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.

Updated post-approval safety of cladribine tablets in the treatment of multiple sclerosis, with particular reference to respiratory viral Infections and COVID-19

Objective: To update on the post-approval safety profile of cladribine tablets 10 mg (3.5 mg/kg cumulative dose over 2 years [CT3.5]) in patients with relapsing multiple sclerosis (MS), including COVID-19 and other respiratory viral infections. Background: Several integrated analyses have reported on the safety of CT3.5 during clinical development for treatment of relapsing MS. Additional real-life safety data have accrued since the approval of CT3.5 in many countries worldwide. In recent months the COVID-19 pandemic has become a concern for MS patients and their healthcare providers in terms of the associated safety of their disease-modifying therapy Design/Methods: Serious and non-serious adverse events (AEs) from post-approval sources (including spontaneous individual case safety reports, non-interventional post-marketing studies, and reports from other solicited sources) are presented to July 2020. AE rates are shown as crude incidences. Results: 3357 AEs were spontaneously reported for the first 18,463 patients who received CT3.5 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%. The pattern of respiratory viral infections (typically non-serious) with post-approval use of CT3.5 was also consistent with that of the clinical development program;crude incidences: H1N1 influenza, 0.01%;influenza, 0.68%;viral infection, 0.27%;and viral upper respiratory tract infection, 0.04%. As of 7 September 2020, the Merck KGaA safety database included 85 cases of suspected COVID-19 in CT3.5-treated patients (confirmed by test, n=38). An update on latest findings on COVID-19 infections will be presented, including analysis of time of infection since treatment where available. Conclusions: The safety profile of CT3.5, including respiratory viral infections, is consistent with previously published integrated safety analyses of the clinical development data.

Updated post-approval safety of cladribine tablets in the treatment of multiple sclerosis, with particular reference to respiratory viral infections

Background: Several integrated analyses have reported on the safety of cladribine tablets 10 mg (3.5 mg/kg cumulative dose over 2 years [CT3.5]) during clinical development for the treatment of patients with relapsing multiple sclerosis (RMS). Additional real-life safety data have accrued since the approval of CT3.5 in many countries worldwide. In recent months the COVID-19 pandemic has become a concern for MS patients and their healthcare providers in terms of the associated safety of their disease-modifying therapy. Objectives: To update on the post-approval safety profile of CT3.5 in patients with RMS, including COVID-19 and other respiratory viral infections. Methods: Serious and non-serious adverse events (AEs) from post-approval sources (including spontaneous individual case safety reports, non-interventional post-marketing studies, and reports from other solicited sources) are presented to Jan 2020. AE rates are shown as crude incidences (events/number of patients). Up-to-date COVID-19 findings are summarized. Results: A total of 2570 AEs were reported for the first 14,813 patients who received CT3.5 post-approval;303 (12%) events were classified as serious and none represented a new safety signal. Crude incidences for AEs of special interest were as follows: severe lymphopenia, 0.002;herpes zoster, 0.008;tuberculosis, 0.0004;severe infections, 0.009;progressive multifocal leukoencephalopathy, 0;opportunistic infections, 0.001;malignancies, 0.0015;and teratogenicity, 0. The majority of opportunistic infections were superficial dermal and mucosal fungal infections that resolved on standard treatments. The pattern of respiratory viral infections (typically non-serious) with post-approval use of CT3.5 was also consistent with that from the clinical development program;crude incidences were as follows: influenza, 0.005;viral infection, 0.002;and viral upper respiratory tract infection, 0.0004. As of 29 Jun 2020, the Merck safety database included 18 cases of confirmed COVID-19 in CT3.5-treated patients. An update on latest findings on COVID-19 infections will be presented, including analysis of time of infection since treatment where available. Conclusions: No new safety signals were identified in the realworld post-approval data of CT3.5, cumulative to Jan 2020. The safety profile of CT3.5, including respiratory viral infections, is consistent with previously published integrated safety analyses of the clinical development data.