Carbidopa-levodopa in Neovascular AMD

Age-related macular degeneration (AMD) is the most common cause of blindness, in individuals
over the age of 50, in the developed world. AMD becomes more common as people age, and is
more common in lightly pigmented individuals. AMD appears more common in patients with
Parkinson's Disease, than in those without. The AREDS nutritional supplements are effective
in slowing the progress of intermediate AMD(5). Most AMD is "dry AMD", which progresses
relatively slowly and may impair vision, but usually does not lead to legal blindness. There
are two forms of AMD, "wet AMD" and geographic atrophy (GA), that can cause more profound
vision loss. In aggregate they occur in about 25% patients with AMD. Wet AMD is due to new
growth of abnormal blood vessels under the retina. The new blood vessels are believed to be
due to an excessive release of vascular endothelial growth factor (VEGF) by the retinal
pigment epithelium(RPE) cells. Wet AMD is now effectively treated with intraocular injections
of VEGF inhibitors. Geographic Atrophy, the other form of advanced AMD, represents focal
death of the RPE cells and overlying neurosensory retina. There is no current treatment for
GA. It is suspected that GA is due in part to a localized inflammatory response, damage to
RPE cells and loss of RPE cell function. It may also be speculated that stimulation of RPE
cells to release a potent neurotrophic factor, pigment epithelium derived factor (PEDF) may
slow progression of GA.

In 2008, Dr. Brian McKay identified a receptor, G protein coupled receptor #143(GPR143), on
the surface of RPE cells and discovered that L-DOPA was the natural ligand or stimulator of
GPR143. Dr McKay showed that treatment of RPE cells with exogenous L-DOPA resulted in the
release of additional PEDF. In subsequent work Dr McKay's group also showed that L-DOPA
stimulation of PEDF in RPE cells was also associated with a decrease in VEGF. Thus, Dr McKay
hypothesized that exogenous L-DOPA may prevent the onset of AMD or progression to wet AMD.

In 2015, Dr McKay and his associates published a paper that showed that patients, who had
been treated with L-DOPA, had a delay in the onset of AMD by 8 years, compared to patients
who had not been treated with L-DOPA. In addition, those who had AMD and went on to develop
wet AMD, did so 5 years later than those with no history of L-DOPA treatment. L-DOPA is an
intermediate in the pigmentation pathway. Dr McKay and his associates suggested that the
reason darkly pigmented races do not get AMD nearly as frequently as lighter pigmented races,
is that they produce more pigment, and thus more L-DOPA to stimulate GPR143 on RPE cells.
According to this hypothesis, the stimulated RPE cells release PEDF and decrease VEGF, which
together are responsible for the protective effect.

Since there are no established animal models for AMD, and L-DOPA has a good safety profile in
healthy volunteers and patients with Parkinson's disease, the Investigators propose a
prospective experiment to determine the safety and tolerability of L-DOPA, in a population of
patients with AMD. The participants will be made aware of potential side effects of L-DOPA,
which are listed in the Informed Consent, during the consent process. Adverse events will be
elicited by questioning the participants at each visit. The participants will also be advised
to call the site, if they have any medical problem between visits.

The Investigators will also use this study to examine whether L-DOPA has a positive effect on
visual acuity and pathologic retinal changes of "wet" AMD. The parameters to be evaluated are
best corrected ETDRS visual acuity, macular thickness by spectral domain optical coherence
tomography (SD OCT), new blood (hemorrhage) by direct retinal examination, or subjective
decrease in vision.

Pharmacology of L-DOPA and carbidopa:

L-DOPA is formed by 3-hydroxylation of tyrosine by tyrosine-3-monooxygenase (tyrosinase).(18)
The primary metabolic pathway of L-DOPA is decarboxylation by amino acid decarboxylase to
dopamine, which is responsible for most, but not all, of its pharmacologic effects and
toxicity. When carbidopa is administered with L-DOPA, systemic levels of L-DOPA double and
central nervous system (CNS) L-DOPA increases from about 1% of the administered dose to about
4%. Levodopa freely passes from the systemic circulation into the retina and brain, but
dopamine and carbidopa do not. Adverse events are markedly decreased when carbidopa is
administered with L-DOPA, because systemic levels of the toxic metabolite of L-DOPA,
dopamine, are markedly reduced. In most patients, 25 mg of carbidopa is sufficient to control
side effects of 100 mg of L-DOPA, primarily nausea, by 90%.

L-DOPA is the natural ligand for GPR143 in the RPE cells. The Investigators' intent is to
increase the L-DOPA available to RPE surface receptors (GPR 143) while minimizing peripheral
toxicity. This concept is unique, because all other uses of L-DOPA rely on CNS conversion of
L-DOPA to dopamine, in order to produce the desired effect.

