A First-in-Human Study of YTB323, a Novel, Autologous CD19

Presented at the 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA, and VirtualPresented at the 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA, and Virtual

A First-in-Human Study of YTB323, a Novel, Autologous CD19-Directed CAR-T Cell Therapy Manufactured Using the Novel T-Charge™ Platform, for the Treatment of Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Oral Presentation 740Ian Flinn, MD

[email protected]

Ian Flinn,1 Ulrich Jäger,2 Nirav Shah,3 Didier Blaise,4 Javier Briones,5 Leyla Shune,6

Nicolas Boissel,7 Attilio Bondanza,8,* Darlene Lu,9 Xu Zhu,9 Boris Engels,9 Jennifer L.

Brogdon,9 Jennifer Mataraza,9 Jaclyn Davis,10 Anne Laure Marchal,8 Luisa Mariconti,8

Michele Moschetta,8 Laure Moutouh-de Parseval,8 Pere Barba,11 Michael Dickinson12

1Sarah Cannon Research Institute and Tennessee Oncology Center for Blood Cancers, Nashville, TN, USA; 2Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Vienna General

Hospital – Medical University of Vienna, Vienna, Austria; 3Medical College of Wisconsin, Milwaukee, WI, USA; 4Département d’Hématologie, Programme de Transplantation et de Thérapie Cellulaire, Centre de

Recherche en Cancérologie de Marseille, Aix-Marseille University, Institut Paoli Calmettes, Marseille, France; 5Hematology Department, Hospital Santa Creu i Sant Pau, Barcelona, Spain; 6University of Kansas

Medical Center, Kansas City, KS, USA; 7Hematology Adolescent and Young Adult Unit, Saint-Louis Hospital, Paris, France; 8Novartis Institutes for BioMedical Research, Basel, Switzerland; 9Novartis Institutes

for BioMedical Research, Cambridge, MA, USA; 10Novartis Institutes for BioMedical Research, East Hanover, NJ, USA; 11Hematology Department, Hospital Universitari Vall d'Hebrón, Universitat Autònoma de

Barcelona, Barcelona, Spain; 12Peter MacCallum Cancer Centre and Royal Melbourne Hospital and the University of Melbourne, Melbourne, Australia.

*Currently employed by AstraZeneca; work was completed while employed by Novartis Institutes for BioMedical Research.

mailto:[email protected]

Presented at the 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA, and VirtualPresented at the 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA, and Virtual

A First-in-Human Study of YTB323, a Novel, Autologous CD19-Directed CAR-T Cell Therapy Manufactured Using the Novel T-Charge™ Platform, for the Treatment of Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Ian Flinn,1 Ulrich Jäger,2 Nirav Shah,3 Didier Blaise,4 Javier Briones,5 Leyla Shune,6

Nicolas Boissel,7 Attilio Bondanza,8,* Darlene Lu,9 Xu Zhu,9 Boris Engels,9 Jennifer L.

Brogdon,9 Jennifer Mataraza,9 Jaclyn Davis,10 Anne Laure Marchal,8 Luisa Mariconti,8

Michele Moschetta,8 Laure Moutouh-de Parseval,8 Pere Barba,11 Michael Dickinson12

Oral Presentation 740

1Sarah Cannon Research Institute and Tennessee Oncology Center for Blood Cancers, Nashville, TN, USA; 2Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Vienna General

Hospital – Medical University of Vienna, Vienna, Austria; 3Medical College of Wisconsin, Milwaukee, WI, USA; 4Département d’Hématologie, Programme de Transplantation et de Thérapie Cellulaire, Centre de

Recherche en Cancérologie de Marseille, Aix-Marseille University, Institut Paoli Calmettes, Marseille, France; 5Hematology Department, Hospital Santa Creu i Sant Pau, Barcelona, Spain; 6University of Kansas

Medical Center, Kansas City, KS, USA; 7Hematology Adolescent and Young Adult Unit, Saint-Louis Hospital, Paris, France; 8Novartis Institutes for BioMedical Research, Basel, Switzerland; 9Novartis Institutes

for BioMedical Research, Cambridge, MA, USA; 10Novartis Institutes for BioMedical Research, East Hanover, NJ, USA; 11Hematology Department, Hospital Universitari Vall d'Hebrón, Universitat Autònoma de

Barcelona, Barcelona, Spain; 12Peter MacCallum Cancer Centre and Royal Melbourne Hospital and the University of Melbourne, Melbourne, Australia.

*Currently employed by AstraZeneca; work was completed while employed by Novartis Institutes for BioMedical Research.

