Treatment of Macular Degeneration and Diabetes is more effective than ever.
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MACULAR DEGENERATION
PREFACE: The future of macular degeneration treatment is exceptionally optimistic. In fact, retinal research into improving efficacy, reducing treatment burden, and even curing the disease via new therapies is leading the way in the entire medical field. This category of research will translate to advancements in the treatment of retinal disease and a number of other general medical disorders.
LATEST AVAILABLE AND UPCOMING TREATMENTS:
- Vabysmo (Faricimab)
- Izervay (Avacincaptad pegol)
- Susvimo (Ranibizumab ocular implant)
- Eylea (Aflibercept)
- Avastin (Bevacizumab)
As the name suggests, macular degeneration involves a degeneration of tissues under the retina. The most common form of macular degeneration is age-related macular degeneration, most prevalent in the population aged 60 and older. Age-related macular degeneration is also most prevalent in Caucasians. It is particularly detrimental to quality of life because it preferentially affects the central vision. For this same reason, its only saving grace is that it will never completely blind a person in that it spares the peripheral vision. With this peripheral vision a person can be reasonably expected to get around, although at its worst macular degeneration will take our ability to read, drive, use a computer, or even recognize faces.
There are two main categories of macular degeneration, dry and wet. Ninety percent of macular degeneration is the dry form which involves a degeneration of the tissues under the retina, and ultimately the retina itself. This form is the earlier and less aggressive form of the disease. It should be understood, however, that dry macular degeneration alone can result in extreme vision loss. The earliest component of dry macular degeneration is the accumulation of deposits, called drusen, under the retina. These drusen can be visible on retinal examination and their concentration and size correlate with the severity of the disease. More advanced forms of dry macular degeneration involve entire patches of degeneration in and under the retina, visible on examination as what is called geographic atrophy. As stated above, although still a dry form of macular degeneration, this can result in markedly reduced vision.
Dry macular degeneration cannot currently be reversed by medical intervention, but to a significant degree, its progression can be slowed or abated with a number of interventions. These include the regular use of eye vitamins which include the minerals and vitamins studied in the Age Related Eye Disease Study or AREDS. Currently the AREDS 2 formula of vitamins and minerals is recommended. Injectables such as Izervay have been developed for dry macular degeneration.
Another important intervention is cessation of smoking, which is an independent risk factor for the progression of macular degeneration to the wet or more aggressive form. Hypertension, or high blood pressure, is still another independent risk factor for the development of wet macular degeneration. Studies show less than half of Americans with hypertension have their blood pressure under control, and in practice this correlates directly with worsening macular degeneration in patients. There is almost never a reason that high blood pressure cannot be controlled, and most often it can be controlled by simply adjusting the dose of anti-hypertensive medications, resulting in a much better chance of maintenance of vision in age-related macular degeneration.
Wet macular degeneration is a more aggressive form of the disease and responsible for most of the vision loss associated with macular degeneration. Approximately 10 to 15% of eyes suffering dry macular degeneration will progress to this more aggressive form. The disease mechanisms involved in wet macular degeneration involve the tissues adjacent to the retina and include increased inflammation, leakage of blood vessels, degeneration of vital tissues, and eventually the growth of new unhealthy blood vessels under the retina. These new blood vessels unfortunately develop most often beneath the macula, which is the part of the retina responsible for fine central vision. It is for this reason the typical vision loss in macular degeneration affects the central and not the peripheral vision. These new unhealthy blood vessels are prone to leakage of fluid and frank bleeding which can lead to scar tissue and further degeneration of the retina if untreated.
In past years, no good treatments for wet macular degeneration existed. Both patients and their retinal specialists could only watch in frustration as precious sight was lost permanently over time. Eventually hot lasers were used with some success, but often with residual vision loss caused by the laser as well as the disease. Photodynamic therapy, or cold laser, eventually allowed for less residual damage and served as an effective treatment for certain lesions. This cold laser, however, still left over half of treated eyes with a loss of vision over time.
In more recent years, steroids and newer medications, including VEGF inhibitors and now newer mechanisms of action, have been used more successfully to limit both the leakage and growth of the unhealthy blood vessels developing in wet macular degeneration. Combinations of these and past treatments are being used with more success than previously could be offered to patients with macular degeneration. These more effective drugs include avastin, Eylea, and Vabysmo which have allowed approximately 90% of macular degeneration patients, receiving early treatment, to maintain or gain vision. Many new treatments are in constant research, but no treatment can substitute for regular examination and early diagnosis. Novel mechanisms of action are under intense research and the pipeline for new medicines is more robust than ever.
