Teriflunomide, a novel oral disease-modifying drug, significantly reduced the annualized relapse rate and the risk of disability progression in relapsing multiple sclerosis by about 30% in a 2-year, phase III trial.
The study of Teriflunomide in Reducing the Frequency of Relapses and Accumulation of Disability in Patients with Multiple Sclerosis (TEMSO), which was sponsored by Sanofi-Aventis, randomized 1,088 patients to receive a single daily dose of 7 mg or 14 mg of teriflunomide or placebo.
The primary end point – the annualized relapse rate – was significantly lower among the 7-mg and 14-mg groups (0.370 and 0.369, respectively) than it was in placebo-treated patients (0.539). These rates represented a statistically significant reduction of 31%, compared with placebo. Patients in the 14-mg group also experienced a significant 30% reduction in the risk of disability progression, Dr. Paul O’Connor reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Teriflunomide is the active metabolite of leflunomide, a synthetic, low-molecular-weight drug that was approved by the U.S. Food and Drug Administration in 1998 for the treatment of rheumatoid arthritis. The metabolite is a reversible inhibitor of the mitochondrial enzyme dihydro-orotate dehydrogenase (DHODH) that exerts anti-inflammatory, antiproliferative, and immunosuppressive effects, but the mechanisms by which it does so are not yet completely understood. Inhibition of pyrimidine biosynthesis (via suppression of DHODH) and interference with tyrosine kinase activity both appear to be involved.
The treatment groups also experienced a significant reduction in brain disease activity as measured by magnetic resonance imaging (MRI). The burden of disease as determined by total lesion volume, for example, was reduced by 39% and 67% in the 7-mg and 14-mg dose groups, respectively, compared with placebo, said Dr. O’Connor of St. Michael’s Hospital, Toronto. He is the principal investigator for TEMSO.
“In my view, teriflunomide is a safe and effective new monotherapy, and it represents a potential first-line treatment for patients with relapsing MS,” he said during a press briefing on the TEMSO findings.
The safety profile of teriflunomide in this study was a particularly strong, positive point, he added. The overall adverse event rates were the same in the placebo and treatment groups, as were the rates of adverse events leading to permanent discontinuation of treatment. Patients in the teriflunomide group experienced more nausea, diarrhea, increases in alanine transferase, and hair thinning than did those in the placebo group, but these effects were mild. Treatment was generally very well tolerated, and no opportunistic infections occurred, he said.
TEMSO participants were adults aged 18-55 years with relapsing MS and a score of 5.5 or lower on the Expanded Disability Status Scale, and had experienced at least one relapse in the year prior to enrollment, or two relapses in the prior 2 years.
The availability of an oral agent for the treatment of this complex and progressively disabling disease is very good news for MS patients, Dr. Giancarlo Comi said during the press briefing.
“Of course it is central in the management of these patients to have available drugs to modify the disease course ... we are literally entering a period where we can provide patients with much better support than ever before,” said Dr. Comi of Clinica Neurologica, Ospedale San Raffaele, Milan, Italy.
Indeed, other ongoing research is also demonstrating the safety and efficacy of teriflunomide, both as monotherapy and in combination with other treatments, said Dr. Mark Freedman of the Multiple Sclerosis Research Clinic at Ottawa (Canada) Hospital. Dr. Freedman and Dr. Comi are investigators in the TEMSO trial.
For example, an open-label extension of a phase II trial of teriflunomide, which was also reported at the ECTRIMS congress, showed that teriflunomide was well tolerated during 8 years of continuous use following a 36-week double-blind portion of the study. Also, teriflunomide in combination with subcutaneous injection of interferon beta-1a has been shown to improve MRI outcomes in MS patients to a significantly greater extent than does interferon beta-1a and placebo.
Dr. Freedman said that the results from a second phase III study of teriflunomide are expected to be reported in 2012.
All three sources disclosed financial relationships with many companies that manufacture drugs for MS, including Sanofi-Aventis.
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欧洲多发性硬化症治疗与研究委员会(ECTRIMS)年会上报告的一项为期2年的Ⅲ期研究(TEMSO)结果显示，具有改善病情作用的新型口服抗风湿药特立氟胺可使复发性多发性硬化症(MS)的年复发率和残疾进展风险显著降低约30%。
本研究纳入1,088例18~55岁的复发性MS成人患者，患者的扩展残疾状态量表评分为≤5.5分，入组前1年内出现至少1次复发或入组前2年内出现2次复发。患者随机接受特立氟胺(每日单次口服7 mg或14 mg)或安慰剂治疗。
结果显示，特立氟胺7 mg组和14 mg组的年复发率(主要研究终点)分别为0.370和0.369，显著低于安慰剂组的0.539，降幅为31%，具有统计学意义。特立氟胺14 mg组的残疾进展风险亦显著降低30%。特立氟胺组经MRI检出的活动性病灶数量也显著减少。与安慰剂组相比，特立氟胺7 mg组和14 mg组的疾病负担(经总病灶体积确定)分别降低39%和67%。
安慰剂组与特立氟胺组的总不良事件发生率相同，导致永久停药的不良事件发生率也相同。特立氟胺组恶心、腹泻、丙氨酸氨基转移酶升高，头发稀疏的发生率高于安慰剂组，但这些不良反应的程度均为轻度。特立氟胺的耐受性总体上非常好，无机会性感染发生。
既往特立氟胺Ⅱ期研究结果显示，36周双盲期后，开放延伸期持续使用特立氟胺8年，显示良好耐受性。
研究者声明接受多家医药公司经济资助。
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