Something of a duel may be shaping up between Menlo Park, Calif.-based Adverum Biotechnologies Inc. with ADVM-022, the phase I gene therapy candidate for wet age-related macular degeneration (AMD) and Regenxbio Inc., of Rockville, Md., with a similar candidate.

Given as a single, intravitreal shot, ADVM-022 deploys a proprietary vector capsid (AAV.7m8) carrying an aflibercept (Eylea, Regeneron Pharmaceuticals Inc.) coding sequence under the control of an expression cassette designed by Adverum. The company unveiled 24-week primary and secondary outcomes from the first cohort of patients in the phase I Optic trial (n=6; dose of 6x10^11 vg/eye) during a podium presentation at the Retina Society's annual meeting in September in London, and 52-week data are expected in the first half of 2020. Dosing of the second cohort of patients (n=6; lower dose of 2x10^11 vg/eye) was completed not long ago, and 24-week data from that group should roll out in the first half of next year as well.

Nearer term, the company will present more clinical data from the first cohort at the Retina Subspecialty Day Program of the American Academy of Ophthalmology (AAO) annual meeting Friday in San Francisco. Regenxbio will, too.

The Retina Society data pleased Cowen analyst Phil Nadeau. No patients needed rescue injections and ADVM-022 produced sustained Improvements in retinal anatomy, leading him to conclude that the candidate is "viable" in the $15 billion wet AMD market. Specifically, as presented by Adverum collaborator Szilard Kiss of Weill Cornell, the results included data from patients who had severe disease with an average of 6.2 injections in the eight months prior to screening and an average annualized injection frequency of 9.3 injections. At baseline, the patients' mean best corrected visual acuity (BCVA) in the study eye was 65.8 letters with a mean central retinal thickness of 369 um. During the 24 weeks following the ADVM-022 injection, no patients required any anti-VEGF rescue shots, as would have been required by the protocol had there been a loss of >10 letters in BCVA from baseline due to retinal fluid observed by spectral domain optical coherence tomography (SD-OCT) or an increase in central subfield thickness >75 um from baseline as assessed by SD-OCT, or the presence of a vision-threatening hemorrhage due to their AMD. With patients having received 6.2 anti-VEGF injections on average during the prior eight months, the fact that there were no anti-VEGF injections over the six months after ADVM-022 represents "a dramatic reduction in the need" for shots, Nadeau said. "Importantly patients saw a coincident reduction in central retinal thickness, with mean reduction of 52.7 um (range of -86.5 um to -18.8 um) after ADVM-022 treatment."

Overall, five of six patients saw a complete response with a total resolution of fluid following the ADVM-022. The sixth patient had polypoidal disease, which is one of the most complicated forms of wet AMD to treat. In that patient, while a complete response was not observed, the level of fluid in the retina was stable compared to baseline and there was no accumulation during the six-month follow-up period. In contrast, that patient had required eight monthly anti-VEGF injections in the eight months prior to therapy with ADVM-022. The patient's contralateral eye (not treated with ADVM-022) continued to require injections of Eylea every four weeks. The mean change in BCVA was -2 letters (the 90% confidence interval was from a reduction in 9.1 letters to an increase of 5.1 letters) over the treatment period. Adverum said that no patient had an ongoing loss of visual acuity during the follow-up period, and that the variability in visual acuity from test to test was likely due to the variability inherent in measuring BCVA. The drug was well-tolerated, with no serious adverse events (AEs), dose-limiting toxicities, or study drug-related systemic AEs turning up. Overall there were 19 ocular AEs deemed potentially related to study drug in the six patients. All had inflammation following the ADVM-022 injection. Fourteen of the AEs were judged mild in severity, while five were moderate and included two cases of intermediate uveitis, one case of vitreous cells and two cases of anterior chamber cells. The inflammation showed up after the end of the taper in oral steroids, and were well managed by topical drops.

Regenxbio, for its part, is advancing RGX-314 as a one-time subretinal treatment for wet AMD that includes the NAV AAV8 vector containing a gene encoding for a monoclonal antibody fragment. The expressed protein is designed to neutralize VEGF activity, modifying the pathway for formation of new leaky blood vessels and retinal fluid accumulation. SVB Leerink analyst Mani Foroohar, who covers Regenxbio, took a somewhat different view of the Adverum results, citing "unanswered questions" that left "breathing room" for RGX-314. "The data appear to be mixed," he wrote in a Sept. 12 report. He conceded the lack of rescue injections but said "vision appeared to deteriorate on average. It is not clear from the readout to what degree vision declined on an individual patient level. [These] data suggest ADVM-022 is potentially active in delivering an expressible gene cassette in wet AMD, but mixed signals in this small dataset should lift some of the competitive overhang on Regenxbio shares," he said.

Cash still pouring into AMD

Regenxbio CEO Kenneth Mills, during the Aug. 7 conference call on second-quarter earnings, pointed to "several important features [of RGX-314] that are differentiators, including the use of our NAV technology, of course the AAV8 vector, which is highly selective for cells in the retina that we want to target for this treatment in wet AMD and other indications that will be responsive to anti-VEGF therapy. We're also using the subretinal route of administration and have initiated and have now completely enrolled a trial that, to my knowledge, is the largest of its kind," with 42 patients on treatment. What's more, the company signed up "a population that's referred to as the hardest-to-treat wet AMD patients," he said, and the company is forging ahead with "what in my view is the current gold standard of safe and effective administration for delivery of AAV to the retina, supported by a lot of preclinical and clinical work [that we] and others have done."

At AAO, results will be presented by Jeffrey Heier, co-president and director of Retina Research at Ophthalmic Consultants of Boston, and primary investigator for the trial. Heier will include data for all five dose cohorts.

Despite approved therapies, including Tuesday's FDA nod for Novartis AG's Beovu (brolucizumab), AMD remains hot. In August, Redwood City, Calif.-based Graybug Vision Inc. raised $80 million in series C financing to support moving its lead candidate, GB-102, into midstage studies in wet AMD and macular edema. Also, Melbourne, Australia-based Opthea Ltd. disclosed positive phase IIb results demonstrating that OPT-302 combination therapy met the primary endpoint of superiority in mean visual acuity gain at 24 weeks compared to Lucentis (ranibizumab, Roche Holding AG/Novartis AG) monotherapy in treatment-naïve patients with wet AMD. The company's lead molecule, OPT-302, is a soluble form of the VEGFR3 or "trap" molecule that blocks the activity of VEGF-C and VEGF-D. In September, Gyroscope Therapeutics Ltd. raised £50.4 million (US$60.5 million) to further development of GT-005, its clinical-stage gene therapy for treating dry AMD, and to advance a second-generation of the subretinal delivery system it gained through its merger with Orbit Biomedical Ltd. (See BioWorld, Aug. 8, 2019, Aug. 22, 2019, and Sept. 4, 2019.)

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