4D Molecular Therapeutics : 710 AEROW Phase 1/2 Interim Clinical Data – June 2024

Aerosolized 4D-710 for the Treatment of Cystic Fibrosis (CF) Lung Disease

Interim Phase 1/2 Safety & Efficacy Data and Program Update

June 6, 2024

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Positive New Data Supports Aerosolized 4D-710's Potential as a Durable Genetic Medicine for Cystic Fibrosis Lung Disease

Wholly-Owned	 Next-generation aerosolized A101 vector for large-market lung diseases:
Pulmonology Franchise	4D-710 for CF & 4D-725 for A1AT deficiency lung diseases

Interim Data from

4D-710 AEROW Phase 1 Dose Exploration Stage

(Single aerosolized dose, Four dose levels ranging from 2.5E14 to 2E15 vg dosed in 10 participants)

Next Steps

Best available data as of May 24, 2024.

Lung Function				Lung Biopsy:
(ppFEV1):		Safety &		Dose-dependent
Improved			4D-710 transgene
	Tolerability:
		expression
(+5% & +6%) in
2 of 3 participants		Well tolerated		Widespread
with >6 months of		at dose levels up to
		CFTR protein
follow up and		1E15 vg
		expression in all
baseline ppFEV1
			doses & all
≤80%				participants studied

Cleared to Begin Phase 2 Expansion Stage (n= up to 9; begin dosing H2 2024):

Expect to evaluate 1E15 vg; inclusion of 5E14 vg dose pending enrollment &

follow-up from 3rd participant in Phase 1 5E14 vg cohort

Pre-existing A101

Immunity:

No effect on:

Transgene Expression

Clinical Activity

Safety

Next interim data update expected mid-2025after completing enrollment and f/u of Phase 2

© 2024 4D Molecular Therapeutics. All Rights Reserved.	3

A101 Lung Vector is Among Three Proprietary, Highly Targeted Next- Generation AAV Vectors Invented at 4DMT & in Clinical Development

VECTOR /

PRODUCT

ESTIMATED

RESEARCH

IND-

PRODUCT

DELIVERY

CANDIDATE

INDICATION

PREVALENCE

CANDIDATE

ENABLING

PHASE 1/2

PHASE 3

RIGHTS

Wet AMD

~3M U.S./EUMM

4D-150

DME

~5M U.S./EUMM

OPHTHALMOLOGY

4D-125

XLRP

~24K U.S./EUMM

R100

4D-110

Choroideremia

~13K U.S./EUMM

Intravitreal

4D-175

Geographic Atrophy

~2.5M U.S./EUMM

Undisc.

Undisclosed Rare Disease

Undisc.

Vector licensed to Astellas

CF Lung Disease

~15K WW

PULMONOLOGY

(mod. ineligible/intol)

4D-710

A101

CF Lung Disease

~90K WW

(combo w/ mods)

Aerosol

4D-725

A1ATD Lung Disease

~200K U.S./EUMM

CARDIOLOGY

Fabry Disease

~50-70K

C102

4D-310*

Cardiomyopathy

U.S./EUMM

IV

CNS

Unnamed

Amyotrophic

~79k

B SERIES

Led by Arbor

Lateral Sclerosis

U.S./EU/UK

Multiple

50/50 WW

*Currently on clinical hold.

© 2024 4D Molecular Therapeutics. All Rights Reserved.

4

CF Lung Disease Has High Unmet Medical Need Despite Modulators

Disease Burden

• Dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein  inability to transport chloride at the apical membrane  thickened mucus
• Lung disease: inflammation, infections, respiratory failure
• Lung function (ppFEV1) annual decline: -1to -2.3%1*,2
• Median survival (Pre-modulators):~40 years3

Epidemiology

• ~105,0004,5 prevalence worldwide: o ~40,000 prevalence in U.S. alone
  o ~1,000 incidence in U.S. alone

Standard of Care

• Daily Supportive Care:

1. Airway clearance (~100 mins)

• 1. Inhaled antibiotics & bronchodilators
• Disease modifying CFTR modulators:
• 1. $9.9 billion annually (2023)6

Illustration by Frank Forney. © 2016 Cengage Learning *Estimate based on DF508 homozygous population, which appears to have a similar rate of decline as Class I (null) variant population. 1. Konstan MW et al. Lancet Respir Med 2017; 5:107-18. 2. Caley et al. Journal of Cystic Fibrosis 2021;20:86-90. 3. Ramsey & Welsh. Am J Respir Crit Care Med 2017;195(9):1092-9. 4. Guo J et al. Journal of Cystic Fibrosis 2022; 21:456-62. 5. Cystic Fibrosis Foundation. 6. Vertex Pharmaceuticals FY 2023 financial results.

ppFEV1, percent predicted forced expiratory volume in 1 second.

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A101: Next-Gen Aerosolized Genetic Medicine Vector for Pulmonology

Prior aerosol gene therapy trials failed to achieve transgene expression in lung1,2; potential limitations:

• Poor mucus penetration
• Inefficient airway cell transduction
• Suboptimal tissue tropism
• Susceptibility to clearance by human AAV immunity

A101 invented at 4DMT to overcome these limitations:

• Mucus penetration efficient
• Transgene expression efficient
• Transduction of multiple airway cell types
• Specificity for lung (>99.9%)
• Resistance to pre-existing human AAV immunity

1. Aitken ML et al. Hum Gene Ther 2001; 12:1907-16. 2. Moss RB et al. Chest 2004;125:509-21.

© 2024 4D Molecular Therapeutics. All Rights Reserved.

