Background: People with Von-Hippel-Lindau (VHL) disease may experience significant vision loss as a result of retinal capillary hemangiomas (RCH), the most common and often earliest manifestation of VHL.

Objective: To investigate the safety and possible efficacy of combination investigational treatment with serial intravitreal injections of E10030, a PDGF-B antagonist, and ranibizumab, a VEGF-A antagonist, in participants with severe ocular VHL disease.

Design: Three participants with severe ocular VHL disease will receive the combination investigational treatment in one eye and will be followed for 104 weeks.

Primary Outcome: The safety of the combination investigational treatment, assessed by tabulation of adverse events reported through Week 52.

Objective: Von Hippel-Lindau (VHL) disease is an autosomal dominant heritable disorder in which multiple benign and malignant neoplasms and cysts of specific histopathologies develop in the kidney, adrenal gland, pancreas, brain, spinal cord, eye, inner ear, epididymis and broad ligament. The disease affects about 7,000 individuals in the United States. Retinal capillary hemangiomas (RCH) are the most common and often the earliest manifestation of VHL disease and may lead to significant vision loss. In some such eyes, inexorable progression of RCH leads to blindness and phthisis bulbi despite aggressive treatment. Levels of vascular endothelial growth factor (VEGF), a potent mediator of angiogenesis and vascular permeability, have been shown to be elevated in multiple cell types deficient in the VHL protein (pVHL). Platelet-derived growth factor (PDGF), which has an important role in stabilization of immature new vessels during angiogenesis, is upregulated in pVHL-defective cell lines and expressed in other pVHL-defective tumors. Anti-VEGF therapy alone had no beneficial effect on ocular VHL disease in two previous phase 1 studies. The objective of this study is to investigate the safety and possible efficacy of combination investigational treatment with serial intravitreal injections of E10030, a PDGF-B antagonist, and ranibizumab, a VEGF-A antagonist, in participants with severe ocular VHL disease.

Study Population: Three participants with severe ocular VHL disease will receive the combination investigational treatment in one eye and will be followed for 104 weeks.

Design: In this phase I/II, single-center, prospective, open label, non-randomized, uncontrolled, single group trial, one eye of eligible participants will be treated with investigational products, E10030, a PDGF-B antagonist, and ranibizumab, a VEGF-A antagonist. Participants will receive combination investigational treatment consisting of intravitreal injections of E10030 (1.5 mg in 0.05 mL) and ranibizumab (0.5 mg in 0.05 mL) every four weeks from baseline through Week 16 (totaling five treatments) and then every eight weeks through Week 48 (totaling nine treatments from baseline). All participants will be followed for 104 weeks.

Outcome Measures: The primary outcome for the study will be safety of the combination investigational treatment, assessed by tabulation of adverse events reported through Week 52. Secondary outcomes will include tabulation of adverse events at Week 104, and the following measures in the study eye at Week 52 and 104: the proportion of participants experiencing reduction in size of at least one RCH in the absence of other ablative treatment (assessed by fundus photography and fluorescein angiography (FA)); the proportion of participants experiencing moderate vision loss (defined as a loss of greater than or equal to 15 letters from baseline on Electronic Visual Acuity (EVA) testing); mean change in visual acuity; change in size of RCH (measured by fundus photography and FA); change in exudation (measured by fundus photography, optical coherence tomography (OCT) and FA); change in epiretinal proliferation, fibrosis or retinal traction (assessed by OCT and fundus photography); proportion of participants undergoing ablative treatment of RCH or ocular surgery; proportion of participants with successful ablative treatment of RCH; and the proportion of participants with appearance of one or more new RCH.

• Participant Eligibility Criteria

The participant must meet all of the eligibility criteria and none of the exclusion criteria below.

INCLUSION CRITERIA:

1. Participant must understand and sign the informed consent.

2. Participant must be 18 years of age or older.

3. Participant must have a diagnosis of VHL disease. In accordance with established criteria for diagnosis, any one of the following will be considered sufficient evidence that VHL disease is present:

   • A family history of VHL disease plus one or more of the following lesions: RCH, spinal or cerebellar hemangioblastoma, pheochromocytoma, multiple pancreatic cysts, epididymal or broad ligament cystadenomas, multiple renal cysts or renal cell carcinoma before age 60 years.
   • Presence of two or more hemangioblastomas of the retina or brain or a single hemangioblastoma in association with a visceral manifestation such as kidney or pancreatic cysts; renal cell carcinoma; adrenal or extra-adrenal pheochromocytomas; endolymphatic sac tumors; papillary cystadenomas of the epididymis or broad ligament; or neuroendocrine tumors of the pancreas.
   • Presence of a known disease-causing germline mutation in the VHL gene.

