X-Linked Myotubular Myopathy (XLMTM)ASPIRO Phase 1/2 Gene Therapy Trial In XLMTM: Interim Safety And Efficacy Findings

Audentes Therapeutics, Inc.

1

Agenda

■ Audentes Team ■ Overview of Some Recent Achievements ■ Overview of Interim Data Findings from the ASPIRO Study ■ Frequently Asked Questions ■ Next Steps ■ Question & Answer Session

2

Audentes Team Represented Today

■ Kim Trant − Head of Patient Advocacy and Engagement

■ Bree Martin − Vice President of Development Operations

■ Jennifer Chu − Senior Project Manager, Development Operations

■ Suyash Prasad − MD, Paediatrician, Senior Vice President and Chief Medical Officer

3

What have we been doing since we last met?

4

We have been growing as a company…

5

First patient in RECENSUS

First patient in INCEPTUS

First patient in ASPIRO

First clinical data from INCEPTUS & ASPIRO

Audentes Company Growth and Development

2014 20152013 2016 2017

Apr 2017 IND approved

(FDA)

Aug 2015 XLMTM

Orphan Designation

Initial proof of concept (POC) established in mouse and dog

models at Genethon

Additional POC studies in mouse and dog models

2012 2018

Jun 2018 Priority Medicines (PRIME) designation

(EMA)

R&D labs open

Large-scale in-house manufacturing and QC facilities open

Expand offices, SF Expand lab ops

Open corporate office, San Francisco

168 employees

Company founded,

1 employee

AAV vectors for gene transfer therapy,

ongoing research

XLMTM(AT132)

Nov 2015 CPVT

Orphan Designation

Jan 2016 Crigler-Najjar

Orphan Designation

LUSTRO Clinical

Assessment/ Run-in Study

Feb 2018: First patient dosed in VALENS Phase

1/2 Study

Jan 2016 Pompe Orphan

Designation

Lawlor et al. Comparative Pathology of XLMTM Review. JNEN

2016

Beggs et al. RECENSUS. Muscle &

Nerve 2018

Kuntz et al. First ASPIRO data. ASGCT 2018

European Family Conference

European Family Conference

European Family Conference

6

We have been contributing to the body of scientific knowledge about XLMTM…

7

Scientific Publications and Presentations

Beggs et al. First RECENSUS publication. Muscle & Nerve, 2018

Lawlor, Schoser, Sewry et al. Comparative Pathology of XLMTM Review. JNEN 2016

ASGCT Oral Presentation 16 May 2018

8

We continue to discuss emerging data and new insights with the scientific and medical community…

9

10

Respiratory Therapy and Pulmonology Meeting

Audentes Board of Scientific and Clinical Advisors

11

We continue our engagement with and learning from the patient community…

12

When asked the question ‘What result would you like to see in your child’ – the mothers answered…

General

• “Cure” • Able to put son in car

& drive independently • More robust

Respiratory

• Independence from machines

• Improved communication

• No respiratory medicines • Breathe independently • Able to swallow • Improved speech • Able to sing • Stability: fewer

infections

Motor

• Able to walk • Able to raise arms

above head • Hold head up more • Sit independently • Reposition

independently • Increase fine motor

skills

XLMTM Patient Advocacy Leader – Physician Advisory Board

14

We dosed the first patient in the ASPIRO study!

15

AT132 for XLMTM Clinical Development Program

16

INCEPTUS Prospective Natural History

Run-in Study in XLMTM Patients

N≈25

Longitudinal baseline and within-patient control for

ASPIRO

Facilitates enrollment in and operational aspects of

ASPIRO

ASPIRO A Phase 1/2 Clinical Study in

XLMTM Patients N=12

Assessment of safety and tolerability and preliminary efficacy

Focus on neuromuscular & respiratory measurements

RECENSUS Retrospective Medical Chart

Review of Patients with XLMTM N=140

Characterize aspects of the disease and medical

management of XLMTM

Identify potential outcome measures for ASPIRO

Initial presentation Q1:17;First publication Q4:17 Prelim. data shared Q4:17

First patient dosed Q3:17;Positive interim data

reported for Cohort 1 in Q1:18

ASPIRO Phase 1/2 Clinical Study

GT administration

Inclusion Criteria

▪ Subject is male ▪ <5 yrs old, or enrolled in

INCEPTUS ▪ Genetically confirmed

XLMTM ▪ Requires ventilator

support

Key Efficacy Assessments

Neuromuscular ▪ CHOP INTEND ▪ MFM-20 ▪ Muscle biopsy ▪ Development

al milestones

Respiratory ▪ Max

Inspiratory Pressure (MIP)

