RGX-314

A human eye with DNA background Taylor Tieden for BioSpace With gene therapies by REGENXBIO and AbbVie, Adverum and others in mid- or late-stage trials, this therapeutic class could soon be an option for this common cause of blindness in the elderly. As gene therapies continue to transform the rare disease treatment landscape, a new generation is on the cusp of breaking through against a highly prevalent disease indication—wet age-related macular degeneration. Age-related macular degeneration (AMD) is the most common cause of vision loss in people over 60. The advanced stage of the disease, wet AMD, occurs in around 10% of cases and results in 90% of legal blindness. In 2019, around 1.5 million people in the U.S. were living with wet AMD. The potential reach of a gene therapy in this common disease space is in stark contrast to the current approved gene therapies for rare disease. REGENXBIO and partner AbbVie are currently conducting the “largest gene therapy program ever run” for their wet AMD candidate, REGENXBIO Chief Medical Officer Steve Pakola told BioSpace . “[Wet AMD gene therapy] is a pretty unique situation,” said Laurent Fischer, CEO of Adverum, a biotech with a mid-stage candidate in the works. Instead of a therapy that costs millions of dollars for thousands of people, he anticipates a price tag of tens of thousands of dollars for millions of people. Gene Therapy Turns Eye Into Drug Biofactory Currently approved gene therapies focus on repairing or replacing a faulty gene that causes the disease. In wet AMD, there is no defective gene, so companies are developing gene therapies to deliver an effective medicine to the eye, Rahul Khurana, a retina specialist at Northern California Retina Vitreous Associates, told BioSpace . Wet AMD is currently treated by anti-VEGF therapies, which block the molecules that lead to the leak of blood or fluid under the retina that blurs the central vision. Khurana said that while these therapies are effective, the burden of ongoing treatment in clinical practice is problematic, with patients regularly needing anti-VEGF injections. Khurana recently published a study showing that one in nine AMD patients treated with anti-VEGF injections became “lost to follow up” and one in seven are not persistent with therapy. “Gene therapy shows a lot of promise for a one-time therapy, or a longer duration therapy, to deliver medicine so patients do not keep returning for regular injections,” Khurana said. “It’s a very creative approach.” Gene therapies by Adverum, 4D Molecular Therapeutics, and REGENXBIO in collaboration with AbbVie are in mid- to late-stage clinical trials. Each involves injections to deliver a therapeutic protein but differs in where those injections are given—behind the retina at the back of the eye (sub-retinal), between the sclera and choroid near the eye’s outer surface (suprachoroidal) or into the fluid that fills the inside of the eye (intravitreal). Sub-Retinal Injection With a pivotal trial already underway, REGENXBIO and AbbVie are furthest along of all the wet AMD gene therapies in development. Pakola said the companies are on track to submit global registration applications in the first half of 2026. REGENXBIO/AbbVie’s ABBV-RGXX-314 is an AAV8 vector containing a gene encoding a monoclonal anti-VEGF antibody fragment. After injection, the retinal tissue produces the anti-VEGF therapeutic protein for an extended timeframe, Pakola explained. While follow up is ongoing for long-term efficacy, the partners have seen stable disease control beyond three and four years, with a dramatic reduction in injection burden, Pakola said. He added that results so far show an 80% reduction in required injections. According to Pakola, AAV8 is one of the most clinically validated vectors in terms of safety and efficacy. With the prescribed seven-week course of prophylactic topical steroids, REGENXBIO has not seen any intraocular inflammation. The sub-retinal delivery method keeps the gene therapy payload at the target tissue, minimizing off-target and systemic exposure, he explained. Sub-retinal delivery is the most invasive of the three approaches as it requires a surgical procedure. The therapy is administered through a vitrectomy, a surgery common to retinal surgeons that takes ten minutes or less, Pakola said. Khurana, who has been involved with REGENXBIO and AbbVie’s clinical trials, believes his patients who require regular injections are “very open to” a one-time surgical option, though he noted that it could be limited to those who are healthy enough for outpatient surgery and willing to be put under anesthesia. In addition to