The Food and Drug Administration (FDA) has accepted for Priority Review the Biologics License Application (BLA) for aflibercept 8mg for the treatment of patients with wet age-related macular degeneration (wAMD), diabetic macular edema (DME), and diabetic retinopathy.

The BLA is supported by data from the phase 3 PULSAR (N=1009; ClinicalTrials.gov Identifier: NCT04423718) and phase 2/3 PHOTON (N=658; ClinicalTrials.gov Identifier: NCT04429503) trials, which compared the efficacy and safety of aflibercept 8mg to Eylea (aflibercept 2mg) in patients with wAME and DME, respectively. Patients were randomly assigned to receive aflibercept 8mg every 12 weeks or every 16 weeks or aflibercept 2mg every 8 weeks. The primary endpoint for both trials was the change from baseline to week 48 in best corrected visual acuity. 

Results from both trials showed that treatment with aflibercept 8mg met the primary endpoint demonstrating noninferior vision gains at week 48 with both the 12- and 16-week dosing regimens after initial monthly doses vs aflibercept 2mg every 8 weeks. The majority of patients treated with aflibercept 8mg were able to maintain the 12- and 16-week dosing regimens through week 48.

In PULSAR, 71% and 67% of wAMD patients treated with aflibercept 8mg 12- and 16-week dosing regimens, respectively, had no retinal fluid in the center subfield compared with 59% of patients who received aflibercept 2mg. The median time to fluid-free subfield was 4 weeks for aflibercept 8mg vs 8 weeks for aflibercept 2mg.

In PHOTON, DME patients treated with aflibercept 8mg 12- and 16-week dosing regimens had a mean reduction in the total area of fluorescein leakage from baseline of 14mm² and 9mm², respectively, vs 9mm² for aflibercept 2mg.

Aflibercept 8mg was found to have a similar safety profile to aflibercept 2mg. No cases of retinal vasculitis, occlusive retinitis or endophthalmitis were observed in either trial.

The FDA has assigned a target action date of June 27, 2023 for the application.

References

1. Aflibercept 8mg BLA for treatment of wet age-related macular degeneration and diabetic macular edema accepted for FDA Priority Review. News release. Regeneron Pharmaceuticals, Inc. Accessed February 23, 2023. https://www.globenewswire.com/news-release/2023/02/23/2614121/0/en/Aflibercept-8-mg-BLA-for-Treatment-of-Wet-Age-Related-Macular-Degeneration-and-Diabetic-Macular-Edema-Accepted-for-FDA-Priority-Review.html.
2. Aflibercept 8mg late-breaking data presented at Retina Society in diabetic macular edema and wet age-related macular degeneration. News release. Regeneron Pharmaceuticals, Inc. November 4, 2022. Accessed February 23, 2023. https://investor.regeneron.com/news-releases/news-release-details/aflibercept-8-mg-late-breaking-data-presented-retina-society.

HealthDay News — Large language models (LLMs) like ChatGPT can respond to patient-written ophthalmology questions and usually generate appropriate responses, according to a study published online August 22 in JAMA Network Open.

Isaac A. Bernstein, from Stanford University in California, and colleagues examined the quality of ophthalmology advice generated by an LLM chatbot compared with ophthalmologist-written advice. The study used deidentified data from an online medical forum, in which patient questions received responses written by ophthalmologists. A masked panel of 8 board-certified ophthalmologists were asked to differentiate between answers generated by the ChatGPT chatbot and answers from ophthalmologists.

Two hundred pairs of user questions and answers were assessed. The researchers found that the mean accuracy was 61.3% for differentiating artificial intelligence (AI) and human responses. Of 800 assessments of chatbot-written answers, 21.0 and 64.6% were marked as human-written and AI-written, respectively. Chatbot answers were more often rated as probably or definitely written by AI compared with human answers. The likelihood of chatbot answers containing incorrect or inappropriate material and likelihood of harm was comparable with human answers.

“We intend for this study to catalyze more extensive and nuanced dialogue and joint efforts surrounding the use of LLMs in ophthalmology among various health care stakeholders, including patients, clinicians, researchers, and policy makers,” the authors write. “The primary goal is to prudently leverage these early research findings to shape the responsible implementation of LLMs in the field of ophthalmology.”

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HealthDay News — For children aged 5 to 12 years with low-to-moderate bilateral myopia, atropine 0.01% eye drops do not slow myopia progression over 2 years of treatment, according to a study published online July 13 in JAMA Ophthalmology.

Michael X. Repka, MD, from the Wilmer Eye Institute in Baltimore, and colleagues conducted a randomized, placebo-controlled trial involving children aged 5 to 12 years with low-to-moderate bilateral myopia (−1.00 to −6.00 diopters [D] spherical equivalent refractive error [SER]). A total of 187 children were included in the study: 125 received atropine and 62 received placebo. Children received treatment for 24 months, followed by six months of observation.

The researchers found that the adjusted mean change in SER from baseline was −0.82 and −0.80 in the atropine and placebo groups, respectively, at the 24-month primary outcome visit (difference, −0.02; 95% CI, −0.19 to +0.15 D). At 30 months, the adjusted difference in mean SER change from baseline was −0.04 D (−0.25 to +0.17 D). From baseline to 24 months, the adjusted mean changes in axial length were 0.44 and 0.45 in the atropine and placebo groups, respectively (difference, −0.002mm [−0.106 to 0.102mm]). From baseline to 30 months, the adjusted difference in mean axial elongation was +0.009mm (−0.115 to 0.134mm).

“Overall, clinical trials investigating atropine, 0.01%, for myopia control, including the well-done study by Repka et al., indicate that stronger concentrations of atropine should be considered for first-line treatment of myopia progression,” write the authors of an accompanying editorial.

