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Corresponding Author: Michael C. Chang, PhD, Department of OMNI Biomarker Development, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080. . Phone: 650-740-7740
Lampalizumab, an antigen-binding fragment of a humanized monoclonal antibody directed against complement factor D (CFD), is designed to treat geographic atrophy (GA) secondary to age-related macular degeneration. Given the lack of clinical efficacy observed in patients with GA in phase 3 Chroma/Spectri trials, we investigated the impact of lampalizumab on the complement system in vivo. We developed 6 novel assays to measure changes in complement pathway activities in aqueous humor samples collected from patients enrolled in these trials.
Design
Chroma/Spectri were double-masked, sham-controlled, 96-week trials.
Participants
Aqueous humor samples from 97 patients with bilateral GA across all groups (ie, intravitreous lampalizumab 10 mg every 6 weeks, every 4 weeks, or corresponding sham procedures) were tested.
Methods
Novel antibody capture assays were developed on the Simoa platform for complement factor B (CFB), the Bb fragment of CFB, intact complement component 3 (C3), processed C3, intact complement component 4 (C4), and processed C4.
Main Outcome Measures
The ratio of processed versus intact complement factors (ie, complement activity) in aqueous humor were assessed.
Results
Patients treated with either of the lampalizumab regimens demonstrated an increase in CFD level at week 24 compared with baseline, along with a corresponding median reduction in the Bb:CFB ratio of 41% to 43%. There were no strong correlations between lampalizumab concentrations in aqueous humor and change in CFD levels or Bb:CFB ratio over time. No change in downstream C3 processing was observed with lampalizumab treatment. Additionally, there was no change in C4 processing.
Conclusions
The collection of aqueous humor samples from patients in Chroma and Spectri trials provided key insights on the effects of lampalizumab, a novel complement inhibitor, on local ocular complement activation. Lampalizumab inhibited the alternative complement pathway in the eyes of patients with GA; however, this did not translate into a measurable reduction in either classical or total complement activity, based on absence of changes in C4 and C3 processing, respectively.
Several studies have shown that polymorphisms in genes encoding proteins in the alternative complement pathway are associated with the risk of developing AMD, including complement component 3 (C3) and complement factors B (CFB), H, and I (CFI).
studies have shown increased levels of complement proteins, including complement factor D (CFD), in the serum of patients with AMD compared with controls.
CFD is a pivotal regulator of the alternative complement pathway that binds to the C3b/CFB complex and cleaves CFB into Ba and Bb. Ba is then released, but Bb remains attached to C3b; this C3bBb complex forms the C3 convertase, which catalyzes additional C3 cleavage (Fig 1).
CFD is the rate-limiting enzyme in the alternative complement pathway and is present in the plasma at low concentrations relative to other complement proteins.
For these reasons, CFD was considered a potential therapeutic target for inhibition of the alternative complement pathway, and consequently, treatment of GA.
Complement inhibition in cynomolgus monkeys by anti–factor D antigen-binding fragment for the treatment of an advanced form of dry age-related macular degeneration.
In in vitro and in vivo studies, lampalizumab inhibited the alternative complement pathway but had no direct effect on the classical or lectin pathways of the complement system.
Complement inhibition in cynomolgus monkeys by anti–factor D antigen-binding fragment for the treatment of an advanced form of dry age-related macular degeneration.
Lampalizumab was investigated in the phase 2 MAHALO trial in 123 patients with GA secondary to AMD, and met the primary endpoint of reducing GA lesion area progression compared with sham treatment.
Efficacy and safety of lampalizumab for geographic atrophy due to age-related macular degeneration: Chroma and Spectri phase 3 randomized clinical trials.
In these identically designed trials, patients with bilateral GA and no prior active choroidal neovascularization in either eye were randomized to receive lampalizumab administered intravitreally (every 6 weeks [Q6W] or every 4 weeks [Q4W]) or sham injections. Among 1881 patients, the adjusted mean increase in GA lesion area from baseline to week 48 was between 1.93 and 2.09 mm2 across all groups in both trials. There were no significant reductions in GA lesion area growth with lampalizumab compared with sham treatment in any group in either study. There was also no observed benefit from lampalizumab treatment in any subgroup, including those with the CFI risk allele.