Interventions such as the use of AREDS 2 supplements, cessation of smoking, aggressive control of blood pressure, diet high in vegetables and low in fats, control of cholesterol, treatment of sleep apnea, and even control of major anxiety can benefit patients with macular degeneration
Age-Related Macular Degeneration
Articles
Real-world efficacy of intravitreal faricimab for neovascular age-related macular degeneration: a systematic review
International Journal of Retina and Vitreous volume 10, Article number: 48 (2024) Cite this article
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Abstract
Background
To systematically review the real-world outcomes of intravitreal faricimab treatment in patients with neovascular age-related macular degeneration (nAMD) to evaluate its efficacy and safety in clinical settings. This study was conducted due to the need for real-world evidence to complement the findings from controlled clinical phase-III trials.
Methods
A systematic literature search was conducted on March 17, 2024, across 11 databases, utilizing search terms specifically tailored each database. All studies were reviewed qualitatively with specific focus on the outcomes of interest: the best-corrected visual acuity (BCVA), the central retina thickness (CRT), and the burden of therapy.
Results
We identified a total of 22 eligible studies of 1762 eyes from 1618 patients with nAMD. Studies reported that intravitreal faricimab injections maintained BCVA in patients with previously treated eyes and demonstrated statistically significant improvement in patients with treatment-naïve eyes. The CRT was reduced after intravitreal faricimab therapy. Faricimab was well-tolerated, with no significant safety concerns identified, and reduced the overall burden of therapy.
Conclusion
Real-world studies corroborate the conclusions drawn from phase-III trials regarding faricimab treatment, demonstrating improvement in both visual and anatomical outcomes. Additionally, no significant safety issues were identified, as the treatment was generally well-tolerated and reduced the overall burden of therapy in the real-world settings.
Introduction
Neovascular age-related macular degeneration (nAMD) is the leading cause of irreversible vision loss among the elderly in developed world [1,2,3]. The disease pathophysiology involves the secretion of vascular endothelial growth factor (VEGF), which lead to the formation of fragile blood vessels that ultimately result in visual impairment [4]. Intravitreal injections of anti-VEGF agents have been effective in improving the functional and anatomical properties of eyes with nAMD [5, 6]. While anti-VEGF agents are effective, their limitations include the requirement for frequent injections and need for long-term treatment for nAMD [7]. To overcome these boundaries, the attention has led to finding more sustainable treatment solutions, including longer acting drugs or agents targeting other pathways [8, 9].
Intravitreal faricimab (Vabysmo, F. Hoffmann-La Roche AG, Basel, Switzerland) is a novel anti-angiopoietin-2 (Ang-2) and anti-VEGF bispecific agent approved by Food and Drug Administration (FDA) and European Medicines Agency (EMA) for treatment of nAMD and diabetic macular edema (DME). Ang-2 functions as a proinflammatory cytokine, which promote neovascularization in the aged retinal micromilleu, and enhances the effect of VEGF on neovascularization [4, 10, 11]. The approval of faricimab was based on four phase 3 studies. TENAYA and LUCERNE for nAMD [12] and YOSEMITE and RHINE for DME [13]. All studies reported visual and anatomical benefits. The mean best-corrected visual acuity (BCVA) change from baseline with faricimab was non-inferior to aflibercept in both TENAYA (5.8 vs. 5.1 ETDRS letter) and LUCERNE (6.6 vs. 6.6 ETDRS letters) [12]. Rates of ocular adverse events were comparable between faricimab and aflibercept [12].
However, the results of clinical trials may not necessarily reflect the results when applied in real-world context [14, 15]. Patients in real-world clinics may not always fit the eligibility criteria of clinical trials and circumstances around routine clinic may differ from those in controlled trials. Furthermore, real-world studies can give insight into outcomes from switching therapies, e.g., in this case from other intravitreal anti-VEGF therapies to faricimab. Therefore, this study aims to evaluate the efficacy and durability of action of intravitreal faricimab in real-world studies of patients with nAMD.
Methods
Protocol and registration
We followed the recommendations of the Cochrane Handbook for the design and conduct of our study [16]. Our protocol registered at PROSPERO (protocol no. CRD42024537080). We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) [17]. According to Danish law, no institutional review board approval is not relevant for systematic reviews.
Eligibility criteria
Population Studies of patients with neovascular AMD. We did not restrict patient population based on any previous treatment. We only considered studies of human patients.
Exposure Intravitreal injection therapy using faricimab 6 mg (0.05 mL).
Outcomes Change from baseline to follow-up in CRT and BCVA as well as the burden of therapy (i.e., number of injections/therapies needed).
Study design Any prospective or retrospective studies with original data of real-world evidence. Case reports, non-peer-reviewed publications and conference abstracts were not eligible. We only considered studies disseminated in English for practical purposes. No restriction was made on the geographical origin of the study or the date of study publication.
Information sources, literature search, and study selection
One trained author (Y.S.) conducted a systematic literature search in 11 databases (PubMed, Embase, Web of Science Core Collection, BIOSIS Previews, Current Contents Connect, Data Citation Index, Derwent Innovations Index, KCI-Korean Journal Database, ProQuest Dissertations & Theses Citation Index, SciELO Citation Index, and the Cochrane Library). All searches were conducted on 17 March 2024. Literature search details for individual databases are available in Supplementary file 1.
