HERV-K Suppression Using Antiretroviral Therapy in Volunteers With Amyotrophic Lateral Sclerosis (ALS)

Objective:

In this Phase I, proof-of-concept study, we aim to determine whether an antiretroviral
regimen approved to treat human immunodeficiency virus (HIV) infection would also suppress
levels of Human Endogenous Retrovirus-K (HERV-K) found to be activated in a subset of
patients with amyotrophic lateral sclerosis (ALS). We propose to measure the of blood levels
of HERV-K by quantitative PCR before, during, and after treatment with an antiretroviral
regimen. We will evaluate the safety of the antiretroviral regimen for participants with ALS
and also explore clinical and neurophysiological outcomes of ALS symptoms, quality of life,
and pulmonary function.

Study Population:

We will study a subset of ALS patients who have blood levels of the HERV-K transcript > 1000
copies/ml. About 30% of ALS patients may have detectable levels of HERV-K; about 20% of
patients with ALS have a level >1000 copies/ml. To show whether the HERV-K could be
suppressed, we will recruit from the approximately 20% of patients with the high levels so
that the antiretroviral effect can be determined.

Design:

This is an open-label study of a combination antiretroviral therapy for 24 weeks in 20
HIV-negative, HTLV-negative ALS patients with high blood levels of HERV-K . The study
duration for each participant will be up to 60 weeks. Participants will be followed regularly
for safety, clinical, and neurophysiological outcomes.

Outcome Measures:

The primary outcome measure will be the percent decline HERV-K concentration measured by
quantitataive PCR. Percent decline for a patient is measured by: 100 x (screening visit -
week 24 visit measurement) / screening visit. The safety of antiretrovirals in volunteers
with ALS as measured by the frequency and type of AEs, the ability to remain on assigned
treatment (tolerability), physical examinations, laboratory test results, vital signs, and
weight/body mass index (BMI). Efficacy will be explored by measuring the change in mean
scores of: the ALS Functional Rating Scale-Revised (ALSFRS-R), the ALS Specific Quality of
Life Inventory-Revised (ALSSQOL-R), the ALS Cognitive Behavioral Screen (ALS-CBS), vital
capacity as measured by handheld spirometer, electrical impedance myography (EIM), the change
in neurofilament levels in blood and/or CSF, and the chanage in uring p75ECD levels.

- INCLUSION CRITERIA:

Subjects must meet all of the following inclusion criteria to be eligible to participate in
this study:

- Age 18 years or older at the time of the screening visit.

- Able to provide informed consent and comply with study procedures.

- ALS diagnosed as probable, laboratory-supported probable or definite according to the
World Federation of Neurology El Escorial revised criteria32 as determined by a
neurologist with neuromuscular subspecialty training.

- Detectable HERV-K viral load in blood at a minimum of 1000 copies/ml as measured by
quantitative PCR at the screening visit.

- Time from symptom onset less than 2 years.

- If taking riluzole or edaravone, must be on a stable dose for at least 30 days prior
to the screening visit, or stopped taking riluzole or edaravone at least 30 days prior
to the screening visit.

- Subject has a competent caregiver who can and will be responsible for administering
study drug. If there is no caregiver, another qualified individual must be available
to do this.

- Subject has established care with a neurologist and will maintain this clinical care
throughout the study.

- Subject has had neuroimaging within the last 18 months.

EXCLUSION CRITERIA:

A participant will be excluded if he or she has any of the following:

- Dependence on daytime mechanical ventilation (invasive or non-invasive, including
Continuous Positive Airway Pressure (CPAP) or Bilevel Positive Airway Pressure (BiPap)
at the time of the screening visit.

- History of having undergone gastrostomy at the time of screening.

- Participation in any other investigational drug trial or using investigational drug
(within 12 weeks prior to Screening and thereafter).

- Known sulfonamide allergy.

- History of positive test or positive result at screening for HIV or HTLV-1.

- Participants must not be able to become pregnant (e.g., post-menopausal for at least
one year, surgically sterile, or using adequate methods of contraception) or
breastfeed for the duration of the study. Adequate methods of contraception include:
implanted contraception, intrauterine device in place for at least 3 months, or
barrier method in conjunction with spermicide. Participants of

childbearing potential must have a negative pregnancy test at screening and be
non-lactating.

- Presence of any of the following clinical conditions at the time of screening:

- Drug abuse or alcoholism

- Unstable medical disease (such as unstable angina or chronic obstructive
pulmonary disease), or active infectious disease (such as Hepatitis C or
tuberculosis), or current malignancy

- Unstable psychiatric illness defined as psychosis or untreated major depression
within 90 days of the screening visit

- Dementia

- Diabetes mellitus

- Hemophilia

- Use of contraindicated medications: amiodarone, dronedarone, lovastatin, simvastatin,
rifampin, rifapentine, rifabutin, cisapride, pimozide, midazolam, triazolam,
dihydroergotamine, ergonovine, ergotamine, methylergonovine, St. John s wort,
alfuzosin, salmeterol, sildenafil for pulmonary arterial hypertension, oxcarbazepine,
phenobarbital, phenytoin or dofetilide.

- Safety Laboratory Criteria at the screening visit:

- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than
3.0 times the upper limit of normal for the NIH Clinical Center.

- Serum creatinine, serum phosphorous, urine glucose, urine protein, total
bilirubin, triglycerides, amylase, or lipase greater than 2.0 times the upper
limit of normal for the NIH Clinical Center.

- Estimated glomerular filtration rate <60mg/dl.

- Creatine kinase greater than 3.0 times the upper limit of normal for the NIH
Clinical Center.

- Platelet concentration of <100,000/ (micro)l.

- PT and PTT >1.2 times the upper limit of normal for the NIH Clinical Center.

- Hemoglobin <10mg/dL.

- Positive Hepatitis B Surface Antigen and Hepatitis C Virus Antibody