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Two pieces of news today, October 21, 2026. Alcon announced the acquisition of Neurotech Pharmaceuticals for $550 million upfront, with additional milestone payments possible. John Kitchens, MD, and Scott Krzywonos break down why the pairing makes sense, what Alcon’s OR infrastructure could mean for Encelto’s adoption, and where the reimbursement path goes from here. Priovant Therapeutics (Roivant Sciences) also announced positive Phase 3 CLARITY results for brepocitinib in non-infectious uveitis. Both trials met their primary endpoints. Scott and John review what this means alongside vamikibart, and why the two drugs are more complementary than competitive. Hosts: John Kitchens, MD, Scott Krzywonos Topics Covered Alcon Acquires Neurotech for $550 Million Encelto (revakinagene taroretcel-lwey) is the only approved treatment for MacTel 2 — an estimated 25,000 US patients, 2,000–3,000 newly diagnosed annually. It’s an OR-delivered encapsulated cell therapy implant requiring surgical expertise, OR relationships, and reimbursement infrastructure. Alcon has all three. Adoption to date: more than 100 surgeries and 700+ patients in the patient portal as of March 2026. Alcon’s network is expected to expand the number of centers offering Encelto significantly. Reimbursement: buy-and-bill at approximately $200,000+ is a meaningful risk for surgery centers. Neurotech’s specialty pharmacy model removed that risk but limited center economics. Alcon’s infrastructure may help centers navigate both pathways. Centers of excellence: neither academic nor private practice dominates. John cites Drew Somerville, MD, a private practice retina specialist in Evansville, Indiana, who built out an Encelto program independently. Alcon can replicate that at scale. Alcon’s broader strategy: Lumithera (photobiomodulation), Aurion Biotech (corneal cell therapy), RxSight partnership (light adjustable lens), and now Neurotech — a consistent pattern of investing in disease-specific technology with a procedural delivery component. Brepocitinib / CLARITY (Priovant Therapeutics / Roivant Sciences) Brepocitinib is an oral TYK2/JAK1 inhibitor, 45mg once daily, already approved for psoriatic arthritis. CLARITY is the sNDA program for non-infectious uveitis (NIU). Study design: CLARITY-1 (N=166) and CLARITY-2 (N=204); 48-week double-masked; mandatory steroid taper to zero — more aggressive than prior NIU trials. Results: cumulative treatment failure at week 48 was 35.4% vs. 78.7% in CLARITY-1 and 32.4% vs. 77.8% in CLARITY-2. Pooled steroid-free quiescence: 62% vs. 20%. Macular edema resolution among patients with baseline ME: 42% vs. 4.8%. Median time to treatment failure not reached in the brepocitinib arm vs. approximately 12 weeks on placebo. Regulatory path: sNDA planned 1H 2027. How it fits with vamikibart: brepocitinib is systemic — whole-eye disease control; vamikibart is intravitreal — macular edema specifically. Complementary, not competitive. Patients with refractory macular edema despite systemic control are the logical combination candidates. Key Takeaways Alcon’s acquisition of Neurotech gives Encelto the OR infrastructure, relationships, and reimbursement support it needs to scale. Good for patients, and for the long-term viability of a therapy with no real comparator. MacTel 2 is likely underdiagnosed. With Alcon behind the treatment, earlier detection and expanded identification are reasonable expectations. Brepocitinib delivers the strongest uveitis Phase 3 data seen to date — 62% steroid-free quiescence vs. 20% placebo under an aggressive steroid taper. sNDA in 1H 2027. Brepocitinib and vamikibart address different aspects of uveitis and are likely to be used together in difficult patients. Credits Production & Marketing: Laura Brown | Business Operations: Liz Hogan 🎧 Listen at RetinUp.com | Apple Podcasts | Spotify | YouTube

Breaking news: EyePoint Pharmaceuticals announced this morning that LUCIA, the second pivotal Phase 3 trial of Duravyu (vorolanib, EYP-1901) for wet AMD, did not achieve the primary endpoint of statistical non-inferiority in mean change in BCVA versus on-label aflibercept. EyePoint is shifting resources away from its wet AMD program and re-focusing efforts on its DME program. John Kitchens, MD, and Scott Krzywonos break down the data — what the secondary endpoints showed, what the safety profile looked like across both trials, and what LUCIA means for TKIs as a class. The conversation closes with a look at why EyePoint still believes Duravyu has a future in DME, and what the COMO and CAPRI trials will need to show. Hosts: John Kitchens, MD, Scott Krzywonos Topics Covered LUCIA Topline Results Primary endpoint: not met. LUCIA did not achieve statistical non-inferiority in mean change in BCVA vs. aflibercept 2mg every eight weeks in 475 patients with wet AMD. Secondary endpoints met: 38% reduction in treatment burden vs. aflibercept (nominal p less than 0.0001); 52% of Duravyu eyes supplement-free through week 56; 71% received zero or one supplement through week 56. Visual improvement was demonstrated — the drug works biologically — but not to the margin required for non-inferiority. Both LUGANO and LUCIA showed the same pattern: durability and anatomic control with treatment burden reduction, but not the vision bar that a regulatory submission requires. Pooled safety: retinal hemorrhage 4.7% (Duravyu) vs. 1.5% (aflibercept); vitreous hemorrhage 2.3% vs. 0.0%; cataract rate comparable between arms. No increase in inflammation with redosing. What the LUGANO Pattern Means In LUGANO, nine patients in the treatment arm drove the primary endpoint miss — six with GA progression, one with a repaired retinal detachment, two with glaucoma. Whether LUCIA showed a similar subgroup pattern or a broader, more global finding was not addressed on the investor call. EyePoint says additional analyses of pooled LUGANO and LUCIA data are ongoing. John’s read: the hemorrhage signal is worth watching for TKIs broadly. Extended dosing intervals without close monitoring may allow lapse of disease control in patients prone to hemorrhage. Identifying those patients earlier — and either monitoring them more closely or switching agents — will be important as TKIs move toward approval. What It Means for TKIs Duravyu’s wet AMD failure does not close the book on TKIs. Axpaxli (Ocular Therapeutix) had a positive superiority study in SOL-1, albeit with an unusual study design that selected for highly responsive patients. What the EyePoint data add is real-world texture: TKIs produce durability and anatomic control, but the vision bar in wet AMD may be harder to clear than expected. The extended interval also raises monitoring questions that approval studies don’t fully answer. Understanding which patients tolerate 6-month dosing — and which don’t — may be essential before widespread clinical adoption. The DME Pivot EyePoint is refocusing resources on Duravyu in DME. The rationale: DME is a multifactorial, inflammatory disease where Duravyu’s mechanism may be more relevant than in wet AMD. The Phase 2 VERONA trial met its primary endpoint in DME with extended time to first supplemental injection. Two pivotal Phase 3 DME trials — COMO and CAPRI — are ongoing. Topline data expected Q4 2027. John’s observation: treatment burden reduction in working-age DME patients carries a different weight than in wet AMD — fewer injections means less time off work, which matters to patients and their employers. DME is also a more forgiving disease for subretinal hemorrhage and does not carry the same atrophy risk that complicated both wet AMD trials. Key Takeaways LUCIA missed its primary endpoint. EyePoint is winding down the wet AMD program and pivoting to DME. The wet AMD TKI chapter for Duravyu is all but closed. The secondary data confirm Duravyu’s biological activity — 52% supplement-free at week 56 — but biological activity and regulatory approval are not the same thing. TKIs as a class still have a future, but the hemorrhage and monitoring data from LUGANO and LUCIA may inform how Axpaxli is positioned if it reaches approval. COMO and CAPRI in DME read out Q4 2027. DME may be where the TKI mechanism ultimately finds its clinical home. Credits Production & Marketing: Laura Brown | Business Operations: Liz Hogan 🎧 Listen at RetinUp.com | Apple Podcasts | Spotify | YouTube

