Aclarubicin for the Treatment of Retinal Vasculopathy With Cerebral Leukodystrophy

Retinal vasculopathy with cerebral leukodystrophy (RVCL) is a very rare and uniformly fatal
genetic condition that affects the microvasculature. Symptoms begin in adulthood (usually in
the 40s) and include loss of vision, mini-strokes, and dementia. RVCL includes three
conditions which were previously thought to be distinct: hereditary endotheliopathy,
retinopathy, nephropathy, and stroke (HERNS); cerebroretinal vasculopathy (CRV); and
hereditary vascular retinopathy (HVR). RVCL is inherited in an autosomal dominant manner and
is caused by carboxyl (C)-terminal heterozygous frameshift (fs) mutations in TREX1 (Three
Prime Repair Exonuclease 1). There is no treatment for RVCL, only symptomatic management.

TREX1 is an endoplasmic reticulum (ER)-associated (i.e., intracellular) enzyme that, in
addition to its DNA repair activities, may regulate sugar metabolism in the ER. TREX1
mutations have also been associated with several autoimmune and autoinflammatory diseases. In
RVCL, fs mutations of TREX1 result in C-terminal truncation and this dysregulates the
oligosaccharyltransferase (OST) complex leading to free glycan release from dolichol
carriers. In mouse models and in patient-derived cells, inhibiting OST with aclarubicin may
correct glycan and immune defects associated with fs mutations of TREX1 (Hasan, M. et al.,
Immunity 43: 1-12, 2015).

Aclarubicin (aka aclacinomycin, aclacinomycin-A) is an anthracycline antibiotic isolated from
Streptomyces galilaeus cultures. Aclarubicin has been shown to have a broad spectrum of
anti-tumor activity. Aclarubicin was utilized for treatment of various cancers in Phase 1 and
2 studies in the United States of American (USA) in the 1980's and 1990's. While no longer
clinically employed in the USA, it is commonly used in China and Japan, often as part of a
combination drug therapy program for certain malignancies.

Aclarubicin is typically administered over 3-5 consecutive days, however, alternative
schedules such as weekly or monthly have been evaluated. In solid tumors, the maximum
tolerated dose (MTD) of 4-day dosing was 30 mg/m2/day; marrow suppression was dose limiting,
otherwise the regimen was well tolerated. Additionally, a Phase II study in acute
myeloblastic leukemia was conducted using 100mg/m2 per day for three days and repeated at
days 14-16 if marrow hypoplasia was not produced. Toxic effects of this regimen included
severe neutropenia, nasea/vomiting, and diarrhea. No changes were noted in left ventricular
ejection fraction or no cardiac symptoms developed.

RVCL is caused by fs mutations in the C-terminus of TREX1 resulting in low-grade free glycan
release, immune activation, and possibly autoantibody production due in part to dysregulation
of the OST complex. Inhibiting OST with aclarubicin corrects these glycan and immune defects
in mouse models and in patient-derived cells. Thus, inhibiting OST with aclarubicin might be
a therapeutic option for patients with RVCL.

Given the poor prognosis of RVCL, the lack of treatment options, and the pre-clinical data on
OST inhibition by aclarubicin in mice, there is strong rationale for conducting a clinical
trial of aclarubicin in patients with RVCL.

In this pilot study, aclarubicin will be administered initially at ~ 20% of the single-agent
maximum tolerated dose (MTD) in oncology studies. Assessments will be made every six months
as to objectives of the study. Patients that do not have clear objective response may have
their dose level increased with permission of the principal investigator permitting the
patient has not previously experienced any toxicities requiring dose modifications. A patient
who has clear objective progression at any time may also have their dose escalated as long as
they have completed 1 full cycle at their current dose level. Maximum dose level will be 24
mg/m2/day. The aim of aclarubicin administration in RVCL is not to induce apoptosis, as in
oncology studies, but rather to modulate intracellular functions and, thus, a reduced dose
will be utilized.

Inclusion Criteria:

1. A diagnosis of Retinal Vasculopathy with Cerebral Leukodystrophy (RVCL)

2. At least 18 years of age at the time of study registration

3. Normal hematologic function defined as: WBC (white blood cell count) > 4 x10⁹/L, ANC
(absolute neutrophil count) ( >1.5 x 10⁹/L and Platelets > 100 x10⁹/L

4. Females of childbearing potential (FCBP) must agree to refrain from becoming pregnant
while on study drug and for 3 months after discontinuation from study drug, and must
agree to use adequate contraception including hormonal contraception, (i.e. birth
control pills, etc), barrier method contraception (i.e. condoms), or abstinence during
that time frame.

5. Able to understand and willing to sign an IRB (Institutional Review Board) approved
written informed consent document (or that of legally authorized representative, if
applicable)

Exclusion Criteria:

1. Acute bacterial, fungal, or viral infection

2. Known human immunodeficiency virus (HIV) or active hepatitis B or C virus infection

3. Pregnant and/or breastfeeding

4. Cardiovascular disease including: congestive heart failure [left ventricular ejection
fraction (LVEF) < 55%] at screening; electrocardiogram (EKG) evidence of acute
ischemia or medically significant conduction system abnormalities; or unstable
arrhythmia or angina

5. Cumulative prior anthracycline dose of 300 mg/m²

6. Known hypersensitivity to one or more of the study agents

7. Currently receiving or has received any investigational drugs within the 14 days prior
to the first dose of study drug

8. Currently receiving or has received any immunosuppressants within the 14 days prior to
the first dose of study drug