its sub-retinal program, the partners are also developing a suprachoroidal route of administration for ABBV-RGX-314, currently in Phase II trials. A needle is inserted into the thin space between the sclera and choroid of the eye for targeted delivery to the retina without surgery. The delivery is compartmentalized, spreading broadly to the retina but not to the vitreous or other parts of the eye, Pakola explained. Intravitreal Injection The third delivery option follows the approach used by current anti-VEGF treatments: intravitreal injection—into the vitreous humor of the eye. This is the approach taken by Adverum, whose gene therapy ixoberogene soroparvovec (ixo-vec) comprises a proprietary vector capsid carrying a coding sequence for aflibercept, the VEGF-A antagonist in Regeneron’s Eylea. Fischer told BioSpace that ixo-vec elicits production of the Eylea drug product in patients’ eyes at low levels for years. “We’re the first to develop this vector that’s been modified to be able to be administered in the front of the eye,” Fischer said, its delivery mimicking the current in-office standard-of-care. “Intravitreal delivery has been the holy grail of ocular gene therapy because it fits in the very busy practices that see up to 100 patients a day.” Overall, clinical data show that ixo-vec has led to a 90% reduction in annualized injections. After 26 weeks, 76% of patients who received the planned Phase III dose were injection free with disease control. In patients with the greatest burden of care—those receiving around ten injections per year—more than 50% are free of injections three years after treatment with ixo-vec, Fischer said. With the use of prophylactic corticosteroids, 100% of patients had no or minimal inflammation. “It’s really a functional cure, disease modifying for most patients, which is really transformative,” Fischer said. Ixo-vec will advance to pivotal studies next year. Meanwhile, 4D Molecular Therapeutics (4DMT) is also developing an intravitreal injection gene therapy called 4D-150, designed to deliver the genes for both aflibercept and an RNA molecule to suppress VEGF-C expression. Like Adverum, 4DMT has designed its own novel, customized vectors to support intravitreal dosing, CEO David Kirn told BioSpace in an email. The company’s Phase II data show an 89% reduction in annualized injection rate with 77% of patients injection-free after 24-weeks, and the treatment was safe and well-tolerated with a prophylactic, topical steroid regimen. 4DMT is currently working with the FDA and EMA under accelerated program designations to finalize its Phase III clinical design, with expectations to initiate the trial in the first quarter of 2025, Kirn said. ‘Immune Privileged’ Gene therapies are typically a one and done treatment. Due to viral vector delivery, gene therapy causes an immune response that prevents redosing. But the eye is “somewhat immune privileged,” Fischer said. Even though the viral delivery will create an immune response in one eye, it does not impact the ability to treat the other eye, he explained. While 42% of wet AMD patients eventually have disease in both eyes, it often develops months or even years after the first eye was treated. With this in mind, Adverum is planning to enroll previous trial participants to have their second eye treated with ixo-vec. The ability to treat both eyes asynchronously while avoiding a systemic immune response has already been demonstrated in a non-human primate. Fischer believes the FDA will want to see bilaterally treated patient data in the eventual BLA filing in order to obtain approval. REGENXBIO is also running a study where patients who have had one eye treated in a prior study can enroll to have the other eye addressed. Twenty patients have been treated with results expected in the next six months, Pakola said. A Widely Accessible Gene Therapy? Whereas rare disease gene therapies that replace or correct a faulty gene carry multi-million-dollar price tags , the cost of wet AMD treatment will be much lower, Pakola said. “Cost isn’t a barrier.” And while there are existing therapies for wet AMD, Pakola noted that payers have been receptive to the value proposition of gene therapy because the burden of ongoing treatment is so high. Fischer pointed out that Medicare Part B spends 13% of its annual budget on AMD drugs alone—around $5 billion. If a patient lives years past treatment, gene therapy could ultimately save Medicare money, he said. “We’re going from incremental benefits to truly transformational with gene therapy,” Fischer said. “And I think that’s . . . the power of regenerative medicine and gene therapy.”

