A Phase I/II Trial for Intravitreous Treatment of Severe Ocular Von Hippel-Lindau Disease Using a Combination of the PDGF Antagonist E10030 and the VEGF Antagonist Ranibizumab

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 (see Appendix 1 for definition) 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 (see Appendix 1 for definition) 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 ADA and/or 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.