Background

In CLARITY and CLARITY Extension (NCT00213135 and NCT00641537, respectively), treatment with cladribine tablets 10 mg (cumulative dose 3.5 mg/kg over 2 years [CT3.5]) significantly reduced relapse rates in patients with relapsing-remitting multiple sclerosis. Moreover, in the CLARITY Extension study, treatment with cladribine tablets for 2 years followed by treatment with placebo for 2 years produced similar clinical benefits to 2 years of cladribine tablets treatment followed by an additional 2 years of treatment, but with a lower risk of higher grade lymphopenia.

Objectives

To assess, post hoc, the temporal occurrence of relapses up to 5 years after treatment initiation with cladribine tablets.

Methods

Patients enrolled into CLARITY treated with CT3.5, and those subsequently receiving CT3.5 (CC7) or placebo (CP3.5) in CLARITY Extension, were included for analysis. The main endpoint was all qualifying relapses reported in CLARITY or CLARITY Extension plus those that occurred during the variable bridging interval (range: 1 day to 118 weeks). A recurrent event analysis was performed to estimate mean cumulative number of relapses over time using a cumulative mean function estimate.

Results

A total of 433 patients from CLARITY treated with CT3.5 were included in this analysis; of these 284 patients entered CLARITY Extension (CP3.5, n=98; CC7, n=186). Recurrent event analysis for the CT3.5 population showed that annual increase in mean cumulative number of relapses was consistently low from Year 2 to Year 5 (range: 0.10–0.15) and was slightly higher in Year 1 (0.17); the 6-month increase in mean cumulative number of relapses was similar in the first 6 months and the second 6 months (0.08 and 0.09, respectively). There were no differences in mean cumulative number of relapses between the CP3.5 and CC7 groups from Year 2 to Year 5. In recurrent event analysis for the CT3.5 population, the yearly increments of mean cumulative function were constant and low from the second treatment to Year 5, supporting the durable efficacy of cladribine tablets (given no increase in relapses following completion of the two courses of cladribine tablets).

Conclusions

Annual increase in mean cumulative number of relapses occurred at a low annualized rate of 0.10 to 0.17 per year to 5 years, almost 4 years after the last dose of cladribine tablets and therefore consistent with durable efficacy. Results also support the early effect of cladribine tablets on relapses, which is apparent in the first year of treatment.

Background

Subcutaneous interferon β-1a (sc IFN β-1a) is a well-established disease-modifying therapy for relapsing multiple sclerosis (RMS). Since its introduction to the market, the estimated cumulative exposure to sc IFN β-1a amounts to 1,766,525 patient-years (to 03 May 2020). 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 report on the post-approval safety profile of sc IFN β-1a in patients with RMS, including COVID-19 and other respiratory viral infections.

Methods

Serious and non-serious adverse events (AEs) from post-approval spontaneous individual case safety reports are presented from February 1998 to May 2020. AE rates are shown as total number of patients. Up-to-date COVID-19 findings are summarized.

Results

A total of 525,268 AEs have been reported, with 6.6% of events classified as serious. No new safety concern has been identified, and there was no trend towards increased respiratory viral infections occurring during sc IFN β-1a treatment. An analysis of the top five most common respiratory viral infection AEs reported spontaneously (influenza, viral infection, H1N1 influenza, viral bronchitis, and viral upper respiratory tract infection) did not reveal any abnormal trend outside the known safety profile of sc IFN β-1a, and cases were typically non-serious. The most commonly reported respiratory viral infection was influenza with 2369 cases (constituting 0.45% of all AEs), followed by viral infection (319), H1N1 influenza (15), viral bronchitis (6), and viral upper respiratory tract infection (5). There was also no suggestion of an increased risk of more severe respiratory viral infection or other adverse drug reactions in patients with RMS and experiencing a respiratory viral infection while being treated with sc IFN β-1a. As of 9 June 2020, the Merck safety database included 23 cases of confirmed COVID-19 in sc IFN β-1a treated MS patients. An update on latest findings on COVID-19 infections will be presented.

Conclusions

Cumulative to May 2020, no new safety concern has been identified from the post-approval data of sc IFN β-1a, including no increased risk for respiratory viral infections.

