Difluprednate

- 6E10 combined with local prophylaxis selected for Phase 3 pivotal trials, with a favorable safety profile and potential best-in-class product profile at 26 weeks - Efficacy: 76% of 6E10 patients were injection free, with maintained visual acuity and fluid control - Safety: 100% of 6E10 difluprednate-alone patients had no or minimal inflammation, and none received corticosteroids for treatment of inflammation beyond the scheduled prophylaxis - Patient Preference Survey: 88% of patients indicated a preference for Ixo-vec over their prior anti-VEGF injections, and 93% would opt to receive Ixo-vec in the other eye - Efficacy and safety with 6E10 at 26-weeks similar to or better than in OPTIC at 2E11, where clinical benefit was demonstrated beyond 3 years - LUNA 9-month landmark analysis and pivotal trial design update anticipated in 4Q 2024 - Webcast to be held today Wednesday, July 17 at 8:00 a.m. EST REDWOOD CITY, Calif., July 17, 2024 (GLOBE NEWSWIRE) -- Adverum Biotechnologies, Inc. (Nasdaq: ADVM), a clinical-stage company pioneering the use of gene therapy as a new standard of care for highly prevalent ocular diseases, today announced results from the landmark 26-week interim analysis of the ongoing LUNA Phase 2 trial of Ixo-vec in patients with wet age-related macular degeneration (AMD). These data are being presented today by Dr. Charles Wykoff at the 42nd Annual Meeting of the American Society of Retinal Specialists in Stockholm, Sweden. “In LUNA, the 26-week landmark analysis demonstrates that Ixo-vec has a potential best-in-class product profile, combining a favorable safety profile and an industry-leading proportion of patients who are free of injections, supporting our selection of the 6E10 dose with a local prophylactic regimen for Phase 3 pivotal studies,” stated Laurent Fischer, M.D., president and chief executive officer of Adverum Biotechnologies. “Our pre-specified Patient Preference Survey, presented today for the first time, supports what we have long believed, that patients want to preserve long-term vision and be free of injections and are not deterred by corticosteroid prophylaxis. Over the next couple quarters, we plan to present data at important 9 month and 1 year timepoints. In OPTIC, nearly all patients who were injection free at 1 year continued to be injection free beyond 3 years.” “The LUNA trial was designed to answer a key question – whether lower doses of Ixo-vec combined with enhanced prophylactic regimens could demonstrate a product profile consistent with or better than that demonstrated in OPTIC. The landmark 6-month interim analysis has achieved this objective,” stated Star Seyedkazemi, Pharm.D., chief development officer of Adverum. “Importantly, at the LUNA 26-week interim analysis, 100% of 6E10 patients have no or minimal inflammation, and no participants received corticosteroids for treatment of inflammation beyond the scheduled prophylaxis. 76% of patients receiving 6E10 are injection free, with stable visual acuity and fluid control. In addition, in the 10 patients who were previously treated with the bi-specific therapy Vabysmo™, all are free of injections, highlighting the ongoing unmet need even with recently approved anti-VEGF therapies.” “Recent data demonstrating that up to 42% of patients stop treatment for wet AMD after 3 years highlights that difficulty with adherence to a regimen of repeated frequent intravitreal injections results in less-than-optimal vision outcomes. This underscores a tremendous unmet need for longer-acting anti-VEGF therapies. As a principal investigator in all of the Ixo-vec gene therapy clinical studies over the last 5+ years, I believe the latest data further demonstrate that Ixo-vec has the potential to shift the treatment paradigm for patients with wet AMD,” said Charles Wykoff, MD, PhD, Director of Research, Retina Consultants of Texas, Professor of Clinical Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital. “From this LUNA landmark analysis and consistent with preclinical data, moving to the lower 6E10 dose resulted in less inflammation while maintaining clinical activity that would represent a significant reduction in treatment burden for many of my patients relative to the standard of care. Importantly, inflammation thus far appears to be clinically manageable and, when present, responsive to local corticosteroids that are well tolerated and routine to administer. I believe Ixo-vec has the potential to deliver a promising product profile for patients, and I look forward to working with the Adverum team as Ixo-vec advances toward pivotal studies next year.” LUNA Trial Background and Baseline Demographics The LUNA trial is an ongoing double-masked, randomized Phase 2 trial. 