4D Molecular Therapeutics (Nasdaq: FDMT, 4DMT or the Company),
a leading clinical-stage genetic medicines company focused on
unlocking the full potential of genetic medicines to treat large
market diseases, today announced positive interim clinical data
from the 4D-710 Phase 1/2 AEROW clinical trial for the treatment of
cystic fibrosis (CF) lung disease. Interim data from the study will
be presented by Jennifer L. Taylor-Cousar, M.D., MSCS, in an oral
presentation titled, “CFTR transgene expression in airway
epithelial cells following aerosolized administration of the
AAV-based gene therapy 4D-710 to adults with cystic fibrosis lung
disease,” at the 47th European Cystic Fibrosis Conference held in
Glasgow, UK on Thursday, June 6 at 5:00 p.m. BST.
“We are pleased with the widespread CFTR transgene and protein
expression in airway cells from all participants at all doses in
the AEROW clinical trial,” said Jennifer L. Taylor-Cousar, M.D.,
MSCS, Professor, Departments of Medicine and Pediatrics, and
Co-Director, Adult Cystic Fibrosis Program, Director, Cystic
Fibrosis Therapeutics Development Center, National Jewish Health
and lead Principal Investigator in the AEROW clinical trial. “The
consistent widespread 4D-710–mediated CFTR expression and initial
clinical activity in Phase 1 are encouraging and suggest that
4D-710 has the potential to be the first treatment option for those
living with cystic fibrosis who do not currently benefit from
available disease-modifying therapies.”
“The clinical data to date from the AEROW clinical trial
continues to strongly support the advancement of 4D-710 to the next
stage of development for CF lung disease,” said Alan H. Cohen,
M.D., SVP, Therapeutic Area Head of Pulmonology of 4DMT. “Based on
the emerging favorable safety and clinical activity profile, we
look forward to beginning our Phase 2 Dose Expansion stage in
participants with mild to moderate lung function impairment, to
confirm the clinical activity of the 1E15 vg dose.”
“The interim data we shared today from the AEROW clinical trial
continues to showcase the breadth and depth of our platform,
product engine and pipeline,” said David Kirn, M.D., Co-Founder and
Chief Executive Officer of 4DMT. “4D-710 is well positioned as the
lead program in our pulmonology portfolio as we move into mid to
late-stage development. These clinical results also support
continued use of our next-generation A101 pulmonary vector for
large-market lung diseases such as alpha-1 antitrypsin deficiency
lung disease, for which we are developing 4D-725, an aerosolized
genetic medicine currently in IND-enabling preclinical
studies.”
AEROW Clinical Trial Phase 1 Dose Exploration Stage
Background & Summary
- 10 participants with CF lung disease
who are ineligible for or intolerant of CFTR modulator therapy have
been enrolled in the Phase 1 Dose Exploration stage across four
dose cohorts:
- 2E15 vg Cohort: n=4
- 1E15 vg Cohort: n=3
- 5E14 vg Cohort: n=2
- 2.5E14 vg Cohort: n=1
- Participants enrolled in the Phase 1
Dose Exploration stage had a broad range of baseline ppFEV1
impairment ranging from 56% to 100%
- Participants received a single
aerosolized dose of 4D-710 administered via an AeroEclipse II
breath-actuated nebulizer
- All results below are based on best
available data as of May 24, 2024
Interim Safety Data
- High Dose – 2E15 vg (n=4):
- Complete resolution of previously
reported serious adverse event (SAE) (pneumonitis not otherwise
specified); ppFEV1 in this participant improved by 6% from baseline
to month 12 (last timepoint assessed)
- Lung biopsy results:
- No evidence of inflammation or
toxicity from histological analysis of tissue samples
- Widespread expression of CFTR
protein compared to normal (non-CF) lung samples and no increase
vs. 1E15 vg dose
- Evidence of consistent CFTR protein
expression in all major airway epithelial cell types, as well as in
interstitial tissue cells; interstitial CFTR expression was not
detected in normal lung control samples
- Based on all available data for 2E15
and 1E15 vg dose level participants, 1E15 vg was selected as the
highest dose for Dose Expansion; 2E15 vg dose will not be further
evaluated
- Lower Doses – 2.5E14 to 1E15 vg
(n=6):
- 4D-710 was well tolerated, with no
4D-710–related adverse events after administration, no
dose-limiting toxicities, and no SAEs
Interim CFTR Biomarker Data
- Biomarker analyses demonstrated
robust, consistent and widespread CFTRDR transgene mRNA and CFTR
protein expression throughout all lung biopsy samples from all
participants at all four dose levels
- Dose-dependent CFTR∆R transgene RNA
expression, with the mean % of airway epithelial cells testing
positive ranging from 14% to 53%
- Robust, widespread and above-normal
CFTR protein expression at all doses
- Protein levels in lung tissue from
4D-710–treated participants 2–4 fold higher than in normal (non-CF)
samples, and ~8-12 fold higher than in CF lung samples
- Protein expression observed in
multiple airway epithelial cell types, including basal cells
- Pre-existing AAV immunity that
cross-reacted with A101 did not affect transgene expression,
biological activity or safety; transgene expression levels,
