Efficacy, Safety and Tolerability of ISIS 304801 in People With Partial Lipodystrophy With an Open-Label Extension

Background:

Lipodystrophy is a rare disease of deficient adipose mass, characterized by severe
hypertriglyceridemia as well as insulin resistance, diabetes mellitus, fatty liver disease,
acute pancreatitis, and early cardiovascular events. Apolipoprotein C-III (apoC-III)
regulates triglyceride metabolism, and apoC-III levels strongly correlate with serum
triglycerides in a variety of patient populations. Patients with genetically low levels of
apoC-III have lower triglycerides and reduced cardiovascular disease, while individuals with
genetically elevated levels of apoC-III have higher triglycerides and increased non-alcoholic
fatty liver disease and insulin resistance. Pharmacologic reduction of apoC-III using
anti-sense oligonucleotides (ASOs) reduce triglycerides by ~60-70% in a tested patient
populations.

Aim:

The purpose of this study is to determine if apoC-III reduction using an ASO to apoC-III
(ISIS 304801) will reduce triglycerides and improve insulin resistance, diabetes, and hepatic
steatosis in patients with lipodystrophy.

The primary hypothesis to be tested is:

1. ISIS 304801will reduce log10 fasting serum triglycerides.

Secondary and tertiary hypotheses to be tested are:

2. ISIS 304801will improve glucose metabolism by improving insulin resistance.

3. ISIS 304801 will reduce hepatic steatosis.

4. ISIS 304801 will improve cardiovascular risk markers.

We will also explore the mechanism of action of apoC-III ASO by studying lipoprotein lipase
activity and lipoprotein particle distribution.

Methods:

This study will enroll up to 20 patients with partial lipodystrophy with a goal of 10 study
completers. The study will be conducted in two phases. The first is a 16-week, randomized,
double-blind, placebo-controlled design. Subjects will be treated with ISIS 304801 at a
target dose of 300 mg per week or placebo. Following this phase, all subjects will enter a 12
month open-label extension in which they will receive active drug. Patients who experience
benefit (triglyceride lowering greater than or equal to 50%) may receive an additional 12
months of open-label drug (up to 24 months, total). Measurement of the primary outcome (serum
triglycerides) and key secondary outcomes will be performed at baseline prior to the
intervention, after 13 weeks (primary outcome only) or 16 weeks (primary and secondary
outcomes) of blinded drug or placebo, and after an additional 4 months of active drug in
subjects initially randomized to placebo.

- INCLUSION CRITERIA:

- Age greater than or equal to 18 years at enrollment (the time of informed consent,
week -1)

- Fasting TG levels greater than or equal to 500 mg/dL (greater than or equal to 5.7
mmol/L) at enrollment. If the fasting TG value is <500 mg/dL (<5.7 mmol/L) but greater
than or equal to 350 mg/dL (greater than or equal to 4.0 mmol/L) up to two additional
tests may be performed in order to qualify, and a single level greater than or equal
to 500 mg/dL will permit enrollment.

OR

- Fasting TG levels greater than or equal to 200 mg/DL (2.6mmol/L) with a hemoglobin A1C
over 7%.

- Willing to maintain their customary physical activity level and to follow a diet
moderate in carbohydrates and fats with a focus on complex carbohydrates and replacing
saturated for unsaturated fats

- Clinical diagnosis of lipodystrophy based on deficiency of subcutaneous body fat in a
partial fashion assessed by physical examination, and low skinfold thickness in
anterior thigh by caliper measurement: men (less than or equal to 10mm) and women
(less than or equal to 22mm), plus one of the following:

- Genetic diagnosis of familial PL (e.g., mutations in LMNA, PPARG, AKT2, or PLIN1
genes) OR

- Family history of familial PL or abnormal and similar fat distribution PLUS
1 minor criterion (below), OR

- 2 minor criteria (below) in the absence of genetic diagnosis of family
history

- MINOR Criteria

- Diabetes mellitus with requirement for high doses of insulin, eg, requiring
greater than or equal to 200 U/day,greater than or equal to 2 U/kg/day, or
currently taking U-500 insulin

- Presence of acanthosis nigricans on physical examination

- History of polycystic ovary syndrome (PCOS) or PCOS-like symptoms
(hirsutism, oligomenorrhea, and/or polycystic ovaries)

- History of pancreatitis associated with hypertriglyceridemia

- Evidence of non-alcoholic fatty liver disease: Hepatomegaly and/or elevated
transaminases in the absence of a known cause of liver disease or
Radiographic evidence of hepatic steatosis (e.g., on ultrasound or CT)

- Satisfy one of the following:

- Females: Non-pregnant and non-lactating; surgically sterile (e.g., tubal
occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy),
post-menopausal (defined as 12 months of spontaneous amenorrhea in females >55
years of age or, in females less than or equal to 55 years, 12 months of
spontaneous amenorrhea without an alternative medical cause and
follicle-stimulating hormone (FSH) levels in the postmenopausal range for the
laboratory involved), abstinent, or if engaged in sexual relations of
child-bearing potential, patient is using an acceptable contraceptive method from
time of signing the informed consent form until at least 13 weeks after the last
dose of Study Drug administration.

