euronext: kds leveraging the natural strengths of humanity
TRANSCRIPT
EURONEXT: KDS
K I A D I S P H A R M A | T E C H N I C A L P R E S E N TAT I O N | J A N U A R Y 2 0 2 1
Leveraging the natural strengths of humanity and our collective immune systems to source the best cells for life
K-NK-cell therapy to treat cancer and infectious disease
K-NK platform
Universal Donor algorithm
Benefit of HLA-KIR mis-match donor NK-cells in HSCT
3
Ruggeri et al, Science 2002 295: 2007
Lower relapse
Lower GVHD and rejection
Higher overall survival
Lower relapse
Giebel et al; Blood 2003
KIADIS PHARMA | www.kiadis.com
Association of KIR-B and number of activating KIRs with relapse-free survival in HSCT
KIADIS PHARMA | www.kiadis.com 4
Cooley, Blood 2010, 116:2411Oevermann, Blood 2014, 124:2744
Association of number of activating KIR receptors and risk of ALL
KIADIS PHARMA | www.kiadis.com 5
Almalte, 2011. Blood 118:1323
Association of high affinity CD16 with survival in solid tumors
6
High affinity CD16Low affinityCD16
Bibeau 2019; Musolino 2008
KIADIS PHARMA | www.kiadis.com
Progression Free Survival Patients with NK cells with high affinity CD16 (10-15% of population):
High affinity CD16
Low affinity CD16
Use of different donors allows reduction of risk of rejection
KIADIS PHARMA | www.kiadis.com 7
Relevant literature:
• Platelet transfusions: Modest risk of alloimmunization from fully mismatched platelets (Bonstein, Blood 2015, 126:3484), median onset 26 days.
• Solid organ transplants: Modest increase in rejection of fully mismatched solid organs (Opelz et al)
• Granulocyte transfusions: 70 percent of patients would become alloimmunized to two donors after receiving 11 transfusions (Ford, Transfusion 1982, 22:498).
Opelz, Transplantation 2007, 84:137
K-NK platform
Manufacturing
K-NK activation and expansion: FC21 feeder cell and PM21 membrane particles
KIADIS PHARMA | www.kiadis.com
Approach Description Product
FC21 (founding technology): Feeder cell expressing mbIL21
K562 tumor cell expressing mbIL21, 41bbL and cancer cell co-stimulatory ligands
• Bridging data on NK cell phenotype from FC21-NK to PM21-NK with clinical material from past/future trials
• FDA approval to start Phase 2 with PM21-NK, after Phase 1 with FC21-NK
PM21 (patented): Membrane particles presenting mbIL21
Membrane fractions of FC21 that preserve native stimulation (generated by ‘breaking up’ FC21 through gas cavitation)
9
K-NK: 6 weeks proliferation without loss of functionality
KIADIS PHARMA | www.kiadis.com
Exponential proliferation with mbIL21 for 6 weeks
Cytotoxicity stable with mbIL21
Prolonged proliferation with mbIL21 versus mbIL15
10
Source: ASGCT 2020 Virtual Annual Meeting, Oyer, et. al., abstract #427
K-NK: prolonged expansion and proliferation due to telomere lengthening (versus mbIL15 expanded NK cells)
Denman et al., PLoSONE, 7(1), 2012
Telomere stability(% change in telomere length)
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)
Telomerase expression
11KIADIS PHARMA | www.kiadis.com
K-NK cryopreservation: with stable post-thaw cytotoxicity and viability
12KIADIS PHARMA | www.kiadis.com
Viability and cytotoxicity of K-NK Drug Substance and Drug Product (IND enabling and full-scale runs)
Ovarian cancer animal model (research)
0100
20
40
60
80
100
20 30 40 50
Time from treatment (days)
Surv
ival (%
)
Untreated
K-NK (fresh)
K-NK (frozen)Viability Cytotoxicity
(2:1 E:T)
0
20
40
60
80
100
Robust Process Performance& Product Characteristics
Perc
en
t
Fresh
Post-Thaw
KIADIS PHARMA | www.kiadis.com | CONFIDENTIAL 13
Advantages of the PM21 (feeder-cell free) approach
Quality controlled including quantification and standardization of protein- and IL21 content
Terminally sterilized
Removal of feeder cells and reduction of feeder cell related impurities
Large scale manufacturing with long shelf life
Improved control over NK cell culture
