Ground-breaking treatment for bullous keratopathy approved in Japan
In March 2023, Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) approved Aurion Biotech’s allogeneic cell therapy, Vyznova, to treat patients with bullous keratopathy. This approval is believed to be the first for an allogenic cell therapy for corneal endothelial disease.
Healthy cells from a donor cornea are propagated in a novel, multistep process, according to a company news release. The ground-breaking innovation is that this approach enables fully differentiated corneal endothelial cells to regenerate outside the body. Cultured cells from 1 donor can be manufactured to produce treatments for more than 100 recipient eyes. Current standards of care require 1 donor cornea for each corneal transplantation procedure.
The eyes of patients with corneal endothelial cell damage cannot regenerate these cells. Following corneal disease or injury, the number of cells decrease and vision can be lost. This new cell therapy improves on the current therapies (penetrating and endothelial keratoplasties) with simplified treatment, and potential complications such as graft detachment, transplant rejection, dislocation, irregular astigmatism and infection have been eliminated, according to the news release.
The cell manufacturing process is fascinating, according to Dr Edward Holland, MD, chair of Aurion Biotech’s Medical Advisory Board, director of cornea services at Cincinnati Eye Institute, and a professor of ophthalmology at the University of Cincinnati in Ohio, US.
Dr Holland explained that the number of human corneal endothelial cells (HCECs) in each individual is finite and that over time they will degrade or deteriorate because of age, disease or surgical trauma. “Once HCECs are gone, they’re gone for good,” he said.
Until very recently, getting fully differentiated HCECs to reproduce in vitro proved extremely challenging. Shigeru Kinoshita, MD, PhD, of the Kyoto Prefectural University of Medicine (KPUM), overcame this hurdle with a breakthrough innovation that enabled these cells to reproduce in the laboratory.1,2
A powerful feature of these manufactured cells is that they are fully differentiated, meaning they do not need to learn to become endothelial cells (unlike stem cells). HCECs have all the inherent characteristics of endothelial cells because they are endothelial cells. This gives practicing ophthalmologists a great deal of confidence in their efficacy and safety profile.
Dr Holland noted that during treatment, the endothelial cells are injected intracamerally into the eye where they repopulate into a healthy monolayer and remove fluid from the cornea, which decreases corneal oedema. The cell therapy procedure is minimally invasive and can be performed relatively rapidly, with a recovery period of approximately 2 to 3 hours for patients.
“The procedure is quite elegant,” Dr Holland explained. “We prepare the patient’s eye as we would for any outpatient ocular surgery. We then make a small incision into the patient’s anterior chamber. With a standard cannula, we ‘polish off’ the diseased endothelium in the central area of the cornea.”
Dr Holland noted that the surgeon can implant the cells into the patient’s anterior chamber using a 27-gauge needle and syringe. “Then the patient lies on his or her stomach for 3 hours, which enables the cells to settle into place and reform a monolayer,” he added. “The next day, the patient can resume most normal activities.”
This procedure is the life’s work of Dr Kinoshita, who noted the procedure “offers the potential to completely transform the treatment paradigm for corneal endothelial disease, with an ample supply of fully differentiated, allogeneic corneal endothelial cells; a minimally invasive, elegant procedure; and potentially less onerous recovery for patients.”
Dr Kinoshita and his colleagues conducted a first-in-human trial of subjects with bullous keratopathy. The 2-year outcomes of the first 11 participants were published in 2018,1 and 5-year outcomes were published in 2021.2 Dr Kinoshita/KPUM out-licensed this intellectual property to Aurion Biotech for clinical development targeting corneal endothelial disease.
Along with a US team of corneal surgeons that included Elizabeth Yeu, MD, John Berdahl, MD, and Matt Giegengack, MD, Dr Holland performed the first cell therapy studies outside of Japan, at the Clinica Quesada in San Salvador, El Salvador, from 2020 to 2022.
In the news release, Aurion reported that treated patients “have experienced clinically meaningful and sustained improvements in key measures of corneal health: visual acuity, central corneal thickness, and endothelial cell density.”1
“The results are just remarkable,” Dr Holland said. “Even in extremely oedematous corneas with bullous keratopathy eyes, we’ve seen tremendous anatomic and functional improvements with full recovery of vision.” Dr Holland pointed out that ophthalmologists will measure the central cornea thickness to determine if the corneal oedema has decreased.
“The functional measure is the best-corrected visual acuity [BCVA],” he said. “After treatment, the corneal oedema is reduced to normal levels, and their visual acuity is significantly improved. It’s remarkable.”