Aerosolized A101-Based Genetic Medicines

Overcome Potential Barriers	Enhanced Transduction
	of Airway Cells

Airway

delivery

AeroEclipse® II

A101

Breath-actuated nebulizer

(FDA Approved)

Aerosolized particle delivery

4D-710

4D-725

CMV173

CFTR∆R

Ubiquitous

SERPINA1

PROMOTER

TRANSGENE

PROMOTER

TRANSGENE

Product

Indication

Prevalence

Preclinical

Phase 1/2

Phase 3

4D-710

CF Lung Disease (monotherapy)

~15K WW

CF Lung Disease (w/ modulators)

~90K WW

4D-725

A1AT Deficiency Lung Disease

~200K U.S./EU

6

Highest Unmet Need in ~35K People with Cystic Fibrosis

4D-710 has the Potential to Treat Cystic Fibrosis Lung Disease Regardless of Genetic Variant

Cystic Fibrosis Population WW

10%

5%

20%

65%

~105k

	Population Segment
		~10k
	Ineligible for CFTR modulators
	Intolerant to CFTR modulators	~5k

Suboptimal response to CFTR	~20k
modulators1

Responsive to CFTR modulators

~70k

Estimated People

study population evaluating 4D-710 as monotherapy

~35k

Potential future 4D-710 study population

Upside if superior dosing, efficacy, and/or safety is demonstrated

CFTR, cystic fibrosis transmembrane conductance regulator. 1. Based on assumptions derived from Middleton, 2019 and CFF registry analysis.

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Phase 1/2 Designed to Identify Doses for Late-Stage Development

Generate Safety, Biomarker & Clinical Activity Data to Determine & Confirm Phase 2 & 3 Dose

1E15 vg

(n=3)

SRT Review

Phase 1 (Dose Exploration)

ppFEV1 Eligibility Criteria: 50% to 100%

2E15 vg

(n=4)

Enroll 3rd Patient to complete cohort

5E14 vg

(n=3) 2.5E14 vg

(n=3)

Phase 2 (Dose Expansion)

ppFEV1 Eligibility Criteria:

50% to 90%

1E15 vg

(Cleared)

5E14 vg (Pending)

Expect to begin dosing (n= up to 9)

H2 2024

Primary Objectives:

• Phase 1: Dose ranging to characterize safety & biomarkers
• Phase 2: Expand in selected dose to confirm clinical activity for Phase 3

Key Endpoints:

• Safety & tolerability
• Lung biomarkers
• Clinical activity

4D-710 Bronchoscopy†

Long-term follow up

D1

1

2

3

6

9

12

15

18

21

24

40 mg oral prednisone*

Month

Scheduled study assessment

*28-day taper. †Endobronchial biopsy (4D-710 transgene and protein expression), pending protocol amendment to allow for 2nd biopsy beyond 12 months. ppFEV1, percent predicted forced expiratory volume in 1 second; SRT, Safety Review Team.

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AEROW To-Date Enrolled pwCF Ineligible or Intolerant to Modulators with a Broad Range of Disease Activity, 5 with Pre-Existing Immunity to A101

		2E15 vg			1E15 vg		5E14 vg	2.5E14 vg
Participant #	1	2	3	4	1	2	3	1	2	1
Age, y	37	27	32	69	36	24	20	42	39	25
Sex	Female	Male	Female	Female	Male	Male	Female	Female	Female	Male
Race/Ethnicity	Non-HispanicNon-HispanicNon-HispanicNon-HispanicNon-Hispanic	Non-Hispanic	Non-Hispanic	Non-Hispanic	Non-Hispanic	Non-Hispanic
White	White	White	White	White	White	White	White	Black	White
CFTR modulator	Ineligible	Ineligible	Ineligible	Intolerant	Intolerant	Ineligible	Ineligible	Intolerant	Ineligible	Ineligible
status
Historical Sweat	84	96	103	114	74	103	110	107	134	120
chloride,mmol/L†
ppFEV1	90	56	80	86	83	69	95	100	77	58
CFQ-R-R score	78	72	89	78	72	61	83	72	78	28

Anti-A101 Ab	Negative	Negative	Negative	Negative	Negative		Pending	Negative
A101-specific T cells		Negative	Negative	Negative	Negative	Pending	Pending	Pending

Best available data as of May 24, 2024. † Sweat chloride normal range ≤29 mmol/L, Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation (2017). pwCF = people with cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; CFQ-R-R, Cystic Fibrosis Questionnaire-revised respiratory domain; NAb, neutralizing antibodies.

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4D-710 Safety & Tolerability: Results with Highest Dose Studied (2E15 vg)

Duration of Follow Up: 13-17 Months (n=4)

 Treatment-related adverse events:

• 1. Transient pneumonitis & FEV1 decline (n=1 participant)*; both resolved
  1. No new SAE
  1. Complete resolution of previously reported SAE (pneumonitis NOS, n=1 participant)
  2. • ppFEV1 improved from baseline (+6% at month 12; last timepoint assessed)
• Lung biopsy biomarkers (weeks 4-8):
• 1. No inflammation or toxicity

1. CFTR protein expression

-

-

-

Significant over-expression: ~400% higher in epithelium compared to normal (non-CF) lung samples

No increase in expression: vs. 1E15 vg dose

Widespread expression in interstitium: negative in normal lung controls

• 1E15 vg selected as highest dose for dose exploration; no further evaluation of 2E15

Best available data as of May 24, 2024. *Both events reported by one study participant (Participant 2). ppFEV1, % predicted forced expiratory volume in 1 second; SAE, serious adverse event; NOS, not otherwise specified.

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