Diabetic Macular Edema, Neovascular Age-related Macular Degeneration
Conditions
Brief summary
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
A Three 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 (wAMD) or Subjects with Diabetic Macular Edema (DME). Stage 1A: Multiple Subcutaneous Dose Open-Label Assessment of Safety, Pharmacokinetics and Pharmacodynamic Response to D-4517.2 Co-administered with Aflibercept in Subjects with wAMD and 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 wAMD
Interventions
DRUGD-4517.2
D-4517.2 (hydroxyl dendrimer VEGFR tyrosine kinase inhibitor)
Sponsors
Ashvattha Therapeutics, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Target population: Inclusion Criteria: Overall Study Inclusion Criteria-For All Subjects: 1. Willing and able to give informed consent, comply with all study procedures, and be likely to complete the study. 2. Demonstrated response to prior anti-VEGF treatment as defined by one or more of the following and as assessed by the Investigator for Stages 1 and 1A and confirmed by the Central Reader for Stage 2: 1. Complete resolution or partial reduction of foveal intra- and/or subretinal fluid ≥ 30% from initial diagnosis as measured by SD-OCT. 2. Increase in BCVA ≥ 2 lines from initial diagnosis using Snellen scale. 3. Female subjects may be enrolled if they are: 1. Not pregnant, lactating, or breastfeeding 2. Documented in medical records or subject self-reported to be surgically sterile or postmenopausal. 3. 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 4. 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. 4. Male subjects with female partners of childbearing potential may be enrolled if they are: 1. Documented to be surgically sterile (vasectomy) in medical records or subject self-reported, or 2. Agree to practice true abstinence during the study and for 30 days after the last IP administration, or 3. 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. 4. Must agree not to donate sperm during study and for 30 days following administration of the last dose of IP. 5. Subjects who complete the Aflibercept Treatment Period in Stage 1 are eligible to enroll in Stage 1A if they meet all eligibility requirements. These subjects will enter the study in the D-4517.2 Treatment Period. 6. Subjects who complete Stage 1 and/or Stage 1A are eligible to enroll in Stage 2 if they meet all eligibility requirements. 7. Ocular media clarity, pupillary dilation and individual cooperation sufficient for adequate fundus imaging in the opinion of the Investigator. 8. Recurrence of intra- or subretinal fluid at study Baseline. This inclusion criterion will be confirmed by the Sponsor or Central Reader in Stages 1 and 1A and by the Central Reader in Stage 2. 9. For subjects with bilateral disease, only one eye per subject can 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 eye with the largest CST will be selected as the study eye. Subjects With wAMD (For all Stages): 10. Male or nonpregnant female adults aged ≥50 years at time of signing the informed consent form (ICF). 11. 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. 12. Previously treated subjects with at least 3 prior IVT injections with an anti-VEGF agent (aflibercept, bevacizumab, faricimab, ranibizumab, or any other approved anti-VEGF agent) with last treatment administered 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. This inclusion criterion will be assessed by the Investigator. 13. For Stage 2, presence of a choroidal neovascular (CNV) lesion secondary to wAMD confirmed by the Central Reader. 14. The Investigator attributes the cause of the decreased vision in the study eye primarily to wAMD. Subjects With DME (For Stages 1 and 1A only): 15. Male or nonpregnant female adults aged ≥18 years at time of signing the ICF. 16. Diagnosis of diabetes mellitus (Type 1 or Type 2). Any of the following will be considered to be sufficient evidence that diabetes is present: 1. Current regular use of oral anti-hyperglycemic agents for the treatment of diabetes. 2. Current regular use of insulin or other injectable drugs (eg, dulaglutide and liraglutide) for the treatment of diabetes. 3. Documented diabetes by American Diabetic Association (ADA) and/or World Health Organization (WHO) criteria. 17. Hemoglobin A1c (HbA1c) ≤12% at Screening. 18. DME defined as macular thickening involving the center of the macula with CST of ≥325 μm using Spectralis® (Heidelberg Engineering, Heidelberg, Germany) SD-OCT at Screening. These inclusion criteria will be assessed by the Central Reader. 19. BCVA letter score between 75 and 23 letters (ETDRS chart) (20/32 to 20/320 Snellen equivalents) inclusive in the study eye at Baseline. 20. Previously treated subjects with at least 5 prior IVT injections with an anti-VEGF agent (aflibercept, bevacizumab, faricimab, ranibizumab, or any other approved anti-VEGF agent) with last treatment administered 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. This inclusion criterion will be assessed by the Investigator. 21. The Investigator attributes the cause of the decreased vision in the study eye primarily to DME.
Exclusion criteria
A subject who meets any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Stage 1 Safety Evaluation | 12 weeks | Safety of single dose of D-4517.2 as measured by Treatment-Emergent Adverse Events (TEAEs) |
| Stage 1A Safety Evaluation | 40 Weeks | Safety of multiple SC doses of D-4517.2 as measured by Treatment-Emergent Adverse Events (TEAEs) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Stage 1: Number of participants with Ocular and non-ocular adverse events (AEs) and serious adverse events (SAEs) observed for D-4517.2 and aflibercept | 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. | Participants with ocular and non-ocular adverse events and serious adverse events as measured by CTCAE v5.0 |
| Stage 1: Number of participants with change in best corrected visual acuity (BCVA) in study eye after each treatment (aflibercept or D-4517.2). | 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. | Participants with change in vision as measured best corrected visual acuity (BCVA) assessment. |
| Stage 1A: Effect of different D-4517.2 dose regimens to maintain BCVA and CST following a single IVT aflibercept dose | 12 weeks of Aflibercept and 40 weeks of D-4517.2 | Change from baseline in study eye BCVA measured by ETDRS letter score and in study eye CST and intra/sub-retinal fluid volume measured by SD-OCT |
| Stage 1A: Pharmacokinetics (Cmax) of D-4517.2 Repeat Dosing | 24 Weeks | D-4517.2 Cmax over the course of the study with repeat dosing |
| Stage 1: 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 | 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). | Change in sub-retinal fluid as measured by spectral domain optical coherence tomography (SD-OCT). |
| Stage 1A: Pharmacokinetics (Tmax) of D-4517.2 Repeat Dosing | 24 Weeks | D-4517.2 Tmax over the course of the study with repeat dosing |
| Stage 1A: Pharmacokinetics (CL/F) of D-4517.2 Repeat Dosing | 24 Weeks | D-4517.2 CL/F over the course of the study with repeat dosing |
| Stage 1A: Rescue Treatment | 12 weeks of Aflibercept and 40 weeks of D-4517.2 | Time in weeks for rescue treatment during each Treatment Period and proportion of treated subjects remaining rescue-free at each study visit |
| Stage 1A: Pharmacokinetics (AUC) of D-4517.2 Repeat Dosing | 24 Weeks | D-4517.2 AUC over the course of the study with repeat dosing |
| Stage 1: Number of participants with duration of effect of D-4517.2 as assessed by changes in subretinal fluid over time up to 12 weeks | 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. | Effect of D-4517.2 as measured by spectral domain optical coherence tomography (SD-OCT). |
Countries
United States
Outcome results
None listed