AVROBIO : ASGCT 2020 Fabry & Cystinosis Data Update

ASGCT 2020

Fabry & Cystinosis Data Update

May 13, 2020

Disclaimer

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2

ASGCT 2020 data update - key takeaways

New data show consistent results across Fabry disease and cystinosis programs

Long-term Fabry patient data	Sustained long-term positive trends
	• Patient 1 in the Phase 2 trial continues to show stable leukocyte and plasma AGA enzyme activity,
	now out 22 months
	• Patient 3 in the Phase 2 trial shows increased leukocyte and plasma AGA enzyme activity,
	decreased plasma lyso-Gb3 level, and stable VCN at new time points
	• All three Phase 1 patients off ERT remain off ERT

First Fabry plato™ patient	plato continues to perform
	• One-month plasma lyso-Gb3 decrease of 43% vs. baseline
	• Three-month leukocyte and plasma enzyme activity levels 3x greater than mean of other three
	patients at same timepoint in Phase 2 trial
	• Rapid neutrophil and platelet recovery with minimal lymphocyte depletion post Bu90 conditioning
Cystinosis Patient 1 data	Positive trends at six months, including kidney function measures
	• eGFR and serum creatinine measures trending positively at 6 months

• Pill burden remains significantly lower than at baseline

3

Multiple programs in the clinic

10 patients dosed to date

Investigational
Gene Therapy	Proof-of-Concept	IND-Enabling	Phase 1/2	Commercial Rights

Fabry	Phase 2	AVROBIO
AVR-RD-01

Gaucher	Phase 1/2	AVROBIO
AVR-RD-02
Cystinosis	Phase 1/2	AVROBIO
AVR-RD-04
Pompe	Preclinical	AVROBIO
AVR-RD-03

IND: Investigational New Drug

4

Fabry Disease

AVR-RD-01

5

Goals for gene therapy in Fabry

disease

Sources: Wanner C et al, Med Genetics and Metab, 2018; Burlina A, JIEMS, 2016

CNS: Central Nervous System; TIA: Transient Ischemic Attack

UNMET NEEDS:

Kidney function

Unmet needs: proteinuria, polyuria, kidney failure

Cardiac function

Unmet needs: left ventricular hypertrophy, fibrosis, heart failure

Neuropathic pain

Unmet needs: pain and burning sensations in hands and feet, pain crises

CNS complications

Unmet needs: TIA/stroke, depression, impaired executive function, white matter hyperintensities

Everyday burden of illness and life expectancy

Unmet needs: fatigue, inability to sweat, joint pain, abdominal pain, diarrhea, vomiting, cloudy vision, hearing loss, tinnitus, rash, angiokeratomas, biweekly infusions, shortened lifespan

6

Two AVR-RD-01 Fabry clinical trials

9 patients dosed across Phases 1 and 2

PHASE 1

Investigator-Sponsored Trial*

Patients

n = 5 (fully enrolled)

On ERT > 6 months prior to enrollment

18-50year-old males

Key Objective

Safety and preliminary efficacy

PHASE 2

AVRO - FAB-201 Trial

Patients

n = 8-12 (4 patients dosed to-date)

Treatment-naive

16-50year-old males

Key Objectives

Safety and efficacy

* Sponsored by FACTs team (Fabry Disease Clinical Research and Therapeutics) in Canada

7

FAB-201 FABRY PHASE 2

New data point

Patient 1: Multiple data trends sustained up to 22 months

Leukocyte + Plasma AGA Enzyme Activity	Plasma Lyso-Gb3 and Total Gb3
				Leukocyte AGA			Lyso-Gb3
				Plasma AGA			Total Gb3
				Missing Plasma AGA Analysis

	Day 0
			Day 0
Infuse AVR-RD-01	Infuse AVR-RD-01
*Lab A: Mayo Clinic Laboratories; Lab B: Rupar Laboratory; Lab A Reference Range: >23.1 nmol/hr/mg; Lab B Reference Range: 24-56 nmol/hr/mg	*Reference Value: 2.4 nM; † Reference Value: 4961 nM; 6012 nM before August 2018 (until Day 28 for Patient 1)
† Reference Range: 5.1-9.2 nmol/hr/mL; AGA: α-galactosidase A	Lyso-Gb3: Globotriaosylsphingosine; Gb3: Globotriaosylceramide

KIDNEY FUNCTION

CARDIAC FUNCTION

Vector Copy Number (VCN)

remains within normal range at 12 mos.

remains within normal range at 12 mos.

