A Study to Assess the Efficacy and Safety of AKST4290 With Aflibercept in Patients With Newly Diagnosed nAMD (PHTHALO-205)

A Double-Masked, Placebo-Controlled, Dose Ranging Study to Evaluate the Efficacy of Oral AKST4290 With Loading Doses of Aflibercept in Patients With Newly Diagnosed Neovascular Age-Related Macular Degeneration

This study will evaluate the efficacy and safety of AKST4290 in combination with aflibercept injections in subjects with newly diagnosed neovascular age-related macular degeneration (nAMD).

Study Overview

• Status: Completed
• Conditions: Neovascular Age-related Macular Degeneration
• Intervention / Treatment: Drug: AKST4290; Drug: Placebo; Drug: Aflibercept

Detailed Description

This is a randomized, double-masked, placebo-controlled, dose-ranging, multicenter study to assess the efficacy and safety of AKST4290 administered orally at 400 mg b.i.d. or 800 mg b.i.d. in combination with intravitreal aflibercept injections (IAI), in subjects with newly diagnosed neovascular age-related macular degeneration (nAMD) who are naïve to treatment with anti-vascular endothelial growth factor (anti-VEGF) medications in the study eye. Subjects will be treated with AKST4290 800 mg daily, 1600 mg daily, or placebo for a total of 36 weeks.

• Study Type: Interventional
• Enrollment (Actual): 107
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Düsseldorf, Germany
    • Internationale Innovative Ophthalmochirurgie GbR
  • Kiel, Germany
    • nordBLICK Augenklinik Bellevue
  • Rheine, Germany
    • Augentagesklinik Rheine
• Hungary
  • Budapest, Hungary
    • Jahn Ferenc Dél-pesti Kórház (Jahn Ferenc South-Pest Hospital)
  • Budapest, Hungary
    • Magyar Honvédség Egészségügyi Központ, Szemészeti Osztály (Medical Centre, Hungarian Defence Forces, Ophthalmology Department)
  • Miskolc, Hungary
    • Borsod-Abaúj-Zemplén Megyei Kórház és Egyetemi Oktató Kórház (Borsod-Abaúj-Zemplén County Hospital and University Teaching Hospital)
  • Pécs, Hungary
    • Ganglion Orvosi Központ
  • Szekszárd, Hungary
    • Szegedi Tudományegyetem Általános Orvostudományi Kar, Szent-Györgyi Albert Klinikai Központ, Szemészeti Klinika, (University of Szeged Faculty of Medicine, Albert-Szent Gyorgyi Health Care, Department of Ophthalmology)
• Poland
  • Bialystok, Poland
    • Tęczówka (IRIS)
  • Bydgoszcz, Poland
    • Specjalistyczny Ośrodek Okulistyczny Oculomedica (Specialized Eye Center Oculomedica)
  • Częstochowa, Poland
    • PROVISUS Sp. z o.o.
  • Gdańsk, Poland
    • Optimum Profesorskie Centrum Okulistyki
  • Kraków, Poland
    • Centrum Medyczne Dietla 19 Sp zoo
  • Lublin, Poland
    • Klinika Chirurgii Siatkówki i Ciała Szklistego Medical University in Lublin
  • Poznań, Poland
    • Szpital Sw. Wojciecha
  • Suwałki, Poland
    • ArtOptica Salon Okulistyczno
  • Tarnów, Poland
    • Centrum Medyczne UNO-MED
  • Warsaw, Poland
    • Central Clinical Hospital of the MSWiA
• United States
  • California
    • Beverly Hills, California, United States, 90211
      • Retina-Vitreous Associates Medical Group
  • Florida
    • Saint Petersburg, Florida, United States, 33711
      • Retina Vitreous Associates of FL
  • Nevada
    • Reno, Nevada, United States, 89502
      • Sierra Eye Associates

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Men and women with newly diagnosed active Choroidal Neovascularization (CNV) secondary to Age-Related Macular Degeneration (AMD), diagnosed by a retinal specialist with all the following characteristics and ophthalmic inclusion criteria applied to the study eye, as assessed by a central reader:

  • Has been examined by a retinal specialist and found to be eligible to receive Intravitreal Aflibercept Injection (IAI) in the study eye.
  • No prior treatment for Neovascular Age-Related Macular Degeneration (nAMD) in the study eye.
  • Study eye has not undergone pars plana vitrectomy or glaucoma filtering surgery.
  • Participation in studies of investigational drugs must have been discontinued within 30 days or 5 half-lives of the drug (whichever was longer) prior to screening.
  • Central subfield thickness (CST) thickness ≥ 250 microns on SD-OCT (spectral domain OCT) (exclusive of subretinal pigment epithelial fluid, inclusive of SRF).
  • Presence of SRF (subretinal fluid) and/or IRF (intraretinal fluid) on SD-OCT.
  • Total lesion size not greater than 12 disc areas (30.48 mm2) (1 disc area = 2.54 mm2) on FA (fluorescein angiography).
  • If present, subretinal hemorrhage must comprise < 50% of the total lesion area on FA, SD-OCT, or FP/FAF (fundus photography/fundus autofluorescence).
  • No subfoveal fibrosis or atrophy on FA, SD-OCT, or FP/FAF.
  • Active CNV (choroidal neovascularization) membranes with subfoveal leakage or juxtafoveal leakage too close for laser photocoagulation.
• BCVA (Best Corrected Visual Acuity) in the study eye between 70 and 24 letters inclusive.
• Body mass index (BMI) between (and inclusive of) 18 and 40 at screening.

