RetinUp Podcast

RetinUp Podcast, LLC

4.3 (8)
Medicine

RetinUp is a podcast exploring the latest in retina science and ophthalmology. Hosted by John Kitchens, MD, and Scott Krzywonos, each episode features expert insights, research breakthroughs, and practical discussions designed for ophthalmologists, retina specialists, and vision science researchers.

1d ago

Big Pharma’s Retina Bets | Don D’Amico, MD, on BRUNELLO | RetinUp Turns One

RetinUp turns one year old. Before the birthday reflections, John Kitchens, MD, and Scott Krzywonos take stock of what the past eighteen months of retina acquisitions actually mean: Merck’s purchase of EyeBio for up to $3 billion, Eli Lilly’s acquisition of Adverum Biotechnologies for up to $262 million, Biogen’s acquisition of Apellis for $5.6 billion, and AbbVie’s licensing partnership with RegenxBio worth up to $1.75 billion. Companies with no prior retina footprint are placing major bets. The conversation covers why, and what comes next. Donald J. D’Amico, MD, then joins to go beyond the press release on the BRUNELLO Phase 2b/3 results for remigromig (Merck) in DME. He explains the Wnt pathway, why the PDR signal is permissive rather than causative, why ranibizumab 0.5mg was the only valid active comparator, how AI accelerated antibody development, and why he sees remigromig as the beginning of a new era in retinal pharmacology, not a one-time event. The episode closes with RetinUp producers Laura Brown and Liz Hogan joining John and Scott to reflect on year one, what surprised them, and where RetinUp goes from here. Hosts: John Kitchens, MD, Scott Krzywonos Topics Covered Big Pharma Comes to Retina Four major deals in eighteen months: Merck/EyeBio (up to $3B, 2024), Eli Lilly/Adverum Biotechnologies (up to 262M, 2025), Biogen/Apellis (5.6B, 2026), AbbVie/RegenxBio licensing partnership (up to $1.75B). Of these, only Apellis had an approved drug at time of acquisition. Why retina: aging patient population, novel biology, a proven track record of drug development (anti-VEGF), and a compressed window between Phase 2 and approval for diseases with clear endpoints. Retina is also a specialty where institutional relationships and a surgical infrastructure matter — the same reasons Alcon’s Neurotech acquisition makes sense. What it signals: the gold rush is not over. Kodiak Sciences, with a multi-indication BLA in Q4 2026, is a prime acquisition target. Earlier-stage companies like Ollin BIo (noted for strong science and team) represent a lower-price entry point. The human infrastructure point: talent migration has accelerated. People from established companies are moving to acquirees or to smaller companies that may themselves be acquired. Keeping the original team intact post-acquisition — as Biogen did with Apellis leadership — matters. EyeBio founders David R. Guyer, MD, and Tony Adamis, MD: John reflects on their track record — co-founders of Eyetech Pharmaceuticals (pegaptanib, the first approved anti-VEGF), now at Merck with remigromig and tiespectus in the pipeline. BRUNELLO Deep Dive with Donald J. D’Amico, MD Study recap: remigromig 0.5 mg and 0.8 mg monthly vs. ranibizumab 0.5 mg monthly in DME with BCVA 24–75 letters and CST 325 µm or greater; 25% previously treated; primary endpoint BCVA change at week 52; both doses met non-inferiority. The Wnt pathway: an evolutionarily conserved pathway with tissue-specific roles in blood-retinal barrier maintenance via the FZD4 receptor in retinal and brain vasculature. The natural agonist, norrin, has been notoriously difficult to mimic pharmacologically because it must simultaneously activate FZD4 and two epitopes of LRP5. Remigromig achieves this with a tetravalent, trispecific antibody — two arms to FZD4, one each to the LRP5 epitopes. A genuine pharmacological achievement. The PDR signal: 6.1–6.7% PDR in remigromig arms vs. 0.9% with ranibizumab. Dr. D’Amico’s view: permissive, not causative. Remigromig is not anti-neovascular; it simply does not suppress PDR the way anti-VEGF does. Comparing to true sham controls in RISE/RIDE (16.3% PDR at one year) and VIVID/VISTA (11.1% at two years), remigromig’s PDR rate appears superior to natural history. Additionally, blood-retinal barrier restoration may itself have some anti-neovascular effect. Nothing in the current data suggests remigromig causes or accelerates PDR. Why ranibizumab 0.5 mg as