Study of Gemcabene in Adults With FPLD

Patients with typical Familial Partial Lipodystrophy Disease (FPLD) have a marked loss of
subcutaneous fat from the extremities and trunk accompanied by a variable amount of excess
fat deposition in the nonlipodystrophic areas such as the face, chin, back, and
intraabdominal regions. Dietary fat restriction and other lifestyle changes are first line
therapy to avoid weight gain, critical for effective management of metabolic complications in
patients with lipodystrophy. However, despite lifestyle changes and conventional hypoglycemic
and hypolipidemic therapies, some FPLD patients continue to have extreme
hypertriglyceridemia, hepatic steatosis, and poorly controlled diabetes.Hypertriglyceridemia
is a common condition of FPLD and serum triglyceride levels of 250-1999 mg/dL, classified as
moderate to severe hypertriglyceridemia, indicate risk for development of very severe
hypertriglyceridemia, causative of pancreatitis and hepatic steatosis. In patients such as
those with FPLD with severe or very severe hypertriglyceridemia, fibrates, omega-3 fatty
acids (OMG-3) and occasionally niacin are first-line therapy. Non-alcoholic fatty liver
disease (NAFLD) is often associated with FPLD. The spectrum of NAFLD associated with FPLD
which appears to be more frequent than what is seen in common Type 2 diabetes and appears
more severe than common forms of NAFLD and very often associated with NASH. The etiology for
the latter is not clear, however, the fact that a mouse model of liver specific laminopathy
develops NASH in a cell -autonomous manner suggests that the specific cellular defects seen
in FPLD may play a role in the development of NAFLD/NASH. Triglyceride content in the liver
is regulated by fatty acid uptake as well as fatty acid and VLDL production rates.
Derangements in these processes, such as excessive production of fatty acids and
triglycerides that can occur with excessive carbohydrate consumption contribute to NAFLD.
Patients with NAFLD compared to controls, present with an atherogenic dyslipidemic profile,
characterized by increased serum levels of triglycerides, ApoB, VLDL-C, and LDL-C with a
proportionally greater content of small dense LDL-C (sdLDL-C) 18-20. NAFLD is also associated
with aberrant nuclear receptor function and systemic inflammation. NAFLD can progress to
NASH. NASH is marked by hepatocyte ballooning and liver inflammation, which may progress to
scarring and irreversible damage. Macro and microscopically, NASH is characterized by lobular
and/or portal inflammation, varying degrees of fibrosis, hepatocyte death and pathological
angiogenesis. At its most severe, NASH can progress to cirrhosis, hepatocellular carcinoma
(HCC) and liver failure. It is estimated that 20-33% NAFLD patients will progress to NASH,
with about 5% ultimately progressing to cirrhosis. Cirrhosis has a reported 7- to 10-year
mortality of 12-25%. As NAFLD and NASH continue to be a growing epidemic, gemcabene's
clinical and preclinical data suggest that this novel agent may provide benefit to patients
with the diagnosis of NAFLD and/or NASH. As such, further development of gemcabene may help
meet an unmet medical need in these patient populations. In Phase 2 studies, gemcabene has
shown triglyceride lowering from 20 to > 50% based on dose and severity of
hypertriglyceridemia and lowering in hsCRP of up to 50%. Additionally, in animal and cell
based models, gemcabene studies have provided evidence demonstrating: reduction in de-novo
lipogenesis, reduction in intrahepatic TG levels, modulation of inflammation and reduction of
the NAFLD activity score, particularly related to hepatic ballooning, steatosis, fibrosis,
and collagen accumulation. As such gemcabene may have utility in hypertriglyceridemia of FLP
and ultimately in the prevention or treatment of NASH in these patients.

- Clinical diagnosis of lipodystrophy based on a lack of body fat in a partial fashion
assessed by physical examination, and at least 1 MAJOR criterion (below):

- Low skinfold thickness in anterior thigh by caliper measurement: men (≤ 10 mm) and
women (≤ 22 mm) OR

- Historic genetic diagnosis of familial partial lipodystrophy (e.g. mutations in LMNA,
PPAR-γ, AKT2, or PLIN1 genes) as supported by source documentation

- Hepatic steatosis (>10% - Stage 2 or 3) as demonstrated by MRI-PDFF;

- Alcohol intake of less than 20 g per day in females and 30 g per day in males (one 12
oz beer, one glass of wine, or 2 oz of spirits or liquor equals roughly 10 g of
alcohol;

- Mean fasting triglyceride value ≥ 250 mg/dL at the Screening Visit;

- Background lipid lowering medications must be stable for at least 6 weeks prior to the
Screening Visit;

- Women patients must not be pregnant or lactating and women of child-bearing potential
must agree to use acceptable methods of contraception throughout the duration of the
study and for 30 days after the last dose of study drug. Male patients must agree to
use contraception by means of a condom and may not donate sperm throughout the
duration of the study and for 8 days after the last dose of study drug.

- Weight greater than 50 kg (~110 lbs); with a body mass index (BMI) of no more than 45
kg/m²;

- Have not used a fibrate with in the last 6 weeks and/or thiazolidinediones (TZDs)
within the last 12 weeks prior to the Screening visit.

- Do not have a hypersensitivity or a history of significant reactions of fibrates.

- Are not currently taking potent CYP3A4 inhibitors such as itraconazole or a macrolide
antibiotic.

- Have a condition or finding which, in the opinion of the Investigator, would
compromise the patient's safety or participation in the study.