To better understand why a clinical effect of lampalizumab might not have been observed in the Chroma and Spectri trials, we investigated the effect of lampalizumab on complement pathway activities. To this end, we developed 6 novel assays using procured aqueous humor samples. Thereafter, aqueous humor samples collected from patients in the Chroma and Spectri trials were analyzed using the final assays.
Methods
Study Design
This was a post hoc study analyzing aqueous humor samples collected from patients included in the Chroma (NCT02247479) and Spectri (NCT02247531) trials. A detailed description of the trial designs has been published previously.
Efficacy and safety of lampalizumab for geographic atrophy due to age-related macular degeneration: Chroma and Spectri phase 3 randomized clinical trials.
Briefly, Chroma and Spectri were 2 identically designed, phase 3, double-masked, sham-controlled trials conducted at 275 sites in 23 countries. Nine-hundred and six patients were enrolled in Chroma and 975 patients were enrolled in Spectri. Patients were randomized in a 2:1:2:1 ratio to receive intravitreous lampalizumab 10 mg Q6W, sham procedure Q6W, lampalizumab 10 mg Q4W, or sham procedure Q4W for 96 weeks. All sites received institutional review board or ethics committee approval before study initiation and all participants provided written informed consent.
Efficacy and safety of lampalizumab for geographic atrophy due to age-related macular degeneration: Chroma and Spectri phase 3 randomized clinical trials.
A mechanistic pharmacokinetic/pharmacodynamic model of factor D inhibition in cynomolgus monkeys by lampalizumab for the treatment of geographic atrophy.
Six novel assays were developed on the Simoa (Quanterix, Billerica, MA, USA) platform to assess complement activity in the eye. The assays were designed to measure levels of full-length CFB; the Bb fragment; full-length C3 (intact C3); the C3c, iC3b, and C3b fragments of C3 (processed C3); full-length complement component 4 (C4; intact C4); and the C4c and C4b fragments of C4 (processed C4).
Fig S2 (available at www.aaojournal.org) shows the configuration of each of the 6 assays. For all assays, the capture antibody was conjugated to carboxylated beads and the detection antibody was biotinylated. Per the standard Simoa assay setup, all assays used streptavidin-conjugated beta-galactosidase and resorufin galactopyranoside from Quanterix to allow for final readout. The CFB assay used a monoclonal capture antibody specific to Ba from AbCam (Cambridge, MA, USA) coupled with a monoclonal detection antibody, GNE Ab 4674, specific to Bb from Genentech, Inc. (South San Francisco, CA, USA). The Bb assay used GNE Ab 4674 as the capture antibody and a Bb neoepitope monoclonal antibody from Quidel (San Diego, CA, USA) as the detection antibody. The intact C3 assay used a polyclonal antibody specific for C3a from R&D Systems (Minneapolis, MN, USA) as the capture antibody and a CappelTM polyclonal antibody against C3 from MP Biomedicals (Solon, OH, USA) as the detection antibody. The processed C3 assay used a monoclonal capture antibody against iC3b/C3b/C3c from Kerafast (Boston, MA, USA) and a polyclonal detection antibody against C3 from Protos Immunoresearch (Burlingame, CA, USA) for detection. The intact C4 assay used a polyclonal capture antibody against C4 from Abbexa (Houston, TX, USA) and a monoclonal detection antibody against C4c from Quidel (San Diego, CA, USA). The processed C4 assay used a monoclonal capture antibody against C4c from United States Biological (Salem, MA, USA) and a monoclonal detection antibody against C4 from LSBio (Seattle, WA, USA).
