PURPOSE
To investigate the safety, tolerability, and efficacy of intravitreal injection of galegenimab, an anti-HtrA1 FAb, in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD).
DESIGN
Phase 2, single-masked, randomized clinical trial.
METHODS
Eligible GA patients with BCVA letter scores of ≥ 24 letters and baseline GA lesion size 2.54∼25.4 mm 2 in the study eye were enrolled. Patients were randomized 2:1:2 to receive 20 mg galegenimab every 4 (Q4W) or 8 weeks (Q8W), or sham Q4/8 W. The primary endpoint was mean change in GA area from baseline to Week 72 measured by fundus autofluorescence. A data monitoring committee (DMC) conducted periodic unmasked review of cumulative safety/limited efficacy data of the ongoing study.
RESULTS
Among 337 patients who received ≥ 1 dose and have at least one postbaseline GA area measurement, the adjusted mean change in GA area from baseline to Week 72 was 2.67, 2.50, and 2.38 mm 2 for the galegenimab Q4W, galegenimab Q8W, and pooled sham arms, respectively. Differences between the treated and sham groups were not statistically significant. However, the rate of intraocular inflammation was high (7.1%, 16/224 patients) among treated patients. The DMC recommended early termination of the study based on an early benefit/risk analysis.
CONCLUSION
Galegenimab administration did not show a difference in mean change in GA area from baseline to Week 72 compared with sham. Inhibition of HtrA1 with a Fab did not slow down GA progression.
G eographic atrophy (GA) secondary to AMD is defined by the presence of sharply demarcated atrophic lesions of the outer retina, resulting from loss of photoreceptors, retinal pigment epithelium (RPE), and underlying choriocapillaris, typically associated with underlying features of AMD such as drusen deposits and subretinal drusenoid material, leading to irreversible loss of visual function. ,
The prevalence of GA increases exponentially with age and approximately quadruples per decade beyond 50 years of age. The global prevalence of AMD is estimated to be around 8.7%; by 2040, global demographic shifts are expected to increase the number of AMD patients to 288 million. The high unmet medical need for GA stems from progressive and severe effects on visual function, high and increasing prevalence, and limited treatment options. In 2023, US Food and Drug Administration (FDA) approved pegcetacoplan and avacincaptad pegol for GA. ,
The ARMS2/HTRA1 region, which includes the high temperature requirement A1 ( HTRA1 ) gene, located in chromosomal region 10q26, was one of the first AMD genetic loci identified and has been replicated in multiple studies with associations seen in both linkage and genome-wide association. HtrA1, a member of the mammalian HtrA serine protease family, has been shown to cleave extracellular matrix proteins that are potentially involved in retinal degeneration, such as EFEMP1 and clusterin, as well as retinol-binding protein 3, a key protein in the visual cycle. In transgenic mice, overexpression of HtrA1 in RPE cells recapitulated cardinal features associated with advanced AMD, including choroidal vasculopathy and severe degeneration of elastic laminae of the Bruch’s membrane. , This phenotype results from HtrA1-induced breakdown of extracellular matrix protein associated with RPE, Bruch’s membrane, and choroid. In the human retina, HtrA1 is expressed by RPE , and horizontal cells, and its expression is increased in the area peri‑lesional to the GA (Genentech, data on file). Taken together, it is hypothesized that excessive retinal activity of HtrA1 induces breakdown of extracellular matrix protein resulting in photoreceptor and RPE atrophy similar to those in AMD pathology.
Galegenimab (FHTR2163, RO7171009) is a fragment antigen-binding (Fab) of a humanized monoclonal antibody directed against the HtrA1 protein, which forms a trimer. Galegenimab achieves inhibition of the HtrA1 protease by forming a macromolecular complex with HtrA1 and binding to each trimeric subunit with three separate anti-HtrA1 Fabs. Its activity has been demonstrated in vitro through blocking proteolysis of biglycan, a substrate for HtrA1, and also an extracellular matrix protein. Since there was no suitable animal model for geographic atrophy, Galegenimab was not tested in animals for its efficacy. Instead, preclinical studies focused on evaluating its pharmacokinetic (PK) and pharmacodynamic (PD) properties, as well as its toxicology profile. The findings from these studies provided support for initiating the Phase 1 clinical trial conducted in patients with GA secondary to AMD. The study showed that intravitreally (IVT) administered galegenimab had a favorable safety and tolerability profile, and elicited a sustained PD effect at the recommended Phase 2 dose of 20 mg. Based on the nonclinical and clinical findings, GAllego was designed to evaluate the safety, tolerability, and efficacy of galegenimab in patients with GA secondary to AMD.
