Mogamulizumab-kpkc - Dosage, Uses, Warnings, and Side Effects

Overview

Mogamulizumab-kpkc is a CC chemokine receptor type 4 (CCR4) drug used to treat adult patients after at least one prior systemic therapy for Sezary syndrome (SS) or with relapsed or refractory mycosis fungoides (MF). It was approved by the United States Food and Drug Administration (USFDA) on August 8th, 2018. This drug is also a second-line agent considered for treating Cutaneous T-cell Lymphoma (CTCL). It is the most recent therapy recommended to control the syndrome and improve patients' quality of life.

How Does Mogamulizumab-kpkc Work?

Mogamulizumab-kpkc belongs to a class of medications called monoclonal antibodies, which activate the immune system to defend or attack cancer cells. It is a first-in-class defucosylated humanized monoclonal antibody used to manage Sezary syndrome and refractory or relapsed MF in adults. The drug selectively targets CCR4, normally expressed in T helper cells (Th2) and regulatory T cells (Treg). After binding to these receptors, the T cell is marked for destruction. Along with the destruction of malignant cells, it also depletes the Th2 and Treg cells, thus reducing the ability of the tumor to sustain growth and survival.

Indications of Mogamulizumab-kpkc:

Mogamulizumab-kpkc is indicated in the treatment of Sezary syndrome and relapsed or refractory mycosis fungoides in adult patients after at least one prior administration of systemic therapy.

Available Doses and Dose Forms:

Mogamulizumab-kpkc is recommended at 1 mg/kg (milligram per kilogram), and administered as an intravenous infusion for at least 60 minutes. The first 28-day regimen is administered on days 1, 8, 15, and 22. Following that, it is administered on days 1 and 15 of each subsequent 28-day cycle until unacceptable toxicity or disease progression. Premedications such as Acetaminophen and Diphenhydramine are administered for the first infusion of Mogamulizumab-kpkc. The drug must not be administered subcutaneously or infused rapidly.

Warnings and Precautions:

• Serious and life-threatening infusion reactions were reported during clinical trials in some patients following the first infusion or shortly after that, which include chills, fever, headache, tachycardia (increased heartbeat), nausea, and vomiting. Therefore, patients must be closely monitored, and premedications such as Acetaminophen and Diphenhydramine can be considered.

• Mogamulizumab-kpkc may cause life-threatening skin reactions, including Toxic Epidermal Necrolysis (TEN) (severe skin reaction) and Stevens-Johnson syndrome (SJS) (a rare and serious disorder of the skin and mucous membrane). In such cases, the treatment is discontinued permanently, and if SJS or TEN is suspected, the treatment must be interrupted and restarted only if these conditions are ruled out. Rashes such as papular maculopapular rash (discolored skin area) or granulomatous dermatitis (skin disorder) can occur. Therefore, patients must be carefully monitored throughout the treatment.

• Mogamulizumab-kpkc can cause serious infections, which include pneumonia (lung infection), sepsis (extreme reaction of the body to infection), or skin infections. Hence, patients must be monitored carefully, and appropriate treatment must be established in case of signs and symptoms of infection.

• Immune-mediated complications such as polymyositis (severe muscle weakness), myocarditis (swelling of heart muscles), pneumonitis (swelling of lung tissues), and hepatitis (swelling of the liver) were reported during trials. Hence, if such complications are suspected or observed, treatment must be interrupted or discontinued. A risk-benefit ratio must be considered in patients with autoimmune diseases.

• Patients undergoing treatment with Mogamulizumab-kpkc are at an increased risk of transplant complications. Hence, patients receiving allogeneic hematopoietic stem cell transplantation (HSCT) must be carefully monitored for any evidence of complications.

For Patients

What Is Sézary Syndrome?

Sezary syndrome and mycosis fungoides are the common forms of cutaneous T cell lymphoma (CTCL). Sezary syndrome is a fast-growing, aggressive, and rare form of cancer that looks similar to eczema or other skin disorders. In this condition, cancerous T cells called Sezary cells are present in the skin, blood, and lymph nodes. Symptoms of Sezary syndrome include swelling of the skin, red and severe itchy rash, hair loss, abnormalities in the fingernails and toenails, and thick skin on the palms and soles. The exact cause of this condition is unknown; hence the diagnosis can be challenging.

What Is Mogamulizumab-kpkc?

Mogamulizumab-kpkc is a prescription medicine used in the treatment of Sezary syndrome and mycosis fungoides in adults whose disease has relapsed, gotten worse, or has not improved even after taking other medicines. It belongs to the group of drugs called monoclonal antibodies that activate the immune system against the attack of cancer cells. The duration of treatment with Mogamulizumab-kpkc depends on the response of the patient to the drug and any associated side effects.

