A Study of the Safety and Tolerability of ASP7317 in Adults Who Are Losing Their Clear, Sharp Central Vision Due to Geographic Atrophy Secondary to Dry Age-related Macular Degeneration

Study Overview
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Brief Summary
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This study is for adults 50 years or older who are losing their clear, sharp central vision. Central vision is needed to be able to read and drive a car. They have been diagnosed with dry age-related macular degeneration (called dry AMD). The macula is the center part of the back of the eye that allows you to see fine detail. In an advanced stage of this disease, areas of the macula die (atrophy), resulting in vision loss. This is called geographic atrophy. This study is looking at a new treatment called ASP7317. It is for slowing or reversing atrophy in dry AMD. ASP7317 is a specially created type of cells derived from human stem cells. ASP7317 cells are injected into the macula of the eye while the person is under anesthesia (local or general). An immunosuppressive medicine (tacrolimus) is also taken around the time of injection of the cells to prevent the body from rejecting them. This study looks at how safe ASP7317 is at 3 different dose levels. Researchers want to learn if the different dose levels of ASP7317 work without causing unwanted medical problems. Each of the 3 doses will be given to 2 groups of people. The first group will be those who have severe vision loss. The second group will be those who have moderate vision loss. The doses are low, medium and high numbers of cells. Tacrolimus will be taken by mouth for 34 days, starting around the time of the injection of ASP7317. In addition, medicines to prevent infection will be taken by mouth for up to 4 weeks starting around the time ASP7317 cells are injected. Each week for the first 4 weeks after the ASP7317 cells have been injected, people taking part in the study will visit the clinic so the researchers can make assessments. Then they will visit again, at weeks 6, 8, 12, 16, 26, and 52 (last week of the study). A substudy will be available at some clinics. These clinics will use a special camera that will allow researchers to look at images of the macular atrophy over time.

Detailed Description
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The study consists of the following periods: Screening (up to 45 days) and the Study Period (52 weeks post treatment).

Official Title
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A Phase 1b, Multicenter, Dose Escalation, Evaluation of Safety and Tolerability of ASP7317 for Geographic Atrophy Secondary to Age-related Macular Degeneration

Conditions
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Age-Related Macular Degeneration

Intervention / Treatment
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* Drug: ASP7317
* Drug: tacrolimus


