Sanofi and its subsidiary Genzyme has reported the top-line results from TENERE, a phase III clinical trial comparing the effectiveness, safety and tolerability of once-daily oral teriflunomide to interferon beta-1a (Rebif), an approved injectable therapy, in people with relapsing forms of multiple sclerosis (RMS).  The TENERE trial, which included 324 patients, is the second completed study of five efficacy studies of teriflunomide in MS, making the clinical programme one of the largest and broadest of any multiple sclerosis agent under development.

No statistical superiority was observed between the Rebif and teriflunomide arms (7mg and 14mg) on risk of treatment failure, the primary composite endpoint of the study. Risk of treatment failure was defined as the occurrence of a confirmed relapse or permanent treatment discontinuation for any cause, whichever came first. In the study, 48.6 per cent of patients receiving 7mg of oral teriflunomide (n=109) and 37.8 per cent of patients receiving 14 mg of oral teriflunomide (n=111) reached the primary endpoint, versus 42.3 per cent of patients receiving interferon beta 1-a (n=104).

The teriflunomide 14 mg daily dose (0.259) and Rebif (0.216) were not distinguishable on the endpoint of estimated annual relapse rate. The rate was higher in the 7mg arm (0.410). The percentage of patients experiencing any treatment emergent adverse events was similar across all arms of the study.  The rate of permanent treatment discontinuation in the study due to a treatment emergent adverse event was higher in the Rebif arm (21.8 per cent vs. 8.2 per cent in the 7mg teriflunomide arm and 10.9 per cent in the 14 mg teriflunomide arm).

Both the 7mg and 14mg doses of teriflunomide were safe and generally well tolerated. Most adverse events observed in the teriflunomide arms were mild in severity, including nasopharyngitis, diarrhoea, hair thinning, and back pain. These occurred with a higher incidence than in the Rebif arm. The most common adverse events observed in the Rebif arm were increases in alanine aminotransferase levels, headache and flu-like symptoms. These occurred with a higher incidence than in the teriflunomide arms. There were no deaths in the trial.

Genzyme anticipates presenting detailed TENERE study findings at a forthcoming medical meeting. The company will also include the results in its application with the EMA for marketing authorization in the European Union, along with results from its successful phase III TEMSO trial. The company expects to file an application for marketing authorization with the EMA in the first quarter of 2012. The US FDA application for teriflunomide was accepted for review by the US FDA in October 2011.

TENERE was a two-year, randomized, rater-blinded comparator study that included 324 people with RMS from 53 centres in 13 countries. Trial participants were 18 years of age or older, with an Expanded Disability Status Scale (EDSS) of 5.5 or less at the initial screening visit. Trial participants were randomized to receive oral teriflunomide, 7 mg or 14 mg, once daily, or interferon beta-1a (Rebif 44mcg tiw new formulation) and were followed for 48 weeks. The primary endpoint was risk of failure as defined by the first occurrence of relapse or permanent study treatment discontinuation for any cause, whichever came first.  Secondary outcome measures included annualized relapse rate, subject-reported fatigue as assessed by the Fatigue Impact Scale (FIS), and subject satisfaction as assessed by the Treatment Satisfaction Questionnaire for Medication (TSQM). Safety and tolerability evaluations were based on adverse events, physical examinations, vital signs and laboratory investigations.  A long-term extension of TENERE is ongoing.

Teriflunomide is an immunomodulatory, disease-modifying oral drug with anti-inflammatory properties, and is under investigation for the treatment of MS. It blocks the proliferation and functioning of activated T and B  lymphocytes – which are thought to be especially damaging in MS – by selectively and reversibly inhibiting a critical mitochondrial enzyme. Slowly dividing or resting lymphocytes are unaffected by teriflunomide, leaving the immune system’s response to infection uncompromised.

Teriflunomide is being studied in a large clinical programme that is expected to include more than 4,000 trial participants in 36 countries. Five efficacy clinical trials are either completed or underway with teriflunomide, making the clinical program one of the largest and broadest of any MS agent under development.  In addition to the TEMSO and TENERE trials, the phase III, placebo-controlled trial TOWER is ongoing in people with RMS. Another phase III study, TOPIC, is underway in early MS or CIS (clinically isolated syndrome). Teriflunomide is also being evaluated as an adjunct therapy to interferon-ß in the phase III TERACLES trial. With up to 10 years of continuous use in a phase II extension, teriflunomide has the longest clinical experience of any investigational oral MS therapy.