Drug Product

140

140

VCN: 0.7

Baseline

120

120

Month 12

100

100

Baseline

80

80

Month 12

60

60

40

40

20

20

0

0

EF (%)

LV Mass

LV Mass Index

mGFR

eGFR

2

2

(Absolute) (g)

(Normalized) (g/m2)

mL/min/1.73 m

mL/min/1.73 m

Day 0

Normal Range

Average 116* mL/min/1.73 m2

Reference Range 64.3 ± 4.2%

138.9 ± 24.5 g

67.8 ± 10.7 g/m2

mGFR/eGFR

Male (20-39 years)

Mean Values ± SD

Male (20-39 years)

Infuse AVR-RD-01

*Source:https://www.kidney.org/atoz/content/gfr

Source: Alfakih K et al, J Magn Reson Imaging, 2003

VCN: Vector Copy Number; PBMCs: Peripheral Blood Mononuclear Cells

mGFR: Measured Glomerular Filtration Rate; eGFR: Estimated Glomerular Filtration Rate

EF: Ejection Fraction; LV: Left Ventricular

Note: Patient #1 had a skin biopsy score of 3 (severe accumulation) at baseline, a score of 2 (moderate accumulation) at 6 months and a score of 1 (mild accumulation) at 12 months

Note: Visualization of multiple biomarkers adjusted to utilize the same statistical scaling ratio across biomarkers (as compared to prior presentation)

8

FAB-201 FABRY PHASE 2 - Cardiac Variant

Patient 2: Multiple data trends sustained up to 1 year*

Leukocyte	+ Plasma AGA Enzyme Activity	Plasma Lyso-Gb3 and Total Gb3
			Leukocyte AGA			Lyso-Gb3
					Total Gb3
			Plasma AGA

*Data from Rupar Laboratory; Reference Range: 24-56 nmol/hr/mg; † Reference Range: 5.1-9.2 nmol/hr/mL; AGA: α-galactosidase A	*Reference Value: 2.4 nM; † Reference Value: 4961 nM; Note: Patient #2 has normal substrate, consistent with late-onset cardiac variant phenotype
Lyso-Gb3: Globotriaosylsphingosine; Gb3: Globotriaosylceramide

KIDNEY FUNCTION

CARDIAC FUNCTION

Vector Copy Number (VCN)

remains within normal range

remains within normal range

140

200

Drug Product

Baseline

VCN: 0.5

120

Month 12

150

100

Baseline

80

100

Month 12

60

40

50

20

0

0

mGFR

eGFR

EF (%)

LV Mass

LV Mass Index

mL/min/1.73 m2

mL/min/1.73 m2

(Absolute) (g)

(Normalized) (g/m2)

Normal Range

Average 99 mL/min/1.73 m2

Reference Range

55-65%

58-91 g/m2

Day 0

mGFR/eGFR

Male (40-49 years)

Mean Values

Male 40-49 years

Infuse AVR-RD-01

Source:https://www.kidney.org/atoz/content/gfr

Source: Alfakih K et al, J Magn Reson Imaging, 2003

VCN: Vector Copy Number; PBMCs: Peripheral Blood Mononuclear Cells

mGFR: Measured Glomerular Filtration Rate; eGFR: Estimated Glomerular Filtration Rate

EF: Ejection Fraction; LV: Left Ventricular

Note: As patient #2 is a cardiac variant of Fabry disease, this patient had a skin biopsy score of 0 (trace or no accumulation) at baseline and at 6 months