comparator: a non-inferiority trial requires an active comparator with an established non-inferiority margin and a primarily monthly dosing label. Ranibizumab is the only drug that meets this criterion. The 0.5 mg dose reflects international standard (US uses 0.3 mg); the trial will be hopefully used for global approval. Combination and duration questions: remigromig was dosed monthly in BRUNELLO, but duration of effect is unknown. Dr. D’Amico raises the possibility that three monthly doses could produce six-to-eight months of efficacy. Combination with anti-VEGF is the logical next step; the mechanism is orthogonal, not competitive. BAROLO companion study expected Q1–Q2 2027. Looking ahead: AI (specifically AlphaFold) played a meaningful role in remigromig’s antibody development by enabling prediction of three-dimensional polypeptide structure — one reason novel antibody development is accelerating. Other potential indications include RVO, wet AMD, uveitic macular edema, and postoperative CME. RetinUp Year One: Reflections from the Team Laura Brown, producer: came in knowing nothing about retina; learned by osmosis; continues to find eyeballs mildly distressing. Hopes for live recording at future meetings (specifically, Hawaii). Liz Hogan, producer: surprised by how welcoming industry partners were from day one; credits John and Scott’s standing in the field with making early conversations easier. Notes that breaking news episodes — sometimes turned around in under 12 hours — are an industry best, and calls out Laura specifically for being reachable at all hours. John Kitchens, MD: proud of the editorial independence, the quality of guests as educators, and the speed of breaking news coverage. Wants to move to weekly episodes and expand into human interest stories — not just data, but the people behind the field. Scott Krzywonos: credits Liz for herding the cats on breaking news days; credits John for cultivating industry relationships built on genuine win-win thinking and unpaid goodwill over many years. Year two outlook: more frequent episodes, possibly additional content channels, continued breaking news coverage, and more human interest storytelling. Key Takeaways The retina acquisition wave is not over. Merck, Lilly, Biogen, and AbbVie have all placed bets; Kodiak and others remain attractive targets. EyeBio’s founders — David Guyer, MD, and Tony Adamis, MD — have now brought two transformative retina drug classes to the field. Remigromig represents a credible second act. Remigromig’s PDR signal is permissive, not causative; cross-trial comparisons suggest remigromig patients fare better than natural history controls. The mechanism is orthogonal to anti-VEGF and is likely to be additive in combination. Year one of RetinUp: 4,786+ downloads, a year of breaking news episodes, and a field that happened to produce more clinical data in twelve months than most specialties see in a decade. Credits Production & Marketing: Laura Brown | Business Operations: Liz Hogan 🎧 Listen at RetinUp.com | Apple Podcasts | Spotify | YouTube
Oct 21

Breaking News: Alcon Acquires Neurotech

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
Oct 19

Breaking News: LUCIA Misses in Wet AMD — EyePoint Shifts to DME

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
Oct 15

AAO 2026 Recap + Vitrectomy for Floaters with Christina Weng, MD, MBA

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
Oct 1

The 2026 Data Recap — What to Watch at AAO Next Week

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.
Sep 28

Breaking News: Kodiak's DAYBREAK Hits — Zenkuda and Tabirafusp-ted Both Positive

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
Sep 25

Breaking News: Merck's Remigromig Hits Primary Endpoint in BRUNELLO for DME [Corrected]

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
Sep 23

Breaking News: Beacon's Gene Therapy Laru-zova Hits Primary Endpoint in VISTA for XLRP

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

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RetinUp is a podcast exploring the latest in retina science and ophthalmology. Hosted by John Kitchens, MD, and Scott Krzywonos, each episode features expert insights, research breakthroughs, and practical discussions designed for ophthalmologists, retina specialists, and vision science researchers.

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