A Study to Evaluate the Safety, Tolerability and Pharmacokinetics of D-4517.2 After Subcutaneous Administration in Subjects With Neovascular (Wet) Age-Related Macular Degeneration (AMD) or Subjects With Diabetic Macular Edema (DME)

Study Overview
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Brief Summary
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A Study to Evaluate the Safety, Tolerability and Pharmacokinetics of D-4517.2 After Subcutaneous Administration in subjects with Neovascular (wet) Age-Related Macular Degeneration (AMD) or subjects with Diabetic Macular Edema (DME)

Detailed Description
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A Two Stage Phase 2 Study: Stage 1: Single Subcutaneous Dose Open-label Assessment of Safety and Pharmacodynamic Response to D-4517.2 (hydroxyl dendrimer VEGFR tyrosine kinase inhibitor) in subjects with Neovascular (wet) Age-Related Macular Degeneration (AMD) or subjects with Diabetic Macular Edema (DME). Stage 2: Visual Examiner-Masked, Randomized Active, Sham and Placebo Controlled Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of a Subcutaneously Administered D-4517.2 to Subjects with Neovascular (wet) Age-Related Macular Degeneration

Official Title
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A Two Stage Phase 2 Study: Stage 1: Single Subcutaneous Dose Open-label Assessment of Safety and Pharmacodynamic Response to D-4517.2 (Hydroxyl Dendrimer VEGFR Tyrosine Kinase Inhibitor) in Subjects With Neovascular (Wet) Age-Related Macular Degeneration (AMD) or Subjects With Diabetic Macular Edema (DME)

Conditions
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Neovascular Age-related Macular Degeneration, Diabetic Macular Edema