Background

Tolerability and adherence to disease-modifying drugs (DMDs) can be influenced by treatment-emergent adverse events (TEAEs) that start shortly after therapy initiation. One potential advantage of cladribine tablets is its short treatment course which may limit TEAEs; patients who receive the approved 3.5 mg/kg dosage only receive doses for two 4 to 5-day periods per treatment year.

Objectives

To identify TEAEs early in the course of treatment in patients enrolled in the Phase 3 CLARITY and ORACLE-MS clinical trials.

Methods

This was a post hoc analysis of safety populations in CLARITY and ORACLE-MS studies. Patients received cladribine tablets 3.5 mg/kg (cumulative dose over 2 years; N=636) or placebo (N=641). The incidence of early adverse events, TEAEs, serious TEAEs, drug-related TEAEs, and TEAEs leading to discontinuation were summarized based on incidence within 2, 6, and 12 weeks (Wk) after commencement of therapy.

Results

The incidence of TEAEs occurring within the first 2–12Wk of treatment across both trials in both treatment groups was generally low, and the majority of events were mild (placebo: 53.8–68.4%; cladribine tablets: 54.4–68.0%). The most common TEAEs by time epoch after initiating placebo and cladribine tablets 3.5 mg/kg treatment, respectively, were: nausea: 3.3% vs. 4.9% (2Wk), 3.7% vs. 6.4% (6Wk), and 4.5% vs. 8.0% (12Wk); fatigue: 2.0% vs. 1.4% (2Wk), 3.1% vs. 2.5% (6Wk), and 4.4% vs. 3.1% (12Wk); headache: 8.3% vs. 9.0% (2Wk), 11.9% vs. 14.8% (6Wk), and 15.1% vs. 18.4% (12Wk); lymphopenia: 0.0% vs. 2.5% (6Wk) and 0.5% vs. 6.8% (12Wk); leukopenia: 0.0% vs. 1.3% (12Wk). Other endpoints will be shown in the final presentation.

Conclusions

Incidence of TEAEs experienced during the first 12 weeks of treatment with cladribine tablets 3.5 mg/kg in Phase 3 clinical trials was low and mostly mild. Nausea, headache, and lymphopenia were seen more frequently in cladribine tablets-treated patients versus those in the placebo group. These findings suggest that cladribine tablets are generally well tolerated, which may facilitate treatment adherence.

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 real-world 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.

Background

Subcutaneous interferon β-1a (sc IFN β-1a) is a well-established disease-modifying therapy for relapsing multiple sclerosis (RMS). Since its introduction to the market, the estimated cumulative exposure to sc IFN β-1a amounts to 1,766,525 patient-years (to 03 May 2020). 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 report on the post-approval safety profile of sc IFN β-1a in patients with RMS, including COVID-19 and other respiratory viral infections.

Methods

Serious and non-serious adverse events (AEs) from post-approval spontaneous individual case safety reports are presented from February 1998 to May 2020. AE rates are shown as total number of patients. Up-to-date COVID-19 findings are summarized.

Results

A total of 525,268 AEs have been reported, with 6.6% of events classified as serious. No new safety concern has been identified, and there was no trend towards increased respiratory viral infections occurring during sc IFN β-1a treatment. An analysis of the top five most common respiratory viral infection AEs reported spontaneously (influenza, viral infection, H1N1 influenza, viral bronchitis, and viral upper respiratory tract infection) did not reveal any abnormal trend outside the known safety profile of sc IFN β-1a, and cases were typically non-serious. The most commonly reported respiratory viral infection was influenza with 2369 cases (constituting 0.45% of all AEs), followed by viral infection (319), H1N1 influenza (15), viral bronchitis (6), and viral upper respiratory tract infection (5). There was also no suggestion of an increased risk of more severe respiratory viral infection or other adverse drug reactions in patients with RMS and experiencing a respiratory viral infection while being treated with sc IFN β-1a. As of 9 June 2020, the Merck safety database included 23 cases of confirmed COVID-19 in sc IFN β-1a treated MS patients. An update on latest findings on COVID-19 infections will be presented.

Conclusions

Cumulative to May 2020, no new safety concern has been identified from the post-approval data of sc IFN β-1a, including no increased risk for respiratory viral infections.