conditions
Improved product safety profile
Simplified and more robust supply chain
K-NK improved safety profile: no contamination with residual tumor cells/DNA in final product, due to PM21
KIADIS PHARMA | www.kiadis.com | CONFIDENTIAL 14
Contamination in final product
Reduction of contamination in PM21 production Reduction of contamination in KNK production
Perc Relevant process steps Perc Relevant process steps
Residual tumor cells
100%
Mechanical rupture of cells, purification, centrifugation,
irradiation (~15.000 Gy), cryopreservation
Residual tumor DNA and Proteins
>99%Centrifugation, gradient
separation >99.9% Medium exchanges; Wash steps
Feeder cell in production process would lead to up to 1% tumor cells and high tumor DNA contamination in final product, leading to higher tumorgenicity and oncogenicity risk: • Feeder cells irradiated at only ~50 Gy and only (partially) lysed by NK cells during production• Cannot wash out tumor cells (NK cell and feeder cell similar size)
GMP material MDACC and Brazil trials: Cryopreserved FC21-NK cells expanded with FC21 clone9.mbIL21GMP material OSU trial: Cryopreserved FC21-NK cells expanded with FC21 clone CSTX002GMP material NK Realm trial: Cryopreserved PM21-NK cells expanded with PM21 particles from CSTX002NK cells in peripheral blood
K-NK: same product across clinical trials (after cryo), different from normal blood NK cells
KIADIS PHARMA | www.kiadis.com 15Source: Trikha et.al., EHA abstract EP1487
Principle component analysis
FC21
(Clo
ne9)
FC21
(CSTX
)
PM
21 (G
MP)
0
20
40
60
80
% lysis
Cytotoxicity Receptor profile
KIADIS PHARMA | www.kiadis.com | CONFIDENTIAL 16Source: Trikha et.al., EHA abstract EP1487
K-NK: same product across clinical trials (after cryo), different from normal blood NK cells
K-NK platform
Engineering
KIADIS PHARMA | www.kiadis.com | CONFIDENTIAL 18
Genetic engineering of NK cells have been limited by poor efficacy and NK cell apoptosis
Efficient genetic engineering of K-NK cells
KIADIS PHARMA | www.kiadis.com | CONFIDENTIAL 19
Proprietary engineering K-NK Knock out by Cas9/RNP gene targeting
20+ receptors- NKp46- NKG2D- KIRs
CD16
K-NK Knock out cell
Proof of concept for proprietary knock out: CD38 KO eliminates Daratumumab mediated K-NK cell fratricide
KIADIS PHARMA | www.kiadis.com 201/15/2021
Wild type NK cells: fratricide
Daratumumab
CD38
Clin Cancer Res. 2018 24(16) 4006-4017
CONFIDENTIAL
Courtesy of D. Lee, G. Ghiaur, et al
No fratricide
Knock out CD38
K-NK CD38 knock out cells: no fratricide
DONOR 1
DONOR 2
DONOR 3
DONOR 4
DONOR 6
DONOR 7
0
20
40
60
80
100
PE
RC
EN
TA
GE
OF
CD
38-K
O E
FF
ICIA
NC
Y
K-NK Knock out: high efficiency and no impact on expansion
KIADIS PHARMA | www.kiadis.com 211/15/2021
High CD38KO efficiency
day 0 day 2 day 4 day 6
0
1×107
2×107
3×107
4×107
Effect of CD38KO on expansion
Time
To
tal N
K n
um
ber
WT
CD38 KO
No impact on NK expansion capacity
CONFIDENTIAL
Courtesy of D. Lee, G. Ghiaur, et al
Proof of concept for Knock out K-NK: Improved efficacy through combination of K-NK CD38KO with Daratumumab
KIADIS PHARMA | www.kiadis.com 221/15/2021
High CD38 expression
Killing through synergy between NK-cells and MAb
Intermediate/Low CD38 expression
Killing through additional synergy between CD38KO NK-
cells and MAb
No CD38 expression
Killing by NK-cells only (Mab independent)
CONFIDENTIALCourtesy of D. Lee, G. Ghiaur, et al
KIADIS PHARMA | www.kiadis.com | CONFIDENTIAL 23
Engineering CAR-K-NK by combining Cas9/RNP gene targeting with AAV6 gene delivery
K-NK Knock in cellCAR-K-NK
CD16CAR
AAV 6
Proof of concept for CAR-K-NK
KIADIS PHARMA | www.kiadis.com | CONFIDENTIAL 24
Kasumi: sensitive to K-NK
Wild
type
NK c
ell
AAV
S1KO
NK c
ells
CD33
CAR-G
en2
NK c
ells
CD33
CAR-G
en4v
2 NK c
ells
0
20
40
60
80
100
Avera
ge s
pecif
ic lysis
(%
)
*
Wild
type
NK c
ell
CD33
CAR-G
en2
NK c
ells
CD33
CAR-G
en4v
2 NK c
ells
0
20