Intervention / Treatment
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* Drug: D-4517.2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Overall Study Inclusion Criteria-For All Subjects: Willing and able to give informed consent, comply with all study procedures, and be likely to complete the study. Demonstrated response to prior anti-VEGF treatment since diagnosis as defined by one or more of the following: Reduction of subretinal fluid or intraretinal fluid of greater than equal to 30% from initial diagnosis as measured by SD-OCT. Elimination of prior sub-foveal fluid from initial diagnosis as measured by SD-OCT. Increase in BCVA of greater than or equal to 2 lines from initial diagnosis using Snellen scale. These inclusion criteria will be assessed by the Investigator for Stage 1. Female subjects may be enrolled if they are: Not pregnant, lactating, or breastfeeding Documented in medical records or patient self-reported to be surgically sterile or postmenopausal. Female subjects of childbearing potential must practice true abstinence for at least 28 days prior to investigational product (IP) administration until 30 days after the last IP administration and have a negative serum and urine pregnancy test at Screening and Baseline Day 1, respectively, or Using 2 forms of highly effective contraception, including 1 physical barrier (condom or diaphragm) plus another method, such as adequate hormonal method (eg, contraceptive implants, injectables, or oral contraceptives) or nonhormonal methods (eg, intrauterine device or spermicidals) from Screening or at least 2 weeks prior to IP administration (whichever is earlier) until 30 days after the last IP administration and having a negative serum and urine pregnancy test at Screening and Baseline Day 1, respectively. Male subjects with female partners of childbearing potential may be enrolled if they are: Documented to be surgically sterile (vasectomy) in medical records or patient self-reported, or Agree to practice true abstinence during the study and for 30 days after the last IP administration, or Agree to use 2 adequate forms of highly effective contraception during the study, 1 of which should be a physical barrier for 30 days after the last IP administration. Must agree not to donate sperm during study and for 30 days following administration of the last dose of IP. Subjects With Wet AMD (For Both Stage 1 and Stage 2): Male or nonpregnant female adults aged ≥50 years at time of signing the informed consent form (ICF). BCVA letter score between 75 and 23 letters (ETDRS chart) (20/32 to 20/320 Snellen equivalents) inclusive in the study eye at baseline and BCVA letter score of at least 35 letters ETDRS chart (20/200 Snellen equivalent) in the non-study eye. For Stage 2, presence of a choroidal neovascular (CNV) lesion secondary to AMD as confirmed by the Central reader. Previously treated with at least 3 prior IVT injections and no more than 36 months of treatment with an anti-VEGF agent (aflibercept, bevacizumab, ranibizumab, or any other approved anti-VEGF agent) with last treatment between 4 and 12 weeks prior to Screening. Administration of IVT anti-VEGF agents prior to enrollment must not be more than 12 weeks apart. Decrease in vision in the study eye determined by Investigator to be primarily the result of exudation from wet AMD. Ocular media clarity, pupillary dilation, and individual cooperation sufficient for adequate fundus imaging in the opinion of the Investigator. Recurrence of subretinal fluid or increase in CST. This inclusion criteria will be confirmed by the Central Reader in Stage 2. For subjects with bilateral disease, only one eye per subject is eligible to participate in the study. In cases where both eyes are eligible, the eye with the worse BCVA at the Screening Visit will be selected as the study eye. If both eyes have the same BCVA, the decision of which eye to select as the study eye will be made by the Investigator. Subjects With DME ( For Stage 1 Only): Male or nonpregnant female adults aged ≥18 years at time of signing the ICF. BCVA letter score between 75 and 23 letters (ETDRS chart) (20/32 to 20/320 Snellen equivalents) inclusive in the study eye at baseline. Diagnosis of diabetes mellitus (Type 1 or Type 2). Any of the following will be considered to be sufficient evidence that diabetes is present: Current regular use of oral anti-hyperglycemic agents for the treatment of diabetes. Current regular use of insulin or other injectable drugs (eg, dulaglutide and liraglutide) for the treatment of diabetes. Documented diabetes by American Diabetic Association (ADA) and/or World Health Organization (WHO) criteria. Hemoglobin A1c (HbA1c) ≤12% (historic values up to 3 months before Screening Visit will be permissible, otherwise study site may collect sample for analysis at Screening). DME defined as macular thickening by SD-OCT involving the center of the macula. A CST of ≥325 μm with Spectralis® (Heidelberg Engineering, Heidelberg, Germany) at Screening. This will be assessed by the Central Reader. Recurrence of subretinal fluid or increase in CST. This inclusion criteria to be confirmed by the Central Reader in Stage 2. The cause of the decreased vision in the study eye has been attributed primarily to DME by the Investigator. History of previous treatment in the study eye with at least 3 prior injections and no more than 36 months of treatment with an anti-VEGF agent (aflibercept, bevacizumab, ranibizumab, or any other approved anti-VEGF agent) with last treatment between 4 and 12 weeks prior to Screening. Administration of IVT anti-VEGF agents prior to enrollment must not be more than 12 weeks apart. Ocular media clarity, pupillary dilation, and individual cooperation sufficient for adequate fundus imaging in the opinion of the Investigator. For subjects with bilateral disease, only one eye per subject is eligible to participate in the study. In cases where both eyes are eligible, the eye with the worse BCVA at the Screening Visit will be selected as the study eye. If both eyes have the same BCVA, the decision of which eye to select as the study eye will be made by the Investigator. Exclusion Criteria: Medical Conditions: History, within 6 months prior to Screening, of any of the following: myocardial infarction, any cardiac event requiring hospitalization, treatment for acute congestive heart failure, transient ischemic attack, or stroke Uncontrolled hypertension with systolic BP ≥160 mmHg and/or diastolic BP ≥100 mmHg (while patient at rest) at the Screening Visit. If the patient's initial reading exceeds these values, a second reading may be taken 30 minutes later on the same day. If the patient's BP is controlled by antihypertensive medication, the patient should be taking the same medication continuously for at least 30 days prior to Day 1. Currently untreated diabetes mellitus or previously untreated subjects who initiated oral or injectable anti-diabetic medication within 3 months prior to Day 1. Uncontrolled diabetes mellitus as defined by HbA1c >12% for DME subjects only. AMD subjects will not have HbA1c assessed at Screening. Chronic renal disease requiring chronic hemodialysis or renal transplantation. Abnormal liver function, as defined by transaminase or total bilirubin 2 times above the upper limit of normal at the Screening Visit. Medical history of Wolff-Parkinson-White Syndrome, family history of long QT, or on medication prolonging QT time or planned initiation during the trial. Known allergy to constituents of the study drug formulation, aflibercept, or clinically relevant hypersensitivity to fluorescein used by the patient during the study. Serious systemic infection: Any active infection for which systemic anti-infectives were used within 4 weeks before randomization. Recurrent or chronic infections or other active infection that, in the opinion of the Investigator, might cause this study to be detrimental to the subject. Any organic or psychiatric disorder, or laboratory abnormality which, in the opinion of the Investigator, will prevent the patient from completing the study activities as in the protocol or interfere with the interpretation of the study results. An underlying condition (including, but not limited to metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, cardiac, infectious, or gastrointestinal) or history of other disease, physical examination finding or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of study drug, might affect interpretation of the results of the study or which, in the opinion of the Investigator, renders the patient at unacceptable risk of treatment complications by participating in the trial Any major illness or surgical procedure within 1 month before Screening History of other diseases, physical examination finding, historical or current clinical lab finding giving reasonable suspicion of condition that contraindicates the use of the IP or that might affect the interpretation of the results of the study or renders the patient at high risk for treatment complications, in the opinion of the Investigator. Positive screen for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibodies, or HIV type 1 and 2 antibodies. Prior/Concomitant Therapy: Participation in any investigational study within 30 days prior to Screening, or planned use of an IP or device during the study; any exposure to a prior investigational drug product must be fully washed out (at least 5 half-lives). Chronic alcohol or drug abuse or any condition that, in the Investigator's opinion, makes them an unreliable study participant or unlikely to complete the trial. Use of systemic medications known to be toxic to the lens, retina or optic nerve (eg, deferoxamine, chloroquine/hydroxy-chloroquine, tamoxifen, phenothiazines, and ethambutol) used during the 6 month or 5 half-lives (whichever is longer) prior to Day 1 or likely need to be used. Use of systemic immunomodulatory treatments (eg, interleukin-6 inhibitors) within 6 months or 5 half-lives (whichever is longer) prior to Day 1. Use of systemic corticosteroids (ie oral, IM, IV, intranasal) within 1 month prior to Day 1 and no corticosteroids anticipated throughout the trial. Systemic treatment for suspected or active systemic infections. Administration of systemic anti-VEGF or pro-VEGF treatment within 180 days or 5 half-lives, whichever is longer, before Screening visit. Any prior concomitant systemic anti-VEGF treatment within 6 months or 5 half-lives, whichever is longer, before randomization visit.