METHODS
STUDY DESIGN AND TREATMENT
GAllego was a Phase 2 multicenter, randomized, single-masked, sham-controlled study. The study consisted of a screening period of up to 120 days, divided into a prebaseline screening period and a baseline screening window, and a treatment period (Day 1 to Week 68 for Q4W treatment arms and Day 1 to Week 64 for Q8W treatment arms), followed by the final study visit at Week 76. The purpose of the prebaseline screening visit was to collect the prebaseline fundus autofluorescence (FAF) images to calculate the prebaseline GA growth rate, which served as a stratification factor in the study. The study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice, and HIPAA-compliant. Approval from the institutional review boards and ethics committees at each participating institution was obtained before study start. The study was registered on clinicaltrials.gov (NCT03972709). Patient consent was obtained before enrollment for both treatment and participation in the research.
Eligible patients were randomized in a 2:1:1:1 ratio to one of four groups: galegenimab Q4W, sham control Q4W, galegenimab Q8W, or sham control Q8W. Galegenimab (20 mg) was administered intravitreally. Randomization was stratified by HtrA1 risk-variant carrier status (carrier vs noncarrier), baseline GA lesion size (< 9.0 mm 2 vs ≥ 9.0 mm 2 ), and annualized prebaseline GA progression rate based on two FAF images (< 1.9 mm 2 /yr vs ≥ 1.9 mm 2 /yr).
COVID-19 had a minimal impact on the study conduct, but led to an increase in sample size. A total of 373 patients were actually randomized with 150 in the galegenimab Q4W arm, 75 in the galegenimab Q8W arm, and 148 in pooled sham arms.
The study was terminated early after the monitoring committee determined that the benefit-risk assessment (unexpectedly high levels of intraocular inflammation (IOI) and no treatment benefit) did not support further treatment with galegenimab
STUDY OBJECTIVES
The primary efficacy objective was to evaluate galegenimab administered Q4W or Q8W in patients with GA secondary to AMD compared with sham on the basis of the mean change in the GA area from baseline to Week 72 as measured by FAF. The secondary efficacy objective evaluated mean change in best corrected visual acuity (BCVA) and low luminescence BCVA scores from baseline to Week 72 as assessed by ETDRS chart. The safety objective was to evaluate the local and systemic safety and tolerability of galegenimab Q4W and Q8W. Secondary and exploratory objectives involved characterization of the pharmacokinetic (PK) profile of galegenimab, evaluation of the immune response to galegenimab, and assessment of PD biomarker activity.
STUDY POPULATION
General inclusion criteria included patients ≥ 60 years of age. Key ocular inclusion criteria of the study eye included: well-demarcated area of GA secondary to AMD with no evidence of prior or active choroidal neovascularization (CNV) with a total GA lesion area ≥ 1 disc area (2.54 mm 2 ) ≤
≤
10 disc area (25.4 mm 2 ) at baseline and must reside completely within the Fundus autofluorescence (FAF) imaging field; the presence of hyperautofluorescence of either banded or diffuse patterns adjacent to GA area; a BCVA letter score of ≥ 24 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (Snellen equivalent of 20/320 or better). GA was required in the nonstudy eye.
Key exclusion criteria of the study eye included: presence of diffuse-trickling, patchy, or minimal (focal) hyperfluorescence pattern adjacent to GA area in the study eye; history of vitrectomy, submacular surgery, or any other surgical intervention for AMD; both eyes: GA due to causes other than AMD; active uveitis and/or vitritis; active, infectious conjunctivitis, keratitis, scleritis, or endophthalmitis.
Patients were enrolled from 71 sites in the United States between June 2019 and October 2022.
