To assess visual acuity (VA) outcomes and antivascular endothelial growth factor (anti-VEGF) treatment intensity in diabetic macular oedema (DMO).
Retrospective analysis was performed in ...treatment-naïve patients with DMO from 2013 to 2018 using a database of aggregated de-identified electronic medical records (Vestrum Health).
At 1 year, 28 658 patient eyes underwent a mean of 6.4 anti-VEGF injections, gaining a mean of +4.2 letters (95% confidence interval for mean gain: +4.0 to +4.5 letters, p<0.001). When stratified by anti-VEGF medication and by years 2013-2018, no clinically meaningful differences in injection frequency or 1-year VA change resulted. At 1 year, 50% of eyes received ≤6 injections, while <20% received 10-13 injections, representing monthly treatment. Mean letters gained at 1 year generally showed a linear relationship with mean number of anti-VEGF injections, beyond two injections. Eyes with good baseline VA (≥20/40) generally were at risk of VA loss at 1 year; those with moderately severe baseline impairment (20/70 to 20/200) who received ≥10 injections improved by a mean of +10.3 letters.
In clinical practice, patients with DMO undergo fewer anti-VEGF injections and exhibit worse visual gains compared with patients in randomised clinical trials. Visual outcomes correlate with treatment intensity at 1 year, with ceiling effects related to baseline VA.
IMPORTANCE: Voretigene neparvovec-rzyl, the first gene therapy approved by the US Food and Drug Administration, was approved for the treatment for RPE65-mediated inherited retinal disease (IRD) in ...December 2017. This gene therapy is associated with high up-front costs and high efficacy, although of unknown duration, and its cost-effectiveness has not been assessed with RPE65 IRD-specific, longitudinal, patient-observation-level data. OBJECTIVE: To assess the incremental cost-effectiveness ratio (ICER) of voretigene neparvovec-rzyl compared with standard care for RPE65-mediated inherited retinal disease. DESIGN, SETTING, AND PARTICIPANTS: In this economic analysis, a health state transition model based on visual acuity and field with a lifetime horizon was developed to estimate the cost-effectiveness of voretigene neparvovec-rzyl. The model was populated with data from a clinical trial of voretigene neparvovec-rzyl to evaluate treatment outcome and a natural history study of RPE65-mediated IRD to examine disease progression. Direct costs were derived from the literature. Indirect costs, including educational attainment, productivity, caregiver burden, and governmental programs, were estimated using published literature and data analysis of public national surveys. A health utility vignette study specific to RPE65-mediated IRD was used for health utility inputs. The cost-effectiveness study described in this article was conducted from September 15, 2017, to August 23, 2018. EXPOSURES: Bilateral voretigene neparvovec-rzyl therapy or standard care. MAIN OUTCOMES AND MEASURES: Incremental cost-effectiveness ratio. RESULTS: The model population included 70 patients with RPE65-mediated IRD, with a mean age of 15 years; 42 of 70 patients (60%) were female. In the base case, voretigene neparvovec-rzyl compared with standard care was associated with lower total costs ($2.2 million vs $2.8 million) and higher quality-adjusted life-years (18.1 vs 8.6). Voretigene neparvovec-rzyl remains cost-effective if at least 8.8% of the long-term treatment effect continues after year 3 when including indirect costs and 43.3% when excluding indirect costs, assuming a cost threshold of $150 000 per quality-adjusted life-year. CONCLUSIONS AND RELEVANCE: Results of this study suggest that voretigene neparvovec-rzyl is cost-effective compared with standard care when using a lifetime horizon, excluding indirect costs, and using a threshold of $150 000 per quality-adjusted life-year.
To determine the long-term effects of ranibizumab (RBZ) in patients with diabetic macular edema (DME).
Prospective, randomized, interventional, multicenter clinical trial.
One hundred twenty-six ...patients with DME.