John Kitchens, MD, and Scott Krzywonos recap the American Academy of Ophthalmology 2026 Annual Meeting in New Orleans — a meeting that delivered on science even as a hurricane threatened attendance. Zenkuda’s 6-month durability data, a first-in-class Wnt agonist for DME, a gene therapy filing for X-linked RP, and a photovoltaic retinal implant nearing FDA review. Plus, a suprachoroidal access device worth watching from SJJ Solutions. Then: Christina Y. Weng, MD, MBA — Professor & Alice R. McPherson Retina Research Foundation Chair in Ophthalmology at Baylor College of Medicine and host of the Retina TL;DR podcast — joins to discuss the cultural and clinical shift around vitrectomy for floaters: who’s a candidate, how the risk-benefit calculus has changed, and what’s driving more academic centers to finally embrace the surgery. Hosts: John Kitchens, MD | Scott Krzywonos Guest: Christina Y. Weng, MD, MBA TOPICS COVERED AAO 2026: What Had the Room Buzzing Zenkuda (tarcocimab tedromer) — Kodiak Sciences Phase 3 DAYBREAK results confirmed noninferiority to aflibercept in wet AMD. 54% of patients reached 6-month dosing under strict treat-to-dryness retreatment criteria — criteria that mirror how many retina specialists already practice. Kodiak plans to file a multi-indication BLA in Q4 2026 across wet AMD, DR, and RVO simultaneously. The companion DAYBREAK arm, KSI-501 (tabirafusp-ted, an IL-6/VEGF bispecific), also met its noninferiority endpoint, though the rationale for IL-6 in wet AMD is weaker than in DME or uveitis. Remigromig (MK-3000) — Merck | BRUNELLO Trial Donald J. D’Amico, MD, presented one-year results from the pivotal Phase 2b/3 BRUNELLO study. Remigromig, a trispecific Wnt pathway agonist, demonstrated noninferior visual acuity gains versus monthly ranibizumab in DME — the first biologic with a novel mechanism to clear that bar. New-onset PDR occurred in roughly 6.5% of remigromig patients versus under 1% with ranibizumab, a difference that warrants monitoring but does not, in John’s read, mean the drug causes PDR. It simply doesn’t suppress it the way anti-VEGF does. Merck says additional safety analyses are underway. Tiespectus (MK-8748), Merck’s Tie2 agonist/VEGF inhibitor bispecific, is now enrolling in the pivotal Phase 2b/3 MALBEC trial for wet AMD. Vamikibart — Genentech/Roche | MEERKAT and SANDCAT One-year Phase 3 data from the MEERKAT and SANDCAT trials showed sustained improvements in visual acuity and central subfield thickness in uveitic macular edema. The FDA has accepted Genentech’s BLA, with an approval decision expected by July 2027. Ozurdex and Iluvien are approved intravitreal options for uveitic macular edema, but both are steroids — vamikibart would be the first non-steroidal intravitreal treatment for the condition. Laru-zova — Beacon Therapeutics | VISTA Trial Robert Sisk, MD, presented Phase 3 VISTA results: 31% of patients in the high-dose group and 24% in the low-dose group gained at least 15 letters in low luminance visual acuity at 12 months. Beacon plans to begin a rolling FDA submission. If approved, laru-zova would be the first approved gene therapy for X-linked retinitis pigmentosa and only the second ocular gene therapy since Luxturna (Spark Therapeutics) in 2017. Questions remain around dose selection, durability, cost, and access. PRIMA Photovoltaic Retinal Implant The PRIMA system — a wireless subretinal photovoltaic implant paired with near-infrared-projecting glasses — received a detailed safety update covering macular holes, hemorrhage, and atrophy expansion. Trade-offs were more favorable than expected, with patients still using the device several years post-implant. Patients average 62 hours of post-implant training before seeing functional benefit. European approval is active; FDA review is possible before the end of 2026. SJJ Solutions — Suprachoroidal Access Device John was invited to see a pre-launch suprachoroidal access device from SJJ Solutions, the same company that makes the zero-fill needles used in his clinic. The device guides a standard needle to the suprachoroidal space reliably regardless of scleral thickness, using a limbus-hugging guide and an incremental advancement ramp. No financial relationship. Vitrectomy for Floaters with Christina Y. Weng, MD, MBA The cultural shift around floaterectomy has been two decades in the making, and Christina Weng has been a central figure in moving it forward. Three drivers she identifies: patients with debilitating symptoms are driving awareness through word of mouth; the premium IOL era has raised the bar on visual quality, making floaters more conspicuous and less tolerable; and advances in surgical technology — higher cut rates, smaller gauge, optimized fluidics — have improved the risk-benefit ratio on both sides of the equation. On patient selection: Christina requires at least six months of symptoms before operating — time for neuroadaptation to run its course. Her ideal candidate is symptomatic, pseudophakic, with a complete PVD, few comorbidities, and realistic expectations. That said, she operates on patients who don’t meet every criterion, with appropriate counseling. In phakic patients, she often proposes combined surgery with a cataract colleague, or defers until after cataract surgery when a PVD may have occurred. The Sebag legacy: John cites the work of Jerry Sebag, MD, on contrast sensitivity and floaters — research showing that vitreous opacities can degrade contrast sensitivity to a degree comparable to a 2–3+ nuclear sclerotic cataract. Insurance coverage has followed the science: this is not a cash-pay elective. It’s a covered surgery. The economics conversation: Academic centers have historically been slower to adopt elective vitreoretinal surgery, and the stigma around floaterectomy — partly clinical, partly financial — has been part of that reluctance. Christina is candid that declining reimbursements and OR access constraints are shaping case mix decisions everywhere, academic and private alike. The shift toward doing more elective cases at academic centers is real, and she frames it as compatible with — not in conflict with — patient-first priorities. KEY TAKEAWAYS Zenkuda’s strict treat-to-dryness protocol yielded 54% six-month durability. Kodiak is filing across wet AMD, DR, and RVO simultaneously in Q4 2026. Remigromig doesn’t cause PDR — it just doesn’t treat it. The path forward is likely combination use with anti-VEGF, not substitution. Vamikibart could give UME patients their first non-steroidal intravitreal option. FDA decision expected July 2027. Laru-zova may be the second approved ocular gene therapy in a decade. For XLRP some patients who’ve been told there’s nothing, the conversation has changed. Vitrectomy for floaters works, insurance covers it, and the risk-benefit math is better than ever. The remaining hurdle is cultural — particularly in academic settings — and that’s shifting. SPONSORS Today’s episode is made possible by Genentech, maker of Vabysmo (faricimab-svoa). Hear peer perspectives and case studies — including Dr. David Eichenbaum unpacking what drying looked like in a real-world DME patient treated with Vabysmo — in their Purple Chair Series at vabysmo-hcp.com. This RetinUp podcast is brought to you by Alcon, a global leader in eye care with an industry-leading breadth of surgical products and solutions, including Unity VCS. Learn more at unityvcs.com. Astellas is focused on the patients who need help the most — those whose lives are impacted by declining or lost vision with no or few therapies available. Learn more at Astellas.com. CREDITS Production & Marketing: Laura Brown | Business Operations: Liz Hogan 🎧 Listen at RetinUp.com | Apple Podcasts | Spotify | YouTube

John Kitchens, MD, and Scott Krzywonos take stock of the biggest retina data readouts of 2026 — from a superiority study from Ocular Therapeutix to a Kodiak comeback and a gene therapy from Beacon that could be the first approval for an inherited retinal disease since Luxturna in 2017. Also discussed: topline data for remigromig (Merck/EyeBio) and Duravyu (EyePoint). The conversation covers what each dataset means in clinical terms, which presentations at AAO are must-attends, and what happens when all these new mechanisms — TKIs, ABC polymers, Wnt pathway agonists, IL-6 inhibitors, and gene therapy — arrive in clinic around the same time. The episode closes with a broader question: are we entering an era of retina that looks more like oncology, where doctors match individual patients to specific treatments rather than relying on trial and error? Hosts: John Kitchens, MD, Scott Krzywonos Topics Covered Axpaxli / SOL-1 (Ocular Therapeutix) A superiority study — rare in retina. Primary endpoint at month 9: Axpaxli patients maintained vision at a significantly higher rate than those treated with a single injection of aflibercept. Study design selected for highly responsive patients, which may have produced a stronger-than-expected control arm response. More than half of aflibercept control patients went six months before needing rescue treatment. Axpaxli holds a Special Protocol Assessment (SPA) from the FDA, which should support a cleaner approval pathway. NDA filing planned for 2026. Darius M. Moshfeghi, MD, presents SOL-1 results at AAO Subspecialty Day, Friday, October 9, 4:35 PM. Duravyu / LUGANO (EyePoint Pharmaceuticals) Phase 3 non-inferiority study for wet AMD. Nine patients in the treatment arm drove the primary endpoint miss. The LUCIA companion study remains the decisive data set; if positive, expect an NDA submission in 1H 2027. Carl D. Regillo, MD, FACS, presents LUGANO results at AAO Subspecialty Day, Friday, October 9, 4:30 PM. Zenkuda / DAYBREAK (Kodiak Sciences) Phase 3 wet AMD study; three arms — Zenkuda (four monthly loading doses, then PRN with zero-fluid-tolerance AI retreatment criteria), tabirafusp-ted (four monthly loading doses, then every-other-month proactively), and aflibercept (three monthly loading doses, then every eight weeks). Zenkuda: 7.2-letter vision gain vs. 7.6 for aflibercept. 54% of patients reached 6-month dosing at year 1 under strict treat-to-dryness criteria. 