An interventional study to evaluate the effects of dosages on the Pharmacokinetics (PK, the measure of how the human body processes a substance), Pharmacodynamics (PD, the measure of what a substance does to the human body), Tolerability (how well a substance is tolerated by participants), and Safety of different dosages of IONIS-TMPRSS6-Lrx when given to healthy participants as either a single subcutaneous (SC, an injection just under the skin) dose, or as multiple SC doses.

Exclusion Criteria34

• 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
• Screening laboratory results as follows, or any other clinically significant abnormalities in screening laboratory values that would render a subject unsuitable for inclusion
• Urine protein/creatinine (P/C) ratio greater than or equal to 200 mg/mg. In the event of P/C ratio above this threshold, eligibility may be confirmed by a quantitative total urine protein measurement of < 150 mg/24 hours
• Positive test (including trace) for blood on urinalysis. In the event of a positive test,
• eligibility may be confirmed with urine microscopy showing < 5 RBC per microliter
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, alkaline
• phosphatase, serum creatinine, blood urea nitrogen (BUN) > the upper limit of the normal range (ULN)
• Fasting blood glucose > ULN
• Platelet count < LLN
• Thyroid-stimulating hormone (TSH) value outside normal range unless approved by the Sponsor Medical Monitor
• Hgb < 15.0 g/dL (male) or < 13.0 g/dL (female)
• Any of the following hematologic parameters outside normal range: MCH, MCV, RBC, and RDW
• Ferritin outside normal range
• Transferrin saturation < 20% or > 50%
• Eligibility of subjects with a known history of anemia must be approved by the Sponsor
• Medical Monitor
• Active infection requiring systemic antiviral or antimicrobial therapy that will not be
• completed prior to Study Day 1
• Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator
• Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C, or chronic hepatitis B
• Uncontrolled hypertension (BP > 160/100 mm Hg) at Screening
• 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 1 month of Screening or 5 half-lives of investigational agent, whichever is longer
• Any history of previous treatment with an oligonucleotide (including siRNA). Subjects who have previously received only a single dose of an Ionis oligonucleotide as part of a clinical study may be included as long as a duration greater than or equal to 4 months has elapsed since dosing
• History of bleeding, diathesis, or coagulopathy
• Regular excessive use of alcohol within 6 months prior to Screening (> 7 drinks/week for females, > 14 drinks/week for males; 1 drink equals 5 ounces [150 mL] of wine or 12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor), or use of soft drugs (such as marijuana) within 3 months prior to Screening, or hard drugs (such as cocaine and phencyclidine) within 1 year prior to Screening, or positive urine drug screen at Screening
• Current use of concomitant medications other than occasional acetaminophen (paracetamol) or ibuprofen unless approved by Sponsor Medical Monitor
• Use of oral anticoagulants
• Smoking > 10 cigarettes per day
• Blood donation of 50 to 499 mL within 30 days of Screening or of > 499 mL within 90 days of Screening
• Have any other conditions that, in the opinion of the Investigator or Sponsor, would make the subject unsuitable for inclusion, or could interfere with the subject participating in or completing the Study