Sunday, 9 February 2014

Clinic Speak: teriflunomide trial (Tower) results

The tortoise finally crosses the finish line; how will teri be used? #MSBlog #MSResearch #ClinicSpeak

"I like to refer to teriflunomide, or teri, as the tortoise of the oral MS DMTs in development. It has been in development for so long we almost forgot it. It has finally arrived in the UK and we will be able to start prescribing it in April. Overall its efficacy puts in the moderate efficacy bracket alongside the IFN-beta and GA. It has a few issues that will make it difficult to use, but this should not prevent it from being prescribed if the will is there. The main issue is abnormal liver function tests and pregnancy."

"About 10% of MSers on the drug will developed abnormalities of their liver function  and as a result the company is recommending that liver enzymes should be assessed before initiation of teri and then every 2 weeks during the first 6 months of treatment, and every 8 weeks thereafter or as indicated by clinical signs and symptoms such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. When one of the liver enzymes ALT or SGPT becomes elevated between 2- and 3-fold the upper limit of normal, monitoring must be performed weekly. Teri should be discontinued if elevated liver enzymes are greater than 3-fold the upper limit of normal. MSers with preexisting liver disease are probably at increased risk of developing elevated liver enzymes when taking when taking teri. Are you up for this monitoring?"

"The other big issue with teri is pregnancy. Although there is limited amount of data from the use of  teri in pregnant women, animal studies have shown reproductive toxicity. It is therefore felt that teri may cause birth defects when administered during pregnancy. Therefore women of childbearing potential have to use effective contraception during treatment and until teri is out of the body. As teri hangs around in the body for months it is possible to rapidly remove the drug from your body by an accelerated elimination procedure; this is done by taking an agent that binds to the drug in the intestines and prevents it from being reabsorbed. We call these agents chelating agents; the two chelating agents that have been tried include cholestyramine and activated powdered charcoal (see summary of product characteristics below for more information)."

"Finally, the other big issue is hair loss or alopecia. This is an unfortunate term in that teri does not cause hair loss but transient thinning of the hair. Hair thinning occurs in ~15% of MSers; it us typically generalised thinning over the scalp; it is not complete hair loss and occurs during the first 6 months of treatment and almost always resolves. It is worth stating this as this side effect is being used unfairly by the competitors to differentiate their products. I heard one rep from a competitor tell me that teri is ideally suited for bald older men with benign MS. Teri does not cause baldness and if manage correctly the pregnancy issue should not be a problem either."


"Horses for courses. Although teri was late out of the blocks it is a daily tablet and has advantages over some of the other agents in terms of its risk profile. There is no way of telling who will be a teri responder or non-responder until you try the drug. Therefore, it may be an appealing drug for some MSers. I am told by me American colleagues who have had access to all three licensed orals for over a year that a large number of MSers who can't tolerate BG12 due to flushing and abdominal symptoms are tolerating teri very well."

"I note one commentator suggested on the blog we should prescribe leflunomide instead of teri to save money. Leflunomide is the prodrug of teri; the body converts leflunomide into teri. Leflunomide is licensed for treating rheumatoid arthritis and is off patent, hence is available in Europe as a generic that is cheap. Can I please remind this commentator that under EU law it is illegal to prescribe an unlicensed drug when there is a licensed drug for that indication."

"We should celebrate the availability of another oral drug for treating RRMS. Twenty years ago we had no licensed disease-modifying treatments for RRMS in Europe; we now have 8 classes (IFNbeta, GA, mitoxantrone (some countries), natalizumab, fingolimod, teriflunomide, BG12/DMF, alemtuzumab)."



BACKGROUND: Teriflunomide is an oral disease-modifying therapy approved for treatment of relapsing or relapsing-remitting multiple sclerosis. We aimed to provide further evidence for the safety and efficacy of teriflunomide in RRMSers.

METHODS: This international, randomised, double-blind, placebo-controlled, phase 3 study enrolled adults aged 18-55 years with relapsing multiple sclerosis, one or more relapse in the previous 12 months or two or more in the previous 24 months but no relapse in the previous 30 days, and an Expanded Disability Status Scale (EDSS) score of 5·5 points or less. Patients were recruited from 189 sites in 26 countries and randomly assigned (1:1:1) to once-daily placebo, teriflunomide 7 mg, or teriflunomide 14 mg via an interactive voice recognition system. Treatment duration was variable, ending 48 weeks after the last patient was included. The primary endpoint was annualised relapse rate (number of relapses per patient-year) and the key secondary endpoint was time to sustained accumulation of disability (an EDSS score increase of at least 1 EDSS point sustained for a minimum of 12 weeks), both analysed in the modified intention-to-treat population (all patients who received at least one dose of assigned study medication). This study is registered with ClinicalTrials.gov, number NCT00751881.

FINDINGS: Between Sept 17, 2008, and Feb 17, 2011, 1169 patients were randomly assigned to a treatment group, of whom 388, 407, and 370 patients received at least one dose of placebo, teriflunomide 7 mg, or teriflunomide 14 mg, respectively. By the end of the study, the annualised relapse rate was higher in patients assigned to placebo (0·50 [95% CI 0·43-0·58]) than in those assigned to teriflunomide 14 mg (0·32 [0·27-0·38]; p=0·0001) or teriflunomide 7 mg (0·39 [0·33-0·46]; p=0·0183). Compared with placebo, teriflunomide 14 mg reduced the risk of sustained accumulation of disability (hazard ratio [HR] 0·68 [95% CI 0·47-1·00]; log-rank p=0·0442); however, teriflunomide 7 mg had no effect on sustained accumulation of disability (HR 0·95 [0·68-1·35]; log-rank p=0·7620). The most common adverse events were alanine aminotransferase increases (32 [8%] of 385 patients in the placebo group vs 46 [11%] of 409 patients in the teriflunomide 7 mg group vs 52 [14%] of 371 patients in the teriflunomide 14 mg group), hair thinning (17 [4%] vs 42 [10%] vs 50 [13%]), and headache (42 [11%] vs 60 [15%] vs 46 [12%]). Incidence of serious adverse events was similar in all treatment groups (47 [12%] vs 52 [13%] vs 44 [12%]). Four deaths occurred, none of which was considered to be related to study drug (respiratory infection in the placebo group, traffic accident in the teriflunomide 7 mg group, and suicide and septicaemia due to Gram-negative infection complicated by disseminated intravascular coagulopathy in the teriflunomide 14 mg group).

INTERPRETATION: Teriflunomide 14 mg was associated with a lower relapse rate and less disability accumulation compared with placebo, with a similar safety and tolerability profile to that reported in previous studies. These results confirm the dose effect reported in previous trials and support the use of teriflunomide 14 mg in patients with relapsing multiple sclerosis.

CoI: multiple

3 comments:

  1. I am on teri right now.

    Do you happen to know if it has any effect on fertility in the longer term?

    ReplyDelete
    Replies
    1. Re: "Do you happen to know if it has any effect on fertility in the longer term?"

      There is no evidence that teri affects long-term fertility. This would be unlikely based on it mode of action.

      Delete
    2. Thank you.

      I hope you keep reporting on teri and its effects on the liver & intestines.

      Delete

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