Safety, Tolerability and PK of Subcutaneous D-4517.2 in Subjects With Wet AMD or DME

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 belikely to complete the study.

2. Demonstrated response to prior anti-VEGF treatment as defined by one or more of thefollowing and as assessed by the Investigator for Stages 1 and 1A and confirmed bythe Central Reader for Stage 2:

3. Complete resolution or partial reduction of foveal intra- and/or subretinalfluid ≥ 30% from initial diagnosis as measured by SD-OCT.

4. Increase in BCVA ≥ 2 lines from initial diagnosis using Snellen scale.

5. Female subjects may be enrolled if they are:

6. Not pregnant, lactating, or breastfeeding

7. Documented in medical records or subject self-reported to be surgically sterileor postmenopausal.

8. Female subjects of childbearing potential must practice true abstinence for atleast 28 days prior to investigational product (IP) administration until 30days after the last IP administration and have a negative serum and urinepregnancy test at Screening and Baseline Day 1, respectively, or

9. 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) ornonhormonal methods (eg, intrauterine device or spermicidals) from Screening orat least 2 weeks prior to IP administration (whichever is earlier) until 30days after the last IP administration and having a negative serum and urinepregnancy test at Screening and Baseline Day 1, respectively.

10. Male subjects with female partners of childbearing potential may be enrolled if theyare:

11. Documented to be surgically sterile (vasectomy) in medical records or subjectself-reported, or

12. Agree to practice true abstinence during the study and for 30 days after thelast IP administration, or

13. Agree to use 2 adequate forms of highly effective contraception during thestudy, 1 of which should be a physical barrier for 30 days after the last IPadministration.

14. Must agree not to donate sperm during study and for 30 days followingadministration of the last dose of IP.

15. Subjects who complete the Aflibercept Treatment Period in Stage 1 are eligible toenroll in Stage 1A if they meet all eligibility requirements. These subjects willenter the study in the D-4517.2 Treatment Period.

16. Subjects who complete Stage 1 and/or Stage 1A are eligible to enroll in Stage 2 ifthey meet all eligibility requirements.

17. Ocular media clarity, pupillary dilation and individual cooperation sufficient foradequate fundus imaging in the opinion of the Investigator.

18. Recurrence of intra- or subretinal fluid at study Baseline. This inclusion criterionwill be confirmed by the Sponsor or Central Reader in Stages 1 and 1A and by theCentral Reader in Stage 2.

19. For subjects with bilateral disease, only one eye per subject can participate in thestudy. In cases where both eyes are eligible, the eye with the worse BCVA at theScreening 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):

20. Male or nonpregnant female adults aged ≥50 years at time of signing the informedconsent form (ICF).

21. BCVA letter score between 75 and 23 letters (ETDRS chart) (20/32 to 20/320 Snellenequivalents) inclusive in the study eye at Baseline and BCVA letter score of atleast 35 letters (ETDRS chart) (20/200 Snellen equivalent) in the non-study eye.

22. Previously treated subjects with at least 3 prior IVT injections with an anti-VEGFagent (aflibercept, bevacizumab, faricimab, ranibizumab, or any other approvedanti-VEGF agent) with last treatment administered between 4 and 12 weeks prior toScreening. Administration of IVT anti-VEGF agents prior to enrollment must not bemore than 12 weeks apart. This inclusion criterion will be assessed by theInvestigator.

23. For Stage 2, presence of a choroidal neovascular (CNV) lesion secondary to wAMDconfirmed by the Central Reader.

24. The Investigator attributes the cause of the decreased vision in the study eyeprimarily to wAMD. Subjects With DME (For Stages 1 and 1A only):

25. Male or nonpregnant female adults aged ≥18 years at time of signing the ICF.

26. Diagnosis of diabetes mellitus (Type 1 or Type 2). Any of the following will beconsidered to be sufficient evidence that diabetes is present:

27. Current regular use of oral anti-hyperglycemic agents for the treatment ofdiabetes.

28. Current regular use of insulin or other injectable drugs (eg, dulaglutide andliraglutide) for the treatment of diabetes.

29. Documented diabetes by American Diabetic Association (ADA) and/or World HealthOrganization (WHO) criteria.

30. Hemoglobin A1c (HbA1c) ≤12% at Screening.

31. DME defined as macular thickening involving the center of the macula with CST of ≥325 μm using Spectralis® (Heidelberg Engineering, Heidelberg, Germany) SD-OCT atScreening. These inclusion criteria will be assessed by the Central Reader.

