Study Evaluating the Safety, Pharmacokinetics and Pharmacodynamics of OPT-302 With or Without Lucentis™ in Patients With Wet AMD

Sponsor

Opthea Limited (Industry)

Overall Status

Completed

CT.gov ID

NCT02543229

Collaborator

(none)

Enrollment

Locations

Arms

26.1

Duration (Months)

3.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this first-in-human study is to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics of OPT-302 administered as monthly intravitreal injections for 3 months with and without Lucentis™ in patients with wet age related macular degeneration (AMD). This study will be conducted in two parts: Part 1 will comprise an open label, sequential dose escalation and Part 2 a randomized dose expansion.

OPT-302 is a soluble form of VEGFR-3 comprising the extracellular domains 1-3 of human vascular endothelial growth factor receptor (VEGFR)-3 and the Fc fragment of human IgG1. It functions by binding and neutralizing the activity of vascular endothelial growth factor (VEGF)-C and VEGF-D on endogenous VEGFR-2 and VEGFR-3.

VEGF-C and VEGF-D promote blood vessel development (angiogenesis) by binding and activating VEGFR-2 and VEGFR-3. VEGF-C is also a potent inducer of vascular permeability or leakage. Angiogenesis and vascular leakage are key hallmarks of wet AMD. Approved therapies for wet AMD include Eylea™ and Lucentis™ which block the activity of VEGF-A, but not VEGF-C or VEGF-D which are alternate members of the same family of molecules.

VEGF-C and VEGF-D can stimulate blood vessel growth and leakage through the same pathway as VEGF-A (via VEGFR-2), as well as through pathways that are independent of VEGF-A (via VEGFR-3). Published studies have also indicated that VEGF-C and VEGF-D play an important role in mediating resistance to therapies that block VEGF-A such as Lucentis™ and Eylea™.

Combination therapy with OPT-302 an anti-VEGF-A agent provides a more complete blockade of the VEGF family. This strategy targets functional redundancy in the VEGF pathway and mechanisms of 'resistance' or sub-response to VEGF-A inhibition.

Condition or Disease	Intervention/Treatment	Phase
Eye Diseases Macular Degeneration Retinal Diseases Retinal Degeneration Neovascularization, Pathologic	Drug: OPT-302 Drug: Lucentis™	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

51 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Phase 1 Dose Escalation Study Evaluating the Safety, Pharmacokinetics and Pharmacodynamics of OPT-302 in Combination With Ranibizumab in Subjects With Wet AMD

Study Start Date :

Jul 1, 2015

Actual Primary Completion Date :

Feb 7, 2017

Actual Study Completion Date :

Sep 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part 1 Dose escalation - Cohort 1 Dose Level 1 of OPT-302 in combination with Lucentis™	Drug: OPT-302 OPT-302 will be administered by intravitreal injection once every month for 3 months Drug: Lucentis™ Lucentis™ (0.5 mg) will be administered by intravitreal injection once every month for 3 months Other Names: Ranibizumab
Experimental: Part 1 Dose escalation - Cohort 2 Dose Level 2 of OPT-302 in combination with Lucentis™	Drug: OPT-302 OPT-302 will be administered by intravitreal injection once every month for 3 months Drug: Lucentis™ Lucentis™ (0.5 mg) will be administered by intravitreal injection once every month for 3 months Other Names: Ranibizumab
Experimental: Part 1 Dose escalation - Cohort 3 Dose Level 3 of OPT-302 in combination with Lucentis™	Drug: OPT-302 OPT-302 will be administered by intravitreal injection once every month for 3 months Drug: Lucentis™ Lucentis™ (0.5 mg) will be administered by intravitreal injection once every month for 3 months Other Names: Ranibizumab
Experimental: Part 1 Dose escalation - Cohort 4 Dose Level 3 of OPT-302 monotherapy	Drug: OPT-302 OPT-302 will be administered by intravitreal injection once every month for 3 months
Experimental: Part 2 Dose expansion - Cohort 5 OPT-302 (at Maximum Tolerated Dose [MTD] or highest dose tested in Part 1) in combination with Lucentis™	Drug: OPT-302 OPT-302 will be administered by intravitreal injection once every month for 3 months Drug: Lucentis™ Lucentis™ (0.5 mg) will be administered by intravitreal injection once every month for 3 months Other Names: Ranibizumab
Experimental: Part 2 Dose expansion - Cohort 6 OPT-302 (at MTD or highest dose tested in Part 1) monotherapy	Drug: OPT-302 OPT-302 will be administered by intravitreal injection once every month for 3 months

Outcome Measures

Primary Outcome Measures

Safety (Adverse Events) [Up to 1 month after the last dose]
Subject incidences of ophthalmic and systemic Adverse Events during study and follow-up period