Ian Flinn, MD

[email protected]

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Presented at the 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA, and Virtual

Disclosures

IF is a consultant for AbbVie, AstraZeneca, BeiGene, Century Therapeutics, Genentech, Gilead Sciences, Great Point Partners, Hutchison

MediPharma, Iksuda Therapeutics, Janssen, Juno Therapeutics, Kite Pharma, MorphoSys, Novartis, Nurix Therapeutics, Pharmacyclics, Roche,

Seagen, Servier Pharmaceuticals, Takeda, TG Therapeutics, Unum Therapeutics, Verastem, Vincerx Pharma, and Yingli Pharmaceuticals;

receives research funding from AbbVie, AstraZeneca, BeiGene, Genentech, Gilead Sciences, Janssen, Juno Therapeutics, Kite Pharma,

MorphoSys, Novartis, Pharmacyclics, Roche, Seagen, Takeda, TG Therapeutics, Unum Therapeutics, Verastem, Acerta Pharma, Agios, ArQule,

Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Curis, Forma Therapeutics, Forty Seven, IGM Biosciences, Incyte, Infinity

Pharmaceuticals, Karyopharm Therapeutics, Loxo, Merck, Pfizer, Portola Pharmaceuticals, Rhizen Pharmaceuticals, Teva, Trillium Therapeutics,

and Triphase Research & Development Corps; is a current employer of Sarah Cannon Research Institute; and holds stock in Johnson & Johnson.

UJ is a consultant for Novartis; receives honoraria from BMS/Celgene, Gilead, Janssen, Novartis and Roche; and reports membership on an

entity’s board of directors or advisory committees for BMS/Celgene, Gilead, Janssen, Novartis, and Roche. NS is a consultant for Kite, Miltenyi

Biotec, Lily, Epizyme, Legend, Incyte, and Umoja, and receives honoraria and research funding from Miltenyi Biotec and Lily. DB receives

honoraria from Jazz Pharmaceuticals. JB and LS have nothing to disclose. NB is a consultant for Novartis, Amgen, Servier, and Pfizer; receives

research funding from Novartis, Amgen, Bristol-Myers Squibb, and Jazz Pharmaceuticals; receives honoraria from Novartis, Amgen, Incyte,

Servier, Bristol-Myers Squibb, Jazz Pharmaceuticals, Celgene, Sanofi, and Pfizer. AB is currently employed by AstraZeneca plc, ended

employment in the past 24 months with Novartis, and is the author of a patent related to abstract. DL is currently employed by Novartis. XZ is

currently employed by NIBR and holds stock in Novartis. BE is currently employed by and holds stocks in Novartis. JLB is currently employed by

NIBR and holds stock in Novartis. JM and JD are currently employed by and hold stock options in Novartis. ALM, LM, MM, and LMP are

currently employed by Novartis. PB receives honoraria from Amgen, BMS, Gilead, Novartis, and Pfizer. MD is a consultant for, receives honoraria

and research funding from, and is a member of the speakers bureau for Novartis, MSD, and Roche; is a consultant for and receives honoraria

from Janssen and Bristol-Myers Squibb; receives research funding from Takeda and Celgene; receives honoraria from Amgen; is a consultant for,

receives honoraria from, and is a member of the speakers bureau for Gilead Sciences; and reports travel, accommodation, and expenses funding

from Roche.


Introduction

• Despite the efficacy of CAR-T cell therapies, many patients fail to respond or relapse after initial response

• The effectiveness of CAR-T cell therapy remains a challenge due to the complexities of traditional manufacturing processes and depletion of naive/Tscm cells, a cellular subset associated with improved antitumor efficacy1

• YTB323 is an investigational CAR-T cell therapy that is manufactured through an innovative process, called T-Charge™, which preserves the naive/Tscm cells in the final product

• YTB323 is currently being evaluated in patients with DLBCL, adult ALL, CLL/SLL (safety only)

– This presentation focuses on evaluation of the feasibility, safety, and preliminary antitumor efficacy of YTB323 in patients with r/r DLBCL

ALL, acute lymphoblastic leukemia; CAR, chimeric antigen receptor; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell leukemia; r/r, relapsed or refractory; SLL, small

lymphocytic lymphoma; Tscm, stem cell memory T cells.

