Supplemental Digital Content is Available in the Text.
The Phase 3 Mylight study confirmed that proposed biosimilar aflibercept (SOK583A1; Sandoz) is clinically equivalent to its reference biologic in treatment outcomes for neovascular age-related macular degeneration. Visual and anatomical outcomes were comparable in both arms. Treatment-related adverse events, immunogenicity outcomes, and pharmacokinetics were also comparable.
Key words: aflibercept, nAMD, anti-VEGF, biosimilar, equivalence, neovascularization, macular, fluid, BCVA, ophthalmology
Abstract
Purpose:
The Phase 3 Mylight study was designed to confirm clinical equivalence of proposed biosimilar aflibercept (SOK583A1; Sandoz [proposed biosimilar aflibercept, SDZ-AFL]) to its reference biologic (Eylea; Regeneron Pharmaceuticals, Inc; Bayer AG [reference aflibercept, Ref-AFL]).
Method:
Mylight was a prospective, double-masked, 2-arm, parallel Phase 3 study. Participants with neovascular age-related macular degeneration were randomized 1:1 to receive eight injections of SDZ-AFL (n = 244) or Ref-AFL (n = 240) over 48 weeks. The primary endpoint was mean change in best-corrected visual acuity score from baseline to Week 8. Secondary endpoints included anatomical outcomes, best-corrected visual acuity at Weeks 24 and 52, safety, and pharmacokinetics.
Results:
Similarity in mean change in best-corrected visual acuity score was established between SDZ-AFL (n = 235) and Ref-AFL (n = 226) at Week 8 (difference: −0.3 [90% CI, −1.5 to 1.0]) and Week 52. No clinically meaningful differences occurred between groups in anatomical outcomes. Safety profiles were similar, with comparable incidences of treatment-related adverse events (SDZ-AFL: 2.5%; Ref-AFL: 2.9%). The incidence of anti-drug antibodies was similar between groups. Systemic free aflibercept concentrations 24 hours postdose were low and comparable between SDZ-AFL and Ref-AFL.
Conclusion:
Proposed biosimilar aflibercept matched reference aflibercept in efficacy, safety, and pharmacokinetics in participants with neovascular age-related macular degeneration. Therefore, this Phase 3 study confirmed biosimilarity of SDZ-AFL to Ref-AFL.
Neovascular age-related macular degeneration (nAMD) is a chronic, progressive eye disease characterized by inflammation, oxidative stress, and neovascularization of the retinal and subretinal space. Abnormal formation of unstable blood vessels and resulting fluid accumulation in the retina leads to visual distortion and central visual loss.1,2 Neovascular age-related macular degeneration is the leading cause of blindness and visual impairment in developed countries.3,4 People with nAMD experience severe impacts on quality of life such as disability and depression.5,6
Neovascular age-related macular degeneration is a growing problem worldwide for an aging population; global incidence is projected to reach 288 million by 2040.4 In 2020, a large-scale cohort study in Finland estimated an incidence rate of 102 cases per 100,000 person-years, a number that has been steadily increasing since 2006.3 Patients with nAMD gain the most benefit from early, continuous, and timely treatment. Treatment goals include reducing vision loss and optimizing patients' visual quality of life.7,8 The treatment landscape of nAMD has been revolutionized with the approval of anti–vascular endothelial growth factor (anti-VEGF) biologic therapies, specifically aflibercept, ranibizumab, brolucizumab, and, more recently, faricimab.9,10
Aflibercept (Eylea; Regeneron Pharmaceuticals, Inc, Tarrytown, NY; Bayer AG [reference aflibercept, Ref-AFL]) is a fusion protein comprising the ligand binding domains of the VEGF receptors 1 and 2, along with the Fc region of human immunoglobulin. Aflibercept neutralizes all VEGF-A and B isoforms and placental growth factor.9 Reference aflibercept gained approval in the United States in 2011, followed by approvals in Europe, Japan, and Australia in 2012 for treating nAMD, based on data from the pivotal VIEW 1 and VIEW 2 studies.9–11
Despite the effectiveness of biologic anti-VEGF therapies in mitigating the impact of nAMD, the cost and treatment burden associated with these therapies remains high. This burden is likely to escalate as the incidence of nAMD continues to rise.4,12 Recent research in the United States has highlighted that outpatient costs for patients with nAMD are primarily driven by anti-VEGF injections.12
Biosimilar medicines offer a promising opportunity to enhance access, reduce treatment costs, and improve adherence to anti-VEGF therapies, potentially alleviating some of the challenges facing patients.13 Sandoz proposed biosimilar aflibercept (SOK583A1 [SDZ-AFL])14 has been developed in line with the rigorous approval process mandated by the European Medicines Agency (EMA), the U.S. Food and Drug Administration (FDA), and the World Health Organization.15–18 These stringent requirements are in place to ensure that a proposed biosimilar medicine, like SDZ-AFL, is as safe and effective as its reference biologic.
