4D Molecular Therapeutics (Nasdaq: FDMT, 4DMT, or the Company), a
genetic medicines company with three novel, highly targeted next
generation AAV vectors currently in human clinical studies, today
announced interim data from the Phase 1/2 AEROW clinical trial
evaluating aerosolized 4D-710 for treatment of cystic fibrosis lung
disease. Results will also be presented at the 2023 North American
Cystic Fibrosis Conference (NACFC) in both plenary and symposium
sessions on November 2-3.
“We are pleased with the safety and tolerability of 4D-710 in
participants in the AEROW study to date. Participants with cystic
fibrosis in this clinical trial do not have the option of treatment
with currently available disease modifying therapies and therefore
have high unmet need,” said Jennifer L. Taylor-Cousar, M.D., MSCS,
Professor, Departments of Medicine and Pediatrics, and Co-Director,
Adult Cystic Fibrosis Program, Director, Cystic Fibrosis Foundation
Therapeutics Development Center, National Jewish Health and lead
Principal Investigator in the AEROW clinical trial, “By delivering
copies of the CFTR∆R transgene to the lung epithelium with a novel
aerosolized AAV and achieving high levels of CFTR protein
expression in airway cells, 4D-710 has the potential to provide
durable benefit in these individuals and potentially all
individuals affected by CF.”
“4D-710, our next generation aerosolized A101 vector, has the
potential to address the limitations of prior aerosol gene
therapies. Initial results from the AEROW study showed that 4D-710
resulted in CFTR expression in lung airways that significantly
exceeded our target profile. Safety and pulmonary function measures
reinforce a promising emerging tolerability and clinical activity
profile,” said David Kirn, M.D., Co-founder and Chief Executive
Officer of 4DMT. “We are also excited to welcome Dr. Alan Cohen as
our Pulmonology Therapeutic Area Head. Alan brings more than 30
years of broad pulmonology expertise including in cystic fibrosis,
alpha-1 antitrypsin deficiency, idiopathic pulmonary fibrosis, plus
biotherapeutics and gene editing development, highlighting our
commitment to pulmonology. Under Alan’s leadership, we expect to
continue advancing the clinical development of 4D-710 for CF lung
disease and 4D-725 for alpha-1 antitrypsin deficiency lung disease
and future lung programs.”
“The high CFTR expression levels and durable clinical activity
of 4D-710 as demonstrated by improvements in quality of life and
stability in ppFEV1 through 12 months in Cohort 1 have never been
achieved with any gene delivery in CF, making a dose reduction
feasible,” said Alan Cohen, M.D., SVP, Therapeutic Area Head of
Pulmonology of 4DMT. “I’m excited to work closely with the CF
Foundation, CF community, and regulatory agencies to advance the
development of 4D-710, a potentially transformative medicine for
people with CF. Given the efficiency we have observed in CF lungs,
one of the most difficult organs for gene delivery vectors, I am
also energized by the potential of A101 to deliver genetic payloads
to treat multiple large-market pulmonology diseases including
alpha-1 antitrypsin deficiency lung disease.”
Data below is from Cohort 1 (1E15 vg, n=3) and Cohort 2 (2E15
vg, n=4) of the ongoing Phase 1/2 AEROW trial.
Safety: Generally Well-Tolerated
- Acute safety (during and up to 4 h
post dosing): Generally well tolerated, no clinically significant
adverse events (AEs); no decrease in ppFEV1 (percent predicted
forced expiratory volume in 1 second) or bronchospasm reported
- Post-dosing safety (follow-up in 7
participants through 4-17 months); best available as of October
2023:
- Generally well-tolerated
- No inflammation observed in biopsies
collected to date in all 7 participants
- No related AEs in 6 of 7 patients at
any timepoint
- Single SAE (participant 3 of 4
dosed in Cohort 2; pneumonitis not otherwise specified): Serious
due to hospitalization (<72 hours). High-resolution computed
tomography (hospital radiologist reading) reported differential
diagnosis as “atypical infection, cryptogenic organizing
pneumonia.” Following discharge, lung lavage bacterial cultures
confirmed Inquilinus limosus infection. Participant was treated
with oral steroids and outpatient IV antibiotics, and AE
subsequently resolved. AE consistent with bacterial pneumonia
(Inquilinus limosus). Principal Investigator reported as possibly
related to 4D-710
Lung Tissue Biomarkers: Expression Significantly
Exceeded Target Profile in All Patients
- Robust and reproducible
4D-710-mediated CFTR protein (by immunohistochemistry, IHC) and RNA
(by in situ hybridization, ISH) expression observed in airway
epithelium 4-8 weeks following aerosol delivery in all 7
participants across all 34 airway biopsy and brushing samples
collected
- CFTR protein detected in ~98% and
~99% of airway epithelial cells in samples from Cohort 1 and 2
participants, respectively versus ~44% of cells in normal control
lung samples
- Mean CFTR protein expression levels
by immunohistochemistry observed in Cohorts 1 and 2 participants
were ~450% of levels in normal control lung samples, and ~1,000% of