1. Fraietta JA, et al. Nat Med. 2018;24(5):563-571.4


YTB323 Is Manufactured Using the T-ChargeTM Platform

• T-ChargeTM minimizes the ex vivo culture time and reduces the manufacturing process time

to <2 days

• Starting from a cryopreserved leukapheresis, T cells are transduced with a lentiviral vector

encoding for the same CAR used for tisagenlecleucel and formulated

• The T-ChargeTM platform preserves naive/Tscm cells in the final product, leading to

potentially higher potency and longer persistence

(Engels B, et al. ASH 2021 Poster 2848; Bu D, et al. ASH 2021 Poster 2770)

ASH, American Society of Hematology; CAR, chimeric antigen receptor; Teff, effector T cells; Tem, effector memory T cells; Tn, naive T cells; Tscm, stem cell memory T cells.5


Study Design: DLBCL Treatment Arm

Expansion partb

3L DLBCL (N=~20)

Enrollment 3L DLBCL (N≥15)

Screening, apheresis,and cryopreservation Optional

bridging chemotherapya

YTB323manufacturing using

T-ChargeTMLymphodepletion

Patient ReceivesYTB323

First efficacy assessment28 days

Key eligibility criteria Study treatment End points

• ≥18 years of age• Measurable disease at enrollment• ECOG PS 0-1• Relapsed/refractory disease• ≥2 lines of prior therapies, including

autologous HSCT

• Lymphodepleting chemotherapy options are–Fludarabine (30 mg/m2 IV daily for 3 days)

+ cyclophosphamide (500 mg/m2 IV daily for 3 days) –Bendamustine 90 mg/m2 IV daily for 2 days

• YTB323 dose levels (single IV dose): DL1, 2.5×106 CAR+ cells; DL2, 12.5×106 CAR+ cells; DL3, 40×106

CAR+ cells

Primary: Incidence of DLTsc and safety to determine a RD

Secondary: Cellular kinetics, ORR, DOR, OS

aOptional bridging therapies were investigator’s decision. bCurrently recruiting in the dose expansion part of the study. cWithin 28 days of receiving YTB323.

3L, third line; DL, dose level; DLBCL, diffuse large B-cell leukemia; DLT, dose-limiting toxicity; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status;

HSCT, hematopoietic stem cell transplant; IV, intravenous; ORR, overall response rate; OS, overall survival; RD, recommended dose. 6


Patient Demographics and Baseline Disease Status

• As of August 20, 2021, 20 patients with

r/r DLBCL received YTB323

– 4 patients at DL1, 16 at DL2a

– The median administered dose of CAR+

viable T cells was 2.5106 cells for DL1

and 12.5106 cells for DL2

– Median lines of prior therapies:

• 2.5 for DL1

• 2 for DL2

Therapy detailsAll Patients

(N=20)

DL1 (N=4) DL2 (N=16)

Median age (range), y 69 (60-74) 66 (41-78)

≥65 y, n (%) 2 (50) 9 (56)

ECOG PS, n (%)

0 4 (100) 11 (69)

1 0 5 (31)

Stage at study entry, n (%)

III 0 (0) 2 (13)

IV 2 (50) 10 (63)

Lines of prior therapies, n (%)

2 2 (50) 11 (69)

3 1 (25) 3 (19)

4 1 (25) 1 (6)

7 0 1 (6)

Elevated LDH,b n (%) 2 (50) 8 (50)

Prior autologous HSCT, n (%) 1 (25) 6 (38)

aThree patients at DL2 received less than the upper dose of CAR+ T cells, but within range. bVaries depending on the upper limit of normal for each site.

DL, dose level; DLBCL, diffuse large B-cell lymphoma; ECOG PS, Eastern Cooperative Oncology Group performance status; HSCT, hematopoietic stem cell transplant; LDH, lactate dehydrogenase;

r/r, relapsed or refractory.7


Best Overall Response and Complete Response Rate Post YTB323

Patients Evaluable for

Efficacy

(N=19)

DL1 (N=4) DL2 (N=15)

Median follow-up, mo 14.01 6.23

ORR (CR+PR), n (%) 3 (75) 12 (80)

CR 3 (75) 11 (73)

PR, n (%) 0 1 (7)

SD, n (%) 0 0

PD, n (%) 1 (25) 2 (13)

Unknown, n (%) 0 1 (7)

aPatients were in CR prior to receiving YTB323 due to either a late effect of prior therapies or bridging chemotherapy.