OCULAR ASSESSMENTS
At each study visit, the following ocular assessments were performed: BCVA as determined by ETDRS chart at a starting distance of 4 meters, preinjection and postinjection intraocular pressure (IOP) measurement of both eyes, slit lamp examination, and dilated binocular indirect high magnification ophthalmoscopy. The following ocular images were obtained from both eyes: digital color fundus photographs, FAF (with keratometry measurements), near infrared (NI) images, spectral domain optical coherence tomography images (SD-OCT), and where available, OCT angiography. All images were transferred digitally, and evaluated and graded for eligibility and safety findings at the central reading center.
SAFETY AND TOLERABILITY ASSESSMENTS
Safety was assessed based on reports of ocular and systemic AEs graded in severity according to the World Health Organization (WHO) toxicity grading scale (in case of AEs not specifically listed in the WHO toxicity grading scale, severity grading was done based on a functional severity grading scale developed by the Division of Microbiology and Infectious Diseases. It also included assessment of changes in BCVA, IOP, slit-lamp findings, indirect ophthalmoscopy, SD-OCT, vital signs, physical findings, ECG, and clinical laboratory results.
PHARMACOKINETICS AND PHARMACODYNAMICS
To characterize the PK profile of galegenimab following single IVT doses, serum and aqueous humor galegenimab concentrations were measured using validated ELISA. A rabbit anti-idiotypic antibody to galegenimab (Genentech, South San Francisco, CA) was used for capture and a biotinylated mouse anti-idiotypic antibody to galegenimab (Genentech) used for detection. The lower limit of quantitation was 50 pg/mL in serum and 150 pg/mL in aqueous humor.
For the Q4W cohort, serum samples were collected on study Days 1 and 8, then Weeks 4, 12, 24, 48, 72, and 76 (or early termination visit); aqueous humor samples were collected on study Day 1, and Weeks 4, 24, 44, and 76. For the Q8W cohort serum samples were collected on Day 1 and 8, then Weeks 8, 24, 48, 72, and 76 (or early termination); aqueous humor samples were collected on study Day 1, and Weeks 8, 24, 48, and 76.
Levels of cleaved Dickkop-related protein 3 (DKK3) were assessed in aqueous humor as a PD biomarker of galegenimab inhibition of HtrA1 protease activity, using a qualified Simoa assay (Quanterix, Billerica, MA) developed in-house. The assay has a lower limit of quantification of 156 pg/mL. Mouse anticleaved DKK3 monoclonal antibody (Genentech) was used for capture and mouse antihuman DKK3 MAB11181 (Bio-Techne R&D Systems, Minneapolis, MN) conjugated to biotin was used for detection. DKK3 levels were measured at baseline and at Week 48.
IMMUNOGENICITY
A validated semi-homogeneous, bridging ELISA was used to detect and measure the levels of serum antidrug antibodies (ADA) to galegenimab. A cut point to determine ADA positivity was established and yielded an untreated positive rate of ∼5% to minimize the potential for false negative results. Antibody titer values of ADA-positive samples were calculated by log transformation of the dilution factor at which the titrated sample crossed the assay cut point. The minimum reportable titer was 1.7. For the Q4W cohort, serum samples were collected on study Day 1 (baseline) and pretreatment on Weeks 4, 12, 24, 48, and 72, as well as on unscheduled visits, and early termination. For the Q8W cohort, serum samples were collected on study Day 1 (baseline) and pretreatment on Weeks 8, 24, 48, and 72, unscheduled visits, and early termination.
In the event of noninfectious IOI, an additional serum ADA and PK sample was to be collected as close as possible to the time of diagnosis.
STATISTICAL ANALYSES
The primary efficacy analysis was based on the modified intent-to-treat (mITT) population who were treated and had at least one postbaseline FAF measurement of the study eye. Sham control patients were pooled. A data-as-observed approach with the mixed model with repeated measures (MMRM) was used to handle missing data in the primary analysis. Prebaseline FAF images and historical ocular images were used to quantify annualized prebaseline GA growth rates. An unstructured covariance matrix was used. Secondary endpoints were analyzed similarly using MMRM but without adjusting the prebaseline GA growth rate.
An initial planned total sample size of 285 was determined by estimating a 15% dropout rate by Week 72 and a standard deviation of 1.82 mm 2 for change from baseline in GA area at Week 72 to provide 80% power to detect a targeted difference of 0.56 mm 2 . Calculations were based on a two-sided t -test at the significance level of 20%. Up to approximately 75 patients were added to the originally planned total sample size as a result of the increase in missed visits, missed dosing, and missed assessments as a consequence of the COVID-19 pandemic. The safety analyses included all patients who received a dose of study drug, with patients grouped according to treatment received.