Key Exclusion Criteria:

• Participation in studies of investigational drugs within 30 days or 5 half-lives of the drug (whichever was longer) prior to screening.
• Known hypersensitivity to the active substance or any of the excipients of AKST4290 or aflibercept.
• Active or suspected ocular or periocular infection and/or active, severe intraocular inflammation.
• Any form of macular degeneration that is not age-related (e.g., Best's disease, Stargardt's disease, Sorsby's disease).
• Additional disease in the study eye that could compromise BCVA (i.e., uncontrolled glaucoma (IOP >24) with visual field loss, clinically significant diabetic macular edema, history of ischemic optic neuropathy or retinal vascular occlusion, vitreomacular traction, high myopia > 6 diopters, or genetic disorders such as retinitis pigmentosa).
• Presence of RPE (Retinal Pigment Epithelium) tears or rips in the study eye.
• Anterior segment and vitreous abnormalities in the study eye that would preclude adequate visualization with FP/FAF, FA, or SD-OCT.
• Intraocular surgery in the study eye within 3 months prior to screening.
• Aphakia or total absence of the posterior capsule (yttrium aluminum garnet [YAG] laser capsulotomy permitted in an eye with a posterior chamber intraocular lens if performed a minimum of 1 month prior to enrollment) in the study eye.
• Known allergy to fluorescein sodium.
• Significant alcohol or drug abuse within past 2 years.
• Based on ECG (electrocardiogram) reading, subjects with a risk of QT prolongation.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: AKST4290 (800 mg) + Aflibercept; Subjects will receive 400 mg AKST4290 twice daily for 36 weeks, in combination with intravitreal aflibercept injection treatment	Drug: AKST4290; Oral AKST4290; Drug: Aflibercept; Aflibercept intravitreal injection
EXPERIMENTAL: AKST4290 (1600 mg) + Aflibercept; Subjects will receive 800 mg AKST4290 twice daily for 36 weeks, in combination with intravitreal aflibercept injection treatment	Drug: AKST4290; Oral AKST4290; Drug: Aflibercept; Aflibercept intravitreal injection
PLACEBO_COMPARATOR: Placebo + Aflibercept; Subjects will receive placebo for 36 weeks, in combination with intravitreal aflibercept injection treatment	Drug: Placebo; Oral placebo; Drug: Aflibercept; Aflibercept intravitreal injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Per the Early Treatment Diabetic Retinopathy Study (ETDRS) Testing Method	Mean change from baseline in Best Corrected Visual Acuity (BCVA) per the Early Treatment Diabetic Retinopathy Study (ETDRS) testing method. BCVA will be assessed using ETDRS charts at 4 meters initial testing distance and assessed in both eyes. Score range is 0 to 93. A higher score indicates better vision.	Baseline to Week 36

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to PRN Injection (Arms 1 and 2 Only)	Time to first use of intravitreal aflibercept injection, as needed (AKST4290 Arms only). UNITS: weeks.	Baseline to Week 36
Median Number of Aflibercept Injections Received Beginning at Week 12	Median number of injections received beginning at Week 12 as a rate. UNITS: number of injections per week from Week 12	Week 12 to Week 36
Percentage of Subjects With Best Corrected Visual Acuity (BCVA) Change of ≥ 15 Letters	Percentage of subjects with Best Corrected Visual Acuity (BCVA) change of ≥ 15 letters at Week 36.	Baseline to Week 36
Mean Change in Central Subfield Thickness (CST) Compared With Control Through Week 12	Mean change in Central Subfield Thickness (CST) compared with control through Week 12. UNITS: micrometre	Baseline to Week 12
Number of Participants With Adverse Events Assessed by Intensity	Number of Participants with Adverse Events categorized by intensity	Screening to Week 40
Mean Change in Best Corrected Visual Acuity (BCVA) Per the Early Treatment Diabetic Retinopathy Study (ETDRS) Testing Method as Compared With Control	Mean change in Best Corrected Visual Acuity (BCVA) letter score per the Early Treatment Diabetic Retinopathy Study (ETDRS) testing method from Week 12 as compared to control at Week 36. BCVA will be assessed using ETDRS charts at 4 meters initial testing distance and assessed in both eyes. Score range is 0 to 93. A higher score indicates better vision.	Week 12 to Week 36
Time to the First Visit Where PRN Injection Criteria Are Met	Time to the first visit where PRN injection criteria are met starting at Week 12 will be calculated in weeks as the first date where PRN injection criteria are first met minus the date of first dose of study drug plus one, divided by seven. Subjects who do not experience the event of interest (meet the criteria for PRN IAI) while on the study will be censored at their last visit completed through Week 36. Units: weeks	Week 12 to the first visit meeting PRN injection criteria through week 36

Collaborators and Investigators

• Sponsor: Alkahest, Inc.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 28, 2020
• Primary Completion (ACTUAL): August 19, 2021
• Study Completion (ACTUAL): September 16, 2021

Study Registration Dates

• First Submitted: March 16, 2020
• First Submitted That Met QC Criteria: April 1, 2020
• First Posted (ACTUAL): April 2, 2020

Study Record Updates

• Last Update Posted (ACTUAL): October 26, 2022
• Last Update Submitted That Met QC Criteria: October 24, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Eye Diseases; Retinal Diseases; Macular Degeneration; Retinal Degeneration
• Additional Relevant MeSH Terms: Eye Diseases; Retinal Degeneration; Retinal Diseases; Macular Degeneration; Wet Macular Degeneration; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Aflibercept
• Other Study ID Numbers: AKST4290-205

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No