Advances in Wet AMD Research

Although intravitreal anti-VEGF injections are an effective therapy for wet AMD, the associated treatment burden is significant, pushing researchers to search for novel approaches. Numerous therapeutics and drug delivery systems are in the research pipeline, offering hope for a reduced treatment burden and improved outcomes in the future.

RECENT UPDATES

IBI302

In April, Innovent Biologics announced that the first patient was successfully dosed in a phase 2 clinical trial of IBI302, a first-in-class ophthalmic recombinant human anti-VEGF and anticomplement bispecific fusion protein.¹ The phase 1 open-label, multicenter, dose-escalation clinical trial enrolled a total of 31 patients and evaluated the safety and tolerability of a single intravitreal injection (IVT) of IBI302 in patients with wet AMD.² The data showed good safety and tolerability, with no serious adverse events or dose-limiting toxicity reported. At week 12, the mean change in BCVA was 4.83, 8.00, and 9.17 letters for the 2-mg IBI302, 4-mg IBI302, and aflibercept groups, respectively, compared with baseline. The treatment groups had reduced central subfield thickness similar to that of the aflibercept group.²

RGX-314

In November, Regenxbio reported 2-year data from all cohorts of its RGX-314 phase 1/2a trial for the treatment of wet AMD and cohort 3 of its long-term follow-up study.^3,4 The therapy was generally well tolerated, and patients in cohorts 3, 4, and 5 experienced improved vision over 2 years and a significant reduction in the need for supplemental anti-VEGF injections. For more on the subretinal delivery of RGX-314 for the treatment of AMD, see Surgical Innovations to Treat Medical Retinal Diseases.

AAVIATE is a phase 2 randomized, active-controlled, dose-escalation trial investigating the efficacy, safety, and tolerability of RGX-314 delivered with the in-office SCS suprachoroidal microinjector (Clearside Biomedical).⁵ The trial is investigating three dose levels: 2.5x10¹¹ genomic copies per eye (GC/eye; cohort 1), 5x10¹¹ GC/eye (cohorts 2 and 3), and 1x10¹² GC/eye (cohorts 4 and 5).

At 6 months, central retinal thickness was stable or improved in cohorts 1 and 2 compared with monthly 0.5 mg ranibizumab, with little to no difference in BCVA between the groups. Treatment with RGX-314 led to a more than 70% reduction in treatment burden at 6 months. The drug has been well tolerated with intraocular inflammation in 26.7% of patients in cohort 1 and 20.0% of patients in cohort 2 at 6 months.⁵

In September, Regenxbio and AbbVie announced a strategic partnership for the development and commercialization of RGX-314.⁶

ADVM-022

ADVM-022 (Adverum Biotechnologies) uses a propriety vector capsid, AAV.7m8, carrying a codon-optimized aflibercept coding sequence under the control of a proprietary expression cassette administered as a one-time IVT. Long-term data from the phase 1 OPTIC trial (n = 30) of ADVM-022 for wet AMD have demonstrated durability and maintained efficacy following a single, in-office IVT injection. Safety and efficacy data showed that 60% of patients were injection-free beyond 1 year, and patients had an 85% reduction in annualized injection frequency following a single low dose (n = 15).⁷

In July, a comparison of the data from the INFINITY clinical trial in patients with diabetic macular edema (DME) and OPTIC showed marked differences in the safety profile between the two patient populations and between the low (2x10¹¹ vg/eye) versus high (6x10¹¹ vg/eye) doses. Adverum no longer plans future development for DME after a dose-limiting toxicity was observed at the high dose in patients with DME. The company will continue to evaluate ADVM-022 at low doses (2x10¹¹ vg/eye and lower) and with alternative prophylactic regimens in a phase 2 clinical trial for wet AMD.⁸

Faricimab

In January, Genentech/Roche announced positive top-line results from two identically designed global phase 3 studies, TENAYA and LUCERNE, evaluating its investigational bispecific antibody, faricimab, in wet AMD. Faricimab targets angiopoietin-2 and VEGF-A. Both studies met their primary endpoint and showed that patients receiving faricimab injections at fixed intervals of up to every 16 weeks achieved visual outcomes that were noninferior to those receiving aflibercept (Eylea, Regeneron) injections every 8 weeks. Nearly half (45%) of patients in both studies were treated with faricimab every 16 weeks during the first year, and it was generally well tolerated with no new or unexpected safety signals. Both trials will continue out to 2 years to evaluate efficacy, durability, and safety, and the AVONELLE-X extension study will generate 4-year long-term data.⁹

In August, the FDA accepted the company’s biologics license application, under priority review, for faricimab.

