EURONEXT: KDS Leveraging the natural strengths of humanity

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


Almalte, 2011. Blood 118:1323

Association of high affinity CD16 with survival in solid tumors

6

High affinity CD16Low affinityCD16

Bibeau 2019; Musolino 2008


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


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


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


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


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


Genetic engineering of NK cells have been limited by poor efficacy and NK cell apoptosis

Efficient genetic engineering of K-NK cells


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


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


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


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


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


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)


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



FC21-NK: Persistence over 8 weeks with repeat infusions in pediatric brain tumor patients


• 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.


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.

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EURONEXT: KDS Leveraging the natural strengths of humanity