0% intraocular inflammation. The key modification from KSI-301: Zenkuda includes 20% free drug for immediate drying effect, with 80% ABC-conjugated drug providing the approximately 20-day half-life and durability. Tabirafusp-ted also met its primary endpoint, but added no additional vision gains vs. aflibercept. IL-6 inhibition may have a stronger case in DME and uveitic macular edema; ALTO Phase 3 in DME is actively enrolling. Kodiak plans a Q4 2026 three-indication BLA for Zenkuda (wet AMD, diabetic retinopathy, RVO). Charles C. Wykoff, MD, PhD, presents DAYBREAK results at AAO Subspecialty Day, Friday, October 9, 4:40 PM. Remigromig / BRUNELLO (Merck) Phase 2b/3 non-inferiority study for DME. Both doses (0.5 mg and 0.8 mg) demonstrated non-inferiority to monthly ranibizumab 0.5 mg at week 52. A Wnt pathway agonist — not an anti-VEGF. Targets endothelial cell tight junctions in the retinal vasculature. Higher rates of PDR and vitreous hemorrhage in the remigromig arms vs. control; full data not yet seen beyond the press release. John's read: likely an add-on to anti-VEGF, not a replacement. Anti-VEGF co-therapy should mitigate the proliferative signal. Target population: the roughly 40% of DME patients with persistent edema despite treatment (per DRCR Protocol I and Protocol T). Monthly dosing is a practical disadvantage vs. Ozurdex; absence of cataract and IOP risk is the advantage. BAROLO companion study expected Q1–Q2 2027. Donald J. D'Amico, MD, presents BRUNELLO results at AAO Subspecialty Day, Saturday, October 10, 5:10 PM. Laru-zova / VISTA (Beacon Therapeutics) Pivotal Phase 3 gene therapy for X-linked retinitis pigmentosa — the first XLRP trial to meet its primary endpoint, and the first potential gene therapy approval in retina since Luxturna in 2017. Primary endpoint: low luminance visual acuity responder rate (gain of 15+ letters at month 12). High-dose arm: 31%. Low-dose arm: 24%. Untreated control: 0%. XLRP is more prevalent than RPE65-mediated LCA and has a characteristic inheritance pattern that may make family-based identification more tractable. Enrollment required VA of 20/32 or better — earlier diagnosis and genetic testing are prerequisites for treatment. Robert A. Sisk, MD, FACS, FASRS, presents VISTA first-time results at AAO Subspecialty Day, Saturday, October 10, 4:13 PM. The Bigger Picture: Precision Retina? The arrival of multiple new mechanisms in close succession — TKIs, ABC polymers, Wnt agonists, IL-6 inhibitors, gene therapy — raises a question Charles C. Wykoff, MD, PhD, floated on the Kodiak investor call: is retina approaching an oncology-style era where specific patients are matched to specific treatments? John's view: we're not there yet. The DRCR Retina Network is well-positioned to run the head-to-head comparison studies that would generate that evidence. AI may eventually help identify disease phenotypes that predict response to one mechanism vs. another — but the data to train it on don't exist yet. Key Takeaways Five major Phase 3 datasets in one year — SOL-1, LUGANO, DAYBREAK, BRUNELLO, and VISTA — each with different mechanisms, endpoints, and implications. Friday and Saturday afternoon at AAO Subspecialty Day are the sessions to be in the room for. TKIs and Zenkuda are both targeting durability in wet AMD but via different mechanisms; real-world data will tell us whether the trial results hold outside controlled conditions. Remigromig's safety signal in BRUNELLO will be the central topic at Dr. Don D'Amico's Saturday talk; the full data, not just the press release, will determine how seriously practices take the PDR risk. VISTA represents a potential turning point for inherited retinal disease — and a reminder that the stakes in retina extend well beyond market dynamics. Credits Production & Marketing: Laura Brown | Business Operations: Liz Hogan 🎧 Listen at RetinUp.com | Apple Podcasts | Spotify | YouTube Sponsors This episode is made possible by Genentech, maker of Vabysmo (faricimab-svoa). Purple Chair series at Vabysmo-HCP.com. This episode is brought to you by Neurotech, makers of Encelto (revakinagene taroretcel-lwey). Learn more at encelto.com/ecp.

Breaking news: Kodiak Sciences announced this morning that both Zenkuda (tarcocimab tedromer) and tabirafusp-ted (KSI-501, tabirafusp alfa tedromer) met their primary endpoints in the Phase 3 DAYBREAK study in wet AMD — non-inferiority in vision gains vs. aflibercept at 1 year. Kodiak plans a Q4 2026 BLA filing for Zenkuda, covering five positive Phase 3 studies across wet AMD, diabetic retinopathy, and RVO. John Kitchens, MD, and Scott Krzywonos break down what makes DAYBREAK's design unusual, why Kodiak's comeback from the KSI-301 miss matters, what 54% of patients on 6-month dosing actually means in a real-world context, and what the tabirafusp-ted data suggest about where IL-6 inhibition fits in retina. Detailed results will be presented at AAO Subspecialty Day by Charles C. Wykoff, MD, PhD, on Friday, October 9, at 4:40 PM local time, New Orleans. Hosts: John Kitchens, MD, Scott Krzywonos Topics Covered DAYBREAK: What the Data Show Study design: Phase 3; treatment-naive wet AMD patients only; three arms — Zenkuda (four monthly loading doses, then PRN based on zero-fluid-tolerance retreatment criteria based on AI volumetric data), tabirafusp-ted (four monthly loading doses, then every-other-month proactively with monthly dosing if needed), and aflibercept 2mg (three monthly loading doses, then every eight weeks); primary endpoint: mean BCVA change from weeks 40 to 48. Zenkuda primary endpoint: met (p=0.0007). Vision gains: 7.2 letters (Zenkuda) vs. 7.6 letters (aflibercept). Central subfield thickness reduction: approximately 135 µm in both arms. Durability: 54% of Zenkuda patients reached 6-month dosing at year 1; 62% reached at least 5 months. Tabirafusp-ted primary endpoint: also met (p=0.0036). Anatomical key secondary endpoint also met (p0.0001). No additional vision gains vs. aflibercept despite the added IL-6 inhibition. Safety: Zenkuda showed 0% intraocular inflammation and a 0.5% cataract adverse event rate (vs. 0.9% for aflibercept). Tabirafusp-ted showed 0% cataract adverse events. What Makes This Design Different Zero-fluid-tolerance retreatment criteria: most trials allow some residual fluid in pursuit of extended intervals. DAYBREAK allowed none — any fluid on AI volumetric analysis triggered retreatment. This is closer to how most retina specialists actually treat in clinic, which may narrow the gap between trial outcomes and real-world results. AI-assisted retreatment: Kodiak used an AI volumetric fluid tool assessing the central 3 mm of the OCT to determine retreatment eligibility. The combination of strict criteria and a 20-day half-life for Zenkuda is what may drive the durability signal. Previously treated patients: DAYBREAK enrolled treatment-naive patients only. The companion ALTO Phase 3 study will assess both treatment-naive and previously treated patients with tabirafusp-ted in DME, actively enrolling now. Kodiak's Comeback from KSI-301 KSI-301, Kodiak's prior ABC-platform agent, missed its primary endpoint. Kodiak modified the approach with Zenkuda, allowing some free drug alongside the conjugated biopolymer to produce immediate effect on loading, then relying on the conjugated drug for durability. The ~20-day intravitreal half-life of Zenkuda exceeds what is seen with conventional anti-VEGF agents. What the Tabirafusp-ted Data Mean for IL-6 No additional vision gains with tabirafusp-ted vs. aflibercept despite monthly/bimonthly dosing. John's read: IL-6 may not add meaningful benefit in treatment-naive wet AMD. Better indications likely exist: uveitic macular edema and DME (where vascular leakage and inflammation are more tightly linked). Post-hoc analyses to identify wet AMD subgroups that might benefit are planned. What's Next Zenkuda BLA: Q4 2026 filing, covering five positive Phase 3 studies across wet AMD, diabetic retinopathy, and RVO. ALTO: Phase 3 study of tabirafusp-ted in DME; enrolling now; includes both treatment-naive and previously treated patients. Full data presentation: Charles C. Wykoff, MD, PhD, presents DAYBREAK results at AAO Subspecialty Day, Friday, October 9, 4:40 PM, New Orleans. Key Takeaways Both Zenkuda and tabirafusp-ted met their primary endpoints in DAYBREAK — Kodiak's comeback from the KSI-301 miss is complete, at least clinically. 54% of Zenkuda patients on 6-month dosing under zero-fluid-tolerance criteria is a meaningful durability signal, and the strict retreatment protocol makes these results more directly comparable to real-world practice than most trials. Tabirafusp-ted's vision data in wet AMD don't support IL-6 as a meaningful add-on in treatment-naive patients; DME and uveitic macular edema remain the more compelling targets. Kodiak plans a Q4 2026 BLA filing for Zenkuda across three indications. If approved, this would be an important new mechanism in wet AMD. Credits Production & Marketing: Laura Brown | Business Operations: Liz Hogan 🎧 Listen at RetinUp.com | Apple Podcasts | Spotify | YouTube

Breaking news: Merck announced this morning that remigromig (MK-3000), its investigational tetravalent tri-specific Wnt pathway agonist, met the primary endpoint of the Phase 2b/3 BRUNELLO trial for diabetic macular edema. Both the 0.5 mg and 0.8 mg doses independently demonstrated non-inferiority to 0.5 mg ranibizumab monthly at week 52. John Kitchens, MD, and Scott Krzywonos break down the topline data, the safety signals to watch (and how they might be mitigated in real-world treatment), where remigromig fits alongside anti-VEGF and steroid therapy, and what the BAROLO companion study needs to show before Merck can engage regulators for approval. Full data presentation by Donald J. D'Amico, MD, at AAO Subspecialty Day, Saturday, October 10, 5:10 PM local time, New Orleans. Editors' Note: A previous version of this episode understated the complexity of the Wnt signalling pathway. It has been edited for accuracy. Hosts: John Kitchens, MD, Scott Krzywonos Topics Covered BRUNELLO: What the Data Show Trial design: randomized, double-masked Phase 2b/3; 984 participants with DME; three arms — remigromig 0.5 mg, remigromig 0.8 mg, and ranibizumab 0.5 mg (active control); all dosed monthly; primary endpoint: mean change from baseline in BCVA at week 52. Primary endpoint: met. Both doses of remigromig independently demonstrated non-inferiority to ranibizumab at week 52. Safety signals: higher rates of proliferative diabetic retinopathy (PDR), vitreous hemorrhage, and treatment discontinuations due to adverse events in the remigromig arms vs. ranibizumab. Further analyses are underway. Merck described both doses as generally well tolerated. The Mechanism: What the Wnt Pathway Does Remigromig is not an anti-VEGF, but rather a tetravalent, tri-specific antibody designed to activate the Wnt