60 patients with wet AMD were enrolled equally across two dose cohorts, 6E10 or 2E11 vg/eye. The trial is designed to inform the selection of Ixo-vec dose(s) and corticosteroid prophylactic regimen(s) for Phase 3 registrational trials. In addition to assessing the two doses of Ixo-vec, LUNA is evaluating enhanced prophylactic regimens, with patients receiving one of two locally administered corticosteroid regimens, with or without oral prednisone. As of the February 14, 2024 data cut-off date for the landmark interim analysis, 58 patients had completed the 26-week study visit, with two discontinuations related to adverse events unrelated to study drug. The trial was designed to assess a broad wet AMD population, including patients requiring frequent anti-VEGF injections before enrolling in LUNA: at baseline, mean annualized prior anti-VEGF injections were 10.1 (2.6 SD), mean central subfield thickness was 350.6 (115.2 SD), and mean BCVA was 72.3 (7.7). At the interim analysis,100% (n=20) of patients receiving the difluprednate-alone prophylactic regimen have completed their prophylaxis regimen, enabling evaluation of this regimen. As previously reported in February 2024, the company implemented a protocol amendment to extend the Ozurdex®-containing regimens with a course of difluprednate drops. As a result of this protocol amendment extending prophylaxis beyond the 26-week interim analysis landmark for some patients, 35.6% of patients in the Ozurdex + difluprednate prophylactic arm have not completed the scheduled regimen as of the 26-week interim analysis data cut-off date, limiting our ability to fully evaluate this prophylactic arm at the interim analysis. The LUNA trial builds on our experience with the OPTIC study, for which landmark 2-year data was published in The Lancet’s eclinicalmedicine and landmark 3-year data was presented at the American Academy of Ophthalmology 2023 Annual Meeting. LUNA Efficacy and Safety Results from the Pre-Specified 26-week Interim Analysis Both the 6E10 and 2E11 doses demonstrated maintenance of visual and anatomic outcomes. Notably, both doses resulted in a potentially best-in-class percentage of patients remaining free of anti-vascular endothelial growth factor (VEGF) injections and reduction in annualized anti-VEGF injections and, with data trending similar to or better than the OPTIC study. Treatment Burden Reduction Ixo-vec demonstrated a significant proportion of patients injection free at both doses at week 26. 6E10: 76% of patients injection free (n=29)2E11: 83% of patients injection free (n=29) Ixo-vec demonstrated a significant reduction in mean annualized anti-VEGF injections at week 26. 6E10: 90% reduction in mean annualized anti-VEGF injections2E11: 95% reduction in mean annualized anti-VEGF injections Visual (BCVA) and Anatomic (CST) Outcomes: Visual acuity was maintained at both dose levels – least squares mean BCVA change from baseline at week 26 (95% CI): 6E10: -1.1 (-3.5, 1.2)2E11: -2.2 (-4.5, 0.2) Fluid control was maintained at both dose levels – least squares mean CST (μm) change from baseline at week 26 (95% CI): 6E10: -12.6 (-30.2, 5.0)2E11: -12.0 (-30.0, 6.0)Sub-group with CST >300 μm at baseline (n=33): -30.2 (-55.2, -5.1) Safety Summary Ixo-vec was well tolerated at both doses. No Ixo-vec-related serious adverse eventsNo episcleritis, vasculitis, retinitis, choroiditis, vascular occlusion, or hypotonyAll Ixo-vec-related adverse events were either mild or moderate. The most common Ixo-vec-related adverse events were dose-dependent anterior inflammation responsive to local corticosteroids and anterior pigmentary changes with no impact on vision Improved inflammatory profile observed with enhanced corticosteroid prophylaxis in LUNA as compared to OPTIC. Oral prednisone did not demonstrate incremental benefit.Ozurdex without difluprednate did not provide adequate prophylaxis. Safety Sub-group Analysis of the Difluprednate-Alone Prophylactic Regimen 100% (n=20) of patients receiving the difluprednate-alone prophylactic regimen have completed their prophylaxis, enabling evaluation of this regimen at the interim analysis.Inflammation was dose-dependent and, when present, was responsive to local corticosteroids. 6E10 (n=10): 100% of patients have no or minimal inflammation (0 or 0.5+ AC cells) at the 26-week timepoint. No participants at 6E10 received corticosteroids for treatment of inflammation beyond the scheduled prophylaxis. 2E11 (n=10): 90% of patients have no or minimal inflammation at the 26-week timepoint. Topical difluprednate effectively managed inflammation when present. Patient Preference Survey 26-Week Results For the LUNA interim analysis, a pre-specified Patient Preference Survey was performed at week 26 to understand patient preferences after receiving Ixo-vec, including whether patients preferred Ixo-vec, along with the accompanying prophylactic regimen, over prior treatments and whether patients would elect to receive Ixo-vec in the fellow eye.At the 26-week landmark analysis, 88% of the entire LUNA patient population responded that they would prefer Ixo-vec therapy over the prior treatment(s) they received, and 93% responded that they would want to receive Ixo-vec in the fellow-eye if they had bilateral disease.Of the