Participation Criteria
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Eligibility Criteria
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General Inclusion Criteria Participant must be willing to take tacrolimus and willing to discontinue any medications that have a known strong interaction with tacrolimus. Participant is able and willing to undertake all scheduled visits and assessments up to the week 52 visit. Participant who is taking an antidepressant must be on a stable and effective dosage and must be willing to take it reliably for as long as it is required. Participant must be willing and medically suitable to undergo monitored anesthesia care during the vitrectomy and subretinal injection. Participant agrees not to participate in another interventional study until the 52-week visit has been completed. Female participant is not pregnant and at least one of the following conditions apply: Not a woman of childbearing potential (WOCBP) WOCBP who agrees to follow the contraceptive guidance from the time of informed consent through at least 52 weeks after investigational product (IP) administration. Female participant must agree not to breastfeed starting at screening and throughout the study period and for 52 weeks after IP administration. Female participant must not donate ova starting at first dose of IP and throughout the study period and for 52 weeks after IP administration. Male participant with female partner(s) of childbearing potential (including breastfeeding partner) must agree to use contraception throughout the treatment period and for 52 weeks after IP administration. Male participant must not donate sperm during the treatment period and for 52 weeks after IP administration. Male participant with pregnant partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy throughout the study period and for 52 weeks after IP administration. Ocular Inclusion Criteria: Study Eye (Both Groups 1 and 2) Participant has bilateral geographic atrophy (GA) secondary to Age-Related Macular Degeneration (AMD). GA is defined as sharply demarcated areas of loss of the retinal pigment epithelial/epithelium (RPE). Participant has no evidence of prior or active choroidal neovascularization (CNV) with optical coherence tomographyangiography (OCT-A) or indocyanine green angiography (ICG-A), as assessed by the reading center. Participant has absence of exudation as assessed by fluorescein angiography (FA) and spectral domain-optical coherence tomography (SD-OCT). Participant has presence of either banded or diffuse hyperautofluorescence in the junctional zone of GA as assessed by the central reading center. Participant has sufficiently clear ocular media, adequate pupillary dilation, and fixation to permit quality fundus imaging. Participant is willing to discontinue vitamins/supplements for AMD (e.g., Age-Related Eye Disease Study [AREDS] 2) at least 30 days before IP administration through 52 weeks after IP administration. Participant is pseudophakic. Ocular Inclusion Criteria: Study Eye (Group 1 only) For Cohort 1, the participant has a BCVA between light perception and </= 23 Early Treatment Diabetic Retinopathy study (ETDRS) letters at the screening visit. For Cohorts 2 and 3, the participant has a BCVA score between 20 (>/= 20/400) and 37 (</=20/200) ETDRS letters at the screening visit. Participant has the total GA area </= 30.5 mm^2 (</=12 disc areas [DA]). Ocular Inclusion Criteria: Study Eye (Group 2 only) Participant has BCVA score between 38 (> 20/200) and 63 (</=20/63) ETDRS letters during the screening visit. Participant has the total GA area of >/= 5.1 mm^2 and < 17.8 mm^2 (>/=2 and </=7 DA, respectively) and must reside completely within the fundus autofluorescence (FAF) imaging field (Field 2 to 30 degree image centered on the fovea). If GA is multifocal, at least 1 focal lesion must be >/= 2.5 mm^2 (>/=1 DA). Participant has a difference in mean mesopic sensitivity </=2 dB between 2 tests at screening. If not </=2 dB, a third test may be conducted and mean values between the second and third assessments must be </=2 dB. General Exclusion Criteria Participant has a history of recurrent varicella zoster virus (VZV) infection or a clinical diagnosis of VZV infection within 4 weeks of the baseline visit. Participant has a history of recurrent cytomegalovirus (CMV) infection or a clinical diagnosis of CMV infection within 4 weeks of the baseline visit. Participant has a positive tuberculosis (TB) test during the screening period by an interferon gamma release assay (e.g., QuantiFERON) within the 6 months prior to the screening. If a participant has tested negative for TB within the 6 months prior to the screening visit, retesting is not required unless clinically indicated. Participant has a history or suspected active infection of toxoplasmosis or presence of elevated immunoglobulin M (IgM) toxoplasmosis titer within 4 weeks of the baseline visit. Participant has an active infection (ocular or non-ocular) requiring the prolonged or chronic use of antimicrobial or anti-infective agents. Participant has a current malignancy or history of malignancy within the past 5 years, except non-metastatic basal or squamous cell carcinoma or keratoacanthoma or Bowen's disease or carcinoma-in-situ of the cervix that has been successfully treated. Participant has a history of a solid organ or bone marrow transplant. Participant has any condition that would prohibit the use of systemic immunosuppression with tacrolimus. Participant is receiving or has received any immunosuppressive therapy (IMT) (other than topical, inhaled or low dose systemic corticosteroid use not exceeding 7.5 mg of prednisone daily [or equivalent]) within 6 weeks or 5 plasma half-lives, whichever is longer, prior to the administration of adjunct study medications. Participant has a history of myocardial infarction in previous 12 months and whose disease is either unstable and/or symptomatic (e.g., angina, dyspnea, etc.). Participant has electrocardiogram (ECG) results that are clinically significant and could either jeopardize the safety of the participant, impact the participant's ability to comply with study visit schedule or impact the validity of the study results. Participants with a mean Fridericia-corrected QT interval of > 430 ms (for males) and > 450 ms (for females) at screening must be cleared by a cardiologist prior to the baseline visit. Participant has a study day diastolic blood pressure > 95 mmHg, at either the screening or baseline visit. Study day blood pressure is defined as the average of the second and third readings at a study visit. If the study day blood pressure exceeds the limits, 1 additional triplicate can be taken. Participant has an estimated glomerular filtration rate (eGFR) of </= 45 mL/min, calculated by the chronic kidney disease epidemiology collaboration (CKD-EPI) equation. Participant has an alanine aminotransferase (ALT), aspartate aminotransferase (AST) or gamma- glutamyltransferase (GGT) and total bilirubin (TBL) >/= 2 times the upper limit of normal (ULN). Participant has severe anemia (hemoglobin < 9 g/dL [male] or hemoglobin < 8 g/dL [female]), leucopenia (white blood cell count < 2500/mm^3), thrombocytopenia (platelet count < 80000/mm^3) or polycythemia (hematocrit > 54% [male] or hematocrit > 49% [female]). Participant has a hemoglobin A1c > 8.5%. Participant has a clinically significant coagulopathy (i.e., activated partial thromboplastin time [aPTT] >/= 1.5 times the ULN and/or prothrombin time adjusted for the international normalized ratio [PT-INR] >/=2.0). Participant has serology results indicative of having syphilis, Lyme disease, human immunodeficiency virus infection or active infection with hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), or varicella-zoster virus (VZV). Participant has a history of familial adenomatous polyposis or inflammatory bowel disease (i.e., Crohn's disease, ulcerative colitis). Participant has a history of allergic reaction to mydriatics or fluorescein. Participant has a history of gene therapy or cell transplant therapy, including ASP7316, in a prior clinical study. Participant has participated in any studies of an investigational drug (excluding vitamins and minerals for AMD studies) within 12 weeks prior to the screening visit. Participant is unwilling to discontinue or avoid any CYP3A4 inducers (e.g., rifampin, rifabutin, phenytoin, carbamazepine, phenobarbital, St John's Wort) or participant is unwilling to discontinue or avoid protease inhibitors (e.g., nelfinavir, telaprevir, boceprevir), direct Factor Xa inhibitors, direct thrombin inhibitors, verapamil, diltiazem or erythromycin while taking tacrolimus. Participant has a positive urine screen for drugs of abuse (amphetamines, barbiturates, benzodiazepines, opiates, cocaine, phencyclidine and methadone), unless the drug is taken for a documented medical condition and under the supervision of a physician. Ocular Exclusion Criteria - Study Eye Participant has macular degeneration due to causes other than AMD (e.g., Stargardt disease, cone rod dystrophy, toxic maculopathies, etc.) Participant has foveal sparing as determined by the presence of potentially viable photoreceptors, as evidenced by presence of ellipsoid zone (EZ) </= 250 microns from the foveal center, based on reading center assessments at the screening visit. Participant has a history of vitrectomy or submacular surgery, or any surgical intervention for AMD. Participant has prior treatment with photodynamic therapy (e.g., Visudyne®), intraocular external-beam radiation therapy or transpupillary thermotherapy. Participant has a history of previous laser photocoagulation for choroidal neovascularization (CNV), diabetic macular edema, retinal vein occlusion and proliferative diabetic retinopathy. Participant has a history of intravitreal drug delivery (e.g., anti-VEGF drugs, anticomplement agents, intravitreal corticosteroid injection or device implantation) within 1 year prior to the screening visit. Participant has an abnormality of vitreoretinal interface (e.g., tractional epiretinal membrane), which can interfere with measurement of macular thickness or with the potential for macular structural damage. Participant has a history of cystoid macular edema, retinal vascular occlusion, central serous chorioretinopathy, macular hole or retinoschisis. Participant has active or history of intraocular inflammation such as uveitis, chorioretinitis and optic neuropathy. Participant has presence of an ocular toxoplasmosis scar. Participant has nevus of Ota (oculodermal melanocytosis), a pigmented choroidal lesion showing characteristics associated with high risk of malignancy (e.g., elevated lesion) or a choroidal nevus in the macula. Participant has pathologic myopia defined as a spherical equivalent of > 8.00 diopters or axial length > 28 mm at the screening visit, or myopic macular degeneration or posterior staphyloma. Participant has glaucoma with uncontrolled intraocular pressure (IOP) (defined as IOP > 30 mmHg despite treatment with anti-glaucoma medication) or is using more than 2 agents to control IOP or a history of glaucoma-filtering surgery. Participant has a history of corneal transplantation. Participant has monocular vision; no light perception in the fellow eye or anophthalmic in the fellow eye. Participant has a contraindication to pupil dilation. Participant has any other ocular condition that can interfere with the assessment of imaging data. ADAPTIVE OPTICS RETINAL IMAGING SUBSTUDY ONLY: Either eye with GA area >/=7 DA, or has photosensitivity, or is at high risk for light hazard, or has a multifocal intraocular lens, or has an optical zone < 5 mm in diameter, or has capsulorhexis smaller than 5 mm. Note: this is not an exclusion criterion for the participant from the study, but only an exclusion of the participant's eye(s) from Adaptive Optics Retinal Imaging substudy.