Note: Visualization of multiple biomarkers adjusted to utilize the same statistical scaling ratio across biomarkers (as compared to prior presentation) * Latest data points for this patient are at the 1-yearfollow-up which = 48 weeks per protocol

9

FAB-201 FABRY PHASE 2

New data point

Patient 3: Data up to 1 year* suggest trend towards durable engraftment

Leukocyte	+ Plasma AGA Enzyme Activity		Plasma Lyso-Gb3 and Total Gb3
			Leukocyte AGA			Lyso-Gb3
					Total Gb3
			Plasma AGA

	Day 0			Day 0
			Infuse AVR-RD-01
Infuse AVR-RD-01
*Data from Rupar Laboratory; Reference Range: 24-56 nmol/hr/mg; † Reference Range: 5.1-9.2 nmol/hr/mL; AGA: α-galactosidase A	*Reference Value: 2.4 nM; † Reference Value: 4961 nM; Lyso-Gb3: Globotriaosylsphingosine; Gb3: Globotriaosylceramide
		Plasma AGA Enzyme Activity			Vector Copy Number (VCN)

Patient 1		Patient 2		Patient 3

Skin Biopsy Score

(Patient 3)

Drug Product VCN: 1.4

Baseline 2

6 months	2

Day 0

Day 0

Infuse AVR-RD-01

Infuse AVR-RD-01

Reference Range: 5.1-9.2 nmol/hr/mL; AGA: α-galactosidase A

VCN: Vector Copy Number; PBMCs: Peripheral Blood Mononuclear Cells

Note: Visualization of multiple biomarkers adjusted to utilize the same statistical scaling ratio across biomarkers (as compared to prior presentation) *1-yearfollow-up = 48 weeks per protocol

10

FAB-201 FABRY PHASE 2

New data point

Patients 1-4: Plasma and leukocyte enzyme activity sustained up to 22 months

Patient #4 dosed using platoTM

Patient 1		Patient 2		Patient 3		Patient 4

Plasma AGA (nmol/hr/mL protein)

Leukocyte AGA

(nmol/hr/mg protein)

AGA: α-Galactosidase A

11

FAB-201 FABRY PHASE 2

New data point

Patients 1-4: Plasma lyso-Gb3 reduction sustained up to 18 months

Patient 1		Patient 2		Patient 3		Patient 4

Reduction from

Baseline to Last

Observation

Patient 1	88%
Patient 2	NA
Patient 3	50%
Patient 4	43%

• Lyso-Gb3:Globotriaosylsphingosine
• Note: Patient #2 has normal substrate, consistent with late-onset cardiac variant phenotype

12

Two AVR-RD-01 Fabry clinical trials

9 patients dosed across Phases 1 and 2

PHASE 1	PHASE 2
Investigator-Sponsored Trial*	AVRO - FAB-201 Trial

Patients

n = 5 (fully enrolled)

On ERT > 6 months prior to enrollment

18-50year-old males

Key Objectives

Safety and preliminary efficacy

FAB-201 = AVRO-RD-01-201 Study

• Sponsored by FACTs team (Fabry Disease Clinical Research and Therapeutics) in Canada ERT: Enzyme Replacement Therapy

13

FABRY PHASE 1

Patients 1-5: Plasma lyso-Gb3 reduction sustained up to 32 months

All patients who have discontinued ERT remain off ERT*

ERT	No Gene		Patient 1		Patient 2		Patient 3		Patient 4		Patient 5
ERT	Tx

					26% reduction
25.3				18.8 from baseline ERT
					OFF ERT
					47% reduction
26.1			14.0	from baseline ERT
		ON ERT
58.5	33.3		43% reduction
			from baseline ERT
					OFF ERT
		35.7		23% increase
29.1		from baseline ERT
					OFF ERT
					37% reduction
15.8	10.0		from baseline ERT
			ON ERT

Gene Tx + ERT Gene Tx + Off ERT

* As of April 27, 2020 (update)

