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Mechanism of Action
Mipomersen is an antisense oligonucleotide targeted to human messenger ribonucleic acid (mRNA) for apo B-100, the principal apolipoprotein of LDL and its metabolic precursor, VLDL. Mipomersen is complementary to the coding region of the mRNA for apo B-100, and binds by Watson and Crick base pairing. The hybridization of mipomersen to the cognate mRNA results in RNase H-mediated degradation of the cognate mRNA thus inhibiting translation of the apo B-100 protein.
The in vitro pharmacologic activity of mipomersen was characterized in human hepatoma cell lines (HepG2, Hep3B) and in human and cynomolgus monkey primary hepatocytes. In these experiments, mipomersen selectively reduced apo B mRNA, protein and secreted protein in a concentration- and time-dependent manner. The effects of mipomersen were shown to be highly sequence-specific. The binding site for mipomersen lies within the coding region of the apo B mRNA at the position 3249-3268 relative to the published sequence GenBank accession number NM_000384.1.
Cardiac ECG Effects
At a concentration of 3.8 times the Cmax of the maximum recommended dose (200 mg subcutaneous injection), mipomersen does not prolong the QTc interval to any clinically relevant extent.
Single- and multiple-dose pharmacokinetics of mipomersen in healthy volunteers and in patients with FH and non-FH has shown that mipomersen plasma exposure increases with increasing dose in the range of 30 mg to 400 mg.
Following subcutaneous injection, peak concentrations of mipomersen are typically reached in 3 to 4 hours. The estimated plasma bioavailability of mipomersen following subcutaneous administration over a dose range of 50 mg to 400 mg, relative to intravenous administration, ranged from 54% to 78%.
Mipomersen is highly bound to human plasma proteins ( ≥ 90%) at clinically relevant concentrations (1-8 μg/mL). Mipomersen has a distribution plasma half-life of approximately 2 to 5 hours.
With once weekly dosing, plasma trough levels increase over time and approach steady-state, typically within 6 months.
Mipomersen is not a substrate for CYP450 metabolism, and is metabolized in tissues by endonucleases to form shorter oligonucleotides that are then substrates for additional metabolism by exonucleases.
The elimination of mipomersen involves both metabolism in tissues and excretion, primarily in urine. Both mipomersen and putative shorter oligonucleotide metabolites were identified in human urine. Urinary recovery was limited in humans with less than 4% within the 24 hours post dose. Following subcutaneous administration, elimination half-life for mipomersen is approximately 1 to 2 months.
No clinically relevant pharmacokinetic interactions were reported between mipomersen and warfarin, or between mipomersen and simvastatin or ezetimibe. The results of these studies are summarized in Figures 1 and 2.
Figure 1: Impact of Other Drugs on Mipomersen
Figure 2: Impact of Mipomersen on the Pharmacokinetics
of Other Drugs
Pharmacokinetics of KYNAMRO in patients with renal impairment has not been established [see Use In Specific Populations].
Animal Pharmacology and/or Toxicology
The principal target organs for mipomersen pathology are the kidneys and liver. These organs represent the highest distribution of compound, and exhibit microscopic changes reflective of cellular uptake in macrophages. The most widespread toxicological effect of mipomersen was a spectrum of inflammatory changes in numerous organs, including lymphohistiocytic cell infiltrates and increases in lymphoid organ weights, associated with increases in plasma cytokines, chemokines and total serum IgG. In a chronic monkey study, multi-focal intimal hyperplasia with mixed inflammatory infiltrates was evident in vascular beds in 2 of 6 monkeys treated for 12 months with 30 mg/kg/week with a no-observed-adverse-effect-level (NOAEL) of 10 mg/kg/week (approximately equal to clinical exposures anticipated from a 200 mg/wk dose based on body surface area comparisons across species).
The safety and effectiveness of KYNAMRO, given as 200 mg weekly subcutaneous injections, as an adjunct to lipid-lowering medications in individuals with HoFH were evaluated in a multinational, randomized (34 KYNAMRO; 17 placebo), placebo-controlled, 26-week trial in 51 patients with HoFH. A diagnosis of functional HoFH was defined by the presence of at least one of the following clinical or laboratory criteria: (1) history of genetic testing confirming 2 mutated alleles at the LDLr gene locus, or (2) documented history of untreated LDL-C > 500 mg/dL and at least one of the criteria (a) tendinous and/or cutaneous xanthoma prior to age 10 years or (b) documentation of elevated LDL-C > 190 mg/dL prior to lipid-lowering therapy consistent with HeFH in both parents. In case a parent was not available, a history of coronary artery disease in a first degree male relative of the parent younger than 55 years or first degree female relative of the parent younger than 60 years was acceptable.
The baseline demographic characteristics were well-matched between the KYNAMRO and placebo patients. The mean age was 32 years (range, 12 to 53 years), the mean body mass index (BMI) was 26 kg/m², 43% were men, and the majority(75%) were Caucasian. In 50 of 51 (98%) patients, the background therapy of maximally tolerated lipid-lowering medication included statins. In total, 44 of the 50 (88%) patients were on maximum-dose statin therapy with or without other lipid-lowering medications. Thirty-eight of the 50 (76%) patients were also taking at least one other lipid-lowering medication, most commonly ezetimibe in 37 of 50 (74%) patients; patients were not on LDL apheresis. Eighty-two percent of the KYNAMRO group and 100% of the placebo group completed the efficacy endpoint at week 28. Adverse events contributed to premature discontinuation for four patients, all in the KYNAMRO group [see ADVERSE REACTIONS].
The primary efficacy endpoint was percent change in LDL-C from baseline to Week 28. At Week 28, the mean and median percent changes in LDL-C from baseline were -25% (p < 0.001) and -19%, respectively, for the KYNAMRO group. The mean and median treatment difference from placebo was -21% (95% confidence interval [CI]: -33, -10) and -19%, respectively. Changes in lipids and lipoproteins through the efficacy endpoint at Week 28 are presented in Table 4.
Table 4: Response to Addition of KYNAMRO™ to
Maximally Tolerated Lipid Lowering Medication in Patients with HoFH
|Mean Baseline LDL-C(mg/dL) (range)||439 (190, 704)||400 (172, 639)|
|Parameter (mg/dL)||Mean or Median Percent Change from Baseline to End of Treatment*||Mean (95% CI) or Median Treatment Difference from Placebo (%)|
|LDL-C †||-25||-3||-21 (-33, -10)|
|Apo B †||-27||-3||-24 (-34, -15)|
|TC †||-21||-2||-19 (-29, -9)|
|Non-HDL-C †||-25||-3||-22 (-33, -11)|
|*End of treatment represents two weeks following final
dose of KYNAMRO, Last observation carried forward (LOCF).
†Denotes statistically significant difference between treatment groups based on the pre-specified gatekeeping method for controlling Type I error among the primary and secondary endpoints.
‡The treatment effect was not consistent across the Phase 3 trials.
£ Medians are presented due to non-normal distribution.
LDL-C percent changes from baseline with KYNAMRO were variable among individuals with HoFH ranging from a 2% increase to an 82% reduction. The LDL-C percent changes from baseline in the placebo group range from a 43% increase to a 33% reduction. Mean LDL-C percent changes over time are presented in Figure 3.
Figure 3: Mean Percent Change in LDL-C in Patients
with HoFH (Completers Population)
Last reviewed on RxList: 2/8/2013
This monograph has been modified to include the generic and brand name in many instances.
Additional Kynamro Information
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