40
60
80
Avera
ge s
pecif
ic lysis
(%
)
********
AML10: insensitive to K-NK
Wild
type
NK c
ell
AAV
S1KO
NK c
ells
CD33
CAR-G
en2
NK c
ells
CD33
CAR-G
en4v
2 NK c
ells
0
20
40
60
80
100
Avera
ge s
pecif
ic lysis
(%
)
* P<0,0001P=0,01
K-NKCAR-K-NK Incremental breadth and potency:
improve efficacy, reduce escape and address heterogenous disease
AAV
S1KO
CD33
CAR-G
en2
CD33
CAR-G
en4v
2
0
100
200
500
1000
1500
% c
han
ge in
cyto
toxic
ity
Kasumi
HL60
AML10
AAV
S1KO
CD33
CAR-G
en2
CD33
CAR-G
en4v
2
0
100
200
500
1000
1500
% c
han
ge in
cyto
toxic
ity
Kasumi
HL60
AML10
K-NK platform
Persistence and proliferation in patient
K-NK: In vivo persistence and proliferation in patients of unique phenotype
KIADIS PHARMA | www.kiadis.com | CONFIDENTIAL 26
Source: Schafer et.al., EHA abstract S284 and EP1487
Program Field Donor
K-NK002 HaploHSCT
Allogeneic/ haplo
K-NK003 AML R/R Allogeneic
Academic study
Neuro-blastoma
Autologous
• At least 5-week persistence
• 30% chimerism
• Proliferation in patient
• Phenotype preserved in patient
K-NK002: immune reconstitution and phenotypic identification in patients (day 14)
KIADIS PHARMA | www.kiadis.com 27Source: Schafer et.al., EHA abstract S284 and EP1487; Ciurea SO, in preparation
35-parameter CyTOF, 8-parameter ViSNE clustering
Healthy Donor K-NK002 Product
Patient
T cells
K-NK002
“Std” NK cells
K-NK002
“Std” NK cells
K-NK002: immune reconstitution and phenotypic identification in patients (day 14)
Patient #302(Day 14)
Patient #74(Day 14)
Healthy donor
K-NK product
CD3 CD56 NKp46 NKG2D CD57 Perforin Ki67
KIADIS PHARMA | www.kiadis.com | CONFIDENTIAL 28Source: Trikha et.al., EHA abstract S284
K-NK002: accumulation and proliferation in patients (multiple doses)
KIADIS PHARMA | www.kiadis.com
Ciurea et al, ASH 2019; Courtesy Dean Lee
Patient 2223690
Patient 2280059
After 2nd dose (>21 days) After 3rd doseAfter 2nd dose (>14 days)
CyTOF: NK-cells mapped on multiple attributes; color indicates quantity of cells;
Profile of healthy blood NK cells:
Profile of K-NK cell drug product:
K-NK cell proliferation
K-NK cell addition and proliferation
K-NK cell proliferation
K-NK cell addition and proliferation
29
K-NK002: proliferation in the patient, more than T-cells
K-NK cells
Std NK cells
T cells
Std
NK
Super
bright N
K T
0
20
40
60
80
100
% K
i67+
of
su
bp
op
ula
tio
n
Std
NK
K-
NK
T-ce
lls
Ki67 expression (proliferation marker) in representative patients (day 14)
Ki67 expression in all patients (all timepoints)
Source: Schafer et.al., EHA abstract S284; Ciurea SO, in preparation
• Flow cytometry of HLA chimerism between patient and donor
• 30% NK cell patient/donor chimerism achieved
• Donor NK-cells detected up to day 49 (5 weeks from last infusion)
• At lowest dose (106
cells/kg)
K-NK003: In vivo persistance for 5 weeks
Patient A Patient B
HLA-A2 HLA-A2 HLA-Bw6
Source: Schafer et.al., EHA abstract S284; Ciurea SO, in preparation
HLA profile of Donor K-NK cells
HLA profile of Donor K-NK cells
HLA profile of Donor K-NK cells
FC21-NK: Persistence over 8 weeks with repeat infusions in pediatric brain tumor patients
KIADIS PHARMA | www.kiadis.com 32
• Phase 1 in 9 children with recurrent medulloblastoma and ependymoma
• Dosing 3 weekly up to 3 cycles; Total 110 intraventricular infusions
• NK cell concentration increased 11-fold in cerebrospinal fluid
• No dose limiting toxicity
• Autologous NK cells expanded with FC21 in academic study
0 4 8
0.1
1
10
100
1000
10000
Week
Cells/u
L
NK cells
Khatua S, Neuro-Onc 2020, in press
Risks associated with our business
33
The following are a selection the key risks that relate to our industry and business, operations and financial condition, and to our shares. For further information on the risks that we are subject to, reference is made to the risk factors included in our financial statements and any prospectus that we may publish from time to time.
