title: Changes in mipomersen dosing regimen provide similar exposure with improved tolerability in randomized placebo-controlled study of healthy volunteers.
abstract: BACKGROUND
  Mipomersen, an apolipoprotein B synthesis inhibitor, demonstrated significant reductions in low-density lipoprotein (LDL) cholesterol, non-high density lipoprotein cholesterol, and apolipoprotein B in 4 phase 3 studies at the FDA-approved subcutaneous dose of 200 mg once weekly.
  
  
  RESULTS
  A short-term phase 1 study in healthy volunteers was conducted to evaluate the relative bioavailability, safety, and tolerability of mipomersen in 2 test dose regimens in reference to the 200 mg weekly dose regimen. Eighty-four adults were randomized to 1 of 3 cohorts (30 mg once daily, 70 mg 3 times weekly, or 200 mg once weekly) and then mipomersen or placebo (3:1 ratio) for 3 weeks of treatment. Comparable mipomersen post-distribution phase plasma concentrations were observed across the 3 dose regimens suggesting similar tissue exposure. Injection site reactions were reported, but did not lead to treatment discontinuation. The median incidence of these responses per injection was decreased by lowering the dose. Signals from a diverse panel of systemic inflammation markers were essentially indistinguishable between dose regimens and placebo treatment. The one exception was a modest transient post-dose elevation of C-reactive protein (CRP) in the mipomersen 200 mg weekly group. This elevation was not associated with an increase in other proinflammatory markers.
  
  
  CONCLUSIONS
  This study demonstrated a similar drug exposure and overall safety profile between the 3 dosing regimens. Exploratory assessment of a diverse panel of biomarkers found no indication of a systemic inflammatory response to mipomersen treatment. These results support assessment of alternative dose regimens in longer-term studies.
  
  
  BACKGROUND
  http://www.clinicaltrials.gov. Unique identifier: NCT01061814.
authors.affiliation: Isis Pharmaceuticals, Inc, Carlsbad, CA.
authors.forename: Joann D
authors.initials: JD
authors.lastname: Flaim
authors.forename: John S
authors.initials: JS
authors.lastname: Grundy
authors.forename: Brenda F
authors.initials: BF
authors.lastname: Baker
authors.forename: Mary P
authors.initials: MP
authors.lastname: McGowan
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
mesh_terms: D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D001682:Biological Availability; D015415:Biomarkers / Q000097:blood; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000139:chemically induced; D018836:Inflammation Mediators / Q000097:blood; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D011792:Quebec; D013997:Time Factors; D055815:Young Adult
chemical_list: D000924:Anticholesteremic Agents; D015415:Biomarkers; D018836:Inflammation Mediators; D009841:Oligonucleotides; C524142:mipomersen
keywords: dosing; inhibitor; pharmacokinetics; randomized controlled trial; safety