An Open-Label, Phase 1 Clinical Study to Evaluate the Safety and Tolerability of Subcutaneous Elamipretide in Subjects With Intermediate Age-Related Macular Degeneration

Study Overview
=================
Brief Summary
-----------------
This is an open-label, Phase 1 single-center study in approximately 40 subjects who have 1 eye with intermediate AMD, including a high-risk drusen without geographic atrophy (GA) subgroup and a noncentral GA subgroup. Eligible subjects will receive 40 mg of elamipretide administered as a once daily 1.0 mL subcutaneous injection for 12 weeks.

Official Title
-----------------
An Open-Label, Phase 1 Clinical Study to Evaluate the Safety and Tolerability of Subcutaneous Elamipretide in Subjects With Intermediate Age-Related Macular Degeneration

Conditions
-----------------
Age-Related Macular Degeneration

Intervention / Treatment
-----------------
* Drug: Elamipretide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: For this study, only 1 eye of an eligible subject will be included and designated as the study eye. However, all specified ophthalmic testing will be performed on both eyes at each time point. A potential subject must meet the following criteria to be eligible for inclusion in the study: Intermediate AMD - noncentral GA disease group: Adults ≥ 55 years of age with 1 eye with intermediate AMD - noncentral GA. No evidence of choroidal neovascularization (active or prior history) in the study eye. Geographic atrophy may be multifocal, but the cumulative GA lesion size must be: ≥ 1.27 mm2 (approximately ≥ 0.5 DA) and ≤ 10.16 mm2 (approximately ≤ 4 DA). Must reside completely within the FAF imaging field (field 2 to 30-degree image centered on the fovea). Presence of measurable hyperautofluorescence adjacent to the discrete foci of GA. OR Intermediate AMD - high-risk drusen without GA disease group: ≥ 55 years of age with one eye with intermediate AMD - high-risk drusen without GA. High-risk drusen is defined as presence of either at least 1 large (≥ 125 µm) druse or multiple medium-size (between 63 and 124 µm) drusen. General (both disease groups): Able to provide informed consent and willing to comply with all study visits and examinations. Women of childbearing potential who are not pregnant or nursing and have a negative serum pregnancy test at screening. Best-corrected visual acuity assessed by ETDRS letters ≥ 55 letters (Snellen equivalent ≥ 20/70). Low-luminance visual acuity deficit (defined as difference between BCVA and LL visual acuity) > 5 letters. Has at least two Low-Luminance Questionnaire sub scale results, in which one of the abnormal subscales is either general dim light vision or dim light reading. The fellow eye may have intermediate AMD without noncentral GA (i.e., high-risk drusen), intermediate AMD with noncentral GA, NV AMD, or central GA. Ongoing treatment with antiangiogenic therapies in the fellow eye is allowable. No evidence of visually significant cataract OR pseudophakia without evidence of posterior capsular opacity. Sufficiently clear ocular media, adequate pupillary dilation, fixation to permit quality fundus imaging, and able to cooperate sufficiently for adequate ophthalmic visual function testing and anatomic assessment. Able to administer SC study drug solution as demonstrated at screening or able to have a care provider or appropriate designee who can administer the study drug (i.e., a capable family member or home health nursing aide). If of childbearing potential or in a relationship with a partner of childbearing potential, are able to abstain from sex or use acceptable contraception during the study and for 3 months after dosing. For men: Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the subject. The subject also agrees to use an acceptable method of contraception should they become sexually active. Subjects must use a condom with spermicide from the date of informed consent until at least 3 months after the last dose of study drug. Periodic abstinence (e.g.calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. For women: abstinence is only acceptable when it is in line with the preferred and usual lifestyle of the subject. The subject agrees to use an acceptable method of contraception should they become sexually active. Maintenance of a monogamous relationship with a male partner who has been surgically sterilized by vasectomy (the vasectomy procedure must have been conducted at least 60 days before the Screening visit or confirmed via sperm analysis), barrier method (e.g., condom or occlusive cap) with spermicidal foam/gel/film/cream AND either hormonal contraception (oral, implanted, or injectable) or an intrauterine device or system are acceptable methods. Ability and willingness to undertake all scheduled visits and assessments. Exclusion Criteria: A subject with study eye who meets any of the following criteria will be excluded from the study: Ocular conditions - study eye Age-related macular degeneration with any evidence of central GA (i.e., involving the fovea). Atrophic retinal disease because of causes other than AMD. Presence or diagnosis of exudative AMD or choroidal neovascularization in the study eye. History of diabetic retinopathy (a history of diabetes mellitus without retinopathy is not a criterion for exclusion). Presence of vitreous hemorrhage. History of retinal detachment or macular hole (stage 3 or 4) in the study eye. Presence of macular pucker. History of uncontrolled glaucoma, defined as advanced cup-to-disc ratio > 0.7 and IOP > 25, with or without topical antihypertensive eye drops; treatment of ocular hypertension or controlled glaucoma are not criteria for exclusion. History of advanced guttae indicative of Fuchs endothelial dystrophy. Presence of visually significant cataract OR presence of significant posterior capsular opacity in the setting of Pseudophakia. Presence of significant keratopathy that would cause scattering of light or alter visual function, especially in LL conditions. Ocular incisional surgery (including cataract surgery) in the study eye within 3 months (i.e. 90 days) before Day 1. Aphakia. History of vitrectomy surgery, submacular surgery, or any vitreoretinal surgery. Prior treatment with Visudyne ® (verteporfin), external-beam radiation therapy (for intraocular conditions), or transpupillary thermotherapy. History of prophylactic subthreshold laser treatment for retinal disease. Previous intravitreal drug delivery (e.g., intravitreal corticosteroid injection, anti-angiogenic drugs, or device implantation) in the study eye. Ocular conditions - either eye Active uveitis and/or vitritis (grade trace or above) in either eye. History of idiopathic or autoimmune-associated uveitis in either eye. Active, infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye. Systemic conditions Known to be immunocompromised or receiving systemic immunosuppression. Any disease or medical condition that in the opinion of the Investigator would prevent the subject from participating in the study or might confound study results. Estimated glomerular filtration rate < 30 mL/minute, by MDRD. Presence or history of clinically significant allergy disease requiring treatment, as judged by the Investigator. Hay fever is allowed unless it is active. General Participation in other investigational drug or device clinical trials within 30 days before enrollment, or planning to participate in any other investigational drug or device clinical trials within 30 days of study completion. History of allergy to fluorescein that is not amenable to treatment. Inability to comply with study or follow-up procedures. Inability to obtain color fundus photograph, FAF, and fluorescein angiography of sufficient quality to be analyzed and interpreted. History of allergic reaction to the investigational drug or any of its components. Current use of or likely need for any excluded medication.

