Oral regimen ‘delays onset of MS’(17/02/15)
For the first time, an oral therapy has been proven to reduce the risk of developing clinically definite multiple sclerosis in patients with a clinically isolated syndrome. In a phase III trial published in the journal Lancet Neurology, Miller et al clarified the role of teriflunomide (Aubagio) in the treatment of early episodes of demyelinating symptoms suggestive of MS.
This randomized, double-blind, placebo-controlled study, known as the TOPIC study, evaluated the safety and efficacy of teriflunomide for patients between 18 and 55 years of age who had experienced their first instance of a clinically isolated syndrome in the 90 days prior to randomization in the trial. Each patient involved in the study was required to have at least 2 MRI-determined lesions (measured using T2-weighted MRI) at least 3 mm in diameter.
Investigators assessed the amount of time between the initial neurologic event and any new neurologic event — an event that would mark the transition from a clinically isolated syndrome to clinically definite MS (CDMS). Secondarily, investigators assessed MRI outcomes, including occurrence of new gadolinium-enhancing or T2 lesions. The study used an intent-to-treat design, but excluded from the study two patients who were randomized to receive teriflunomide but never received a dose of study medication.
Two different regimens of daily teriflunomide significantly reduced the risk of conversion to CDMS. The 7-mg dose reduced the risk of developing CDMS by 31.4 per cent, and the 14-mg dose reduced the risk of developing CDMS by 34.9 per cent.
Adverse events (AEs) occurring in the trial included increased liver enzyme levels, hair thinning, diarrhea, paresthesia, and upper respiratory tract infection. Each of these AEs occurred in at least 10 per cent of patients using teriflunomide, and occurred at a rate at least two percentage points higher than in patients receiving placebo.
Serious AEs included increased liver enzyme levels, which occurred in two per cent of each treatment group—including the placebo group.
The TOPIC study is the first to evaluate the efficacy of an oral treatment in reducing the risk of progression from a clinically isolated demyelinating syndrome to clinically definite MS.
Source: HCPLive Copyright HCPLive 2006-2013 Intellisphere, LLC (17/02/15)
The US Food and Drug Administration (FDA) approved Genzyme’s application to include new information about its multiple sclerosis drug teriflunomide (Aubagio) on its label.
The new labeling content is efficacy and safety data from two Phase III trials of the drug. One trial, a study known as TOPIC is described in the Sept., 2014 issue of The Lancet Neurology. In it Aaron Miller, MD and colleagues report that in 618 relapsing-remitting multiple sclerosis patients assigned to the drug or placebo those who got the drug had a significantly reduced risk of relapse. The patients got a single daily oral dose of either 14 mg or 7 mg (or placebo) for up to 108 weeks.
The study was conducted from Feb 13, 2008 to Aug. 22, 2012 at 112 medical centers in 20 countries. The patients getting teriflunomide did better than placebo at either dosage at preventing relapses without serious side effects.
Miller is medical director of The Corinne Goldsmith Dickinson Center for Multiple Sclerosis at the Mount Sinai Hospital in New York, NY. In a statement from Genzyme, Miller said “Aubagio is the only oral multiple sclerosis treatment that has demonstrated a positive effect on disability progression in two Phase III clinical studies and is the only oral therapy with supporting published efficacy data on the treatment of patients who have experience a first clinical attack.”
The drug was originally approved for US use in 2012. Pooled data from TOPIC and two other studies involving 2,000 subjects found that though patients experienced adverse events including decreased white blood cell count, peripheral neuropathy, skin reactions and increased blood pressure, the rate at which the subjects reported these events was about the same as in subjects who were taking placebos.
The drug is an immunomodulator with anti-inflammatory properties. It is believed to reduce the number of activated lymphocytes in the central nervous system. It is contraindicated for patients with severe liver problems and in women who are pregnant or may become pregnant since animal studies indicate teratogenicity.
Source: HCPLive Copyright HCPLive 2006-2014 Intellisphere, LLC (21/10/14)
Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial.
Miller AE, Wolinsky JS, Kappos L, Comi G, Freedman MS, Olsson TP, Bauer D, Benamor M, Truffinet P, O'Connor PW; TOPIC Study Group.
BACKGROUND: Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis. We aimed to assess the efficacy and safety of teriflunomide in patients with a first clinical episode suggestive of multiple sclerosis.
METHODS: In this randomised, double-blind, placebo-controlled, parallel-group study, we enrolled patients aged 18-55 years with clinically isolated syndrome (defined as a neurological event consistent with demyelination, starting within 90 days of randomisation, and two or more T2-weighted MRI lesions ≥3 mm in diameter) from 112 centres (mostly hospitals) in 20 countries. Participants were randomly assigned (1:1:1) in a double-blind manner (by an interactive voice response system) to once-daily oral teriflunomide 14 mg, teriflunomide 7 mg, or placebo, for up to 108 weeks. Patients, staff administering the interventions, and outcome assessors were masked to treatment assignment. The primary endpoint was time to relapse (a new neurological abnormality separated by ≥30 days from a preceding clinical event, present for ≥24 h in the absence of fever or known infection), which defined conversion to clinically definite multiple sclerosis. The key secondary endpoint was time to relapse or new gadolinium-enhancing or T2 lesions on MRI, whichever occurred first. The primary outcome was analysed for the modified intention-to-treat population; safety analyses included all randomised patients who were exposed to the study drug, as treated. This trial is registered with ClinicalTrials.gov, number NCT00622700.
