Study to Investigate the Efficacy, Safety and Durability of Faricimab in Caucasian Patients With Polypoidal Choroidal Vasculopathy (MONDEGO)

A Phase IV, Multicentre, Open-label, Single-arm Study to Investigate the Efficacy, Safety and Durability of Faricimab (RO6867461) in Caucasian Patients With Polypoidal Choroidal Vasculopathy

The goal of this clinical trial is to assess the efficacy, safety and durability of faricimab in caucasian patients with polypoidal choroidal vasculopathy (PCV). The main question it aims to answer is:

To evaluate the efficacy of intravitreal (IVT) injections of faricimab 6 milligrams (mg) on Best Corrected Visual Acuity (BCVA) outcomes in caucasian patients with symptomatic macular PCV.

Participants will undergo ophthalmic examination, safety assessment and treatment with faricimab according to a patient specific treat and extend regimen.

Polypoidal choroidal vasculopathy (PCV) was first described in 1982 by Yannuzzi as a choroidal vasculopathy leading to haemorrhagic and exudative macular degeneration. More than four decades later, the pathogenesis of the disease remains uncertain with authors considering PCV a subtype of neovascular age-related macular degeneration (nAMD) while others advocate a separate clinical entity and adequate treatment is still an unmet need.

Several studies have reported an association between PCV and major and minor interethnic classification differences regarding morphological alterations, prevalence, genetic associations, lesion location, and results after anti-vascular endothelial growth factor (VEGF) treatment, among others. For instance, the reported prevalence of PCV in patients with neovascular AMD ranges from 4% to 9,8% in Caucasians and from 22% to 55% in Asians. However, a recent study reported a much higher prevalence in Caucasians (22,1%), suggesting that PCV may actually be underdiagnosed in this population.

Today, intravitreal (IVT) anti-VEGF therapy plays a key role in the management of PCV and has become the standard of care. The anti-permeability property of anti-VEGF agents, such as aflibercept and ranibizumab, play a role in reducing the exudation from abnormal choroidal vessels and polypoidal lesions, thereby decreasing the subretinal fluid and preserving vision.

Although the current standard of care has demonstrated clinical benefit for patients with PCV, many limitations exist in understanding the disease as a result of its heterogeneity in clinical features and treatment outcomes. The burden of frequent injections, incomplete polypoidal lesion closure, and the risk and unpredictability of lesion relapse reinforce the need to develop new treatments for patients with PCV. This population is at risk of disease relapse, retinal haemorrhage, and vision loss, and is appropriate for inclusion in this clinical trial.

Faricimab is a novel humanized bispecific Immunoglobulin G1 (IgG1) monoclonal antibody that selectively binds with high affinity to VEGF-A and angiopoietin-2 (Ang-2). Faricimab was studied for the treatment of neovascular AMD (nAMD) in the global Phase III Studies TENAYA (ClinicalTrials.gov identifier: NCT03823287) and LUCERNE (ClinicalTrials.gov identifier: NCT03823300) and is currently being studied in the long-term extension Study AVONELLE-X (ClinicalTrials.gov identifier: NCT04777201). The TENAYA (ClinicalTrials.gov identifier: NCT03823287) and LUCERNE (ClinicalTrials.gov identifier: NCT03823300) studies consistently showed that faricimab, given at intervals of up to 16 weeks, offered non-inferior vision gains compared with aflibercept, given every 2 months in the first year. Approximately 50% of participants eligible for extended dosing with faricimab were able to be treated every 4 months, and nearly 80% of participants every 3 months or longer. However, patients with symptomatic macular PCV were under-represented in the faricimab Phase III pivotal Studies TENAYA (ClinicalTrials.gov identifier: NCT03823287) and LUCERNE (ClinicalTrials.gov identifier: NCT03823300).

The purpose of this study is to assess the efficacy, durability, and safety of faricimab 6 mg IVT administered at up to 24-week intervals in the treatment-naive study eye of Caucasian patients with symptomatic macular PCV. This study will add to the evidence base for the benefit-risk profile of faricimab IVT injection in Caucasian patients with symptomatic macular PCV.

The study consists of a screening period of up to 28 days (Days -28 to -1) in length and an approximately 100-week study treatment period consisting of a Treatment Initiation period (Weeks 1-12) and the treat and extend (T&E) regimen period (Weeks 20-Week 100).

General Inclusion Criteria:

Potential participants are eligible to be included in the study only if all of the following criteria apply:

• Signed ICF
• Age ≥ 50 years at the time of signing the ICF
• Caucasian
• Participants who are able to comply with the study protocol, in the investigator's judgment
• For female participants of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception as defined below:

Female participants must remain abstinent or use contraceptive methods with a failure rate of < 1% per year, during the treatment period and for at least 3 months after the final dose of faricimab.

A female participant is considered to be of childbearing potential if she is post-menarche, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). Per this definition, a female participant with a tubal ligation is considered to be of childbearing potential. The definition of childbearing potential may be adapted for alignment with local guidelines or regulations.

Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.

The reliability of sexual abstinence should be evaluated concerning the duration of the clinical trial and the preferred and usual lifestyle of the individual.

Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not adequate methods of contraception.

If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local ICF.