- Phase 2b ODYSSEY Trial in Wet AMD Remains on Track with Topline Data Expected in Late Q3 2024 - - ODYSSEY Safety Review Committee Recommends Trial Continue as Planned with no Serious Adverse Events Observed - - Recent Key Opinion Leader Webinar Highlighted the Broad Applicability and Real-World Experience of Suprachoroidal Drug Delivery - ALPHARETTA, Ga., Aug. 12, 2024 (GLOBE NEWSWIRE) -- Clearside Biomedical, Inc. (Nasdaq: CLSD), a biopharmaceutical company revolutionizing the delivery of therapies to the back of the eye through the suprachoroidal space (SCS®), today reported financial results for the second quarter ended June 30, 2024, and provided a corporate update. “Our Phase 2b ODYSSEY clinical trial utilizing CLS-AX (axitinib injectable suspension) in patients with wet AMD continues to advance on track and on time with topline data expected in late Q3 2024,” said George Lasezkay, PharmD, JD, President and Chief Executive Officer. “In July, the Safety Review Committee reviewed masked safety data and noted that there have been no drug-related Serious Adverse Events (SAEs), including no endophthalmitis or retinal vasculitis, and recommended the trial continue as planned without modifying the protocol. Both arms of the ODYSSEY trial have completed six months of treatment, with CLS-AX being re-dosed per protocol in the CLS-AX arm. Re-dosing with CLS-AX is an important and differentiating feature of the ODYSSEY trial, and the re-dosing data will be valuable as we evaluate the effects of CLS-AX in this chronic disease and plan our Phase 3 clinical development program.” Dr. Lasezkay continued, “Several noteworthy events have also occurred featuring our commercial product, XIPERE®1, for the treatment of patients with macular edema associated with uveitis. Most importantly, our Asia-Pacific partner, Arctic Vision, reported positive results from their Phase 3 trial for XIPERE, known as ARCATUS in China, and announced that new drug applications (NDAs) for ARCATUS have been accepted for review in Australia and Singapore. In addition, data presented on the real-world use of XIPERE in the United States has shown the product has excellent durability as 87.7% of eyes did not require an injected or implanted corticosteroid for 6 months after a single dose of XIPERE2.” “In May 2024, consensus guidelines for drug delivery by suprachoroidal administration, co-authored by 16 practicing retinal physicians, were published in the prominent journal, RETINA®. The article describes the physicians’ best practices for injection into the suprachoroidal space. These valuable guidelines, combined with our progress with CLS-AX and the promising real-world and Phase 3 data from XIPERE continue to demonstrate the advantages of suprachoroidal administration utilizing our proprietary SCS Microinjector® to deliver therapies to the back of the eye for the treatment of a variety of retinal diseases,” concluded, Dr. Lasezkay, Key Highlights Topline data expected in late third quarter of 2024 from Phase 2b ODYSSEY clinical trial of CLS-AX using suprachoroidal delivery in neovascular age-related macular degeneration (wet AMD).Clearside’s Asia-Pacific partner, Arctic Vision, reported positive topline results from its Phase 3 clinical trial of ARCATUS® for the treatment of uveitic macular edema in China and announced that NDAs for ARCATUS have been officially accepted in Australia and Singapore.Clearside hosted its Suprachoroidal Delivery Key Opinion Leader webinar highlighting broad applicability and real-world experience with suprachoroidal drug delivery and SCS development opportunities, including wet AMD and geographic atrophy. The replay of this event is available on the Clearside website under the Investors section: Events and Presentations.Ophthalmology Science published an article summarizing safety and tolerability data from OASIS, Clearside’s Phase 1/2a Open-Label, Dose-Escalation trial of CLS-AX (axitinib injectable suspension) in wet AMD. The full publication can be accessed here.RETINA®, The Journal of Retinal and Vitreous Diseases published consensus guidelines for drug delivery via Suprachoroidal Space (SCS®) injection. The full publication can be accessed here.Clearside’s gene therapy partner, REGENXBIO, reported progress on their ABBV-RGX-314 programs delivered via suprachoroidal injection with Clearside’s SCS Microinjector®. REGENEXBIO announced that they expect to initiate a global