Regulatory Decision Summary for Mavenclad

The efficacy of oral cladribine in the treatment of Relapsing Remitting Multiple Sclerosis (RRMS) was established solely on the results of the pivotal Phase III CLARITY study; in addition to the CLARITY study, results from Phase IIIb CLARITY Extension (EXT), Phase III ORACLE MS, and Phase IIb ONWARD studies were used to support the safety profile of oral cladribine use in RRMS. The CLARITY study was a Phase III randomized, double-blind, 3-arm, placebo-controlled, multi-center clinical trial to evaluate the efficacy and safety of oral cladribine over 2 years in subjects with early and moderately advanced RRMS (0 to 5.5 Expanded Disability Status Score, i.e. EDSS). Subjects (n = 1,326) were randomized 1:1:1 to receive oral cladribine 3.5 mg/kg cumulative dose, oral cladribine 5.25 mg/kg cumulative dose, or placebo. The specific pharmacokinetic/pharmacodynamic profile of cladribine results in a unique dosage regimen, i.e. one dose of oral cladribine per day during 4 to 5 consecutive days followed by a second week of treatment 28 days later at the beginning of treatment year 1 and treatment year 2 (a total of up to 20 days of treatment over 2 years).

Both oral cladribine treatment groups met the primary endpoint in reducing the qualifying relapse rate for the intent-to-treat population; secondary endpoints of proportion of relapse-free subjects, time to 3-month confirmed EDSS progression and Magnetic Resonance Imaging (MRI) endpoints of number of T1 gadolinium-positive (Gd+) lesions, active T2 lesions and combined unique lesions were also met. However, the high oral cladribine 5.25 mg/kg cumulative dose did not provide any further benefit on clinical and MRI outcomes.

The safety profile of oral cladribine has been assessed from all studies of cladribine in MS, including the long-term follow-up registry PREMIERE. As a result of both the integrated and trial-specific safety analyses, and the known mechanism of action of cladribine, the following important risks have been identified:

• Severe (Grade ≥3) lymphopenia and herpes zoster infection;
• Opportunistic infections (including tuberculosis and progressive multifocal leukoencephalopathy);
• Malignancies;
• Teratogenicity/adverse pregnancy outcomes.

Risk mitigation measures have been outlined in the Product Monograph for management of these risks and include appropriate contraindications, guidance, screening and monitoring measures. For managing risk of severe, sustained lymphopenia, criteria for initiation of cladribine treatment in year 1 as well as retreatment in year 2 are recommended, i.e., patients are required to have a normal lymphocyte count, which is within the normal range or not worse than Grade 1 lymphopenia before retreatment in year 2. The treatment course in year 2 can be delayed for up to 6 months to allow for recovery of lymphocyte counts. If the necessary recovery does not occur within this time, the patient should not be re-treated with cladribine. For management of herpes zoster infections, recommendations include vaccination of varicella antibody-negative patients prior to initiation of cladribine treatment, and vigilance for signs and symptoms of any infection. Similarly for management of severe and opportunistic infections, cladribine is contraindicated for immunocompromised patients, for patients with latent or active infections including active chronic bacterial, fungal or viral infections (e.g. hepatitis, tuberculosis), and for patients with a history of progressive multifocal leukoencephalopathy. Screening and monitoring measures for infections have been communicated in the Product Monograph. With respect to the risk of malignancy, an increased number of malignant events were noted in association with cladribine treatment compared to placebo; this risk is also associated with approved second-line MS agents. The risk of malignancies is addressed in the product labeling and includes a contraindication of cladribine use in MS patients with an active malignancy. Patients with prior history of malignancy were excluded from trial participation, thus an individual benefit-risk evaluation has been recommended for these patients before initiating treatment.

Due to the mechanism of action of cladribine and based on non-clinical safety evaluation, teratogenicity is considered an important risk. Although no case of congenital malformation has been reported, this risk has been addressed in the product labeling and includes contraindicating cladribine use in pregnant women, excluding pregnancy in women of childbearing potential prior to treatments in year 1 and year 2, and guidance on effective contraceptive use in both male and female patients during treatment and for at least 6 months after the last cladribine dose. As a precaution in patients who have previously been treated with immunomodulating or immunosuppressive agents, treatment with oral cladribine is recommended to be only initiated if lymphocyte counts are considered within the normal range. Caution has been indicated in the product label for subsequent use of immunomodulating or immunosuppressive agents after treatment with cladribine due to potential additive effect on the immune system.

At this point in time, considering the above safety issues identified during the review, the benefit-risk profile for oral cladribine in the treatment of RRMS is favourable when Mavenclad is not used as a first-line agent in the treatment of RRMS as described in the Product Monograph.