Christina Weng, MD, MBA, Baylor College of Medicine, Houston, Texas

It is exciting that the US Food and Drug Administration (FDA) has given Adverum Biotechnologies the green light to proceed with its OPTIC phase 1 trial evaluating ADVM-022, especially in light of the “robust preliminary anatomical response” observed in the first cohort in the absence of any serious adverse effects. Interestingly, instead of escalating the dose per protocol, the investigators have decided to de-escalate the dose three-fold (2x10¹¹ vector genomes [vg]/eye) for their second cohort.

While it is ideal to ultimately identify the lowest effective dose, I do wonder how this reverse dose-seeking approach might affect later trial phases. Ophthalmic gene therapy is still in its infancy, and a big unanswered question concerns sustainability. We do not yet know if cellular transduction always results in permanent transgene expression in vivo. There may come a point in the future where it would be beneficial to evaluate a dose higher than 6x10¹¹ vg/eye from an efficacy or durability standpoint. Nevertheless, this progress in retinal gene therapy is extremely encouraging, and I look forward to hearing the first set of 24-week primary and secondary outcomes soon.

David Brown, MD, FACS, Retina Consultants of Houston, Texas

The May 16 Adverum press release announced 3 positive developments in the company’s quest to commercialize an intravitreal gene delivery system for continuous anti-VEGF production. First, the FDA clinical hold was lifted on the OPTIC phase 1 trial so that the human AMD trial can continue to a second cohort. ADVM stated that the independent Data Monitoring Committee has reviewed the first cohort (1 patient out to 6 months) and found no serious adverse events had occurred and agreed that the study could proceed. Most interesting was that Adverum reported that “based on the robust preliminary anatomical response observed to date in the first cohort (n=6), Adverum will begin dosing the second cohort at a lower dose of 2 x 10¹¹ vg/eye, three times lower than the dose used in the first cohort.” This implies that the company’s single intravitreal injection of a modified viral vector is actually producing enough anti-VEGF construct to potentially treat wet AMD. While these data are certainly preliminary, they are an encouraging development for both the company and our patients.

Szilard Kiss, MD, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, New York

It’s reassuring to see that the FDA has lifted the clinical hold on the ongoing phase 1 OPTIC trial evaluating anti-VEGF gene therapy for neovascular AMD. Moreover, it is encouraging that Adverum has decided to go to a lower dose in the second cohort of subjects based on anatomical responses noted in the first cohort. I am also delighted to see that the first subject in that second cohort was recently dosed with ADVM-022. ADVM-022 (AAV.7m8-aflibercept) is a gene-therapy vector designed specifically to be given via an in-office intravitreal injection for the long-term treatment of wet AMD following a single administration. There is a great unmet need in this space. Given the burden of repeated intravitreal injections for the lifetime of the patient, combined with the epidemic of chronic undertreatment noted in “real-world” studies (and the resultant suboptimal visual outcomes), sustained anti-VEGF delivery strategies, such as gene therapy, will undoubtedly play a major role in our future armamentaria for wet AMD, diabetic retinopathy, diabetic macular edema, and retinal vein occlusion. However, the specific details of the safety and efficacy profile an intravitreal gene therapy approach remain to be determined. We await Adverum’s presentation of the 24-week primary and secondary outcomes in the second half of 2019.

Aaron Osborne, MBBS, Chief Medical Officer, Adverum Biotechnologies

Intravitreal injections of anti-VEGF agents have reduced AMD-associated blindness and preserved independence for many patients, making VEGF suppression one of the most important advances in ophthalmology. Unfortunately, for people with wet AMD, the real-world vision outcomes of anti-VEGF treatment do not match the results seen in clinical trials. This is largely due to the need for frequent injections with existing therapies, resulting in undertreatment and failure to maintain vision. There is therefore a need for anti-VEGF therapies that can provide sustained VEGF suppression without the need for frequent injections.

This key unmet need continues to drive our development of ADVM-022, which was designed specifically for the treatment of this challenging disease through providing durable expression of therapeutic levels of intraocular anti-VEGF protein in a single intravitreal injection. ADVM-022 has the potential to preserve vision and become an important therapeutic option for physicians and patients. Adverum is committed to partnering with the retina community to advance the science around ADVM-022 in order to help improve outcomes for patients with wet AMD and their caregivers. We look forward to sharing the first clinical data on ADVM-022, the 24-week data from the first cohort of patients in the OPTIC study, at the Retina Society meeting in London on Thursday, September 12, 2019. RP