One author (Y.S.) removed all duplicates and obviously irrelevant reports. Two authors (N.N. and S.N.) independently screened full text of the remaining records for eligible studies. Reference lists were screened for further eligible studies. Disagreements between authors were discussed until consensus, and if consensus could not be reached, a third author (Y.S.) made the final decision.
Data collection and extraction, risk of bias within studies, and data synthesis
Two authors (N.N. and S.N.) independently extracted data and evaluated risk of bias within studies. Data were extracted on study and population characteristics, treatment details, and clinical outcomes at baseline and follow-up. Since we expected studies to be primarily retrospective cohort studies, we used the Newcastle–Ottawa Scale for the evaluation of risk of bias within studies [18]. Disagreements between authors were discussed until consensus, and if consensus could not be reached, a third author (Y.S.) made the final decision.
All studies were reviewed qualitatively in text and in tables. Due to the heterogeneity of the available studies, meaningful quantitative analyses were not possible.
Results
Study selection process
Our literature search identified 509 records of which 216 were duplicates and 256 were obviously irrelevant. The 37 remaining records were examined in full text for eligibility. Of these, 15 were excluded as they did not fulfill our eligibility criteria. Thus 22 studies were eligible for inclusion in our review (Fig. 1).
Fig. 1
PRISMA flow diagram of study selection processFull size image
Characteristics of studies
We identified 22 eligible studies of real-world evidence published between March 23, 2023, and February 28, 2024 [19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40]. These studies summarized data from 1762 eyes of 1618 patients. Studies reported outcomes from patients in USA (n = 883), Japan (n = 532), UK (n = 131), Switzerland (n = 26), and Denmark (n = 46). Patients had a mean age of 70.2–83.0 years and 776 (52%) were females. Study designs were predominantly retrospective cohorts, although three studies were retrospective interventional studies. Seventeen studies were studies of switchover from aflibercept, bevacizumab, ranibizumab, or brolucizumab to faricimab. Study and population characteristics are summarized in detail in Table 1.
Table 1 Study characteristicsFull size table
Studies evaluated treatment of 6.0 mg faricimab. Seven studies did not specify the dose of faricimab but were not excluded, as their inclusion remained pertinent to assessing the safety profile of faricimab. Seventeen studies were switch-over from a previous treatment to faricimab, and five studies was on treatment-naïve eyes. The follow-up regimen ranged from three to 12 months. Treatment details and follow-up regimens for each study are summarized in Table 2.
Table 2 Treatment details in individual studiesFull size table
Efficacy of faricimab in treatment naïve eyes with nAMD
Five studies investigated the effect of faricimab in treatment-naïve eyes with nAMD [21, 28, 30, 31, 40]. Hara et al. [21] reported no significant improvement in BCVA (0.46 ± 0.41 logMAR before the treatment vs. 0.44 ± 0.45 logMAR after), CRT decreased from 498 ± 227 μm to 217 ± 74 μm, and no adverse events were reported [21]. Maruyama-Inoue et al. [28] reported that BCVA improved (0.36 ± 0.33 logMAR before the treatment vs. 0.28 ± 0.32 logMAR after), that central foveal thickness (CFT) decreased from 407 ± 187 μm to 226 ± 94 μm, and that no adverse event was reported [28]. Matsumoto et al. [30] reported that BCVA improved (0.32 ± 0.40 logMAR before treatment vs. 0.17 ± 0.33 logMAR after) and that one eye of 30 eyes in study in total developed intraocular inflammation (IOI) [30]. The mean intended injection interval at the last visit was 12.7 weeks [30]. Mukai et al. [31] reported that BCVA improved (0.40 ± 0.42 logMAR before treatment vs. 0.32 ± 0.43 logMAR after), that CRT decreased from 357 ± 165 μm to 175 ± 91 μm, and two cases of retinal pigment epithelium (RPE) tears [31]. After 3 months, 82% of eyes were reported to have obtained a dry macula [31]. Tanaka et al. [40] reported that BCVA improved (0.29 ± 0.30 logMAR before treatment vs. 0.18 ± 0.32 logMAR after the treatment, p = 0.00049), that CRT decreased from 325 ± 193 μm to 164 ± 90 μm, and one case of RPE tear [40]. After 4 months, 77% of eyes were reported to have obtained a dry macula [40].
