Sanofi launches new once-daily oral treatment for RRMS

multiple sclerosisThe drug was launched by Sanofi at the recent Neurological Association of South Africa Congress. Speaking at the launch, Prof Heinz Wiendl, Head of the Department of Neurology at the University of Münster (Germany), said the drug has one of the longest clinical trial histories and has had robust and recurring results that confirm its safety and efficacy.

Since 2005, ten clinical trials involving more than 4000 patients have been conducted. Since then, Aubagio has been approved for use in patients with relapsing-remitting MS (RRMS) in 70 countries. In approximately 85% of cases, the disease initially manifests as RRMS, which is characterised by episodes of neurological worsening followed by at least partial recovery.

Treatment

MS therapies available in SA include injectable, intramuscular and intravenous treatment such as beta-interferon, natalizumab, glatirameracetate, as well as oral agents such as fingolimod and now Aubagio.

Prof Wiendl, who is a world-renowned neurologist and who has been involved in a number of MS studies, recommends the following treatment algorithm:

Highly active MS: Recommended treatments include fingolimod and natalizumab. Mild/moderate MS: Approximately 70%-90% of patients fall into this category. Recommended treatments include teriflumonide, beta-interferon and glatiramer acetate.

Relapse therapy: Recommended treatments include methylprednisolone pulse therapy and plasma separation.

According to Prof Wiendl, it is extremely important that physicians choose and use treatment that is appropriate for the individual patient. MS treatment goals include inhibiting the disease course, disease stabilisation (no evidence of disease activity), improvement, and cure.

What is your treatment philosophy?

The question that physicians involved in the treatment of patients with MS should ask themselves is: What is the best mode of action to treat an individual patient? Should you be reactive (start safe and smooth) or proactive (hit hard and early)?

Traditionally, neurologists adopted a reactive approach and adapted treatment as the disease progressed, but according to Prof Wiendl, this approach is no longer appropriate. Optimisation of treatment in the early stages of the disease is the way to go, he believes.

New developments

The development of new drugs has vastly improved the outcomes of patients who have shown a non-response or suboptimal-response to drugs traditionally used in MS treatment.

“If treatment does not work optimally, you now have the option to move your patients to better treatment by either switching within first-line therapies or moving a patient with very active disease to second- or third-line treatment. Treatment switches and sequences are extremely important and decisions should be based on what is best for the patient.”

The development of oral therapies such as Aubagio offers patients, who did not show improvement with injectable therapies, an effective, alternative and convenient option, said Prof Wiendl.

Prior to treatment initiation, he recommends that the various treatment options are discussed with the patient, provide information about the mode of administration (oral or injectable), inform the patient about the key side effects – relative and absolute contra-indications and how to monitor his/her disease progression.

Is there a rule that determines which therapy is best for which patient? No, the decision should be made by the patient, stressed Prof Wiendl.

All drugs have advantages and disadvantages. The advantages of interferons/copaxone include the fact that they have been around for quite some time and have been shown to have no serious long-term effects. However, said Prof Wiendl, the disadvantage of these drugs is that they are injectables, which most patients find cumbersome. Another disadvantage is their ‘marginal’ effect on disease progression and the fact that they are not effective in all patients, he added.

The advantages of Aubagio are that it is an oral drug, which most patients seem to prefer, and it is taken once daily (14mg). The disadvantage of the drug is the fact that is has a very long half-life period and requires a wash out procedure over a period of two to three weeks. Fortunately, accelerated elimination procedures are available, which reduce the drugs’ plasma levels by as much as 50% on day one.

Mode of action

The primary mode of action of Aubagio in MS is hypothesised to relate to its effects on the proliferation of stimulated lymphocytes. Upon activation, lymphocytes undergo division via the cell cycle, that comprises an S (‘synthesis’) phase (during which DNA is copied), and M (‘mitosis’) phase (during which the dividing cell splits into daughter cells), separated by G (‘gap’) phases. DNA synthesis in S phase requires the provision of new building blocks, including pyrimidine and purine bases.