Excess VEGF is the mediator of the retinal neovascularization and other retinal pathological
changes in "wet" AMD. Intraocular injections of anti-VEGF antibodies is the standard of care
in "Wet" AMD. Several publications, including Lim et al, show that with careful monitoring of
the visual acuity and retinas of patients with wet AMD, if there is no progression, there are
no long-term adverse consequences of delaying initiation of anti-VEGF therapy for up to 4
weeks. The patients will be monitored at weekly intervals, for up to 4 weeks, for indications
for initiation of anti-VEGF injections.

Criteria for anti-VEGF injections

This will be based on: weekly evaluation of ETDRS visual acuity (decrease of 5 letters from
previous visit); increased macular thickness (compared to normal and previous visit as
measured by OCT; new blood (hemorrhage) on direct retinal examination; or subjective decrease
in vision. If any of these criteria are met, or if, in the opinion of the Ophthalmologist,
the patient requires anti-VEGF therapy, the patient will have an anti-VEGF intraocular
injection. If none of these criteria are met at visits 2, 3 or 4, with patient agreement,
anti-VEGF injection will not be done, and the patient will be reevaluated in 1 week. The
patients will receive an anti-VEGF injection at the end of the 4th week, if they have not
received one earlier. Whenever a patient receives the first anti-VEGF injection,
participation in this protocol will end. At that point, the patient will be able to enroll in
Study 0002, Proof of Concept and Dose Ranging Study of carbidopa-levodopa in Neovascular AMD.

Treatments:

Randomized assignment to carbidopa-levodopa 25-100 mg tablets dosed hs or carbidopa-levodopa
25-100 mg tablets dosed 3 times daily, in the morning, with supper and hs. The second dosing
regimen is the equivalent of a moderate dose of carbidopa-levodopa in patients with
Parkinson's disease (maximum daily dose of levodopa 200-800 mg).

Number of participants: Up to 52 completed, randomized using a table of random numbers.

Informed Consent will be completed at the first visit. Duration: up to 32 days of treatment.
Visits will occur at 5-8 day intervals. Overall trial duration for enrollment and treatment,
screening 5 patients per week, will be approximately 10 months.

Primary Endpoint: A statistically significant improvement (5 letters) by carbidopa-levodopa
treatment in ETDRS visual acuity.

Measurements:

Demographics at Visit 1; Medical History and Physical Examination at Visit 1;
Electrocardiogram(ECG), complete blood count(CBC), Chem 20 and HbA1C at Visit 1; Vital signs
at Visits 1,2,3,4 and 5; Non-directed assessment of adverse events at Visits 1,2,3,4 and 5.
SD OCT at Visits 1,2,3,4,5; Pill count at Visits 2,3,4 and 5;

Statistics: Analysis of Variance with Independent Variables for each arm and comparing arms:

ETDRS visual acuity, central retinal (macular) thickness, presence of hemorrage and duration
of treatment prior to initiation of anti VEGF intraocular injections.

Inclusion Criteria:

1. A diagnosis of AMD with choroidal neovascularization (CNV) in one eye;

2. Not previously treated with anti-VEGF injections;

3. Normal or dry AMD of any grade in the second eye;

4. Age 50-85 years;

5. Willingness to maintain AREDS vitamin supplements throughout the study, or remain off
these supplements for the duration of the study, if not taking them prior to the
study;

6. Signed Informed Consent.

Exclusion Criteria:

1. Any current use of L-DOPA containing medication or dopamine agonist medication, or any
planned use of any of these agents, except for study medication, during the study;

2. Concurrent use of monoamine oxidase (MAO) inhibitors;

3. Any eye condition, disease, or history of trauma in either eye, which can impair
vision, except cataract or cataract surgery;

4. BCVA worse than 20/160 in the better eye;

5. Wet AMD in the second eye;

6. Neurologic conditions which can impair vision;

7. Parkinson's Disease;

8. Significant orthostatic hypotension, defined as a drop in systolic blood pressure,
immediately upon changing from the supine to standing position, of >19 mmHg, or a
symptomatic drop in systolic blood pressure, immediately upon changing from the supine
to standing position;

9. Significant ECG abnormalities, as judged by the Investigator;

10. Estimated glomerular filtration rate (eGFR) <20 ml/min;

11. Liver enzymes >3 X the upper limit of normal;

12. HbA1C >9.0;

13. Any other significant lab abnormalities, as judged by the Investigator;

14. Women of childbearing potential;

15. Known retinal hemorrhage;

16. Subjects who are not fluent in English.