Subjects were randomized 1:1:1 to receive 0.5 mg RBZ at baseline and months 1, 3, and 5 (group 1), focal or grid laser photocoagulation at baseline and month 3 if needed (group 2), or a combination of 0.5 mg RBZ and focal or grid laser at baseline and month 3 (group 3). Starting at month 6, if retreatment criteria were met, all subjects could be treated with RBZ.
The mean change from baseline in best-corrected visual acuity (BCVA) at month 24.
After the primary end point at month 6, most patients in all groups were treated only with RBZ, and the mean number of injections was 5.3, 4.4, and 2.9 during the 18-month follow-up period in groups 1, 2, and 3, respectively. For the 33 patients in group 1, 34 patients in group 2, and 34 patients in group 3 who remained in the study through 24 months, the mean improvement in BCVA was 7.4, 0.5, and 3.8 letters at the 6-month primary end point, compared with 7.7, 5.1, and 6.8 letters at month 24, and the percentage of patients who gained 3 lines or more of BCVA was 21, 0, and 6 at month 6, compared with 24, 18, and 26 at month 24. The percentage of patients with 20/40 or better Snellen equivalent at month 24 was 45% in group 1, 44% in group 2, and 35% in group 3. Mean foveal thickness (FTH), defined as center subfield thickness, at month 24 was 340 μm, 286 μm, and 258 μm for groups 1, 2, and 3, respectively, and the percentage of patients with center subfield thickness of 250 μm or less was 36%, 47%, and 68%, respectively.
Intraocular injections of RBZ provided benefit for patients with DME for at least 2 years, and when combined with focal or grid laser treatments, the amount of residual edema was reduced, as were the frequency of injections needed to control edema.
Proprietary or commercial disclosure may be found after the references.
Introduction: The Tie-2/Angiopoietin pathway is a therapeutic target for the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Activation of Tie-2 ...receptor via Ang-1 maintains vascular stability to limit exudation. Ang-2, a competitive antagonist to Ang-1, and VE-PTP, an endothelial-specific phosphatase, interfere with the Tie-2-Ang-1 axis, resulting in vascular leakage.
Areas covered: Faricimab, a bispecific antibody that inhibits VEGF-A and Ang-2, is in phase 3 trials for nAMD and DME. Nesvacumab is an Ang-2 inhibitor; when coformulated with aflibercept, it failed to show benefit over aflibercept monotherapy in achieving visual gains in phase 2 studies of nAMD and DME. ARP-1536 is an intravitreally administered VE-PTP inhibitor undergoing preclinical studies. AKB-9778 is a subcutaneously administered VE-PTP inhibitor that, when combined with monthly ranibizumab, reduced DME more effectively than ranibizumab monotherapy in a phase 2 study. AKB-9778 monotherapy did not reduce diabetic retinopathy severity score compared to placebo. AXT107, currently in the preclinical phase, promotes conversion of Ang-2 into a Tie-2 agonist and blocks signaling through VEGFR2 and other receptor tyrosine-kinases.
Expert opinion: Tie-2/Angiopoietin pathway modulators show promise to reduce treatment burden and improve visual outcomes in nAMD and DME, with potential to treat cases refractory to current treatment modalities.
Injection of pharmacotherapy into the suprachoroidal space, between the sclera and choroid, is an alternative delivery technique developed with the rationale of providing higher drug concentrations ...to posterior ocular structures compared with other intraocular and periocular injection procedures. This study was conducted to evaluate the safety and efficacy of suprachoroidally injected triamcinolone acetonide formulation (CLS-TA), a suspension of triamcinolone acetonide, in improving vision among patients with noninfectious uveitis complicated by macular edema (ME).
Phase 3 masked, randomized trial.
One hundred sixty patients with ME secondary to noninfectious uveitis. Patients were required to have a best-corrected visual acuity (BCVA) of 5 or more Early Treatment Diabetic Retinopathy Study (ETDRS) letters (Snellen equivalent, 20/800) and 70 or fewer ETDRS letters read (Snellen equivalent, 20/40) in the study eye.
