Autolus Therapeutics : AUTO1 ASH Presentation

Disclosures

• Novartis, Gilead, Celgene speaker fees

ALLCAR19: UPDATED DATA USING AUTO1, A NOVEL FAST-OFF RATE

CD19 CAR IN ADULT RELAPSED/REFRACTORY B-ACUTE

LYMPHOBLASTIC LEUKAEMIA

Claire Roddie, Maeve A O'Reilly, Maria A V Marzolini, Leigh Wood, Juliana Dias Alves Pinto, Mahnaz Abbasian, Ketki Vispute, Mark W Lowdell, Graham Wheeler, Joanna Olejnik, Bilyana Popova, Kim Champion, Alexia Gali, Yashma Pathak, Victoria Spanswick, Helen Lowe, John A Hartley, Farzin Farzaneh, David Linch, Martin Pule and Karl Peggs

2

Adult B-Acute Lymphoblastic Leukemia:

Current standard of care

• Adult B-ALL prognosis is poor; long-term remission rates limited to 30-40%
• • 50% of all adult patients will relapse, with 5-year OS 7% (Fielding et al., 2007)
• Currently the only curative option for r/r ALL is allo-SCT in CR2, but <50% achieve CR2
• Blinatumomab and inotuzumab ozogamicin act as a bridge to allo-SCT (Topp et al. 2015; Kantarjian et al., 2019)
• CD19 CAR T can deliver excellent response rates but with considerable toxicity, particularly in elderly patients
• • Currently available CARs: high affinity CD19 binders
  • AUTO1: Lower affinity CD19 binder with fast off-rate*
  • • Physiological T-cell activation
    • Reduced toxicity
    • Improved engraftment
    • Potential long-term persistence, to deliver sustained responses

*Ghorashian S, Pule MA, Amrolia P et al. Nature Medicine 2019.

ALLCAR19 Study Design:

B-ALL arm

AUTO1 Manufacturing

AUTO1 Infusion Leucapheresis/Enrolment

Day 0	Day 9
*	**
Bridging Therapy as

Necessary

Day-6

Registration	Pre-Conditioning
	Flu 30mg/m2
	Cy 60 mg/kg

Day 0

BM blasts ≤20%

Infuse 100 x 106 CD19 CAR T-cells

Day 0

BM blasts >20%

Infuse 10 x 106 CD19 CAR T-cells

1st Disease

Assessment

Day 28

M24 EoS

Safety & Efficacy

Follow Up

Day 9

Infuse 310 x 106 CD19 CAR T-cells

Day 9

Infuse 400 x 106 CD19 CAR T-cells

No G3-5 CRS/ICANS

ALLCAR19 (NCT02935257)

ALLCAR19 Study:

Endpoints and Eligibility

Primary Endpoints

• Grade 3-5 toxicity causally related to the ATIMP
• Feasibility of adequate leucapheresis & generation of AUTO1 CAR T-cells

Secondary Endpoints

• Depth of response at 1 and 3 months post ATIMP
• Persistence of CD19CAR T-cells in peripheral blood
• Incidence and duration of hypogammaglobulinaemia & B-cell aplasia
• Relapse rate, disease-free, overall survival, 1 & 2 years

Inclusion

• Age 16 to 65 years
• High risk or relapsed histologically confirmed CD19+ B- ALL following standard therapy requiring salvage in whom alternative therapies are deemed inappropriate by their treating physician

Exclusion

• CD19 negative disease
• Overt CNS involvement/isolated extramedullary disease
• Active hepatitis B, C or HIV infection
• Stem Cell Transplant patients only: no active GVHD
• Significant neurotoxicity following blinatumomab

No exclusion for prior blinatumomab or inotuzumab ozogamicin

ALLCAR19 Manufacturing:

Product Characteristics & Feasibility

Registered

n = 26

Enrolled/Leucapheresed

n = 25

Manufactured

n = 24

4 died of PD or infection in bridging

Treated

n = 20

• 100% of successful harvests result in a QP released product
• Semi-automatedclosed manufacturing process was used in 18/24 products
• Advantages of closed process includes:
• • rapid, standardised manufacture
  • trend towards lower exhaustion markers
  • enrichment for Tcm and Tnaive CAR+ cells (47%)
• Mean transduction efficiency 66.5%
• • range 50 ‒ 83%

Temra	Tnaïve
17%	17%

Tem	Tcm
30%
36%

Patient Characteristics:

Treated (n=20)

Baseline Characteristics	N=20 (%)
Median age, years (range)	43 (18-62)
Gender	13M/7F
Chromosomal/Molecular status
•	Ph+ (bcr-abl)	6	(30%)
•	MLL	1	(5%)
•	Other	8	(40%)
•	Normal	4 (20%)
•	Failed	1	(5%)
Prior lines of treatment
•	Median (range)	3	(2-6)
•	Prior Inotuzumab	10 (50%)
•	Prior Blinatumomab	5 (25%)
•	Prior allo-HSCT	13 (65%)
	- sibling/haplo/VUD	4p/1p/8p

