Failed cell therapy study offers positives, raises new questions
Patients with a history of frequent anti-vascular endothelial growth factor (anti-VEGF) injections for the treatment of age-related macular degeneration (AMD) may not be the best potential candidates for encapsulated cell technology (ECT).
ECT contains human cell lines that are capable of producing a variety of proteins. After a single surgical implantation, they can produce proteins for up to two years or more, according to Szilard Kiss, MD, assistant professor of ophthalmology; director of clinical research at Weill Cornell Medical College, New York.
“These cell lines survive even after being inside the human eye for six months,” Dr. Kiss said.
A phase II study was initiated to compare the third generation of ECT (Neurotech, Cumberland, RI) to aflibercept (Eylea, Regeneron Pharmaceuticals). The study planned to enroll 90 subjects, with a primary outcome of non-inferiority to aflibercept alone after 108 weeks. Among the patient entry criteria, all patients had to have shown a response to aflibercept before randomization.
The patient profile was similar to other anti-VEGF treatment studies, with a best corrected visual acuity (BCVA) between 80 letters (20/25) and 35 letters (20/200) at baseline; limited pathology (such as fibrosis, scarring, or atrophy); good optical coherence tomography (OCT) response to injections; and having gone through at least three previous injections, with the last injection no more than four months before study enrollment.
“The goal was to have fewer than 20% of patients needing a rescue injection during the follow-up period,” Dr. Kiss said.
Unfortunately, there was not a significant difference between the implanted patients and those that received aflibercept. Those subjects that went on to 24 weeks may appear to have gained “a little bit of vision, and one subject seemed to benefit,” Dr. Kiss said. The OCT results “show a saw-toothed pattern that we can see in patients who are treated with aflibercept every 8 weeks.”
Although the responses “look impressive,” most subjects underwent rescue injections of aflibercept, Dr. Kiss said.
The time to rescue injections actually occurred as soon as 4 weeks after the implantation. And as such, “there was early termination of the study, because it was not going to meet the primary endpoint of fewer than 20% needing injections,” Dr. Kiss said.
However, the implantation itself was deemed successful, as the cells survived and produced the anti-VEGF molecule, but the amount that was produced was significantly below the 12 μg/mL necessary.
There were two outlier subjects who had received an aflibercept injection alone about 10 days before the explant, and before measuring anti-VEGF activity. Dr. Kiss believes that to be the cause of the higher numbers compared to other subjects in the study.
“None of the explants who did not receive aflibercept right before the explant produced enough anti-VEGF activity,” he said.
However, there had been indications the technology would be successful for this indication—a patient who had undergone six aflibercept injections during the previous year before enrollment did not need any injections (rescue therapy) during the 28 weeks before the AMD study terminated.
On the positive side, Dr. Kiss said the study results created new questions for the technology—including whether the approach could achieve better outcomes compared to “real-world” experience with other patient populations since the cell viability and stability was good.
The third generation ECT (NCT-503-3) did achieve the goal of improved VEGF-receptor production by at least 2-fold compared to double ECT (NT-503-2) implants. Further, while VEGF levels were not detectable, a complex formation was observed in the preliminary native gel.
While the AMD study has been halted, the company is investigating the technology in an ongoing phase II study in conjunction with the MacTel Project to investigate the long-term delivery of ciliary neurotrophic factor (CNTF) in people with macular telangiectasia (MacTel). A pilot study of neuro-enhancement in subjects with early visual impairment in collaboration with clinicians at Stanford University is also under way.
Most promising is that ECT is “a unique and versatile drug delivery platform, with more than 1,000 patient years of safety data,” Dr. Kiss added. The long-term continuous release of therapeutic proteins via ECT “remains a viable and effective way to treat chronic ocular conditions.”