Switchover to faricimab treatment in eyes with nAMD previously treated with other anti-VEGF therapies
Fourteen studies evaluated the effect a switchover from any previous intravitreal anti-VEGF treatment to faricimab [19, 20, 22,23,24, 26, 27, 32,33,34,35,36, 38, 39]. Cheng et al. [19] reported that BCVA remained stable (0.59 ± 0.45 logMAR before vs. 0.58 ± 0.45 logMAR after the switch), that median central subfield thickness (CST) decreased from 342 μm to 318 μm, and no serious adverse events [19]. Grimaldi et al. [20] reported that BCVA remained stable (median 0.35 logMAR before vs. 0.30 logMAR after the switch), that median CST decreased from 357 μm to 292 μm, one case of RPE tear, and no serious adverse events [20]. Time interval between the injections increased from 4.0 weeks to 6.0 weeks after the switch [20]. Hikichi [22] reported that BCVA remained stable (mean 0.38 logMAR before vs. 0.31 logMAR after the switch), that mean CFT decreased from 372 μm to 272 μm, and no adverse events [22]. The mean interval of injections increased from 6.7 weeks to 10.5 weeks after the switch [22]. Inoda et al. [23] reported that BCVA remained stable (0.34 ± 0.37 logMAR before vs. 0.36 ± 0.40 logMAR after the switch), that mean CST remained stable (242 ± 72 μm before the switch vs. 242 ± 82 μm after), and no adverse events [23]. The treatment intervals were similar to those before the switch [23]. Kataoka et al. [24] reported that BCVA remained stable (0.3 ± 0.4 logMAR before the switch vs. 0.3 ± 0.4 logMAR after), that mean CRT decreased from 320 ± 181 μm to 302 ± 143 µm, and reported one case of mild iritis [24]. The mean interval of injections increased from 4.4 weeks to 8.7 weeks after the switch [24]. Kishi et al. [26] reported that BCVA remained stable (0.26 ± 0.34 logMAR before the switch vs. 0.23 ± 0.37 logMAR after), that mean CRT significantly decreased from 320 ± 179 μm to 312 ± 189 μm, and one case of RPE tear [26]. The mean interval of injections increased from 5.9 weeks to 6.1 weeks after the switch [26]. Leung et al. [27] reported that BCVA improved (0.33 ± 0.32 logMAR before the switch vs. 0.27 ± 0.32 logMAR after) and that CRT decreased from 312 ± 87 μm to 287 ± 71 μm. Two eyes developed endophthalmitis, four eyes developed RPE tears, and three eyes developed subretinal hemorrhages [27]. The interval of injections increased from 5.2 weeks to 7.6 after the switch [27]. Ng et al. [32] reported that BCVA remained stable (0.47 ± 0.34 logMAR before the switch vs. 0.49 ± 0.36 after) and that central macular thickness (CMT) decreased from 344 ± 96 μm to 320 ± 98 μm [32]. Pandit et al. [33] reported that BCVA remained stable (0.58 ± 0.54 logMAR before the switch vs. 0.55 ± 0.52 logMAR after), that mean CFT decreased from 355 μm to 306 μm, and no adverse events [33]. The interval of injections was increased from 36 to 43 days [33]. Raimondi et al. [34] reported that BCVA remained stable (65 ± 12 ETDRS letters before the switch vs. 65 ± 13 ETDRS letters after), that CMT decreased from 330 ± 103 μm to 287 ± 73 μm, and no adverse events [34]. Rush (2023) reported that BCVA improved (mean 0.72 logMAR before the switch to 0.59 logMAR), that mean CMT decreased from 395 µm to 350 μm, and no adverse events [35]. Dry macula with a treatment interval ≥ 8 weeks was achieved in 31.5% (17/54) [35]. Schneider et al. [36] reported that BCVA remained stable (median 74 ETDRS letters before the switch vs. 74 after), that median CRT decreased from 252 μm to 232 μm, and no adverse events [36]. Szigiato et al. [38] reported that BCVA remained stable (median 62.9 ETDRS letters before the switch vs. 62.7 ETDRS letters after) and that CRT decreased from 267 ± 65 μm to 250 ± 59 μm [38]. One patient developed IOI requiring cessation of further intravitreal faricimab injections [38]. No other adverse event was reported [38]. The interval of injections increased from 5.6 weeks to 6.8 weeks [38]. Tamiya et al. reported that BCVA remained stable (0.21 ± 0.18 logMAR before the switch vs. 0.24 ± 0.13 logMAR after), that CRT decreased from 193 ± 109 μm to 182 ± 105 μm, and no adverse events [39]. Notably, 25% of the eyes that showed dry macula at month two had no fluid recurrence for up to 4 months [39].
Studies in which the entire nAMD treatment service, i.e., both treatment-naïve and existing patients, are switched over to faricimab
Three studies included patients with both treatment-naïve eyes and those who had previously received treatment [25, 29, 37]. Khanani et al. [25] reported that BCVA improved in both the switch-over eyes (from mean 58 ETDRS letters to 61 ETDRS letters) as well as the treatment-naïve eyes (from mean 51 ETDRS letters to 59 ETDRS letters), with the latter group experiencing the greatest improvement [25]. The mean CST decreased significantly in both the switch-over and the treatment-naïve eyes [25]. One case of IOI was reported [25]. No serious adverse events were reported [25]. Matsubara et al. [29] reported that BCVA improved (median 0.046 logMAR before treatment vs. 0.072 logMAR after), that median CST decreased from 329 μm to 319 μm, and no adverse events [29]. Stanga et al. [37] reported that BCVA improved both in treatment-naïve eyes (from 0.33 ± 0.29 logMAR to 0.30 ± 0.29 logMAR) and switch-over eyes (from 0.61 ± 0.75 logMAR to 0.39 ± 0.54 logMAR) [37]. The CRT decreased both in treatment-naïve eyes (from 875 ± 511 μm to 537 ± 352 μm) and in switch-over eyes (from 256 ± 13 μm to 245 ± 15 μm). No adverse events were reported [37]. A complete resolution of SRF was observed in six out of eight eyes (75%) and of IRF in 2 out of 3 eyes (66.67%) [37].