pathway, which is involved in the repair and maintenance of the blood-retinal barrier. The target: endothelial cell tight junctions in the retinal vasculature — specifically relevant in DME, where vascular leakage is the central pathology. Where It Fits: Combination vs. Monotherapy BRUNELLO was a monotherapy study — remigromig was not tested in combination with anti-VEGF. Why: a combination study would likely have required a superiority design (a higher bar than noninferiority). Merck's clearest regulatory path was monotherapy noninferiority first. If approved, John expects remigromig to function as an add-on, not a replacement — similar to how a second-line glaucoma agent like brimonidine coexists with prostaglandin analogs. The target patient: the roughly 40% with persistent DME edema after anti-VEGF (per DRCR Protocol I and T data). Ranibizumab is a defensible comparator: RIDE/RISE and Protocol T all-comers data show no statistically significant difference vs. aflibercept across the full population. Competitive Context: Ozurdex and Tiespectus If approved, remigromig may compete most directly with Ozurdex (dexamethasone intravitreal implant 0.7 mg, AbbVie) in the non-anti-VEGF DME add-on space. Monthly dosing is remigromig's disadvantage vs. Ozurdex's less frequent schedule; the absence of cataract and IOP risks is its advantage. Tiespectus (MK-8748): Merck's second ophthalmology program — a bispecific antibody that directly activates Tie2 and inhibits VEGF. Being studied first in wet AMD. John's view: remigromig gets Merck on base; tiespectus has home run potential if the data hold. What's Next BAROLO: the companion Phase 2b/3 trial in DME; topline data expected Q1–Q2 2027. Remigromig is also being evaluated in SUPER TUSCAN, a Phase 2 proof-of-concept study in wet AMD and RVO. Any regulatory submission pathway for DME depends on the totality of BRUNELLO and BAROLO together. Full data: Donald J. D'Amico, MD, presents BRUNELLO 1-year results at AAO Subspecialty Day, Saturday, October 10, 5:10 PM, New Orleans. Key Takeaways BRUNELLO hit its primary endpoint — remigromig is non-inferior to ranibizumab in DME, representing the first positive Phase 3 data for a non-anti-VEGF, non-steroid DME treatment. The PDR and vitreous hemorrhage signals are real and need characterization; anti-VEGF co-therapy may be the practical mitigation, but that remains to be demonstrated in a combination study. Remigromig is likely an add-on, not a replacement — the 40% of patients with persistent DME edema on anti-VEGF are the target population. BAROLO data (Q1–Q2 2027) will determine whether Merck has a regulatory submission package. Tiespectus follows behind. Credits Production & Marketing: Laura Brown | Business Operations: Liz Hogan 🎧 Listen at RetinUp.com | Apple Podcasts | Spotify | YouTube

Breaking news: Beacon Therapeutics announced positive topline data from the VISTA pivotal trial of laru-zova (laruparetigene zovaparvovec) for X-linked retinitis pigmentosa (XLRP) — the first gene therapy trial in XLRP to reach its primary endpoint. John Kitchens, MD, and Scott Krzywonos break down the study design, the FDA-endorsed low luminance visual acuity endpoint, what the dose response data actually says (or doesn't say), and what could complicate the path to approval. The VISTA data will be presented in full by Robert A. Sisk, MD, at AAO Subspecialty Day on Saturday, October 10, at 4:13 PM local time in New Orleans. Hosts: John Kitchens, MD, Scott Krzywonos Topics Covered VISTA Trial: What the Data Show Study design: 85 males aged 12–48 with XLRP; enrollment visual acuity 20/32 to no worse than 20/200; high- and low-dose arms compared with untreated control patients (no sham arm); 1-year primary endpoint. Primary endpoint: low luminance visual acuity (LLVA) responder rate — defined as a gain of ≥15 letters at month 12. High-dose arm: 31% of patients reached this threshold. Low-dose arm: 24%. Untreated control arm: 0%. The differential between treated and untreated is the signal; the difference between dose arms is small. Secondary endpoints: gain of ≥10 letters in LLVA (low dose 59%, high dose 48%, untreated 4%); mean macular sensitivity on microperimetry (statistically significant in the low dose, not the high dose). Safety: described as good in the press release; no major safety signals reported. The FDA-Endorsed Endpoint LLVA measures vision under reduced light conditions — the primary functional deficit in XLRP. Standard BCVA is not well-suited for a disease where night vision failure is the central complaint. Before study launch, Beacon likely aligned with the FDA on this endpoint — a pre-agreement that doesn't guarantee approval but confirms both parties entered the trial with shared expectations on how benefit would be measured. Dose Response and Approval Path The absence of a clear dose response — low dose slightly outperforming high dose on some endpoints — may raise FDA questions about dose selection. Gene therapy pharmacokinetics are not always linear, which provides some rationale. Manufacturing capacity and scalability will also be subject to scrutiny, given the novelty of the platform. Beacon has announced plans to pursue regulatory submissions, including to the FDA. Clinical Context XLRP is more prevalent than RPE65-mediated LCA (the target of Luxturna, Spark Therapeutics) and has a characteristic X-linked inheritance pattern — affected males, carrier females — that may make family-based identification more feasible than prior inherited retinal disease programs. Enrollment in VISTA required VA of 20/32 or better, which means earlier diagnosis and genetic testing will be essential to identify candidates before disease progression. The first full data presentation: Robert A. Sisk, MD, Professor of Ophthalmology, Cincinnati Eye Institute/University of Cincinnati, presents VISTA first-time results at AAO Subspecialty Day, Saturday, October 10, 4:13 PM local time, New Orleans. Key Takeaways VISTA is the first gene therapy trial in XLRP to reach its primary endpoint — the first potential gene therapy approval in retina since Luxturna in 2017. The FDA-endorsed LLVA endpoint reflects a deliberate effort to measure what actually matters to patients with XLRP: the ability to function in low light. Earlier diagnosis and genetic testing will be prerequisites for treatment; the X-linked inheritance pattern may make family-based identification more tractable than prior IRD programs. Full data at AAO Sub Day, October 10, 4:13 PM local time. More to come. Credits Production & Marketing: Laura Brown | Business Operations: Liz Hogan 🎧 Listen at RetinUp.com | Apple Podcasts | Spotify | YouTube

John Kitchens, MD, and Scott Krzywonos break down the AAO 2026 annual meeting in New Orleans (October 9–12) — whether it still matters, what to catch at Subspecialty Day, and which late-breaking Phase 3 data presentations could move the field. Each host shares their top four talks, and the Vitreoretinal View covers the surgical program. A quick correction from the prior episode: the SOL-1 primary endpoint was at month 9, not month 6, as stated in our previous episode. Corrections welcome at [email protected]. Hosts: John Kitchens, MD, Scott Krzywonos Topics Covered AAO 2026: Does It Still Matter? In-person attendance may be down post-COVID, but virtual access has expanded the meeting's reach significantly. Still a premier venue for late-breaking Phase 3 data and surgical education. New Orleans in October doesn't hurt. John is on the podium in two places: the 2026 Debate Session (Friday, 2:45 PM — No Flap for Macular Hole) and a vitrectomy for floaters talk at Refractive Subspecialty Day. Plus, John pays tribute to Kirk Packo, MD — the legendary AAO debater — and his famous 2006 New Orleans talk calling out industry over Avastin access. John's Top Four Talks No. 4 — Friday, 5:10 PM: Ehsan Rahimy, MD, presents 36-month safety data from the PRIMA photovoltaic retinal implant trial in geographic atrophy. A European device that has hit mainstream news; risk of accelerating atrophy and debate over whether VA gains reflect true restoration or magnification make this one to watch. No. 3 — Friday, 5:05 PM: Raj K. Maturi, MD, presents 12-month topline results from the Phase 2 ArMaDa trial of OCU-410, a modifier gene therapy for GA. Back-to-back with PRIMA; gene therapy for GA is the right target given the need for sustained delivery. No. 2 — Saturday, 4:56 PM: Arshad M. Khanani, MD, MA, presents Phase 2 ELAAVATE data for RGX-314 (Regenxbio), a subretinal gene therapy for center-involved DME. Subretinal and suprachoroidal delivery routes both in development; data could signal what gene therapy for DME looks like before the Phase 3 wave hits. No. 1 — Saturday, 5:10 PM: Donald J. D'Amico, MD, presents the BRUNELLO pivotal trial results for Remigromig (MK-3000, Merck) in DME — a Wnt pathway inhibitor that targets endothelial cell tight junctions rather than VEGF. A genuinely new mechanism; if it wins on VA and drying, it could be additive to anti-VEGF. Monthly ranibizumab as the comparator is defensible given the ride/rise data and Protocol T all-comers results. Merck's second program, tuspetinib (Tie2 activator, ANG1 pathway), is next up in the pipeline. Scott's Top Four Talks No. 4 — Friday, 8:30 AM: Jason Hsu, MD (Wills Eye Hospital), Top Journal Articles That Influenced My Practice. Not a single dataset — a real-world appraisal of what actually breaks through into practice. No. 3 — Saturday, 4:37 PM: Nisha Acharya, MD, presents week 52 MEERKAT and SANDCAT data for vamikibart in uveitic macular edema. Week 16 data were presented at AAO 2025 and ARVO 2026; the 1-year read will be more definitive. Interesting wrinkle: higher dose won in MEERKAT, lower dose in SANDCAT. No. 2 — Friday, 4:40 PM: Charles C. Wykoff, MD, PhD, presents the