treatment: CNS disease

1 week after last NK cell infusion: inflammation

6 weeks after last NK cell infusion: disease free

Courtesy L. Silla; HCPA - UFRGS

KIADIS PHARMA | www.kiadis.com Courtesy S. Ciurea, MDACC

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Head and neck cancer: Intratumoral delivery

Ovarian cancer: Intraperitoneal delivery

LOCAL DELIVERY FOR EARLY PROOF OF MECHANISM (BIOPSIES, DIAGNOSTICS)


K-NK00X: potential solid/blood tumor programs

Approved mAb Main indications

DaratumumabElotuzumab

Multiple myeloma

RituximabNon Hodgkins Lymphoma

Trastuzumab Breast cancer; Ovarian cancer

Avelumab Lung cancer

CetuximabColon cancer; Head and Neck cancer

COMBINE WITH APPROVED ANTIBODIES FOR ENHANCED ADCC

Melanoma: Intratumoral delivery

Kiadis K-NK Clinical development outline

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2024

PRODUCT INDICATION CLINICAL STUDIES

K-NK002Blood cancer

K-NK003 AML R/R

K-NK00XSolid tumors

Ph 2/3 Adaptive Design

Phase 1/2a

Phase 1/2 BMT CTN (add-on bridge to OTS)

Ph 2/3 Adaptive Design versus PTCy

Phase 1 dose finding & safety

Phase 2a expansion Phase 2 basket

studyPhase 3

indications

Signal Activity studies


K-NK platform:

Off-the-shelf potent, high dose NK cells based on universal donor

Kiadis K-NK platform: addressing key NK critical attributes


KIADIS PLATFORM BENEFITS

Potent, safe and persistent

PM21 (mbIL-21 and

41bbL particles)

• Hyperfunctional phenotype with high cytotoxicity and antitumor IFNγ and TNF release (without gene engineering)

• In vivo persistence (no senescence)

Off-the-shelfUniversal adult

donor

• Fully licensed and mature NK cells• Activating/inhibiting receptor profile optimized

for all patients (HLA-KIR mismatch)

Large scale industrial manufacturing

PM21 (mbIL-21and

41bbL particles)

• High yield/long culture allow high dosing and low COGS (>1000 doses/batch feasible)

• Cryopreserved• No feeder/tumor cell materials in final product

mbIL-21

4-1bbL

K-NK cell industrial manufacturing platform with PM21 particles

Acquisition of donor

cells from the clinic

Prodigy/Clinimacs+GRex

NK cell enrichment; Stimulation using

PM21 particles

Hollow fiber/LovoHarvest and

concentrationFormulation in cryo-

preservative

XuriExpansion in a

bioreactor

ViaFreeze Cryo-

preservation

Day 0 - 7 Day 7 - 13 Day 14 Day 14

PM21: mbIL-21 and 41bbL particles Native membrane particles presenting mbIL21 and 41bbL

No intact tumor cells in final product (regulatory advantage)

21KIADIS PHARMA | www.kiadis.com

K-NK cells with mbIL-21: longer expansion (no senescence observed)


mbIL-21: Telomere stability(not with mbIL-15)

PM21: Long expansion(longer than PM15)

IL2 NK

IL2+

IL15

NK

IL2+

IL21

NK

0.00

0.01

0.02

0.03

0.04

0.05p=0.0088

p=0.0142

!"#$

!"#$!"%&'

!"#$!"#%&

NK cells. CFSE dilution and TERT expression in response to used cytokine combinations

TE

RT

exp

resio

n (A

U)

mbIL-21: Telomerase expression(not with mbIL-15)

Oyer et al., Cytotherapy, 18, 2016 Denman et al., PLoSONE, 7(1), 2012

K-NK cells with PM21: scale-ability, high dose and attractive cost of goods


59

3225

5551

1 2 3 4 5

Run of >3 weeks: Under development

Run of 2 weeks: Up to 60 B cells

Bill

ion

ce

lls

5 consecutive engineering runs

>1000 DOSES/BATCH*60 DOSES/BATCH*

* Assuming 10^7 cells/kg per dose

K-NK cells with mbIL-21: hyperfunctional NK cells withupregulated activating and inhibiting receptors and metabolism


mbIL-21: enhanced NK cell glycolysis

mbIL-21: Upregulation of activating and inhibitory receptors

Schafer et al., Journal of Allergy and Clinical Immunology, 2018

Gly

coly

sis

Gly

coly

tic C

apac

ity

Gly

coly

tic R

eser

ve0

20

40

60

80

100

EC

AR

(m

pH

/min

)

Fresh NK cells

K-NK cells

K-NK cells with mbIL-21: strong anti-tumor activity and anti-tumor cytokine secretion


