New Data at ECTRIMS Highlight Positive Benefit-Risk Profile of Mavenclad in Relapsing Multiple Sclerosis (2)

- The CLARITY (Cladribine Tablets Treating MS Orally) study: a two-year Phase III placebo-controlled study designed to evaluate the efficacy and safety of MAVENCLAD(R) as a monotherapy in patients with RRMS. - The CLARITY extension study: a two-year Phase III placebo-controlled study following on from the CLARITY study, designed to evaluate the safety and efficacy of MAVENCLAD(R) over an extended administration for four years. - The ORACLE MS (Oral Cladribine in Early MS) study: a two-year Phase III placebo-controlled study designed to evaluate the efficacy and safety of MAVENCLAD(R) as a monotherapy in patients at risk of developing MS (patients who have experienced a first clinical event suggestive of MS). - The ONWARD (Oral Cladribine Added ON To Interferon beta-1a in Patients With Active Relapsing Disease) study: a Phase II placebo-controlled study designed primarily to evaluate the safety and tolerability of adding MAVENCLAD(R) treatment to patients with relapsing forms of MS, who have experienced breakthrough disease while on established interferon-beta therapy. - PREMIERE (Prospective Observational Long-term Safety Registry of Multiple Sclerosis Patients Who Have Participated in Cladribine Clinical Studies) study: interim long-term follow-up data from the prospective registry, PREMIERE, to evaluate the safety and efficacy of MAVENCLAD(R)

The clinical development program of Cladribine in MS comprises more than 10,000 patient years of data with over 2,700 patients included in the clinical trial program, and more than 10 years of observation in some patients.

EU Indication    MAVENCLAD(R) (cladribine tablets) is indicated for the treatment of adult patients with highly active relapsing multiple sclerosis (RMS) as defined by clinical or imaging features.

Important EU Safety Information    Contraindications:    MAVENCLAD(R) is contraindicated in patients with hypersensitivity to the active substance, human immunodeficiency virus (HIV), active chronic infection (tuberculosis or hepatitis), active malignancy, moderate to severe renal impairment (creatinine clearance <60 mL/min), and those who are pregnant and breast-feeding. MAVENCLAD(R) is also contraindicated in immunocompromised patients, including patients currently receiving immunosuppressive or myelosuppressive therapy.

Special warnings and precautions for use:  The most clinically relevant adverse reactions were lymphopenia and herpes zoster.

Haematology  Decreases in neutrophil count, red blood cell count, haematocrit, haemoglobin or platelet count compared to baseline values have been observed in clinical studies, although these parameters usually remain within normal limits.

Additive haematological adverse reactions may be expected if cladribine is administered prior to or concomitantly with other substances that affect the haematological profile

Lymphocyte counts must be determined

- before initiating MAVENCLAD(R) in year 1, - before initiating MAVENCLAD(R) in year 2, - 2 and 6 months after start of treatment in each treatment year. If the lymphocyte count is below 500 cells/mmcubed, it should be actively monitored until values increase again.

Infections  Cladribine can reduce the body's immune defence and may increase the likelihood of infections. HIV infection, active tuberculosis and active hepatitis must be excluded before initiation of cladribine.

The incidence of herpes zoster was increased in patients on cladribine. If lymphocyte counts drop below 200 cells/mmcubed, anti-herpes prophylaxis according to local standard practice should be considered during the time of grade 4 lymphopenia. Interruption or delay of MAVENCLAD(R) may be considered until proper resolution of the infection.

Cases of progressive multifocal leukoencephalopathy (PML) have been reported for parenteral cladribine in patients treated for hairy cell leukaemia with a different treatment regimen.

In the clinical study data base of cladribine in MS (1,976 patients, 8,650 patient years) no case of PML has been reported. However, a baseline magnetic resonance imaging (MRI) should be performed before initiating MAVENCLAD(R) (usually within 3 months).

About Rebif(R)  Rebif(R) (interferon beta-1a) is a disease-modifying drug used to treat relapsing forms of multiple sclerosis (MS) and is similar to the interferon beta protein produced by the human body. The efficacy of Rebif(R) in chronic progressive MS has not been established. Interferon ss is thought to help reduce inflammation. The exact mechanism is unknown.

Rebif(R), which was approved in Europe in 1998 and in the US in 2002, is registered in more than 90 countries worldwide. Rebif(R) has been proven to delay the progression of disability, reduce the frequency of relapses and reduce MRI lesion activity and area+.

Rebif(R) can be administrated with the RebiSmart(R) electronic auto-injection device (not approved in the US), or with the RebiDose(R) single-use disposable pen, or the manual multidose injection pen RebiSlide(TM). Rebif(R) can also be administered with the autoinjector Rebiject II(R) or by manual injection using ready-to-use pre-filled syringes. These injection devices are not approved in all countries.

In January 2012, the European commission approved the extension of the indication of Rebif(R) in early multiple sclerosis. The extension of the indication of Rebif(R) has not been submitted in the United States.

Rebif(R) should be used with caution in patients with a history of depression, liver disease, thyroid abnormalities and seizures. Most commonly reported side effects are flu-like symptoms, injection site disorders, elevation of liver enzymes and blood cell abnormalities. Patients, especially those with depression, seizure disorders, or liver problems, should discuss treatment with Rebif(R) with their doctors.

Rebif(R) (interferon beta-1a) is approved in the United States for relapsing forms of MS.  RebiSmart(R), an electronic device for self-injection of Rebif(R), is also not approved in the United States. Cladribine Tablets is an investigational product and not approved for use in any indication in the United States.

+The exact correlation between MRI findings and the current or future clinical status of patients, including disability progression, is unknown.

About Multiple Sclerosis  Multiple sclerosis (MS) is a chronic, inflammatory condition of the central nervous system and is the most common, non-traumatic, disabling neurological disease in young adults. It is estimated that approximately 2.3 million people have MS worldwide. While symptoms can vary, the most common symptoms of MS include blurred vision, numbness or tingling in the limbs and problems with strength and coordination. The relapsing forms of MS are the most common.

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