DAYBREAK Phase 3 trial for Kodiak Sciences — a three-arm study comparing KSI-301 (ABC anti-VEGF), KSI-501 (ABC anti-VEGF + anti-IL-6), and aflibercept. First time (we think) a sponsor has run two of their own candidates head-to-head against a control. No. 1 — Saturday, 4:13 PM: Robert A. Sisk, MD, presents first-time pivotal VISTA trial results for laru-zova gene therapy (Beacon Therapeutics) for X-linked RP. Could be the second gene therapy approved in retina, and the first since Spark in 2017. Larger treatable population than RPE65-mediated LCA; safety around subretinal delivery in a pigmented retina will be key. Vitreoretinal View: Surgical Talks at Subspecialty Day Friday, 8:16 AM — Ninel Z. Gregori, MD: Subretinal administration of photoreceptor precursor cells in RP (Surgical Videos: Cool Cases and Complications). Subretinal photoreceptor delivery is distinct from gene therapy; anatomic and functional outcomes to watch. Friday, 11:04 AM — Aleksandra V. Rachitskaya, MD: When to Worry and When Not to Worry About Retinoschisis. Schisis-related detachments are technically demanding with high PVR risk; looking for pearls on when to operate, laser options, tamponade choice. Friday, 11:11 AM — Colin A. McCannel, MD: A Decade of 27-Gauge Vitrectomy Surgery. Less than 5% of US surgeons use 27-gauge; Alcon Unity system is optimizing flow and stiffness. Does 25-gauge still do everything 27 can without the compromises? Saturday, 3:45 PM — Omesh P. Gupta, MD: Gore-Tex Scleral-Fixated IOL Technique (How Do I Do It). Saturday, 3:52 PM — Murtaza K. Adam, MD: Yamane Technique IOL Placement (How Do I Do It). Saturday, 4:06 PM — Glenn C. Yiu, MD, PhD: Suprachoroidal Injection Tips and Tricks. Increasingly relevant as suprachoroidal gene therapy delivery (RGX-314) advances and approved suprachoroidal steroid delivery matures. Key Takeaways AAO 2026 features an unusually dense late-breaking data slate: BRUNELLO, DAYBREAK, VISTA, MEERKAT/SANDCAT, PRIMA, and ArMaDa all read out at the same meeting. BRUNELLO is the most mechanistically novel: a Wnt pathway inhibitor for DME that could eventually combine with anti-VEGF. VISTA is the most consequential for the inherited retinal disease field if positive. Suprachoroidal delivery and 27-gauge vitrectomy are two surgical trends worth watching across multiple talks. Correction: the SOL-1 primary endpoint was at month 9, not month 6, as stated on our previous episode. Sponsors This episode is made possible by Genentech, maker of Vabysmo (faricimab-svoa). Hear peer perspectives and case studies in the Purple Chair series, including Dr. David A. Eichenbaum on a real-world DME patient, at Vabysmo-HCP.com. This episode is brought to you by Alcon, a global leader in eye care, including Unity VCS. Learn more at unityvcs.com. Credits Production & Marketing: Laura Brown | Business Operations: Liz Hogan 🎧 Listen at RetinUp.com | Apple Podcasts | Spotify | YouTube

John Kitchens, MD, and Scott Krzywonos take stock of the three biggest retina news stories of 2026 — the SOL-1 superiority data for Axpaxli (Ocular Therapeutix), the FDA approval of Lytenava (Outlook Therapeutics), and the LUGANO Phase 3 (near) miss for Duravyu (EyePoint Pharmaceuticals) — and look ahead to three imminent late-phase readouts that could reshape the field before year's end: DAYBREAK for Zenkuda (Kodiak), BRUNELLO for Restoret (Merck/EyeBio), and ARCHER 2 for vonaprument (Annexon). Carl J. Danzig, MD, then joins for a candid conversation about leaving a solo retina practice after 14 years, navigating a non-compete, commuting across Alligator Alley, and what it actually costs — personally and professionally — to make a major mid-career professional transition. He recently joined Fort Lauderdale Eye Institute as one of four retina specialists, beginning to see patients there on August 24, 2026. Hosts: John Kitchens, MD, Scott Krzywonos Topics Covered 2026 Pipeline Check-In: Catching Our Breath Axpaxli / SOL-1 (Ocular Therapeutix): first superiority study in retina; at week 36, 74% of Axpaxli patients maintained vision vs. 56% on a single aflibercept injection; at 1 year, 66% of Axpaxli patients had not lost 10 letters; NDA filing planned for 2026. Lytenava (Outlook Therapeutics): FDA-approved July 2026 for wet AMD — the first FDA-approved ophthalmic formulation of bevacizumab; measured commercial rollout planned for Q4 2026; full commercialization early 2027. Key unresolved question: impact on compounded bevacizumab access, particularly for non-wet AMD indications including DME, CRVO, BRVO, and myopic CNV. Duravyu / LUGANO (EyePoint Therapeutics): primary non-inferiority endpoint missed in the full dataset; attributed to nine outlier patients in the treatment arm with vision loss unrelated to wet AMD; ad hoc analysis excluding those patients showed non-inferiority; LUCIA companion study topline data expected Q4 2026. 2026 Pipeline Check-In: What's Coming Kodiak Sciences — DAYBREAK (Zenkuda / KSI-501): Phase 3 non-inferiority study for wet AMD; two investigational arms vs. aflibercept; topline data expected September 2026. Kodiak's prior KSI-301 missed its primary endpoint; lessons learned informed DAYBREAK's design. Merck — BRUNELLO (Restoret / MK-3000): Wnt pathway agonist antibody acquired via EyeBio; Phase 3 non-inferiority trial for DME; data expected within 4 to 6 weeks of recording; a second Merck program — an ang-1 upregulator and VEGF inhibitor designed to activate the Tie2 receptor rather than merely inhibiting ang-2 — follows behind. Annexon — ARCHER 2 (vanoprument / ANX007): C1q complement inhibitor for GA; distinct mechanism from C3 (pegcetacoplan) and C5 (avacincaptad pegol) inhibitors; Phase 2 showed a visual acuity benefit without slowing lesion growth; hypothesis: C1q inhibition protects photoreceptors upstream of RPE loss, with atrophy reduction expected to emerge over 12–24 months; Phase 3 primary endpoint is vision preservation, not lesion growth. Carl J. Danzig, MD, on Switching Practices at Mid-Career Background: Temple University medical school, Wills Eye tumor research, residency at Charles Drew (transferred to SUNY Downstate after program closure), fellowship at UT Southwestern; joined Rand Eye Institute as the practice's first and only retina specialist in 2012. Solo practice realities: PI on 59 clinical trials as a solo retina specialist in an anterior segment practice; required extensive coverage arrangements and leveraged a full network of South Florida retina colleagues; elected to Retina Society. Why he left: felt like "salmon swimming against the current" in an anterior segment culture; outgrowing his role; needed partners, shared call, and a practice aligned with his research identity and professional goals. The transition year: geographic restriction meant commuting from Fort Lauderdale to Bonita Springs (Advanced Retina Institute) — across Alligator Alley — Tuesday through Thursday most weeks; often away five to six nights at a time including commercial speaking and international meetings. The real costs: income went to zero during the gap; anxiety about the non-compete timeline; mental load of solo parenting for his wife; being a diminished version of himself at home after long stretches away. "Phil Rosenfeld, MD, told me I jumped out of an airplane holding my family's hand and no one had a parachute." Fort Lauderdale Eye Institute: one of four retina specialists; seven minutes from home; active clinical trial program; practice aligned with his values. First patient day: August 24, 2026. Advice to anyone considering a mid-career move: know your worth, don't undervalue yourself, move sooner rather than later if the fit is wrong, and build your network before you need it. Key Takeaways The three biggest retina stories of 2026 — SOL-1, Lytenava, and LUGANO — set up a fall season with multiple Phase 3 readouts that could further reshape the treatment landscape. Annexon's ARCHER 2 is the most mechanistically distinct GA program in Phase 3 — a C1q inhibitor targeting photoreceptors upstream of RPE loss. Leaving a practice at mid-career is a financial, legal, logistical, and deeply personal decision — Carl Danzig's year-long transition is a useful blueprint for anyone considering it. Network-building early in training is the single most durable investment a retina specialist can make. Sponsors This episode is made possible by Genentech, maker of Vabysmo (faricimab-svoa). Hear peer perspectives and case studies in the Purple Chair series at Vabysmo-HCP.com. This episode is brought to you by Ocular Therapeutix, a biopharmaceutical company working to redefine the retina experience across drug development, treatment, and outcomes. Learn more at OCUTX.com. Credits Production & Marketing: Laura Brown | Business Operations: Liz Hogan 🎧 Listen at RetinUp.com | Apple Podcasts | Spotify | YouTube

