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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© 2024 4D Molecular Therapeutics. All Rights Reserved. |
2 |
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:
- Airway clearance (~100 mins)
-
- Inhaled antibiotics & bronchodilators
- Disease modifying CFTR modulators:
-
- $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.
© 2024 4D Molecular Therapeutics. All Rights Reserved. |
5 |
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.
© 2024 4D Molecular Therapeutics. All Rights Reserved. |
7 |
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.
© 2024 4D Molecular Therapeutics. All Rights Reserved. |
8 |
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.
© 2024 4D Molecular Therapeutics. All Rights Reserved. |
9 |
4D-710 Safety & Tolerability: Results with Highest Dose Studied (2E15 vg)
Duration of Follow Up: 13-17 Months (n=4)
Treatment-related adverse events:
-
- Transient pneumonitis & FEV1 decline (n=1 participant)*; both resolved
- No new SAE
- Complete resolution of previously reported SAE (pneumonitis NOS, n=1 participant)
-
- ppFEV1 improved from baseline (+6% at month 12; last timepoint assessed)
- Lung biopsy biomarkers (weeks 4-8):
-
- No inflammation or toxicity
- 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.
© 2024 4D Molecular Therapeutics. All Rights Reserved. |
10 |
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4D Molecular Therapeutics Inc. published this content on 06 June 2024 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 06 June 2024 11:57:25 UTC.