Risk of bias within studies
The evaluation of risk of bias within studies was made using the Newcastle–Ottawa Quality Assessment Scale for cohort studies. All studies were evaluated on selection-, comparability-, and outcome categories. All studies scored 0 point in non-exposed cohort (selection #2) as all studies, except two studies, involved a switch-over from a previous treatment to faricimab. The two studies were Hara et al. [21] and Maruyama-Inoue et al. [28], which investigated the relationship between a previous treatment and faricimab. All studies received a high-quality score, and Hara et al. [21] and Maruyama-Inoue et al. [28] scored a maximum score. Details of the risk of bias within studies are summarized in Table 3.
Table 3 Risk of bias within individual studiesFull size table
Discussion
In this systematic review, our aim was to evaluate the efficacy and durability in intravitreal faricimab treatment in patients with nAMD. Overall, existing real-world evidence presents a pattern of BCVA improvement and CRT decrease in treatment-naïve eyes, and stable BCVA with longer treatment duration in switch-over eyes. Many patients were able to achieve a dry macula, also in cases of switch-over from other intravitreal anti-VEGF therapies with inadequate treatment response. Overall, studies also reported that faricimab was well-tolerated with only rare incidences of adverse events (retinal pigment epithelium tears, mild iritis, endophthalmitis, subretinal hemorrhages, or IOI).
Preclinical studies of Ang-2 inhibition in choroidal neovascularization in mice showed that inhibiting Ang-2 led to reduced vascular leakage and lesion numbers [11, 41]. Combination therapy with both Ang-2 inhibitor and anti-VEGF was superior to anti-VEGF alone [11, 41]. These findings in preclinical studies underscore the pathophysiological rationale for the efficacy of the bispecific anti-Ang-2 and anti-VEGF faricimab.
Hara et al. [21] and Maruyama-Inoue et al. [28] compared faricimab with another anti-VEGF treatments in their respective cohorts in a real-world setting. In contrast to the findings of the TENAYA and LUCERNE trials, which concluded that faricimab was non-inferior to aflibercept [12]; Hara et al. [21] concluded that faricimab was inferior to aflibercept in terms of BCVA gain [21]. Both the group of faricimab treated eyes and the aflibercept treated eyes seemed to be comparable in their baseline characteristics [21]. More comparative real-world studies, preferably with larger study sample size are warranted to further explore this discrepancy between the real-world evidence as suggested by Hara et al. [21] and the results of the TENAYA and LUCERNE trials [12]. Maruyama-Inoue et al. [28] attributed the rapid improvement in BCVA in intravitreal brolucizumab treatment group to differences in molecular weight and affinity for VEGF between the two anti-VEGF treatments [28]. Brolucizumab has a lower molecular weight, which might facilitate the delivery of more active molecules per injection and potentially allow for more effective tissue penetration and increased efficacy [42]. However, one complicating factor of brolucizumab therapy is that it is associated with a different safety profile in terms of a higher incidence of IOI, retinal vasculitis, and retinal vascular occlusion [43].
Taken together, studies illustrated that a switch to faricimab allowed for a statistically significant extension of treatment intervals, which may reduce injection frequency and present a possibility to reduce the logistical, financial, and emotional burdens associated with regular hospital visits. Thus, real-world evidence as presented in this review suggests that faricimab therapy lowers the burden of treatment for patients with nAMD.
There are several limitations to our systematic review. The included studies lack a control group for treatment comparison, which makes it difficult to draw definitive conclusions when comparing to other anti-VEGF therapies. In addition, most studies were relatively small retrospective studies, which in terms of clinical evidence has certain biases. However, studies were available from different centers from different countries, which is a benefit in terms of the generalizability and applicability of our findings. Moreover, a limitation of this systematic review is that it was not a Cochrane review, which methodologically is seen as gold standard among many colleagues.
In conclusion, the existing real-world evidence of intravitreal faricimab therapy find that it can maintain BCVA in the majority of the patients, reduces the CRT, and does this while reducing the burden of therapy. These real-world studies align with the results from the controlled experimental trials [12]. Therefore, faricimab as a first-line therapy holds potential to, at least to a certain degree, alleviate the important burden of therapy in patients with nAMD [7, 44].
Availability of data and materials
All data generated or analysed during this study are included in this published article and its supplementary information files.
