What Is Alemtuzumab (Campath, Lemtrada)? FDA Approval, Licensing and Reimbursement in Turkey

• FDA Approved: Yes (Initial approval date: May 7, 2001)
• Brand Names: Campath, Lemtrada (the brand approved for multiple sclerosis in Turkey)
• Active Ingredient: Alemtuzumab
• Route of Administration: Intravenous (IV) infusion
• Class: Anti-CD52 monoclonal antibody
• Category: Biological response modifier
• Manufacturer: Genzyme
• Distribution in Turkey: Sanofi İlaçları Ltd. Şti.
• Approved Cancer Indications: Relapsed and/or refractory B-cell chronic lymphocytic leukemia (B-CLL) — Used after fludarabine treatment failure in patients previously treated with alkylating agents.

What Is Alemtuzumab?

Alemtuzumab is a monoclonal antibody targeting the 21 to 28 kDa cell-surface protein CD52. Marketed as Campath and Lemtrada, it is used for B-cell chronic lymphocytic leukemia and relapsing-remitting multiple sclerosis. 

How Does It Work?

1. The CD52 protein is found on immune cells including B and T lymphocytes, NK cells, monocytes and macrophages. Alemtuzumab recognizes and destroys these cells, helping the immune system eliminate them.
2. CD52 is absent from the surfaces of stem cells and mature plasma cells. Alemtuzumab therefore destroys only its targeted cells without affecting stem cells or plasma cells.
3. Alemtuzumab eliminates cancer cells through two mechanisms: antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cell lysis. These processes allow the immune system to detect and destroy cancer cells.

What Is the CD52 Antigen?

The CD52 antigen is present on various hematopoietic cells, including B and T lymphocytes, natural killer cells, monocytes, and macrophages. Alemtuzumab binds this antigen to destroy cells. Suppressing the immune system aims to stop tumor cell growth and spread.

FDA Approval History

1. May 7, 2001: Campath (alemtuzumab) received FDA approval for relapsed and/or refractory B-cell chronic lymphocytic leukemia (B-CLL).
2. June 12, 2012: Genzyme applied to the FDA and European Medicines Agency (EMA) for Lemtrada (alemtuzumab) to treat multiple sclerosis (MS).
3. August 27, 2012: Genzyme provided an update on its United States Lemtrada application.
4. January 28, 2013: The FDA accepted Genzyme's application for Lemtrada (alemtuzumab) in multiple sclerosis (MS) for review.
5. December 30, 2013: Genzyme received a complete response letter from the FDA regarding its Lemtrada (alemtuzumab) application.
6. November 14, 2014: The FDA approved Lemtrada (alemtuzumab) for relapsing multiple sclerosis (MS).

Licensing in Turkey

The initial license date was 20.07.2018. The licensed therapeutic indications in Turkey are:

Disease-modifying monotherapy in adults with highly active relapsing-remitting multiple sclerosis (RRMS) in the following groups:

• Highly active disease despite a complete, appropriate course of at least two disease-modifying treatments.

• Rapidly evolving RRMS defined by 2 or more disabling relapses and 1 or more gadolinium-enhancing brain MRI lesions, or a significant increase in T2 lesion burden compared with a previous MRI.

Is Alemtuzumab Reimbursed?

Turkey's Social Security Institution (SGK) covers treatment for licensed MS indications under specified conditions, rather than for a cancer diagnosis.

Price: Mabcampath 30 mg 3x1 vials 2.184.94 TL. 

Dosage and Administration

Treatment starts with a 3 mg intravenous (IV) infusion, gradually increasing to 10 mg and then 30 mg as tolerated. The 30 mg dose is given three times weekly (Monday, Wednesday, Friday), for a maximum of 12 weeks.

Mechanisms of Resistance

Resistance may be associated with low or absent CD52 antigen expression on tumor cells, reducing alemtuzumab's effectiveness against its CD52 target. Changes in the immune system may also reduce activity.

Absorption

Alemtuzumab is given intravenously directly into the circulation and therefore does not undergo gastrointestinal absorption.

Distribution

It targets circulating cells expressing CD52. Plasma levels reach steady state with dosing three times weekly.

Metabolism

Metabolism has not been extensively characterized. Half-life is approximately 12 days, with minimal clearance by the liver and kidneys.

Drug Interactions

No specific interaction studies are known for alemtuzumab, but combining it with other immunosuppressive medicines should be assessed carefully.

Precautions

1. It must not be used in patients with active systemic infections, HIV positivity, AIDS, or known type 1 hypersensitivity or anaphylactic reactions to alemtuzumab or its components.
2. Before infusion, patients should receive acetaminophen (650 mg orally) and diphenhydramine (50 mg orally) to reduce infusion reactions.
3. Start with 3 mg as a daily intravenous infusion over 2 hours. If tolerated, gradually increase the daily dose to 10 mg and then 30 mg. Give 30 mg 3 times weekly (Monday, Wednesday, Friday) for a maximum of 12 weeks. Alemtuzumab must never be given by IV push or bolus.
4. Monitor carefully for infusion-related events, generally occurring within the first 30-60 minutes after infusion starts and most often during the first treatment week. Measure pulse, blood pressure, and temperature every 15-30 minutes.
5. At treatment initiation, provide anti-infective prophylaxis to reduce the risk of serious opportunistic infections.
6. Monitor complete blood counts and platelets weekly during treatment. Stop treatment if severe hematologic toxicity develops.
7. The strongest antitumor effects occur in peripheral blood, bone marrow, and spleen. Lymph nodes, particularly large, bulky nodes, are less responsive.
8. Pregnancy category C: Alemtuzumab should be given during pregnancy only when necessity is clearly established. Avoid breastfeeding during treatment and for 3 months after the last dose.

Adverse Effects

Listed from most to less frequent:

1. Infusion-related symptoms include fever, chills, nausea, vomiting, urticaria, rash, headache, diarrhea, dyspnea, and/or hypotension, generally during the first treatment week.
2. Immunosuppression increases opportunistic infections, including Pneumocystis jiroveci (PJP), cytomegalovirus (CMV), herpes zoster, Candida, Cryptococcus, and Listeria. Anti-infective prophylaxis is recommended. CD4 and CD8 counts recover slowly and may take a year to return to normal.
3. Bone marrow suppression most commonly presents as neutropenia; anemia and thrombocytopenia may also occur. Rarely, pancytopenia (reduced counts of all blood cells) and bone marrow hypoplasia occur.