CI, confidence interval; CR, complete response; DL, dose level; ORR, overall response rate; PD, progressive disease; PR, partial response.8

Patients Evaluable for

Efficacy at Month 3

(N=19)

DL1 (N=4) DL2 (N=15)

CR at Month 3, n (%) 1 (25) 11 (73)

CR at last assessment before YTB323,a n (%) 1 (25) 2 (13)

PR, n (%) 0 0

SD, n (%) 0 0

PD, n (%) 3 (75) 2 (13)

Unknown 0 2 (13)


Patients Responded to YTB323 at DL1 and DL2

• All patients at DL1 and DL2 received a

CAR-T dose within the allowed range

– 2 patients with PD received less than

the targeted dose of 12.5106 CAR+ cells

at DL2

– In DL1 and DL2, 2/4 (50%) and 2/15

(13%) patients, respectively, progressed

after experiencing PR/CR

– In DL2, 11/15 patients experienced CR

at 3 months

Patients with DLBCL received YTB323

at DL1 and DL2

3 prior lines3 prior lines3 prior lines3 prior lines3 prior lines



2 prior lines2 prior lines2 prior lines2 prior lines


2 prior lines2 prior lines2 prior lines2 prior lines2 prior lines2 prior lines

3 prior lines3 prior lines3 prior lines3 prior lines3 prior lines3 prior lines3 prior lines

2 prior lines2 prior lines2 prior lines2 prior lines2 prior lines2 prior lines2 prior lines2 prior lines2 prior lines






2 prior lines2 prior lines2 prior lines

2 prior lines2 prior lines2 prior lines





–6 –3 –2 –1 0 1 3 6 9 12 15 20Months post YTB323 Infusion

Start of BT

End of BT

PDSDPR

CRUNK

Dose LevelDL1: 2.5×106

DL2: 12.5×106

Arrow denotes ongoing efficacy assessments. Gray bars represent screening assessments.

BT, bridging therapy; cCR, continuous complete response; CR, complete response; DL, dose level; DLBCL, diffuse large B-cell lymphoma; PD, progressive disease; PR, partial

response; SD, stable disease.9


At DL1 and DL2, YTB323 Had a Favorable Overall Safety Profile

Treated Patients

(N=20)

Adverse Events,a n (%) DL1 (N=4) DL2 (N=16)

Any AE (all grade) 4 (100) 16 (100)

Grade ≥3 4 (100) 12 (75)

Deathb 2 (50) 3 (19)

Related to YTB323 0 (0) 0 (0)

Adverse Events,a n (%)

Treated Patients

(N=20)

DL1 (N=4) DL2 (N=16)

CRS, any gradec 1 (25) 5 (31)

Neurological AEs, any grade 1 (25) 4 (25)

Infections, any grade 2 (50) 3 (19)

Infections, grade ≥3 1 (25) 1 (6)

MedDRA version 24.0 and CTCAE version 5.0 have been used for the reporting of AEs.aAll AEs were reported regardless of study drug relationship. bThree deaths were due to

disease progression (1 and DL1 and 2 and DL2), 1 was due to intestinal hemorrhage (at DL2),

and 1 was due to sepsis (1 at DL1). cGrading of CRS according to Lee criteria (Lee 2014).

AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; CRS, cytokine

release syndrome; DL, dose level; MedDRA, Medical Dictionary for Regulatory Activities.10

Hematology Laboratory

Abnormalities Post YTB323a

Treated Patients

(N=20)

DL1 (N=4) DL2 (N=16)

Cytopenia, any grade 4 (100) 16 (100)

Cytopenia, grade ≥3 4 (100) 16 (100)


CRS Was Generally Low Grade and Had a Later Onset Than Other CAR-T Therapies

• A total of 5 patients

experienced grade 1/2 CRS

• One patient experienced

grade 4 CRS at DL2, which

met DLT criteria

Treated Patients

(N=20)

DL1 (N=4) DL2 (N=16)

CRS,a n (%) 1 (25) 5 (31)

Grade 1/2 1 (25) 4 (25)

Grade 3/4 0 1 (6)

CRS management,b n (%)

Systemic anti-cytokine therapy, n (%) 0 4 (80)

Tocilizumab 0 4 (80)

Corticosteroids 0 2 (40)

Median time to onset, d (range) 9 (9-9) 11 (1-17)

Admitted to ICU, n (%) 0 2 (40)

Median time to resolution, d (95% CI) 5 (NE-NE) 2 (1-NE)

aGrading of CRS was according to Lee criteria (Lee 2014). bTherapy for CRS management was administered to DL2 patients only.

