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

• ClinicalTrials.gov Identifier: NCT02543229
• Recruitment Status: Completed
• First Posted: September 7, 2015
• Last Update Posted: November 6, 2017
• Sponsor: Opthea Limited
• Information provided by (Responsible Party): Opthea Limited

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 (Clinical Trial)
• 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: July 2015
• Actual Primary Completion Date: February 7, 2017
• Actual Study Completion Date: September 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 Name: 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 Name: 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 Name: 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 Name: 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 :

1. Safety (Adverse Events) [ Time Frame: 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 :

1. Mean change in Best Corrected Visual Acuity (BCVA) from baseline [ Time Frame: 6 months ]
   Mean change in Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA from baseline
2. Mean change in central retinal thickness from baseline [ Time Frame: 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)
3. Mean change in Choroidal Neovascularization (CNV) lesion area from baseline [ Time Frame: 6 months ]
   Change in CNV size according to fluorescein angiogram
4. Mean number of retreatment injections of anti-VEGF-A therapy during long term follow-up (week 12 to 24) [ Time Frame: 3 months ]
5. Need for 'rescue therapy' with ranibizumab in subjects receiving OPT-302 monotherapy [ Time Frame: 3 months ]
6. Assess the Pharmacokinetic profile of OPT-302 alone and in combination with ranibizumab following intravitreal administration [ Time Frame: Up to 28 days post-dose ]
   Mean systemic OPT-302 Concentration-Time profile
7. Anti-OPT-302 antibody formation [ Time Frame: Pre-dose and up to 3 months post-dose ]
   Incidence of anti-OPT-302 antibody formation

Other Outcome Measures:

1. Exploratory: Changes in the systemic blood levels of angiogenesis-related biomarkers [ Time Frame: 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

• Ages Eligible for Study: 50 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

United States, Arizona

Opthea Investigative Site

Phoenix, Arizona, United States, 85014

United States, California

Opthea Investigative Site

Beverly Hills, California, United States, 90211

Opthea Investigative Site

Sacramento, California, United States, 95819

Opthea Investigative Site

Santa Maria, California, United States, 93454

United States, Florida

Opthea Investigative Site

Fort Myers, Florida, United States, 33912

Opthea Investigative Site

Pensacola, Florida, United States, 32503

Opthea Investigative Site

Winter Haven, Florida, United States, 33800

United States, Kansas

Opthea Investigative Site

Wichita, Kansas, United States, 67214

United States, New Jersey

Opthea Investigative Site

Bloomfield, New Jersey, United States, 07003

United States, North Carolina

Opthea Investigative Site

Charlotte, North Carolina, United States, 28210

United States, Ohio

Opthea Investigative Site

Cleveland, Ohio, United States, 44122

United States, South Carolina

Opthea Investigative Site

West Columbia, South Carolina, United States, 29169

United States, Texas

Opthea Investigative Site

Abilene, Texas, United States, 79606

Opthea Investigative Site

Willow Park, Texas, United States, 76087

Sponsors and Collaborators

Opthea Limited

Investigators

• Study Director: Clinical Research; Opthea Limited

More Information

• Responsible Party: Opthea Limited
• ClinicalTrials.gov Identifier: NCT02543229
• Other Study ID Numbers: OPT-302-1001
• First Posted: September 7, 2015
• Last Update Posted: November 6, 2017
• Last Verified: November 2017

Additional relevant MeSH terms:

Macular Degeneration; Eye Diseases; Retinal Diseases; Retinal Degeneration; Neovascularization, Pathologic; Metaplasia; Pathologic Processes; Eye Diseases, Hereditary; Ranibizumab; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors; Antineoplastic Agents