Mogamulizumab

Mogamulizumab is a defucosylated, humanised IgG1 kappa immunoglobulin produced in Chinese hamster ovary cells by recombinant DNA technology. It binds selectively to CCR4 on the surface of target cells and depletes them. In mycosis fungoides and Sézary syndrome, CCR4 expression is inherent to the malignant T cells.

Mechanism of Action

• Target: CCR4 is a G protein-coupled receptor for CC chemokines that is involved in the movement of lymphocytes to various organs, including the skin. It is expressed on the surface of some cancer cells, including T-cell malignancies such as MF and SS.
• Cell depletion: by binding to CCR4, mogamulizumab causes depletion of the cells that carry it. DrugBank adds that the antibody can block CCR4-mediated signalling and chemokine-driven cell migration, can trigger antibody-dependent cell-mediated cytotoxicity against CCR4-positive T cells, and also depletes regulatory T cells, which suppress anti-tumour immunity.
• Clinical study: efficacy in MF and SS was established in a phase 3, multicentre, open-label trial (0761-010) in 372 adults randomised 1:1 to mogamulizumab or vorinostat (186 in each arm). Patients on vorinostat with disease progression or unacceptable toxicity could cross over to mogamulizumab.

Pharmacokinetics

• Population analysis: pharmacokinetics were evaluated in adults with T-cell leukaemia-lymphoma and cutaneous T-cell lymphoma over doses of 0.01 to 1 mg/kg; the population analysis included 444 patients from six trials. Exposure increased in proportion to dose between 0.1 and 1.0 mg/kg.
• Absorption: mogamulizumab is given intravenously, so it is immediately and completely bioavailable.
• Distribution: the geometric mean central volume of distribution is 3.57 L.
• Metabolism: the metabolic pathway has not been characterised; like endogenous IgG, it is expected to be degraded by catabolic pathways into small peptides and amino acids.
• Elimination: the geometric mean clearance is 12.0 mL/h and the elimination half-life is 17 days.
• Linearity and accumulation: pharmacokinetics are linear from 0.01 to 1 mg/kg. Steady state is reached after 12 weeks of repeated dosing, with 1.7-fold systemic accumulation.
• Special populations: mild to severe renal impairment (creatinine clearance below 30 mL/min in only 2 patients) produced no clinically important differences in clearance. Mild and moderate hepatic impairment need no dose adjustment; severe hepatic impairment has not been studied.

• Mycosis fungoides (MF) and Sézary syndrome (SS): treatment of adult patients who have received at least one prior systemic therapy.

• Hypersensitivity to mogamulizumab or to any of the excipients.

The most frequently reported serious adverse reactions were pneumonia, pyrexia, infusion-related reaction and cellulitis. The most frequently reported adverse reactions were infusion-related reaction and drug rash (drug eruption); most were non-serious and of grade 1 or 2. Severe reactions included grade 4 respiratory failure (1.1%), and the grade 5 reactions were polymyositis and sepsis (0.5% each).

Very common (≥1/10): infections (including folliculitis, cellulitis, candidiasis, pneumonia, sepsis, skin infection, otitis externa, herpes zoster, staphylococcal skin infection, urinary tract infection, herpes simplex and cytomegalovirus), infusion-related reaction, headache, constipation, diarrhoea, nausea, stomatitis, fatigue, peripheral oedema, pyrexia, drug eruption (including skin rash).

Common (≥1/100 to <1/10): anaemia, neutropenia, leukopenia, thrombocytopenia, hypothyroidism, vomiting, colitis, upper respiratory tract infection, increased alanine aminotransferase, increased aspartate aminotransferase, increased blood alkaline phosphatase, decreased lymphocyte count.

Uncommon (≥1/1,000 to <1/100): acute hepatitis, hepatitis, tumour lysis syndrome.

Not known: granuloma, including granuloma of the skin (scalp, periauricular area and trunk) and of bone (sternum, skull, spine, ribs and pelvis).

Important serious reactions are severe drug rash (Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients with T-cell lymphomas other than MF or SS), infusion-related reactions, serious infections and tumour lysis syndrome.

No interaction studies have been performed.

• Immune-modulating and other MF/SS therapies: the combination of mogamulizumab with systemic immune-modulating medicinal products, or with other licensed therapies for MF or SS, has not been studied and is not recommended, in view of the risk of severe infection.
• Corticosteroids: topical steroids or low doses of systemic corticosteroids may be used during treatment. The risk of serious infection and viral reactivation may be higher with systemic immunosuppressive agents.

Treatment must be started and supervised by physicians experienced in the treatment of cancer, and must be given only by healthcare professionals in an environment where resuscitation equipment is available. Mogamulizumab is for intravenous infusion only. It must not be given subcutaneously or intramuscularly, by rapid intravenous administration or as an intravenous bolus. Dilution before administration is described in section 6.6 of the SmPC.

Recommended Dose

• Dose: 1 mg/kg as an intravenous infusion over at least 60 minutes.
• Schedule: weekly on days 1, 8, 15 and 22 of the first 28-day cycle, then every two weeks on days 1 and 15 of each following 28-day cycle, until disease progression or unacceptable toxicity.
• Premedication: an antipyretic and an antihistamine are recommended before the first infusion. If an infusion reaction occurs, premedication is given before later infusions.

Dose Modification

• Drug rash: for a grade 2 or 3 (moderate or severe) rash, interrupt treatment and treat the rash until it improves to grade 1 or less (mild), then treatment may resume. For a life-threatening (grade 4) rash, stop permanently.
• Infusion-related reactions: for grade 1 to 3 reactions, interrupt the infusion temporarily and treat the symptoms. When the infusion restarts after the symptoms resolve, the rate is reduced by at least 50%; if the reaction recurs, consider stopping the infusion. For a life-threatening (grade 4) reaction, stop permanently.