Jay S. Duker, MD, President & CEO of EyePoint Pharmaceuticals, joins John and Scott to parse the LUGANO Phase 3 topline data — just three days after release. He walks through Duravyu's MOA, what the nine outlier patients in the study actually represent, why the secondary data are compelling, and what LUCIA needs to show for an NDA filing in 1H 2027. Then Miles Harper stops by the VitreoRetinal View to discuss why some innovations in the OR fail, why others succeed, and which surgical applications of AI might feasibly appear in the near future. Show Notes: Guest: Jay S. Duker, MD – President & CEO, Board Director, EyePoint Pharmaceuticals; former Professor & Chair, Department of Ophthalmology, Tufts Medical Center and Tufts University School of Medicine Show Summary Three days after EyePoint Pharmaceuticals released topline LUGANO Phase 3 data, Jay S. Duker, MD, President & CEO, joins John Kitchens, MD, and Scott Krzywonos to break down what the results actually mean. Duravyu (vorolanib) missed its primary non-inferiority endpoint in the full dataset of LUGANO — confounded by nine patients in the treatment arm who lost 15 or more letters for reasons unrelated to wet AMD control. Dr. Duker explains what those nine cases represent, why the secondary data tell a different story, and what LUCIA — the companion Phase 3 trial with topline data expected in Q4 2026 — will need to show for an NDA submission in 1H 2027. John and Scott offer their own read on the interview: what surprised them, why the re-randomization analysis matters, and why TKIs are still likely to have a meaningful role in retina. In the Vitreoretinal View segment, industry consultant and friend of the pod Miles Harper stops by to examine why some surgical innovations fail while others experience modest success. Scott and Miles also speculate as to which surgical applications of AI technology could soon enter the stage. Hosts: John Kitchens, MD, Scott Krzywonos Topics Covered Duravyu: Mechanism & Background Vorolanib is a small-molecule TKI with activity against all VEGF receptors — working intracellularly at the receptor level, unlike approved anti-VEGFs that block the ligand extracellularly. Additional activity against PDGF (antifibrotic) and JAK1 (anti-inflammatory via IL-6 pathway). Delivered via Durasert E bioerodible sustained-release insert; 2.7 mg every six months. Previously tested orally in wet AMD with efficacy but hepatotoxicity at 200–300 mg daily; intravitreal dose results in only picogram-level systemic absorption. Tested in DAVIO (Phase 1), DAVIO 2 (Phase 2 wet AMD, 100% previously treated), and VERONA (Phase 2 DME) before Phase 3. LUGANO Results: The Good Safety: no increase in cataracts or IOP; single case of intraocular inflammation (0.5%); only 6% discontinuation rate in each arm, none due to study drug; safety confirmed with re-injection at month eight — the first TKI Phase 3 trial to read out with re-injection data. Anatomic control: 4-µm difference in retinal thickness vs. aflibercept 2 mg at week 56. Supplement-free subgroup (~54% of Duravyu eyes at week 56) was non-inferior to the control arm with only a 3-µm OCT difference. Treatment burden: 42% reduction vs. on-label aflibercept; approximately two fewer injections per year. At week 32, 76% of Duravyu patients were supplement-free. Previously treated population: 25% of patients were previously treated — the first wet AMD Phase 3 trial to include this population; informed by DAVIO 2, which enrolled 100% previously treated patients and produced strong results. LUGANO Results: The Primary Endpoint Miss Control arm outlier performance: historically, ~4% of aflibercept 2 mg patients lose 15+ letters in Phase 3 wet AMD trials; in LUGANO, only 0.5% did — an extraordinary result that raises questions about randomization luck rather than drug performance. The nine outlier patients: six lost vision due to GA progression, two due to glaucoma, one due to retinal detachment (repaired, but phakic — developed cataract). EyePoint's position: these losses were not related to Duravyu or lack of wet AMD control; GA data from the trial does not support drug-induced acceleration. Re-randomization analysis: EyePoint randomly redistributed the 15+ letter losers across both arms ten times; in every simulation, Duravyu was non-inferior, with a mean difference of -1.3 to -2.0 letters — well within the non-inferiority margin. Regulatory Path Forward LUCIA topline data expected Q4 2026; if positive, NDA submission planned for 1H 2027. Precedents for one positive and one missed Phase 3: pegcetacoplan (DERBY/OAKS) and Lytenava. Dr. Duker: the FDA evaluates totality of data including safety, burden reduction, and clinical benefit — a positive LUCIA plus the LUGANO secondary data could constitute a compelling package. Key Takeaways Duravyu's LUGANO miss appears to be driven by statistical bad luck — nine patients, unrelated to wet AMD, in one arm — not a drug failure. The secondary data are strong. The re-randomization analysis gives meaningful confidence that regression to the mean in LUCIA should produce a non-inferior result. A positive LUCIA trial, combined with LUGANO's secondary data, may be sufficient for FDA approval — precedent exists for one missed and one positive Phase 3. TKIs work as a class: treatment-free interval data from LUGANO are consistent with SOL-1, regardless of primary endpoint outcome. Credits Production & Marketing: Laura Brown | Business Operations: Liz Hogan 🎧 Listen at RetinUp.com | Apple Podcasts | Spotify | YouTube

Breaking news: EyePoint Pharmaceuticals announced LUGANO Phase 3 topline data this morning. Duravyu, an investigational sustained-release TKI for wet AMD, did not meet its primary non-inferiority endpoint in the full dataset — confounded by nine patients in what EyePoint is calling an asymmetric cohort. John Kitchens, MD, and Scott Krzywonos break down what it means, what comes next, and why TKIs still win as a class. Show Summary Breaking news: EyePoint Pharmaceuticals announced topline data from LUGANO, the first of two pivotal Phase 3 trials evaluating Duravyu (vorolanib) for wet AMD, on the morning of August 17, 2026. The primary non-inferiority endpoint was not met in the full dataset. EyePoint attributes this to an asymmetric cohort of nine patients in the treatment arm whose outcomes significantly skewed the results. In an unplanned ad hoc analysis excluding those nine patients, Duravyu was non-inferior to aflibercept 2 mg. Safety was clean, treatment-free intervals were compelling, and the companion LUCIA study remains on track for Q4 2026 topline data. John Kitchens, MD, and Scott Krzywonos recorded this episode before the market opened to break down the study design, the ad hoc analysis question, and what the FDA is likely to do with these data. Plus, they examine why TKIs as a class — and some other companies — may be the real winners from this morning's news. Hosts: John Kitchens, MD, Scott Krzywonos Topics Covered LUGANO Topline Data: What Happened Study design: randomized, double-masked, non-inferiority trial; Duravyu 2.7 mg every six months vs. aflibercept 2 mg every other month (EOM); 211 patients in the treatment arm; a significant percentage of patients were previously treated — an unusual and real-world-reflective design feature; primary endpoint assessed at weeks 52 and 56. Primary endpoint: not met in the full dataset; control arm performed exceptionally well — no patients lost three or more lines of vision in the first six months, compared to approximately 5% in historical wet AMD Phase 3 comparators. The asymmetric cohort: nine patients in the treatment arm drove the primary endpoint miss; EyePoint characterizes these as an atypical subgroup. In an unplanned ad hoc analysis excluding these nine patients, Duravyu was non-inferior to the control arm. Ad hoc analysis: not a pre-specified endpoint; FDA may consider it but likely will not base approval on it alone. The key question is whether LUCIA — the companion trial — delivers a clean positive result. John's view: LUCIA will need to be positive for any approval pathway; the FDA has approved products on one pivotal trial before (e.g., pegcetacoplan in DERBY/OAKS), so a strong LUCIA result may be sufficient. Treatment-free intervals: approximately 42% reduction in treatment burden vs. aflibercept; roughly consistent with data from SOL-1 — validating the TKI mechanism as durable. At week 32, 76% of Duravyu patients were supplement free. Safety: clean; no ocular inflammation, vasculitis, or unexpected safety signals; consistent with prior TKI studies and anti-VEGF experience. What It Means for the Field TKIs win as a class: treatment-free interval data confirm durability and mechanism; the question is not whether TKIs work but how they will be positioned alongside next-generation anti-VEGFs. Second-generation anti-VEGFs as potential beneficiaries: aflibercept 8 mg and faricimab approximate extended intervals with approved labeling; a delayed or complicated TKI approval pathway could strengthen their near-term positioning. Study design implications: John raises the question of whether future TKI trials will exclude patients with geographic atrophy or other confounders; enrollment criteria may tighten, potentially slowing trial timelines. AI and enrollment: Scott raises the possibility that AI-assisted health record analysis could better identify appropriate candidates in real time — particularly relevant as trials increasingly enroll previously treated patients. What's Next LUCIA topline data: expected Q4 2026; if positive, EyePoint plans NDA submission in 1H 2027. Upcoming RetinUp episode: John and Scott plan to speak with someone from EyePoint Pharmaceuticals to go deeper on the data; additional subgroup analyses will be presented at the Retina Society Annual Meeting, September 23–26, 2026. Key Takeaways LUGANO missed its primary endpoint, but EyePoint argues the result was driven by nine atypical patients — not a failure of the drug. The ad hoc analysis showing non-inferiority is hypothesis-generating, not approval-enabling; LUCIA must be positive for an NDA to proceed. TKIs work: treatment-free interval data from LUGANO are consistent with SOL-1, reinforcing the class mechanism. All eyes are on LUCIA in Q4 2026. Credits Production & Marketing: Laura Brown | Business Operations: Liz Hogan 🎧 Listen at RetinUp.com | Apple Podcasts | Spotify | YouTube

