A Study Of The Response to Treatment After Transition to The Port Delivery System With Ranibizumab [Susvimo (Ranibizumab Injection)] In Patients With Neovascular Age-Related Macular Degeneration Previously Treated With Intravitreal Agents Other Than Ranibizumab

Study Overview
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Brief Summary
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Study ML43000 is a Phase IV multicenter, open-label (BCVA assessor-masked) study designed to assess the response to treatment with SUSVIMO Q24W in patients with nAMD who have been previously treated with anti-VEGF agents other than ranibizumab. The substudy will evaluate the impact on corneal endothelial cells with SUSVIMO refilled every 24 weeks (Q24W) in patients with neovascular age-related macular degeneration (nAMD).

Official Title
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A Phase IV, Multicenter, Open-Label, Single-Arm Study Of The Response to Treatment After Transition to The Port Delivery System With Ranibizumab [Susvimo (Ranibizumab Injection)] In Patients With Neovascular Age-Related Macular Degeneration Previously Treated With Intravitreal Agents Other Than Ranibizumab

Conditions
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Neovascular Age-related Macular Degeneration

Intervention / Treatment
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* Device: SUSVIMO (ranibizumab injection)
* Drug: LUCENTIS (ranibizumab injection)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Ocular Inclusion Criteria Initial diagnosis of nAMD within 6 to 18 months prior to screening Previous treatment with at least 3 anti-VEGF injections other than ranibizumab for nAMD per standard of care within 9 months prior to Day 1 (SUSVIMO implantation); the most recent anti-VEGF injection must have occurred within 12 weeks of PDS implantation. The last 2 anti-VEGF injections for nAMD prior to screening must be with either bevacizumab or aflibercept Availability of historical visual acuity data and SD-OCT imaging prior to the first anti-VEGF IVT treatment for nAMD Availability of comprehensive historical anti-VEGF injection data including anti-VEGF agent administered and date of administration from the first anti-VEGF treatment for nAMD Demonstrated response to prior anti-VEGF intravitreal treatment since diagnosis BCVA of 34 letters (approximate 20/200 Snellen equivalent) or better, using ETDRS chart at a starting distance of 4 meters at screening and enrollment All subtypes of nAMD lesions are permissible nAMD lesions at the time of diagnosis must involve the macula (6 mm diameter centered at the fovea) Sufficiently clear ocular media and adequate pupillary dilation to allow for clinical examination and analysis and grading by the central reading center of SD-OCT images Substudy Inclusion Criteria General Inclusion Criteria General inclusion criteria for this substudy are consistent with the inclusion criteria of the parent study ML43000. In addition, a signed Informed Consent for this substudy is required for participation. Exclusion Criteria Prior Ocular Treatment Study Eye Prior vitrectomy surgery, submacular surgery, or other surgical intervention for AMD Prior pars plana vitrectomy surgery Prior treatment with ranibizumab Prior treatment with verteporfin for injection, external-beam radiation therapy, or transpupillary thermotherapy Previous treatment with corticosteroid intravitreal injection Previous intraocular device implantation excluding intraocular lenses Previous laser (any type) used for AMD treatment History of vitreous hemorrhage History of rhegmatogenous retinal detachment History of glaucoma-filtering surgery, tube shunts, or microinvasive glaucoma surgery History of corneal transplant History of conjunctival surgery in the superotemporal quadrant Prior participation in a clinical trial involving any intravitreal anti-VEGF agents Fellow (Non-Study) Eye • Previous PDS implantation Either Eye Previous intraocular surgery (including cataract surgery) within 6 months of study enrollment Prior treatment with brolucizumab Prior treatment with any anti-VEGF biosimilar agents Prior treatment with external-beam radiation therapy or brachytherapy MNV (CNV) Lesion Characteristics Study Eye Subretinal hemorrhage that involves the center of the fovea, if the hemorrhage is greater than 0.5-disc area (1.27 mm2) in size at screening Subfoveal fibrosis or subfoveal atrophy Either Eye MNV due to other causes, such as ocular histoplasmosis, trauma, or pathologic myopia MNV masquerading lesions (e.g., cone dystrophy, adult vitelliform dystrophy, pattern dystrophy) Concurrent Ocular Conditions Study Eye Retinal pigment epithelial tear Any concurrent intraocular condition (e.g., cataract, glaucoma, diabetic retinopathy, or epiretinal membrane) that would either require surgical intervention during the study to prevent or treat visual loss that might result from that condition or affect interpretation of study results Retinal tears or peripheral retinal breaks on depressed fundus exam that are untreated, or treated within the 3 months prior to study enrollment Aphakia or absence of the posterior capsule Previous violation of the posterior capsule is also an exclusion criterion unless it occurred as a result of