Ages Eligible for Study
-----------------
Minimum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Both arms received 40 mg dose of elamipretide administered once daily as a 1.0mL SC injection.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intermediate AMD - HRD without GA<br>Participants had one 1 eye with intermediate age-related macular degeneration with high-risk drusen without geographic atrophy [GA]), i.e. the presence of either at least 1 large (≥125 μm) druse or multiple medium-size (63-124 μm) drusen. Participants received 40 mg dose of elamipretide administered once daily as a 1.0mL SC injection. | Drug: Elamipretide<br>* 40 mg dose of elamipretide administered once daily as a 1.0mL SC injection.<br>* Other names: MTP-131; Bendavia;|
| Experimental: Intermediate AMD with NCGA<br>Participants had 1 eye with intermediate AMD with noncentral geographic atrophy [NCGA]; i.e. evidence of GA with cumulative area ≥1.27 mm2 (approximately 0.5 disc area[DA]) by fundus autofluorescence (FAF) that spared the fovea (defined as retinal pigment epithelium (RPE) and outer retina intact by spectral-domain optical coherence tomography [SD-OCT]). Participants in this arm also received 40 mg dose of elamipretide administered once daily as a 1.0mL SC injection. | Drug: Elamipretide<br>* 40 mg dose of elamipretide administered once daily as a 1.0mL SC injection.<br>* Other names: MTP-131; Bendavia;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Standard Luminance Best-corrected Visual Acuity (BCVA) | Change from Baseline in Mean Standard Luminance Best-corrected Visual Acuity (BCVA) at 4 meters, letters from Baseline to Day 7, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, and Week 28. | Day 0 (Baseline to Day 7, and to Weeks 4, 8, 12, 16, 20, 24, and 28. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Low Luminance Best-Corrected Visual Acuity (LLBCVA) | Change from Baseline in Mean Low Luminance Best-Corrected Visual Acuity (LLBCVA) from Baseline (Day 0) to Day 7, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, and Week 28. | Baseline to Day 7, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, and Week 28. | 
| Change From Baseline in Mean Dark Adaptometry | Change from Baseline in Mean Dark Adaptometry from Baseline to Week 24- at 0% 25%, 50%, 75% Bleach Level. Dark adaptometry, used to evaluate night blindness by measuring the absolute thresholds of rod sensitivity, was performed within 14 days before Day 0 and at all in-person visits except for Day 7. Dark adaptation is the delayed recovery of light sensitivity in darkness following prior light exposure (photobleaching). The observed and change from baseline recovery scores (in minutes) for each bleach level (0%, 25%, 50%, and 75%) were summarized descriptively for each eye at each visit and were presented in a listing. Shorter recovery times are better than longer recovery times. | Baseline (Day 0) and Week 24 | 
| Mean Treatment Compliance (%) of Administration of Subcutaneous Elamipretide | Mean percentage of treatment compliance of administration of subcutaneous elamipretide. The number of injections (diary) and vials used was used to compute % compliance over the duration of the subject's participation in the trial. Percentage can range from 0-100%, where 0% means the participant followed the correct dosing 0% of the time, and 100% compliance means the participant followed the correct dosing 100% of the time, with a higher % meaning a better outcome. | Baseline through Week 28 | 
| Mean Number of Home Health Visits to Administer Elamipretide | Mean Number of Home Health Visits Necessary for Participant or Caregiver to Learn How to Administer Elamipretide | Baseline (Day 0) through Week 24 | 
| Change From Baseline in Mean Area of Geographic Atrophy by Fundus Autofluorescence | Change from Baseline in Mean Area of Geographic Atrophy (GA) by Fundus Autofluorescence (FAF) at Week 24. Fluorescein angiography (FA) was used to examine the circulation of the retina and choroid using fluorescein dye and a specialized camera to trace the dye. Fundus autofluorescence imaging of the retinal pigment epithelium and neurosensory retina was performed within 14 days of Day 0 and at every visit with the exception of Day 0 and Day 7. Atrophy is characterized by loss of the retinal pigment epithelium (RPE), overlying photoreceptors and underlying choriocapillaris. Greater area affected means a worse outcome than smaller area affected. | Baseline (Day 0) to Week 24 | 