Special Populations

• Elderly: no dose adjustment.
• Renal impairment: no dose adjustment in mild to severe impairment (population pharmacokinetic analysis).
• Hepatic impairment: no dose adjustment in mild or moderate impairment; not studied in severe impairment.
• Children and adolescents: safety and efficacy below 18 years of age have not been established; no data are available.

Missed Dose

Poteligeo should be given within 2 days of the scheduled day. If a dose is missed by more than 2 days, the next dose is given as soon as possible, and the schedule then resumes with doses based on the new scheduled days.

Traceability

To improve the traceability of biological medicinal products, the name and batch number of the product given should be clearly recorded.

Dermatologic Reactions

Drug rash (drug eruption) has occurred, some of it severe or serious. In patients with T-cell lymphomas other than MF or SS, serious skin reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) were reported in less than 1% of patients in clinical trials and after marketing, some with fatal outcome. Patients should be monitored closely for signs of SJS or TEN. If they occur, treatment is interrupted and not restarted unless SJS or TEN is ruled out and the skin reaction has resolved to grade 1 or less; appropriate medical therapy is given.

Infusion-Related Reactions

Acute infusion-related reactions were mostly mild or moderate, with a few severe (grade 3) reactions. Most occur during or shortly after the first infusion (all within 24 hours of administration), and the incidence falls with later treatments. Patients should be monitored carefully during and after the infusion. If an anaphylactic reaction occurs, mogamulizumab must be stopped immediately and permanently and appropriate medical therapy given.

Infections

Patients with MF or SS treated with mogamulizumab are at increased risk of serious infection and viral reactivation. They should be monitored for signs and symptoms of infection and treated promptly. Patients should be tested for hepatitis B infection before treatment starts; those who test positive for current or previous hepatitis B infection should be referred to a physician with expertise in hepatitis B for advice on measures against reactivation.

Stem Cell Transplantation

Complications, including severe graft-versus-host disease, have been reported in patients with T-cell lymphomas other than MF or SS who received an allogeneic haematopoietic stem cell transplant after mogamulizumab. The risk of transplant complications is higher if mogamulizumab is given within a short time (about 50 days) before the transplant, and patients should be followed closely for early signs. The safety of mogamulizumab after autologous or allogeneic transplant has not been studied.

Tumour Lysis Syndrome

Tumour lysis syndrome has been observed, most often during the first month of treatment. Patients with rapidly proliferating tumours and a high tumour burden are at risk. Electrolytes, hydration and renal function should be monitored closely by laboratory and clinical tests, particularly in the first month, and managed according to best medical practice, which may include aggressive hydration, correction of electrolyte abnormalities, anti-hyperuricaemic therapy and supportive care.

Cardiac Disorders

One case of acute myocardial infarction occurred in a clinical trial patient with MF or SS. In patients with other T-cell lymphomas there was one report of stress cardiomyopathy and one of acute myocardial infarction. Patients with risk factors for cardiac disease should be monitored and appropriate precautions taken.

Large Cell Transformation

Data in patients with large cell transformation are limited.

Excipients

The product contains less than 1 mmol sodium per dose, that is, it is essentially sodium-free. Each vial contains 1 mg of polysorbate 80 (0.2 mg/mL), and polysorbates may cause allergic reactions.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should use effective contraception during treatment and for at least 6 months afterwards.
• Pregnancy: there are no data in pregnant women. Mogamulizumab crosses the placental barrier in cynomolgus monkeys; apart from the pharmacological effect in foetuses, animal studies do not indicate direct or indirect harmful effects on reproduction. As a precaution, it is preferable to avoid its use during pregnancy.
• Breastfeeding: it is unknown whether mogamulizumab passes into human milk. Human IgG is excreted in milk during the first few days after birth and falls to low concentrations soon afterwards, so a risk to the breast-fed child cannot be excluded in that short period. Afterwards Poteligeo could be used during breastfeeding if clinically needed.
• Fertility: there are no clinical data and no specific animal studies of fertility. No adverse effects on male or female reproductive organs were seen in repeat-dose studies in cynomolgus monkeys.

Effect on Driving

Mogamulizumab has a minor influence on the ability to drive and use machines. Fatigue may occur after administration.

Store unopened vials in a refrigerator at 2–8 °C. Do not freeze. Keep the vial in the outer carton to protect it from light. Cold-chain handling at 2–8 °C applies in transport and storage until the infusion is prepared. Each vial holds 5 mL of solution in a 10 mL type I glass vial with a rubber stopper, aluminium seal and polypropylene flip-off cap; one vial per pack.

• Unopened vial: 3 years.
• After opening: Poteligeo has no preservative; once opened, it should be diluted and infused immediately.
• Prepared infusion: chemical and physical in-use stability has been shown for 24 hours at 25 °C under ambient room light, including the time in the infusion bag during the infusion. From a microbiological point of view the product should be used immediately. If it is not, the user is responsible for in-use storage, which must not exceed a total of 24 hours at 2–8 °C and only when dilution took place under controlled and validated aseptic conditions.

Prescription only (Rx). Poteligeo is a medicinal product subject to restricted medical prescription (Annex II B). Treatment is started and supervised by physicians experienced in the treatment of cancer and is given in an environment with resuscitation equipment, so it is supplied to the hospital or clinic that administers it, with the cold chain at 2–8 °C maintained.