levels in control lung samples from individuals with CF
- All major airway cell types
expressed CFTR protein and CFTR∆R RNA, including long-lived basal
cells and secretory (Goblet) cells
- In situ hybridization (ISH) for RNA
confirmed widespread, reproducible CFTR∆R transgene expression in
all lung samples evaluated in all participants; positive signal
observed in 40% and 53% of airway epithelial cells in samples from
Cohort 1 and 2 participants, respectively. More cells were positive
by IHC than by ISH
Biomarker |
Lung Biopsy Measure* |
Control (Normal Lung)(n=10 biopsy samples) |
Control (CF Lung)(n=35 biopsy
samples) |
Cohort 1(1E15 vg, n=5 biopsy samples) |
Cohort 2(2E15 vg, n=8 biopsy samples) |
CFTR ProteinExpression(by IHC) |
Mean (range) % of airway cells (+) |
44%(17-73%) |
18%(1-62%) |
98%(93-100% |
>99%**(99-100%) |
Mean (Range) Intensity (H-Score) |
47(17-75) |
19(1-68) |
205(133-253) |
225**(143-280) |
* ISH and IHC scoring performed with machine learning-assisted
image analysis software (Visiopharm), with review and confirmation
by independent certified M.D. pathologist masked to lung tissue
source
** CFTR expression observed in Cohort 2 was not statistically
significantly increased compared to Cohort 1
Cohort 1 Clinical Activity: Durable Through 12 Months
and Beyond
- Clinical activity assessments
collected through 12 months (amendment planned to collect
additional follow-up data after 12 months):
|
Participant with moderate lung impairment by
ppFEV1 (n=1) |
Participants with mild/no lung impairment by
ppFEV1 (n=2) |
Lung
Function(ppFEV1)
Absolute ∆ from baseline over 12 months |
+1% to +10% improvement |
Stable (±2%) |
Quality of Life (CFQ-R-RD*) ∆
from baseline over 12 months |
Mean increase of 8.4 to 11.1 points over 12 month
period consistently above MCID (MCID=±4); all 3 participants
consistently improved beyond MCID |
* Cystic Fibrosis Questionnaire-Revised respiratory domain
symptom scoreMCID, minimal clinically important difference
- In all 3 participants, no pulmonary
exacerbations were reported beyond 3 months through up to 17 months
of follow-up
- Cohort 2 clinical activity pending
following additional follow-up (consistent with Cohort 1 clinical
activity reporting timeline)
Next Steps for 4D-710 Clinical Development
- Cohort 1 dose level (1E15 vg)
selected to continue into Phase 2
- Dose ranging continues (5E14 – 2E15
vg) with lung biopsy CFTR expression profile significantly
above normal controls, demonstrating the feasibility of effective
treatment at lower doses; first participant dosed in lower dose
Cohort 3 (5E14 vg)
- Additional functional measures
added to AEROW study following strong proof-of-concept for above
normal CFTR expression in airways: high-resolution computed
tomography (HRCT), lung clearance index (LCI), mucociliary
clearance index (MCI), number & severity of bacterial pulmonary
exacerbations
- FDA feedback on development plan
for monotherapy & approved CF modulator combination regimens
expected to be shared in Q1 2024
- Next interim Phase 1 data update
expected mid-2024
Increased Financial Commitment from Cystic Fibrosis
Foundation (The CF Foundation) Brings Total Historical Commitment
to Over $20 Million
- 4DMT has been supported by the CF
Foundation since 2016, including a 2017 research agreement (“CF
Foundation Agreement”) to discover and develop optimized next
generation AAV vectors for use in genetic medicines targeting lung
airway cells in people with CF
- In August 2023 the Company executed
an amendment to the CF Foundation Agreement increasing the funding
commitment under that agreement by $2.8 million to a total of $6.3
million, which covers anticipated spend for further development of
our aerosolized lung epithelium gene delivery vectors
- In 2020 and 2021, the CF Foundation
invested $14 million in 4DMT equity to support the development of
4D-710
Webcast Details:
Title: |
4D-710 Phase 1/2 AEROW Interim
Clinical Data and Program Update Webcast and Q&A |
Date/Time: |
Wednesday, November 1, 2023 at
4:30 p.m. ET |
Registration: |
Link |
An archived copy of the webcast will be available for up to one
year by visiting the “Investors & Media” section of the 4DMT
website at the following link:
https://ir.4dmoleculartherapeutics.com/events.
About 4D-710 and Cystic Fibrosis Lung
Disease
4D-710 is comprised of our targeted and evolved next generation
vector, A101, and a codon-optimized CFTR∆R transgene. 4D-710 has
the potential to treat a broad range of people with cystic
fibrosis, independent of the specific CFTR mutation, and is
designed for aerosol delivery to achieve CFTR expression within
lung airway epithelial cells. 4D-710 is being initially developed
for the approximately 15% of people whose disease is not amenable
to existing CFTR modulator medicines (based on variant-eligibility
and/or drug intolerance) targeting the CFTR protein. In people with
CFTR mutations whose disease is amenable to modulator medicines,
the improvement in lung function is incomplete and is variable. We
therefore expect to potentially develop 4D-710 in this broader
population, as a single agent and/or in combination with CFTR
modulator small molecule medicines.
