A Safety and Efficacy Study of AEGR-733 to Treat Homozygous Familial Hypercholesterolemia (FH)

Homozygous familial hypercholesterolemia (FH) is a serious life-threatening genetic disease.
Total plasma cholesterol levels are generally over 500 mg/dl and markedly premature
cardiovascular disease is the major consequence. Untreated, most patients develop
atherosclerosis before age 20 and generally do not survive past age 30. The primary goal of
therapy involves reducing cholesterol (specifically, LDL cholesterol) and preventing coronary
artery disease. Unfortunately, patients with homozygous FH are minimally responsive or
unresponsive to available drug therapy and thus there are limited treatment options. The
current standard of care is LDL apheresis, a physical method of removing the plasma of LDL
cholesterol which can transiently reduce cholesterol by more than 50%. However, there is
rapid re-accumulation of LDL cholesterol in plasma, and therefore apheresis has to be
repeated frequently (every 1-2 weeks) and requires 2 separate sites for IV access. Although
anecdotally this procedure may delay the onset of atherosclerosis, it is laborious,
expensive, and not readily available. Furthermore, although it is a procedure that is
generally well tolerated, the fact that it needs frequent repetition and IV access can be
challenging for many of these young patients. Therefore, there is a tremendous unmet medical
need for new medical therapies for this orphan disease.

AEGR-733 is a novel oral therapeutic agent for hypercholesterolemia. Its mechanism involves
inhibition of microsomal triglyceride transfer protein, resulting in a reduction of LDL
cholesterol. Earlier studies in patients with homozygous FH reveal AEGR-733 is highly
effective in lowering LDL cholesterol, yet long term safety and efficacy need to be
established.

Inclusion Criteria:

1. Males and females at least 18 years of age

2. Diagnosis of functional homozygous FH by at least one (a-c) of the following clinical
criteria:

- documented functional mutation(s) in both LDL receptor alleles or alleles known
to affect LDL receptor functionality OR

- skin fibroblast LDL receptor activity less than 20% normal OR

- untreated TC greater than 500 mg/dL AND TG less then 300 mg/dL AND both parents
have documented TC greater than 250 mg/dL

3. Concurrent lipid lowering medication/apheresis must be stable for at least 6 weeks
before the baseline visit and must remain stable for the first 26 weeks.

4. Body weight at least 40 kg and less than 136 kg

5. Negative screening pregnancy test if female of child-bearing potential (females of
child-bearing potential and all males must be following a medically accepted form of
contraception)

6. Subjects must be willing to comply with all study-related procedures

Exclusion Criteria:

1. Uncontrolled hypertension

2. History of chronic renal insufficiency

3. History of biopsy proven cirrhosis or abnormal LFTs at screening (AST or ALT greater
than 2 x upper limit of normal and/or Total Bilirubin greater than or equal to 1.5
mg/dl unless patient has unconjugated hyperbilirubinemia due to Gilbert's syndrome)

4. Chronic hepatitis B or chronic hepatitis C

5. Any major surgical procedure occurring less than 3 months prior to the screening visit

6. Cardiac insufficiency defined by the NYHA classification as functional Class III or
Class IV

7. Previous organ transplantation

8. History of a non-skin malignancy within the previous 3 years

9. Male subjects reporting more than 2 drinks per day or females reporting more than 1
drink per day (1 drink= 12 oz beer, 1 oz hard liquor, 5 oz wine).

10. Participation in an investigational drug study within 6 weeks prior to the screening
visit

11. Known significant gastrointestinal bowel disease or malabsorption such as inflammatory
bowel disease or chronic pancreatitis requiring use of daily pancreatic enzymes.

12. Serious or unstable medical or psychological conditions that, in the opinion of the
investigator, would compromise the subject's safety or successful participation in the
study.

13. Certain prohibited medications known to be potentially hepatotoxic, especially those
that can induce microvesicular or macrovesicular steatosis. These include but are not
limited to: accutane, amiodarone, heavy acetaminophen use (4g/day greater than 3 x q
week), methotrexate, tetracyclines,and tamoxifen

14. Documented diagnosis of any of the following pulmonary conditions: Asthma, Chronic
Obstructive Pulmonary Disease (COPD), Idiopathic pulmonary fibrosis

15. Documented diagnosis of any of the following liver diseases: Nonalcoholic
Steatohepatitis, Alcoholic liver disease, Autoimmune hepatitis, primary biliary
cirrhosis, primary sclerosing cholangitis, Wilson's disease, hemochromatosis, alpha 1
anti-trypsin deficiency.

16. Current use of corticosteroids or betaine