Mipomersen

Mechanism of Action

Mipomersen is a 20-base pair, 2’-O-methoxyethyl modified antisense oligonucleotide complementary to human apolipoprotein B-100 messenger RNA.[3] Mipomersen aims to identify and hybridize with the human apolipoprotein B-100 mRNA via the traditional deoxyribonucleotide or ribonucleotide base pairing mechanism. The interface between the complementary mipomersen therapeutic oligonucleotide with the newly synthesized human apolipoprotein B-100 leads to the degradation of the messenger RNA. Most frequently, the hybridization of mipomersen to its target mRNA leads to the recruitment of RNase H1, a catalytic enzyme that degrades ribonucleic acid in the cellular cytoplasm.[4] 

By directly reducing and eliminating the cytoplasmic apolipoprotein B-100 messenger RNA concentration, mipomersen plays a crucial role in lowering the ribosomal production of the final, folded apolipoprotein B-100 polypeptide. This therapy ultimately leads to decreased production of protein human apolipoprotein B-100 and, therefore, reduces the production of low-density lipoprotein and lower-low-density lipoprotein cholesterol. Mipomersen functioned consistently across all species in tested human volunteers and patients.

Pharmacokinetics

Absorption 

Following administration, mipomersen is well absorbed in the site of injection. This absorption has been observed to be rapid and extensive, independent of the dosage injected. It has been noted that mipomersen achieves a peak plasma concentration at 3 to 4 hours following introduction subcutaneously. The measured half maximal effective concentration (EC50) for mipomersen in plasma was 18 ± 4 ng/ml. It has been estimated that the absolute bioavailability of mipomersen is within the range of 54 to 78%.

Distribution

As mipomersen is injected, it has been noted that this synthetic oligonucleotide is extensively bound to plasma proteins (>85%) in systemic or vascular circulation. It can rapidly enter tissues through cell-surface protein interactions. While bound to plasma proteins in circulation, the half-life of mipomersen in plasma is 2 to 5 hours. This time range represents the transfer of mipomersen from the blood into the tissue. Mipomersen interacts mainly with serum albumin, along with various other serum proteins. The Kd associated with mipomersen’s binding to serum albumin is approximately 150 μM. Dose-saturation studies on mice have demonstrated that the binding of mipomersen to plasma protein is saturated at doses exceeding 20 to 30 mg/kg.

Mipomersen is predominantly distributed to the liver, where cells specialize in apolipoprotein B-100 synthesis. Studies have also demonstrated that mipomersen demonstrates no adverse effect on the concentrations of PCSK9 in human plasma.

Studies in mice and monkey experiments have shown that mipomersen dose-dependently reduces apolipoprotein B-100 concentrations and has no effect on high-density lipoprotein cholesterol levels (HDL-C). Further experimentations have demonstrated that mipomersen achieves steady-state tissue concentrations following the 6-months mark post-administration.[5]

Metabolism

Unlike non-nucleic acid therapeutics, mipomersen is not metabolized by cytochrome P450 or other traditional drug-metabolizing enzymes in the liver. Mipomersen is instead a target of endonucleases in tissues. These endonucleases digest the oligonucleotide to form shorter strands of deoxynucleotides. These deoxynucleotides are further digested and metabolized by tissue exonucleases.[6]

Excretion 

In the tissues, like other small oligonucleotides, mipomersen is slowly degraded via exonuclease metabolism and excreted with other nuclease-digested metabolites in urine. The elimination half-life of mipomersen following cessation of administration is 1 to 2 months. The half-life of elimination is independent of the dosages administered to the human patient.[7]

Administration

Mipomersen is a chemically synthesized therapeutic preformulated in a syringe containing 200 mg/ml of mipomersen in saline. Mipomersen is administered subcutaneously once weekly. Vials or pre-filled syringe of mipomersen is only intended for single use. Each vial or syringe contains 200 mg of mipomersen in 1 mL of a buffered solution. Storage of the vial or syringe is recommended at 4 degrees C for long-term storage. The vial or syringe should be allowed to reach room temperature for at least 30 minutes following removal from the refrigerator. Before administration, the vial should be visually inspected and ensure no visible particulates in the solution or cloudy substance exist.

The therapeutic should be injected into the thigh region, outer area of the upper arm, or abdomen. Avoid injection into tattooed or scarred skin or sites of active skin injury, which include inflammation, skin infections, and skin rashes.

Adverse Effects

In phase 3 of the clinical trials, common adverse events reported mainly were injection-site reactions which include pain, erythema, and pruritus. Two days following administration, approximately 30% of patients reported flu-like symptoms when receiving mipomersen therapy. These symptoms include chills, myalgia, arthralgia, fatigue, or malaise. Other participants reported malaise, arthralgia, fatigue, chills, and myalgia.[8] Some data from phase 3 clinical trials displayed significant alanine aminotransferase (ALT) elevations in the groups administered with mipomersen compared to the control.[9]

Mipomersen usage is also cautioned when ingesting other hepatotoxic medications, which include methotrexate, tamoxifen, isotretinoin, and alcohol.[8]

Strategies to mitigate the adverse events listed above have been explored. Randomized controlled trials by Reeskamp et al. evaluated the efficacy and safety of administering mipomersen 3-times weekly at a dose of 70 mg. The researchers found that such modifications to the administration reduce the adverse effects while improving tolerability to mipomersen.[10]

84% of patients receiving mipomersen therapy have reported injection site reactions. These local effects typically include erythema, pain, pruritus, local swelling, and tenderness. To minimize the adverse effects of injection site reactions, the provider must adhere to the proper technique for the subcutaneous administration of therapeutics.