FINDINGS: Between Feb 13, 2008, and Aug 22, 2012, 618 patients were enrolled and randomly assigned to teriflunomide 14 mg (n=216), teriflunomide 7 mg (n=205), or placebo (n=197). Two patients in each of the teriflunomide groups did not receive the study drug, so the modified intention-to-treat population comprised 214 patients in the teriflunomide 14 mg group, 203 in the teriflunomide 7 mg group, and 197 in the placebo group. Compared with placebo, teriflunomide significantly reduced the risk of relapse defining clinically definite multiple sclerosis at the 14 mg dose (hazard ratio [HR] 0·574 [95% CI 0·379-0·869]; p=0·0087) and at the 7 mg dose (0·628 [0·416-0·949]; p=0·0271). Teriflunomide reduced the risk of relapse or a new MRI lesion compared with placebo at the 14 mg dose (HR 0·651 [95% CI 0·515-0·822]; p=0·0003) and at the 7 mg dose (0·686 [0·540-0·871]; p=0·0020). During the study, six patients who were randomly assigned to placebo accidently also received teriflunomide at some point: four received 7 mg and two received 14 mg. Therefore, the safety population comprised 216 patients on teriflunomide 14 mg, 207 on teriflunomide 7 mg, and 191 on placebo. Adverse events that occurred in at least 10% of patients in either teriflunomide group and with an incidence that was at least 2% higher than that with placebo were increased alanine aminotransferase (40 [19%] of 216 patients in the 14 mg group, 36 [17%] of 207 in the 7 mg group vs 27 [14%] of 191 in the placebo group), hair thinning (25 [12%] and 12 [6%] vs 15 [8%]), diarrhoea (23 [11%] and 28 [14%] vs 12 [6%]), paraesthesia (22 [10%] and 11 [5%] vs 10 [5%]), and upper respiratory tract infection (20 [9%] and 23 [11%] vs 14 [7%]). The most common serious adverse event was an increase in alanine aminotransferase (four [2%] and five [2%] vs three [2%]).
INTERPRETATION: TOPIC is to our knowledge the first study to report benefits of an available oral disease-modifying therapy in patients with early multiple sclerosis. These results extend the stages of multiple sclerosis in which teriflunomide shows a beneficial effect.
FUNDING: Genzyme, a Sanofi company.
Source: Lancet Neurol. 2014 Oct;13(10):977-86. doi: 10.1016/S1474-4422(14)70191-7. Epub 2014 Sep 2.& Pubmed PMID: 25192851 © 2014 Elsevier Ltd (23/09/14)
Genzyme's plans to grow its multiple sclerosis business in Europe continued with the launch of two new treatments in the Republic of Ireland.
The company, which serves as the biotech arm of French pharma firm Sanofi, today launched the injectable Lemtrada (alemtuzumab) in the country just weeks after oral multiple sclerosis (MS) treatment Aubagio (teriflunomide) hit the market.
Lemtrada will be made available to adults with active relapsing-remitting multiple sclerosis (RRMS), in accordance with its approval from the EC. It is to be given as an intravenous infusion in two annual treatment courses.
Aubagio is also available for adults with active RRMS, although it is one of several new MS treatments that come in an oral formulation, offering greater convenience to patients. It is to be taken once daily.
According to Genzyme, there are 8,000 people in Ireland with MS and around 85% will be affected by RRMS.
The launch of Lemtrada follows a recommendation in July this year from the National Centre for Pharmacoeconomics (NCPE), which provides guidance on what drugs should be reimbursed on Ireland's healthcare system to the Health Service Executive (HSE).
By contrast, Aubagio was turned down by the NCPE in June with after its assessment found that the drugs cost was not justified by its benefits.
However, in a conversation with PMLiVE, Henry Featherstone, director of public affairs at Genzyme UK & Ireland confirmed that Genzyme has since held discussions with the HSE and they have agreed that the drug can be reimbursed in Ireland.
As for where the drugs fit on the MS treatment pathway, Featherstone said that the broad indications for both products allowed doctors to discuss suitable options with patients. Further down the line, however, it's possible that Aubagio will be better suited as a first-line treatment for people with MS, while Lemtrada will be reserved for more aggressive forms of the disease.
"We hope to have these treatments available to as many people with MS as possible," Featherstone told PMLiVE. "We passionately believe in these products."
Backing Featherstone's belief, both drugs are making headway in western Europe where Lemtrada had revenues of €10m for the first six months of the year and Aubagio had revenues of €38m.
It's a different story for Lemtrada in the US, however, as the drug was turned down by the FDA at the start of 2014, much to the shock of Genzyme and Sanofi.
The decision, which was based on concerns over the drug's safety, drew criticism from the healthcare community and dozens of US doctors added their name to an open letter to the FDA to appeal the negative guidance.
Source: PMLive © PMGroup Worldwide Ltd 2014 (03/09/14)