Retinal Artery Occlusion

The primary endpoint miss was driven fully by the 20-week data, which was the only measure out of 10 in which UBX1325 was inferior to aflibercept.\n Unity Biotechnology’s investigational eye treatment failed to match Eylea at 20 weeks—part of the mid-stage trial’s primary endpoint and the only time stamp out of 10 in which the candidate was inferior to Regeneron’s blockbuster.Despite the miss, Mizuho analysts still highlighted possible paths forward for the candidate in a March 24 note.Investors didn\'t appear to be buying this optimistic outlook, sending Unity’s stock sliding 33% from $1.82 per share at market close last Friday to $1.20 as of 11 a.m. ET Monday.The topline results come from the California company’s phase 2b study, dubbed Aspire, which is evaluating intravitreal UBX1325, a small molecule designed to inhibit BCL-xL. The double-masked trial enrolled 52 patients with previously treated, active diabetic macular edema (DME).Participants were randomized to receive either 10 μg of UBX1325 or 2 mg of aflibercept—sold under brand names Eylea and Zaltrap—every eight weeks for six months.The study missed the primary endpoint, which measured non-inferiority compared to aflibercept using the average Best Corrected Visual Acuity (BCVA) letter change from baseline at 20 and 24 weeks.Across the 20- to 24-week average, patients in the UBX1325 arm gained 3.7 letters from baseline versus a 5.1 gain for patients in the control arm. The 88% confidence interval narrowly missed the 90% pre-specified threshold. While the combined measure was the study’s main endpoint, the miss was driven fully by the 20-week data, which was the only measure out of 10 across 36 weeks in which UBX1325 was inferior to aflibercept.At 24 weeks, the investigational treatment was tied to a 5.2 letter gain in visual acuity, compared to 4.8 in the control arm.Though complete data for 36-week treatment is expected later this quarter, a 5.5 letter gain was recorded for the patients (about 75% of total) included so far.Furthermore, the biotech’s data found that UBX1325 was actually superior to aflibercept at seven of the 10 time points in a pre-specified population with moderately aggressive disease. The population represents about 60% of patients and is a group Mizuho analysts flagged as a potential path forward for the drug.“We are excited that UBX1325 showed robust vision improvements in a difficult to treat patient population,” Unity CEO Anirvan Ghosh, Ph.D., said in a March 24 release. “The results also suggest that UBX1325 may provide greater vision gains than standard of care in patients with moderately aggressive disease. We look forward to advancing UBX1325 to late-stage studies against aflibercept in DME patients with inadequate response to anti-VEGF therapies.”The investigational treatment demonstrated a favorable safety and tolerability profile, with no cases of intraocular inflammation, retinal artery occlusion, endophthalmitis or vasculitis reported across multiple studies, according to Unity. Mizuho analysts pointed to the primary endpoint measure likely favoring aflibercept, more prior Vabysmo patients in the investigational arm and a longer average time of DME diagnosis for the UBX1325 arm as all possibly contributing to the study’s primary endpoint fail.  Previously, Unity tested out UBX1325 in wet age-related macular degeneration—also against Eylea. The candidate passed the main goal of a phase 2 trial that measured safety but failed to significantly improve vision for all patients when compared to the Regeneron blockbuster.It’s a great day for Regeneron as Unity is the second biotech to report a miss against its eye injection. Just this morning, Australia-based Opthea’s asset failed to match Eylea in a phase 3 test, leaving the biotech to question its own future.