How Effective Is Mogamulizumab-kpkc?

Sezary syndrome and mycosis fungoides are often challenging to treat if they become resistant to initial systemic treatment. These conditions may also interfere with transplantation procedures. Hence, there was a desperate need for new treatment options to achieve better disease control. Recent studies have demonstrated that Mogamulizumab-kpkc has a Progression-Free Survival (PFS) benefit. During clinical trials, the drug had a PFS median of 7.7 months compared to 3.1 months in Vorinostat. Mogamulizumab-kpkc was well tolerated, with common adverse effects such as fatigue, diarrhea, rash, and infusion-related reactions. Various studies have suggested that the drug is safe and effective for mycosis fungoides and Sezary syndrome, wherein durable responses are required.

How Should Mogamulizumab-kpkc Be Taken?

Mogamulizumab-kpkc is available as a solution to be injected intravenously (IV) by a healthcare professional in a medical office. It is usually infused for around 60 minutes and administered once a week for the first four doses, followed by every other week as long as the treatment is recommended.

What Are the Side Effects of Mogamulizumab-kpkc?

Some of the serious side effects of Mogamulizumab-kpkc include;

• Signs of infection include fever, sore throat, cough, and other flu-like symptoms.

• Itching, rash, blisters, or peeling of skin.

• Painful ulcers in the nose, mouth, throat, and genital area.

• Nausea.

• Diarrhea.

• Stomach pain.

• Frequent and painful urination.

• Easy bleeding or bruising.

Some of the common side effects include:

• Constipation.

• Decreased appetite.

• Headache.

• Difficulty sleeping.

• Depression.

• Muscle pain or spasm.

• Dry skin.

• Hair loss.

• Swelling of hands, feet, lower legs, and ankles.

What Must the Patient Inform the Doctor Before Taking Mogamulizumab-kpkc?

• Patients must tell the doctor if they are allergic to Mogamulizumab-kpkc, infusions, or any other medications before starting the treatment.

• Before starting treatment with Mogamulizumab-kpkc, patients must inform the doctor if they have an autoimmune disease, liver disease including hepatitis B, respiratory problems, or previously had a stem cell transplant using cells from a donor.

• Female patients must tell the doctor if they are pregnant or planning to become pregnant or lactating before taking the Mogamulizumab-kpkc injection. Patients must immediately inform the doctor if they become pregnant during treatment.

• Patients must inform the healthcare provider if they are taking any medications, vitamins, nutritional supplements, or over-the-counter (OTC) medicines before starting the treatment with Mogamulizumab-kpkc.

• Patients must inform the doctor that they receive Mogamulizumab-kpkc before surgery or dental treatments.

What Are the Precautionary Measures to Be Followed While Taking Mogamulizumab-kpkc?

• A pregnancy test is conducted for females who can become pregnant, and a birth control method would be recommended to prevent pregnancy during treatment. It must also be used for at least three months following the last dose of Mogamulizumab-kpkc.

• Patients must contact the doctor immediately if they experience any infusion reactions or other side effects, skin rash, fever, or infection while receiving Mogamulizumab-kpkc.

• Post-transplant complications may occur following an allogeneic hematopoietic stem cell transplant after receiving Mogamulizumab-kpkc.

Dietary Considerations

Patients can follow a normal diet during the treatment with Mogamulizumab-kpkc unless the doctor recommends any restrictions.

Missed Dose

Mogamulizumab-kpkc must be administered within two days of the scheduled dose, and if a dose is missed, it must be received as soon as possible, after which the regular dosing schedule must be resumed.

Overdose

In case of an overdose or any severe side effects, or if the patient is experiencing seizures or trouble breathing, a healthcare provider must be contacted immediately.

Storage

Mogamulizumab-kpkc vials must be stored in the original package under refrigeration at two to eight degrees (36 to 46 degrees Fahrenheit) to protect from light until required to be used. The medication must not be shaken or frozen.

For Doctors

What Are the Pharmacological Aspects of Mogamulizumab-kpkc?

Mechanism of Action: Mogamulizumab-kpkc is a humanized IgG1 kappa defucosylated monoclonal antibody that selectively binds to CCR4, a receptor involved in the trafficking of lymphocytes to different organs. CCR4 is located on the surface of T-cell malignancies, regulatory T-cells, and T helper cells. Studies have demonstrated that the drug binds and targets a cell for Antibody-Dependent Cytotoxicity (ADCC), which results in the depletion of target cells.