patients receiving 6E10 and the difluprednate-alone prophylactic regimen: 100% responded that they would prefer Ixo-vec therapy over the prior treatments received; and,100% responded that they would want to receive Ixo-vec in the fellow eye. Upcoming Anticipated Milestones 2H 2024: Continued FDA and EMA formal and informal regulatory interactions4Q 2024: Presentation of landmark LUNA 9-month analysis4Q 2024: Phase 3 pivotal trial design update1Q 2025: Presentation of landmark LUNA 52-week analysisH1 2025: Planned initiation of Phase 3 trial Webcast Details The live webcast will be accessible under Events and Presentations in the Investors section of the company's website. Listeners can register for the webcast via this webcast link. Analysts wishing to participate in the question-and-answer session should use this dial-in link. A replay of the webcast will be available on the company’s website shortly after the conclusion of the webcast. About Wet Age-Related Macular Degeneration Wet AMD, also known as neovascular AMD or nAMD, is a VEGF driven advanced form of AMD affecting approximately 10% of patients living with AMD associated with the build-up of fluid in the macula and the retina. Wet AMD is a leading cause of blindness in people over 65 years of age, with approximately 20 million individuals worldwide living with this condition. New cases of wet AMD are expected to grow significantly worldwide as populations age. AMD is expected to impact 288 million people worldwide by 2040, with wet AMD accounting for approximately 10% of those cases. Additionally, wet AMD is a bilateral disease, and incidence of nAMD in the second eye is up to 42% in the first two to three years. The current standard of care requires frequent life-long repeated bolus injections of anti-VEGF in the eye. IVT gene therapy has the promise to preserve vision and reduce most or all injections for the life of the patient by delivering stable therapeutic levels of anti-VEGF to control macular fluid. About Ixo-vec in Wet AMD Adverum is developing ixoberogene soroparvovec (Ixo-vec, formerly referred to as ADVM-022), its clinical-stage gene therapy product candidate, for the treatment of wet AMD. Ixo-vec utilizes a proprietary vector capsid, AAV.7m8, carrying an aflibercept coding sequence under the control of a proprietary expression cassette. Unlike other ophthalmic gene therapies that require surgery to administer the gene therapy under the retina (sub-retinal approach), Ixo-vec is designed to be administered as a one-time IVT injection in the physician’s office, deliver long-term efficacy, reduce the burden of frequent anti-VEGF, optimize patient compliance and improve vision outcomes for patients with wet AMD. In recognition of the need for new treatment options for wet AMD, FDA granted Fast Track designation for Ixo-vec for the treatment of wet AMD. Ixo-vec has also received PRIME designation from the EMA and the Innovation Passport from the United Kingdom’s Medicines and Healthcare Products Regulatory Agency for the treatment of wet AMD. About Adverum Biotechnologies Adverum Biotechnologies (NASDAQ: ADVM) is a clinical-stage company that aims to establish gene therapy as a new standard of care for highly prevalent ocular diseases with the aspiration of developing functional cures to restore vision and prevent blindness. Leveraging the capabilities of its proprietary intravitreal (IVT) platform, Adverum is developing durable, single-administration therapies, designed to be delivered in physicians’ offices, to eliminate the need for frequent ocular injections to treat these diseases. Adverum is evaluating its novel gene therapy candidate, ixoberogene soroparvovec (Ixo-vec, formerly referred to as ADVM-022), as a one-time, IVT injection for patients with neovascular or wet age-related macular degeneration. Additionally, by overcoming the challenges associated with current treatment paradigms for debilitating ocular diseases, Adverum aspires to transform the standard of care, preserve vision, and create a profound societal impact around the globe. For more information, please visit www.adverum.com. Forward-looking Statements Statements contained in this press release regarding events or results that may occur in the future are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements include but are not limited to statements regarding the favorable safety profile and potential best-in-class efficacy of Ixo-vec, anticipated timing of interim data and trial design update for the Phase 2 LUNA trial and initiation of a Phase 3 trial, and the potential of Ixo-vec to shift the treatment paradigm for patients with wet AMD. Actual results could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, including risks inherent to, without limitation: Adverum’s novel technology, which makes it difficult to predict the timing of commencement and completion of clinical trials; regulatory uncertainties; enrollment uncertainties; the results of early clinical trials not always being predictive of future clinical trials and results; and the potential for future complications or side effects in connection with use of Ixo-vec. Additional risks and uncertainties facing Adverum are set forth under the caption “Risk Factors” and elsewhere in Adverum’s Securities and Exchange Commission (SEC) filings and reports, including Adverum’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2024 filed with the SEC on May 9, 2024 and subsequent filings with the SEC. All forward-looking statements contained in this press release speak only as of the date on which they were made. Adverum undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law. Inquiries: Adverum Investor Relations Email: ir@adverum.com