Ages Eligible for Study
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Minimum Age: 18 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neovascular Age-related Macular Degeneration<br>Cohort A1 - 0.25 mg/kg of D-4517.2 Cohort B1 - 0.5 mg/kg of D-4517.2 Cohort C1 - 1.0 mg/kg of D-4517.2 Cohort D1 - 2.0 mg/kg of D-4517.2 | Drug: D-4517.2<br>* D-4517.2 (hydroxyl dendrimer VEGFR tyrosine kinase inhibitor)<br>|
| Experimental: Diabetic Macular Edema<br>Cohort B2 - 0.5 mg/kg of D-4517.2 Cohort C2 - 1.0 mg/kg of D-4517.2 Cohort D2 - 2.0 mg/kg of D-4517.2 | Drug: D-4517.2<br>* D-4517.2 (hydroxyl dendrimer VEGFR tyrosine kinase inhibitor)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Treatment-Emergent Adverse Events [Safety] | Safety of single dose of D-4517.2 as measured by treatment-related adverse events as assessed by CTCAE v5.0 | Safety and tolerability of a single SC dose of D-4517.2 at 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with a reduction in sub-retinal fluid after a single intravitreal (IVT) dose of aflibercept and a single SC dose of D-4517.2 | Change in sub-retinal fluid as measured by spectral domain optical coherence tomography (SD-OCT). | Within subject, percent reduction in subretinal fluid volume in study eye after IVT aflibercept and D-4517.2 at 2, 4, 6, 8, and 12 weeks post-dose measured by spectral domain optical coherence tomography (SD-OCT). | 
| Number of participants with duration of effect of D-4517.2 as assessed by changes in subretinal fluid over time up to 12 weeks | Effect of D-4517.2 as measured by spectral domain optical coherence tomography (SD-OCT). | Within subject, central subfield thickness (CST) in study eye after IVT aflibercept and D-4517.2 at 2, 4, 6, 8, and 12 weeks post-dose as assessed by SD-OCT. | 
| Number of participants with Ocular and non-ocular adverse events (AEs) and serious adverse events (SAEs) observed for D-4517.2 and aflibercept | Participants with ocular and non-ocular adverse events and serious adverse events as measured by CTCAE v5.0 | By dose level, mean difference in percent reduction in subretinal fluid in study eye after IVT aflibercept and D-4517.2 at 2, 4, 6, 8, and 12 weeks post-dose as measured by SD-OCT. | 
| Number of participants with change in best corrected visual acuity (BCVA) in study eye after each treatment (aflibercept or D-4517.2). | Participants with change in vision as measured best corrected visual acuity (BCVA) assessment. | Change from baseline in BCVA in study eye as assessed by early treatment of diabetic retinopathy scale (ETDRS) after each treatment (aflibercept and D-4517.2) at 4, 6, 8, and 12 weeks post-dose. |