pivotal trial in the first half of 2025 for the treatment of diabetic retinopathy, and that their Phase 2 ALTITUDE® trial is now enrolling a new cohort of patients with center-involved diabetic macular edema (DME). In addition, REGENEXBIO announced their AAVIATE® Phase 2 trial in wet AMD is initiating enrollment in a new cohort at dose level 4.3Multiple data presentations on the use of Clearside’s suprachoroidal delivery platform were featured at prominent medical meetings, including the Association for Research in Vision and Ophthalmology (ARVO), Clinical Trials at the Summit and Retinal Imaging Biomarkers and Endpoints Summit.Glenn Yiu, MD, PhD, Professor of Ophthalmology at the University of California, Davis, was appointed to Clearside’s Scientific Advisory Board (SAB) in July 2024. Dr. Yiu, a board-certified vitreoretinal surgeon, leads the translational research program at UC Davis studying AMD and other retinal diseases, with focus on ocular imaging technologies, gene editing and delivery, and animal models of retinal disease.Tony Gibney was appointed to Clearside’s Board of Directors in April 2024. Mr. Gibney is an experienced biotechnology executive and former investment banker who brings over 25 years of experience dedicated to advising biotechnology companies on business strategy, collaborations, financings, and mergers and acquisitions. Second Quarter 2024 Financial Results License and other revenue for the second quarter of 2024 was $90,000, compared to $1.0 million for the second quarter of 2023. The revenue primarily related to payments pursuant to Clearside’s license agreements and revenue for services and the sales of SCS Microinjector kits to licensees.Research and development expenses for the second quarter of 2024 were $4.6 million, compared to $4.9 million for the second quarter of 2023. The decrease was primarily related to the CLS-AX program ($0.2 million), development of the SCS Microinjector ($0.2 million), and preclinical work ($0.1 million). This was partially offset by a $0.2 million increase in employee related costs.General and administrative expenses remained constant at $3.1 million in the second quarter of 2024 and 2023.Interest income for the second quarter of 2024 was $0.4 million compared to $0.5 million for the second quarter of 2023. The decrease was due to the lower balance of cash, cash equivalents and short-term investments.Other income for the second quarter of 2024 was $1.9 million, compared to $0 for the second quarter of 2023. Other income for the second quarter of 2024 was due to the change in fair value of the warrant liabilities from the prior March 31, 2024 valuation date.Non-cash interest expense remained constant at $2.3 million in the second quarter of 2024 and 2023. Non-cash interest expense was comprised of imputed interest on the liability related to the sales of future royalties and the amortization of the associated issuance costs.Net loss for the second quarter of 2024 was $7.6 million, or $0.10 per share of common stock, compared to net loss of $9.1 million, or $0.15 per share of common stock, for the second quarter of 2023.As of June 30, 2024, Clearside’s cash, cash equivalents and short-term investments totaled $29.4 million. The Company believes it will have sufficient resources to fund its planned operations into the third quarter of 2025. Additional Information In lieu of a second quarter 2024 conference call, the Company hosted a Suprachoroidal Delivery Key Opinion Leader Webinar on Wednesday, July 24, 2024. The replay of this event is available on the Clearside website under the Investors section: Events and Presentations. Quarterly earnings conference calls are expected to resume with the third quarter 2024 financial results. About Clearside Biomedical, Inc. Clearside Biomedical, Inc. is a biopharmaceutical company revolutionizing the delivery of therapies to the back of the eye through the suprachoroidal space (SCS®). Clearside’s SCS injection platform, utilizing the Company’s patented SCS Microinjector®, enables an in-office, repeatable, non-surgical procedure for the targeted and compartmentalized delivery of a wide variety of therapies to the macula, retina, or choroid to potentially preserve and improve vision in patients with sight-threatening eye diseases. Clearside is developing its own pipeline of small molecule product candidates for administration via its SCS Microinjector. The Company’s lead