Cystic fibrosis is an inherited, progressive disease caused by
mutations in the CFTR gene. It affects the lungs, pancreas, and
other organs. According to the CF Foundation, nearly 40,000 people
in the United States and more than 105,000 people worldwide are
living with cystic fibrosis, with approximately 1,000 new cases of
cystic fibrosis diagnosed in the United States each year. Lung
disease is the leading cause of morbidity and mortality in people
with cystic fibrosis. Cystic fibrosis causes impaired lung
function, inflammation and bronchiectasis and is commonly
associated with persistent lung infections and repeated
exacerbations due to the inability to clear thickened mucus from
the lungs. People with cystic fibrosis require lifelong treatment
with multiple daily medications. The complications of the disease
result in progressive loss of lung function and hospitalizations,
and ultimately lead to end-stage respiratory failure.
About 4DMT
4DMT is a genetic medicines company with three novel, highly
targeted next generation AAV vectors currently in human clinical
studies targeting multiple large market diseases in ophthalmology
and pulmonology, plus other therapeutic areas. 4DMT seeks to unlock
the full potential of genetic medicines using its proprietary
invention platform, Therapeutic Vector Evolution, which combines
the power of the Nobel Prize-winning technology, directed
evolution, with approximately one billion synthetic AAV
capsid-derived sequences to invent customized and evolved vectors
for use in our product candidates. All of our vectors are
proprietary to 4DMT and were invented at 4DMT, including the
vectors utilized in our clinical-stage and preclinical pipeline
product candidates: R100, A101, and C102. The Company is initially
focused on five clinical-stage product candidates in three
therapeutic areas for both rare and large market diseases:
ophthalmology, pulmonology, and cardiology. The 4DMT customized and
evolved vectors were invented with the goal of being delivered at
relatively low doses through clinically routine, well-tolerated,
and minimally invasive routes of administration, transducing
diseased cells in target tissues efficiently, having reduced
immunogenicity and, where relevant, having resistance to
pre-existing antibodies. 4DMT is currently advancing five product
candidates in clinical development: 4D-150 for wet AMD and DME,
4D-710 for cystic fibrosis lung disease, 4D-310 for Fabry disease
cardiomyopathy, 4D-125 for XLRP, and 4D-110 for choroideremia. The
4DMT preclinical product candidates in development are: 4D-175 for
geographic atrophy and 4D-725 for AATLD.
4D-150, 4D-710, 4D-310, 4D-125, and 4D-110 are our product
candidates in clinical development and have not yet been approved
for marketing by the US FDA or any other regulatory authority. No
representation is made as to the safety or effectiveness of 4D-150,
4D-710, 4D-310, 4D-125, or 4D-110 for the therapeutic uses for
which they are being studied.
4D Molecular Therapeutics™, 4DMT™, Therapeutic Vector
Evolution™, and the 4DMT logo are trademarks of 4DMT.
Forward Looking Statements:
This press release contains forward-looking statements within
the meaning of the Private Securities Litigation Reform Act of
1995, as amended, including, without limitation, implied and
express statements regarding the therapeutic potential, and
clinical benefits of 4DMT’s product candidates, as well as the
plans, announcements and related timing for the clinical
development of and regulatory interactions regarding 4D-710 and
4D-725. The words "may," “might,” "will," "could," "would,"
"should," "expect," "plan," "anticipate," "intend," "believe,"
“expect,” "estimate," “seek,” "predict," “future,” "project,"
"potential," "continue," "target" and similar words or expressions
are intended to identify forward-looking statements, although not
all forward-looking statements contain these identifying words. Any
forward looking statements in this press release are based on
management's current expectations and beliefs and are subject to a
number of risks, uncertainties and important factors that may cause
actual events or results to differ materially from those expressed
or implied by any forward-looking statements contained in this
press release, including risks and uncertainties that are described
in greater detail in the section entitled "Risk Factors" in 4D
Molecular Therapeutics’ most recent Quarterly Report on Form 10-Q
as well as any subsequent filings with the Securities and Exchange
Commission. In addition, any forward-looking statements represent
4D Molecular Therapeutics' views only as of today and should not be
relied upon as representing its views as of any subsequent date. 4D
Molecular Therapeutics explicitly disclaims any obligation to
update any forward-looking statements. No representations or
warranties (expressed or implied) are made about the accuracy of
any such forward looking statements.
Contacts:
Media:
Katherine SmithEvoke CanaleKatherine.Smith@evokegroup.com
Investors:
Julian PeiHead of Investor Relations and Corporate
Communicationsjpei@4dmt.com267-644-5097
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