Aubagio blocks de novo pyrimidine synthesis by specific non-competitive, reversible inhibition of the mitochondrial enzyme dihydro-orotate dehydrogenase or DHODH, an enzyme expressed at high levels in proliferating lymphocytes.

Aubagio-mediated blockade of pyrimidine synthesis interrupts the cell cycle in S phase and exerts a cytostatic effect on proliferating T and B cells, limiting their involvement in the inflammatory processes involved in the MS pathogenesis.

Safety and efficacy

The safety and efficacy of Aubagio have been shown in a number of randomised controlled trials. Among the most notable are:

  • The randomised trial of oral teriflunomide for relapsing MS or Temso study
  • The oral teriflunomide for patients with relapsing MS or Tower study
  • Characterising the impact of teriflunomide on adaptive immune cell subsets, repertoire and function in patients with RRMS known as Teri-Dynamic
  • The teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing MS: a randomised, controlled phase 3 trial or Tenere study.
  • The oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis or Topic study.

The primary endpoint of the Temso randomised, placebo-controlled trial, conducted by O’Connor et al, was to determine the effect of teriflunomide on annual relapse rates. The secondary endpoint was confirmed progression of disability for at least 12 weeks. Some 1088 patients participated in the study.

The researchers found that teriflunomide reduced the annualised relapse rate (0.54 for placebo versus 0.37 for teriflunomide at either 7mg or 14mg), with relative risk reductions of 31.2% and 31.5%, respectively.

The proportion of patients with confirmed disability progression was 27.3% with placebo, 21.7% with teriflunomide at 7mg, and 20.2% with teriflunomide at 14mg. Both teriflunomide doses were superior to placebo on a range of end points measured by magnetic resonance imaging (MRI).

The higher dose also led to a significant reduction of the MRI T2 lesion volume and prolonged the time to a confirmed progression of disease. The time to the next relapse was increased significantly in both groups. All in all, teriflunomide was well tolerated and only a minority of the patients experienced side effects.

The most common side effects were diarrhoea, nausea, and hair thinning. According to Prof Wiendl, hair loss occurred in 10%-15% of patients during the first weeks of treatment, after which it lessened and was later reversed.

The results of the nine-year follow up of the TEMSO study was published in 2016. The aim of the study, conducted by O’Connor et al, was to report safety and efficacy outcomes after nine years of treatment with teriflunomide.

A total of 742 patients participated in this extension study. Patients treated with teriflunomide continued their original dose, while those previously receiving placebo were randomised 1:1 to teriflunomide 14mg or 7mg.

According to the researchers, soon after the extension started, annualised relapse rates and gadolinium-enhancing T1 lesion counts fell in patients switching from placebo to teriflunomide, remaining low thereafter. Disability remained stable in all treatment groups (median Expanded Disability Status Scale score ≤2.5, probability of 12-week disability progression ≤0.48).

They concluded that the safety observations were consistent with the core trial, with no new or unexpected adverse events in patients receiving teriflunomide for up to nine years. Disease activity decreased in patients switching from placebo and remained low in patients continuing on teriflunomide.

The aim of the Tower study, conducted by Confavreux et al, was to provide further evidence for the safety and efficacy of teriflunomide in patients with relapsing MS. This was an international, randomised, double-blind, placebo-controlled, phase 3 study involving 1169 patients. Patients were randomly assigned (1:1:1) to once-daily placebo, teriflunomide 7 mg, or teriflunomide 14mg.

Treatment duration was variable; ending 48 weeks after the last patient was included. The primary endpoint was annualised relapse rate and the key secondary endpoint was time to sustained accumulation of disability.

By the end of the study, the annualised relapse rate was higher in patients assigned to placebo (0.50) than in those assigned to teriflunomide 14mg (0·32) or teriflunomide 7mg (0.39). Compared to placebo, teriflunomide 14mg reduced the risk of sustained accumulation of disability. Teriflunomide 7mg had no effect on sustained accumulation of disability. The most common adverse events were alanine aminotransferase increases, hair thinning, and headache.