Ocular Inclusion Criteria for study eye:

• Sufficiently clear ocular media and adequate pupillary dilatation to allow acquisition of good quality retinal images to confirm diagnosis

• Confirmed diagnosis, by the Reading Centre, of naïve symptomatic macular PCV defined by the following:

  • Active macular polypoidal lesions shown by ICGA AND
  • Presence of exudative or haemorrhagic features involving the macula as identified by the investigator using multimodal images.

• BCVA scores of 78-24 ETDRS letters, inclusive (20/32 to 20/320 approximate Snellen equivalent), using the ETDRS protocol and assessed at the initial testing distance of 4 meters [see the BCVA Standard Operational Procedures (SOP) for additional details] on study Day 1.

General Exclusion Criteria

Potential participants are excluded from the study if any of the following criteria apply:

• Treatment with investigational therapy (device, drug, or traditional medicine with the exception of vitamins and minerals) within 3 months prior to initiation of study treatment on study Day 1

• Any major illness or major surgical procedure within 1 month before screening

• Active cancer within the 12 months prior to study Day 1 except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, and prostate cancer with a Gleason score of ≤ 6 (Grade Group of 1) and a stable prostate-specific antigen for ≥ 12 months

• Continuous use of any medications and treatments indicated below:

  • Systemic anti-VEGF therapy
  • Systemic drugs known to cause macular oedema (fingolimod, tamoxifen)
  • Other experimental therapies (except those comprising vitamins and minerals) and therapies that claim to have an effect on macular pathology (e.g., kallidinogenase)

• Systemic treatment for suspected or active systemic infection on study Day 1

• Ongoing use of prophylactic antibiotic therapy may be acceptable after discussion with the Medical Monitor.

• Uncontrolled blood pressure, defined as systolic blood pressure > 180 mmHg and/or diastolic blood pressure > 100 mmHg while the participant is at rest on study Day 1

• History of stroke (cerebral vascular accident) or myocardial infarction within 6 months prior to study Day 1

• History of other diseases, metabolic dysfunction, physical examination finding, or historical or current clinical laboratory findings giving reasonable suspicion of a condition that contraindicates the use of the IMP or that might affect the interpretation of the results of the study or renders the participant at high risk for treatment complications in the opinion of the investigator

• History of severe allergic reaction or anaphylactic reaction to a biologic agent or known hypersensitivity to any component of the faricimab injection, study-related procedure preparations (including fluorescein and indocyanine green dyes), dilating drops, or any of the anaesthetic and antimicrobial preparations used by a participant during the study

• Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 28 days after the final dose of faricimab

Ocular Exclusion Criteria

Potential participants are excluded from the study if any of the following criteria apply to both eyes:

• History of idiopathic or autoimmune-associated uveitis in either eye
• Active ocular inflammation or suspected or active ocular or periocular infection in either eye on study Day 1

Participants who meet any of the following ocular criteria for the study eye will be excluded from study entry:

• Any history or presence of macular pathology unrelated to PCV affecting vision or contributing to the presence of macular haemorrhage, IRF, or SRF

• Retinal pigment epithelial tear involving the macula on study Day 1

• Diagnosis with or suspected of having narrow-angle glaucoma who have not undergone iridotomy. The inclusion of these patients will be conditional upon prior referral to the relevant specialist for appropriate treatment to enable participation in the study.

• On FFA/colour fundus photograph (CFP):

  • Subretinal haemorrhage of > 4 macular photocoagulation study disc area and/or that involves the fovea
  • Fibrosis or atrophy of > 50% of the total lesion area and/or that involves the fovea
  • Any concurrent intraocular condition (e.g., amblyopia, aphakia, retinal detachment, cataract, diabetic retinopathy or maculopathy, or epiretinal membrane with traction) that, in the opinion of the investigator, could either reduce the potential for visual improvement or require medical or surgical intervention during the study
  • Current vitreous haemorrhage on study Day 1
  • Advanced/or uncontrolled glaucoma
  • Spherical equivalent of refractive error demonstrating more than 8 dioptres of myopia

• Any prior or concomitant treatment for PCV or other retinal diseases, including, but not restricted to, IVT treatment (e.g., faricimab, anti-VEGF, steroids, tissue plasminogen activator, ocriplasmin, C3F8, air), periocular pharmacological intervention, argon laser photocoagulation, verteporfin PDT, diode laser, transpupillary thermotherapy, or ocular surgical intervention

• Any cataract surgery or treatment for complications of cataract surgery with steroids or yttrium-aluminum-garnet (YAG) laser capsulotomy within 3 months prior to study Day 1

• Any other intraocular surgery (e.g., pars plana vitrectomy, glaucoma surgery, corneal transplant, or radiotherapy)

• Prior periocular pharmacological or IVT treatment (including anti-VEGF medication) for other retinal diseases

• Continuous use of any medications and treatments indicated below:

  • IVT anti-VEGF agents (other than study-assigned faricimab)
  • IVT, periocular (subtenon), steroid implants (i.e., Ozurdex®, Illuvien®), or chronic topical ocular corticosteroids (defined as continuous usage for 100 days or longer)
  • Concurrent use of any macular photocoagulation or PDT with verteporfin Participants who have a non-functioning fellow (non-study) eye, defined as either BCVA of hand motion or worse, or no physical presence of non-study eye (i.e., monocular), at both the screening and study Day 1 visits will be excluded from study entry.