To demonstrate that the 6 assays could capture dynamic activation of the complement pathways, 25 micrograms of lampalizumab or glycoprotein D Fab (control Fab) were added to normal human serum aliquots (0.5 ml each) and either the alternative or classical complement pathway was activated with zymosan (0.5 mg/ml final concentration) or heat-aggregated gamma globulin (0.5 mg/ml final concentration), respectively, followed by incubation at 37°C. At regular time points from 0 to 30 or 60 minutes, portions of the samples were collected, and the activation was stopped by adding ethylenediaminetetraacetic acid and storing on ice. After each time course was complete, the resulting samples were measured using microtiter plate assays.
Overall, all 6 novel assays were found to have good sensitivity and specificity (Table S1, available at www.aaojournal.org) for measuring the activation of the alternative and classical complement pathways (Appendix and Fig S3A–C, available at www.aaojournal.org).
Aqueous Humor Sample Collection and Testing
Optional aqueous humor samples were collected from patients who consented to the procedure and sample acquisition. The aqueous humor sample was collected in the clinic by the treating physician before any treatment was administered. The collection consisted of an anterior chamber paracentesis whereby a drop of topical anesthetic was placed on the cornea and a 30-gauge needle was passed through the limbus into the anterior chamber and approximately 0.1 mL of aqueous fluid was removed. All samples were subsequently frozen, shipped on dry ice, and stored at < -70˚C at a central laboratory prior to analysis.
Longitudinal baseline and week 24 aqueous humor samples were selected for analysis in a blinded manner across all treatment (lampalizumab Q6W and lampalizumab Q4W) and sham groups (sham Q6W and sham Q8W) in the Chroma and Spectri trials. Each sample was tested in duplicate with each of the 6 complement assays developed for this study.
Statistical Analysis
We calculated the percent coefficient of variation (CV%) for each analyte in every sample by dividing the standard deviation by the mean and multiplying by 100. Samples with CV% greater than 30% were excluded from the analysis (n = 2). For the remaining samples, their mean values were analyzed. Results below the limit of quantification were assigned the value of the assay lower limit of quantification.
For each complement pathway, we calculated the ratio of the processed form to the intact form (ie, complement activity). Percentage changes from baseline were calculated by subtracting the baseline value from the week 24 value and dividing the result by the baseline value. Correlations were calculated using Spearman’s rho, a nonparametric measure for the strength of association. A Wilcoxon rank-sum test with continuity correction was used to assess differences between treatment groups.
Results
Pharmacodynamic Effect of Lampalizumab
Aqueous humor samples of 100 patients from Chroma and Spectri trials balanced by treatment groups (lampalizumab Q6W, and lampalizumab Q4W) and sham group for two time points (baseline and week 24) were collected. After excluding patients with duplicate CV% values greater than 30% (n = 2) and those without paired baseline/week 24 detectable samples for all complement assays (n = 1) , 97 patients were included in the analysis population. Table 2 shows that demographic and baseline characteristics were balanced between the 3 groups of patients.
