FDA Approves Kimmitrak for Uveal Melanoma Treatment

■ Immunocore announced that its T-cell receptor (TCR) Kimmitrak (tebentafusp-tebn), was approved by the FDA for the treatment of adult patients with unresectable or metastatic uveal melanoma (mUM). This is the first TCR therapeutic to receive regulatory approval from the FDA, the first bispecific T-cell engager to receive FDA approval to treat a solid tumor, and the first and only therapy for the treatment of unresectable or metastatic uveal melanoma to receive FDA approval. The FDA approval was based on a randomized, pivotal phase 3 clinical trial that evaluated overall survival (OS) of Kimmitrak compared to investigator’s choice (pembrolizumab, ipilimumab, or dacarbazine) in patients with previously untreated mUM. A cohort of 378 patients was randomized in a 2:1 ratio to either Kimmitrak or investigator’s choice. Kimmitrak demonstrated unprecedented median OS benefit as a first-line treatment. The OS hazard ratio (HR) in the intent-to-treat population favored Kimmitrak, HR=0.51 (95% CI: 0.37, 0.71); P<.0001, over investigator’s choice (82% pembrolizumab; 13% ipilimumab; 6% dacarbazine).

“This approval represents a major paradigm shift in the treatment of metastatic uveal melanoma, and for the first time offers hope to those with this aggressive form of cancer,” John Kirkwood, MD, director of the Melanoma Center at the UPMC Hillman Cancer Center, said in a news release.

TRIBUTE: JERRY HELZNER

BY JENNIFER FORD, SENIOR MANAGING EDITOR

With deep sadness we acknowledge the passing of Gerald “Jerry” Helzner, contributing editor to Retinal Physician since its debut in 2004. Jerry enjoyed a long career in journalism, and he chose to spend more than 2 decades of it covering ophthalmology, specifically and very notably retina. He amassed an encyclopedic knowledge of the retina industry, which he used to write insightful pieces for the Subspecialty News, Future File, Innovation in Retina, and Retina Conversations columns. He was passionate about accurate reporting, and he skillfully covered the many recent developments that have revolutionized the treatment of retinal disease, including the advent of anti-VEGF therapy and gene therapy. He also contributed meaningfully to Ophthalmology Management, Glaucoma Physician, and New Retinal Physician. His enthusiasm, dedication, and integrity will be sorely missed.

See a collection of Jerry’s contributions to Retinal Physician: https://bit.ly/3u9aCRt

ProQR Sepofarsen Trial Fails to Meet Treatment Endpoints

■ ProQR Therapeutics announced that its pivotal Illuminate phase 2/3 trial of sepofarsen for the treatment of CEP290-mediated Leber congenital amaurosis 10 (LCA10) did not meet its primary endpoint of best corrected visual acuity (BCVA) at month 12, nor did it meet notable secondary endpoints. No benefit was observed in either treatment arm vs sham. “Given the results observed in earlier studies of sepofarsen, the Illuminate trial results are unexpected and disappointing, especially for people living with LCA10,” Daniel A. de Boer, founder and CEO of ProQR Therapeutics, said in a news release.

Illuminate, a randomized, sham-controlled trial, enrolled 36 participants aged 8 years or older with genetically confirmed LCA10, at 14 study sites in 9 countries. Participants were randomized to 3 equal groups (1:1:1) of the target registration dose sepofarsen (160 μg/80 μg loading dose/maintenance doses), a low dose of sepofarsen for masking (80 μg/40 μg loading dose/maintenance doses), or sham procedure, with sepofarsen administered via intravitreal injection and the sham procedure mimicking an injection with no drug or injection given.

Key findings from the top-line results include the following: At month 12, the mean change from baseline in BCVA in the 160/80 μg dose group was -0.11 logMAR (P=.96), in the 80/40 μg group it was -0.13 logMAR (P=.97), and in the sham group it was -0.12 logMAR. For secondary endpoints full-field stimulus test (FST) and mobility, there was also no difference between the treated and sham groups in the top-line analysis. “This was not the outcome we had hoped for and we share in the disappointment many are feeling in the community,” said Benjamin R. Yerxa, chief executive officer at the Foundation Fighting Blindness. “We will continue to work alongside ProQR to learn more from the ongoing analyses and as they work to advance RNA therapies to potentially help children, adults, and families who are affected by rare genetic eye diseases.”