ASTCT, American Society for Transplantation and Cellular Therapy; CI, confidence interval; CRS, cytokine release syndrome; DL, dose level; DLT, dose-limiting toxicity;

ICU, intensive care unit; N/A, not applicable; NE, not estimable.11


Neurological Adverse Reactions

• The majority of the neurological ARs reported were grade 1 events, except at DL2:

– One event of grade 2 seizure that resulted in a grade 3 ICANS

– One event of grade 3 ICANS

Treated Patients

(N=20)

DL1 (N=4) DL2 (N=16)

Neurological ARs, n (%) 1 (25) 4 (25)

Median time to onset, d (range) 7 (7-7) 6.5 (2-16)

Patients with at least 1 event, n (%)

ICANS 0 1 (6)

Aphasia 1 (25) 0

Muscular weakness 0 1 (6)

Seizure 0 1 (6)

Confusional state 0 1 (6)

Median time to resolution, d (95% CI) 5 (NE-NE) 14 (1-NE)

MedDRA version 24.0 and CTCAE version 5.0 were used for the reporting of AEs.

AR, adverse reaction; CTCAE, Common Terminology Criteria for Adverse Events; CI, confidence interval; DL, dose level; ICANS, immune

effector cell-associated neurotoxicity syndrome; MedDRA, Medical Dictionary for Regulatory Activities; NE, not estimable.

12


Cellular Kinetics of YTB323

• At a 25-fold lower dose, YTB323 expansion (Cmax

and AUC0-28d) at DL2 is comparable to and at the

higher end of tisagenlecleucel expansion in

patients with DLBCL1

• Time to peak YTB323 expansion (Tmax) in patients

with DLBCL showed a delay compared to

tisagenlecleucel (16 days vs 9 days by flow in

JULIET), as predicted based on preclinical

models

• Long-term persistence data are still emerging

– CAR expression was detectable by flow for at least 9

months at DL2; 3/7 patients show persistence at 6 months

Data cutoff: August 20, 2021

Points represent means and bars

represent standard deviation at

each planned sampling time point.

100.0

Days post CART infusion

CD

3+

CA

R19+

% b

y f

low

0 30 60 90 120 150 180

10.0

1.0

0.1

CA

R19 q

PC

R (

co

pie

s/u

g D

NA

)

1e+05

Days post CART infusion0 30 60 90 120 150 180

1e+04

1e+03

1e+02

1e+01

Dose Group

Dose 2 (12.5e6)

Dose 2 partial (>2.5×106 and <12.5×106)

Dose 1 (2.5e6)

Tisagenlecleucel in JULIET

AUC, area under the curve; CAR, chimeric antigen receptor; Cmax, maximum concentration;

DL, dose level; DLBCL, diffuse large B-cell leukemia; Tmax, time to peak expansion.

1. Awasthi R., et al. Blood Adv. 2020;4(3):560-572.

13


The T-ChargeTM Process Preserves the Stemness and Memory Phenotype of the Leukapheresis

• Bulk RNAseq analysis demonstrated that YTB323, produced from the T-ChargeTM process,

retained a naive stem-like gene signatureS

tem

ness G

en

e S

et

Sco

re

p=0.0093

T C

ell

Mem

ory

Dif

fere

nti

ati

on

Gen

e S

et

Sco

re

p=0.98

Leukapheresis Cell Product Leukapheresis Cell Product

3.60

3.55

3.50

3.45

3.40

3.35

3.30

3.25

5.0

5.2

5.4

5.6

5.8

RNAseq, ribonucleic acid sequencing.14


Conclusions

• YTB323 had a favorable safety profile and demonstrated efficacy across DL1 and DL2

– Dose escalation is ongoing at DL3 (40106 CAR+ cells), RD remains to be identified

• YTB323 is effective with comparable in vivo expansion to tisagenlecleucel in DLBCL at a 25-fold lower

dose

• YTB323 merits continued exploration as a therapy for the treatment of adult patients with r/r DLBCL

Also at ASH 2021: Sperling A, et al. Phase I Study of PHE885, a Fully Human BCMA-Directed CAR-T

Cell Therapy for Relapsed/Refractory Multiple Myeloma Manufactured in <2 days Using the T-

ChargeTM Platform. Poster 3864.

ASH, American Society of Hematology; DL, dose level; DLBCL, diffuse large B-cell lymphoma; RD, recommended dose; r/r, relapsed or refractory.15


Acknowledgments

• The authors sincerely thank

– The patients and their families

– The principal investigators and support staff

• The study was sponsored by Novartis Pharmaceuticals Corporation

• All analyses in this presentation were conducted by Novartis

• Medical writing support was provided by Jacqueline R. Ward, PhD, of Healthcare

Consultancy Group, LLC, and was funded by Novartis Pharmaceuticals Corporation

Ian Flinn, MD

[email protected]


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A First-in-Human Study of YTB323, a Novel, Autologous CD19