Table 2Demographic and Baseline Characteristics of Patients Providing Aqueous Humor Samples
Characteristic
Sham (n = 30)
LQ6W (n = 32)
LQ4W (n = 35)
Overall (N = 97)
Sex, n (%)
Female
16 (53.3)
21 (65.6)
25 (71.4)
62 (63.9)
Male
14 (46.7)
11 (34.4)
10 (28.6)
35 (36.1)
Age at parent reference date, years
Mean
79.7 (8.04)
79.1 (8.61)
80.1 (7.96)
79.6 (8.13)
Median [min, max]
80.5 [60.0, 93.0]
81.5 [61.0, 92.0]
81.0 [63.0, 93.0]
81.0 [60.0, 93.0]
Tobacco use, n (%)
Current
3 (10.0)
1 (3.1)
4 (11.4)
8 (8.2)
Never
10 (33.3)
19 (59.4)
9 (25.7)
38 (39.2)
Previous
17 (56.7)
12 (37.5)
22 (62.9)
51 (52.6)
Baseline study eye GA area by FAF, mm2
Mean
6.33 (2.87)
9.54 (4.92)
8.63 (3.33)
8.22 (4.00)
Median [min, max]
5.54 [2.94, 13.9]
8.57 [2.63, 17.7]
7.82 [4.25, 17.3]
7.82 [2.63, 17.7]
Baseline study eye GA lesion contiguity, n (%)
Multifocal
24 (80.0)
27 (84.4)
30 (85.7)
81 (83.5)
Not multifocal
6 (20.0)
5 (15.6)
5 (14.3)
16 (16.5)
Baseline study eye location of GA lesion, n (%)
Nonsubfoveal
14 (46.7)
16 (50.0)
19 (54.3)
49 (50.5)
Subfoveal
16 (53.3)
16 (50.0)
16 (45.7)
48 (49.5)
Baseline aqueous humor total CFD, ng/ml
Mean
47.6 (24.8)
51.0 (33.9)
54.5 (26.7)
51.2 (28.6)
Median [min, max]
44.6 [17.2, 128]
42.4 [15.0, 148]
51.7 [20.4, 128]
47.5 [15.0, 148]
Change in GA area from baseline to week 24, mm2
Mean
1.13 (0.999)
1.04 (0.718)
1.00 (0.689)
1.05 (0.798)
Median [min, max]
0.950 [0.140, 3.93]
0.910 [0.0200, 2.66]
0.920 [0.110, 2.52]
0.940 [0.0200, 3.93]
Missing
1 (3.3)
0
1 (2.9)
2 (2.1)
Change in GA area from baseline to week 48, mm2
Mean
2.15 (1.45)
2.06 (1.26)
2.16 (1.32)
2.13 (1.33)
Median [min, max]
1.72 [0.500, 6.20]
1.71 [0.220, 5.25]
1.79 [0.520, 5.11]
1.73 [0.220, 6.20]
Intact C3, ng/ml
Mean
4260 (3600)
4930 (3390)
5160 (2940)
4810 (3290)
Median [min, max]
3260 [763, 20 200]
4010 [751, 13 700]
4700 [1350, 12 700]
3970 [751, 20 200]
Processed C3, ng/ml
Mean
2230 (1740)
2660 (2030)
2530 (1370)
2480 (1710)
Median [min, max]
1880 [666, 9970]
2100 [309, 7740]
2220 [729, 7120]
2060 [309, 9970]
Intact C4, ng/ml
Mean
844 (685)
937 (988)
890 (634)
891 (775)
Median [min, max]
584 [160, 2930]
790 [64.7, 4750]
748 [195, 2990]
697 [64.7, 4750]
Processed C4, ng/ml
Mean
335 (194)
373 (289)
367 (203)
359 (231)
Median [min, max]
309 [93.5, 866]
298 [40.4, 1100]
340 [112, 1060]
317 [40.4, 1100]
CFB, ng/ml
Mean
723 (425)
758 (445)
858 (447)
784 (439)
Median [min, max]
600 [239, 2400]
736 [128, 1670]
729 [249, 2070]
668 [128, 2400]
Bb, ng/ml
Mean
136 (96.8)
174 (149)
168 (95.8)
160 (116)
Median [min, max]
114 [40.1, 502]
125 [22.8, 520]
150 [38.5, 443]
125 [22.8, 520]
C3 = complement component 3; C4 = complement component 4; CFB, complement factor B; CFD, complement factor D; FAF = fundus autofluorescence; GA = geographic atrophy; LQ4W = lampalizumab every 4 weeks; LQ6W = lampalizumab every 6 weeks; max = maximum; min = minimum; SD = standard deviation.
Proof of target engagement was evident by similar, marked percentage increases in CFD levels in the aqueous humor at week 24 compared with baseline in the lampalizumab Q6W group (median, +91.6%; mean, +97.0%) and Q4W group (median, +124.0%; mean, +144.0%), consistent with previous preclinical observations
Complement inhibition in cynomolgus monkeys by anti–factor D antigen-binding fragment for the treatment of an advanced form of dry age-related macular degeneration.