Lyso-Gb3: Globotriaosylsphingosine; ERT: Enzyme Replacement Therapy; Tx: Therapy

14

FABRY PHASE 1

Patients 1-5: Leukocyte and plasma enzyme activity sustained up to 32 months

Consistent trends across all patients, 4 patients > 1 year

		350
			Patient 1	Patient 2	Patient 3	Patient 4	Patient 5
Leukocyte AGA Activity	(nmoles/hr/mg protein)	300
00	=
250
150
100
		50
		0

Day 0

Infuse AVR-RD-01

		12
Plasma AGA Activity		10
(nmol/hr/mL)	8
6
4
2
		0

Day 0

Infuse AVR-RD-01

AGA: α-Galactosidase A

15

FABRY PHASE 1

VCN stable at 32 months with consistent trend across all other patients

4 patients with 1+ years data

Drug Product

VCN

Patient 1	0.7
Patient 2	1.4
Patient 3	0.8
Patient 4	1.4
Patient 5	1.2

VCN (per cell)

1.6

Patient 1		Patient 2		Patient 3		Patient 4		Patient 5

1.4

1.2

1

0.8

0.6

0.4

0.2

0

Day 0

Infuse AVR-RD-01

Note: 0.1 VCN is indicative of approx. 5-10% of all nucleated cells having an average of 1-2 copies of the transgene

VCN: Vector Copy Number

16

FABRY PHASE 1

Patient 1: Kidney function stable at 32 months

ERT	No	Gene	ERT + Gene Therapy	Gene Therapy
ERT	Tx

Normal Kidney

Function

Mild CKD

Moderate CKD

Severe CKD

eGFR: Estimated Glomerular Filtration Rate; ERT: Enzyme Replacement Therapy; TX: Therapy; CKD: Chronic Kidney Disease

17

Phase 1 Fabry (5 patients) and FAB-201 (4 patients)

No unexpected safety events

No SAEs related to AVR-RD-01 drug product

AEs and SAEs reported

Phase 1 AEs (n = 128):	Phase 1SAEs (n = 2):
• Generally consistent with	• Febrile neutropenia (grade 3)
myeloablative conditioning,	• Thrombophlebitis (grade 2)
underlying disease or
pre-existing conditions

or trends identified

FAB 201 AEs (n = 98):

• Generally consistent with myeloablative conditioning, underlying disease or pre-existing conditions
• • Grade 1 or 2 (n = 72)
  • Grade 3 or 4 (n = 30)

FAB 201 SAEs: (n = 4)

Pre-treatment and prior to conditioning

• Seizure (grade 2)

Post-treatment

• Dehydration, nausea, vomiting (grade 3)
• Febrile neutropenia (2 patients, grade 3 & 4)

Note: Safety data cut November 26, 2019

AE: Adverse Event; SAE: Serious Adverse Event

NOTE: AVR-RD-01 is an investigational gene therapy

Anti-AGA antibodies

• Pre-existinglow titers detected in 4 patients

18

Cystinosis

AVR-RD-04

19

Goals for gene therapy in

cystinosis

UNMET NEEDS:

Kidney function

Unmet needs: renal Fanconi syndrome, proteinuria, chronic kidney disease, kidney failure

Vision

Unmet needs: corneal cystine accumulation, photophobia, involuntary eyelid closure

Endocrine disorders

Unmet needs: softening/weakening of bones, bone pain, rickets, long bone deformations, hypophosphatemia, delayed growth, hypothyroidism, pancreatic insulin insufficiency, diabetes, infertility

CNS complications

Unmet needs: myopathy, hypotonia, tremors, difficulty swallowing, neurodevelopmental issues (speech and walking delay and cognitive impairment)

Everyday burden of illness and life expectancy

Unmet needs: medications multiple times per day that cause GI discomfort and sulfur body and breath smell, shortened lifespan

Sources: Ariceta G et al, Nephrol Dial Transplant, 2015; Elmonem M et al, Orphanet Journal of Rare Diseases, 2016; Gahl et al, NEJM, 2002; Bois et al, J Med Genet, 1976