Across all DME patients dosed to date, 4D-150 continues to be well tolerated with no intraocular inflammation observed at any timepoint or dose level 3E10 vg/eye demonstrated strong signals of clinical activity with sustained gain of BCVA of +8.4 letters and reduction of CST of -194 µm from baseline through Week 32 3E10 vg/eye achieved an 86% reduction in injection burden vs. projected on-label aflibercept 2mg Q8W and dose response with 61% reduction vs. 1E10 vg/eye, with 0.6 mean supplemental injections per patient through Week 32 FDA aligned with proposed single Phase 3 clinical trial being acceptable for the basis of a BLA submission for 4D-150 in DME, based on review of data from SPECTRA and PRISM (wet AMD) clinical trials to date and planned global Phase 3 clinical development program for wet AMD EMERYVILLE, Calif., Jan. 10, 2025 (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 topline interim data from Part 1 of the SPECTRA clinical trial evaluating 4D-150 in diabetic macular edema (DME) and alignment with the U.S. Food and Drug Administration (FDA) on registrational pathway for 4D-150 in DME. “The promising initial safety and clinical activity data of 4D-150 in DME patients, together with the promising results in wet age-related macular degeneration (wet AMD), reinforces the potential applicability of 4D-150 across multiple VEGF-driven retinal diseases,” said Carlos Quezada-Ruiz, M.D., FASRS, SVP, Therapeutic Area Head, Ophthalmology. “4D-150 represents a potentially transformative new therapeutic option for the approximately one million DME patients in the U.S. alone. 4D-150 has the potential to set a new backbone therapy providing multi-year sustained VEGF inhibition in the retina with a single, safe, intravitreal injection. If approved, 4D-150 could significantly reduce the need for frequent bolus injections and address the current real-world challenge of patient adherence to therapy, thereby leading to better disease management and vision outcomes.” Clinical Trial Design & Interim Data from 4D-150 SPECTRA Part 1 Clinical Trial (Data Cutoff of December 13, 2024): Objectives: Evaluate safety and tolerability and identify dose level for further evaluation Utilized stringent supplemental aflibercept criteria and enrolled patients with high central subfield thickness (CST) to maximize patient safety and assess initial clinical activity Study Population: 22 patients enrolled across 3 dose levels: 3E10 vg/eye (n=9), 1E10 vg/eye (n=12), 5E9 vg/eye (n=1); 1 patient in 1E10 vg/eye arm terminated the study due to death unrelated to 4D-150, prior to completion of a post-baseline assessment Safety (n=21): 4D-150 was well tolerated with no intraocular inflammation at any timepoint All patients completed the 16-week topical corticosteroid taper on schedule and remained completely off steroids No hypotony, endophthalmitis, vasculitis, choroidal effusions or retinal artery occlusions Efficacy Results Through 32 Weeks: 3E10 vg/eye arm: Sustained gain of best corrected visual acuity (BCVA) of +8.4 letters Sustained reduction of CST, as measured by optical coherence tomography (OCT), of -194 µm Supplemental injections: Post-aflibercept loading doses (3), 3E10 vg/eye achieved substantially fewer supplemental injections compared to 1E10 vg/eye and projected on-label aflibercept 2mg Q8W: Mean injections per patient: 3E10 vg/eye: 0.6, 1E10 vg/eye: 1.4, projected on-label aflibercept 2mg Q8W: 4.0 3E10 vg/eye demonstrated a reduction of 61% vs. 1E10 vg/eye 3E10 vg/eye demonstrated a reduction of 86% vs. projected on-label aflibercept 2mg Q8W 0-1 injections: 8 of 9 overall (3E10 vg/eye) vs. 5 of 10 (1E10 vg/eye, 1 patient missed Week 24-32 visits) Injection-free: 5 of 9 overall (3E10 vg/eye) vs. 2 of 10 overall (1E10 vg/eye) 5 of 8 in patients treated per protocol (3E10 vg/eye) Results to be presented in a corporate webcast on February 10, 2025 52-week interim data update expected at a scientific conference in mid-2025 Data slides can be found on the “Investors” section of the 4DMT website at https://ir.4dmoleculartherapeutics.com/ Utilized stringent supplemental aflibercept criteria and enrolled patients with high central subfield thickness (CST) to maximize patient safety and assess initial clinical activity 22 patients enrolled across 3 dose levels: 3E10 vg/eye (n=9), 1E10 vg/eye (n=12), 5E9 vg/eye (n=1); 1 patient in 1E10 vg/eye arm terminated the study due to death unrelated to 4D-150, prior to completion of a post-baseline assessment 4D-150 was well tolerated with no intraocular inflammation at any