Contraindications

Mipomersen contraindications include:

• Patients with moderate or severe hepatic impairment (Child-Pugh category B or C). Furthermore, mipomersen is also contraindicated in patients with elevated transaminase levels in the serum and/or active liver disease.[8]
• Patients with pre-existing and known hypersensitivity allergic reactions to any therapeutic component.[8]

Mipomersen therapy for patients already on intense lipid-decreasing therapy and demonstrating elevated cardiovascular risk has shown to be well-tolerated in phase 3 studies.[11]

Monitoring

Due to safety concerns related to hepatotoxicity reported in clinical trials, it is recommended that serum alanine aminotransferase (ALT), aspartate transaminase (AST), total bilirubin, and alkaline phosphate levels are measured before initiation of treatment and are constantly monitored for the duration of treatment.[12] Administration of mipomersen should be halted if serum alanine aminotransferase (ALT) and aspartate transaminase (AST) levels exceed three times the limit of normal and/or if liver toxicity is noted to be clinically significant.[13]

It is also noted that the consumption of alcohol when taking mipomersen should be limited to only one alcoholic drink per day. This is due to alcohol possibly causing increased hepatic fat levels, which may exacerbate liver injury. Frequent monitoring of liver-related tests is recommended.

There are no clinically relevant drug interactions between mipomersen and warfarin as indicated by clotting assays, such as activated partial thromboplastin time (aPTT) and prothrombin time (PT). There are also no pharmacokinetic interactions between mipomersen and simvastatin or ezetimibe. However, drug-specific events cannot be completely ruled out before more extensive, larger, and long-term trials are conducted.

As observed in this randomized, placebo-controlled trial of mipomersen, McGowan et al. reported instances of cardiovascular events. Furthermore, since proteinuria is a risk factor for cardiovascular events, the link between proteinuria and mipomersen must be further investigated to rule out non-specific drug interactions.[9] This is compounded by the observation that mipomersen localizes in the kidney and the liver. Recent studies have demonstrated the association between alcohol-independent fatty liver disease and chronic kidney disease.[14] 

Therefore, it is recommended that continued monitoring of kidney function and health is observed. A renal panel assay will rule out potential kidney impairment or disease for the duration of taking mipomersen.

Toxicity

In the literature, there are no reported overdoses of mipomersen. In clinical trials, there was no difference in the adverse reactions observed in patients receiving the normal dose of 200 mg once weekly and patients receiving a higher dose of 300-400 mg once weekly for 13 weeks. However, patients with higher doses of mipomersen experienced more frequent and severe adverse reactions than patients receiving regular doses. There is currently no reported overdose treatment for mipomersen. It is unlikely that hemodialysis is useful in treating mipomersen overdose since mipomersen is tightly bound to plasma proteins.

Caution is advised when using mipomersen with other medications known to cause hepatotoxicity, increase transaminase levels or increase hepatic fat. Such medications are isotretinoin, acetaminophen, and isotretinoin when administered for more than three days per week, with a dosage of 4 g per day or more.

No studies currently observe the effects of concomitantly using mipomersen with other low-density lipoprotein-lowering therapeutic agents that increase hepatic fat. Therefore, it is not recommended for such a combination to be administered to the patient.

Enhancing Healthcare Team Outcomes

The success of mipomersen therapy depends on the patient's medication adherence, which may lower the effectiveness of mipomersen and promote the adverse effects of hypercholesterolemia. Some barriers exist to successful mipomersen therapy, such as a lack of understanding of the importance of low-density lipoprotein (LDL)-lowering therapy, experience with adverse effects, frequency of therapy, and treatment cost. These factors may present a strong barrier against the patients, which may cause the patient to forgo mipomersen therapy.

As mentioned previously, lifestyle changes are significant to the success of therapy and the patient's overall health. Therefore, healthcare professionals and clinicians (such as allopathic medical doctors (MDs), doctors of osteopathic medicine (DOs), doctors of podiatric medicine (DPMs), and advanced practice providers) must emphasize the importance of modifications to the patient's lifestyle.[15] 

Clinicians must provide valuable advice and guidance to the patients regarding diet choices, exercise, or decreasing weight if necessary. If the clinicians are facing difficulties observing such changes, they may refer the patient to registered dieticians (RDs) who can oversee these lifestyle changes for the patients over a more extended period.

The healthcare professional must also understand that the patient may face these barriers to therapy and must help the patient recognize and combat them. Furthermore, the patient needs to receive support from clinicians, allied health professionals, and nurses who can counsel patients on how they are advised to receive therapy and check their adherence to the treatment.[16]

Pharmacists also play a crucial role in the patient's health as they can counsel the patient on optimization strategies for therapy and ensure that the patient does not suffer from adverse drug-drug interactions.[17] Pharmacists must also report back to the patient's primary care clinician or clinician overseeing their care so that the clinician is aware of the patient's updates and adherence to therapy. There are examples of how the patient's care can be overseen by a multidisciplinary team of health care practitioners, who all work towards improving the patient's health outcomes and ensuring the patient's adherence to mipomersen therapy.[18]