CNS: Central Nervous System; GI: Gastrointestinal

20

Investigator-sponsored* study of AVR-RD-04 in cystinosis patients

First patient dosed

	Patients
	Up to 6 patients
	Adults and adolescents
	Cohorts 1-2 ≥18 years; Cohort 3 ≥14 years
	Male and Female
	On oral and ophthalmic cysteamine
PHASE 1/2	Key Objectives
Investigator-Sponsored Trial*

Safety and efficacy

• Sponsored by University of California, San Diego Note: AVR-RD-04 aka CTNS-RD-04

21

PATIENT 1

Cystinosis

AVR-RD-04

Phase 1/2

Patient Characteristics

Age of symptom onset / diagnosis

Age dosed with

AVR-RD-04

Gender

Mutation

Primary disease signs and SoC treatment related symptoms, including

Granulocyte Cystine levels at baseline (nmol half cystine per mg protein)*

Comments

0 year / 8 months

20 years

Male

Allele 1: LDM1

Allele 2: Nt1035 (insC)

• Fanconi syndrome
• Polyuria
• Corneal abnormalities
• Mild photophobia
• Vomiting

7.8

NO kidney transplant

• Cysteamine 1125 mg p.o. every 12 h/day since 2009; discontinued prior to AVR-RD-04 infusion
• Cysteamine eyedrops 4-5x/day
• Concomitant medications not listed

Note: AVR-RD-01 aka CTNS-RD-04

22

CYSTINOSIS PHASE 1/2

New data point

Patient 1: Initial data indicate positive trends across multiple measures

CLINICAL LAB MEASURES	BIOMARKER ENDPOINTS

	Baseline			38
									eGFR (mL/min/1.73m2)
	3 Months			40
					normal range: >90
Kidney	6 Months							52
Function	Baseline
	2.2
					Serum Creatinine (mg/dL)
	3 Months	2.1
		normal range: 0.7-1.2
	6 Months
	1.6

Urine Volume	Baseline	4.1
24 Hour Urine
Volume in L	3 Months	2.6

Levels	Baseline	2,187
of Cystine
in Skin*	3 Months	1,493
μm3

• Experimental in vivo confocal microscopy
• Two skin areas, behind the ear and 'optional', averaged
• Analysis and quantification (3D Image-Pro software)

VCN		Average Granulocyte Cystine
(vcn/dg)		Level
(Drug Product = 2.1)	(µmol half cystine/g protein)
1 Month	2.9	Baseline1.3	1.5		1.5
7.8
2 Months	3.0	1 Month		1.3
3 Months	2.0	2 Months		1.5
		3 Months		1.5

Asymptomatic Heterozygous Carrier Granulocyte Cystine Range: 0.2 - 1 .9 µmol half cystine/g protein

Source: Gertsman I et al., Clinical Chemistry, 2016

VCN: Vector Copy Number; CTNS: Cystinosin, Lysosomal Cystine Transporter; mRNA: Messenger Ribonucleic Acid; eGFR: Estimated Glomerular Filtration Rate; SCr: Serum Creatinine *Data obtained using a novel experimental methodology utilizing in vivo confocal microscopy, to image crystals in the skin behind the ear

23

CYSTINOSIS PHASE 1/2

New data point

Patient 1: Reduced treatment burden at 6 months

Number of Medications and Supplements

(max per day)

Before

Gene Therapy

ON Cysteamine

After Gene Therapy

(at 6 months post-gene therapy)

OFF Cysteamine

52 20

NOTE: Investigational gene therapy

24

Phase 1/2 Cystinosis 1 patient dosed

No unexpected safety events or trends identified

Note: Safety database cut as of January 27, 2020

AE: Adverse Event; SAE: Serious Adverse Event

No AEs or SAEs related to AVR-RD-04 drug product

No SAEs reported

AEs reported

• Consistent with myeloablative conditioning and underlying disease
• N = 22 (moderate = 9, mild = 13)
  Pre-treatment and prior to conditioning (n = 6, not all events listed)
• • Diarrhea, hypokalemia, dizziness
  • Dehydration, vomiting

