A Randomized, Double Blind, Placebo-Controlled, Dose Titration, Phase 2 Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ISIS 494372 Administered Subcutaneously to Patients with High Lipoprotein(a)

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. Males or females aged 18-75 inclusive
3. Satisfy the following:
a. 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 *55 years, 12 months of spontaneous amenorrhea, without an alternative medical cause and FSH levels in the postmenopausal range for the laboratory involved), abstinent or if engaged in sexual relations of child-bearing potential, subject is using an acceptable contraceptive method (see section 6.3.1) from the time of signing the informed consent form until at least 16 weeks after the last dose of study drug
b. Males must be surgically sterile, abstinent or if engaged in sexual relations with a female of child-bearing potential, the patient must be using an acceptable contraceptive method (refer to Section 6.3.1) from the time of signing the informed consent form until at least 16 weeks after the last dose of Study Drug
4. BMI *40 kg/m2
5. Lipoprotein(a) *125 and <438 nmol/L (*50 and >175 mg/dL) at time of screening (Cohort A) Lipoprotein(a) * 438 nmol/L (* 175 mg/dL) at time of screening (Cohort B)

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. Clinically significant abnormalities in screening laboratory values that would render a patient unsuitable for inclusion, including the following:
a. Urine protein/creatinine (P/C) ratio *0.2 mg/mg. In the event of a P/C ratio above this threshold, eligibility may be confirmed by a quantitative total urine protein measurement of <150 mg/24 hr
b. Positive test (including trace) for blood upon urinalysis. In the event of a positive test, eligibility may be confirmed with a urine microscopy showing *5 red blood cells (RBCs) per high power field
c. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 x ULN
d. Bilirubin > ULN. Patients with Gilbert*s syndrome (elevated indirect bilirubin with normal direct bilirubin and normal ALT and AST) may be eligible after discussion with Medical Monitor
e. Alkaline phosphatase, serum creatinine or BUN > ULN
f. Platelet count 3.Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1
4.Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator
5.Known history or positive test for human immunodeficiency virus (HIV), hepatitis C, or chronic hepatitis B
6.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
7.Treatment with another Study Drug, biological agent, or device within one month of screening, or 5 half-lives of study agent, whichever is longer
8.Treatment with any non-ISIS oligonucleotide (including siRNA) at any time or prior treatment with an ISIS oligonucleotide or siRNA within 9 months of screening. Patients that have previously received only one dose of an ISIS oligonucleotide as part of a clinical study may be included as long as *4 months has elapsed since dosing.
9.History of bleeding diathesis or coagulopathy
10.Recent history of, or current drug or alcohol abuse
11. Use of statins, ezetimibe, niacin, fish oil or other products containing omega-3 fatty acids (including OTC preparations)or fibrates unless on a stable regimen for at least 8 weeks prior to screening and will remain on a stable regimen through the end of the Post-Treatment Evaluation Period
12. Use of testosterone, estrogens, progesterone or progestins unless on a stable regimen for at least 8 weeks prior to screening and will remain on a stable regimen through the end of the Post-Treatment Evaluation Period
13. Patients who are currently receiving apheresis to reduce elevated levels of lipids
14. Use of concomitant drugs (including herbal or OTC medications other than ibuprofen, paracetamol, topical aspirin based analgesics, antihistamine, or topical steroids * 1% hydrocortisone) unless authorized by the Sponsor Medical Monitor
15. Blood donation of 50-499 mL within 30 days of screening or of > 499 mL within 8 weeks of screening
16. Have any other conditions, which, in the opinion of the Investigator would make the patient unsuitable for inclusion, or could interfere with the patient participating in or completing the study