The companion piece to RetinUp’s previous episode on biosimilars is here, featuring an oncologist who has lived through biosimilar disruption for the past decade. Stephen "Fred" Divers, MD, CMO of the American Oncology Network, joins John and Scott to share what oncology has learned from nearly a decade of biosimilar use: the ASP deterioration cycle, payer formulary pressure, the race to the bottom, and what retina should do differently as its own biosimilar era accelerates. During the Vitreoretinal View segment, John discusses his fresh move to Boulder, sharing what it's like to operate in a new OR for the first time in years — new staff, new preferences to rebuild, and a new clinical reality: operating at 5,400 feet above sea level requires adjusting gas concentrations, counseling patients about altitude travel, and understanding why the vacuum on a vitrectomy machine behaves differently. Hosts: John Kitchens, MD, Scott Krzywonos Topics Covered Biosimilars in Oncology: Lessons for Retina (Stephen "Fred" Divers, MD) History: biosimilars entered the EU in 2005, the US in 2008 under the 351(k) pathway; oncology has roughly a decade of meaningful real-world experience. The ASP deterioration cycle: when biosimilars enter the market, manufacturers offer rebates to drive prescribing behavior; those rebates fold into ASP prospectively at roughly six months, causing progressive price deflation. With each additional market entrant, competition intensifies and the race to the bottom accelerates. The life cycle: the first biosimilar offers meaningful margin; by the second or third entrant, margins erode significantly. Manufacturers may pull products, let ASP reset, then reinsert. Ironically, the originator drug can eventually offer the best margin — after cycling through multiple biosimilars. Payer formulary mandates: when payers limit formulary to a single biosimilar, practices can become underwater if that product takes a price increase before ASP catches up. Dr. Divers' approach: push back on single-product mandates and discourage manufacturers from taking price increases after securing guaranteed market share. Formulary management: keep less than 48 hours of drug on hand; constantly renegotiate contracts as new biosimilars enter; treat formulary decisions as a quarterly exercise, not an annual one. Patient experience: biosimilar transitions are largely invisible to patients from an efficacy and safety standpoint; batch-to-batch variability exists even within originator biologics, which is part of the scientific rationale for the biosimilar framework. 340B context: a program originally designed for underserved clinics treating HIV patients that expanded exponentially into hospital systems, now accounting for 50–60% of drug dispensing nationally. Creates perverse incentives that complicate biosimilar adoption decisions in oncology. What retina should do differently: build operational flexibility for frequent formulary changes; don't set and forget; invest in pharmacy infrastructure; expect continuous renegotiation; and be prepared for the margin on any given biosimilar to disappear faster than anticipated. Vitreoretinal View: Operating in a New OR — and at Altitude John has joined Rocky Mountain Retina Associates in Boulder, Colorado, alongside Geeta Lalwani, MD. New OR realities: starting fresh means rebuilding every case card preference — forceps, drape, glove size, block needle, prep protocol, etc. An email requesting a case card was the prompt that made John realize how much institutional knowledge travels with a surgeon invisibly. First days: stick with the familiar; introduce changes only once settled. Forceps especially — "like tennis shoes, you don't change brands that often." Alcon and Zeiss reps were on-site to support the transition. Operating at altitude (5,400 feet): SF6 gas concentration must be reduced compared to sea level use; John typically uses 28–30% SF6 at Lexington's elevation; this must be adjusted in Boulder. Patients must be counseled against travel above 7,000–9,000 feet until the bubble resolves — patients who live at altitude must plan accordingly. Vacuum performance: the Alcon Constellation cannot achieve the same vacuum at 5,400 feet as at sea level; surgeons operating at altitude should be aware of this mechanical limitation and adjust technique accordingly. Key Takeaways Biosimilar margins are meaningful early and deteriorate fast — retina specialists should plan for continuous formulary management, not annual decisions. Payer formulary mandates to a single biosimilar are the highest-risk scenario; practices should push back and keep options open. Biosimilars are clinically safe and effective; the challenge is entirely economic and operational, not clinical. Operating in a new OR requires rebuilding institutional knowledge from scratch — and at altitude, requires recalibrating both gas concentrations and patient counseling. Sponsors RetinUp is an editorially independent podcast supported with advertising. This episode is made possible by Genentech, maker of Vabysmo (faricimab-svoa). Watch their Purple Chair Series at Vabysmo-hcp.com. Learn more about Alcon’s Unity VCS at UnityVCS.com. Credits Production & Marketing: Laura Brown | Business Operations: Liz Hogan 🎧 Listen at RetinUp.com | Apple Podcasts | Spotify | YouTube

Bob Jahr, President & CEO of Outlook Therapeutics, joins John and Scott for one of his first interviews since the Lytenava (bevacizumab-vikg) FDA approval on July 24, 2026. He walks through the long road to approval — three complete response letters, a formal dispute resolution appeal, and a final label in hand without a single additional safety or efficacy data commitment — and shares what's ahead for the US commercial launch. Scott then sits down with Miles Harper, an independent consultant who has spent his career at the intersection of ophthalmology, medical devices, and market access — including years at Zeiss and then the start-up Beyeonics. The conversation covers what it actually means to be the connective tissue in a field driven by innovation, and what happens at a major meeting like AAO when you're not tied to a booth or a session. Hosts: John Kitchens, MD, Scott Krzywonos Topics Covered Bob Jahr on the Lytenava Launch The road to approval: Outlook received three complete response letters before winning a formal dispute resolution appeal; approval granted July 24, 2026, without any additional safety, efficacy, or post-marketing commitments — a rare outcome for an appeal. What a CRL is: the FDA's formal notice that a submitted package does not meet approval criteria; may cite data interpretation, endpoint alignment, safety, efficacy, or manufacturing issues. Triggers an opportunity for type A meetings with the FDA to seek clarity before resubmission. Launch timeline: Lytenava will be in market channels by end of 2026; full commercial team and field force active January 2027. Q4 2026 will focus on early adopter engagement, payer conversations, and practice manager outreach. Manufacturing: 100% US-based; drug product and drug supply split between Texas and San Diego; entire global supply produced domestically. Commercial infrastructure: field reimbursement managers, key account managers, and a sales force are being built now; patient assistance programs and free product support confirmed; samples under evaluation based on community input. Pricing: not yet announced but imminent; Outlook is threading a narrow needle between patient affordability, payer access, and practice economics. Bob emphasizes long-term pricing sustainability and predictability enabled by their own IP and permanent J code. Compounded bevacizumab: Outlook's stated position is to bring a new option in, not take options away. Bob declined to speculate on regulatory action vis-a-vis compounding but confirmed it is not within Outlook's control. Europe as a preview: approved in Germany, Austria, and UK in June 2025 for wet AMD; key learnings include listening to stakeholders before launch, identifying early adopters, and clearly differentiating Lytenava from biosimilars. Miles Harper on Ophthalmology Consulting Background: years at Zeiss in ophthalmology, followed by four years at the surgical startup Beyeonics; now an independent consultant focused on pre-commercial strategy and early market access for device and technology companies. Core value proposition: helping companies understand the real-world market value of a product — not just whether it works, but how it fits into clinical workflows, who the actual end user is, and whether it solves a problem that physicians and technicians actually have. Intraoperative OCT as a case study: a technology that has existed for roughly 10 years but whose clinical utility has lagged behind its promise — a useful example of innovation that hasn't yet found its footing in the OR workflow. Conference strategy: value at major meetings like AAO comes from hallway conversations, random encounters, and informal relationship-building — not sessions or booths. Preparation begins months in advance by getting on calendars; the real work happens in real time on the floor. Miles will return for a future episode focused on specific technologies that succeeded or struggled in the ophthalmology market. Key Takeaways Lytenava's US launch is on track for Q4 2026 customer engagement and full commercialization in January 2027; pricing announcement is imminent. The formal dispute resolution process that led to Lytenava's approval is rare — fewer than 8% of appeals are granted, per Outlook President & CEO Bob Jahr — and Outlook did so without any additional data commitments. Pricing will determine everything: Bob Jahr is clear that Outlook is thinking about affordability and sustainability, but the number itself has not yet been released. In ophthalmology consulting, the most valuable conversations happen in the hallway, not the boardroom — and the best advisors help companies understand who actually uses their product and why. Sponsors This episode is made possible by Genentech, maker of Vabysmo (faricimab-svoa). Follow Vabysmo on LinkedIn to hear from leading experts on their real-world experience, and watch the Purple Chair series at Vabysmo-HCP.com. Credits Production & Marketing: Laura Brown | Business Operations: Liz Hogan 🎧 Listen at RetinUp.com | Apple Podcasts | Spotify | YouTube