yttrium-aluminum garnet (YAG) laser posterior capsulotomy in association with prior, posterior chamber intraocular lens implantation Spherical equivalent of the refractive error demonstrating more than 8 diopters of myopia or evidence of pathologic myopia on depressed fundus exam Preoperative refractive error that exceeds 8 diopters of myopia, for patients who have undergone prior refractive or cataract surgery Spherical equivalent of the refractive error demonstrating more than 5 diopters of hyperopia Preoperative refractive error that exceeds 5 diopters of hyperopia, for patients who have undergone prior refractive or cataract surgery Uncontrolled ocular hypertension or glaucoma Scleral pathology in the superotemporal quadrant (e.g., scleral thinning or calcification) Conjunctival pathologies in the superotemporal quadrant History or presence of severe posterior blepharitis, recurrent chalazia or hordeolum, severe dry eye syndrome, or severe allergic conjunctivitis Ectropion, entropion or other impairment of the upper or lower eyelid impacting lid functionality needed to protect the ocular surface from exposure Trichiasis Corneal neuropathy Lagophthalmos or incomplete blink Active or history of facial nerve palsy/paresis Fellow (Non-Study) Eye Concurrent intraocular condition that would require surgical intervention during the study (e.g., cataract, glaucoma surgery) Concurrent PDS implantation Either Eye Any active or history of uveitis (e.g., idiopathic, drug-associated or autoimmuneassociated) Active or history of keratitis, scleritis, or endophthalmitis Active ocular or periocular infection (i.e. conjunctivitis, dacryocystitis etc.) Active or history of Sjogrens syndrome or keratoconjunctivitis sicca Active or history of floppy eyelid syndrome Active or history of chronic eye rubbing Active thyroid eye disease Concurrent Systemic Conditions Uncontrolled blood pressure Active or history of autoimmune diseases such as rheumatoid arthritis, lupus, granulomatosis with polyangiitis (Wegner's), etc. History of stroke within the last 3 months prior to screening Uncontrolled atrial fibrillation within 3 months of screening History of myocardial infarction within the last 3 months prior to screening History of other disease, metabolic dysfunction, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of ranibizumab or placement of the implant and that might affect interpretation of the results of the study or renders the patient at high risk of treatment complications, in the opinion of the investigator Current active systemic infection Use of any systemic anti-VEGF agents Chronic use of oral corticosteroids Active cancer within 12 months of enrollment except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, and prostate cancer with a Gleason score of ≤ 6 and a stable prostate-specific antigen for > 12 months Previous participation in any non-ocular (systemic) disease studies of investigational drugs within 1 month prior to screening (excluding vitamins and minerals) Use of antimitotic or antimetabolite therapy within 30 days or 5 elimination half-lives of the screening visit Pregnant or breastfeeding, or intention to become pregnant during the study Women of childbearing potential, must have a negative urine pregnancy test result within 28 days prior to initiation of study treatment. If the urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. Substudy Exclusion Criteria Exclusion criteria for this substudy are consistent with the exclusion criteria of the parent Study ML43000 Fellow (Non-Study) Eye Prior vitrectomy surgery, submacular surgery, or other surgical intervention for AMD Prior pars plana vitrectomy surgery Previous intraocular device implantation excluding intraocular lenses History of glaucoma-filtering surgery, tube shunts, or microinvasive glaucoma surgery Prior participation in a clinical trial involving any intravitreal anti-VEGF agents Either Eye Intraocular laser therapy including selective laser trabeculoplasty, yttrium-aluminum garnet (YAG), prophylactic peripheral iridotomy within 1 year of screening, or YAG capsulotomy within 3 months of screening Contact lens wear in either eye within 2 months of screening Any prior ocular trauma (blunt or penetrating) History of corneal transplantation, including partial-thickness corneal grafts (e.g., Descemet membrane endothelial keratoplasty, Descemet stripping endothelial keratoplasty) Concurrent Ocular Conditions Fellow Eye • Aphakia or absence of the posterior pole Either Eye Corneal ECD < 1500 cells/mm2 in either eye at screening as determined by the independent reading center Fuchs endothelial corneal dystrophy Grade ≥ 2 Previous corneal endothelial cell damage, including from blunt or surgical trauma (including complicated cataract surgery resulting in complicated lens placement such as anterior chamber intraocular lens, sulcus intraocular lens, aphakia, etc.) Any ocular condition that precludes obtaining an analyzable specular microscopy image Active or history of corneal edema Active or history of corneal dystrophies Active or history of iridocorneal endothelial syndrome Active or history of pseudoexfoliation syndrome Active or history of herpetic keratitis or kerato-uveitis (including herpes simplex virus and herpes zoster virus)