In total, 130 patients with corneal endothelial disease have been treated with this cell therapy.
Cell therapy differs from endothelial keratoplasty in several important ways, Dr Holland explained. Although corneas are the most frequently transplanted organ, worldwide there is a chronic shortage.
For every 70 diseased eyes, there is only 1 donor cornea available.3 And endothelial keratoplasty requires the use of 1 donor cornea for each diseased eye. In contrast, Aurion can manufacture up to 100 doses from a single donor (enough to treat 100 eyes) and may be able to manufacture more than 1000 doses soon. Once approved throughout the world, Aurion’s cell therapy manufacturing could effectively eliminate this worldwide chronic shortage of donor corneal tissue.
Next, the postoperative recovery period for patient experience with cell therapy is much less onerous than for endothelial keratoplasty, where patients must lie flat on their backs for 1 to 2 days for the donor corneal tissue graft to adhere properly to the patient’s cornea. Even with cooperative patients there is still a significant graft detachment rate, with endothelial keratoplasty, especially with the Descemet’s membrane endothelial keratoplasty procedure.2
In addition, the number of cells transplanted with cell therapy will be significantly greater than with endothelial keratoplasty, which will result in longer corneal surgical success and a reduction in the need for repeat surgery. Equally important, this procedure is quite accessible to the broader ophthalmology community, as compared with endothelial keratoplasty, which is performed almost exclusively by corneal specialists. “It’s my expectation that a larger population of ophthalmologists will embrace cell therapy, for all of these reasons,” Dr Holland said.
Japan’s PMDA approved Vyznova based on the results achieved in 65 patients in 3 Japanese clinical trials, including a first-in-human trial with 38 patients, an endothelial cell dose ranging trial with 15 patients, and a confirmatory trial with 12 patients.3
The primary efficacy end point of these studies was the proportion of patients who achieved a corneal endothelial cell density of 1000 or more cell/mm2; the main secondary efficacy end points were the proportion of subjects with a central corneal thickness (CCT) of less than 630 microns and the proportion of subjects with a 2-line (0.2 logarithm of the minimum angle of resolution [logMAR]) improvement or greater in BCVA.
In the first-in-human trial, investigators evaluated the safety of 1 intracameral injection of cultured corneal endothelial cells. They reported that the proportion of patients who achieved an endothelial cell density of 1000 cells/mm2 or greater was 91% 24 months after treatment; 85% achieved a CCT of less than 630 microns, and 94% achieved a 2-line (0.2 LogMAR) BVCA improvement or higher at 24 months.
In the cell dose ranging trial, the 15 patients were randomly assigned to 1 intracameral injection of a low cell dose (2.0 × 105), a medium cell dose (5.0 × 105), or a high cell dose (1.0 × 106 ). Each group contained 5 patients. The proportions of patients who achieved an endothelial cell density of 1000 cells/mm2 or more at 12 weeks were 80%, 100%, and 100%, respectively. When the results from the 3 groups were combined, 92.9% reached that end point. The proportions of subjects who achieved a CCT below 630 μm at 12 months were 80%, 80%, and 100%, respectively. When the data from the 3 groups were combined, 87% had a 2-line at 12 months.
In the confirmatory trial, the proportion of subjects who achieved a corneal endothelial cell density of 1,000 cells/mm2 or more at 24 weeks was 100.0%. The proportion who achieved a CCT less than 630 μm at 24 weeks was 75%; 100% achieved a 2-line BVCA improvement or better at 24 weeks.
One dose of the cultured endothelial cells regardless of the dose was well tolerated in the 3 studies and had a favourable safety profile in adult patients with corneal endothelial dysfunction. No treatment-related ocular or systemic serious adverse events were observed.
The most common ocular adverse events (more than 2 events in any trial) were ocular pain, eyelid oedema, cystoid macular oedema, increased tearing and increased intraocular pressure. The most common nonocular adverse events (more than 2 events in any trial) were nasopharyngitis, constipation, diarrhea, musculoskeletal pain and insomnia.
In the US, Aurion Biotech is preparing to submit an Investigational New Drug application to initiate clinical trials, with additional clinical development plans under way in the European Union.
In Japan, now that the team has received regulatory approval, the next step is to solicit reimbursement approval. The team anticipates that effort will involve the better part of the rest of 2023.
Edward Holland, MD, is chair of Aurion Biotech’s Medical Advisory Board, director of cornea services at Cincinnati Eye Institute, and a professor of ophthalmology at the University of Cincinnati in Ohio, US.