Treatment as Onset can slow development of MS

Miller AE, Wolinsky JS, Kappos L, Comi G, Freedman MS,
Olsson TP, Bauer D, Benamor M, Truffinet P, O’Connor PW; for the TOPIC
Study Group. 
teriflunomide for patients with a first clinical episode suggestive of
multiple sclerosis(TOPIC): a randomised, double-blind,
placebo-controlled, phase 3 trial.
 Lancet Neurol. 2014 . pii: S1474-4422(14)70191-7

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.

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, number NCT00622700.

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 (19% 14mg, [17% in 7 mg group vs 14% in the
placebo group), hair thinning (12% 14mg/ 6% 7mg/8% placebo),
diarrhoea (11%/14%/ vs 6% placebo), 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

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.

ProfG or NeuroDocG may comment on this further but this trial reports on the effect of giving aubagio (teriflunamide). In this study aubagio was given to people with clinically isolated syndrome and reduced the risk of getting additional attacks and converting to MS by about 40%, The risks were associated with digestive problems and hair thinning. Aubagio is similar in activity to the beta interferons but have the advantage of being a pill. In UK treatment at CIS needs evidence of disease being MS, suvh as with MRI lesions. However, this current study shows that if you treat early then you can have an therapeutic effect, however we can do better. This is not the first study of an oral effective agent in clinically isolated syndrome as movectro, which was temporary available in Australia and Russia was tested and slowed the conversion rate by about 70%. Therefore one may suspect that the “available” DMT that are more effective than aubagio may have greater efficacy however it is up to the manufacturers to prove it.

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  • Thank you MouseDoctor. Despite being the first line oral therapy approved in MS in the UK, I'd like to remind our readers that Avonex (CHAMPS) study achieved a 44% reduction in conversion to clinically definite MS (CDMS), whilst Betaferon (BENEFIT) reduced the risk of CDMS by 41%. Also these are not head to head comparisons!

    MouseDoctor the key here is early treatment and I want be the first or the last neurologist to tout this; we should all stop being 'nancy pansies'. Although approved by NICE and NHS England – Aubagio/terflunomide's achilles heel is the monthly blood tests for the first six months – which is a tall feet in an a cash/resource strapped NHS. Maybe Genzyme can offer something here? cf. JCV testing by Biogen for natalizumab. If we wait longer BG-12 may even receive its NHS England go ahead, and is much easier to institute!

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