Secondary Outcome Measures

Mean change in Best Corrected Visual Acuity (BCVA) from baseline [6 months]
Mean change in Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA from baseline
Mean change in central retinal thickness from baseline [6 months]
Changes in intra- or sub-retinal fluid measured as mean change in central retinal thickness or macula volume by Spectral Domain Optical Coherence Tomography (SD-OCT)
Mean change in Choroidal Neovascularization (CNV) lesion area from baseline [6 months]
Change in CNV size according to fluorescein angiogram
Mean number of retreatment injections of anti-VEGF-A therapy during long term follow-up (week 12 to 24) [3 months]
Need for 'rescue therapy' with ranibizumab in subjects receiving OPT-302 monotherapy [3 months]
Assess the Pharmacokinetic profile of OPT-302 alone and in combination with ranibizumab following intravitreal administration [Up to 28 days post-dose]
Mean systemic OPT-302 Concentration-Time profile
Anti-OPT-302 antibody formation [Pre-dose and up to 3 months post-dose]
Incidence of anti-OPT-302 antibody formation

Other Outcome Measures

Exploratory: Changes in the systemic blood levels of angiogenesis-related biomarkers [3 months]
Change in systemic blood levels of angiogenesis-related biomarkers including, but not limited to: Vascular Endothelial Growth Factor A (VEGF-A), VEGF-C, VEGF-D, soluble VEGFR-2 and soluble VEGFR-3.

Eligibility Criteria

Criteria

Ages Eligible for Study:

50 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Able and willing to provide written informed consent
Age ≥ 50 years of either gender
Active CNV lesions secondary to AMD (i.e., subretinal or intraretinal fluid on SD-OCT and / or leakage on fluorescein angiography)
Either no previous treatment in the study eye with IVT anti-VEGF-A therapy (treatment naïve) or prior IVT anti-VEGF-A therapy (previously treated) with sub-optimal response to treatment and the need for additional treatment
Best corrected visual acuity in the study eye, using ETDRS testing, of 20/320 or better (Snellen equivalent) in Part 1 (dose escalation) and between 20/40 and 20/320 (Snellen equivalent), inclusive, in Part 2 (dose expansion).
Women of child bearing potential and male subjects with female partners of child bearing potential must be practicing effective contraception during the trial and for at least 3 months following the last dose of study medication

Exclusion Criteria:

Previous or concurrent use of systemic anti-VEGF-A agents
Most recent IVT injection of bevacizumab or ranibizumab <28 days prior to screening or aflibercept <42 days prior to screening
Previous treatment with photodynamic therapy, thermal laser or external beam radiation in the study eye
Concurrent treatment in either eye for any ocular condition with an investigational drug or device that has not received regulatory approval
Anatomic damage to the center of the fovea including fibrosis and scarring making up

50% of total lesion area including the CNV in the study eye

Geographic atrophy involving the center of the fovea in the study eye
History or presence of a retinal pigment epithelial tear
Presence of polypoidal choroidal vasculopathy (if in the opinion of the investigator, anti-VEGF treatment would not be of benefit) or retinal angiomatous proliferation
Active or recent (within 4 weeks) intraocular inflammation (grade trace or above) in the study eye
History of rhegmatogenous retinal detachment or macular hole in the study eye
History of vitrectomy
Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye
History of vitreous hemorrhage within 4 weeks prior to screening in the study eye
History of major ocular surgery within prior 6 months or anticipated within next 3 months following dosing on day 1
Uncontrolled glaucoma in the study eye (defined as intraocular pressure of >25 mmHg despite treatment with maximal medical therapy)
Uncontrolled hypertension ≥180 mmHg systolic or ≥110 mmHg diastolic at baseline
Uncontrolled diabetes mellitus (Disease must be controlled with hemoglobin A1c (HgbA1c) < 9.0%)
Clinical evidence of diabetic retinopathies, diabetic macular edema or any other vascular disease affecting the retina, other than AMD, in either eye that, in the opinion of the investigator, would be likely to limit improvement in the macular anatomy and/or function
Pregnancy or lactation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Opthea Investigative Site	Phoenix	Arizona	United States	85014
2	Opthea Investigative Site	Beverly Hills	California	United States	90211
3	Opthea Investigative Site	Sacramento	California	United States	95819
4	Opthea Investigative Site	Santa Maria	California	United States	93454
5	Opthea Investigative Site	Fort Myers	Florida	United States	33912
6	Opthea Investigative Site	Pensacola	Florida	United States	32503
7	Opthea Investigative Site	Winter Haven	Florida	United States	33800
8	Opthea Investigative Site	Wichita	Kansas	United States	67214
9	Opthea Investigative Site	Bloomfield	New Jersey	United States	07003
10	Opthea Investigative Site	Charlotte	North Carolina	United States	28210
11	Opthea Investigative Site	Cleveland	Ohio	United States	44122
12	Opthea Investigative Site	West Columbia	South Carolina	United States	29169
13	Opthea Investigative Site	Abilene	Texas	United States	79606
14	Opthea Investigative Site	Willow Park	Texas	United States	76087