Patients were randomized 3:2 to suprachoroidally injected CLS-TA or sham treatment, with administrations at day 0 and week 12.
The primary end point was improvement from baseline of 15 or more ETDRS letters in BCVA at week 24. The secondary end point was reduction from baseline in central subfield thickness (CST) at week 24.
In the CLS-TA arm, 47% of patients gained 15 or more ETDRS letters in BCVA versus 16% in the control arm (P < 0.001), meeting the primary end point. Mean reductions in CST from baseline were 153 μm versus 18 μm (P < 0.001). No serious adverse events (AEs) related to treatment were reported. Corticosteroid-associated AEs of elevated intraocular pressure occurred in 11.5% and 15.6% of the CLS-TA and control groups, respectively. Cataract AE rates were comparable (7.3% and 6.3%, respectively).
Patients in the CLS-TA study arm experienced clinically significant improvement in vision relative to the sham procedure, demonstrating the efficacy of suprachoroidal injection of CLS-TA for the treatment of ME in a vision-threatening disorder.
Glaucoma is a progressive optic neuropathy and a leading cause of irreversible blindness. The disease has conventionally been characterized by an elevated intraocular pressure (IOP); however, recent ...research has built the consensus that glaucoma is not only dependent on IOP but rather represents a multifactorial optic neuropathy. Although many risk factors have been identified ranging from demographics to co-morbidities to ocular structural predispositions, IOP is currently the only modifiable risk factor, most often treated by topical IOP-lowering medications. However, topical hypotensive regimens are prone to non-adherence and are largely inefficient, leading to disease progression in spite of treatment. As a result, several companies are developing sustained release (SR) drug delivery systems as alternatives to topical delivery to potentially overcome these barriers. Currently, Bimatoprost SR (Durysta
TM
) from Allergan plc is the only FDA-approved SR therapy for POAG. Other SR therapies under investigation include: bimatoprost ocular ring (Allergan) (ClinicalTrials.gov identifier: NCT01915940), iDose
®
(Glaukos Corporation) (NCT03519386), ENV515 (Envisia Therapeutics) (NCT02371746), OTX-TP (Ocular Therapeutix) (NCT02914509), OTX-TIC (Ocular Therapeutix) (NCT04060144), and latanoprost free acid SR (PolyActiva) (NCT04060758). Additionally, a wide variety of technologies for SR therapeutics are under investigation including ocular surface drug delivery systems such as contact lenses and nanotechnology. While challenges remain for SR drug delivery technology in POAG management, this technology may shift treatment paradigms and dramatically improve outcomes.
Introduction: Dry age-related macular degeneration (AMD) and Stargardt Macular Dystrophy (STGD1) result in vision loss due to progressive atrophy of the macula and lack of effective treatments. ...Numerous studies have implicated complement-associated inflammation as a contributor to both diseases.
Areas covered: The complement factor D inhibitor, lampalizumab, failed to halt geographic atrophy (GA) progression in phase 3 studies. The complement factor 3 (C3) inhibitor, APL-2, has shown potential to reduce GA growth in a phase 2 trial, supporting advancement to phase 3 trials. The intravenous complement factor 5 (C5) inhibitor, eculizumab, failed to halt GA progression in a phase 2 study. Another C5 inhibitor, avacincaptad pegol, is delivered by intravitreal injection, and will be studied for safety and preliminary signs of efficacy for AMD and STGD1 patients in phase 2 trials. LFG316 (C5 inhibitor) and CLG561 (properdin inhibitor) failed to halt GA progression in phase 2 studies. A phase 1 trial is evaluating the effects of combining LFG316 and CL561. Complement inhibition by gene therapy will be explored in the phase 1 trial of HMR59 in AMD patients.
Expert opinion: While complement inhibition has not yet demonstrated the ability to halt GA progression in a phase 3 trial, further study is warranted.