• We are dependent on external funding in the foreseeable future and require substantial additional funding to continue our operations, including during the next twelve months. If we are unable to raise funding when needed or on acceptable terms, we could be forced to delay, reduce or terminate our development programs and may be unable to continue as a going concern and ultimately go into insolvency.
• We have a history of operating losses and will continue to incur operating losses for the foreseeable future. We may never achieve profitability, while our net losses are expected to fluctuate significantly.• We are early in our development efforts and all of our programs are in early stage clinical development or preclinical development. If we are unable to advance our programs through clinical development,
obtain regulatory approval and commercialize one or more of our product candidates, we may never generate any product revenue and our business will be materially adversely affected.• Our NK-cell platform and the technologies we are using are new and unproven. The use of NK-cells expressed with PM21 particles and the use of universal donors for NK-cells is a novel and unproven
therapeutic approach without any clinical studies in humans with NK-cells produced with our NK-platform having been performed yet, and our development of our NK-platform and our NK-programs may never lead to a marketable product.
• In relation to our lead program K-NK002 and K-NK003, investigator-initiated proof-of-concept studies have been performed, which may affect the reliability of the results and data generated in these studies and the extent that these are of use for the further development of these programs.
• We may experience setbacks in our clinical trials, including delays in commencing, conducting or completing, inability to commence, conduct or complete, or inconclusive or negative results, all of which could have a material adverse effect on our business, financial condition, results of operations and prospects.
• Due to our limited resources and access to capital, we must prioritize development of certain programs and our decision to pursue these programs may prove to be unsuccessful as they may never receive regulatory approval or achieve profitability.
• We currently rely on a single contract manufacturing organization to provide supplies of our product candidates for our planned clinical trials. We expect to increase manufacturing capacity by using existing or other CMOs and potentially in the future developing our own manufacturing facilities for clinical trials and commercial production of our products. We have no experience operating a manufacturing facility, and we may not be successful in developing our own manufacturing facilities or capacity in the future if we chose this route. If we cannot manufacture our product candidates in sufficient amounts, with CMOs or ourselves, at acceptable costs and on a timely basis, we may be unable to supply sufficient products for clinical trials or to support commercialization.
• In order to have sufficient NK-cells for our planned clinical trials we need to improve and scale up our NK-cell manufacturing process. This could require the process or parts thereof to be changed, which may require revalidation, additional comparability or bridging clinical trials and regulatory vetting and we may experience setbacks in our trials if we do not succeed in improving and upscaling this process or experience delays.
• We rely on third parties who license intellectual property rights to us, including intellectual property relating to our NK-platform. If any such license is terminated, we may be unable to commercialize and market our products candidates.
• The price of our shares may be volatile and fluctuate significantly.• Ownership of our shares is highly concentrated and the interests of our significant shareholders may conflict with the interests of our other shareholders. • Future sales and issuances, or the possibility of future sales or issuances, of a substantial number of shares could significantly lower the price of our shares and dilute the interests of shareholders.• There may be limited liquidity of our shares, which may affect the price of the shares and make it difficult for investors to sell shares at or above the price paid for them or at all.• We may implement anti-takeover protection that may prevent a change of control, and Dutch corporate law contains provisions that may delay or discourage a takeover attempt.
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.