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.

Methods and 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.

Clinical trial registration url: http://www.clinicaltrials.gov. Unique identifier: NCT01061814.

Keywords: dosing; inhibitor; pharmacokinetics; randomized controlled trial; safety.

Figures

Figure 1.

Evaluation of mipomersen in alternative dose regimens. Study design (A) and flow of participants (B) through the study. In the study design diagram, R denotes randomization, ratios are indicated above by cohort (R1) and active to placebo (R2), and the asterisk (*) indicates the time point for exploratory efficacy measurements, Day 28. †One subject discontinued dosing in the 30 mg group for asthenia and atrial flutter—both events were considered unlikely related to study drug. ‡Two subjects discontinued dosing in the 70 mg group: one subject for gastroesophageal reflux disease, this event was considered possibly related to study drug; and one subject for ALT and AST ≥3×ULN, muscle tightness, increase in lactate dehydrogenase and creatine kinase, these events were considered unrelated to study drug. ALT indicates alanine transaminase; AST, aspartate transaminase; QD, once daily; QW, once weekly; TIW, 3 times a week; ULN, upper limit of normal.

Figure 2.

Mean mipomersen plasma concentrations over time by dose regimen. A, 0 to 24 hours after the first dose. B, 0 to 35 days after the last dose. QD indicates once daily; QW, once weekly; TIW, 3 times a week.

Figure 3.

Effect of SC dosing regimen on serum IL‐6 and CRP levels. A, Relative median levels after first and last dose‐by‐dose regimen cohort. B, Individual maximum post‐dose changes after first and last dose by treatment groups. Median and interquartile range values are provided in Tables 5 and 6. *Dose day, samples collected pre‐dose. CRP indicates C‐reactive protein; IL, interleukin; MIPO, mipomersen; PBO, placebo; QD indicates once daily; QW, once weekly; SC, subcutaneous; TIW, 3 times a week.

Figure 4.

Effect of SC dosing regimen on inflammation biomarkers. Type I interferons, IFN‐α and ‐β (A); chemokines, MIP‐1α, and MCP‐1 (B); immune cell signaling and activation, IL‐1β, and IL‐13 (C); complement split products, Bb and C5a (D); and IL‐6 and CRP (E). Data presented are the median absolute changes from baseline (BSLN), ± the interquartile range (IQR). Bb and C5a indicates complement split products; CRP, C‐reactive protein; IFN, interferon; IL, interleukin; MCP‐1, monocyte chemotactic protein 1; MIP‐1α, macrophage inflammatory protein 1 alpha; QD indicates once daily; QW, once weekly; SC, subcutaneous; TIW, 3 times a week.