The purpose of this study is to to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ISIS-FGFR4RX.

Inclusion Criteria:

1. Must have given written informed consent (signed and dated) and any authorizations required by local law and be able to comply with all study requirements

2. Male or female patients between the age of 18-65 years, inclusive

   • Females: Must be post-menopausal (defined as 12 months of spontaneous amenorrhea in females > 55 years of age or, in females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative medical cause and FSH levels in the postmenopausal range for the laboratory involved)
   • Males: Surgically sterile, abstinent or if engaged in sexual relations with women of childbearing potential, patient is utilizing an acceptable contraceptive method during and for 5 months after the last dose of ISIS 463588 or placebo (Study Drug)

3. Body Mass Index (BMI) between 30.0 and 40.0 kg/m2, inclusive

4. Patients who are willing to comply with all scheduled visits, treatment plans, laboratory tests and other study procedures

5. Agree to abstain from alcoholic beverages for at least 48 hours prior to clinic visits

6. Agree to maintain current diet and exercise regimen from Screening until End-of-Study

Exclusion Criteria:

1. Clinically significant abnormalities in medical history (e.g., previous acute coronary syndrome within 6 months of Screening, major surgery within 3 months of Screening) or physical examination
2. Positive test for HIV, hepatitis B or C at Screening
3. Hypothyroidism or Hyperthyroidism
4. Weight change > 5% in the 3 months prior to Screening