Next-generation Sequencing Enables Uveal Melanoma Diagnosis From Single Biopsy

■ Castle Biosciences, Inc has announced publication of a study demonstrating that genetic sequencing with a combination of DecisionDx-UM, DecisionDx-PRAME, and DecisionDx-UMSeq allows for highly accurate analysis of RNA and DNA from a single biopsy sample for patients with uveal melanoma (UM). The study was published in the peer-reviewed journal Ocular Oncology and Pathology. It was designed to evaluate the analytical performance of the DecisionDx-UMSeq panel, which can be run from the same fine-needle aspiration biopsy (FNAB) or formalin-fixed paraffin-embedded (FFPE) biopsy sample that is used to run the DecisionDx-UM test.

DecisionDx-UMSeq is Castle’s 7-gene test that uses next-generation sequencing (NGS) to identify somatic mutations relevant to UM. This information, together with results from the DecisionDx-UM gene expression profile test, is designed to help build a comprehensive genomic profile of an individual UM tumor from a single biopsy, which can then be used to inform patient care. DecisionDx-UM is the standard of care in the management of newly diagnosed UM in the majority of ocular oncology practices in the United States.

“The study results demonstrated that running the DecisionDx-UMSeq panel in combination with DecisionDx-UM and DecisionDx-PRAME produced highly accurate results using only a single biopsy sample. Patients with the rare and deadly uveal melanoma have limited biopsy tissue available, so it is critical to gather as much molecular information from the tumor as possible to help physicians make the most informed management decisions for their patients,” said J. William Harbour, MD, professor and chair of the Department of Ophthalmology at UT Southwestern Medical Center, in a news release.

AMD Patients Need Not Delay Cataract Surgery Per NEI Analysis

■ People with age-related macular degeneration (AMD) can undergo cataract surgery without fear of worsening their disease, according to the latest analysis of data from the Age-Related Eye Disease Study 2 (AREDS2), a clinical trial sponsored by the National Eye Institute (NEI). Data from the analysis were gathered in a 5-year study that tested combinations of dietary supplements for their ability to slow AMD progression. “The results of this study will help people with AMD and their care providers more accurately weigh the pros and cons of cataract surgery,” Emily Chew, MD, director, NEI Division of Epidemiology and Clinical Applications, said in a news release.

Chew et al conducted analyses of a subset of 4,553 AREDS2 participants’ eyes to assess whether cataract surgery increased the risk of progression to advanced AMD. They included only eyes that, at the start, lacked signs of advanced AMD and had not had cataract surgery. Eyes that later developed cataract and were treated with surgery were compared with similar AREDS2 participants who did not undergo cataract surgery.

The researchers found no increased risk of advanced AMD among participants who underwent cataract surgery, compared with cataract surgery-free eyes. Diagnosis of advanced AMD was determined by a variety of criteria, including retinal changes or treatment for AMD.

Dr. Chew pointed out that today’s phacoemulsification causes less trauma and inflammation than older techniques and this might explain why past studies saw an association between cataract surgery and progression to advanced AMD and the NEI-sponsored study did not.

GEM103 Studies End Successfully With Primary Goals Met

■ Gemini Therapeutics, Inc. announced the completion of its phase 2a studies of GEM103, a recombinant form of human complement factor H protein (CFH) designed to address both complement hyperactivity and restore retinal health in patients with AMD. Having achieved the primary goal of assessing GEM103’s safety and tolerability, as well as the primary goal of assessing GEM103’s safety and tolerability as an add-on to aflibercept for the treatment of wet AMD, these studies will end with patients returning for a final safety visit.

Analysis of the 62 patients enrolled in the main (ReGAtta) study showed that more than 9 months of GEM103 exposure was generally well tolerated, able to durably reduce biomarkers of complement activation, and able to maintain supraphysiologic levels of CFH. The wet AMD arm of the study investigated the safety and tolerability of GEM103 as an adjunct to aflibercept. Analysis showed that intravitreal GEM103 plus aflibercept was generally well tolerated, and the safety profile was generally consistent with the sham plus aflibercept arm.

Complement factor H levels remained supraphysiologic and greater than 5 times above baseline at the trough timepoints for 6 months. “The ReGAtta and wet AMD clinical studies have achieved their intended purpose of evaluating GEM103’s safety and tolerability and have also provided data indicating that GEM103 had biological activity and sustained supraphysiologic PK levels at both monthly and every-other-month doses,” said Jason Meyenburg, Gemini’s chief executive officer, in a news release. The company intends to provide an update regarding GEM103’s continued clinical development by the end of the first quarter of 2022.

First Patients Enrolled in Phase 2a BETTER Study of Wet AMD and DME

■ Isarna Therapeutics announced that it has begun enrolling patients in the BETTER study, a parallel, 2-segment phase 2a clinical study to evaluate ISTH0036 in patients with wet AMD and diabetic macular edema (DME). Investigators aim to enroll as many as 24 patients for each indication. The study, which is being carried out at clinical trial centers in Austria and India, will explore the prevention of fibrosis and epithelial-mesenchymal transition as a key differentiator to currently approved anti-angiogenic therapies.