program, CLS-AX (axitinib injectable suspension), for the treatment of neovascular age-related macular degeneration (wet AMD), is in Phase 2b clinical testing. Clearside developed and gained approval for its first product, XIPERE® (triamcinolone acetonide injectable suspension) for suprachoroidal use, which is available in the U.S. through a commercial partner. Clearside also strategically partners its SCS injection platform with companies utilizing other ophthalmic therapeutic innovations. For more information, please visit clearsidebio.com and follow us on LinkedIn and X. Cautionary Note Regarding Forward-Looking Statements Any statements contained in this press release that do not describe historical facts may constitute forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements may be identified by words such as “believe”, “expect”, “may”, “plan”, “potential”, “will”, and similar expressions, and are based on Clearside’s current beliefs and expectations. These forward-looking statements include statements regarding the clinical development of CLS-AX, the expected timing of topline results from the ODYSSEY clinical trial, the potential benefits of CLS-AX, Clearside’s suprachoroidal delivery technology and Clearside’s SCS Microinjector® and Clearside’s ability to fund its operations into the third quarter of 2025. These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements. Risks and uncertainties that may cause actual results to differ materially include uncertainties inherent in the conduct of clinical trials, Clearside’s reliance on third parties over which it may not always have full control and other risks and uncertainties that are described in Clearside’s Annual Report on Form 10-K for the year ended December 31, 2023, filed with the U.S. Securities and Exchange Commission (SEC) on March 12, 2024 and Clearside’s other Periodic Reports filed with the SEC. Any forward-looking statements speak only as of the date of this press release and are based on information available to Clearside as of the date of this release, and Clearside assumes no obligation to, and does not intend to, update any forward-looking statements, whether as a result of new information, future events or otherwise. 1XIPERE® (triamcinolone acetonide injectable suspension) for suprachoroidal use is being commercialized by Bausch + Lomb who has the exclusive license for the commercialization and development of XIPERE in the United States and Canada. Arctic Vision has the exclusive license for the commercialization and development of XIPERE, in Greater China, South Korea, Australia, New Zealand, India and the ASEAN Countries. XIPERE was approved by the U.S. Food and Drug Administration in October 2021 and is commercially available in the U.S. A link to the full prescribing information is available at https://www.xipere.com/hcp/#isi. 2Yiu, Glen, “Suprachoroidal Drug Delivery in the Real World”, Clinical Trials at the Summit Meeting, June 2024 3ALTITUDE® and AAVIATE® are registered trademarks of REGENXBIO, Inc. Investor and Media Contacts: Jenny Kobin Remy Bernarda ir@clearsidebio.com(678) 430-8206 -Financial Tables Follow- CLEARSIDE BIOMEDICAL, INC.̶Selected Financial Data (in thousands, except share and per share data)(unaudited) Statements of Operations Data Three Months EndedJune 30, Six Months EndedJune 30, 2024 2023 2024 2023 License and other revenue $90 $1,018 $320 $1,022 Operating expenses: Cost of goods sold — 213 — 213 Research and development 4,603 4,948 10,218 9,399 General and administrative 3,077 3,127 5,901 6,285 Total operating expenses 7,680 8,288 16,119 15,897 Loss from operations (7,590) (7,270) (15,799) (14,875)Interest income 419 458 767 950 Other income, net 1,917 — 418 — Non-cash interest expense on liability related to the sales of future royalties (2,340) (2,294) (4,743) (4,461)Net loss $(7,594) $(9,106) $(19,357) $(18,386)Net loss per share of common stock — basic and diluted $(0.10) $(0.15) $(0.27) $(0.30)Weighted average shares outstanding — basic and diluted 74,731,139 61,654,520 72,292,183 61,413,343 Balance Sheet DataJune 30, December 31, 2024 2023 Cash and cash equivalents$18,238 $28,920 Short-term investments 11,122 — Total assets 33,934 34,018 Liabilities related to the sales of future royalties, net 46,731 41,988 Warrant liabilities 9,121 — Total liabilities 62,219 49,930 Total stockholders’ deficit (28,285) (15,912) Source: Clearside Biomedical, Inc.