clinical activity and safety were similar regardless of
pre-existing immunity
Interim Clinical Activity Data
- All participants in 2E15 vg and 1E15
vg Cohorts had at least 12 months of follow up (maximum duration of
ppFEV1 assessments per original protocol) and had generally stable
or improved in ppFEV1 at 12 months
- Two of three participants with
baseline mild to moderate lung function impairment (ppFEV1 40-80%)
showed clinically meaningful improvement in ppFEV1 at 12 months:
- 2E15 vg Cohort: +6%
- 1E15 vg Cohort: +5%
- Quality of Life (CFQ-R-R) scores in
1E15 vg Cohort showed durable and clinically meaningful mean
improvement throughout 12 months
Next Steps and Upcoming Expected Milestones for
4D-710
- Advancing to AEROW Phase 2 Dose
Expansion stage (n= up to 9), enrollment to begin in H2 2024
- 1E15 vg dose level cleared for
enrollment
- Inclusion of 5E14 vg dose pending
enrollment and follow-up of third participant in Phase 1
- Amendment to AEROW protocol
submitted to the Cystic Fibrosis Foundation-supported Therapeutics
Development Network to open a new cohort to evaluate 4D-710 in
participants on CFTR modulators with persistent moderate to severe
CF lung disease; enrollment expected to begin in H2 2024
- Interim data update from AEROW
clinical trial is expected in mid-2025
- Following supportive Phase 2 data,
Phase 3 initiation is expected in H2 2025
Corporate Webcast Details:
Title: |
4D-710 Phase 1/2 AEROW Interim
Clinical Data & Program Update |
Date/Time: |
Thursday, June 6, 2024 at 8:00
a.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: https://ir.4dmoleculartherapeutics.com/events.
The presentation from the 47th European Cystic Fibrosis
Conference will also be available on the 4DMT website:
https://4dmoleculartherapeutics.com/pipeline/#posters-and-publications.
About Cystic Fibrosis Lung Disease
Cystic fibrosis (CF) is an inherited progressive disease caused
by variants in the CFTR gene. It affects the lungs, pancreas and
other organs. According to the Cystic Fibrosis Foundation, nearly
40,000 people in the United States and more than 105,000 people
worldwide are living with CF, with approximately 1,000 new cases of
CF diagnosed in the United States each year. Lung disease is the
leading cause of morbidity and mortality in people with CF. CF
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 CF require lifelong treatment with multiple
daily medications. The complications of the disease result in
progressive loss of lung function, increasing need for IV
antibiotics and hospitalizations, and ultimately leading to
end-stage respiratory failure.
About 4D-710
4D-710 combines our targeted and evolved next generation AAV
vector, A101, with a codon-optimized CFTR∆R transgene. 4D-710 has
the potential to treat a broad range of people with CF, independent
of the specific CFTR mutation, and is designed for aerosol delivery
to achieve targeted CFTR expression within lung airway epithelial
cells. 4D-710 is being developed for approximately 35% of people
with CF initially. The AEROW Phase 1/2 clinical trial focuses
initially on the ~15% of people with CF whose disease is not
amenable to existing CFTR modulator medicines (based on
variant-eligibility and/or drug intolerance). In people with CFTR
variants that are amenable to modulator medicines, the improvement
in lung function is variable and often incomplete. We therefore
expect to develop 4D-710 for use in this broader “on modulator”
population. 4D-710 has received the Rare Pediatric Disease
Designation and Orphan Drug Designation from the U.S. Food and Drug
Administration (FDA).
About 4DMT
4DMT is a leading clinical-stage genetic medicines company
focused on unlocking the full potential of genetic medicines to
treat large-market diseases in ophthalmology and pulmonology.
4DMT’s proprietary invention platform, Therapeutic Vector
Evolution, 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 wholly owned and partnered product
candidates. Our product design, development, and manufacturing
engine help us efficiently create and advance our diverse product
pipeline with the goal of revolutionizing medicine with potential
curative therapies for millions of patients. Currently, 4DMT is
advancing five clinical-stage and two preclinical product
candidates, each tailored to address rare and large market diseases
in ophthalmology, pulmonology and cardiology. In addition, 4DMT is
also advancing programs in CNS through a gene editing partnership.
4D Molecular Therapeutics™, 4DMT®, 4D®, Therapeutic Vector
Evolution™, and the 4DMT logo are trademarks of 4DMT.
All of our product candidates are in clinical or preclinical
development and have not yet been approved for marketing by
the U.S. Food and Drug Administration (FDA) or any other
regulatory authority. No representation is made as to the safety or
effectiveness of our product candidates for the therapeutic uses
for which they are being studied.
Learn more at www.4DMT.com and follow us on LinkedIn.
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 SmithInizio Evoke
CommsKatherine.Smith@inizioevoke.com
Investors:
Julian PeiHead of Investor Relations and Corporate
FinanceInvestor.Relations@4DMT.com
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