Leukemia Burden Prior to	N=20 (%)
Lymphodepletion
Morphological disease
•	≤ 5% blasts	7 (35%)
•	5 - 49% blasts	4 (20%)
•	≥ 50% blasts	9 (45%)
CNS status at registration
•	CNS 1	0	(0%)
• CNS II - III	0	(0%)
Other extranodal sites	3	(16%)

20 patients have been infused (data cut off 12-Nov-2020)

AUTO1 Pharmacokinetics:

Expansion and Persistence by qPCR

M12

* Mueller, KT et. al. Blood 130(21) 2017

ALL-16 developed a HAMA reaction to reject CAR

Safety Profile

CRS (Lee Criteria)	Neurotoxicity (ICANS#)	≥ Grade 3 Cytopenia	Day -6	At Day 28
• CRS (any) in 10/20	• ICANS (any) in 4/20	• ≥ Grade 3 Neutropenia	7/20	8/17
•	Grade 2 in 7/20	•	Grade 2 in 1/20
•	≥ Grade 3 CRS in 0/20	•	Grade 3 in 3/20

• CRS
• • All patients who developed Grade 2 CRS had high burden B-ALL
  • Tocilizumab was used in 7/20 patients (35%)
• Neurotoxicity (ICANS)
• • ≥ Grade 2 ICANS was reported in 4/20 patients: all had ≥ 50% blasts; all cases were preceded by CRS
  • 3/4 cases resolved to G1 in <24h with steroids, 1/4 cases resolved to G1 in 72h with steroids
• ≥ Grade 3 neutropenia:
• • Pre-datedtreatment in 7/20 patients
  • At Day 28, 8/17 evaluable patients had ≥ Grade 3 neutropenia with most resolving by Month 2/3
• 7/20 patients died on study:
• • 2/20 died from progressive B-ALL
  • 1/20 died post-progression from allo-transplant-related complications (VOD/sepsis)
  • 4/20 from infection: 2/4 before D28 (sepsis; invasive fungal); 1/4 at M6 in CR (MDR-pseudomonas in blood); 1/4 at M3 of

COVID-19

# Immune Effector Cell Associated Neurotoxicity Syndrome

CRS & NT will be graded using the ASTCT/ASBMT Consensus Grading (Lee et al. 2019)

Efficacy & Duration

	ALL-29
	ALL-24							Median follow-up 16.9 months (range 0.6 - 30.5 m)
	ALL-22
	ALL-20
Process	ALL-19
ALL-16
	ALL-18
Closed	ALL-17
ALL-15
	ALL-14
	ALL-13
	ALL-12
	ALL--11
	ALL-09
Process	ALL-07
ALL-06
	ALL-05
Open	ALL-03
ALL-01
	ALL-02
	0	3	6	9	12	15	18	21	24	27	30	33
	0	3	6	9	12	15	18	21	24	27	30	33
	Patient ID				Duration (months)
	Complete Remission		MRD negative CR (PCR/Flow)			CD19 -ve Relapse		Allogenic BMT
	Not Evaluable		Ongoing Disease				CD19 +ve Relapse		Death

MRD < 10-4 by PCR or < 5 x 10-4 based on limits of detection of assay

Data cutoff 12-Nov-2020, Evaluable = All patients with at least M1 follow-up or death prior to Month 1.

AUTO1: Efficacy Overview

		All patients	Closed process
		Est [95% CI]	Est [95% CI]
	N *	19	13
	ORR	84%	92%
	MRD Neg CR	84%	92%
DOR
	Median	Not reached	Not reached
	6 months	81% [52%, 94%]	83% [48%, 96%]
	12 months	68% [39%, 85%]	65% [31%, 85%]
EFS
	Median	Not reached	Not reached
	6 months	69% [43%, 85%]	85% [52%, 96%]
	12 months	52% [28%, 71%]	60% [29%, 81%]
OS
	Median	Not reached	Not reached
	6 months	68% [43%, 84%]	85% [51%, 96%]
	12 months	63% [37%, 80%]	76% [43%, 92%]

N = All patients with at least M1 follow-up or RIP prior to Month 1. Event = death or morphological relapse.