DATA SHARING
For eligible studies qualified researchers may request access to individual patient level clinical data through a data request platform. At the time of writing this request platform is Vivli: https://vivli.org/ourmember/roche/ . For up to date details on Roche’s Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here: https://www.roche.com/innovation/process/clinical-trials/data-sharing . Anonymized records for individual patients across more than one data source external to Roche can not, and should not, be linked due to a potential increase in risk of patient re-identification.
RESULTS
PATIENT CHARACTERISTICS AND DISPOSITION
A total of 372 patients were enrolled in the study and received study drug, of which 173 (47%) completed study treatment and 199 (53%) discontinued treatment. The most common reasons for treatment discontinuation were due to study termination by the sponsor (32%), withdrawal by subject (10%), and AEs (5%), which were balanced across arms ( Figure 1 ).
Overall, the majority of patients were female (60%) and white (98%) with the median age of 78.5 years (range 60-97 years). Ocular baseline characteristics in the study eye were generally well-balanced across treatment arms, except for BCVA and proportion of subfoveal GA cases, which differed to a greater extent between the galegenimab Q4W and the pooled sham control arms than between the galegenimab Q8W and the pooled sham control arms ( Table 1 ).
| Galegenimab Q4W ( n = 149) | Galegenimab Q8W ( n = 75) | Sham Control ( n = 148) | All Patients ( N = 372) | |
|---|---|---|---|---|
| Age in Years, Mean (Range) | 78.9 (60-94) | 78.4 (62-92) | 78.0 (60-97) | 78.4 (60-97) |
| Sex, n (%) | ||||
| Male | 60 (40.3) | 25 (33.3) | 65 (43.9) | 150 (40.3) |
| Female | 89 (59.7) | 50 (66.7) | 83 (56.1) | 222 (59.7) |
| Ethnicity, n (%) | ||||
| Hispanic or Latino | 3 (2.0) | 4 (5.3) | 3 (2.0) | 10 (2.7) |
| Not Hispanic or Latino | 143 (96.0) | 71 (94.7) | 145 (98) | 359 (96.5) |
| Not Stated | 3 (2.0) | 0 (0) | 0 (0) | 0 (0) |
| GA Lesion Contiguity—Foveal Center Involved, n (%) | ||||
| Yes | 102 (69) | 59 (79) | 118 (80) | 279 (75) |
| No | 47 (32) | 16 (21) | 30 (20) | 93 (25) |
| GA area (mm 2 ) by FAF, Total (Range) | 8.87 (2.6-18.7) | 9.01 (2.6-18.5) | 9.07 (2.7-18.9) | 8.98 (2.6-18.9) |
| ETDRS Visual Acuity Score, Mean (SD) | 57.3 (18) | 52.0 (17) | 53.4 (16) | 54.7 (17.1) |
| Intraocular Pressure (mmHg), Mean (Range) | 15.3 (9-22) | 14.8 (9-23) | 15.0 (8-24) | 15.1 (8-24) |
| HtrA1 Risk-Variant Carrier (%) | 63.8 | 64 | 63.5 | 63.7 |
EFFICACY
The primary efficacy endpoint was the mean change in the GA area from baseline to Week 72 as measured by FAF. The analysis was based on the mITT population (galegenimab Q4W, n = 138; galegenimab Q8W, n = 67; sham pooled n = 132). Due to high rates of early discontinuation, a progressively smaller portion of patients had GA area measurements over the course of the trial. At Week 72, the adjusted mean increase in GA lesion from baseline in the mITT population was 2.60 mm 2 , 2.43 mm 2 , and 2.31 mm 2 in the galegenimab Q4W arm, galegenimab Q8W arm, and the pooled sham control arm, respectively ( Figure 2 ). The differences in the adjusted mean change of the GA lesion area (galegenimab minus sham) at Week 72 were 0.29 mm 2 ( P = .1206) for galegenimab Q4W and 0.12 mm 2 ( P = .6127) for galegenimab Q8W. Differences between the galegenimab treated and sham groups were not statistically significant.
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