Post-treatment (n = 16, not all events listed)

• Alopecia, intermittent diarrhea, vomiting
• Mucositis, intermittent febrile neutropenia, intermittent epistaxis
• Intermittent blurry vision, intermittent hypokalemia, mucoceles
• Thrombocytopenia

25

plato™

--

AVROBIO's foundation designed to

scale gene therapy worldwide

State-of-the-art technologies including

automated manufacturing platform

Optimized	Redefines manufacturing
for performance	best practices

26

plato™: Three upgrades designed to optimize potency, safety and durability

	Increase	Increase		Increase	Increase
UPGRADES	enzyme	transduction	Increase	marrow space /	consistency
activity	efficiency	VCN	engraftment	and safety

1 | Vector

2	| Conditioning	*
3	| Automation

Upgrades designed to increase Vector Copy Number (VCN),

enzyme activity, chimerism and durability

* TDM (therapeutic drug monitoring)

27

plato™	VECTOR UPGRADE:
UPGRADE	Metrics compared to academic process
1
	FAB-201 patient #4 drug product data with plato™

Enzyme Activity (nmol/hr/mL)

VCN (per diploid genome)

Transduction Efficiency (%)

122.2x

Increase vs. Mean

60

2.2x

10
8
6
Mean = 4.8
4
2
6.4	5.3	2.6	10.7
0

PATIENT 1 PATIENT 2 PATIENT 3 PATIENT 4

FAB-201

VCN: Vector Copy Number; FAB-201:AVR-RD-01 Study

NOTE: Data is from drug product

Increase vs. Mean

1.6
1.4
1.2
1	Mean = 0.9
0.8
0.6
0.4
0.2	0.7	0.5	1.4	1.6
0

PATIENT 1 PATIENT 2 PATIENT 3 PATIENT 4

FAB-201

Increase vs. Mean

50
40
30
Mean = 23.3
20
10
16.2	30.0	23.7	50.7
0
PATIENT 1	PATIENT 2	PATIENT 3	PATIENT 4
	FAB-201

28

plato™	VECTOR UPGRADE:
UPGRADE	Metrics compared to academic process
1
	FAB-201 and AVR-RD-04 drug product data

				VCN (per diploid genome)	2.2x
								Increase
		2	2					vs. Mean*
					1.8x
FAB-201 with plato™	1.8	1.8
			Increase
•	4-plasmid vector (LV2)	1.6	1.6				vs. Mean
•	Bu TDM conditioning	1.4	1.4
•	Automated manufacturing	1.2	1.2
		1	1	Mean = 0.9
AVR-RD-04 with "plato-like"	0.8
		0.8
•	4-plasmid vector	0.6	0.
•	Bu TDM conditioning
0.4	0.
•	Manual manufacturing
0.2	0.
		0.7	0.5	1.4	1.6	2.0*
		0	0
			PATIENT 1	PATIENT 2	PATIENT 3	PATIENT 4	PATIENT 1
					FAB-201		CYS-101

BU TDM: Busulfan Therapeutic Drug Monitoring; VCN: Vector Copy Number; FAB-201:AVR-RD-01 Study; CYS-101:AVR-RD-04 Study; LV: Lentiviral Vector

• Manufactured at UCLA using UCLA's assays and methodologies
  NOTE: Data is from drug product

	Transduction Efficiency (%)
60	60			2.2x
				Increase
50	50			vs. Mean
40	40
30	30
	Mean = 23.3
20	20
10	10
0	16.2	30.0	23.7	50.7
	PATIENT 1	PATIENT 2	PATIENT 3	PATIENT 4
		FAB-201

