Impact of the Arrival on the French Market of New First Line Oral Treatments on the Delay Between MS Onset and First Disease Modifying Treatment (DMTs) Administration

Multiple sclerosis is known to be the first non traumatic cause of disability in young people. Multiple sclerosis is described as a chronic inflammatory immune-mediated disease of the central nervous system.

Only a few disease modifying treatments where available before 1994, but in two decades, the therapeutic armamentarium was reinforced by many more and more effective drugs for RRMS .They tend to extend time to conversion towards a defined MS after the first relapse and between relapses and have a notable action on the decreasing clinical and radiological disease activity.

First line of disease modifying treatments (DMTs), IFN β-1a and glatiramer acetate are known to have a favorable benefit-to-risk profile in RRMS, they reduce relapse rate and MRI activity of the disease, but their efficacy remains limited. They do not stop the disease progression but only slow down it for a while. Otherwise four drugs cyclophosphamide, mitoxantrone, natalizumab and fingolimod were used as second-line therapy or as first-line for rapidly evolving RRMS. Whereas second line DMTs cyclophosphamide and mitoxantrone were merely an alternative to pharmacological run away, natalizumab and fingolimod proved to be two effective drugs of second line DMTs. Natalizumab impressively inhibits inflammatory process of MS, with >65% reduction in relapses during 2 years of treat¬ment, and >90% suppression of new inflammatory MRI lesions and fingolimod suppresses MS disease activity with 55-60% of lower relapses rates and a remarkable decrease of visible MRI activity . In 2014 alemtuzumab received FDA approval and joined the other second line treatment but it is still not commercialized in France. Recently years two new first line treatments teriflunomide and dimethyl fumarate have made their entry on the market. The main advantage of these both treatments is their mode of administration. Whereas the two first line treatments are under injectable form, teriflunomide and dimethyl fumarate can be administered per os, and so facilitate the therapy compliance for newly-diagnosed RRMS patients. In TEMSO, a phase III multicentric double-blinded study with teriflunomide 14 mg once a day versus placebo, teriflunomide shows both efficacy in reducing from 31,5% relapse rate in 2 years and a significant 80.4% of reduction of MRI activity for T1 enhanced lesions by gadolinium. Risk of disability progression is also significantly reduced of 29.8%, as compared with placebo. Efficacy and safety phase 3 trial study DEFINE assessed efficacy of BG-12 (dimethyl fumarate) 240 mg given orally either twice daily significantly reduced the risk of relapse by 49% or compared with placebo at 2 years. On ARR, there were relative reductions of 53% .The probability of confirmed 12-week disability progression was reduced by 38%. In an MRI sub-study the mean number of new or newly enlarging T2 lesions was reduced by 85% . A clear efficacy on disease activity is shown when comparing respectively dimethylfumarate and teriflunomide with placebo.

However the efficacy on clinical symptoms and disease activity isn't significantly better than that of the first line's treatments of references. Compare to glatiramer acetate, dimethyl fumarate shows no significant greater clinical effect on the disease . No significant annual relapses rate difference was shown either between teriflunomide and interferon ß-1a . The most interesting progress of these two molecules lies in their easier mode of administration and the inherent change of medical practices.

Diagnosis and therapeutic delays have already proved to be some remarkable health indicators in numerous chronic or serious diseases. In cancers, "diagnostic delays" and "therapeutics delays" are demonstrated to have an negative impact survival and mortality . Various delays may occur at different stages of health care. On the one hand diagnosis delays are a complex association of "patients delay" (from onset of symptoms to their first presentation), depending on patients factors as behavior or social background, "referral delay" (from general practician's medical consultation to a specialist one), and finally "delay to lead a diagnosis" (time required to undergo specialized medical examinations). On the other hand therapeutics delays (from diagnosis to start of the treatment) are more associated with health system process (15,16).