ISTH0036 suppresses transforming growth factor-beta (TGF-β) protein production via antisense mechanisms. The TGF-β protein is chronically elevated in ophthalmic, fibrotic, immunologic, and cancerous diseases. The phase 2a trial will gather data on the reduction of retinal fluid and central macular thickness as the primary endpoint and improvement of visual acuity (VA) as a secondary endpoint during a treatment period of 7 months, followed by a 2-month safety follow-up. The durability of ISTH0036, which showed target suppression in preclinical models for more than 4 months, will be evaluated. Patients selected for the trials will include those who are newly diagnosed, those who are treatment-naïve, and those who have already been treated with anti-VEGF therapeutics.

“Based on the positive results from our phase 1 study supporting the safety of ISTH0036 and the encouraging data from preclinical studies in retinal disease, Isarna has committed to exploring ISTH0036 in ophthalmic indications where TGF-β plays a vital role in disease progression and where we see the greatest potential value for patients,” Prof. Marion Munk, chief medical officer of Isarna Therapeutics, said in a news release.

Novartis Acquisition Adds Novel Investigational GA Therapy to Its Portfolio

■ Novartis announced that it has entered into an agreement to acquire the outstanding share capital of the UK-based ocular gene therapy company Gyroscope Therapeutics. The acquisition will add GT005, an investigational gene therapy for the treatment of people with geographic atrophy (GA), to the Novartis portfolio.

The safety and efficacy of GT005 for the treatment of GA secondary to AMD is currently being evaluated in a phase 1/2 clinical trial and 2 phase 2 clinical trials. GT005 has received Fast Track designation from the FDA for the treatment of people with GA. GT005 is designed as an AAV2-based, one-time investigational gene therapy for GA secondary to AMD that is delivered subretinally. It aims to restore balance to an overactive complement system — a part of the immune system — by increasing production of the CFI protein. It is believed that increasing CFI production could reduce inflammation, with the goal of preserving a person’s eyesight.

“Novartis has a well-established expertise in ocular gene therapies that will position us well to continue developing this promising one-time treatment,” Marie-France Tschudin, president of Novartis Pharmaceuticals, said in a news release. “This acquisition is one more step forward in our commitment to delivering innovation in ophthalmology to treat and prevent blindness worldwide.”

New Data Released From Phase 2 KALAHARI DME Trial

■ Oxurion reported the latest outcomes from part A of its 2-part phase 2 KALAHARI clinical trial, a randomized, multicenter study to assess the dose level of multiple THR-149 injections and to evaluate the efficacy and safety of THR-149 vs aflibercept for the treatment of DME. The new data, which are derived from a post-hoc analysis of an OCT biomarker assessment, revealed a >9 letter gain in mean BCVA that was maintained for 4 months, with no rescue treatment required. The data also demonstrated THR-149’s ability to stabilize the central subfield thickness (CST). Arshad M. Khanani, MD, MA, director of clinical research at Sierra Eye Associates in Reno, Nevada, reported the latest data at the virtual 2022 Angiogenesis, Exudations, and Degeneration Meeting, hosted by Bascom Palmer Eye Institute.

THR-149 is a potent plasma kallikrein inhibitor being developed for the 40% to 50% of DME patients showing suboptimal response to anti-VEGF therapy. “The newest data continue to highlight THR-149’s compelling safety and efficacy profile in patients with DME. For patients who are suboptimal responders to standard of care anti-VEGF therapy, the post-hoc analysis of the high-dose cohort in the KALAHARI trial showed encouraging gains in BCVA, with more than 80% of patients gaining at least 5 letters and 50% of patients gaining at least 10 letters 4 months after the last THR-149 injection. In addition, CST was stable up to month 6. These results demonstrate the potential of THR-149 to make a meaningful difference to this patient population, which if left untreated would be expected to experience a further deterioration in their vision,” Dr. Khanani said in a news release.

Ribomic Reveals Early Data From Phase 2 RBM-007 Wet AMD Trial

■ Ribomic Inc, a pharmaceutical company specializing in aptamer therapeutics, announced preliminary results from its phase 2 TOFU study of RBM-007 in patients with wet AMD. The TOFU study is a double-masked, randomized, active-controlled phase 2 trial, with a cohort of 86 participants. The study’s purpose is to evaluate the efficacy and safety of RBM-007 monotherapy and RBM-007 in combination with Eylea compared to Eylea monotherapy in patients with wet AMD who were previously treated with anti-VEGF drugs. RBM-007 monotherapy or RBM-007 in combination with Eylea did not demonstrate vision improvement over Eylea monotherapy in this patient population. RBM-007 is a novel oligonucleotide-based aptamer with potent anti-FGF2 (fibroblast growth factor 2) activity. FGF2 is implicated not only in angiogenesis, but also in fibrosis in several diseases, including wet AMD.