; this effect was not observed in the sham group (median, –2.6%; mean, +7.5%; Fig 4A). Only a moderate correlation was observed between the percentage change from baseline to week 24 in CFD levels and lampalizumab concentration in aqueous humor (Spearman’s rho = 0.583; Fig S5A, available at www.aaojournal.org).
Figure 4(A) Total complement factor D (CFD) levels (ng/ml) and (B) Bb:complement factor B (CFB) ratio. Plots on left show values at baseline and week 24; plots on right show percentage change from baseline to week 24. LQ4W = lampalizumab every 4 weeks; LQ6W = lampalizumab every 6 weeks.
Complement factor B and Bb levels in the aqueous humor at baseline and week 24 by treatment and sham groups are shown in Fig S6 (available at www.aaojournal.org). Fig 4B show that there was a reduction in the Bb:CFB ratio from baseline to week 24 in the lampalizumab Q6W group (median, –41.3%; mean, –40.5%) and Q4W group (median, –43.4%; mean, –40.3%). A similar reduction was also observed in the combined Q6W and Q4W group (median, –42.4%; mean, –40.4%). Conversely, there was a small increase in the Bb:CFB ratio from baseline to week 24 in the sham group (median, +0.26%; mean, +9.04%; P < 0.001 for lampalizumab versus sham groups). These results confirmed that lampalizumab engaged and inhibited the target alternative complement pathway. Similar reductions in the Bb:CFB ratio in the lampalizumab Q6W and Q4W groups as well as no meaningful correlation between Bb:CFB ratio and percent changes from baseline to week 24 in either CFD (Fig S7A, available at www.aaojournal.org) or lampalizumab (Fig S5B, available at www.aaojournal.org; Spearman’s rho = 0.272) levels observed in aqueous humor suggested that maximum target inhibition had been achieved and dosing with higher concentrations or more frequent dosing would be unlikely to result in greater inhibition of the alternative complement pathway.
Effect of Lampalizumab on Downstream and Classical Complement Pathway Activity
No change in C3 levels (P = 0.23; Fig S8A, available at www.aaojournal.org) or C3 processing (Fig 9A) was observed in lampalizumab-treated patients compared with the sham group despite the observed reduction in Bb:CFB ratio. There was also no correlation between magnitude of changes in processed C3:intact C3 and either Bb:CFB ratios or CFD levels in patients treated with lampalizumab (Fig S7B, available at www.aaojournal.org and Fig S8B, available at www.aaojournal.org; Spearman’s rho = 0.28 for lampalizumab Q6W and 0.06 for lampalizumab Q4W), illustrating that no discernable inhibition of intact C3 processing was evident, even in those patients who had the strongest inhibition of CFB processing. Similarly, no meaningful change in C4 levels (P = 0.75; Fig S10A, available at www.aaojournal.org) or C4 processing (Fig 9B) was observed in lampalizumab-treated patients compared with sham group, and there was no consistent relationship between the magnitude of changes in processed C4:intact C4 and the Bb:CFB ratio (Fig S10B, available at www.aaojournal.org; Spearman’s rho = –0.27 for lampalizumab Q6W and +0.28 for lampalizumab Q4W). These results suggest that the lack of observed inhibition of C3 processing in lampalizumab-treated patients was not due to compensatory activation of the classical pathway.
Figure 9(A) Processed complement component 3 (C3):intact C3 ratio and (B) processed complement component 4 (C4):intact C4 ratio. Plots on left show values at baseline and week 24; plots on right show percentage change from baseline to week 24. LQ4W = lampalizumab every 4 weeks; LQ6W = lampalizumab every 6 weeks.
Six novel assays were developed specifically to measure complement protein concentrations in aqueous humor, assess target engagement and pathway inhibition by lampalizumab, and characterize the resulting effect on the complement system. The aim was to gain better mechanistic insight into the effect of lampalizumab on the complement system in the context of a negative readout from the phase 3 Chroma and Spectri trials in patients with GA.
Efficacy and safety of lampalizumab for geographic atrophy due to age-related macular degeneration: Chroma and Spectri phase 3 randomized clinical trials.