"On first blush," Mizuho analysts have dubbed Adverum Biotechnologies’ new data positive. Adverum Biotechnologies' gene therapy for wet age-related macular degeneration (AMD) reduced treatment burden and maintained visual acuity in a phase 2 study, though a full picture can't be formed yet from the slice of early data. The company's stock has fallen 18% to $2.28 compared to yesterday's market close price of $2.80 as of 10:45 a.m. ET today. The data center around ixo-vec, an AAV-based gene therapy formerly known as ADVM-022 but renamed in 2022. Adverum had previously assessed the intravitreal injection in diabetic macular edema, an effort that was eventually discontinued after a patient went blind in the treated eye. Now, interim ixo-vec data come from a phase 2 wet AMD study dubbed LUNA, with Adverum claiming the preliminary results demonstrate "potential best-in-class clinical activity in hard-to-treat patients including treatment burden reduction and maintenance of both visual acuity and anatomic endpoints." The phase 2, double-masked trial is designed to evaluate the safety and efficacy of a single IVT injection of ADVM-022 at one of two doses, a high dose (2E11 vg/eye) and low dose (6E10 vg/eye), accompanied by one of four prophylactic corticosteroid treatment regimens designed to reduce anticipated inflammation that is associated with AAV-based gene therapy. Among the 60 patients in the trial, no serious adverse events tied to the gene therapy were reported, according to Adverum. The biotech said ixo-vec was generally well tolerated, though specific safety data were not shared. According to Adverum, the best performing prophylactic regimen appears to be a combination of Ozurdex and Durezol eye drops, with "the vast majority of patients" receiving the combo having no inflammation and over 90% of patients having minimal inflammation.   On the efficacy side, the biotech reported maintenance of both visual acuity and anatomic endpoints that measures central subfield thickness (CST). In a sub-group analysis of patients with higher baseline CST, a greater CST reduction was seen, according to Adverum. When looking at treatment burden reduction at 26 weeks, ixo-vec demonstrated annualized reduction in anti-vascular endothelial growth factor (anti-VEGF) injection rates of 90% among the 19 patients in the 6E10 cohort and 94% of the 20 patients in the 2E11 arm. At 26 weeks, ixo-vec demonstrated injection free rates of 68% for the 6E10 group and 85% of the patients in the 2E11 cohort. "Our goal with Ixo-vec is to provide patients virtually injection-free management of their wet AMD lasting years and potentially for life," Adverum CEO Laurent Fischer, M.D., said in a Feb. 8 release, dubbing ixo-vec a "one-and-done" gene therapy on a call with Fierce Biotech.  Mizuho analysts' "initial reaction" to the data was positive: "On first blush, we saw no serious adverse events, and with respect to efficacy, the data appear to be better than that recently reported from two wAMD gene therapy competitors over the past week." The analyst firm is referring to data from competitor 4D Molecular Therapies and Regenxbio, both of which recently dropped respective phase 2 data in the indication.     4DMT reported an 89% and 85% reduction in annualized anti-VEGF injection rates in its high (3E10 vg/eye) and low (1E10 vg/eye) dose arms for 4D-150, rates slightly lower than those seen for Adverum. Regenxbio’s AbbVie-partnered ABBV-RGX-314 demonstrated the highest reduction in treatment burden in more than 50 patients receiving the third dose level, with an 80% reduction in annualized injection rate. Mizuho wasn’t quick to form a hard opinion, though, noting that “it may take time to fully digest the totality of this data set and others before we understand fully the efficacy and safety profile of ixo-vec and how it may stack up against its competitors.” Adverum is expected to share a 26-week interim analysis from LUNA in mid-2024. The biotech anticipates engaging in official discussions with the FDA about phase 3 trial design after those results are shared, Fischer told Fierce, with a potential phase 3 launch slated for the first half of 2025. Editor's note: This story was updated at 12:35 p.m. ET on Feb. 8 to include commentary from Adverum CEO Laurent Fischer.