Post-approval safety of cladribine tablets with particular reference to COVID-19 outcomes: An update

Introduction: The safety profile of cladribine tablets 10 mg (CladT;3.5 mg/kg cumulative dose over 2 years) from the phase III clinical development programme for relapsing multiple sclerosis (MS) is well characterised (Cook et al. MSaRD 2019;29:157- 167). Additional real-life safety data have accrued since the approval of CladT in >80 countries worldwide. Objectives: To update on the post-approval safety profile of CladT in patients with relapsing MS, with particular reference to COVID-19. Methods: We previously reported on outcomes for 46 CladTtreated patients with relapsing MS and confirmed or suspected COVID-19 (Jack et al. MSaRD 2020;46:102469). Here, we update on these findings, to 15 March 2021, based on cases reported to the Merck KGaA Global Patient Safety Database. Cases meeting the criteria of hospitalized, medically significant, or fatal were designated as serious, and outcomes were classified as per usual pharmacovigilance practice. Serious and non-serious adverse events (AEs) from post-approval sources (including spontaneous individual case safety reports, non-interventional postmarketing studies, and reports from other solicited sources) are also presented. Results: As of 15 March 2021, the safety database included 367 reported cases of COVID-19 in CladT-treated patients (confirmed by test, n=219;serious cases, n=49);6 patients had symptoms compatible with COVID-19 but were not evaluated further since they were subsequently reported to have negative PCR tests. Of 361 evaluable patients, a total of 187 (52%) were recovered/ recovering at the time of reporting;there was 1 fatality in a patient with suspected COVID-19. To date, 3357 AEs have been reported for the first 18,463 patients who received CladT post-approval;435 (13%) of these events were serious. Crude incidences for AEs of special interest: severe lymphopenia, 0.21%;herpes zoster, 1.07%;tuberculosis, 0.05%;severe infections, 1.23%;progressive multifocal leukoencephalopathy, 0%;opportunistic infections, 0.04%;malignancies, 0.23%;and congenital anomalies, 0%. Conclusions: Regarding COVID-19, CladT-treated patients do not appear to be at greater risk of serious disease and/or a severe outcome vs the general and MS populations. Overall, the postapproval safety profile of CladT is consistent with previously published safety findings from the clinical development programme and ongoing phase IV studies.