The collection of aqueous humor samples was important for studying ocular complement activation and the local effects of lampalizumab. Previous research has provided evidence for systemic, rather than local, complement activation in AMD, thereby supporting the analysis of aqueous humor samples.
In the samples from patients in the Chroma and Spectri trials, a 92% to 124% median increase in CFD levels, and a resulting median reduction in the Bb:CFB ratio of 41% to 43%, was observed, confirming that lampalizumab was effectively binding its target and inhibiting the alternative complement pathway. This increase in CFD is attributed to slower clearance of the lampalizumab–CFD complex relative to unbound CFD, and is consistent with previous preclinical studies
Complement inhibition in cynomolgus monkeys by anti–factor D antigen-binding fragment for the treatment of an advanced form of dry age-related macular degeneration.
Similar changes in both CFD levels and the Bb:CFB ratio were observed between the 2 lampalizumab dosing schedules. While a modest correlation was observed between the aqueous humor concentration of lampalizumab and changes in CFD levels, no meaningful correlation was observed between lampalizumab concentrations and changes in the Bb:CFB ratio, suggesting that maximum pathway engagement with lampalizumab was achieved. Thus, there remains the question as to why a greater reduction in the Bb:CFB ratio was not observed. One explanation is that while previous free target suppression models estimate that only 0.001% to 0.01% of the CFD relative to baseline levels may be unbound and active at the time of aqueous humor sampling,
A mechanistic pharmacokinetic/pharmacodynamic model of factor D inhibition in cynomolgus monkeys by lampalizumab for the treatment of geographic atrophy.
any residual CFD activity remaining in the presence of these saturating levels of lampalizumab may have driven the generation of Bb. Alternatively, it is worth noting that the vast majority of complement protein, including CFB, is produced in the liver and enters the circulation before reaching target organs such as the eye.
It is therefore possible that the residual Bb detected after lampalizumab treatment may largely have been generated in the periphery rather than within the eye, a notion supported by the fact that plasma levels of Ba have been reported to be much higher than in aqueous humor.
A limitation of our assays is that these are unable to distinguish between the disease-relevant Bb that was generated within the eye versus the inactive Bb that was produced elsewhere in the periphery. Finally, while care was taken to minimize ex vivo complement activation during testing, unintended activation during sample handling and laboratory processing cannot be ruled out entirely.
Despite the significant reduction in alternative pathway activation, we observed no change in downstream C3 processing using our assays; this finding was surprising and may help explain the lack of clinical efficacy observed in the Chroma and Spectri trials. One explanation for this result is that the classical pathway plays a larger primary or compensatory role in C3 activation in the eye than previously assumed. However, it is worth noting that we also observed no change in C4 processing in the presence of lampalizumab and thus, believe it unlikely for classical pathway compensation to be the sole explanation for this result. Another possibility worth considering is that given the nature of the alternative pathway as a positive amplification loop, it is possible that some residual alternative pathway activity remains within the eye in the presence of lampalizumab; this in turn may be sufficient to fully activate downstream C3 processing (Fig 11). Finally, similar to the theory that peripherally generated Bb may be entering the eye, we also consider it possible that a significant amount of peripherally generated processed C3 is entering the eye, thus, preventing our ability to detect more subtle changes in C3 processing that occurred within the eye (Fig 11). Plasma levels of processed C3 are 15-fold higher than in the aqueous humor, while intact C3 levels are 353-fold higher.
along with the fact that we can detect changes in CFB processing despite similar differences in plasma versus aqueous humor concentrations would suggest that this hypothesis is unlikely .
Figure 11Schematic showing potential hypotheses for lower-than-expected reduction in CFB cleavage with CFD inhibition by lampalizumab
Other complement pathway inhibitors are currently in development for GA. One example is pegcetacoplan (APL-2; Apellis Pharmaceuticals, Waltham, MA, USA), which directly targets and inhibits C3, and has shown promising phase 2 and 3 results for reducing the growth rate of GA lesions and slowing disease progression.
