Kynamro - Drug Monograph

Introduction

Kynamro (mipomersen sodium) is an antisense oligonucleotide inhibitor developed by Kastle Therapeutics (formerly Genzyme Corporation/Ionis Pharmaceuticals) for the treatment of homozygous familial hypercholesterolemia (HoFH). Approved by the FDA in January 2013, Kynamro represents a novel therapeutic approach for patients with this rare genetic disorder who have limited treatment options. As an orphan drug, it addresses a significant unmet medical need in managing severely elevated cholesterol levels.

Mechanism of Action

Kynamro exerts its pharmacological effects through an antisense mechanism targeting apolipoprotein B-100 (apo B-100) mRNA. The drug is a 20-mer phosphorothioate oligonucleotide complementary to the coding region of human apo B-100 mRNA. By binding specifically to this mRNA, Kynamro promotes its degradation through RNase H-mediated cleavage, thereby reducing the translation of apo B-100 protein. This results in decreased production and secretion of very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), ultimately leading to reduced circulating levels of LDL-cholesterol, lipoprotein(a), and total cholesterol.

Indications

Kynamro is indicated as an adjunct to lipid-lowering medications and diet for the treatment of homozygous familial hypercholesterolemia (HoFH). This approval is specifically for patients confirmed through genetic testing or clinical criteria who have inadequate response to other lipid-lowering therapies. The drug is not indicated for heterozygous FH or other forms of hypercholesterolemia.

Dosage and Administration

• Renal impairment: No dosage adjustment recommended
• Hepatic impairment: Contraindicated in moderate or severe hepatic impairment
• Pediatric use: Safety and effectiveness not established
• Geriatric use: Limited data available

Pharmacokinetics

Contraindications

• Moderate or severe hepatic impairment (Child-Pugh B or C)
• Active liver disease or unexplained persistent elevations in serum transaminases
• Hypersensitivity to mipomersen sodium or any component of the formulation
• Pregnancy (based on animal data showing fetal harm)

Warnings and Precautions

• Increased liver transaminases: ALT elevations ≥3× ULN occur in approximately 10% of patients
• Hepatic steatosis: Monitor via MRI or other appropriate imaging
• Injection site reactions: Common (≥90% of patients); including redness, pain, and discoloration
• Flu-like symptoms: Reported in approximately 30% of patients
• Cardiovascular events: Monitor for increased cardiovascular risk
• Renal impairment: Use with caution in severe renal impairment

Drug Interactions

• Other hepatotoxic drugs: Increased risk of liver injury (avoid concomitant use)
• Warfarin: Potential interaction requiring INR monitoring (theoretical based on mechanism)
• Other antisense oligonucleotides: No specific data available
• Immunosuppressants: Limited data on interactions

Adverse Effects

• Injection site reactions (redness, pain, pruritus, swelling)
• Flu-like symptoms (fever, chills, malaise)
• Nausea
• Headache
• Elevated transaminases

• Hepatotoxicity (steatosis, steatohepatitis)
• Cirrhosis (reported in clinical trials)
• Cardiovascular events
• Severe injection site reactions
• Hypersensitivity reactions

Monitoring Parameters

• Complete metabolic panel including ALT, AST, bilirubin
• Lipid profile
• Pregnancy test (if applicable)
• Hepatic imaging (consider baseline MRI)

• ALT/AST: Monthly for first year, then every 3 months
• Lipid profile: Every 3 months
• Hepatic imaging: Annually or if transaminases elevated
• Injection sites: Regular inspection
• Cardiovascular assessment: Regular monitoring

• Continue liver function monitoring for at least 6 months after discontinuation

Patient Education

• Understand the risk of liver toxicity and importance of regular monitoring
• Proper injection technique and site rotation
• Recognition and management of injection site reactions
• Monitoring for flu-like symptoms (typically diminish with continued treatment)
• Importance of continuing other lipid-lowering therapies and dietary modifications
• Report any signs of liver dysfunction (jaundice, dark urine, abdominal pain)
• Use effective contraception during treatment
• Regular follow-up with healthcare provider essential

References

1. FDA Prescribing Information: Kynamro (mipomersen) [January 2013] 2. Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375(9719):998-1006. 3. McGowan MP, Tardif JC, Ceska R, et al. Randomized, placebo-controlled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering therapy. PLoS One. 2012;7(11):e49006. 4. Visser ME, Wagener G, Baker BF, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial. Eur Heart J. 2012;33(9):1142-1149. 5. Santos RD, Duell PB, East C, et al. Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2-year follow-up results. Lancet Diabetes Endocrinol. 2015;3(12):943-950. 6. European Medicines Agency. Assessment Report: Kynamro. EMA/CHMP/454317/2012.