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ASP7317 Dose Escalation (Group 1)<br>Group 1 will consist of participants with Severe Vision Impairment. Successive cohorts of participants (3 participants/ cohort) will be treated in each escalating dose cohort (cohort 1: low cells/dose; cohort 2: medium cells/dose; cohort 3: high cells/dose). Sentinel dosing will be required for each dose level. After the first participant in Group 1 dose cohort is dosed and followed for 3 weeks, the independent Data Safety Monitoring Board (DSMB) will review the 3-week safety data and recommend if the second and third participants in Group 1 dose cohort may be treated. The DSMB recommendation to progress to the next dosing cohort will be based on 3-week follow-up safety review of the second and third participants in the preceding dose cohort. Participants will receive tacrolimus twice daily starting at baseline through week 4. | Drug: ASP7317<br>* subretinal injection<br>Drug: tacrolimus<br>* oral<br>* Other names: Prograf®;|
| Experimental: ASP7317 Dose Escalation (Group 2)<br>Group 2 will consist of participants with Moderate Vision Impairment. Successive cohorts of participants (3 participants/ cohort) will be treated in each escalating dose cohort (cohort 4: low cells/dose; cohort 5: medium cells/dose; cohort 6: high cells/dose). Dosing in cohort 4 (low cells/dose) may commence following the DSMB recommendation to begin dosing in Group 1 cohort 2 (medium cells/dose). Dosing in Group 2 cohort 5 (medium cells/dose) may commence following DSMB review of the 3-week safety data of the first participant in Group 1 cohort 2 (medium cells/dose). Similarly, dosing in Group 2 cohort 6 (high cells/dose) may commence following DSMB review of 3-week safety data of the first participant in Group 1 cohort 3 (high cells/dose). Participants will receive tacrolimus twice daily starting at baseline through week 4. | Drug: ASP7317<br>* subretinal injection<br>Drug: tacrolimus<br>* oral<br>* Other names: Prograf®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as assessed by incidence, frequency and severity of treatment emergent adverse events (TEAES) | Adverse events (AEs) will be coded using Medical Dictionary for Regulatory Activities (MedDRA). An Adverse Event is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of ASP7317, the adjunct study medications and the study procedures, whether or not considered related to ASP7317, the adjunct study medications and the study procedures. A Treatment Emergent Adverse Event (TEAE) is defined as an AE beginning or worsening in severity after starting administration of the adjunct study medication. | Up to 52 Weeks | 
| Safety as assessed by incidence, frequency and severity of Serious Adverse Events (SAEs) | An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; results in congenital anomaly or birth defect or other medically important events. | Up to 52 Weeks | 
| Safety assessed by Adverse Events (AEs) of special interest | AEs of special interest include: ectopic or proliferative cell growth (retinal pigment epithelial/epithelium (RPE) or non-RPE) with adverse clinical consequence; any new diagnosis of an immune-mediated disorder; any new cancer, irrespective of prior history; unexpected, clinically significant AEs possibly related to the cell transplant procedure; immunosuppressive therapy (IMT) or ASP7317 (e.g., graft failure or rejection). | Up to 52 Weeks | 
| Number of participants with cellular graft failure or rejection | Evidence of cellular graft failure or rejection will be assessed by best corrected visual acuity (BCVA), slit lamp examination, dilated indirect ophthalmoscopy, fundus photographs, spectral domain-optical coherence tomography (SD-OCT) and fluorescein angiography (FA), when performed. | Up to 52 Weeks | 
| Incidence of cellular graft failure or rejection | Evidence of cellular graft failure or rejection will be assessed by best corrected visual acuity (BCVA), slit lamp examination, dilated indirect ophthalmoscopy, fundus photographs, spectral domain-optical coherence tomography (SD-OCT) and fluorescein angiography (FA), when performed. | Up to 52 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change from baseline in the square root transformation of Geographic Atrophy (GA) area in study eye and fellow eye | GA will be measured by blue-light and near-infrared fundus autofluorescence (NIR FAF) (definitely decreased autofluorescence (DDAF)) and spectral domain-optical coherence tomography (SD-OCT) (area of ellipsoid zone (EZ) defect, area of outer nuclear layer (ONL) defect). | Baseline, Weeks 26 and 52/End of Study (EOS) | 
| Mean change from baseline in best corrected visual acuity (BCVA) score in study eye and fellow eye | BCVA will be measured by an assessor certified to use the Early Treatment of Diabetic Retinopathy Study (ETDRS) method. The BCVA score (in letter units) will be reported. | Baseline, Weeks 1, 4, 6, 8, 12, 16, 26 and 52/End of Study (EOS) | 
| Mean change from baseline in area of Geographic Atrophy (GA) (mm^2) in study eye and fellow eye | GA will be measured by blue-light and near-infrared fundus autofluorescence (NIR FAF) (definitely decreased autofluorescence (DDAF)) and spectral domain-optical coherence tomography (SD-OCT) (area of ellipsoid zone (EZ) defect, area of outer nuclear layer (ONL) defect). | Baseline, Weeks 26 and 52/End of Study (EOS) | 
| Mean percent change from baseline in area of Geographic Atrophy (GA) (mm^2) in study eye and fellow eye | GA will be measured by blue-light and near-infrared fundus autofluorescence (NIR FAF) (definitely decreased autofluorescence (DDAF)) and spectral domain-optical coherence tomography (SD-OCT) (area of ellipsoid zone (EZ) defect, area of outer nuclear layer (ONL) defect). | Baseline, Weeks 26 and 52/End of Study (EOS) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Geographic Atrophy, Age-related Macular Degeneration, ASP7317