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

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

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 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

Resource links provided by the National Library of Medicine

Drug Information available for: Ranibizumab

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




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.



Information from the National Library of Medicine

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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02543229


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

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

Additional relevant MeSH terms:
Macular Degeneration
Neovascularization, Pathologic
Eye Diseases
Retinal Diseases
Retinal Degeneration
Metaplasia
Pathologic Processes
Ranibizumab
Immunologic Factors
Physiological Effects of Drugs
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Antineoplastic Agents