Abbreviations
Ang-2:
Angiopoietin-2
BCVA:
Best-corrected visual acuity
CFT:
Central foveal thickness
CMT:
Central macular thickness
CRT:
Central retinal thickness
CST:
Central subfield thickness
DME:
Diabetic macular edema
EMA:
European Medical Agency
FDA:
Food and Drug Administration
nAMD:
Neovascular age-related macular degeneration
RPE:
Retinal pigment epithelium
VEGF:
Vascular endothelial growth factor
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- Department of Ophthalmology, Odense University Hospital, Odense, Denmark
Nasratullah Nasimi, Safiullah Nasimi, Jakob Grauslund & Anna Stage Vergmann - Department of Clinical Research, University of Southern Denmark, Campusvej 55, 5230, Odense, Denmark
Jakob Grauslund, Anna Stage Vergmann & Yousif Subhi - Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark
Jakob Grauslund - Department of Ophthalmology, Vestfold Hospital Trust, Tønsberg, Norway
Jakob Grauslund - Department of Ophthalmology, Rigshospitalet, Copenhagen, Denmark
Yousif Subhi - Department of Ophthalmology, Zealand University Hospital, Roskilde, Denmark
Yousif Subhi
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Authors N.N., S.N., J.G., A.S.V., and Y.S. designed the study protocol. Authors N.N., S.N., and Y.S. performed study selection, study eligibility, data extraction, and risk of bias assessment. Authors N.N., S.N., J.G., A.S.V., and Y.S. drafted the manuscript. Authors N.N., S.N., J.G., A.S.V., and Y.S. finalized the manuscript and approved its submission for publication.
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Additional file 1 of Real-world efficacy of intravitreal faricimab for neovascular age-related macular degeneration: a systematic review
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Nasimi, N., Nasimi, S., Grauslund, J. et al. Real-world efficacy of intravitreal faricimab for neovascular age-related macular degeneration: a systematic review. Int J Retin Vitr 10, 48 (2024). https://doi.org/10.1186/s40942-024-00566-0
- Received04 June 2024
- Accepted08 July 2024
- Published12 July 2024
- DOIhttps://doi.org/10.1186/s40942-024-00566-0
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International Journal of Retina and Vitreous
ISSN: 2056-9920
Macular Degeneration
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Ann Med Surg (Lond). 2024 May; 86(5): 2413–2416.Published online 2024 Apr 3. doi: 10.1097/MS9.0000000000002021PMCID: PMC11060312PMID: 38694318
“Izervay (avacincaptad pegol): paving the way for vision preservation in geographic atrophy”
Laiba Shakeel, MBBS,a Afsheen Khan, MBBS,a and Aymar Akilimali, MD
bAuthor information Article notes Copyright and License information PMC Disclaimer
Abstract
Age-related macular degeneration (AMD) is a progressive retinal disease that primarily affects the macula, leading to central vision loss and impaired color vision. Among its most severe forms is geographic atrophy (GA), which results in irreversible central blindness. While numerous risk factors, including age, smoking, and genetics, contribute to the development of AMD, effective treatment options for GA have been limited. This article centers on Izervay [avacincaptad pegol (ACP)], an FDA-approved drug designed to address the unmet medical needs of patients with GA secondary to AMD. The pathophysiology of GA involves oxidative damage, chronic inflammation, and cell death, primarily due to complement system dysregulation. Previous treatments for GA have shown limited efficacy, leaving patients searching for more effective solutions. Izervay, with its unique mechanism of action, inhibits complement protein C5, disrupting the formation of the membrane attack complex and slowing retinal cell degeneration. Clinical trials have demonstrated Izervay’s ability to significantly reduce the growth of GA lesions, offering hope for improved outcomes. Additionally, the drug has exhibited a tolerable safety profile, with common side effects including conjunctival hemorrhage and increased intraocular pressure. Izervay represents a breakthrough in AMD treatment, offering the potential to preserve vision in those at risk of irreversible vision loss due to GA. While further research is necessary to evaluate long-term efficacy and accessibility, its approval opens new possibilities in AMD management, transforming the lives of individuals affected by this condition.
Keywords: aptamers, complement C5, complement membrane attack complex, geographic atrophy, macular degeneration, nucleotideGo to:
Introduction
Age-related macular degeneration (AMD) is a progressive retinal disease primarily affecting the macula, responsible for visual acuity and color vision. Pathological changes in the deeper retinal layers and surrounding vasculature result in central vision loss. While age represents the most significant risk factor for AMD, others include smoking, elevated BMI, hypertension, hyperlipidemia, and heredity1. Around one million individuals experience geographic atrophy (GA), a severe form of dry AMD, with 160 000 new cases reported annually2. AMD has three phases: early, intermediate, and advanced, the latter being divided into dry AMD and wet (neovascular) AMD3. Atrophic lesions in the outer retina characterize GA, while wet AMD involves blood vessel leakage into the macula, leading to abrupt vision impairment. GA, unlike wet AMD, is a chronic condition that ultimately results in irreversible central blindness, with a median progression time to permanent blindness estimated at 6.2 years4.