DOR, EFS and OS data are preliminary considering the small n

ALLCAR19 Study:

Extending Eligibility to Indolent NHL, HG-NHL and CLL

Cohort 1: Indolent B-NHL

(Dose = 200 million CD19 CAR T-cells)

• relapsed/refractory (r/r) Follicular Lymphoma
• r/r Mantle Cell Lymphoma
• r/r Marginal Zone Lymphoma
• ≥2 prior lines of therapy including Rituximab and anthracycline

Cohort 2: High grade B-NHL

(Dose = 200 million CD19 CAR T-cells + Pembrolizumab)

• r/r DLBCL, PMBCL, transformed FL
• not Richter's transformation
• ≥2 prior lines of therapy including Rituximab and anthracycline

Cohort 3: CLL/SLL

(Dose = 230 million CD19 CAR T-cells/ split dose)

• r/r CLL/SLL
• ≥2 prior lines of therapy including Ibrutinib/BTKi

ALLCAR19 Study:

Cohort 1:Indolent NHL- products and demographics

Registered

n = 8

Enrolled/Leucapheresed

n =8

2 currently in manufacture

Manufactured

n = 6

2 pending infusion

Treated

n = 4

Temra Tnaïve

21% 10%

Tcm

Tem26%

43%

• N=6 products QP released
• Semi-automated,closed manufacturing
• Tcm/Tnaive CAR+ (36%)
• Transduction efficiency (mean 76%)

Baseline Characteristics

N=8 (%)

Median age, years (range)	57 (39 - 68)
Gender	6M/2F
Histological diagnoses
•	MCL	2	(25%)
•	FL	6 (75%)
Disease Stage
•	Stage I/II	0	(0)
•	Stage III/IV	8	(100%)
Prior lines of treatment
•	Median (range)	3	(2-4)
•	Prior ASCT	4 (50%)
•	Prior allo-HSCT	1	(12.5%)
	- sibling/haplo/VUD	0p/0p/1p

4 patients have been infused (data cut off 12-Nov-2020)

ALLCAR19 Study:

Cohort 1:Indolent NHL- toxicity, responses, engraftment

Toxicity			Responses based on Lugano Criteria and IHC (CD20)
									PRE-LD	MONTH 1
		n = 4
						n = 4
	CRS
	any grade	3/4				CMR	4/4
	≥ Grade 2	0/4
				PR	0/4
	Neurotoxicity (ICANS)					SD	0/4
	any grade	0/4
				PD	0/4

≥ Grade 3 Neutropenia
Day -6	0/4
Day 28	0/4
Engraftment
	Serial LN Biopsies, CD20 by IHC, Dr Teresa Marafioti, UCL

AUTO1:

Conclusions

• Tolerable Safety Profile was observed:
• • Despite high disease burden and despite heavily pre-treated patient population on study
  • • No Grade 3 CRS was observed
    • Only 3/20 patients developed Grade 3 ICANS (rapid resolution with steroids)
• Robust expansion and prolonged CAR persistence was observed
• Efficacy in adult r/r ALL:
• • MRD negative CR was achieved in 16/19 (84%) patients at 1 month
  • EFS at 6 and 12 months is 69% and 52% respectively, in all treated patients
  • Responses are durable and ongoing CRs observed beyond 24 months, supporting the development of AUTO1 as a stand-alone therapy
• Promising early activity and safety has been observed in indolent NHL

Global Phase Ib/II AUTO1 study in r/r ALL has started

Acknowledgements

UCL Cancer Institute

Martin Pule

Karl Peggs

Teresa Marafioti

Paul Maciocia

Pati Wawzyniecka

Gordon Cheung

Leyla Mekkaoui

David Linch

Marina Mitsikakou

Ketki Vispute

Rajeev Gupta

CCGTT

Juliana Pinto

Amaia Cadinanos

Mahnaz Abbassian

Leticia Bosshard

Louisa Green

Mhairi Vaughn

Vitoria Meyer

Mark Lowdell

Rita Rego

Owen Bain

Fiona O'Brien

UCLH

Maeve O'Reilly

Maria Marzolini

Leigh Wood

Clemency Every-Clayton

Lorna Neill

Strachan MacKenzie

Chloe Marden

Diana Palomares Munoz

UCL CABI

Mark Lythgo

Tammy Kalber

Vector (RCTS)

Farzin Farzaneh

Sabine Downing

Lucas Chan

UCL ECMC GCLP Lab

John Hartley

Helen Lowe

Victoria Spanswick

Alexia Gali

Yashma Pathak

UCL Institute of Child Health

Waseem Qasim

Adrian Thrasher

Sameer Fahetullah

Lauren Nickolay

Barry Flutter

UCL CTC

Bilyana Popova

Graham Wheeler

Jo Olejnik

Laura Clifton Hadley

Kim Champion

GOSH

Sara Ghorashian

Persis Amrolia

Autolus

Shaun Cordoba

Shimobi Onouha

Vijay Reddy

Virginie Cerec

Nushmia Khokhar

Michael Zhang

A huge thank you to the patients and their families