Cladribine as Injection May Limit Relapsing MS Progression for Years
Patients with relapsing multiple sclerosis (MS) treated with subcutaneous cladribine saw limited disease progression over a follow-up period of up to 20 years, especially with increased cumulative dosing, according to a recent study.
Subcutaneous (SC) cladribine is administered as an under-the-skin injection. It is a formulation different from Mavenclad, marketed by EMD Serono (Merck KGaA outside of the U.S. and Canada), an oral formulation of cladribine that is approved to treat relapsing MS.
The study, “Long-Term Safety and Efficacy of Subcutaneous Cladribine Used in Increased Dosage in Patients with Relapsing Multiple Sclerosis: 20-Year Observational Study,” was published in the Journal of Clinical Medicine.
Cladribine is a disease-modifying therapy that works by reducing the number of immune cells, namely B-cells and T-cells, thus decreasing the harmful immune response seen in MS.
Mavenclad is available as 10 milligram tablets with a fixed cumulative dose of 3.5 mg/kg of body weight, divided into two treatment cycles with a one-year interval.
The CLARITY Phase 3 trial showed that the therapeutic effects of Mavenclad last three to four years after the treatment begins. However, it is unclear whether repeated dosing with a higher cumulative dose than the approved 3.5 mg/kg is an option for long-term efficacy.
To address this question, researchers tested an off-label SC formulation of cladribine in 52 patients diagnosed with relapsing MS and treated at the Lublin MS center in Poland from 1996 to 2020.
Patients were given SC cladribine at a 1.8 mg/kg cumulative dose, which was divided into six courses administered every five weeks for four to six days, depending on the patient’s body weight.
The dosing of 1.8 mg/kg was used to mimic the approved 3.5 mg/kg used orally with Mavenclad. The subcutaneous injection uses a smaller dose because the therapy’s availability in the body is nearly double when given orally.
Following this treatment period, referred to as induction therapy, patients were offered maintenance therapy for five to 20 years. This consisted of repeated courses of SC cladribine at an annual dose of 0.3 mg/kg (administered over four to six days, depending on a patient’s body weight).
Patients in the maintenance treatment group received varying cumulative doses while those receiving only the induction treatment had five years of follow-up with the initial induction dosing.
Among the 52 patients analyzed, 41 received an increased cumulative dose of SC cladribine (higher than the induction dose of 1.8 mg/kg), and the other 11 received the standard induction dose. In total, 11 patients completed the 20-year observation period.
The expanded disability status scale (EDSS) was used to evaluate patients’ changes in disability levels over time.
Results showed that over the 20-year period, there was a gradual increase in the EDSS score, indicating disease progression and greater disability.
The risk of disease progression in patients was then analyzed in relation to basic demographic and clinical characteristics. Starting with treatment induction, the median time to EDSS score progression was five years. The likelihood of not having an EDSS score increase was 37% at five and 10 years, and 18% at 15 years.
Researchers found that an increase of 1 mg/kg in cumulative cladribine dose was associated with a 7% reduction in the risk of disease progression.
The team then further assessed EDSS score change between year 1 (the end of induction treatment) and years five and 10. There were not enough patients to robustly analyze the change at years 15 and 20.
Results showed that at both years five and 10, an overall higher cumulative cladribine dose was associated with better outcomes without clinical progression based on EDSS score. Additionally, more advanced disability at baseline (meaning a higher EDSS score) was associated with a higher risk of disease progression at year 5.
Regarding safety, no patient died or experienced severe events leading to treatment withdrawal. Most medical events reported by patients seemed to be related to co-existing diseases and not to SC cladribine treatment.
Two patients suspended their maintenance treatment
based on medical status, one due to breast cancer with ultimately good outcomes and one due to tuberculosis, which was treated with full recovery.
“The results are consistent with previously reported safety data for cladribine tablet treatment,” the researchers wrote.
Overall, the findings “indicate that treatment with [SC] cladribine with increased cumulative maintenance dosing was associated with disease stability and a favorable safety profile over a prolonged period of follow-up (up to 20 years) in patients with relapsing multiple sclerosis,” the researchers wrote.
Nonetheless, the team noted that the study design and limited number of patients “warrant cautious interpretation” and that more studies should be conducted to confirm the findings.