This article is focused on Izervay, an FDA-approved drug for GA secondary to AMD. It provides an insight into its characteristics, mechanism of action, and potential role in managing GA secondary to AMD. It also explores other possible treatment options, enhancing the understanding of Izervay’s benefits in treating this disorder.
Pathophysiology
GA secondary to AMD is a complex condition influenced by environmental stressors and aging factors. It involves accumulating oxidative damage, resulting in drusen deposits between the retinal pigment epithelium (RPE) and Bruch’s membrane. Excessive drusen accumulation triggers chronic inflammation through the complement cascade. This inflammation can lead to the death of crucial cells like photoreceptors, RPE, and choriocapillaris, causing sharply defined atrophic lesions and exposing choroidal vessels4. The complement system plays a significant role, with C3 and C5 fragments found in Drusen4 (Refer to Fig. Fig.1).1). GA results in scotomas and visual impairments, even outside the fovea. It features atrophic lesions progressing from the outer retina towards the fovea, leading to irreversible vision loss4,5. Proper regulation of the complement system is essential, and genetic mutations in the regulatory complement protein are common in individuals with dry AMD6.
Pathophysiology of geographic atrophy.
Previous treatment
Treatment options for AMD secondary to GA have been explored with varying degrees of success. Unlike exudative AMD, which can be effectively managed with antivascular endothelial growth factor medications, available treatments for GA have limited proven efficacy. Patients have been recommended lifestyle changes, nutritional supplements, and vitamins, but their effectiveness in managing GA still needs to be proven7.
Several potential therapies have been investigated, including Brimonidine, a selective 2 adrenergic receptor agonist that has shown promise in providing neuroprotection by stimulating cell survival signaling and the production of brain-derived neurotrophic factor. However, it has also been associated with vascular injury and side effects like conjunctivitis and eye discomfort8.
NGM621, a humanized monoclonal antibody targeting complement C3, aimed to slow GA progression but fell short in the Phase 2 clinical trial, CATALINA, regarding its primary endpoint9. Gene therapies are promising to improve retinal disease treatment, with GT005, an investigational gene therapy seeking to enhance complement factor I (CFI) production, which can help restore complement system balance and reduce inflammation. Ongoing Phase 2 clinical trials, EXPLORE and HORIZON, further investigate the administration of GT005 in GA patients10.
Izervay, a novel treatment for GA, demonstrates promising efficacy compared to existing therapies. While Syfovre, the first FDA-approved GA treatment, exhibits a 36% slowdown in disease progression with monthly injections by targeting the immune system protein C3, it also raises concerns due to the rare but severe side effect of retinal vasculitis, which can lead to blindness by blocking retinal blood flow. In contrast, Izervay offers a potentially safer alternative, providing comparable efficacy without the same risk of severe adverse effects. Its effectiveness, safety profile, and overall outcomes suggest it is a valuable contender in GA treatments11.
Izervay (avcincaptad pegol)
The FDA’s approval of Izervay [avacincaptad pegol (ACP)] represents a significant advancement in addressing the unmet medical needs of patients with GA secondary to AMD. ACP is an RNA aptamer, a PEGylated oligonucleotide, that plays a pivotal role in inhibiting complement protein C5. The primary action of ACP is the inhibition of C5, a component of the complement system. By binding to C5, this drug effectively prevents the cleavage of C5 into its biologically active fragments, C5a and C5b. This inhibition is significant because it disrupts the subsequent formation of the membrane attack complex (MAC). Inhibiting these C5-mediated has the potential to slow the progression of retinal cell degeneration in GA, offering therapeutic benefits. In patients with AMD, the growth of GA reflects the loss of photoreceptors and the underlying disease progression. Studies GATHER1 and GATHER2, which investigated the efficacy of ACP, revealed notable reductions in the rate of GA growth throughout treatment. This reduction in GA progression during the first year of ACP treatment demonstrates the drug’s potential to slow the advancement of GA secondary to AMD12.
Izervay’s unique mechanism of action in inhibiting complement protein C5 and preventing MAC formation represents a revolutionary breakthrough in treating GA associated with AMD.
