Neovascular Age-related Macular Degeneration
Conditions
Keywords
Macular Degeneration, Retinal Degeneration, Retinal Diseases, Eye Diseases
Brief summary
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).
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.
Interventions
Sponsors
Alkahest, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Per the Early Treatment Diabetic Retinopathy Study (ETDRS) Testing Method | Baseline to Week 36 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to PRN Injection (Arms 1 and 2 Only) | Baseline to Week 36 | Time to first use of intravitreal aflibercept injection, as needed (AKST4290 Arms only). UNITS: weeks. |
| Median Number of Aflibercept Injections Received Beginning at Week 12 | Week 12 to Week 36 | Median number of injections received beginning at Week 12 as a rate. UNITS: number of injections per week from Week 12 |
| Mean Change in Central Subfield Thickness (CST) Compared With Control Through Week 12 | Baseline to Week 12 | Mean change in Central Subfield Thickness (CST) compared with control through Week 12. UNITS: micrometre |
| Percentage of Subjects With Best Corrected Visual Acuity (BCVA) Change of ≥ 15 Letters | Baseline to Week 36 | Percentage of subjects with Best Corrected Visual Acuity (BCVA) change of ≥ 15 letters at Week 36. |
| Mean Change in Best Corrected Visual Acuity (BCVA) Per the Early Treatment Diabetic Retinopathy Study (ETDRS) Testing Method as Compared With Control | Week 12 to Week 36 | 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. |
| Time to the First Visit Where PRN Injection Criteria Are Met | Week 12 to the first visit meeting PRN injection criteria through week 36 | 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 |
| Number of Participants With Adverse Events Assessed by Intensity | Screening to Week 40 | Number of Participants with Adverse Events categorized by intensity |
Countries
Germany, Hungary, Poland, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AKST4290 (800 mg) + Aflibercept Subjects will receive 400 mg AKST4290 twice daily for 36 weeks, in combination with intravitreal aflibercept injection treatment
AKST4290: Oral AKST4290
Aflibercept: Aflibercept intravitreal injection | 36 |
| AKST4290 (1600 mg) + Aflibercept Subjects will receive 800 mg AKST4290 twice daily for 36 weeks, in combination with intravitreal aflibercept injection treatment
AKST4290: Oral AKST4290
Aflibercept: Aflibercept intravitreal injection | 35 |
| Placebo + Aflibercept Subjects will receive placebo for 36 weeks, in combination with intravitreal aflibercept injection treatment
Placebo: Oral placebo
Aflibercept: Aflibercept intravitreal injection | 36 |
| Total | 107 |
Baseline characteristics
| Characteristic | AKST4290 (800 mg) + Aflibercept | AKST4290 (1600 mg) + Aflibercept | Placebo + Aflibercept | Total |
|---|---|---|---|---|
| Age, Continuous | 76.4 years STANDARD_DEVIATION 8.84 | 74.7 years STANDARD_DEVIATION 7.42 | 73.8 years STANDARD_DEVIATION 9.34 | 75.0 years STANDARD_DEVIATION 8.57 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 35 Participants | 35 Participants | 35 Participants | 105 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 36 Participants | 35 Participants | 35 Participants | 106 Participants |
| Region of Enrollment Hungary | 5 participants | 4 participants | 4 participants | 13 participants |
| Region of Enrollment Poland | 29 participants | 28 participants | 30 participants | 87 participants |
| Region of Enrollment United States | 2 participants | 3 participants | 2 participants | 7 participants |
| Sex: Female, Male Female | 22 Participants | 25 Participants | 21 Participants | 68 Participants |
| Sex: Female, Male Male | 14 Participants | 10 Participants | 15 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 36 | 1 / 35 | 0 / 36 |
| other Total, other adverse events | 26 / 36 | 26 / 35 | 20 / 36 |
| serious Total, serious adverse events | 3 / 36 | 3 / 35 | 0 / 36 |
Outcome results
Primary
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.
Time frame: Baseline to Week 36
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AKST4290 (800 mg) + Aflibercept | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Per the Early Treatment Diabetic Retinopathy Study (ETDRS) Testing Method | 10.4 score on a scale | Standard Deviation 10.26 |
| AKST4290 (1600 mg) + Aflibercept | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Per the Early Treatment Diabetic Retinopathy Study (ETDRS) Testing Method | 6.7 score on a scale | Standard Deviation 7.89 |
| Placebo + Aflibercept | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Per the Early Treatment Diabetic Retinopathy Study (ETDRS) Testing Method | 13.7 score on a scale | Standard Deviation 7.6 |
Secondary
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.