timepoint All patients completed the 16-week topical corticosteroid taper on schedule and remained completely off steroids No hypotony, endophthalmitis, vasculitis, choroidal effusions or retinal artery occlusions All patients completed the 16-week topical corticosteroid taper on schedule and remained completely off steroids 3E10 vg/eye arm: Sustained gain of best corrected visual acuity (BCVA) of +8.4 letters Sustained reduction of CST, as measured by optical coherence tomography (OCT), of -194 µm Supplemental injections: Post-aflibercept loading doses (3), 3E10 vg/eye achieved substantially fewer supplemental injections compared to 1E10 vg/eye and projected on-label aflibercept 2mg Q8W: Mean injections per patient: 3E10 vg/eye: 0.6, 1E10 vg/eye: 1.4, projected on-label aflibercept 2mg Q8W: 4.0 3E10 vg/eye demonstrated a reduction of 61% vs. 1E10 vg/eye 3E10 vg/eye demonstrated a reduction of 86% vs. projected on-label aflibercept 2mg Q8W 0-1 injections: 8 of 9 overall (3E10 vg/eye) vs. 5 of 10 (1E10 vg/eye, 1 patient missed Week 24-32 visits) Injection-free: 5 of 9 overall (3E10 vg/eye) vs. 2 of 10 overall (1E10 vg/eye) 5 of 8 in patients treated per protocol (3E10 vg/eye) Sustained gain of best corrected visual acuity (BCVA) of +8.4 letters Sustained reduction of CST, as measured by optical coherence tomography (OCT), of -194 µm Mean injections per patient: 3E10 vg/eye: 0.6, 1E10 vg/eye: 1.4, projected on-label aflibercept 2mg Q8W: 4.0 3E10 vg/eye demonstrated a reduction of 61% vs. 1E10 vg/eye 3E10 vg/eye demonstrated a reduction of 86% vs. projected on-label aflibercept 2mg Q8W 0-1 injections: 8 of 9 overall (3E10 vg/eye) vs. 5 of 10 (1E10 vg/eye, 1 patient missed Week 24-32 visits) Injection-free: 5 of 9 overall (3E10 vg/eye) vs. 2 of 10 overall (1E10 vg/eye) 5 of 8 in patients treated per protocol (3E10 vg/eye) 3E10 vg/eye: 0.6, 1E10 vg/eye: 1.4, projected on-label aflibercept 2mg Q8W: 4.0 3E10 vg/eye demonstrated a reduction of 61% vs. 1E10 vg/eye 3E10 vg/eye demonstrated a reduction of 86% vs. projected on-label aflibercept 2mg Q8W 8 of 9 overall (3E10 vg/eye) vs. 5 of 10 (1E10 vg/eye, 1 patient missed Week 24-32 visits) 5 of 9 overall (3E10 vg/eye) vs. 2 of 10 overall (1E10 vg/eye) 5 of 8 in patients treated per protocol (3E10 vg/eye) 4D-150 DME Phase 3 Regulatory Update & Next Steps 3E10 vg/eye has been selected as the Phase 3 dose Based on data generated to date for 4D-150 in both the SPECTRA and PRISM clinical trials, FDA is aligned that a single Phase 3 clinical trial, combined with data from the two planned Phase 3 clinical trials in the 4FRONT wet AMD program, would be acceptable as the basis of a BLA submission for 4D-150 in DME Per FDA feedback, the Company may proceed to Phase 3 (SPECTRA Part 2 no longer needed) and is aligned with key design elements of a Phase 3 clinical trial with approximately 300-400 patients total with a primary endpoint of BCVA noninferiority vs. on-label aflibercept 2mg (5 loading doses and Q8W), and revised supplemental injection criteria (less stringent compared to Part 1 SPECTRA, in line with prior successful Phase 3 DME clinical trials) Next steps for DME development to be presented in a corporate webcast on February 10, 2025 “The highly differentiated tolerability and promising clinical activity profile to date for 4D-150, and supportive feedback we received from the FDA in both wet AMD and DME, is a testament to 4D-150’s differentiated product design based on our proprietary R100 vector and our strong team, including our global Ophthalmology Advisory Board,” said David Kirn, M.D., Co-founder and Chief Executive Officer of 4DMT. “The alignment with the FDA on the design and path forward for a single Phase 3 trial in DME is a positive step forward in our ability to realize 4D-150’s potential as a pipeline-in-a-product, which may unlock DME as a second large market indication shortly after wet AMD." About 4D-150 4D-150 is a potential backbone therapy that is designed to provide multi-year sustained delivery of anti-VEGF (aflibercept and anti-VEGF-C) from the retina with a single, safe, intravitreal injection. 4D-150 utilizes our customized and evolved intravitreal vector, R100, which was invented at 4DMT through our proprietary Therapeutic Vector Evolution platform. 