Biosimilar molecules are approved based on an evidential data package demonstrating analytical, functional, and clinical similarity to the reference molecule. In this manner, compared with the Phase 3 stage of a new molecule, which looks to establish efficacy and safety, biosimilar “Phase 3” studies are designed to confirm equivalence of a proposed biosimilar to its reference in a clinical setting with a sensitive patient population.15,16 Here, we present the findings of the Phase 3 Mylight study (NCT04864834),19 confirming that SDZ-AFL is clinically equivalent to its reference biologic in efficacy, safety, immunogenicity, and pharmacokinetics (PK) in patients with nAMD.
Methods
Study Design
Mylight was a prospective, international, multicenter, randomized, parallel-arm, double-masked study conducted in patients with nAMD. The primary objective was to establish similarity in efficacy between SDZ-AFL and Ref-AFL in mean change from baseline in best-corrected visual acuity (BCVA) at Week 8 of treatment. Similarity was defined according to the EMA and FDA guidelines. For the EMA, similarity was defined as the 95% confidence interval (CI) for the difference in mean change within ±3.5 letters. For the FDA, similarity was defined as the 90% CI for the difference in mean change within ±3.0 letters. Secondary objectives included a comparative analysis of anatomical outcomes, BCVA at Weeks 24 and 52, safety, immunogenicity, and PK.
Mylight had a total duration of 52 weeks. After a 2-week screening period, eligible participants were assessed during a treatment period (Week 0–48) and a follow-up period (Week 48–52) (Figure 1). Participants in the study were randomized across 103 sites located in 16 countries across North America, Europe, Asia, and Australia.
Fig. 1.
Mylight study design patients received their first injection of the relevant study drug at Day 1 at Visit 2. PK samples were taken at Day 1 (predose) and at Day 2 (postdose). IVT, intravitreal injection; V, visit; W, week.
The study was approved by an Independent Ethics Committee before initiation. The design and implementation of this clinical study adhered to the guidelines set forth by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use Harmonized Tripartite Guidelines for Good Clinical Practice, in compliance with applicable local regulations, including European Directive 2001/20/EC and US CFR 21, and in alignment with the ethical principles established in the Declaration of Helsinki. All enrolled participants provided written informed consent before entering the study.
Participants
The study enrolled both male and female participants aged 50 years or older, with treatment-naive, active choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). Key eligibility criteria included that the study eye was diagnosed with active CNV lesions (Type 1 and/or Type 2) secondary to AMD and/or retinal angiomatous proliferation lesions (Type 3), affecting the central fovea defined by the presence of leakage on fluorescein angiography, and intraretinal or subretinal fluid on optical coherence tomography. All images were assessed by the Duke Reading Center, Duke University, Durham, NC. Participants were excluded if they had received previous treatment with anti-VEGF therapy in either eye or systemically use of any investigational drug(s) in either eye before the baseline assessment, receipt of approved treatments for nAMD (excluding vitamin and dietary supplements) in the study eye, receipt of any approved treatment for nAMD in the study eye at any time before the baseline assessment, presence of other causes of CNV (e.g., pathologic myopia, angioid streaks), any active or suspected intraocular or periocular infection in the study eye, or intraocular inflammation in the study eye (see Supplemental Digital Content 1, http://links.lww.com/IAE/C274 for full inclusion and exclusion criteria).