3.3x

Increase

vs. Mean*

76.0*

PATIENT 1

CYS-101

29

plato™	PRECISION CONDITIONING UPGRADE:
UPGRADE	Targeted busulfan intended to balance
2

optimal engraftment with enhanced safety

Meta-analysis of 465 patients identified optimal exposure

Optimized precision dosing designed to enhance tolerability

Lowest rate of adverse events in the Bu90 range

Bu: Busulfan; AUC: Area Under the Curve

Sources: Bartelink IH et al, Lancet Haematol, 2016

Adverse Event Probability

0.8	Graft Failure	Increased Toxicity

0.6	Optimal
Exposure

0.4

0.2

0.0

50

70

90

110

130

Busulfan Cumulative AUC (mg x hr/L)

Non-Malignant Disorders (n=465 patients)

30

plato™	PRECISION CONDITIONING UPGRADE:	New
point
		data
UPGRADE	Rapid neutrophil and platelet recovery with minimal
2
	lymphocyte depletion using Busulfan TDM
Absolute Neutrophil Count (ANC)	Platelet Count	Absolute Lymphocyte Count

		Cystinosis Patient 1: Busulfan			Fabry Patients 1 - 3: Mel		Fabry Patient 4: Bu90-TDM
Fabry: Patients #1-3 Melphalan 100mg/m2; Patient #4 Busulfan 'AUC 90'; Cystinosis: Patient #1 Busulfan 'AUC 90'
Threshold levels for prophylactic supportive care in HSC Tx; ANC <0.5 x 109 per liter (AABB); Platelets <10 X 109 cells/L (AABB)
NOTE: Neutrophil counts - G-CSF administration post gene therapy: Pt 1: 7 Doses, Day 7 - 14, Pt 2: 11 Doses, Day 7 - 17, Pt 3: 6 Doses, Day 7 - 12, Pt 4: 5 Doses, Day 8 - 12
NOTE: Platelet counts - Platelet Transfusion: Pt 1: Day 10; Pt 2, 3: Day 11, Pt 4: no transfusion
TDM = Therapeutic Drug Monitoring; G-CSF = Granulocyte-colony stimulating factor

31

plato™

UPGRADE

2

TRANSDUCED CD34+ CELLS

PRECISION CONDITIONING UPGRADE:

Designed to access "hard-to-reach"

compartments

CNS/PNS

Microglia

MICROGLIA

Neuron

Viscera

Potential for widespread

microglia engraftment

BRAIN

throughout the brain

Busulfan crosses blood-brain barrier

and eliminates resident microglia cells

making space for gene-modified cells

Enzyme

Astrocyte

IN THE

BONE

MARROW

Busulfan eliminates

BONE MARROW

PERIPHERAL TISSUE

hematopoietic (CD34+)

stem and progenitor cells

making space for gene-

modified cells

Granulocyte

Bloodstream

Bone

HSC

Progenitors

Mature

area

area

cells area

Lymphocyte

Monocyte

Mature

Blood Cells

Enzyme

Enzyme

Macrophage

32

plato™	AUTOMATION UPGRADE:
UPGRADE	Designed to deliver large-scale manufacturing
3
	Differentiated, cost-effective approach

1 Vector production

HIGH VOLUME / TITRE

Vector with disease-specific transgene

Large bioreactor

200 liter serum-free suspension culture

Frozen in

aliquots

to streamline supply chain

2 Drug product production

INCREASE CONSISTENCY

Automated, closed system

CD 34+ hematopoietic stem cells

Cryopreserved to enable convenient dosing

3 Scalable, global production suites

COST-EFFECTIVESCALE-OUT

*

Illustrative

* European manufacturing capabilities planned for 2H 2020; manufacturing capabilities currently in place in U.S. & Australia

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plato™

UPGRADE

3

AUTOMATION UPGRADE:

Poised to manufacture at scale

Designed to optimize potency and safety, and overcome historic CMC bottlenecks

V E C T O RD R U G P R O D U C T

2,400	PATIENTS	2,400	PATIENTS
	ANNUALLY		ANNUALLY

~50 patients per run 100 patients per unit per year

~12 runs per year per suite	8 automated units per suite
(200 L scale bioreactor runs (109 titre))

4 production suites

3 global production suites

Illustrative

34

	New
plato™	3 UPGRADES IN PLACE: point
data
UPGRADE	plato™ metric compared to academic process
1, 2,3