| Change From Baseline in Mean Area of Geographic Atrophy as Measured by Spectral-Domain Optical Coherence Tomography (SD-OCT) | Change from Baseline in Mean Area of Geographic Atrophy by Sector as measured by Spectral-Domain Optical Coherence Tomography (SD-OCT) at Week 24 | Baseline to Week 24 | 
| Change From Baseline in Mean Reading Acuity Test: With Standard Luminance | Change from Baseline in Mean Reading Acuity Test: Mean Critical Print Size with Standard Luminance in Weeks 4, 8, 12, 16, 20, 24 and 28 as measured by the Logarithm of the Minimum Angle of Resolution LogMAR chart. Scores range from -0.3 to 1.0, where higher number means worse acuity/worse outcome, a lower number means better acuity/better outcome. | Baseline and Weeks 4, 8, 12, 16 20, 24 and 28 | 
| Change From Baseline in Mean Reading Acuity Test: Low Luminance | Change from Baseline in Mean Reading Acuity Test: Mean Critical Print Size with Low Luminance in Weeks 4, 8, 12, 16, 20, 24 and 28 as measured by the Logarithm of the Minimum Angle of Resolution LogMAR chart. Scores range from -0.3 to 1.0, where higher number means worse acuity/worse outcome, a lower number means better acuity/better outcome. | Assessed at screening, baseline, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, and Week 28 | 
| Change From Baseline in National Eye Institute Visual Function Questionnaire-39 (VFQ-39) Score Standard Luminance | Change from baseline (Day 0) at Week 12, 24 and 28. National Eye Institute Visual Function Questionnaire-39 (VFQ-39) score measures health-related quality of life of subjects with visual impairment, in 12 domains: general vision, ocular pain, near activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-specific role difficulties, vision-specific dependency, driving, color vision, and peripheral vision and 1 composite score. Each domain is converted to a 0 to 100 scale; the lowest and highest possible scores are set at 0 and 100 points, respectively. Higher score means higher functioning. Scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score. For the composite score, the vision-targeted sub-scale scores are averaged, excluding the general health questions. Domain scores from each cohort are averaged and the change from baseline per domain is calculated. | Assessed at baseline (Day 0), Week 12, Week 24 and Week 28 | 
| Change From Baseline in Mean Low Luminance Questionnaire (LLQ) Score | Change from baseline (Day 0) at Week 12, Week 24, and Week 28 in LLQ score. The LLQ is a 32-item questionnaire with six subscales related to low luminance settings: driving, mobility, extreme lighting, general dim lighting, and peripheral vision. Each question is scored on a scale ranging from 0, or maximal difficulty, to 100, or no difficulty in low luminance settings. Higher scores mean better functioning. The questions are assigned to different subscales and are averaged to generate one score per subscale. After weighting each subscale for the number of questions, the weighted subscales are averaged to generate a composite LLQ score. | Baseline (Day 0), Week 12, and Week 24 and Week 28 | 
| Change From Baseline in Mean Mesopic Light Sensitivity | Change from baseline in mean mesopic light sensitivity for Weeks, 4, 8, 12, 16, 20, and 24 as assessed by microperimetry for number of loci <25dB and <14dB. Mesopic microperimetry, used to measure retinal sensitivity, was performed within 14 days before Day 0 and at all in-person visits except for Day 7. | Baseline (Day 0) and Weeks 4,8,12,16,20,and 24 | 
| Change From Baseline in Mean Retinal Pigment Epithelium - Drusen Complex (RPEDC) Thickness as Measured by SD-OCT | Change from baseline in mean retinal pigment epithelium - drusen complex (RPEDC) thickness as Measured by SD-OCT by sector at Week 24 | Baseline (Day 0) and Week 24 | 
| Change From Baseline in Mean Retinal Pigment Epithelium-Drusen Complex Volume | Change from baseline in mean Retinal Pigment Epithelium-Drusen Complex volume at Week 24 by sector | Baseline (Day 0) to Week 24 |