Introduction: The eye is a target for investigational gene therapy due to the monogenic nature of many inherited retinal and optic nerve degenerations (IRD), its accessibility, tight blood-ocular ...barrier, the ability to non-invasively monitor for functional and anatomic outcomes, as well as its relative immune privileged state.Vectors currently used in IRD clinical trials include adeno-associated virus (AAV), small single-stranded DNA viruses, and lentivirus, RNA viruses of the retrovirus family. Both can transduce non-dividing cells, but AAV are non-integrating, while lentivirus integrate into the host cell genome, and have a larger transgene capacity.
Areas covered: This review covers Leber's congenital amaurosis, choroideremia, retinitis pigmentosa, Usher syndrome, Stargardt disease, Leber's hereditary optic neuropathy, Achromatopsia, and X-linked retinoschisis.
Expert opinion: Despite great potential, gene therapy for IRD raises many questions, including the potential for less invasive intravitreal versus subretinal delivery, efficacy, safety, and longevity of response, as well as acceptance of novel study endpoints by regulatory bodies, patients, clinicians, and payers. Also, ultimate adoption of gene therapy for IRD will require widespread genetic screening to identify and diagnose patients based on genotype instead of phenotype.
INTRODUCTIONWith the recent FDA approvals of pegcetacoplan (SYFOVRE, Apellis Pharmaceuticals) and avacincaptad pegol (IZERVAY, Astellas Pharmaceuticals), modulation of the complement system has ...emerged as a promising therapeutic approach for slowing progression of geographic atrophy (GA) in AMD.AREAS COVEREDThis article reviews the current understanding of the complement system, its role in AMD, and the various complement-targeting therapies in development for the treatment of GA, including monoclonal antibodies, aptamers, protein analogs, and gene therapies. Approved and investigational agents have largely focused on interfering with the activity of complement components 3 and 5, owing to their central roles in the classical, lectin, and alternative complement pathways. Other investigational therapies have targeted formation of membrane attack complex (a terminal step in the complement cascade which leads to cell lysis), complement factors H and I (which serve regulatory functions in the alternative pathway), complement factors B and D (within the alternative pathway), and complement component 1 (within the classical pathway). Clinical trials investigating these agents are summarized, and the potential benefits and limitations of these therapies are discussed.EXPERT OPINIONTargeting the complement system is a promising therapeutic approach for slowing the progression of GA in AMD, potentially improving visual outcomes. However, increased risk of exudative conversion must be considered, and further research is required to identify clinical criteria and best practices for initiating complement inhibitor therapy for GA.
The acute and chronic effects of repeated intravitreal antivascular endothelial growth factor (VEGF) injections on intraocular pressure have not been fully characterized, and the development of ...sustained ocular hypertension could adversely affect patients who are at risk of glaucomatous optic neuropathy. As expected, volume-driven, acute ocular hypertension immediately follows intravitreal injection, but this pressure elevation is generally transient and well tolerated. Several medications have been investigated to limit acute ocular hypertension following anti-VEGF therapy, but the benefits of pretreatment are not conclusive. Chronic, sustained ocular hypertension, distinct from the short-term acute ocular hypertension after each injection, has also been associated with repeated intravitreal anti-VEGF injections. Risk factors for chronic ocular hypertension include the total number of injections, a greater frequency of injection, and preexisting glaucoma. Proposed mechanisms for chronic ocular hypertension include microparticle obstruction, toxic or inflammatory effects on trabecular meshwork, as well as alterations in outflow facility by anti-VEGF agents. Although limiting anti-VEGF therapy could minimize the risk of both acute and chronic ocular hypertension, foregoing anti-VEGF therapy risks progression of various macular diseases with resulting permanent central vision loss. While definitive evidence of damage to the retinal nerve fiber layer is lacking, patients receiving repeated injections should be monitored for ocular hypertension and patients in whom sustained ocular hypertension subsequently developed should be periodically monitored for glaucomatous changes with optic nerve optical coherence tomography and static visual fields.
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