Cladribine tablets, a novel intermittent immunosuppressant expected soon in North America, has been shown to be highly efficacious in reducing annualized relapse rates (ARR) and disability progression over a sustained period, according to the most recent data.
In the phase III CLARITY trial, subjects were randomized to placebo or one of two doses of cladribine tables (3.5 mg/kg or 5.25 mg/kg cumulative dose over two years) for two years (Giovannoni et al. N Engl J Med 2010;362:416-426). Cladribine 3.5 mg/kg was superior to placebo with respect to ARR (0.14 vs. 0.33), proportion of patients relapse-free (79.7% vs. 60.9%), and proportion free of three-month confirmed disability progression (85.7% vs. 79.4%). The mean number of active T2 lesions and gadolinium-enhancing lesions was reduced 73.4% and 85.7%, respectively, versus placebo.
The proportion of patients with no evidence of disease activity (NEDA) was 47% (Giovannoni et al. Lancet Neurol 2011;10:329-337). For the subgroup with highly active disease, the NEDA rate was 43.2% versus 8.7% with placebo (odds ratio 8.02) (Giovannoni et al. ECTRIMS 2017; abstract P1143).
An independent analysis extracted quality of life data from Euro Quality of Life 5 dimension (EQ-5D) and MS-QOL-54 questionnaires administered during CLARITY (Afolabi et al. ECTRIMS 2017; abstract P823). Baseline OoL scores correlated with EDSS. At 96 weeks, patients receiving cladribine 3.5 mg/kg showed significant improvements in EQ-5D, with a trend to improvement in MS-QOL-54 at week 96.
The most common adverse events in CLARITY were headache (24.2% vs. 17.2% with placebo), lymphopenia (21.6% vs, 1.8%), nasopharyngitis (14.4% vs. 12.9%), and upper respiratory tract infection (12.6% vs. 9.7%) (Giovannoni 2010).
Patients completing the trial were eligible for an extension study. The study was not pre-planned, so there was a delay of up to about 2.5 years (median 40.3 weeks) before entry (Giovannoni et al. Mult Scler 2017; epublished August 1, 2017). Subjects initially receiving cladribine 3.5 mg/kg were re-randomized to the same dose or placebo; placebo patients were switched to cladribine 3.5 mg/kg; and the 5.25 mg/kg group was randomized to the 3.5 mg/kg dose or placebo.
Of particular interest was the group that received cladribine 3.5 mg/kg followed by placebo (CP3.5), since this would be the usual dosing schedule in practice. ARR remained low (0.15) after two years in the extension (up to 5.5 years after the last dose due to the treatment gap); 75% of patients in this group remained relapse-free. These findings suggest that a majority of patients receiving a two-year regimen will be well-maintained for >4 years without re-dosing. In addition, 73% had no gadolinium-enhancing lesions, although there was a trend to greater MRI activity with a longer treatment gap (Giovannoni et al. ECTRIMS 2016; abstract P636). Thus, the development of new lesion activity may be an early indication of the need for re-treatment.
Cladribine is a lymphocyte-depleting agent, and a number of new studies have examined lymphocyte kinetics during treatment. Cladribine tablets are administered for five days in weeks 1 and 5 in Year 1, and weeks 1 and 5 in Year 2. In Year 1, CD4+ cells reached the nadir (55% below baseline) at week 8 (i.e. 3 weeks after the last dose), but remained above the lower limit of normal (LLN) at the time of Year 2 dosing. During Year 2, the nadir was below the LLN (66% below baseline) at week 12 (i.e. in the second month after the last dose), returning to the LLN by week 96 (Soelberg-Sorensen et al. ECTRIMS 2017; abstract P655). CD8+ counts were less affected, reaching a nadir (37% below baseline) at week 16 in Year 1, and week 24 in Year 2. CD8+ counts did not go below the LLN. There was more profound depletion of CD19+ B cell counts (90% at week 8 of Year 1, and 85% reduction at week 3 in Year 2), but more rapid recovery, with B cell counts returning to the LLN by about 6-9 months after the last dose in Years 1 and 2.
Severe lymphopenia was common in clinical trials of cladribine tablets (20-25% with transient Grade 3 or 4), in part because patients with low lymphocyte counts were re-dosed in Year 2. Treatment recommendations were subsequently introduced, which required normal lymphocyte counts (≥ 1.0 × 109/L) before initiating cladribine tablets, and Grade 0 or 1 lymphopenia (≥ 0.8 × 109/L) at the time of re-dosing. In the subgroup of patients randomized to re-dosing (cumulative dose, 7.0 mg/kg) who met these criteria, 89% of patients were eligible for re-treatment (Grade 0 or 1 lymphopenia) at the end of Year 1 (week 48), according to an analysis of data from CLARITY and its extension (Cook et al. ECTRIMS 2017; abstract P666). The overall incidence of Grade 3 lymphopenia was 1% at weeks 24, 36 and 48 of Year 1. Moreover, subsequent re-treatments were not associated with an increased risk of Grade 3 lymphopenia. Re-treatment can be delayed for up to 6 months until lymphocyte counts recover in the minority of patients not immediately eligible for additional therapy.
Transient periods of Grade 3 lymphopenia are associated with an increased risk of infections, according to a new integrated safety analysis (Cook et al. ECTRIMS 2017; abstract P1142). The incidence of infections during periods of severe lymphopenia was 57.53 per 100 patient-years compared to 24.50 outside of those periods. The types of infections seen with and without lymphopenia were similar. A majority of infections, such as nasopharyngitis (incidence 13.48 during periods of lymphopenia), upper respiratory tract infections (9.67), and pharyngitis (4.51) were easily treatable. The only infection of note was herpes zoster (incidence 4.50 vs. 0.73 per 100 PY), although the number of cases was small (n=4) and all cases were mild-to-moderate in severity.
No cases of progressive multifocal leukoencephalopathy have been reported in MS patients receiving cladribine tablets. Three cases of pulmonary tuberculosis have been reported. In the European monograph, screening for latent infections, notably TB and hepatitis B and C, is required prior to initiation of cladribine tablets in Years 1 and 2 (European Medicines Agency, Summary of product characteristics, August 22, 2017. Free full text at www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004230/WC500234561.pdf
No head-to-head trials have compared cladribine tablets with other disease-modifying therapies. To date, only one preliminary study from the MSBase group has examined this issue using a propensity score-matched analysis (Kalincik et al. ECTRIMS 2017; abstract P1138). The database included 5279 relapse-onset MS patients treated for >1 year with cladribine tablets, interferon-beta-1a SC, fingolimod or natalizumab. Cladribine was superior to IFN-beta, similar to fingolimod, and inferior to natalizumab with respect to the probability of remaining relapse-free. The probability of remaining progression-free was similar with cladribine, IFN-beta and fingolimod, and superior with natalizumab. However, the probability of disability improvement was higher with cladribine compared to IFN-beta, fingolimod and natalizumab. The authors concluded that cladribine tablets could be associated with superior recovery from disability relative to other disease-modifying therapies.