Participants were randomized 1:1 to receive SDZ-AFL or Ref-AFL. Participants received one injection containing 2 mg of active ingredient at baseline, Week 4, and Week 8, then every 8 weeks thereafter (Weeks 16, 24, 32, 40, and 48).
Outcomes and Endpoints
The primary endpoint of this study was mean change from baseline in BCVA score at Week 8, as evaluated using Early Treatment of Diabetic Retinopathy Study testing charts and protocol. Secondary endpoints included mean change from baseline in BCVA score at Weeks 24 and 52, mean change in central subfield foveal thickness (CSFT) measured using spectral-domain optical coherence tomography from baseline to Weeks 1, 4, 8, 24, and 52, and mean change in CNV lesion size, as determined through fluorescein angiography, from the screening period to Weeks 8 and 52.
Safety monitoring included the incidence of ocular and nonocular adverse events (AEs) through 52 weeks. Safety assessments were conducted during each visit, including physical examination, vital signs, ophthalmic examinations, and laboratory evaluation, as well as monitoring and recording type, frequency, and severity for all AEs.
In addition, the development of binding and neutralizing anti-drug antibodies (ADAs) up to Week 52 was evaluated. Immunogenicity assessments involved the measurement of ADA levels in serum for all study participants using a validated screening assay and a subsequent confirmatory specificity assay. Blood samples for ADA analysis were collected from all participants at various timepoints, including baseline and Weeks 1, 4, 8, 16, 24, 40, and 52. Subjects who were ADA-positive at baseline were excluded from the statistical immunogenicity analysis. Participants were assessed as positive for ADAs if a sample tested as positive above a validated screening cut-point and a secondary confirmatory assay (see Supplemental Digital Content 2, http://links.lww.com/IAE/C275, for assay cut-points).
Finally, a PK subset of approximately 20 participants in each arm was planned to have plasma and serum samples collected at 24 hours postdose at baseline and Week 8 to determine free and total aflibercept concentrations.
Statistical Analysis
A sample size of 460 randomized participants was calculated as sufficient to achieve at least 90% power to establish equivalence for the primary endpoint, including an expected dropout rate of 5% (see Supplemental Digital Content 3, http://links.lww.com/IAE/C276 and Supplemental Digital Content 4, http://links.lww.com/IAE/C277, for sample size calculations and analysis sets).
Analysis of covariance was performed, including treatment as a factor, with baseline BCVA and age as continuous covariates. The least-squares means for the treatments were calculated and the CIs for the difference in the two treatments was obtained from the analysis of covariance model.
Consistent with the two one-sided tests for bioequivalence at the 2.5% significance level, 95% CIs for change from baseline in BCVA were derived for the EMA. Similarly, a 5.0% significance level and 90% CIs for change from baseline in BCVA were obtained for the FDA. Sensitivity analysis to compare the results from the analysis of covariance model for the primary analysis with a mixed model for repeated measures was performed using the per-protocol set. Additional supplementary analyses were performed on the full analysis set using the same statistical model of analysis of covariance as for the primary analysis and against an mixed model for repeated measures.
The mean change in BCVA score from baseline to Weeks 24 and 52, mean change in CSFT (as determined by spectral-domain optical coherence tomography from the Central Reading Center) from baseline to Weeks 1, 4, 8, 24, and 52, and mean change of CNV lesion size using fluorescein angiography from screening period to Weeks 8 and 52 were summarized descriptively by treatment. Free (plasma) and total (serum) aflibercept concentration data were summarized descriptively by treatment and sampling time point, including the frequency (n, %) of concentrations below the lower limit of quantification and reported as zero.
Safety assessments included ocular, nonocular, and systemic treatment-emergent adverse events (TEAEs), ophthalmic examinations, vital signs, laboratory results, postinjection assessments, and measurement of ADAs. For all immunogenicity analyses, incidence of participants who developed binding ADAs and neutralizing antibodies by visit and overall were descriptively compared between treatments.
Results
Participant Demographics and Baseline Characteristics
In total, 485 participants were randomized, with 244 participants receiving SDZ-AFL and 240 participants receiving Ref-AFL (Figure 2). Treatment groups were well balanced across their baseline characteristics and demographics (Table 1).
Fig. 2.