KSI-301

The phase 2b/3 DAZZLE study is a global, multicenter, randomized study designed to assess the durability, efficacy, and safety of KSI-301 (Kodiak Sciences), an investigational anti-VEGF therapy built on the company’s antibody biopolymer conjugate. Patients with treatment-naïve wet AMD are randomly assigned to receive either KSI-301 on an individualized dosing regimen (every 3 to 5 months) or to receive aflibercept every 8 weeks, each after 3 monthly loading doses. The 1-year data showed that 66% of wet AMD patients in the treatment arm achieved a 6-month or longer treatment-free interval at 1 year. An average of two retreatments were given over the 10 months following three loading doses. Moreover, 78% of treated patients were on a 4-month or longer interval at 1 year. More than half (54%) of wet AMD patients required only one retreatment. A mean 5.7 letter improvement, to 69.7 ETDRS letters (~20/40 Snellen), was observed.¹⁰

GB-102

In September, Graybug Vision reported a full-data analysis from the 18-month ALTISSIMO trial, a masked, controlled phase 2b study consisting of two doses—1 mg and 2 mg—of GB-102 and a single control arm of patients on 2 mg aflibercept for the treatment of wet AMD. GB-102 is a proprietary formulation of sunitinib malate injected intravitreally twice a year. The primary endpoint included median time to first supportive therapy with an anti-VEGF agent. Secondary endpoints consisted of safety and pharmacodynamics, measured as the mean change in BCVA and central subfield thickness.¹¹

The trial consisted of two phases, the first being a 12-month treatment phase where patients were dosed at day 1 and month 6, while the control arm received every-other-month aflibercept. The second phase included 6 months of observation to determine the effect duration.¹¹

The 18-month data showed that 58% of patients participated in the extended study, and 11 participated in the 1 mg GB-102 arm, 55% of whom achieved treatment duration for 12 months or longer and maintained visual acuity and central subfield thickness. The injection burden was reduced by 73% on an annualized basis for 1 mg GB-102 patients who took part in the extended study. GB-102 was well tolerated and sustained a favorable safety profile during the extended phase. No drug-related adverse events or vision-threatening inflammation was reported.¹¹

EYP-1901

In November, EyePoint Pharmaceuticals announced positive interim safety data from its phase 1 clinical trial of EYP-1901, a sustained delivery anti-VEGF treatment targeting wet AMD. EYP-1901 combines a bioerodible formulation of the Durasert (EyePoint Pharmaceuticals) sustained-release technology with vorolanib, a tyrosine kinase inhibitor (TKI).¹²

The ongoing phase 1 DAVIO open-label, dose-escalation trial has enrolled 17 wet AMD patients across three dose cohorts. All patients were previously treated with anti-VEGF therapies. At least 6 months after dosing, no serious adverse events were reported, and there have been no reported adverse events related to significant intraocular inflammation, BCVA reduction, or IOP elevation. At 4 and 6 months, 76% and 53% of patients did not require rescue following a single dose of EYP-1901, respectively. Patients experienced a 79% reduction in treatment burden at 6 months, and a median time to rescue of 6 months.¹²

TRIALS TO WATCH

OPT-302 (Opthea Limited) is a soluble form of the human VEGF receptor-3, expressed as an Fc-fusion protein designed to inhibit VEGF-C and VEGF-D. Opthea is currently recruiting approximately 990 treatment-naïve patients each into the phase 3 SHORE and COAST trials to assess the efficacy and safety of intravitreal 2.0 mg OPT-302 in combination with ranibizumab or aflibercept compared with ranibizumab or aflibercept monotherapy, respectively.¹³

Cohort 2 of OASIS, the phase 1/2a clinical trial of CLS-AX (Clearside Biomedical) in patients with wet AMD, completed dosing. CLS-AX is a proprietary suspension of axitinib for suprachoroidal injection. Axitinib is a TKI approved to treat renal cell cancer that achieves pan-VEGF blockade, directly inhibiting VEGF receptors 1, 2, and 3 with high potency and specificity.

OASIS is an open-label, dose-escalation trial in wet AMD patients to assess the safety and tolerability of a single dose of CLS-AX. All patients in cohort 2 received aflibercept at their first visit and a single dose of CLS-AX at their second visit 1 month later. The primary endpoint for the trial will assess the safety and tolerability of CLS-AX at 3 months.¹⁴

OTX-TKI (Ocular Therapeutix) is a bioresorbable hydrogel implant incorporating axitinib being evaluated for wet AMD and other retinal diseases. Interim data from the phase 1 clinical trial assessing the safety and biological activity of the implant showed no serious ocular adverse events or IOP elevations. At month 2, some subjects in the 400 µg and 600 µg treatment arms experienced reduced central subfield thickness and durability up to 12 months; one patient experienced treatment effect for 17 months. To date, OTX-TKI has been generally well tolerated and showed preliminary biological signals of durability.¹⁵

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CONCLUSION

Ultimately, the success of one or more of these investigational therapies is likely to generate a paradigm shift in the management of wet AMD, particularly if substantially better durability is achieved. With an increasingly robust research pipeline, the future is bright for our fight against blindness from this condition.