4. Any female participant of childbearing potential must not be pregnant or breast-feeding, must have a negative pregnancy test at screening and must be willing to undergo pregnancy testing immediately prior to each treatment.

5. Any female participant of childbearing potential and any male participant able to father children must have (or have a partner who has) had a hysterectomy or vasectomy, be completely abstinent from intercourse or must agree to practice two effective methods of contraception throughout the course of the study and for at least two months following the last administration of combination investigational treatment. Acceptable methods of contraception include:

   • hormonal contraception (i.e., birth control pills, injected hormones, dermal patch or vaginal ring),
   • intrauterine device,
   • barrier methods (diaphragm or condom) with spermicide, or
   • surgical sterilization (hysterectomy, tubal ligation or vasectomy).

EXCLUSION CRITERIA:

1. Participant has a history or evidence of significant cardiac disease (for example, use of cardiac medications aside from agents to control blood pressure, past acute coronary syndrome, past myocardial infarction, past revascularization procedure or arrhythmias requiring past or present treatment).

2. Participant has a history of stroke or transient ischemic attack.

   Note: cerebrovascular manifestations and/or complications of central nervous system hemangioblastomas are not exclusionary, in the absence of past stroke or transient ischemic attack.

3. Participant has used systemic medication with significant anti-VEGF or anti-PDGF activity within 30 days of study entry or expects use of such a medication within 12 months of study entry.

4. Participant is medically unable to comply with study procedures or follow-up in the judgment of the investigator.

5. Participant has a diagnosis of diabetic mellitus (type 1 or type 2). Any one of the following will be considered sufficient evidence that diabetes is present:

   • Current regular use of insulin for the treatment of diabetes,
   • Current regular use of oral anti-hyperglycemia agents for the treatment of diabetes,
   • Hemoglobin A1C of greater than or equal to 6.5%, or
   • Documented diabetes by the American Diabetes Association (ADA) and/or World Health Organization (WHO) criteria.

Study Eye Eligibility Criteria

The participant must have at least one eye meeting all inclusion criteria and none of the exclusion criteria listed below.

INCLUSION CRITERIA:

1. Participant has at least one RCH secondary to VHL disease in the study eye that fulfills the following criteria:

   1. The RCH must exhibit growth potential with consequent threat to vision. Growth potential with consequent threat to vision is defined by AT LEAST ONE of the following:

      • Associated intra- or sub-retinal exudation or lipid deposition that, in the judgment of the investigator, reflects ongoing vascular incompetence and is not solely reflective of residual changes following previous treatment or solely secondary to coexistent retinal traction.
      • Increased size of the tumor compared to a previous time point as assessed by fundus photography or FA.
      • Associated intra-, sub- or pre-retinal hemorrhage not secondary to previous treatment, as assessed by fundus photography or FA.
      • The presence of dilated and/or tortuous feeder vessels.
      • Vitreous cell or haze indicative of vitreous exudation, in the absence of other ocular features potentially responsible for such findings.

   2. The RCH, in the judgment of the investigator, is NOT readily treatable using thermal laser because of its size, posterior location, poor previous response to conventional therapy, association with significant exudation, epiretinal proliferation, associated vascular abnormalities such as vascular proliferation or diffusely incompetent retinal vessels, or other factors predictive of a poor response to standard of care approaches.

2. The study eye must have clarity of ocular media and degree of pupil dilation sufficient to permit adequate fundus photography.

EXCLUSION CRITERIA:

1. The study eye has present or chronic ocular or periocular infection (including any history of ocular herpes zoster).

2. The study eye has chronic glaucoma; OR has received anti-glaucoma medication at any time within 90 days of study entry; OR has significant ocular hypertension, defined as documented intraocular pressure of greater than or equal to 28 mmHg on any occasion in the absence of self-limited acute glaucoma, OR greater than or equal to 24 mmHg on at least two occasions in the absence of self-limited acute glaucoma.

   Note: History of self-limited acute glaucoma in a study eye, if now resolved and not expected to recur, is not exclusionary. History of glaucoma or ocular hypertension in the fellow eye, if not felt to significantly impact risk of glaucoma in the study eye, is not exclusionary.

3. The study eye has undergone any surgical procedure within 60 days prior to study entry (inclusive of cryotherapy or thermal laser).

4. The study eye has a history of intravitreal injection of an anti-VEGF agent (such as bevacizumab, ranibizumab or aflibercept) within 42 days prior to study entry.

5. The study eye has a history of intravitreal or periocular injection of long-acting corticosteroids (such as triamcinolone acetonide) within 90 days of study entry or history of any sustained-release ocular drug delivery device with reasonable expectation of residual activity in the study eye.

Choice of Study Eye in Cases of Bilateral Eligibility

If both eyes of a participant meet the criteria described above, the investigator will choose to enroll one eye in consultation with the participant.