In the developed world, AMD is the most common cause of blindness among patients 50 years of age and older, affecting more than 1 million people in the United States and 5 million people globally.^1,2 This progressive disease is comprised of two types: dry and neovascular. The late stage of dry AMD is geographic atrophy (GA), and this year the first FDA-approved therapy for reducing GA progression was launched: Syfovre (pegcetacoplan, Apellis Pharmaceuticals). This agent can reduce the rate of GA lesion growth through intravitreal injections that are administered monthly or every other month.

Fortunately, ophthalmologists and patients will soon have more options. In fact, 2023 is a landmark year for treating GA.

A second intravitreal therapy, avacincaptad pegol (ACP, Iveric Bio), has shown that monthly injections significantly reduced GA lesion growth rate at the 12-month primary endpoint in both pivotal Phase 3 trials, GATHER1 and GATHER2. The FDA has granted the new drug application (NDA) for ACP priority review with a prescription drug user fee act (PDUFA) goal date of mid-August 2023.

Here we review GA therapies currently in Phase 2/3 clinical trials or just approved.

FIRST, DRY AMD AND GA DETAILS

In dry AMD, the Bruch’s membrane is thickened with basal linear and laminar deposits below the retinal pigment epithelium (RPE). Subretinal drusenoid deposits and pigment abnormalities may also be observed.³ GA presents with well-demarcated atrophic lesions involving photoreceptors, RPE and choriocapillaris. GA lesions typically grow in area over time, and this progression can lead to severe central vision loss if the growth expands into the fovea.⁴

COMPLEMENT CASCADE INHIBITORS

Pegcetacoplan (APL-2)

Approved by the FDA earlier this year, Syfovre is a modified PEGylated peptide, inhibiting C3 convertase and blocking propagation to downstream components of the common pathway of the cascade (Figure). Two pivotal Phase 3 studies, OAKS and DERBY, investigated intravitreal administration of APL-2 in subjects with GA secondary to AMD. In OAKS, APL-2 15 mg achieved its primary endpoint in reducing lesion growth at month 12 in both the monthly (EM) and every-other-month (EOM) dosing arms. In DERBY, however, the primary endpoint was just missed with EM dosing demonstrating a 12% (p=0.0528) reduction and the EOM dosing demonstrating 11% (p=0.0750) reduction.⁵

Importantly, APL-2’s treatment effect appeared to increase in the second year of the study with growth reductions of 19% (EM) and 16% (EOM) in OAKS, and 22% (EM) and 18% (EOM) in DERBY from baseline to month 24.⁶ At 24 months, APL-2 demonstrated an intraocular inflammation (IOI) rate of 3.8% in the EM combined arms and 2.1% in the combined EOM arms.⁷ Infectious endophthalmitis occurred with a total of four cases across the active treatment arms. A total of 10 cases of ischemic optic neuropathy were observed across both trials. APL-2 treatment did increase the risk of developing choroidal neovascularization (CNV) with rates of 11.9% EM, 6.7% EOM and 3.1% sham at 24 months.

For more on pegcetacoplan, see Rx Perspective, page 47.

Avacincaptad pegol

Therapeutics targeting C5 are attractive as it is a downstream target and preserves the favorable functions of the complement cascade. ACP, an intravitreal PEGylated RNA aptamer, binds C5, which prevents cleavage of C5 and decreases membrane attack complex (MAC) formation, ultimately inhibiting the final step of the complement cascade, which can lead to cell lysis and death (Figure).⁸ ACP has completed two pivotal studies, GATHER1, a Phase 2/3 clinical trial, and GATHER2, a second confirmatory Phase 3 trial.

GATHER1 enrolled subjects with non-center point involving GA. Mean GA lesion size was measured via fundus autofluorescence (FAF) over 18 months. In part 1, 77 patients were randomized 1:1:1 to receive monthly sham injections, 1 mg ACP or 2 mg ACP. In part 2, 209 patients were randomized 1:2:2 to receive monthly sham injections, 2 mg ACP or 4 mg ACP. The primary endpoint was change in GA growth rate at 12 months. A reduction in GA lesion size was demonstrated following six monthly injections of either 2 mg ACP or 4 mg ACP. Over 18 months, patients demonstrated a 28.11% (p=0.0072) and a 29.97% (p=0.0051) mean GA lesion reduction in the 2 mg ACP arm and 4 mg ACP arm, respectively.⁹ Intravitreal ACP was well tolerated with no drug specific adverse events (AEs) reported.

In GATHER2, only patients with non-foveal GA were enrolled (n=447) and randomized 1:1 to receive monthly 2 mg ACP or sham for 12 months. After month 12, those receiving 2 mg ACP were then re-randomized into either continuing monthly ACP or extending to EOM. Patients receiving sham continued monthly injections from month 12 through month 23. At 12 months, patients demonstrated a 17.7% (p=0.0039) reduction in mean rate of GA growth (slope) compared to sham. ACP was generally well tolerated; no cases of endophthalmitis, IOI or ischemic optic neuropathy (ION) were reported.¹⁰ Rates of new CNV in GATHER1 were 9% in the treatment arm and 3% in the sham arm, with rates of 6.7% in the treatment arm and 4.1% in the sham arm in GATHER2.