1. Innovent Biologics. Innovent announces first patient dosed in the phase 2 clinical trial of IBI302, a first-in-class ophthalmic anti-VEGF and anticomplement bispecific fusion protein for neovascular age-related macular degeneration [press release]. April 29, 2021. Accessed September 22, 2021. cn.innoventbio.com/en/#/news/240

2. Wang F, Sun X, Shujie Lu S. A multidose phase 1b study of IBI302 in patients with neovascular AMD. Presented at AAO 2021; November 12, 2021; New Orleans, LA.

3. Regenxbio. Regenxbio announces additional positive interim phase I/IIa and long-term follow-up data of RGX-314 for the treatment of wet AMD [press release]. February 16, 2021. Accessed September 22, 2021. regenxbio.gcs-web.com/news-releases/news-release-details/regenxbio-announces-additional-positive-interim-phase-iiia-and

4. NIH US National Library of Medicine. Pivotal 1 study of RGX-314 gene therapy in participants with nAMD (ATMOSPHERE). Accessed September 22, 2021. clinicaltrials.gov/ct2/show/NCT04704921

5. Avery RL. Two year results from the subretinal RGX-314 gene therapy phase 1/2a study for the treatment of nAMD, and an update on suprachoroidal trials. Presented at AAO 2021; November 12, 2021; New Orleans, LA.

6. Abbvie. Abbvie and Regenxbio announce eye care collaboration [press release]. September 13, 2021. Accessed September 22, 2021. news.abbvie.com/news/press-releases/abbvie-and-regenxbio-announce-eye-care-collaboration.htm

7. Adverum Biotechnologies. Adverum Biotechnologies presents long-term data through March 10, 2021 from the OPTIC trial of ADVM-022 intravitreal gene therapy in treatment-experienced wet AMD Patients at ARVO 2021 [press release]. May 1, 2021. Accessed September 22, 2021. investors.adverum.com/news/news-details/2021/Adverum-Biotechnologies-Presents-Long-term-Data-through-March-10-2021-from-the-OPTIC-Trial-of-ADVM-022-Intravitreal-Gene-Therapy-in-Treatment-experienced-Wet-AMD-Patients-at-ARVO-2021-2021-5-1-2021-5-1/default.aspx

8. Adverum Biotechnologies. Adverum provides update on ADVM-022 and the INFINITY trial in patients with diabetic macular edema [press release]. July 22, 2021. Accessed September 22, 2021. investors.adverum.com/news/news-details/2021/Adverum-Provides-Update-on-ADVM-022-and-the-INFINITY-Trial-in-Patients-with-Diabetic-Macular-Edema/default.aspx

9. Roche. New phase III data show Roche’s faricimab is the first investigational injectable eye medicine to extend time between treatments up to four months in two leading causes of vision loss, potentially reducing treatment burden for patients [press release]. February 12, 2021. Accessed September 22, 2021. www.roche.com/media/releases/med-cor-2021-02-12.htm

10. Kodiak Sciences. Kodiak Sciences announces 1-year durability, efficacy and safety data from ongoing phase 1b study of KSI-301 in patients with wet age-related macular degeneration, diabetic macular edema and retinal vein occlusion at the Angiogenesis, Exudation and Degeneration 2021 Annual Meeting [press release]. February 13, 2021. Accessed September 22, 2021. ir.kodiak.com/news-releases/news-release-details/kodiak-sciences-announces-1-year-durability-efficacy-and-safety

11. Graybug Vision reports analysis of data from the six-month extension study of the ALTISSIMO phase 2b trial in wet AMD [press release]. September 28, 2021. Accessed November 3, 2021. investors.graybug.vision/news-releases/news-release-details/graybug-vision-reports-analysis-data-six-month-extension-study

12. EyePoint Pharmaceuticals reports positive interim safety and efficacy data from phase 1 DAVIO clinical trial evaluating EYP-1901 for the treatment of wet AMD [press release]. November 13, 2021. Accessed November 16, 2021. www.multivu.com/players/English/8984051-eyepoint-pharmaceuticals-wet-amd-phase-1-davio-trial-efficacy-results

13. Wet AMD phase 3 pivotal trials. Opthea. Accessed November 26, 2021. opthea.com/wet-amd-trials-phase-3/

14. Clearside biomedical announces completion of dosing in cohort 2 of phase 1/2a clinical trial of CLS-AX (axitinib injectable suspension) in wet AMD patients [press release]. September 21, 2021. Accessed November 3, 2021. ir.clearsidebio.com/news-releases/news-release-details/clearside-biomedical-announces-completion-dosing-cohort-2-phase

15. Moshfeghi AA, Wong JG, Chang AA, et al. Phase 1 trial of a novel, hydrogel-based, intravitreal axitinib implant for the treatment of neovascular AMD. Poster presented at AAO 2021; November 12, 2021; New Orleans, LA.