CONSORT diagram of study flow. W, week.
Table 1.
Baseline Demographics and Anatomical Characteristics (FAS)
| Baseline Characteristics | SDZ-AFL | Ref-AFL |
| n = 243 | n = 240 | |
| Demographic characteristics | ||
| Age, years | ||
| Mean (SD) | 75.8 (7.82) | 75.7 (7.72) |
| Median (range) | 76.0 (53–94) | 76.0 (54–94) |
| Age, n (%) | ||
| <75 years old | 103 (42.4) | 98 (40.8) |
| ≥75 years old | 140 (57.6) | 142 (59.2) |
| Sex, n (%) | ||
| Female | 137 (56.4) | 136 (56.7) |
| Male | 106 (43.6) | 104 (43.3) |
| Region, n (%) | ||
| United States of America | 46 (18.9) | 42 (17.5) |
| Europe | 158 (65.0) | 161 (67.1) |
| Rest of world | 39 (16.0) | 37 (15.4) |
| Anatomical characteristics | ||
| BCVA, letters | ||
| Mean (SD) | 59.7 (10.05) | 59.4 (10.37) |
| Median (range) | 61.0 (38–73) | 61.5 (38–73) |
| CNV lesion size, mm2 | ||
| Mean (SD) | 5.7590 (5.03035) | 5.4383 (4.62344) |
| Median (range) | 43.660 (0–33.382) | 39.000 (0–28.630) |
| Lesion type, n (%) | ||
| Predominantly classic | 8 (3.3) | 13 (5.4) |
| Minimally classic | 12 (4.9) | 17 (7.1) |
| Classic | 198 (81.5) | 182 (75.8) |
| Occult | 19 (7.8) | 21 (8.8) |
| CNV absent | 6 (2.5) | 6 (2.5) |
| Missing | 0 | 1 (0.4) |
| CSFT, µm | ||
| Mean (SD) | 493.8 (169.25) | 471.8 (163.85) |
| Median (range) | 455.0 (186–1,104) | 426.0 (163–1,082) |
| Subretinal fluid present, n (%) | 222 (91.4) | 224 (93.3) |
| Intraretinal fluid present, n (%) | 134 (55.1) | 134 (55.8) |
FAS, full analysis set.
Efficacy
The primary analysis confirmed comparable efficacy of SDZ-AFL and Ref-AFL in mean change in BCVA (Figure 3). At Week 8, the treatment difference in mean change from baseline in BCVA in the per-protocol set was −0.3 (90% CI, −1.5 to 1.0) and within the predefined U.S. FDA and EMA equivalence margins (−3, 3, and −3.5, 3.5, respectively). Sensitivity analyses showed a similar result in other analysis sets (see Table, Supplemental Digital Content 5, http://links.lww.com/IAE/C278, for sensitivity analyses).
Fig. 3.
Mean change in BCVA at all visits (PPS). PPS; per-protocol set.
Descriptive secondary analyses showed that the mean change in BCVA score was comparable between treatment groups at all other timepoints up to Week 52. The proportions of participants maintaining vision (losing <15 letters on the BCVA) were comparable between the two treatment arms: 16.7% and 17.2% of those who received SDZ-AFL and Ref-AFL, respectively (risk difference: −0.441 [95% CI, −7.345 to 6.4635]) (see Figure, Supplemental Digital Content 6, http://links.lww.com/IAE/C279). Similarly, the proportion of participants with moderate visual gains (gain of ≥15 letters on the BCVA) was comparable between the two treatment arms: 20.3% and 23.8% of participants who received SDZ-AFL and Ref-AFL, respectively (risk difference: −3.524 [95% CI, −11.14 to 4.0931]).
Mean changes from baseline in CSFT were comparable between the SDZ-AFL and the Ref-AFL groups for participants at all timepoints up to Week 52 (Figure 4A). Mean change in CNV lesion size was comparable between treatment groups at Weeks 8 and 52, respectively (Figure 4B).
Fig. 4.
A. Mean change in CSFT from baseline up to Week 52 (FAS). B. Mean change in CNV from baseline up to Week 52 (FAS). FAS, full analysis set.