Breaking news: the US Food and Drug Administration approved Lytenava (bevacizumab-vikg, Outlook Therapeutics) on July 24, 2026 — making it the first and only FDA-approved ophthalmic formulation of bevacizumab for the treatment of wet AMD in the United States. John Kitchens, MD, and Scott Krzywonos break down what this approval means in real-world terms: the upside for practices and patients, the unresolved questions around compounded bevacizumab, and what the pricing decision will ultimately determine. They also preview their upcoming interview with Bob Jahr, CEO of Outlook Therapeutics — one of his first since the approval. Hosts: John Kitchens, MD, Scott Krzywonos Topics Covered The Lytenava Approval: What We Know Lytenava (bevacizumab-vikg) approved July 24, 2026 for neovascular AMD; first and only FDA-approved ophthalmic formulation of bevacizumab; already approved in the Germany and UK (June 2025) for wet AMD. Approval pathway: Outlook first submitted a BLA in 2022; received a complete response letter in August 2023; resubmitted February 2025; received a second CRL in December 2025; resubmitted June, 2026; approved July, 2026. The upside: for the first time, retina specialists have access to a bevacizumab formulation developed specifically for intravitreal use — with validated manufacturing, FDA-approved labeling, and ongoing pharmacovigilance. A pre-filled syringe formulation eliminates the variability associated with compounding. Launch timeline: Outlook anticipates a measured commercial launch by end of 2026; pricing not yet announced. The Unresolved Questions Compounded bevacizumab: once an FDA-approved ophthalmic bevacizumab exists, regulators may restrict compounding; compounding pharmacies may independently pull back given liability concerns. Access for non-wet AMD indications (eg, DME, CRVO, BRVO)— remains a critical concern. Tiered therapy: compounded bevacizumab currently sits at the front of many insurer step therapy requirements due to its low cost. How Lytenava is priced will determine whether it inherits that position or disrupts it — and whether patients on fixed incomes retain access to affordable first-line therapy. Not a biosimilar: Lytenava is an FDA-approved ophthalmic formulation of bevacizumab — not a biosimilar. This distinction matters for how it is classified under tiered therapy and step therapy protocols. Preview: Bob Jahr, CEO of Outlook Therapeutics John and Scott will speak with Bob Jahr, CEO of Outlook Therapeutics, in an upcoming episode — one of his first interviews since the approval. Topics will include launch timing, pricing strategy, support programs for practices and patients, and Outlook's position on compounded bevacizumab. Key Takeaways Lytenava is a genuine milestone — the first FDA-approved ophthalmic bevacizumab after more than two decades of off-label compounded use. Everything hinges on pricing: responsible pricing could expand access and legitimize the category; aggressive pricing could restrict it. Compounded bevacizumab's future is uncertain — regulatory and liability pressure could reduce access for patients using it for non-wet AMD indications. The Bob Jahr interview is coming soon — subscribe to catch it as soon as it drops. Credits Production & Marketing: Laura Brown | Business Operations: Liz Hogan 🎧 Listen at RetinUp.com | Apple Podcasts | Spotify | YouTube

Show Notes: Guests: Devon Ghodasra, MD – Partner, Southeastern Retina Associates, Chattanooga, Tennessee Vas Sadda, MD – Director, Artificial Intelligence & Imaging Research, Doheny Eye Institute; Professor of Ophthalmology, David Geffen School of Medicine at UCLA Show Summary Scott Krzywonos starts the show solo this week — John Kitchens, MD, is in the middle of a move from Kentucky to Colorado and will share more about his new practice in a future episode. But don’t worry: John is here for our two interviews. Devon Ghodasra, MD, of Southeastern Retina Associates joins to share a detailed, practice-tested approach to biosimilar adoption — from building a physician committee and vetting products, to scripting patient conversations and navigating billing hiccups. This is Part 1 of a two-part biosimilar series; Part 2 will feature an oncologist whose specialty has nearly a decade of biosimilar experience to draw from. SriniVas R. Sadda, MD — the world's most published author on ultra-widefield imaging — closes the episode in the Image of the Month segment. He showcases a 40-year-old patient with pathologic myopia and a peripheral detachment. Optos Silverstone RGB imaging and swept-source ultra-widefield OCT revealed a schisis detachment that had been difficult to appreciate on standard examination, ultimately changing the clinical management plan. Hosts: John Kitchens, MD, and Scott Krzywonos Topics Covered Biosimilars in Retina Practice: A Practice-Tested Playbook (Devon Ghodasra, MD) Pre-implementation: Southeastern Retina Associates formed a physician biosimilar committee to evaluate safety and efficacy data before adoption; pivotal trials for Byooviz were central to early confidence-building in ranibizumab biosimilars. Implementation strategy: the practice adopted a unified, practice-wide switch to Cimerli on January 1, 2024 — a process Dr. Ghodasra calls an "insurance blizzard" timing mistake, but instructive nonetheless. Pavblu is (for now) the most commonly used agent across the practice. Patient communication: brief, confident, focused scripting is key. Reassure first — is it safe, will it work as well? Avoid technical language; explain that it's made from living cells and can't be identical, but has been thoroughly evaluated by the FDA. Mention financial flexibility for the healthcare system if relevant. Loop back to reassurance at the end. When costs go up: address the possibility proactively before patients see their EOB. Frame around financial flexibility and the value of having more treatment options — including supply chain resilience. Handling pushback: rare when the science is explained clearly. Dr. Ghodasra's approach: "What I would be comfortable with for my own mother" tends to close the conversation. Vetting biosimilars: beyond FDA approval, key factors include manufacturer reliability in biologics, dedicated retina support, copay assistance and patient programs, and willingness to engage with physicians and practices rather than exclusively with payers. Syringe characteristics and pre-filled vs. vial-drawn formulations also matter. Billing pitfalls: new biosimilars launch with temporary J codes before permanent Q codes are assigned — claims denials and delayed payments are common. Getting your feet wet with a biosimilar that already has a permanent Q code is the safest first step. Image of the Month: Peripheral Schisis Detachment (SriniVas R. Sadda, MD) Case: 40-year-old male with pathologic myopia, lost to follow-up for several years; presented for routine follow-up. RGB vs. RG imaging: side-by-side comparison shows how true-color RGB removes the green cast of traditional RG imaging, enabling better appreciation of color differences in pathology — particularly for inflammatory lesions, fibrosis, and white retinal changes. Especially valuable for trainees whose fundus examination experience sets the baseline for image interpretation. Findings in this case: peripheral atrophy, tilted nerve, macular atrophic changes, pigmentary changes inferiorly, and a retinal detachment visible temporally — more apparent on RGB than RG. Swept-source ultra-widefield OCT: confirmed a schisis detachment with an outer retinal break; vitreous still attached in this younger patient, likely contributing to the initial schesis. A deep staphyloma was also identified — relevant to surgical planning, as it increases the risk of primary vitrectomy failure and may favor a scleral buckle approach. Fluorescein angiography: obtained to exclude other contributors to the detachment; revealed RPE staining inferiorly (chronicity) and retinal vessel staining temporally (newer involvement as schisis progressed). Management: laser barricade per patient preference; patient declined more invasive intervention at this time. Clinical pearl: ultra-widefield peripheral OCT can be placed anywhere the OptoMap image is obtained — making peripheral retinal OCT highly accessible even for less experienced imagers. Key Takeaways Biosimilar adoption requires upfront investment in physician education, patient scripting, and billing preparation — but the payoff in financial flexibility and patient access is real. Vetting biosimilars goes beyond safety data: manufacturer commitment to ophthalmology, patient support programs, and payer engagement strategies all matter when choosing which product to stock. True-color RGB ultra-widefield imaging changes what you can see — particularly for inflammatory disease, fibrosis, and subtle color-based pathology — and may be especially valuable for trainees. Swept-source ultra-widefield OCT can define the limits of peripheral detachments that are difficult to appreciate by color imaging alone, and can change surgical planning. Watch RetinUp on YouTube If you want to see the visuals associated with RetinUp, or just prefer YouTube as a podcast streamer, find us on YouTube: youtube.com/@RetinUpPodcast Sponsors This episode is made possible by Genentech, maker of Vabysmo® (faricimab-svoa). Watch the Purple Chair series at Vabysmo-HCP.com. The images featured in this episode were captured using the Optos Silverstone RGB. Learn more about Silverstone RGB at Optos.com/products/silverstone. Credits Production & Marketing: Laura Brown | Business Operations: Liz Hogan 🎧 Listen at RetinUp.com | Apple Podcasts | Spotify | YouTube