Three Ribomic studies are currently ongoing for wet AMD: the active-controlled, double masked TOFU study; the single-arm, open-label RAMEN extension trial; and the TEMPURA study, an investigator-sponsored trial of treatment naïve wet AMD patients. Preliminary interim TEMPURA data evaluating the safety and efficacy of RBM-007 monotherapy are showing improvement in vision and retinal anatomy. Additional analyses of secondary endpoints of TOFU are ongoing. The company is planning to share the detailed TOFU results along with those from its RAMEN extension study and TEMPURA study as a full data set.

Positive Interim Phase 2 RGX-314 Data Reported

■ Regenxbio announced positive interim data from the ongoing phase 2 Altitude trial of RGX-314 for the treatment of diabetic retinopathy (DR) without center-involved diabetic macular edema (CI-DME) using in-office suprachoroidal delivery. RGX-314 is being investigated as a potential one-time gene therapy for the treatment of wet ARMD and DR. The data were presented at the virtual 2022 Angiogenesis, Exudation, and Degeneration conference, by Michael A. Klufas, MD, from Wills Eye Hospital in Philadelphia, Pennsylvania.

Twenty patients in cohort 1 were randomized to receive RGX-314 at a dose level of 2.5x10¹¹ genomic copies per eye (GC/eye) vs observational control at a 3:1 ratio. Cohort 2 will include 20 patients randomized to receive RGX-314 at an increased dose level of 5x10¹¹ GC/eye vs observational control at a 3:1 ratio. Cohort 3 is designed to evaluate RGX-314 at the same dose level as cohort 2 in 20 patients who are neutralizing antibody (NAb) positive. Enrollment is ongoing in cohorts 2 and 3, at a dose level of 5x10¹¹ GC/eye. Patients in this trial do not receive prophylactic immune suppressive corticosteroid therapy before or after administration of RGX-314.

Among the data released: 47% of patients in cohort 1 treated with RGX-314 demonstrated a ≥2 step improvement from baseline on the ETDRS-DRSS at 6 months, compared to 0% of patients at 3 months; and in-office suprachoroidal delivery of RGX-314 continues to be well tolerated in 15 patients in cohort 1 with no drug-related serious adverse events at 6 months, and no intraocular inflammation has been observed. A 2-step improvement in DRSS has been accepted as a pivotal endpoint by the FDA for DR clinical trials.

“I am encouraged by the clinical improvement of disease severity observed in the Altitude trial of RGX-314,” Dr. Klufas said in a news release. “Globally, DR is the leading cause of blindness in working-age adults, and these patients are in need of new treatment options. I look forward to further investigation of RGX-314 as a potentially compelling treatment option for patients with DR.”

Ophthalmic Technician Training Gets Digital Update

■ Alchemy Vision Project announced an updated release of ENTRY, its digital curriculum focused entirely on ophthalmic technician training. The online educational resource provides standardized training for technicians in a video-based format with support from a team of certified ophthalmic technicians and certified ophthalmic medical technologists.

The new edition of the digital curriculum includes a personalized learning roadmap tailored to each technician’s skills and needs, a frequently updated library of lessons, quizzes, assignments, a final exam, and an assortment of adaptable study tools to support the training needs of eye care teams. A notable addition to the updated curriculum is live-streamed lessons from industry professionals such as Nicole Fram, MD, Paul Singh, MD, Mitchell Shultz, MD, Eduardo Besser, MD, and Felicia Lew, OD.

New CCO Appointed to Eye-Tracking Software Developer Appoints

■ C. Light Technologies, a company known for development of retinal eye tracking software, announced the appointment of Lon Dowell to the position of Chief Commercial Officer. Mr. Dowell brings more than 30 years of experience in strategic planning, operations, and leadership for global medical device companies including Zeiss, Leica, and Topcon, among others. Mr. Dowell will lead the company’s commercial strategy including marketing and sales. He will collaborate on the assessment of partnership opportunities to optimize the value of C. Light Technologies’ growing business in the neurodegenerative and ophthalmic markets.

“Lon brings extensive commercial experience and unique perspective on multimodal imaging and interoperability. We are excited that he has joined our growing team to greatly enhance our commercialization efforts,” said COE/founder Christy Sheehy, PhD, in a news release. RP