The proportion of participants with intraretinal fluid at Weeks 8 and 52 was comparable between treatment arms. By Week 52, 23.9% of participants receiving SDZ-AFL had intraretinal fluid on optical coherence tomography versus 24.3% of those who received Ref-AFL (risk difference: −0.45 [95% CI, −8.407 to 7.5057]). These secondary endpoints were not powered for statistical testing; the risk difference with 95% CI are presented here for descriptive purposes only.
Safety
The frequency of TEAEs were comparable between both treatment groups (Table 2): 73.4% and 72.5% of participants experienced at least one TEAE after SDZ-AFL and Ref-AFL, respectively. The frequency of TEAEs suspected to be treatment-related was also comparable between treatment arms: 2.5% and 2.9% of participants experienced at least one treatment-related TEAE among those receiving SDZ-AFL and Ref-AFL, respectively. Treatment discontinuation because of TEAEs was reported in 4.5% and 3.3% of patients in the SDZ-AFL and Ref-AFL arm, respectively.
Table 2.
AEs Occurring in the Mylight Study (SAS)
| SDZ-AFL (n = 244) | Ref-AFL (n = 240) | Total (N = 484) | |
| Adverse Event Category, n (%) | |||
| No. of subjects with at least one TEAE | 179 (73.4) | 174 (72.5) | 353 (72.9) |
| TEAE suspected to be treatment-related | 6 (2.5) | 7 (2.9) | 13 (2.7) |
| Ocular TEAE in the study eye suspected to be related to study procedure | 28 (11.5) | 26 (10.8) | 54 (11.2) |
| Ocular TEAE in the study eye suspected to be related to study procedure and study drug | 1 (0.4) | 1 (0.4) | 2 (0.4) |
| Severe TEAE suspected to be treatment-related | 1 (0.4) | 0 (0.0) | 1 (0.2) |
| SAE | 39 (16.0) | 30 (12.5) | 69 (14.3) |
| SAE suspected to be treatment-related | 2 (0.8) | 1 (0.4) | 3 (0.6) |
| TEAE leading to study drug discontinuation | 11 (4.5) | 8 (3.3) | 19 (3.9) |
| AE leading to death | 5 (2.0) | 1 (0.4) | 6 (1.2) |
| SAEs, n (%) | |||
| Ocular SAEs in the study eye, number of subjects with at least one event | 4 (1.6) | 2 (0.8) | 6 (1.2) |
| Retinal hemorrhage | 2 (0.8) | 0 (0.0) | 2 (0.4) |
| Vitreoretinal traction syndrome | 1 (0.4) | 0 (0.0) | 1 (0.2) |
| Retinal detachment | 0 (0.0) | 1 (0.4) | 1 (0.2) |
| Visual impairment | 0 (0.0) | 1 (0.4) | 1 (0.2) |
| Ophthalmic herpes zoster | 1 (0.4) | 0 (0.0) | 1 (0.2) |
| Ocular SAEs in the fellow eye, number of subjects with at least one event | 0 (0.0) | 2 (0.8) | 2 (0.4) |
| Retinal hemorrhage | 0 (0.0) | 1 (0.4) | 1 (0.2) |
| Visual acuity reduced | 0 (0.0) | 1 (0.4) | 1 (0.2) |
| No. of subjects with at least one nonocular SAE | 35 (14.3) | 27 (11.3) | 62 (12.8) |
| Cardiac disorders | 8 (3.3) | 7 (2.9) | 15 (3.1) |
| Nervous system disorders | 6 (2.5) | 1 (0.4) | 7 (1.4) |
| Injury, poisoning, and procedural complications | 5 (2.0) | 1 (0.4) | 6 (1.2) |
| Gastrointestinal disorders | 5 (2.0) | 2 (0.8) | 7 (1.4) |
| Respiratory, thoracic, and mediastinal disorders | 4 (1.6) | 4 (1.7) | 8 (1.7) |
| General disorders and administration site conditions | 3 (1.2) | 1 (0.4) | 4 (0.8) |
| Infections and infestations | 3 (1.2) | 5 (2.1) | 8 (1.7) |
| Neoplasms benign, malignant, and unspecified (including cysts and polyps) | 3 (1.2) | 5 (2.1) | 8 (1.7) |
| Musculoskeletal and connective tissue disorders | 2 (0.8) | 2 (0.8) | 4 (0.8) |
| Vascular disorders | 2 (0.8) | 2 (0.8) | 4 (0.8) |
SAS, safety analysis set.
