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 data from the
Phase 2 PRISM clinical trial evaluating intravitreal 4D-150 in wet
age-related macular degeneration (wet AMD) patients with severe
disease activity and a high treatment burden. Data presented at the
Angiogenesis, Exudation, and Degeneration 2024 Conference by Arshad
M. Khanani, M.D., M.A., FASRS, consisted of 24-week landmark
results from the randomized Phase 2 Dose Expansion cohort of the
PRISM clinical trial.
“We are thrilled today to announce positive interim results that
strongly validate 4D-150’s potential as a safe, convenient, durable
and transformational intravitreal therapeutic for wet AMD patients,
with a goal of preserving vision for the longer term,” said David
Kirn, M.D., Co-founder and Chief Executive Officer of 4DMT. “We
believe 4D-150 has the potential to disrupt the current treatment
paradigm in these patients and that these results continue to
highlight the power and value of our intravitreal R100 vector
invented at 4DMT. I would like to thank the patients and
investigators who are participating in the PRISM trial who helped
to achieve this important milestone.”
“We are pleased by the robust clinical activity demonstrated in
this severe disease activity patient population with high treatment
burden. We believe these positive interim Phase 2 results
demonstrate a differentiated product profile for the treatment of
wet AMD, including in these most difficult to treat patients that
have not been studied adequately in prior clinical trials,” said
Robert Kim, M.D., Chief Medical Officer. “We look forward to
discussions with regulators to align on a Phase 3 development plan
expedited by FDA RMAT and EMA PRIME designations to advance 4D-150
with the goal of providing a compelling new treatment option for
millions of patients suffering from these blinding VEGF-driven
retinal diseases.”
“Wet AMD is a chronic disease, and many of our patients require
long-term, frequent intravitreal injections. Unfortunately,
under-treatment and suboptimal disease control contribute to vision
loss in the real world," said Arshad M. Khanani, M.D., M.A., FASRS,
Director of Clinic Research at Sierra Eye Associates, Reno, Nevada.
"I am encouraged by the potential of a one-time intravitreal
injection of 4D-150 for treating wet AMD. Results from the Phase 1
and interim results from Phase 2 cohorts of the PRISM study confirm
that 4D-150 is well tolerated and maintains stable visual acuity in
previously treated high-need patients. 4D-150 also significantly
reduces treatment burden while effectively controlling disease
activity without fluid fluctuations. I believe 4D-150 has the
potential to revolutionize the treatment approach for our patients
with wet AMD, and I am looking forward to participating in the
Phase 3 trials."
Phase 2 PRISM Clinical Trial Dose Expansion Cohort
Background & Summary Baseline Characteristics
The Dose Expansion cohort of the PRISM study is a randomized,
controlled Phase 2 clinical trial evaluating 4D-150 in previously
treated wet AMD patients with severe disease activity (≥325 µm
central subfield thickness (CST) measured by optical coherence
tomography (OCT) and presence of subretinal or intraretinal fluid)
and a high treatment burden (≥6 anti-VEGF injections in the prior
12 months).
The trial enrolled 51 patients with severe disease activity and
treatment burden:
- Mean CST: 442 µm
- Mean anti-VEGF injections in the
prior 12 months (actual): 9.6
- Mean time since diagnosis (years):
3.1
Enrolled patients were randomized 2:2:1 to receive a single high
(3E10 vg/eye) or low (1E10 vg/eye) intravitreal dose of 4D-150 or
intravitreal aflibercept 2 mg every 8 weeks (control).
Phase 2 PRISM Topline Interim Results (Data cutoff:
January 19, 2024)
- A single intravitreal dose of
4D-150 demonstrated favorable safety results through the data
cutoff date (all ophthalmic exams through up to 48 weeks of
follow-up):
- No significant intraocular
inflammation
- High dose: None
- 97% (38 of 39 pts) completed
20-week prophylactic topical corticosteroid taper on schedule
- Low dose: Single eye at week 16 had
1+ anterior mixed (pigmented & white blood) cells, resolved by
next visit and completed prophylactic topical corticosteroid taper
by week 26
- All patients currently off
steroids
- No 4D-150–related serious adverse
events (SAEs) or study eye SAEs
- No hypotony, endophthalmitis,
retinal vasculitis, choroidal effusions, or retinal artery
occlusions
- 24-week landmark analysis for key
efficacy endpoints:
- Treatment burden reduction:
- 89% and 85% reduction in annualized
anti-VEGF injection rates in the high (3E10 vg/eye) and low (1E10
vg/eye) 4D-150 dose arms, respectively
- 84% and 90% of patients received 0
or 1 supplemental aflibercept injection in the high and low 4D-150
dose arms, respectively
- 63% and 50% of patients were
supplemental aflibercept injection-free in the high and low 4D-150
dose arms, respectively
- Visual and retina anatomic outcomes
(difference in the average of week 20 & 24 adjusted mean change
from baseline vs. aflibercept control arm):
- Best corrected visual acuity
