Upload
others
View
2
Download
0
Embed Size (px)
Citation preview
EURONEXT: KDS
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
different from those anticipated by such statements. The use of words such as “may”, “might”, “will”, “should”, “could”, “expect”, “plan”, “anticipate”, “believe”,
“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
on current estimates, assumptions and expectations by our management that, although we believe to be reasonable, are inherently uncertain. All forward-looking
statements are subject to risks and uncertainties that may cause actual results to differ materially from those that we expected. Any forward-looking statement speaks
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
information, future events or otherwise, except as required by law. This presentation is not, and nothing in it should be construed as, an offer, invitation or
recommendation in respect of our securities, or an offer, invitation or recommendation to sell, or a solicitation of an offer to buy, any of our securities in any
jurisdiction. Neither this presentation nor anything in it shall form the basis of any contract or commitment. This presentation is not intended to be relied upon as
advice to investors or potential investors and does not take into account the investment objectives, financial situation or needs of any investor.
KIADIS PHARMA | www.kiadis.com
Kiadis: Proprietary K-NK cell cancer immunotherapy
3
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 in haploHSCT 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 PHARMA | www.kiadis.com
Kiadis K-NK Pipeline: Blood tumors and solid tumors, entering Phase 1/2 in 2020
4
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
KIADIS PHARMA | www.kiadis.com
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
KIADIS PHARMA | www.kiadis.com
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)
KIADIS PHARMA | www.kiadis.com 11
Chemo inhibits NK-cell killing
Patient own NK cells are important to fight disease,
yet not functional
Chemo sensitizes
tumor to NK-cell killing
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 al, 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 particles** Contemporaneous MDACC control based on 95 patients*** n=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 SCHEDULE FOLLOW UP OUTCOMES
n=25 104 to 108
cells/kg
Day -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’
KIADIS PHARMA | www.kiadis.com
74%
45%** **
**
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
KIADIS PHARMA | www.kiadis.com 14
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
15
PATIENTS DOSINGFOLLOW
UPOUTCOMES
MD Anderson Cancer Center (n=8)
• 4 median prior treatments
• 3/8 relapsed after prior HSCT
• 43% median BM blasts
6 doses (11 days) of
106 cells/kg plus FLAG
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 Center(n=8)HCPA, Porto Alegre, Brazil(n=5)
• 4 median prior treatments
• 7/13 relapsed after prior HSCT
• 45% median BM blasts
5-6 doses (11 days) of 106 to 107
cells/kg plus FLAG
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
17
Head and neck cancer: Intratumoral delivery
Ovarian cancer: Intraperitoneal delivery
LOCAL DELIVERY FOR EARLY PROOF OF MECHANISM (BIOPSIES, DIAGNOSTICS)
KIADIS PHARMA | www.kiadis.com
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
18
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
KIADIS PHARMA | www.kiadis.com
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 PHARMA | www.kiadis.com 20
KIADIS PLATFORM BENEFITS
Potent, safe and persistent
PM21 (mbIL-21 and
41bbL particles)
• Hyperfunctional phenotype with high cytotoxicity and antitumor IFNγ and TNF release (through stimulation, without genetic engineering)
• In vivo persistence (no senescence, self stimulation)
Off-the-shelfUniversal adult
donor
• Fully licensed and mature NK cells• Profile optimized for all patients (e.g., HLA-KIR
mismatch)
Large scale industrial manufacturing
PM21 (mbIL-21and
41bbL particles)
• Prolonge 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)
KIADIS PHARMA | www.kiadis.com 22
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
KIADIS PHARMA | www.kiadis.com 23
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
KIADIS PHARMA | www.kiadis.com 24
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
KIADIS PHARMA | www.kiadis.com 25
Denman et al., PLoSONE, 7(1), 2012
Strong cytotoxicity (equal to mbIL-15)
Strong anti-tumor cytokine secretion and self stimulation(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-6
Su
pe
rna
tan
t [p
g/m
l]
K-NK cells: reduced sensitivity to TGFb inhibition through activation (no genetic engineering)*
KIADIS PHARMA | www.kiadis.com 26
Expansion conditioning
Pe
rce
nt S
pe
cific
Ly
sis
Std
Exp
ansi
on
Mod E
xpan
sion
0
20
40
60
80
No TGFb
+ TGFb
Cytotoxicity assay
p = p = 0.0006 0.0219
p = 0.0029
p = 0.0080
MG63
Overnight
TGFβ: - + - +
Culture: Control TGFβi
Overnight
TGFβ: - + - +
Culture: Control TGFβi
Strong cytotoxicityStrong anti-tumor cytokine secretion
Foltz et al., Cancers, 10, 2018
*Patent pending
K-NK cells with mbIL21: cytotoxicity against range of solid tumor and blood cancer cell lines
KIADIS PHARMA | www.kiadis.com 27
RS4
11
MOLT
-4
K56
2
Rh3
0
SJ-
GBM
2
NB-e
bcl
Rh4
1
TC-7
1
COG-L
L-31
7
CHLA
-136
CHLA
-10
CHLA
-9
Ram
os RD
RH-1
8
CHLA
-258
NB-1
643
Kas
umi-1
CHLA
-266
CCRF-C
EM
Kar
pas-
299
CHLA
-90
Nalm
-6
BT-
12
-20
-10
0
10
20
30
40
50
60
70
80
90
100
Cell Lines
% S
pecif
ic lysis
Donor 1Donor 2Donor 3Donor 4
Oyer et al., Oncoimmunology, 2018, Ray et al., Ped Blood Cancer, 2019
K-NK Universal Donor: proprietary* algorithm to select optimal donors for all patients
KIADIS PHARMA | www.kiadis.com 28
Optimized activating receptors
Optimized HLA-KIR mismatching
Favourable NKG2A/NKG2C ratios
*Patent pending
Donors that are optimal for all patients, no need for patient-donor matching
(similar principle as in blood transfusion: O negative blood type suitable for all blood transfusion recipients)
Optimal NK-cells have:
High number of activating receptors leads to better outcomes
KIADIS PHARMA | www.kiadis.com 29
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 improves relapse outcomes
KIADIS PHARMA | www.kiadis.com 30
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 Transplants with HLA-KIR mismatch: lower relapse
NK-cell platforms - overview
KIADIS PHARMA | www.kiadis.com 31
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 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
32
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 PHARMA | www.kiadis.com
Leadership team
KIADIS PHARMA | www.kiadis.com 33
ARTHUR LAHRChief Executive Officer
SCOTT A. HOLMESChief Financial Officer
DIRK de NAEYERChief Operations Officer
ANDREW SANDLER, MDChief Medical Officer
ROBERT FRIESENChief Scientific Officer
MARK WEGTER, ChairmanPartner LSP
BERNDT MODIGFormer CFO Prosensa
OTTO SCHWARZFormer COO, Actelion
ROBERT SOIFFER, MDProf Harvard, Director HSCT Dana Farber, Chair CIBMTR, board member NMDP
MARTIJN KLEIJWEGTFounder of LSP
SUBHANU SAXENAFormer head of global product strategy and commercialisation, ExCom member, Novartis
SELECT MANAGEMENT TEAM MEMBERS SUPERVISORY BOARD
AMY SULLIVANSr. VP, Corporate Affairs
Kiadis news flow
34
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
Start clinical signal study solid/blood tumor trial
Preclinical data solid/blood tumors
Pharma/biotech BD partnership
Interim clinical data solid/blood tumor trial(s)
Start multiple clinical studies solid/blood tumor
KIADIS PHARMA | www.kiadis.com
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.