- Males: Surgically sterile, abstinent, or if engaged in sexual relations with a
female of child bearing potential, patient is utilizing an acceptable
contraceptive method from the time of signing the informed consent form until at
least 13 weeks after the last dose of study drug administration.

Note: Abstinence is only an effective method of birth control when this is the preferred
and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation,
symptothermal, post-ovulation methods), declaration of abstinence for the duration of a
trial and withdrawal are not acceptable methods of contraception.

EXCLUSION CRITERIA:

- A diagnosis of generalized lipodystrophy

- Current or history of autoimmune diseases (even with a diagnosis of PL) unless
approved by the Investigator and Sponsor Medical Monitor

- Acute pancreatitis within 4 weeks of enrollment

- History within 6 months of enrollment of acute or unstable cardiac ischemia
(myocardial infarction, acute coronary syndrome, new onset angina), stroke, transient
ischemic attack, or unstable congestive heart failure requiring a change in medication

- Major surgery within 3 months of enrollment

- History of heart failure with New York Heart Association functional classification
(NYHA) greater than Class II

- Uncontrolled hypertension (blood pressure [BP] >160/100 mm Hg)

- Any of the following laboratory values at enrollment:

- Cardiac troponin T >ULN

- Measured or estimated (in case of triglycerides > 400 mg/dL) LDL-C >130 mg/dL on
maximal tolerated statin therapy

- Hemoglobin HbA1c greater than or equal to 9.5%

- Hepatic:

- Total bilirubin >ULN

- ALT >3.0 x ULN. Higher levels will be permitted after a safety review by a
hepatologist, that includes no evidence of cirrhosis.

- AST >3.0 x ULN. Higher levels will be permitted after a safety review by a
hepatologist, that includes no evidence of cirrhosis.

- Renal:

- Persistently positive (2 out of 3 tests greater than or equal to trace
positive) for blood on urine dipstick. In the event of a positive test
eligibility may be confirmed with urine microscopy showing less than or
equal to 5 red blood cells per high power field (urine will be screened at
admission and repeated if abnormal). If RBC are high every effort will be
made to determine if the source is renal or benign, such as from menstrual
bleeding. If the presence of RBC is determined to be from a non-renal
source, the PI will make the decision to proceed with protocol testing
and/or randomization.

- Two out of three consecutive tests greater than or equal to 1+ for protein
on urine dipstick. In the event of a positive test eligibility may be
confirmed by either a spot urine albumin to creatinine ratio <1000mg/g or a
quantitative total urine albumin measurement of < 1g/24 hrs (urine will be
screened at admission and repeated if abnormal)

- Estimated creatinine clearance calculated according to the formula of
Cockcroft and Gault <60 mL/min

- Platelet count below 140,000 K/uL

- Clinically significant (as determined by the Investigator or Sponsor)
abnormalities on laboratory examination that will increase risk to the patient or
interfere with data integrity

- Uncontrolled hypothyroidism (abnormal thyroid function tests should be approved by the
Investigator)

- History within 6 months of enrollment of screening of drug or alcohol abuse

- History of bleeding diathesis or coagulopathy or clinically significant abnormality in
coagulation parameters at enrollment

- Active infection requiring systemic antiviral or antimicrobial therapy that will not
be completed prior to enrollment

- Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C
or chronic hepatitis B

- Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or
carcinoma in situ of the cervix that has been successfully treated

- Treatment with another investigational drug, biological agent, or device within one
month of enrollment, or 5 half-lives of investigational agent, whichever is longer

- Unwilling to comply with contraceptive and lifestyle (diet/exercise) requirements

- Use of any of the following:

- Use of metreleptin within the last 3 months prior to enrollment

- Antidiabetic, lipid lowering, or atypical antipsychotic medication, unless on a
stable dose for at least 3 months prior to enrollment

- Insulin unless on a stable daily insulin dose regimen (+/- 20 %) for at least 4
weeks prior to enrollment

- Use of nicotinic acid or derivatives within the last 4 weeks prior to enrollment

- Systemic corticosteroids or anabolic steroids within 6 weeks prior to enrollment
unless approved by the Investigator

- Antihypertensive medication unless on a stable dose for at least 4 weeks prior to
enrollment

- Tamoxifen, estrogens or progestins unless on a stable dose for at least 4 months
prior to enrollment and dose and regimen expected to remain constant throughout
the study

- Oral anticoagulants unless on a stable dose for at least 4 weeks prior to
enrollment and regular clinical monitoring is performed

- Prior exposure to ISIS 304801

- Anti-obesity drugs [e.g., the combination of phentermine and extended-release
topiramate (Osymia, orlistat (Xenical), liraglutide [rDNA origin] injection
(Saxenda) and lorcaserin (Belvig), phentermine, amphetamines, herbal
preparations] within 12 weeks prior to screening

- Any other medication unless stable at least 4 weeks prior to enrollment
(occasional or intermittent use of over-the-counter medications will be allowed
at Investigator s discretion)

- Blood donation of 50 to 499 mL within 30 days or of >499 mL within 60 days

- Have any other conditions, which, in the opinion of the Investigator or the Sponsor
would make the patient unsuitable for inclusion, or could interfere with the patient
participating in or completing the study