At the 2019 meeting of the Retina Society in London, United Kingdom, Adverum Biotechnologies reported interim 24-week data from the OPTIC trial, a phase 1 study of intravitreal gene therapy with ADVM-022 (aav.7m8-aflibercept) for wet AMD. The results were presented by Szilard Kiss, MD. Retinal Physician asked several retina specialists and a company representative to weigh in on the data.

Robert L. Avery, MD
California Retina Consultants, Santa Barbara, California

The Retina Society presentation was very exciting to me. Initially, I was a bit disappointed because I saw that there was inflammation in all patients. It was encouraging that the inflammation seemed to be self-limited, although I would have preferred more details of its treatment in this safety study. However, I felt that the proof-of-concept component of this study was more important. There has been concern as to whether or not intravitreal injection would produce sufficient transduction to be efficacious, with recent animal studies showing transduction not only at the fovea, but also in the far retinal periphery. After seeing the optical coherence tomography (OCT) images from before and after ADVM-022 injection, with 5 of 6 showing complete resolution of all fluid, I am convinced that this delivery is having a biologic effect. One patient had 109 previous injections with fluid shown after each of the 5 pre ADVM-022 injections, but the retina was flat for 26 weeks after the treatment. Hence, my overall impression of this talk was very positive, as intravitreal delivery would be preferred to subretinal, if it works, and this talk showed that it can work, albeit with some inflammation, which is reportedly manageable. This therapy seems viable with the usual caveat that further study is needed.

David S. Boyer, MD
Retina-Vitreous Associates Medical Group, California

The Adverum data that were presented were extremely exciting. I believe that many listening to the presentation did not completely understand the significance. This was a phase 1, first-in-human trial to determine the safety and possible efficacy of the Adverum gene therapy administered intravitreally in a group of subjects that required frequent intravitreally anti-VEGF injections (average 6.2 injections in previous 8 months) to maintain a relatively dry OCT. The study demonstrated both safety and efficacy in almost every patient. The patients did not show a worsening of the OCT edema, and they maintained vision. The major side effect of uveitis was mild and controllable with steroid eye drops. Other gene therapies have shown similar inflammation. The lower dose was considered because of the outstanding results in the high-dose group. This treatment may be able to maintain patients’ vision without frequent injections. I look forward to the phase 2 trials, which hopefully will reproduce these excellent results.

Charles C. Wykoff, MD, PhD
Retina Consultants of Houston, Houston, Texas

Gene therapy holds tremendous promise. A one-time intervention to establish an intraocular biofactory that produces a sustained amount of a therapeutic anti-VEGF protein could be tremendously valuable in the management of exudative retinal diseases. It is an exciting time, with 2 major programs exploring this possibility for nAMD in human studies, one by subretinal delivery following pars plana vitrectomy in the operating room (Regenxbio) and the other by standard intravitreal delivery without vitrectomy (Adverum).

There are 3 key angles to consider in Adverum’s recent data release summarizing outcomes of 6 patients, cohort 1, through week 24. These eyes had a history of substantial anti-VEGF treatment burden before enrollment in this phase 1 study, having received a mean of 35 prior injections.

First, safety is a crucial issue to consider with any first-in-human study, and especially with a new platform such as ADVM-022. The report of no serious adverse events, no drug-related nonocular adverse events, and no adverse events meeting criteria for dose-limiting toxicity is positive and encouraging. Inflammation in all patients is notable, with report of 5 moderate adverse events, all related to inflammation. Over time, it will be important to understand the duration of this inflammation and the details of how these eyes were managed.

Second, anatomic data were impressive, with a mean CST reduction of 52.7 microns through week 24. Third, from a functional perspective, VA appeared to be maintained on average, with 2 mean letters lost. While no eye received a rescue injection, others have noted that the 90% confidence intervals at week 24 appear relatively large. It is worth noting that this variability in VA change appears similar at multiple reported time points and may be attributed to the patient population being studied, as it is consistent with the variability previously reported in large phase 3 wet AMD clinical trials.

These data appear positive. I look forward to longer-term follow-up and additional studies of ADVM-022.

Aaron Osborne, MBBS
Adverum Biotechnologies, Inc.

We are very encouraged by the 24-week data from the OPTIC phase 1 clinical study. In the study, a single intravitreal injection of AVDM-022 prevented signs of disease progression in all patients through week 24. Also, 5 of the 6 patients demonstrated complete resolution of retinal fluid by week 24 on OCT. As such, no anti-VEGF rescue injections were required. Given the patients’ history of frequent anti-VEGF injections due to active disease, these data provide compelling evidence of a therapeutic biologic effect after ADVM-022 treatment.

On OCT, mean central retinal thickness reduced from baseline to 24 weeks, with a point estimate of -52.7 micrometers, and the 90% confidence intervals for the change both being below zero. These reductions reflect the resolution of retinal fluid and absence of new signs of exudation. Additional data out to a median of 34 weeks were presented at AAO showing that BCVA was maintained, with a mean change of -1.5 letters. Anatomic improvements seen on OCT were also sustained in all patients. In the 8 months prior to entering OPTIC, these patients received a total of 37 anti-VEGF injections; with a median of 8 months follow-up post ADVM-022 administration, zero anti-VEGF injections have been required.

In phase 1 studies, assessment of safety is of key importance, and we were pleased to report that ADVM-022 was safe and well tolerated. Intraocular inflammation was the most common adverse event reported; this was generally mild and responsive to steroid eye drops. For the third cohort of patients in OPTIC, oral steroid prophylaxis has been replaced by steroid eye drop prophylaxis. Overall, we believe ADVM-022 represents a promising therapeutic approach, with potential to deliver long-lasting benefits from a single intravitreal injection in patients with wet AMD. RP