Denman et al., PLoSONE, 7(1), 2012

Strong cytotoxicity (equal to mbIL-15)

Strong anti-tumor cytokine secretion (substantially higher than mbIL-15)

Fre

sh

mbIL

15

mbIL

21

Fre

sh

mbIL

15

mbIL

21

Fre

sh

mbIL

15

mbIL

21

Fre

sh

mbIL

15

mbIL

21

1

10

100

1000

10000

IFNg TNF IL-2 IL-6IFNg TNF IL-2 IL-6S

up

ern

ata

nt [p

g/m

l]

K-NK Universal Donor: proprietary* algorithm to select optimal donors for all patients


Optimized activating receptors

Optimized HLA-KIR mismatching

Favourable NKG2A/NKG2C ratios

*Patent pending

Selection of donors that are optimal for all patients (similar as with O negative blood type, no need for patient-donor matching)

High number of activating receptors leads to better outcomes


Haploidentical HSCT from KIR ligand-mismatched donors with activating KIRs reduces nonrelapse mortality

Mancusie et al, Blood, 2015 125125(20):3173-82.

‘In 69 transplant pairs with donor-vs-recipient NK-cell alloreactivity, transplantation from donors with KIR2DS1 and/or KIR3DS1 is associated with improved outcomes’

2 3 4 50

20

40

60

80

100

Number of Donor Activating KIR

Perc

ent sp

eci

fic ly

sis

slope ¹ 0? p = 0.0002

NK cells with more activating KIRs induce stronger lysis

KIR-HLA mismatch has anti-tumor effect


KIR mismatch

Low relapse

Ruggeri et al, Science 2002 295: 2007

Donor NK cells express matching KIRs

Donor cells express self HLAs

HLA-C1

KIR2DL2/3

HLA-C2KIR2DL1

HLA-Bw4

KIR3DL1

HLA-KIR match: NK-cell inhibition HLA-KIR mismatch: lower relapse

NK-cell platforms - overview


OFF THE SHELF PLATFORM

EXPANSION & ACTIVATION PLATFORM

APPROACH TO ENHANCE POTENCY

Kiadis Universal adult donor (optimal fully licensed donor)

PM21: mbIL21 and 41bbL particles (no tumor cells in final product)

• Ex vivo activation optimizations (hyperfunctional and persistent NK phenotype, optimized for solid tumor micro-environment)

Fate iPSC (stem cell line) Feeder cells (tumor cell line) with mbIL21/mbIL15

• Genetic engineering e.g., high affinity CD16 and CAR19

Nkarta Adult donor Feeder cells (tumor cell line) with mbIL15

• Genetic engineering, e.g., co-stimulation and CAR

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CHIARA BONINI, MDProfessor of Hematology at the Università Vita-Salute San Raffaele, Milan

MICHAEL CALIGIURI, MDDeana and Steve Campbell Physician-in-Chief Distinguished Chair

ELAINE MARDIS, PhDCo-executive Director of the Institute for Genomic Medicine at Nationwide Children's Hospital

HELEN HESLOP, MD, DScProfessor at Baylor College of Medicine

TODD FEHNIGER, MD, PhDAssociate Professor at the Department of Medicine, Washington University School of Medicine in St Louis

CARL JUNE, MDThe Richard W. Vague Professor in Immunotherapy in the Department of Pathology and Laboratory Medicine at the Perelman School of Medicine of the University of Pennsylvania

DEAN LEE, MD, PhDDirector of the Cellular Therapy and Cancer Immunotherapy Program for Nationwide Children’s Hospital’s Division of Hematology/Oncology/BMT and Center for Childhood Cancer and Blood Diseases

KRISHNA KOMANDURI, MDMedical Director of the hematopoietic stem cell transplant program at the University of Miami Sylvester Cancer Center

Scientific Advisory Board


Kiadis news flow

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2020 2021

HSCT blood cancers

Start NK-REALM Phase 1/2 trial (with US BMT CTN)

Safety lead in read out and interim data NK-REALM trial

AML R/R Start AML R/R Phase 1/2a trial Interim data AML R/R trial

Other solid/blood tumors

Preclinical data solid/blood tumors

Start clinical signal study solid/blood tumor trial

Pharma/biotech BD partnership

Interim clinical data solid/blood tumor trial(s)

Start multiple clinical studies solid/blood tumor


When it comes to life-threatening diseases, we are one family. Kiadis is leveraging the natural strengths of humanity and our collective immune systems to source the best cells for life.

Our uncompromising approach to serve patients, their families and care givers aims to minimize harm and maximize help – delivering personalized treatments for every single patient to offer hope, reduce suffering and provide new life.

euronext: kds leveraging the natural strengths of humanity ... · euronext: kds kiadis pharma |...

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