REPORT FROM THE AMERICAN ACADEMY OF NEUROLOGY (AAN) ANNUAL MEETING, PHILADELPHIA PA, APRIL 26-MAY 3, 2014 – The following is a summary of key safety results presented at AAN for current MS therapies.
Teriflunomide: A pooled analysis of four trials (phase II, TEMSO, TOWER, TOPIC; n=3044) found that the most common adverse effects were hair thinning, diarrhea, ALT elevation, headache and nausea (Leist et al. AAN 2014; abstract P2.203). The discontinuation rate due to adverse effects for teriflunomide 14 mg/day and 7 mg/day was 12.5% and 11.2%, respectively versus 7.5% with placebo. Serious infections were uncommon ( 2.7%). No new safety signals were identified.
In the long-term extension of TEMSO, the annualized relapse rate in patients treated for up to nine years declined to 0.17 and 0.20 with teriflunomide 14 mg and 7 mg/day, respectively; ARR during the core study was 0.37 (Freedman et al. AAN 2014; abstract P3.150). For patients switching from placebo, the ARR was 0.18 and 0.23 at up to nine years. Only 468 of the original cohort (43%) were included in the analysis. During long-term follow-up, the incidence of adverse effects peaked in the first six months and declined thereafter.
Fingolimod: Cardiac safety at first dose was evaluated in the 1-week START study ongoing in Germany (Limmroth et al. AAN 2014; abstract P2.197). According to the interim analysis (n=1230), the incidence of second-degree AV block (Mobitz I or higher) was 1.6%. The incidence of bradycardia (< 45 beats/minute) was 0.7%.
In the LONGTERMS extension study of phase II/III trials and phase IIIb trials (FIRST, FIRST-LATAM, TOFINGO, VERIFY) (combined n=1655), the most common adverse effects were nasopharyngitis (11.9%), headache (9.9%) and upper respiratory tract infection (6.2%) (Cohen et al. AAN 2014; abstract P2.210). Cardiovascular effects post first dose included hypertension (3.6%), bradyarrhythmia (2%) and QT prolongation (0.7%). Comparisons of the incidence rates of adverse effects in the LONGTERMS cohort versus the Core cohort (patients completing 1-2 years in FREEDOMS, FREEDOMS II and TRANSFORMS) indicated that the risk of adverse events declined with continued dosing. The sole exception was the incidence of leucopenia/lymphopenia, which increased from 4.6% to 6.9%.
In the 24-month interim analysis of the PANGAEA observational study (n=3641), the most common adverse effects were lymphopenia (8.87%) and nasopharyngitis (7.58%) (Ziemssen et al. AAN 2014; abstract P3.152). The incidence of hypertension was 2.58%. A total 4.7 % of fingolimod-treated patients discontinued due to adverse effects.
Natalizumab: The evolution of anti-JC virus antibody status during natalizumab therapy was examined in an Austrian cohort study (Wipfler et al. AAN 2014; abstract P2.253). Prior to treatment, 34 of 53 patients (64%) were antibody-negative. Antibody-positive patients were categorized according to the anti-JCV antibody index as low risk (< 1.5) and high risk (>1.5); 10 of 19 (53%) were low risk at baseline. During natalizumab treatment, 9 of 34 (26%) Ab-negative patients seroconverted, including one patient who directly converted to the high-risk group. Six of 10 (60%) of low-risk Ab-positive patients switched to high risk during treatment. One patient with a high-risk anti-JCV Ab index developed PML.
The accuracy of anti-JCV Ab testing was modelled to estimate the false-negative rate following recent reports of two cases of PML developing in patients who were anti-JCV Ab-negative (Carruthers et al. AAN 2014; abstract P2.247). Calculations were based on published serology data and a range of JCV serology test sensitivities/specificities. The model estimated that the probability of at least three PML cases in the false-negative group ranged from fair (11-17%) to high (89-95%). Following the two PML cases in Ab-negative patients, the U.S. product label for Tysabri was modified to show an estimated PML incidence in anti-JCV Ab-negative patients of < 1 cases per 1000 (previously < 1/10,000). The revised U.S. indication also states that physicians should consider whether the expected benefit of natalizumab is sufficient to offset the risk of PML (Tysabri Product Monograph, revised December 2013).
Alemtuzumab: A four-year follow-up of the phase III CARE-MS studies (n=563) reported that the incidence of thyroid events was 35.1% (Twyman et al. AAN 2014; abstract P2.199). The incidence of serious thyroid events was 3.5%. All but one of the thyroid cases were detected within 48 months of the last dose. In line with this observation, the Canadian product monograph requires monthly blood monitoring for 4 years after the last administered dose. Thyroid events peaked at year 3 and declined (to 9.4%) in year 4.
Dimethyl fumarate: In the ongoing ENDORSE extension of phase III studies (DEFINE, CONFIRM; pooled n=1736), the overall incidence of serious adverse effects was 18-19% for patients continuing on DMF 240 mg BID or TID (Phillips et al. AAN 2014; abstract P2.200). Discontinuations due to adverse effects occurred in 4-6%, but were substantially higher (14-23%) in patients who switched from glatiramer acetate or placebo to DMF. The incidence of serious infections or hepatic events was low (3% or less for both).
In the phase II EXPLORE study, the safety of DMF 240 mg TID as an add-on therapy with interferon-beta or glatiramer acetate was investigated in 104 patients with ongoing disease activity during monotherapy with an injectable (Viglietta et al. AAN 2014; abstract S4.002). The most common adverse effects with IFN/DMF and GA/DMF were flushing (42%, 53%), diarrhea (32%, 15%) and abdominal pain (21%, 6%). At week 24, the mean decrease in lymphocyte counts was 22% and 7%, respectively (vs. 18% with DMF TID in phase III studies). There was a transient increase in liver transaminases during combination therapy. The risk of infections did not appear to be increased.
A single-centre observational study looked at the tolerability of DMF in the first few months after treatment initiation (Cohn et al. AAN 2014; abstract P2.214). A total of 380 MS patients were prescribed DMF during the period May-July 2013. Mean patient age was 46 years; mean duration of MS was 9 years. In 91% of cases, DMF was the second-line agent. DMF was associated with a high rate of early adverse effects, notably flushing (46.4%) and GI symptoms (43.6%). At a mean follow-up of 66 days, 15.7% had discontinued treatment; the mean time to stopping DMF was 36.9 days.Forty of 44 patients (90.9%) who stopped DMF did so because of adverse effects. Poor gastrointestinal tolerability was the most common reason for early discontinuation of DMF.
Guest Reviewer: Dr. Daniel Selchen, Head of Neurology, St. Michael’s Hospital, Toronto, Canada