Time frame: Week 12 to Week 36
Population: Reported data follows the pre-specified analyses and tables generated per the Statistical Analysis Plan for additional analyses of the primary endpoint. Change from Week 12 in BCVA ETDRS letters read is reported for the AKST4290 combined group and Placebo and will include a similar REML-based MMRM analysis as described for the primary endpoint; a covariate of letters read at Week 12 will be included in lieu of baseline letters read.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AKST4290 (800 mg) + Aflibercept | Mean Change in Best Corrected Visual Acuity (BCVA) Per the Early Treatment Diabetic Retinopathy Study (ETDRS) Testing Method as Compared With Control | 1.1 score on a scale | Standard Deviation 5.98 |
| AKST4290 (1600 mg) + Aflibercept | Mean Change in Best Corrected Visual Acuity (BCVA) Per the Early Treatment Diabetic Retinopathy Study (ETDRS) Testing Method as Compared With Control | 2.3 score on a scale | Standard Deviation 5.35 |
Secondary
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
Time frame: Baseline to Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AKST4290 (800 mg) + Aflibercept | Mean Change in Central Subfield Thickness (CST) Compared With Control Through Week 12 | -135.3 micrometre | Standard Deviation 122.66 |
| AKST4290 (1600 mg) + Aflibercept | Mean Change in Central Subfield Thickness (CST) Compared With Control Through Week 12 | -162.7 micrometre | Standard Deviation 118.91 |
| Placebo + Aflibercept | Mean Change in Central Subfield Thickness (CST) Compared With Control Through Week 12 | -159.5 micrometre | Standard Deviation 128 |
Secondary
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
Time frame: Week 12 to Week 36
Population: The number of injections received per week is defined as the number of IAIs received on or after Week 12 (PRN or scheduled injections) divided by (the analysis Week visit date \[or EOS date if subject terminates study early\] minus date of Week 12 visit plus one, divided by seven). Data reported reflects subjects with available data for those having received injections from week 12.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AKST4290 (800 mg) + Aflibercept | Median Number of Aflibercept Injections Received Beginning at Week 12 | 0.082 number of injections per week |
| AKST4290 (1600 mg) + Aflibercept | Median Number of Aflibercept Injections Received Beginning at Week 12 | 0.083 number of injections per week |
| Placebo + Aflibercept | Median Number of Aflibercept Injections Received Beginning at Week 12 | 0.125 number of injections per week |
Secondary
Number of Participants With Adverse Events Assessed by Intensity
Number of Participants with Adverse Events categorized by intensity
Time frame: Screening to Week 40
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AKST4290 (800 mg) + Aflibercept | Number of Participants With Adverse Events Assessed by Intensity | Severe TEAE | 3 Participants |
| AKST4290 (800 mg) + Aflibercept | Number of Participants With Adverse Events Assessed by Intensity | Mild TEAE | 15 Participants |
| AKST4290 (800 mg) + Aflibercept | Number of Participants With Adverse Events Assessed by Intensity | No TEAE | 10 Participants |
| AKST4290 (800 mg) + Aflibercept | Number of Participants With Adverse Events Assessed by Intensity | Moderate TEAE | 8 Participants |
| AKST4290 (1600 mg) + Aflibercept | Number of Participants With Adverse Events Assessed by Intensity | Severe TEAE | 9 Participants |
| AKST4290 (1600 mg) + Aflibercept | Number of Participants With Adverse Events Assessed by Intensity | Moderate TEAE | 7 Participants |
| AKST4290 (1600 mg) + Aflibercept | Number of Participants With Adverse Events Assessed by Intensity | No TEAE | 9 Participants |
| AKST4290 (1600 mg) + Aflibercept | Number of Participants With Adverse Events Assessed by Intensity | Mild TEAE | 10 Participants |
| Placebo + Aflibercept | Number of Participants With Adverse Events Assessed by Intensity | No TEAE | 16 Participants |
| Placebo + Aflibercept | Number of Participants With Adverse Events Assessed by Intensity | Mild TEAE | 11 Participants |
| Placebo + Aflibercept | Number of Participants With Adverse Events Assessed by Intensity | Moderate TEAE | 8 Participants |
| Placebo + Aflibercept | Number of Participants With Adverse Events Assessed by Intensity | Severe TEAE | 1 Participants |
Secondary
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.
Time frame: Baseline to Week 36
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AKST4290 (800 mg) + Aflibercept | Percentage of Subjects With Best Corrected Visual Acuity (BCVA) Change of ≥ 15 Letters | 30.6 percentage of participants |
| AKST4290 (1600 mg) + Aflibercept | Percentage of Subjects With Best Corrected Visual Acuity (BCVA) Change of ≥ 15 Letters | 14.3 percentage of participants |
| Placebo + Aflibercept | Percentage of Subjects With Best Corrected Visual Acuity (BCVA) Change of ≥ 15 Letters | 41.7 percentage of participants |
Secondary
Time to PRN Injection (Arms 1 and 2 Only)
Time to first use of intravitreal aflibercept injection, as needed (AKST4290 Arms only). UNITS: weeks.
Time frame: Baseline to Week 36
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AKST4290 (800 mg) + Aflibercept | Time to PRN Injection (Arms 1 and 2 Only) | 20.6 weeks |
| AKST4290 (1600 mg) + Aflibercept | Time to PRN Injection (Arms 1 and 2 Only) | 20.1 weeks |
Secondary
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
Time frame: Week 12 to the first visit meeting PRN injection criteria through week 36
Population: Data reflects subjects having received injections from week 12. Subjects who do not experience the event of interest (i.e., receive a PRN injection, meet the criteria for PRN IAI) while on the study were censored at their last visit completed through Week 36, as applicable.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AKST4290 (800 mg) + Aflibercept | Time to the First Visit Where PRN Injection Criteria Are Met | 20.6 weeks |
| AKST4290 (1600 mg) + Aflibercept | Time to the First Visit Where PRN Injection Criteria Are Met | 20.1 weeks |
| Placebo + Aflibercept | Time to the First Visit Where PRN Injection Criteria Are Met | 20.4 weeks |