Phase 2 Double-Masked Placebo-Controlled Dose-Finding Study of Danicopan in Geographic Atrophy Secondary to Age-Related Macular Degeneration

The primary objective of this study is to evaluate the **efficacy**, safety, and pharmacokinetics of danicopan in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD). This is clinically relevant as GA is a progressive condition leading to vision loss, and understanding the impact of danicopan could offer a potential therapeutic option for managing this condition.

Secondary objectives include:

• Evaluating the effect of danicopan on disease progression using anatomical measures in the study eye.
• Assessing the effect of danicopan on disease progression using functional measures in the study eye.
• Evaluating the effect of danicopan on patient-reported outcomes (PROs) in patients with GA secondary to AMD.
• Assessing the pharmacokinetics (PK) and pharmacodynamics (PD) of danicopan in patients with GA secondary to AMD.
• Evaluating the safety and tolerability of danicopan in patients with GA secondary to AMD.

The clinical trial involves a total of **213 participants** diagnosed with **geographic atrophy (GA) secondary to age-related macular degeneration (AMD)**. The study population includes both male and female subjects aged 60 years and older. Participants were selected based on specific criteria, including the presence of GA secondary to AMD in at least one eye, with a visual acuity range of 84 to 24 letters (20/20 to 20/320) as measured by Early Treatment Diabetic Retinopathy Study charts. The total GA lesion area per eye must be between 0.5 to 17.76 mm², and if multifocal, at least one focal lesion must be ≥ 0.5 mm². The entire GA lesion must be more than 1 μm outside of the foveal center. The trial does not include a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted. The selection process ensures a representative sample of the target demographic, focusing on the efficacy, safety, and pharmacokinetics of danicopan in this patient group.

The clinical trial is a **Phase 2**, double-masked, placebo-controlled, dose range finding study designed to evaluate the efficacy, safety, and pharmacokinetics of **danicopan** in patients with **geographic atrophy** secondary to **age-related macular degeneration**. The trial employs a randomized, double-blind, controlled design to ensure unbiased results. The study is expected to last until August 2025, with participant involvement spanning up to 104 weeks from the initial screening visit.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (≥ 60 years), presence of geographic atrophy in at least one eye, and specific visual acuity requirements. Following successful screening, participants will be randomized to receive either the investigational product, ALXN 2040, or a placebo, both administered as film-coated tablets for oral use. The maximum daily dose of ALXN 2040 is 400 mg, with a total treatment period of up to 105 weeks.

Study visits will occur at regular intervals to monitor the primary endpoint, which is the change from baseline to Week 52 in the square root of the total geographic atrophy lesion area in the study eye, as measured by fundus autofluorescence. Secondary endpoints include changes in lesion area, visual acuity, and retinal integrity over 104 weeks, as well as the incidence of treatment-emergent adverse events. Follow-up visits will assess these parameters at Weeks 52 and 104, with additional assessments of pharmacokinetic and pharmacodynamic biomarkers.

The end-of-study visit will conclude the participant's involvement, with a comprehensive evaluation of all study parameters. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or if the study is terminated for any reason. The trial is conducted in accordance with regulatory guidelines to ensure the safety and well-being of all participants.

The clinical trial involves the administration of **danicopan**, an experimental medication identified by the product code ALXN 2040. Danicopan is a small molecule drug formulated as a **film-coated tablet**. The active substance, danicopan, is chemically synthesized and is also known by its synonyms ACH-0144471 and ACH-4471. The pharmaceutical form of the medication is designed for **oral use**. The maximum daily dose of danicopan is 400 mg, with a total maximum dose of 292,100 mg over a treatment period of 105 days. The study aims to evaluate the efficacy, safety, and pharmacokinetics of danicopan in patients with **geographic atrophy** secondary to **age-related macular degeneration**.

In addition to the experimental treatment, a **placebo** matching ALXN 2040 is utilized in the study. The placebo is designed to mimic the appearance of the danicopan film-coated tablet but does not contain any active pharmaceutical ingredients. The use of a placebo allows for a double-masked, placebo-controlled study design, which is essential for assessing the true efficacy and safety profile of the experimental medication. The placebo is administered in the same manner as the active treatment to maintain the integrity of the study's blinding process.

The efficacy of danicopan in patients with **Geographic Atrophy (GA)** secondary to Age-Related Macular Degeneration (AMD) will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline to week 52 in the square root of the total GA lesion area in the study eye, as measured by fundus autofluorescence (FAF). Secondary endpoints include changes from baseline to weeks 52 and 104 in the total GA lesion area, macular ellipsoid zone (EZ) and outer retinal integrity, and subretinal pigment epithelium (sub-RPE) compartment/drusen/RPE complex, all measured by spectral-domain optical coherence tomography (SD-OCT).

Additional secondary endpoints involve changes in monocular Best Corrected Visual Acuity (BCVA) and Low Luminance Visual Acuity (LLVA) scores, assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart, and changes in monocular reading speeds, evaluated by the Minnesota Low Vision Reading Test (MNRead) Acuity Charts or Radner Reading Chart. The study will also measure changes in the National Eye Institute Visual Function Questionnaire (NEI VFQ-25) scores. Pharmacokinetic parameters such as plasma concentration of danicopan and pharmacodynamic biomarkers, including ex vivo serum alternative pathway activity and plasma Bb concentration, will be monitored up to 4 hours postdose. The incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and ocular TEAEs and SAEs will be recorded throughout the study duration, from day 1 through week 104.