4DMT Presents Positive Interim Data from Phase 1/2 AEROW Clinical Trial of Aerosolized 4D-710 for Modulator-Ineligible/-Intolerant Cystic Fibrosis at 47th European Cystic Fibrosis Conference
4D Molecular Therapeutics (Nasdaq: FDMT) announced positive interim data from its Phase 1/2 AEROW clinical trial of aerosolized 4D-710 for treating cystic fibrosis (CF) lung disease. Clinically meaningful improvements in pulmonary function (ppFEV1) were observed in 2 of 3 participants with mild to moderate baseline lung function impairment over 12 months. The treatment was well tolerated across all doses up to 1E15 vg, and widespread CFTR transgene expression was observed in lung biopsies from all participants. The 1E15 vg dose has been cleared for Phase 2 Dose Expansion, expected to begin in H2 2024, with further interim data anticipated in mid-2025.
- Clinically meaningful improvements in ppFEV1 at 12 months in 2 of 3 participants with mild to moderate baseline lung function (ppFEV1 50-80%).
- 4D-710 was well tolerated at doses up to 1E15 vg with no dose-limiting toxicities or serious adverse events.
- Widespread and dose-dependent CFTR transgene RNA and protein expression observed in all lung biopsies from participants.
- Pre-existing AAV immunity did not affect transgene expression, biological activity, or safety.
- Enrollment for Phase 2 Dose Expansion stage expected to begin in H2 2024, with next interim data update expected in mid-2025.
- Only 2 of 3 participants with baseline mild to moderate lung function impairment showed clinically meaningful improvement.
- A serious adverse event (pneumonitis) was previously reported in the high-dose cohort (2E15 vg), although it was resolved.
- The 2E15 vg dose will not be further evaluated due to it not providing significant benefits over the 1E15 vg dose.
- The Phase 2 Dose Expansion stage will only begin in H2 2024, delaying potential confirmation of clinical activity.
Insights
The interim data from the Phase 1/2 AEROW clinical trial demonstrating clinically meaningful improvements in lung function for cystic fibrosis patients is promising. The marked increase in ppFEV1 by 5-6% in participants with mild to moderate baseline lung impairment is a key indicator of the therapy's potential efficacy. This improvement suggests that aerosolized 4D-710 could become a viable treatment option, addressing a significant unmet medical need for patients who are ineligible or intolerant of existing CFTR modulator therapies. Furthermore, the observation that pre-existing AAV immunity did not impact transgene expression or safety indicates a potentially broader applicability of this gene therapy across the cystic fibrosis patient population. The durability of these effects over a 12-month period also suggests lasting benefits, which is critical for the chronic management of cystic fibrosis.
In the short term, these data could bolster investor confidence, particularly as the company progresses towards Phase 2. However, the long-term potential hinges on sustained efficacy and safety in larger cohorts, as well as successful progression to Phase 3 trials. Investors should remain mindful of the inherent uncertainties in early-stage clinical development but can view these results as a positive step forward.
From a financial perspective, the positive interim data from the AEROW clinical trial could significantly enhance 4DMT's valuation and market position. The observed improvements in lung function present a compelling case for potential future revenue streams, especially for a therapy targeting a large market disease like cystic fibrosis. The fact that 4D-710 has shown promise in modulator-ineligible and -intolerant patients opens up a niche yet substantial market segment, which could drive higher market penetration upon successful approval.
Moreover, the transition to Phase 2 Dose Expansion signifies critical progress in the drug development pipeline, which is often seen as a positive signal by the market. The anticipated start of enrollment in H2 2024 and the upcoming data update in mid-2025 provide clear milestones for investors to track. These future catalysts may contribute to stock price appreciation if the results continue to be favorable. Nonetheless, potential investors should remain cautious of the typical clinical and regulatory risks associated with drug development.
The gene therapy landscape for cystic fibrosis is highly competitive and innovative, making these interim results particularly noteworthy. The successful demonstration of widespread CFTR expression in airway cells and the absence of dose-limiting toxicities highlight the therapeutic's strong profile. The 4D-710's potential to address a segment of the cystic fibrosis population that isn't served by current treatments could position it favorably against existing therapies like those from Vertex Pharmaceuticals.
Given the significant market potential and the current lack of effective therapies for modulator-ineligible and -intolerant patients, 4D-710 could capture a significant market share if it continues to demonstrate efficacy and safety in further trials. The planned enrollment for Phase 2 and subsequent Phase 3 initiation in 2025 are critical milestones that could influence competitive positioning. Thus, keeping an eye on the progress and data updates from these stages will be essential for understanding 4DMT's market potential and competitive edge.
- Clinically meaningful improvements in ppFEV1 at 12 months observed in 2 of 3 participants with mild to moderate baseline lung function impairment (ppFEV1 50
-80% ) and >6 months follow up
- Aerosolized 4D-710 was well tolerated at doses up to 1E15 vg (n=6)
- Dose-dependent and widespread 4D-710-mediated CFTR transgene RNA and protein expression observed in all lung biopsies from all participants evaluated to date
- Pre-existing AAV immunity cross-reactive with A101 did not affect transgene expression, biological activity or safety
- 1E15 vg dose cleared for evaluation in Phase 2 Dose Expansion stage; enrollment expected to begin in H2 2024 and next interim data update expected in mid-2025
- Company to host live webcast today at 8:00 a.m. ET with Dr. Jennifer L. Taylor-Cousar, lead Principal Investigator in the AEROW clinical trial
EMERYVILLE, Calif., June 06, 2024 (GLOBE NEWSWIRE) -- 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% to100% - 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
- Complete resolution of previously reported serious adverse event (SAE) (pneumonitis not otherwise specified); ppFEV1 in this participant improved by
- 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
- 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% to53% - 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
- Dose-dependent CFTR∆R transgene RNA expression, with the mean % of airway epithelial cells testing positive ranging from
- 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%
- 2E15 vg Cohort: +
- Two of three participants with baseline mild to moderate lung function impairment (ppFEV1 40
- 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
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 Smith
Inizio Evoke Comms
Katherine.Smith@inizioevoke.com
Investors:
Julian Pei
Head of Investor Relations and Corporate Finance
Investor.Relations@4DMT.com
FAQ
What were the key findings from the interim data of the AEROW clinical trial for 4D-710?
What is the significance of the 1E15 vg dose in the AEROW clinical trial for 4D-710?
How did pre-existing AAV immunity affect the AEROW clinical trial results for 4D-710?
When is the next interim data update for the AEROW clinical trial expected?
What was the outcome of the high-dose (2E15 vg) cohort in the AEROW clinical trial?