▪ Ventilator use

Enrollment Plan

▪ N=12, roll-over from INCEPTUS

▪ Cohort 1: 1x1014 vg/kg dose, 6 treated patients plus a randomized, delayed-treatment, concurrent control patient

▪ Dose escalation TBD

Open-label, ascending-dose, safety and preliminary efficacy study

Weeks 9–16 taper

Wk 12Wk 11Wk 10Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 Wk 6 Wk 8 Wk 9Wk 7

Assessments

Neuromuscular Respiratory Developmental milestones Muscle biopsy

INCEPTUS Subjects

Wk 13 Wk 14

Weeks 1 – 8 Prednisolone 1mg/kg/day

BL Wk 15 6 mos. 12 mos.Wk 16 9 mos.

17

ASPIRO Clinical Study Sites

18

ASPIRO Cohort 1 – 1x1014 vg/kgSeven patients have been transitioned from INCEPTUS into ASPIRO

Interim data as of May 12, 2018

▪ Ventilator status at screening / baseline (hours per day): – Patient 1: 12 h of BiPAP – Patient 2: 22 h of invasive ventilation – Patient 3: 24 h of invasive ventilation – Patient 4: 12 h of BiPAP – Patient 5: 22.7 h of invasive ventilation – Patient 6: 24 h of invasive ventilation – Patient 7: 23.5 h of invasive ventilation

ASPIRO Follow-up

INCEPTUS Natural History Run-in Study

Age at baseline and follow up durationAge at ASPIRO Baseline (yrs)

0.8

2.6

4.1

4.0

Subject Number

Pt 1

Pt 3

Pt 2

Pt 4 (Ctl)

0 -12 months 1 year 2 years 4 years3 years

Coho

rt 1

1.0

0.8

0.8

Pt 5

Pt 7

Pt 6

Expa

nsio

n

19

Preliminary Data from the first 6 dosed patients in ASPIRO

20

Before I start, some important things to remember

■ Regulatory agencies have not approved the Audentes investigational gene therapy product as safe or effective, as it is still undergoing formal assessment in clinical trials

■ This is interim data − We cannot make any firm conclusions on the interim findings of the clinical

trial until after all enrolled subjects are dosed and evaluated for the duration of the study, and the full scope of data is collected and analyzed

■ We are a public company, and certain information may not be disclosed until done so in a public setting

21

Safety and Tolerability from ASPIRO

22

Safety Findings to Date

■ Ongoing safety assessments are critical to proper determination of potential safety issues and adverse events.

■ There have been a total of 24 adverse events (AEs) reported in ASPIRO, which have been managed with medical treatment. − Six of these adverse events were classified as serious adverse events (SAEs)

• five (5) occurred in one participant (4 of them possibly related to drug) • one occurred in the the delayed treatment control participant who has not been

dosed − Seven (7) non-serious adverse events that were possibly or probably related to the

investigational product occurred in a total of two participants.

23

Efficacy Data - Neuromuscular FunctionCHOP-INTEND and Developmental Milestones

24

Significant Improvements in Neuromuscular Function as Assessed by the CHOP-INTEND Scale

Interim data as of May 12, 2018

CHO

P IN

TEN

D S

CORE

0

10

20

30

40

50

60

70

Age (Years)

0 1 3 4 5

Patient 17Patient 8Patient 5Patient 20Patient 21Patient 19Patient 12 (Control)

Maximum score = 64 points (normally reached by 3-6 months of age) CHOP-INTEND score

Patient #Baseline Score in ASPIRO

Most recent score (Wk)

Change from baseline (%)

1 29 64 (Wk 24) 35 (121%)

2 45 59 (Wk 24) 14 (31%)

3 34 43 (Wk 12) 9 (26%)

4 (Ctrl) 49 49 (Wk 24) 0 (0%)

5 36 50 (Wk 4) 14 (39%)

6 39 43 (Wk 4) 4 (10%)