Clinical trial
The safety and efficacy of ACP, a C5 inhibitor, were assessed for GA secondary to AMD in a randomized, double-masked, sham-controlled clinical trial (As shown in the Table Table1).1). In this randomized control trial, participants had to be at least 50 years old and have best-corrected visual acuity in the study eye that fell between 20/25 and 20/320 to be eligible. The GA had to be nonfoveal centered, secondary to AMD, and partially positioned within 1500 mm of the foveal center. In part 1 of the trial, 77 participants were randomized into three groups receiving monthly intravitreal injections of ACP at 1 mg, ACP at 2 mg, or a sham treatment. In the second half, 209 participants were randomized into three groups receiving monthly ACP at 2 mg, ACP at 4 mg, or a sham treatment. When compared to their respective sham groups, the effects of ACP treatment on GA growth were seen as early as month 6, with a 28.4% reduction for avacincaptad 2 mg and a 26.6% reduction for ACP 4 mg dose. When compared with their respective sham-control groups, the mean GA growth rate was seen to have decreased by 30.5 and 25.6%, respectively, after receiving monthly therapy with ACP 2 mg and 4 mg without undergoing square root transformation from baseline to month 12. ACP treatment was generally well-tolerated, and ocular adverse events were mainly related to the injection procedure. The study concluded that ACP at 2 and 4 mg demonstrated a continued reduction in GA progression and tolerability13. Similarly, A phase 3 trial, GATHER2, involved 448 participants from 205 retina clinics, research hospitals, and academic institutions worldwide. To qualify, patients need to have the best corrected visual acuity in the study eye between 20/25 and 20/320 and noncentrepoint involving GA to be 50 years of age or older aimed to evaluate the safety profile of ACP 2 mg in reducing GA lesion growth over 12 months. The patients were randomized in a 1:1 ratio, receiving ACP and sham. Of the patients in the ACP 2 mg group, 154 (68%) were female, and 71 (32%) were male; in the sham group, there were 156 (70%) female and 66 (30%) male patients. A significant difference in growth of 0·056 mm/year was observed between the ACP 2 mg group and the sham group from baseline to month 12. The trial found that ACP was well-tolerated and considerably slackened the growth of GA lesions compared to sham treatment. This suggests that ACP has the potential to alter the disease progression for patients with GA, offering hope for improved outcomes14.
Table 1
Summarised clinical trials showing the efficacy of izervay
Study IDPhaseSample sizeOutcomesGATHER-1 TRIAL (NCT02686658)13Phase 2/3Two hundred eighty-six participants with geographic atrophy, aged 50 or olderTreatment with Avacincaptad pegol showed a reduction in the mean rate of geographic atrophy growth over the 18 monthsGATHER-2 TRIAL(NCT04435366)23Phase 3Four hundred forty-eight people with geographic atrophy secondary to AMD, aged 50 or olderAvacincaptad pegol was well-tolerated and significantly slowed the growth of geographic atrophy lesions compared to sham treatmentOpen in a separate window
Reference:
Jaffe GJ, et al. 202113.
Khanani, et al. 202314.
Recommend dosage and side effects
Izervay (ACP) carries specific potential side effects and precautions that should be carefully considered upon use. Mild side effects reported include eye pain, blurred vision, eye floaters, swelling or irritation around the eyelashes, and temporary red or bloody spots on the white part of the eye. Additionally, mild allergic reactions have been observed. More severe complications such as endophthalmitis (severe inflammation inside the eye), detached retina, increased risk of ‘wet’ AMD, and increases in eye pressure have also been reported. Before using Izervay, it is vital to confirm that the patients are not allergic to the active ingredient ACP or any other components in the medication. Izervay should not be used in ocular or periocular infections or active intraocular inflammation cases15. In addition to these adverse effects, Izervay costs around $2100 per injection. The high cost can affect its use as a sustainable treatment option and can hinder patient compliance with the entire treatment process11.
The recommended dosage for Izervay is a 2 mg intravitreal injection administered by a qualified physician once monthly for 12 months. It is imperative to store Izervay in the refrigerator within the temperature range of 2°C–8°C (36°F–46°F) and avoid freezing or shaking the vial15.
Conclusion
In conclusion, Izervay (ACP) represents a significant milestone in the treatment of GA associated with AMD. By decelerating the progression of GA, it offers the hope of maintaining a better vision for an extended period. Administered via intravitreal injection, Izervay demonstrates promise as a vital intervention for those at risk of irreversible vision loss due to GA. As we move forward, it is crucial to conduct further research and clinical trials to assess its long-term efficacy and safety. Moreover, efforts should be made to increase its production, making it readily accessible worldwide and cost-effective to improve the quality of life for individuals affected by GA while alleviating the healthcare system’s burden. Izervay’s approval opens new possibilities in AMD treatment, enhancing the prospects of preserving vision, and ultimately transforming the lives of those afflicted by this condition.
Ethical approval
Ethics approval was not required for this editorial.
Consent
Informed consent was not required for this editorial.
Sources of funding
The authors did not receive any financial support for this work. No funding has been received for the conduct of this study.
Author contribution
L.S.: conceptualization and project administration; L.S. and A.K.: original draft of manuscript; A.A.: reviewing and editing the manuscript; A.K.: visualization.
Conflicts of interest disclosures
Not applicable.
Research registration unique identifying number (UIN)
Not applicable.
Guarantor
Laiba Shakeel and Aymar Akilimali.
Data availability statement
Not available.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgements
The authors would like to thank the direction of Medical Research Circle (MedReC) of Democratic Republic of the Congo for the realization of this present paper.
Footnotes
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Published online 3 April 2024
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