(BCVA): –1.8 and +1.8 Early Treatment Diabetic Retinopathy Study
(ETDRS) letters for the 3E10 and 1E10 vg/eye 4D-150 dose arms,
respectively
- Central subfield thickness (CST):
–8.3 and +29.9 µm for the 3E10 and 1E10 vg/eye 4D-150 dose arms,
respectively; highlights notable reduction in retinal anatomical
variability in high dose arm across all timepoints
PRISM Phase 1 Long-Term Follow-Up Update (Data cutoff:
January 19, 2024)
- Safety results maintained in all 15
patients treated to date (up to 104 weeks of follow-up) with no new
inflammation and no change in steroid status
- Three patients treated with high
dose (3E10 vg/eye) 4D-150 were previously reported to be
injection-free after 52 weeks of follow-up; all 3 patients remained
injection-free through 80–104 weeks (up to 2 years) of
follow-up
Additional 4D-150 Program Updates
- 110 patients have been enrolled and
dosed to date with 4D-150 in the following cohorts: PRISM Dose
Exploration (N=15), Dose Expansion (N=41, excluding control arm),
Population Extension (N=32), and SPECTRA Dose Confirmation (N=22)
- No clinically significant
treatment-emergent inflammation reported
- Enrollment
completed ahead of schedule in Phase 2 PRISM Population Extension
cohort evaluating 4D-150 in wet AMD patients with broader disease
severity (no minimum CST) and lower treatment burden (1-6 anti-VEGF
injections in prior 12 months, ≥1 in last 12 weeks), with 32
patients dosed with 3E10 or 1E10 vg/eye of 4D-150
- Pivotal study planning ongoing with
FDA and EMA under RMAT and PRIME designations
- 4DMT plans for the first Phase 3
study to be a BCVA non-inferiority study vs aflibercept 2 mg every
8 weeks; 3E10 vg/eye has been selected as study dose
- Application of preliminary Phase 3
eligibility criteria for BCVA and CST to the PRISM Dose Expansion
Phase 2 study (16 of 20 in high dose 4D-150 arm and 6 of 10 in
aflibercept arm met criteria) demonstrated:
- BCVA: +3.3 letters favoring high
dose 4D-150 vs. aflibercept
- CST: –99.0 µm favoring high dose
4D-150 vs. aflibercept
- Anti-VEGF treatment burden: 90%
reduction in annualized injection rate (88% received 0 or 1
injection, 63% were injection-free)
- Enrollment and dosing completed in
Phase 2 SPECTRA Part 1 Dose Confirmation cohort evaluating 4D-150
in diabetic macular edema (DME), with 22 patients dosed with 3E10
or 1E10 vg/eye of 4D-150
Upcoming 4D-150 Milestones
- Additional FDA and EMA interactions
planned in Q2 2024, with an update expected in Q3 2024
- Phase 2 PRISM Population Extension
cohort evaluating 4D-150 in wet AMD patients with broader disease
severity: Initial interim 24-week landmark data analysis is
expected in H2 2024
- Phase 2 SPECTRA Part 1 Dose
Confirmation cohort evaluating 4D-150 in DME: Initial interim
24-week landmark data analysis is expected in H2 2024
- Initiation of first Phase 3 study
is expected in Q1 2025
A slide presentation with detailed results can be accessed
here.
Corporate Webcast Details to Discuss the
Results:
Title: |
4D-150 Randomized Phase 2 Dose
Expansion in Severe Disease Activity Wet AMD with High Treatment
Burden: Interim Clinical Data & Program Update |
Date/Time: |
Monday, February 5, 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 at the following link:
https://ir.4dmoleculartherapeutics.com/events.
About 4D-150 for Wet AMD
4D-150 is comprised of our customized and evolved intravitreal
vector, R100, and a transgene cassette that expresses both
aflibercept and a VEGF-C inhibitory RNAi. This dual-transgene
payload inhibits four members of the VEGF angiogenic family of
factors that drive wet AMD and DME: VEGF A, B, C and PlGF. R100 was
invented at 4DMT through our proprietary Therapeutic Vector
Evolution platform; we developed this platform utilizing principles
of directed evolution, a Nobel Prize-winning technology. 4D-150 is
designed for single, low-dose intravitreal delivery for transgene
expression from the retina without significant inflammation.
About Wet AMD
Wet AMD is a highly prevalent disease with estimated incidence
rate of 200,000 new patients per year in the United States. It is
estimated that the total prevalence of wet AMD in certain major
markets, including the United States and the European Union (major
markets), and Japan, will be greater than 4 million individuals in
the next five years. Wet AMD is a type of macular degeneration
where abnormal blood vessels (choroidal neovascularization or CNV)
grow into the macula, the central area of the retina. As a
consequence, CNV causes swelling and edema of the retina, bleeding
and scarring, and causes visual distortion and reduced visual
acuity. The proliferation and leakage of abnormal blood vessels is
stimulated by VEGF. This process distorts and can potentially
destroy central vision and may progress to blindness without
treatment.
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 helps 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™, 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 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-150. 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
CommunicationsInvestor.Relations@4DMT.com267-644-5097
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