The Teri-Dynamic study by Wiendl et al, examined the effects of teriflunomide on the population dynamics, function and repertoire of adaptive immune cell subsets in patients with RRMS. The study included 38 patients with RRMS, who received once-daily oral teriflunomide 14mg for 24 weeks, and 19 healthy controls, who were not treated.

The researchers found teriflunomide lowered lymphocyte counts, increased CD4+/CD8+ T-cell ratios, and resulted in reciprocally increased iTreg and reduced Th1 frequencies. Deep sequencing analysis showed that teriflunomide significantly reduced clonal diversity of CD4+ T cells.

The Tenere study by Vermersch et al compared the efficacy of teriflunomide to subcutaneous interferon beta-1a in patients with relapsing MS. Previous studies showed that teriflunomide significantly reduced the annualised relapse rate and disability progression. This phase 3, blinded study compared teriflunomide with interferon-beta-1a (IFNβ-1a).

Some 324 patients with relapsing MS were randomised (1:1:1) to oral teriflunomide 7mg or 14mg, or subcutaneous IFNβ-1a 44µg. The primary endpoint was time to failure, defined as first occurrence of confirmed relapse or permanent treatment discontinuation for any cause. Secondary endpoints included annualised relapse rates, Fatigue Impact Scale (FIS) and Treatment Satisfaction Questionnaire for Medication (TSQM). The study was completed 48 weeks after the last patient was randomised.

No difference in time to failure was observed. There was no difference in the annualised relapse rate between teriflunomide 14mg and IFNβ-1a, but the annualised relapse rate was significantly higher with teriflunomide 7mg. FIS scores indicated more frequent fatigue with IFNβ-1a, though differences were only significant with teriflunomide 7mg. TSQM scores were significantly higher with teriflunomide.

Wolinsky et al assessed the efficacy and safety of teriflunomide in patients with a first clinical episode suggestive of MS. This was a randomised, double-blind, placebo-controlled, parallel-group study, involving 618 patients. Patients between the ages of 18 and 55, diagnosed 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 ≥3mm in diameter), were eligible. They were randomly assigned (1:1:1) in a double-blind manner to once-daily oral teriflunomide 14mg, teriflunomide 7mg, or placebo, for up to 108 weeks.

The primary endpoint was time to relapse (a new neurological abnormality separated by ≥30 days from a preceding clinical event, present for ≥24h in the absence of fever or known infection), which defined conversion to clinically definite multiple sclerosis. The secondary endpoint was time to relapse or new gadolinium-enhancing or T2 lesions on MRI, whichever occurred first.

The researchers found compared with placebo, teriflunomide significantly reduced the risk of relapse defining clinically definite MS at the 14mg dose and at the 7mg dose. In addition, they found that teriflunomide reduced the risk of relapse or a new MRI lesion compared with placebo at the 14mg dose and at the 7mg dose.

Relative versus absolute risk reduction

In conclusion, Prof Wiendl explained that treatment effects with respect to placebo can be expressed as either absolute or relative reduction in relapse rate. Because patient populations in trials do not have identical ‘risk’ of relapse, placebo arms may differ in a number of events, he said.

Annualised relapse rates in the placebo arm of clinical trials have decreased over time. For an identical absolute reduction in number of relapses co-affected by treatment, a higher number of events in the placebo groups will result in lower relative risk reduction measured. Number needed to treat range from 4.5 – 5.3 with fingolimod and 5.6 – 5.9 with teriflunomide.

Conclusion

Aubagio has been available as first-line oral therapy in South Africa from the beginning of February. According to Johannesburg-based neurologist Prof Dr Dominic Giampaolo, the efficacy of Aubagio seems to be exceeding the initial trial results. This suggests a second mode of action – probably antiviral – that is currently being investigated. Prof Giampaolo is the convener of the South African MS guideline committee. It is expected that the committee will release a revised guideline soon.

Reference:
  • Retief C, Giampoalo D. Multiple Sclerosis. Neuron Special Edition, 2017.
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