Apellis Announces Top-Line Results from Phase 3 DERBY and OAKS Studies in Geographic Atrophy (GA) and Plans to Submit NDA to FDA in the First Half of 2022. Apellis Pharmaceuticals Inc., 2021. Available at: https://investors.apellis.com/news-releases/news-release-details/apellis-announces-top-line-results-phase-3-derby-and-oaks. Accessed August 9, 2022.
Similarly, avacincaptad pegol (Iveric Bio, New York, NY, USA), a C5 inhibitor, significantly reduced the GA growth rate in eyes with AMD over a 12-month period in a randomized, controlled phase 2/3 clinical trial.
Another approach being investigated is targeting the alternative pathway using systemic CFB antisense oligonucleotides; the aim is to reduce complement activation in the eye by inhibiting the primary source of plasma CFB in the liver, which in turn reduces ocular CFB.
Although confirmatory clinical data are needed, these strategies could potentially be more effective at inhibiting the C3 complement pathway than the targeting of CFD by lampalizumab.
We showed that lampalizumab inhibited the cleavage of intact CFB into Bb in the eyes of patients with GA, as expected; however, this did not translate into a downstream reduction in complement pathway activation. Further assessment is required to clarify the role of the complement pathways in GA.
Table S1Sensitivity and Specificity Results for Each of the 6 Assays
Assay Sensitivity
Assay Specificity
Assay (Range of Lower Limit of Quantification–Upper Limit of Quantification) (ng/ml)
We acknowledge Teresa Davancaze for development of the CFD assay and sample testing support, Patrick Zoder for sample testing project management support, Eric Wakshul for assay development technical support, Janis Allen for assay development project management support, and Kelly Loyet for provision of assay protocols and reagents. We also acknowledge the contributions of all the Chroma and Spectri patients and investigators.
Complement inhibition in cynomolgus monkeys by anti–factor D antigen-binding fragment for the treatment of an advanced form of dry age-related macular degeneration.
Efficacy and safety of lampalizumab for geographic atrophy due to age-related macular degeneration: Chroma and Spectri phase 3 randomized clinical trials.
A mechanistic pharmacokinetic/pharmacodynamic model of factor D inhibition in cynomolgus monkeys by lampalizumab for the treatment of geographic atrophy.
Apellis Announces Top-Line Results from Phase 3 DERBY and OAKS Studies in Geographic Atrophy (GA) and Plans to Submit NDA to FDA in the First Half of 2022. Apellis Pharmaceuticals Inc., 2021. Available at: https://investors.apellis.com/news-releases/news-release-details/apellis-announces-top-line-results-phase-3-derby-and-oaks. Accessed August 9, 2022.
Data were previously published in an abstract in ARVO 2020; however, due to the COVID-19 pandemic, data were not presented at the meeting.
Financial Support
Genentech, Inc., a member of the Roche Group, provided financial support for the study and participated in the study design; conducting the study; data collection, management, analysis, and interpretation; and preparation, review, and approval of the manuscript. Third-party writing assistance was provided by Nibedita Gupta, PhD, CMPP, of Envision Pharma Group, and was funded by Genentech, Inc.
Conflict of Interest
The authors have made the following disclosures:
R.E.: Employee — Genentech, Inc.
V.S.: Employee — Genentech, Inc.
L.A.H.: Employee — Genentech, Inc.
M.C.C.: Employee — Genentech, Inc.
All authors report support from Genentech, Inc., a member of the Roche Group, for third-party writing assistance for this manuscript.
Address for reprints: Michael C. Chang, PhD, Genentech, Inc., 1 DNA Way, Building 46, Room B46SHARED-1, South San Francisco, CA 94080, E-mail: [email protected], Phone: 650-740-7740
Précis
In phase 3 Chroma and Spectri trials, lampalizumab-mediated inhibition of the alternative complement pathway did not translate into a measurable reduction in classical or total complement activity in eyes of patients with geographic atrophy.
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