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Retinal Physician

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CLINICAL TRIAL DOWNLOAD: Data on a Gene Therapy for Dry and Wet AMD

A phase 1 clinical trial program is targeting both disease states.

By: Pravin U. Dugel, MD
Retinal Physician April 1, 2020 Vol 17, Issue April 2020 Page(s): 16-17

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Hemera Biosciences’ lead candidate is an AAV2 gene therapy called AAVCAGsCD59 (HMR59) that is injected in the vitreous cavity and administered in the office. The transgene product is a soluble form of the normal membrane bound protein CD59 that blocks membrane attack complex (MAC). Membrane attack complex is the final step of the complement cascade and is linked to the formation of geographic atrophy (GA) and VEGF upregulation. Retinal Physician asked several leading retina specialists to weigh in on the data available from Hemera on this ongoing study.

Jeffrey S. Heier, MD
Ophthalmic Consultants of Boston, Boston, Massachusetts

Hemera’s phase 1 AMD program consists of 2 separate and distinct trials: HMR-1001 in dry AMD patients with geographic atrophy (GA); and HMR-1002 in neovascular AMD (nAMD). Both studies are based on the principle that the complement system in general, and MAC more specifically, is involved in the development of GA and plays a role in the formation of choroidal neovascularization (which was supported by preclinical evaluation).

Pravin U. Dugel, MD, is managing partner with Retinal Consultants of Arizona in Phoenix. He reports no related disclosures. Jeffrey S. Heier, MD, is co-president and director of retina research at Ophthalmic Consultants of Boston. Dr. Heier reports that he is principal investigator for Hemera Biosciences’ phase 1 gene therapy program in dry and wet AMD. David Sarraf, MD, is a clinical professor of ophthalmology in the Retinal Disorders and Ophthalmic Genetics Division of the Stein Eye Institute, UCLA, Los Angeles, California. Dr. Sarraf reports consultancy to Amgen, Bayer, Novartis, and Genentech; research grants from Genentech and Regeneron; and speaker fees from Novartis. Mark Gillies, MB, BS, PhD, FRANZCO, is director of research at the Save Sight Institute of the University of Sydney in Sydney, Australia. Dr. Gillies reports advisory board participation, honoraria, and travel support from Novartis, Bayer, Allergan, and Roche.

HMR-1001 was injected in 17 eyes with GA. Three dose cohorts were studied, and AAVCAGsCD59 was delivered intravitreally. The treatment was well tolerated, and there was no dose-limiting toxicity. Four eyes developed inflammation, graded as mild, and resolved with either topical steroid therapy (in 2) or observation (in 2). Two of these 4 patients required pressure-lowering drops as well. While this phase 1 trial was not powered to demonstrate efficacy, the majority of the patients in the high-dose cohort showed a rate of GA progression that was slower than that of historical controls (2 of the patients with inflammation demonstrated accelerated growth). No patients converted to nAMD.

HMR-1002 was injected in 24 patients. Two doses are being studied: 3.56x1011vg and 1.071x1012vg. Patients receive an initial anti-VEGF injection, then AAVCAGsCD59 7 days later. In HMR-1002, a short course of oral steroids is administered. Despite the short course of steroids, 3 patients had inflammation, again mild, and were treated with topical steroids in 2, and topical steroids and a second short course of oral steroids in the third with resolution of the inflammation. Of patients with at least 6 months of therapy, 4 of 22 (18%) have not required retreatment (Figure 1).

Figure 1. Interim results of the HMR-1002 wet AMD study (final subject enrolled January 2020). Twenty-four subjects have been enrolled to date. Eleven subjects have finished the month 12 visit and have received a mean of 2.5 injections from month 1 through month 12. Eyes that respond very rapidly to anti-VEGF with no fluid on OCT at day 7 and day 30 have a better response to AAVCAGsCD59 with a mean number of anti-VEGF injections of 1.2. Overall, 4 subjects of 22 that have a minimum of 6 months follow-up have not required additional anti-VEGF injections (anti-VEGF brand is at the discretion of the physician and subject) from month 1 through month 12. FIGURE AND DATA COURTESY OF HEMERA BIOSCIENCES.
Figure 1. Interim results of the HMR-1002 wet AMD study (final subject enrolled January 2020). Twenty-four subjects have been enrolled to date. Eleven subjects have finished the month 12 visit and have received a mean of 2.5 injections from month 1 through month 12. Eyes that respond very rapidly to anti-VEGF with no fluid on OCT at day 7 and day 30 have a better response to AAVCAGsCD59 with a mean number of anti-VEGF injections of 1.2. Overall, 4 subjects of 22 that have a minimum of 6 months follow-up have not required additional anti-VEGF injections (anti-VEGF brand is at the discretion of the physician and subject) from month 1 through month 12. FIGURE AND DATA COURTESY OF HEMERA BIOSCIENCES.

Hemera’s gene therapy program for GA offers an obvious conceptual advantage over current GA trials in later phase development that require regular intravitreal injections. These treatments, if efficacious, will require regular, indefinite, therapy. Gene therapy, on the other hand, offers the potential for a single injection lasting for 1 year or longer. The safety of Hemera’s GA trial coupled with the possible efficacy signal has led them to move forward with a soon-to-be-initiated phase 2 trial. The nAMD trial is ongoing, with a possible signal of reduced need for intravitreal injections. However, longer follow-up is necessary to better assess this effect.

David Sarraf, MD
Stein Eye Institute, UCLA, Los Angeles, California

My first impression is that the phase 1 data are encouraging. There were no major adverse events associated with HMR-1001, although 3 out of 11 patients, receiving the highest dose, experienced mild uveitis and vitritis that required 6 to 8 weeks of anti-inflammatory therapy, which is a concern. Systemic steroids have been subsequently instituted as part of the standard therapeutic protocol, which will make this treatment more cumbersome for patients with additional systemic concerns.

While this is a phase 1 trial not designed to judge efficacy, it is encouraging that 9 out of 11 cases illustrated a slower rate of GA progression as compared to sham arms of prior GA studies. Using a control arm from prior studies is not a valid comparison, but it does provide a bit of encouragement to move forward with more definitive testing of efficacy. A gene therapy provides the benefit of requiring fewer injections to treat AMD patients should the drug show efficacy and safety with future trials.

Mark Gillies, MB, BS, PhD, FRANZCO
Director of research, Save Sight Institute of the University of Sydney, Sydney, Australia

These are very early stage studies. Retina specialists are always hopeful for a different approach to complement inhibition, and this approach offers something different. Those looking at the data will keep their eyes on inflammation, which occurred in 4 of 17 eyes (not “rare”), although it is hard to see how this would have caused the atrophy to grow so much faster in the 2 eyes highlighted when it was mild and transitory. The atrophy in the remaining eyes appeared to have grown more slowly than controls from recent clinical trials, although it is not known whether the groups matched well. I am very much looking forward to seeing the results of the phase 2 and then the phase 3 trial. RP

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