Serious AEs (SAEs) occurred at similar rates in both treatment arms: 16.0% and 12.5% of those receiving SDZ-AFL and Ref-AFL, respectively. Two events in the SDZ-AFL and one event in the Ref-AFL arm were considered related to treatment. Six deaths were reported during the study: five in the SDZ-AFL group and one in the Ref-AFL group. The deaths were considered not related to study treatment or procedure and can be attributed to the subjects' medical conditions.
Two cases of intraocular inflammation occurred in the study eye during the study period: one moderate intraocular inflammation and one case of intraocular inflammation with retinal vasculitis in the Ref-AFL group; both were suspected to be related to the study treatment and led to study drug discontinuation. An SAE of ophthalmic herpes zoster in SDZ-AFL group was reported. It was not suspected to be related to the study treatment or study procedure. In addition, one ocular SAE of vitreoretinal traction syndrome occurring in the SDZ-AFL group was suspected to be related to the study treatment and led to study drug discontinuation. No case of endophthalmitis or retinal vascular occlusion were reported.
Immunogenicity
Comparable proportions of participants were positive for preexisting ADAs (1.2% and 1.7% in the SDZ-AFL and Ref-AFL arms, respectively), in line with the incidence of 1% to 3% reported in historic aflibercept studies.20 All predose ADA-positive samples were nonneutralizing. The majority of participants were ADA-negative throughout the study, and ADA incidence was low up to Week 52: 0.9% (2/234) of participants receiving SDZ-AFL and 2.6% (6/231) of participants receiving Ref-AFL became ADA-positive.
All participants who became ADA-positive developed neutralizing antibodies. Most ADA-positive samples were titer-negative or had a low titer of 1:10. Comparable rates of ocular AEs occurred in ADA-positive and ADA-negative participants, suggesting that these AEs were not associated with ADA positivity; however, the low rates of ADA positivity preclude a conclusive correlative analysis. None of the ocular TEAEs reported for the study eye in ADA-positive subjects were outside of the known safety profile for aflibercept nor did they constitute any new risks.
Pharmacokinetics
Systemic concentrations of free aflibercept 24 hours postdose were low and comparable between treatment arms. At Day 2, the mean SDZ-AFL concentration was 32.0 ng/mL (range: 0–91.2; n = 21), and the mean Ref-AFL concentration was 33.3 ng/mL (range: 7.7–93.4; n = 20). At Day 58, the mean SDZ-AFL concentration was 31.7 ng/mL (range: 0–80.9; n = 22) and the mean Ref-AFL concentration was 33.6 ng/mL (range: 0–97.2; n = 17). Systemic concentrations of total aflibercept were low and comparable between treatment arms (see Table, Supplemental Digital Content 7, http://links.lww.com/IAE/C280, for total drug concentrations).
Discussion
The results confirm the comparable efficacy, safety, immunogenicity, and PK between SDZ-AFL and Ref-AFL in patients with nAMD. Statistical equivalence within predefined margins was confirmed for the primary endpoint of mean change from baseline in BCVA at Week 8. This was further supported by sensitivity analyses of the primary endpoint. Descriptive analyses showed that comparability between SDZ-AFL and Ref-AFL was maintained in all secondary efficacy endpoints at all timepoints.
No new safety signals were identified during the study, and the safety profiles of SDZ-AFL and Ref-AFL remained equivalent. There was no difference in the rates of TEAEs, and few TEAEs in either arm were suspected to be treatment-related. There were low rates of TEAEs leading to treatment discontinuation, and SAEs suspected to be treatment-related.
The treatment groups showed an equivalent immunogenicity profile. The study cohort had a baseline level of ADAs in line with previously reported rates.20 Incidences of ADA positivity were low throughout the study, although all participants who became positive invariably developed neutralizing antibodies. Although this incidence is higher than that seen in previously published data, it should be noted that the sensitivity of the neutralizing antibody assay used in this study (43 ng/mL) was higher than that in previous publications.20 None of the ocular TEAEs reported for the study eye in ADA-positive subjects were outside of the known safety profile for aflibercept nor did they constitute any new risks. Few participants became ADA-positive, so a correlative analysis between immunogenicity and inflammation risks could not be performed.