ACP is the first investigational therapeutic to treat GA secondary to AMD that has achieved its prespecified primary endpoint of reduction in mean growth rate of GA in two separate pivotal Phase 3 clinical trials.¹¹

IN PHASE 2 TRIALS

ANX007

Therapeutics currently in Phase 2 investigation for the treatment of GA include ANX007 (Annexon Biosciences), danicopan (Alexion Pharmaceuticals) and IONIS-FB-L_RX (IONIS Pharmaceuticals).

ANX007 inhibits C1q, which is the initiating step of the classical pathway of the complement cascade. ANX007 is delivered as a monthly intravitreal injection and is being compared to sham injections in the ongoing Phase 2 ARCHER trial with a primary outcome measure of GA lesion growth rate at 12 months.¹²

Topline results from ARCHER demonstrated a 6.2% GA lesion growth rate reduction (p=0.526) in the EM group, a 1.3% reduction (p=0.896) in the EOM group and a 3.7% reduction (p=0.673) in the pooled treatment group, with all failing to reach statistical significance and not meeting the primary endpoint.¹³ However, a 72% reduction in the risk of 15-letter BCVA loss (p=0.006) in the EM group, a 48% reduction (p=0.064) in the EOM group and a 59% reduction (0.008) in the pooled treatment group are promising for preservation of visual acuity and may lead to further development of ANX007.

Danicopan

Danicopan is an oral complement factor D inhibitor targeting the alternative complement pathway. It is currently under evaluation in the Phase 2 ALXN2040-GA-201 trial. Subjects are randomized to one of three doses of danicopan or placebo for 52 weeks. In the second year of the study, placebo subjects are re-randomized to one of three doses of danicopan, while subjects initially randomized into the danicopan treatment groups continue receiving danicopan to their original assigned dose.

Interim futility and dose-response analysis will be performed at weeks 28 and 52, allowing for identification of optimal dosing in the second year if statistically valid. The primary outcome measure is the change in GA lesion growth area at 52 weeks.¹⁴

IONIS-FB-L_RX

IONIS-FB-L_RX is a subcutaneous injection of an antisense molecule that targets mRNA to inhibit production of complement factor B in the alternative complement pathway. It is administered every 4 weeks. This agent is currently under investigation in the Phase 2 GOLDEN trial, which is comprised of two stages. Stage 1 focuses on dose-escalation, in which about 60 subjects are randomized to one of three doses of IONIS-FB-L_RX or sham. In stage 2, approximately 270 subjects are randomized to one of two active treatment doses or sham. The primary endpoint is the change in GA lesion area at month 12.¹⁵

OCULAR GENE THERAPY

Gene therapies promote advancements in retinal disease treatments. An adeno-associated virus 2 (AAV2)-based investigational therapeutic, GT005 (Gyroscope Therapeutics), aims to restore complement homeostasis via increasing production of complement factor I (CFI) protein. CFI is a natural complement system down-regulator, thus increasing its expression naturally reduces inflammation.¹⁶ Current trials, FOCUS (Phase 1/2), EXPLORE (Phase 2) and HORIZON (Phase 2), are investigating transvitreal subretinal administration of GT005 in GA patients.

JNJ-1887 (Johnson & Johnson Vision) is an ocular gene therapy product that increases production of a soluble CD59 glycoprotein, a naturally occurring MAC-inhibitor protein. A Phase 1 study (HMR-1001) demonstrated safety and tolerability across three dose levels over 2 years of follow-up.¹⁷ A Phase 2 study was recently initiated (CR109236) to evaluate efficacy via change in GA lesion are from baseline to month 18.

Ocular gene therapy appears relatively safe thus far in the GA population. However, continuous investigation on ocular gene therapy is necessary to further evaluate safety to optimize delivery methods and ensure disease resolution.

STEM CELL THERAPY

Stem cell transplants have demonstrated favorable treatment potential for GA secondary to AMD, as regeneration of RPE and compromised photoreceptors can preserve visual function.¹⁸

Patient- and disease-specific cells can be produced via induced pluripotent stem cells and can derive RPE and photoreceptor cells, promoting minimal immune rejection risk.¹⁹

The safety and tolerability of human embryonic stem cell-derived RPE cells, OpRegen, are being investigated in a Phase 1/2a study in which 24 patients were enrolled and divided into four cohorts, depending on vision (cohorts 1-3: <20/200; cohort 4: 20/64). OpRegen cells were implanted in the eye via pars plana vitrectomy (n=17) and retinotomy or via a suprachoroidal route (n=7). Cohort 4 (<20/64) demonstrated maintenance or improvement of baseline visual acuity.²⁰ Transplantation of OpRegen cells in patients diagnosed with GA secondary to AMD was well tolerated, with no reports of severe adverse events. OpRegen is being developed under a collaboration between Genentech, Lineage and Roche.

Further breakdown of clinical trials investigating therapeutics for GA via various treatment modalities are listed in the online version of this article.

CONCLUSION

An extraordinary milestone in GA treatment has recently been achieved with the FDA approval of Syfovre. GA patients, for the first time, have a treatment that can alter their disease course and slow progression over time.

Additionally, the clinical development pipeline for GA is robust, providing further encouragement for patients, especially with the spectrum of novel mechanisms and pathways to address the multifactorial pathology of GA. The majority of recent investigational therapies have focused on reducing GA progression to slow vision loss over time, while some are seeking cell replacement. OM

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