7 43

25

Multiple Motor Developmental Milestones Achieved

Interim data as of May 12, 2018

First-year developmental

milestones in healthy children

Patient 1 (0.8y)

Baseline Week 24

Rolling over

Head Control

Sitting unassisted >5 sec

-

-

-

Patient 2 (4.1y)

Baseline Week 24 Baseline Week 12 Baseline Week 24

Patient 3 (2.6y)

Patient 4 (Control-4.0y)

-

-

-

+

+

+

-

-

-

-

-

-

-

+

+

-

+

-

+

+

+

Additional observations

• Oral feeding • Standing w/

support • �Loudness

• Standing w/ support

• Scooting & crawling

• �Loudness

• Increased trunk strength

• �Loudness

26

Efficacy Data - Respiratory Function Maximal Inspiratory Pressure and Ventilator Dependence

27

Significant Improvements in Respiratory Function as Assessed by Maximal Inspiratory Pressure (MIP)

Interim data as of May 12, 2018

MIP

(cm

H2O

)

0

27.5

55

82.5

110

Baseline Week 1 Week 4 Week 12 Week 24

Patient 17Patient 8Patient 5Patient 20Patient 21Patient 19Patient 12 (Ctrl)

Estimated normal minimal pressures in healthy children

Maximum Inspiratory Pressure (cmH2O)

Patient #Baseline

Pressure in ASPIRO

Most recent Pressure (Wk)

Change from baseline (%)

1 33 89 (Wk 24)

56 (170%)

2 44 104 (Wk 24)

60 (136%)

3 26 48 (Wk 12)

22 (85%)

4 (Ctrl) 58 46

(Wk 24)-12

(-21%)

5 14 33 (Wk 4)

19 (136%)

6 35 63 (Wk 4)

28 (80%)

7 29

28

Ventilator Dependence Within the Previous 24 Hours First treated patient has reached ventilator independence

Interim data as of May 12, 2018

Vent

ilato

r D

epen

denc

e ov

er

prio

r 24

h

0

4

8

12

16

20

24

Month -13 Month -10 Month -7 Month -4 Month -1 Week 4 Week 20

INCEPTUS Visits ASPIRO Visits

Patient 1

Patient 2

Patient 3

Patient 4 (Ctrl) Patient 5

Patient 6

Patient 7

29

Clinical Assessment Videos

30

ASPIRO Key Findings and Program Next Steps

■ Well tolerated during administration and manageable safety profile to date

■ Improvements in neuromuscular and respiratory function have been seen

■ Progressive qualitative improvements in disease severity observed in all treated patients

■ Plan to review muscle biopsy data in conjunction with all safety and efficacy data to inform further dosing decisions and ongoing conduct of the study

Interim data as of May 12, 2018

It is important to understand that regulatory agencies have not approved the Audentes investigational gene therapy product as safe or effective, as it is still

undergoing formal assessment in clinical trials. The investigational gene therapy product is not approved for commercial sale and is

only being used in clinical trial settings.

31

Frequently Asked QuestionsThere are many “unknowns"

■ Will the number of participants in the clinical trial increase? What would determine that?

■ In the SMA clinical trials, they were stopped early due to positive results, do you anticipate that happening for the XLMTM clinical trial?

■ Will the clinical trial results in young children translate to older children? How would the impact on older children be measured?

■ What is the expanded access (early access, compassionate use) policy?

■ What happens next?

32

We would like to acknowledge the many contributors that have gotten us to this point!

Anna Buj Bello Genethon

Martin K. (Casey) Childers David Mack University of Washington, USA

Alan H. Beggs Children’s Hospital Boston, USA

Michael Lawlor Children’s Hospital and Medical College of Wisconsin, USA

• Audentes team members • Audentes Board of Scientific and Clinical

Advisors • Principal investigators and their teams

• Nancy Kuntz • Perry Shieh • Barbara Smith and Barry Byrne • James Dowling • Carsten G Bönnemann • Wolfgang Müller-Felber • Laurent Servais • Francesco Muntoni

• Study expert trainers

The children, families and the entire XLMTM patient community for their cooperation and participation in these studies

• Patient Advocacy Organizations • The Myotubular Trust • ZNM – Zusammen Stark! • The Joshua Frase

Foundation • MTM-CNM Family

Connection • Where There’s a Will

There’s A Cure Foundation for Myotubular Myopathy

33

Questions???