Pharmacodynamics: The drug exposure-response relationship and the pharmacodynamics of Mogamulizumab-kpkc need to be clearly understood. However, as a monoclonal antibody, Mogamulizumab-kpkc blocks T cell proliferation and reduces malignancy. In response to the ligands, CCR4 also promotes the migration of T cells to extranodal sites, including the skin.

Pharmacokinetics

• Absorption: After administering Mogamulizumab-kpkc, the concentrations increased proportionally over a dose range of 0.01 to 1.0 mg/kg, which is approximately 0.01 to one time the recommended dose. On repeated dosing, a steady concentration was obtained after eight doses in about 12 weeks with a systemic accumulation of 1.6 fold and area under the curve (AUC) at 5577 mcg/hr/mL (micrograms per hour per milliliter). The maximum concentration of the drug (C Max) is 32 mcg/mL (micrograms per milliliter), and the trough concentration (Cmin) is 11 mcg/mL.

• Distribution: The approximate central volume of distribution of Mogamulizumab-kpkc is 3.6 L (20 percent).

• Elimination: The terminal half-life of Mogamulizumab-kpkc is 17 days, and the clearance is around 12 mL/h (milliliter per hour).

Drug Interactions:

Drug interaction studies have not been performed with Mogamulizumab-kpkc. However, patients taking the following drugs with Mogamulizumab-kpkc must be closely monitored:

• Ponesimod.

• Siponimod.

• Efgartigimod.

• Rozanolixizumab.

• Trastuzumab.

• Ublituximab.

• Dengue vaccine.

Clinical Studies:

The safety and efficacy of Mogamulizumab-kpkc were evaluated in Phase 1 and 2 studies involving pretreated patients of CTCL. Phase 1 study demonstrated no toxicity that was dose limiting and IV infusion of Mogamulizumab-kpkc once a week for two weeks at doses - 0.1, 0.3, and 1 mg/kg, followed by observation for two weeks.

In Phase 2, Mogamulizumab-kpkc 1 mg/kg was dosed in a similar schedule to the Phase I study, followed by infusions administered every two weeks until disease progression. Nausea was most commonly observed, followed by chills, headache, and infusion reactions. The Overall Response Rate (ORR) observed amongst 38 patients who were evaluated was 36.8 percent, with patients of SS demonstrating a higher response rate than those with MF.

The efficacy of Mogamulizumab-kpkc was evaluated in an open-label, randomized multicenter trial in adults suffering from MF or SS who have undergone at least one exposure to systemic therapy. About 372 patients were randomized in a ratio of 1:1 to receive either Mogamulizumab-kpkc or Vorinostat. Mogamulizumab-kpkc was administered at 1 mg/kg IV over 60 minutes. On days 1, 8, 15, and 22 in the first cycle of 28 days, followed by days 1 and 15 in subsequent cycles. Vorinostat was administered orally every day at a dose of 400mg. The average duration of exposure to Mogamulizumab-kpkc was 5.6 months, with 23 percent having exposure for 12 months. In contrast, the median exposure to the group receiving vorinostat was 2.8 months, with 22 percent of patients receiving the same for six months. The efficacy parameters selected were Progression-Free Survival (PFS), and Overall Response Rate (ORR) based on the measure of disease in skin, blood, viscera, and lymph nodes. The trial demonstrated PFS was significantly prolonged in the group receiving Mogamulizumab-kpkc compared to the group receiving Vorinostat.

Nonclinical Toxicology

Carcinogenicity and genotoxicity studies of Mogamulizumab-kpkc have not been conducted. Specific studies have yet to be performed to evaluate the potential effects of Mogamulizumab-kpkc on fertility. However, animal studies conducted on sexually mature monkeys up to 26 weeks have demonstrated that no related toxic effects were observed in male and female reproductive organs.

Specific Considerations

• Pregnancy: There is no data available regarding the use of Mogamulizumab-kpkc in pregnant women to determine congenital disabilities, miscarriage, or any adverse effects of the drug on the fetus or the mother.

• Lactation: No information is available regarding the presence of Mogamulizumab-kpkc in human milk, its effects on the breastfed infant, or milk production. Therefore, the benefits of breastfeeding and the potential adverse effects of Mogamulizumab-kpkc on the lactating infant must be considered, along with the necessity of the drug for the mother.

• Pediatric Use: The safety and effectiveness of Mogamulizumab-kpkc have not been established in pediatric patients.

• Geriatric Use: No significant differences in the effectiveness of Mogamulizumab-kpkc were observed in geriatric patients compared to younger patients. However, a higher rate of severe adverse reactions was seen in patients aged above 65 years when compared to patients below 65 years.