FAB-201 THREE MONTH data for patient #4 with plato™ vs. patients #1-3

Plasma Enzyme Activity	Leukocyte Enzyme Activity
(nmol/hr/mL)	2.9x	(nmol/hr/mg)	3.2x
	Increase vs. Mean		Increase vs. Mean

Mean = 1.6

Mean = 18.3

2.7	1.4	0.6	4.6	26.0	24.8	4.1	57.9

FAB-201:AVR-RD-01 Study

35

ASGCT 2020 data update - key takeaways

New data show consistent results across Fabry disease and cystinosis programs

Long-term Fabry patient data	Sustained long-term positive trends
	• Patient 1 in the Phase 2 trial continues to show stable leukocyte and plasma AGA enzyme activity,
	now out 22 months
	• Patient 3 in the Phase 2 trial shows increased leukocyte and plasma AGA enzyme activity,
	decreased plasma lyso-Gb3 level, and stable VCN at new time points
	• All three Phase 1 patients off ERT remain off ERT

First Fabry plato™ patient	plato continues to perform
	• One-month plasma lyso-Gb3 decrease of 43% vs. baseline
	• Three-month leukocyte and plasma enzyme activity levels 3x greater than mean of other three
	patients at same timepoint in Phase 2 trial
	• Rapid neutrophil and platelet recovery with minimal lymphocyte depletion post Bu90 conditioning
Cystinosis Patient 1 data	Positive trends at six months, including kidney function measures
	• eGFR and serum creatinine measures trending positively at 6 months

• Pill burden remains significantly lower than at baseline

36

Appendix

37

FAB-201 FABRY PHASE 2

Patient 1: 87% substrate reduction in kidney biopsy

at 1 year

Average

number of Gb3

inclusions

per peritubular

capillary (PTC)

Mean Number of Gb3 Inclusions per PTC

4.5

4

3.5

3

2.5

2

1.5

1

0.5

0

3.55

3.55

0.47

• Unpaired t-test for difference between n=55 PTCs at baseline vs. n=101 PTCs at 1 year; p < 0.0001
• Error bar represents the standard deviation

Baseline	1 Year
	(48 weeks)

Baseline: The last available, non-missing observation prior to AVR-RD-01 infusion

Note: With respect to Fabry disease, Gb3 inclusions per PTC is interchangeable with GL-3 inclusions per KIC

FAB-201-1: First patient in FAB-201 clinical trial

PTC: Peritubular Capillary; Gb3: Globotriaosylceramide; GL-3: Globotriaosylceramide; KIC: Kidney Interstitial Capillary

38

New collaborations advancing leadership in lentiviral gene therapy

Fully Automated Bu-TDM Immunoassay

• AVROBIO and Saladax announced agreement to develop and validate Saladax's fully automated nanoparticle immunoassay kit
• Designed to work on most automated hospital analyzers
• Regular technician, 24/7 analysis possible with results anticipated in minutes using only microLs of blood
• Designed to analyze 10-100s samples per machine/hour
• Expected to eliminate Bu degradation errors as assay conducted in real-time at the point of care
• Scalable

Antibody-Drug Conjugate

• AVROBIO and Magenta announced research & clinical collaboration agreement to evaluate Magenta's preclinical CD117-targeted antibody conjugate to amanitin (MGTA-117) in conjunction with AVROBIO investigational gene therapies
• Designed to deplete only hematopoietic stem and progenitor cells
• Has shown promising data in non-human primates
• MGTA-117currently in IND-enabling studies
• Each party retains commercial rights to its own programs

39

Hematopoietic reconstitution occurs in two distinct phases

A few thousand long-term engrafting cells stably sustain levels of transgene product

First wave of short-term progenitor cells start to exhaust with

progressive takeover by a smaller population of long-term engrafting cells

Clonal Population

Long-term engrafting cells

Short-term progenitor cells

0 - 3	6 - 12	24 - 48
	Time after GT (months)

Source: Biasco L et al, Cell Stem Cell, 2016

40