Limited and comparable systemic exposure was reported after intravitreal injection administration of SDZ-AFL and Ref-AFL. Systemic concentrations of free aflibercept were low and comparable between treatment arms. Free aflibercept was measured in plasma to avoid the release of VEGF from platelets because quantification in serum may underestimate the systemic levels of free aflibercept. The plasma concentrations of free aflibercept measured around the expected time to maximum drug concentration (Tmax) were far below the concentration required to half maximally bind systemic VEGF (2.91 µg/mL)21 and are too low to induce any systemic pharmacodynamic effects.22 The concentrations of free drug at Day 2 and Day 58 were also comparable, confirming the lack of accumulation of free aflibercept after intravitreal injection administration of SDZ-AFL and Ref-AFL.
The study was designed in line with the evidential requirements for a proposed biosimilar. The lack of racial diversity may be considered a limitation of this study because many enrolled participants were White Europeans or Americans. Another perceived limitation may be that the data presented in this study confirm the efficacy and safety of SDZ-AFL up to a maximum of 52 weeks. Therefore, the long-term safety and efficacy of the proposed biosimilar after 1 year posttreatment are currently unconfirmed; however, given the demonstration of equivalence reported here, it would be expected that the long-term treatment response will be aligned to that of Ref-AFL.
Proposed biosimilar aflibercept represents an opportunity to expand the accessibility of anti-VEGF treatments available to patients with nAMD and thus improve their outcomes and reduce the cost of treatment to patients and health care systems evident in this increasing patient population.4,7,12,13
Conclusions
The Mylight study confirmed that SDZ-AFL is clinically equivalent to its reference in clinical efficacy, safety, immunogenicity, and PK. There were no clinically relevant differences between the two treatments after 1 year of follow-up. Proposed biosimilar aflibercept represents a proposed biosimilar medicine to Ref-AFL that may play a future role in supporting optimized care for patients with nAMD.
Supplementary Material
Supplementary Material
Acknowledgments
The authors thank all investigators and participating patients who contributed to the successful conduct of the Mylight study (NCT04864834).
Footnotes
Medical writing assistance was provided by Peter Hardwidge at Syneos Health, UK, and funded by Hexal AG (a Sandoz company), Holzkirchen, Germany. Final editorial approval of the content rested with the authors.
Arnaldo F. Bordon: Consultant with AbbVie, Bayer, Janssen, and Sandoz; speaker with Bayer; consultant and speaker with Alcon and Roche. Peter K. Kaiser: Consultant with AAVAntgarde Bio, Alcon, AbbVie, Allgenesis, Bayer, Bausch and Lomb, Biogen Idec, Boehringer Ingelheim, Coherus, Genentech/Roche, Innovent, Kanghong, Novartis, Ocular Therapeutix, Regeneron, RegenxBio, Samsung Bioepis, and 4D Molecular Therapeutics. A. Wolf: Consultant with AbbVie, Bayer, Boehringer Ingelheim, Novartis, Pixium, Roche, Sandoz, and Zeiss. L. Cen, J. Heyn, D. Urosevic, F. Dodeller, and L. Allmannsberger are employees of Sandoz/Hexal AG (a Sandoz company). R. Silva: Consultant: Bayer, AbbVie, THEA, Sandoz, and Roche.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.retinajournal.com).
Contributor Information
Arnaldo F. Bordon, Email: afbordon@gmail.com.
Peter K. Kaiser, Email: pkkaiser@gmail.com.
Armin Wolf, Email: Armin.Wolf@uniklinik-ulm.de.
Liyi Cen, Email: liyi.cen@sandoz.com.
Jens Heyn, Email: jens.heyn@sandoz.com.
Dragan Urosevic, Email: dragan.urosevic@sandoz.com.
Francis Dodeller, Email: francis.dodeller@sandoz.com.
Lisa Allmannsberger, Email: lisa.allmannsberger@sandoz.com.
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