32. BCVA letter score between 75 and 23 letters (ETDRS chart) (20/32 to 20/320 Snellenequivalents) inclusive in the study eye at Baseline.

33. Previously treated subjects with at least 5 prior IVT injections with an anti-VEGFagent (aflibercept, bevacizumab, faricimab, ranibizumab, or any other approvedanti-VEGF agent) with last treatment administered between 4 and 12 weeks prior toScreening. Administration of IVT anti-VEGF agents prior to enrollment must not bemore than 12 weeks apart. This inclusion criterion will be assessed by theInvestigator.

34. The Investigator attributes the cause of the decreased vision in the study eyeprimarily to DME.

Exclusion Criteria:

A subject who meets any of the following exclusion criteria will not be eligible for inclusion in the study:

Medical Conditions:

1. History, within 6 months prior to Screening, of any of the following: myocardialinfarction, any cardiac event requiring hospitalization, treatment for acutecongestive heart failure, transient ischemic attack or stroke.

2. Uncontrolled hypertension with systolic BP ≥160 mmHg and/or diastolic BP ≥100 mmHg (while subject at rest) at the Screening Visit. If the subject's initial readingexceeds these values, a second reading may be taken 30 minutes later on the sameday. If the subject's BP is controlled by antihypertensive medication, the subjectshould be taking the same medication continuously for at least 30 days prior to Day

4. Currently untreated diabetes mellitus, uncontrolled diabetes mellitus defined asHbA1c > 12%, or previously untreated subjects with diabetes mellitus who initiatedoral or injectable anti-diabetic medication within 3 months prior to Day 1.

5. Chronic renal disease requiring chronic hemodialysis or renal transplantation.

6. Abnormal liver function, as defined by transaminase or total bilirubin 2 times abovethe upper limit of normal at the Screening Visit.

7. Medical history of Wolff-Parkinson-White Syndrome, family history of long QT orplanned initiation or currently on medication prolonging QT time during the trial.

8. Known allergy to constituents of the study drug formulation, aflibercept, orclinically relevant hypersensitivity to fluorescein used by the subject during thestudy.

9. Serious systemic infections:

10. Any active infections for which systemic anti-infectives were used within 4weeks before Screening Visit.

11. Recurrent or chronic infections or other active infections that, in the opinionof the Investigator, might cause this study to be detrimental to the subject.

12. Any organic or psychiatric disorder, or laboratory abnormality which, in the opinionof the Investigator, will prevent the subject from completing the study activitiesas in the protocol or interfere with the interpretation of the study results.

13. An underlying condition (including, but not limited to metabolic, hematologic,renal, hepatic, pulmonary, neurologic, endocrine, cardiac, infectious, orgastrointestinal) or history of other disease, physical examination finding orclinical laboratory finding giving reasonable suspicion of a disease or conditionthat contraindicates the use of study drug, might affect interpretation of theresults of the study or which, in the opinion of the Investigator, renders thesubject at unacceptable risk of treatment complications by participating in thetrial.

14. Any major illness or surgical procedure within 1 month before Screening.

15. History of other diseases, physical examination finding, historical or currentclinical laboratory finding giving reasonable suspicion of condition thatcontraindicates the use of the IP or that might affect the interpretation of theresults of the study or renders the subject at high risk for treatmentcomplications, in the opinion of the Investigator.

16. Positive screen antibodies for hepatitis B or hepatitis C virus subsequentlyconfirmed to suggest active infection, or HIV type 1 or 2 antibodies. Prior/Concomitant Therapy:

17. Participation in any investigational study within 30 days prior to Screening, orplanned use of an IP or device during the study; any exposure to a priorinvestigational drug product must be fully washed out (at least 5 half-lives).

18. 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.

19. Use of systemic medications known to be toxic to the lens, retina or optic nerve (eg, deferoxamine, chloroquine/hydroxy-chloroquine, tamoxifen, phenothiazines, andethambutol) used during the 6 month or 5 half-lives (whichever is longer) prior toDay 1 or likely need to be used.

20. Use of systemic immunomodulatory treatments (eg, interleukin-6 inhibitors) within 6months or 5 half-lives (whichever is longer) prior to Day 1.