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SUSVIMO<br>Participants will have the implant (filled prior to implantation with approximately 20 uL of the 100-mg/mL formulation of ranibizumab [approximately 2-mg dose of ranibizumab]) surgically inserted in the study eye at the Day 1 visit following their enrollment visit. After the initial fill of the implant with ranibizumab, patients will receive implant refill-exchanges at fixed 24-week intervals. | Device: SUSVIMO (ranibizumab injection)<br>* The ranibizumab 100 mg/mL will be administered to participants via the SUSVIMO Ocular Implant (IMP)<br>Drug: LUCENTIS (ranibizumab injection)<br>* Ranibizumab (intravitreal 0.5-mg injections of 10 mg/mL formulation) will be used in the study eye as supplemental treatment. If a study patient discontinues study treatment, he/she may start receiving intravitreal ranibizumab injections in the study eye, per investigator's discretion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change from baseline in Best Corrected Visual Acuity (BCVA) letter score at Week 40, as assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart at a starting distance of 4 meters | PDS 100 mg/mL Q24W in nAMD particpants previously treated with intravitreal anti-VEGF agents other than ranibizumab | Baseline up to Week 40 | 
| Substudy: Change in corneal endothelial cell density (ECD) from baseline at Week 48 in the study eye as compared with the fellow eye, as assessed by specular microscopy |  | Baseline up to Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change from baseline in BCVA letter score at Week 40, as assessed using the ETDRS visual acuity chart at a starting distance of 4 meters | PDS 100 mg/mL Q24W in participants with nAMD by subgroup as defined by the last two consecutive anti-VEGF agent administered to the study eye prior to Day 1, aflibercept or bevacizumab | Baseline up to Week 40 | 
| Percentage of participants with BCVA score of 69 letters (approximate 20/40 Snellen equivalent) or better at each scheduled visit over time to Week 52 |  | Baseline up to Week 52 | 
| Percentage of participants who lose < 15, < 10, < 5, or gain ≥ 0, > 0, ≥ 5, ≥ 10, or ≥15 letters in BCVA score from enrollment at each scheduled visit over time to Week 52 |  | Baseline up to Week 52 | 
| Annualized rate of ranibizumab treatments during the study compared with annualized rate of intravitreal anti-VEGF treatments prior to screening |  | Baseline up to approximately 12 months | 
| Mean change in center point thickness (CPT) from baseline on spectral-domain optical coherence tomography (SD-OCT) at each scheduled visit over time to Week 52 |  | Baseline up to Week 52 | 
| Percentage of participants who do not require supplemental treatment with intravitreal LUCENTIS (ranibizumab injection) 0.5 mg prior to protocol-specified refill-exchanges |  | Day 1 to Week 48 | 
| Percentage of participants with and without subretinal (SRF) and/or intraretinal fluid (IRF) on SD-OCT at enrollment and over study duration |  | Baseline up to approximately Week 52 | 
| Percentage of participants with ocular serious adverse events (SAEs) |  | Day 1 up to approximately Week 52 | 
| Percentage of participants with ocular adverse events of special interest (AESIs) |  | Day 1 to Week 52 | 
| Percentage of participants with adverse device effects (ADEs) in the course of the study |  | Day 1 to Week 52 | 
| Percentage of participants with ocular AESIs during the postoperative period |  | Baseline up to 37 days of initial implantation | 
| Percentage of participants with ocular AESIs during the intermediate postoperative period |  | 38 to 93 days after implantation | 
| Percentage of participants with ocular AESIs during the follow-up period | The investigator will follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent. | Week 52 | 
| Change in corneal ECD from baseline at Week 24 in the study eye as compared with the fellow eye |  | Baseline up to Week 24 | 
| Change in the coefficient of variation (CV) of corneal endothelial cell area (standard deviation of the cell area/mean cell area) from baseline at Weeks 24 and 48 in the study eye as compared with the fellow eye |  | Baseline, Week 24, Week 48 | 
| Change in percentage of hexagonal endothelial cells |  | Baseline, Week 24, Week 48 |