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Patricia Farris, MD, from Tulane University School of Medicine in New Orleans, and colleagues examined the comprehensive efficacy and tolerability of topical 0.1% stabilized bioactive retinol. Six vehicle-controlled studies of 0.1% stabilized bioactive retinol in women with mild-to-moderate signs of photodamage were included in the analysis. A total of 237 participants received retinol and 234 received vehicle.

The researchers found greater improvements from baseline in all signs of photoaging for retinol vs vehicle as early as week 4 and through 12 weeks of application. Irritation was experienced by few participants; all events were transient and mild to moderate. Erythema and skin scaling/peeling were the most common signs of irritation.

“At the time of this publication, our analysis represents one of the largest datasets demonstrating the clinical benefit and tolerability of retinol,” the authors write. “These pooled results demonstrate that a well-formulated topical retinol at a strength of 0.1% can be an effective cosmeceutical solution for individuals seeking to improve signs of photoaging.”

Several authors disclosed ties to pharmaceutical and dermatology companies, including Kenvue, which funded the study.

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Diabetic Macular Edema Treatments

HealthDay News — US regulators inspecting a factory in India that has been linked to contaminated eye drops have uncovered a laundry list of problems. An outbreak of eye infections involving products made at the factory stems from exposure to Pseudomonas aeruginosa. So far, 3 people have died, while there have been 8 reports of lost vision and dozens of infections.

US Food and Drug Administration inspectors were at Global Pharma Healthcare Ltd.’s factory from February 20 through March 2, where they identified dirty equipment and clothing, as well as a lack of other safeguards.

The FDA issued citations to the company after what appears to be the agency’s first-ever visit to the plant. “You used a manufacturing process that lacked assurance of product sterility,” the FDA said in the citation document. Artificial tears drops and ointment involved include those branded as EzriCare and Delsam Pharma. Those products have already been recalled.

Among the many problems identified by the FDA were that surfaces touched by product packaging “were not cleaned, sanitized, decontaminated, or sterilized.” A machine used to fill the product into bottles had a “black, brown greasy deposit” on one of its parts, though company logs said the machine had been cleaned weeks before and not used since. Records about cleaning of filling machines and spaces also had gaps and discrepancies, CBS News reported.

The company was also apparently not doing some important testing to ensure that the products were sterile or other tests to determine that the ingredients supplied to the company were in fact what they were supposed to be. “Your firm failed to conduct at least one test to verify the identity of each component of a drug product. Your firm also failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals,” the inspectors wrote.

Some testing of the unopened artificial tears early in the outbreak did not find bacteria, but it was found in already-opened bottles. However, the FDA later “found unopened tubes to be contaminated with bacteria,” CBS News reported. The FDA did not say whether the strain of bacteria it found is the same as that seen in the outbreak.

CBS News Article

FDA-Approved Biosimilars

The Food and Drug Administration (FDA) has approved Hepzato Kit (melphalan/Hepatic Delivery System [HDS]) as a liver-directed treatment for adult patients with metastatic uveal melanoma (mUM) with unresectable hepatic metastases affecting less than 50% of the liver and no extrahepatic disease, or extrahepatic disease limited to the bone, lymph nodes, subcutaneous tissues, or lung that is amenable to resection or radiation.

The Hepzato Kit is designed to administer melphalan directly to the liver via the HDS, allowing for higher drug exposure in target tissues without an increase in systemic toxicity. While the hepatic venous blood is filtered during drug infusion and subsequent washout during a percutaneous hepatic perfusion (PHP) procedure, the HDS is able to isolate the liver resulting in locoregional delivery of a relatively high dose of the chemotherapy.

The approval was based on data from the single-arm, multicenter, open-label, phase 3 FOCUS study (ClinicalTrials.gov Identifier: NCT02678572) that evaluated the efficacy and safety of Hepzato Kit during a PHP procedure in 91 patients with hepatic-dominant ocular melanoma. Study participants received 3mg/kg of melphalan administered intraarterially using the HDS every 6 to 8 weeks for up to 6 infusions. The primary endpoint was the objective response rate (ORR). The key secondary endpoint included duration of response (DOR).

Results showed an ORR of 36.3% (95% CI, 26.4%-47.0%) in patients with hepatic and extrahepatic lesions (n = 91), of which 7.7% had complete response and 28.6% had partial response. Among responders, median DOR was 14 months (95% CI, 8.3-17.7); 70% had a DOR lasting at least 6 months and 30% had a DOR lasting at least 12 months. The disease control rate (DCR) was 73.6% (95% CI, 63.3%-82.3%).

As for safety, the most common adverse reactions (≥20%) were thrombocytopenia, fatigue, anemia, nausea, musculoskeletal pain, leukopenia, abdominal pain, neutropenia, vomiting, increased alanine aminotransferase, prolonged activated partial thromboplastin time, increased aspartate aminotransferase, increased alkaline phosphatase, and dyspnea.

The prescribing information for Hepzato Kit includes a Boxed Warning regarding the risks for severe peri-procedural complications and myelosuppression. Due to these risks, Hepzato Kit is only available through a restricted program called the Hepzato Kit Risk Evaluation and Mitigation Strategy (REMS). Patients should be evaluated for severe peri-procedural complications during and for 72 hours after administration of Hepzato, and monitored for hematologic laboratory parameters.

Hepzato Kit is supplied with the Hepzato 5×5 Drug Pack and the HDS. Each 5×5 Hepzato Kit Drug Pack includes Hepzato (mephalan) and diluents for reconstitution and dilution. The product is expected to be available in the fourth quarter of 2023.