21. Use of systemic corticosteroids (ie, oral, IM, IV, intranasal) within 1 month priorto Day 1 and no corticosteroids anticipated throughout the trial.

22. Systemic treatment for suspected or active systemic infections.

23. Administration of systemic anti-VEGF or pro-VEGF treatment within 180 days or 5half-lives, whichever is longer, before Screening Visit.

24. Received blood transfusion within 3 months prior to the Screening Visit. Ocular Exclusion Criteria For Study Eye:

25. High risk proliferative diabetic retinopathy (DR) as assessed by the Investigator.

26. Any history of or ongoing rubeosis iridis.

27. Prior macular photocoagulation (defined as ≥ 100 burns placed previously outside ofthe posterior pole) in the study eye prior to Screening or expected to be receivedbetween the Screening Visit and Day 1.

28. History of treatment with periocular or IVT corticosteroids in the study eye in thepast 3 months and no such treatment planned for the time between Screening and Day

30. Treatment of DME or DR with macular laser.

31. Any intraocular surgery (eg, Cataract surgery) performed within 3 months prior toScreening or planned during the trial in the study eye.

32. Spherical equivalent of the refractive error in the study eye demonstrating morethan -8 diopters of myopia (prior to cataract or refractive surgery) at theScreening Visit.

33. Uncontrolled intraocular pressure (IOP), defined as an IOP ≥ 25 mmHg, despiteantiglaucoma medications in the study eye(s) at the time of Screening or controlledglaucoma that requires management with >2 topical hypotensive medications.

34. Presence of any clinically significant epiretinal membrane or vitreomacular tractionin the study eye(s).

35. History or evidence of any of the following surgeries or procedures in the studyeye(s):

36. Sub-macular surgery or other surgical intervention.

37. Prior retinal detachment or macular hole interventions.

38. History of vitreoretinal surgery or vitrectomy.

39. Photodynamic therapy or thermal laser retinal treatment of the macula or fovea.

40. Intraocular laser treatments for glaucoma (eg, selective laser trabeculoplastyor peripheral iridotomy).

41. Glaucoma filtering surgery (eg, trabeculectomy) or glaucoma drainage device (eg, Ahmed valve or Baerveldt valve) including minimally invasive glaucomashunts (eg, minimally invasive glaucoma surgery.

42. Neodymium: yttrium-aluminum-garnet (Nd:YAG) laser capsulotomy within the 30days prior to the Screening Visit.

43. Corneal refractive procedures (laser-assisted in situ keratomileusis [LASIK] orphotorefractive keratectomy) within the 6 months prior to the Screening Visitor planned during the study.

44. Corneal transplantation surgery.

45. History or clinical evidence of other concurrent conditions deemed by theInvestigator likely to impact the subject's clinical safety or interfere withinterpretation of study results including, but not limited to:

46. Inflammatory conditions of the anterior or posterior segment (eg, chronickeratoconjunctivitis, uveitis, retinal vasculitis, neuritis, iritis, scleritis,or blepharitis) in either eye.

47. Subretinal hemorrhage that is ≥ 50% of the total CNV lesion area.

48. Any vitreous opacity that prevents proper visualization of the fundus and/oradversely alters visual acuity, in the opinion of the Investigator.

49. Prior radiation therapy in the region of the eyes.

50. Presence of fibrosis as measured by SD-OCT and assessed by the Central Reader inStages 1 and 1A. Fibrosis or atrophy of more than 50% of the lesion size and/orinvolving the foveal center of the study eye at Screening; these criteria will beassessed by the Central Reader in Stage 2.

51. Current or history of vitreous hemorrhage in the study eye within 3 months ofScreening.

52. Any history of active or suspected ocular or periocular bacterial, viral, fungal orparasitic infections (eg, infectious or noninfectious conjunctivitis, keratitis,scleritis, endophthalmitis or other) in either eye within 30 days prior to ScreeningVisit. Other:

53. Has any finding that, in the view of the Investigator or Medical Monitor, wouldcompromise the subject's safety requirements.

54. Any previous treatment with ILUVIEN, Ozurdex, or Retisert (fluocinolone acetonideIVT implant) in the non-study eye.

55. DME subjects who have BCVA of hand motion or worse in the non-study eye ornon-physical presence of a non-study eye (ie, monocular).