4D-150 is being developed for wet AMD and DME which both affect millions of patients globally, with the goal of freeing patients from burdensome injections while preserving vision. About DME DME, or diabetic macular edema, is a complication of diabetic retinopathy and is a highly prevalent disease with significant unmet medical need and poor treatment adherence. It is estimated that there are approximately one million individuals with DME in the U.S. according to published data. DME is characterized by inflammation swelling in the macula due to leakage from blood vessels, which can lead to vision loss. DME is typically treated with intravitreal anti-VEGF agents administered approximately every 4-12 weeks, although patient compliance with therapy is poor and results in high unmet medical need. About 4DMT 4DMT is a late-stage biotechnology 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 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 lead program 4D-150 is a potential backbone therapy that is designed to provide multi-year sustained delivery of anti-VEGF (aflibercept and anti-VEGF-C) targeted to the retina with a single, safe, intravitreal injection. Our second core program is 4D-710, which is the first known genetic medicine to demonstrate, in the lungs of people with cystic fibrosis (CF), successful delivery and expression of the CFTR transgene and initial clinical activity signals after aerosol delivery of a gene therapy. 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 and market potential 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 filed on November 13, 2024 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 Media@4DMT.com Investors: Julian Pei Head of Investor Relations and Corporate Finance Investor.Relations@4DMT.com

iStock, Love Employee 4D Molecular Therapeutics reported its experimental gene therapy demonstrated a nearly 90% reduction in the need for annualized standard-of-care injections in patients with wet age-related macular degeneration. 4D Molecular Therapeutics announced on Wednesday that its investigational gene therapy 4D-150 demonstrated durable clinical activity in the Phase I/II PRISM study of patients with wet age-related macular degeneration. In a 30-patient cohort, 4D-150 cut the need for standard-of-care injections by 89% through 52 weeks of follow-up, and 70% of these patients were injection-free, according to 4DMT’s announcement. In another cohort of 27 patients with severe disease, the need for standard-of-care treatment dropped by 83% and 44% were injection-free. The gene therapy also resulted in sustained benefits in terms of central subfield thickness and mean best-corrected visual acuity. In terms of safety, PRISM found 4D-150 to be well-tolerated. The frequency for of intraocular inflammation (IOI) was consistent with approved anti-VEGF therapies, which are currently widely used to treat age-related macular degeneration (AMD). Overall, 4DMT documented two IOI episodes in all 71 wet AMD patients enrolled, yielding an incidence rate of 2.8%. There were no cases of retinal artery occlusions, hypotony, vasculitis, choroidal effusions and endophthalmitis related to the gene therapy. 4DMT CEO David Kirn in a statement called 4D-150 a “potentially paradigm shifting product candidate,” noting that PRISM’s findings highlight “clear reduction in overall treatment burden and potential multiyear clinical benefit in previously treated patients.” The California-based biotech will continue to invest in 4D-150’s development, Kirn said, and push it into late-stage studies. Alongside the PRISM readout on Wednesday, 4DMT detailed the design of its Phase III 4FRONT development program for 4D-150, which is set to include two double-masked, randomized non-inferiority trials, compared with on-label treatment with Bayer and Regeneron’s Eylea (aflibercept). The gene therapy will be given at a single 3E10 vg/eye dose. The first study under this program, dubbed 4FRONT-1, has a target enrollment of 500 patients and is set to start in the first quarter of 2025, Kirn said. The Phase III program design is in alignment with feedback from the FDA under its Regenerative Medicine Advanced Therapy Designation, according to 4DMT. 4D-150 is an investigational gene therapy that uses an intravitreal vector to deliver a transgene that encodes for aflibercept—the active ingredient of Eylea—and an RNAi molecule that blocks the VEGF-C protein. This mechanism of action allows 4D-150 to suppress four different VEGF proteins in the eye, disrupting the key disease pathway in wet AMD. With 4D-150, 4DMT is seeking to offer a one-time alternative to Eylea, which is injected into the eye every eight weeks , following an initiation regimen. Eylea has become a top-selling treatment in the ophthalmology space. In 2023, the product brought in $5.9 billion in sales worldwide.