Phase III trials demonstrate promise for new oral treatments

Novartis's fingolimod, a sphingosine‐1‐phosphate receptor modulator that reduces lymphocyte infiltration into the CNS and may also have neuroprotective activity, has been compared with placebo (New Engl J Med 2010;362:387‐401) and interferon beta‐1a (New Engl J Med 2010;362:402‐15) in patients with relapsing‐remitting MS and milder disability (Expanded Disability Status Scale (EDSS) score 0‐5.5) an average of seven to eight years after diagnosis.

The two‐year placebo‐controlled trial included 1272 patients aged 18‐55 years with at least one relapse in the previous year, or two in the previous two years, and a mean EDSS of 2.3‐2.5. Two dosages of fingolimod were included (0.5mg and 1.25mg daily); both were significantly superior to placebo but there was little difference between them in efficacy.

Fingolimod improved the annualised relapse rate (0.16 and 0.18 with 1.25mg and 0.5mg vs 0.40 with placebo) and reduced the risk of disability progression by about 30 per cent, with a cumulative probability of progression of about 17 per cent compared with 24 per cent with placebo.

These gains were matched by improvements in MRI outcomes, including fewer new or enlarging lesions, more patients free of lesions, a decrease in lesion volume and smaller reductions in brain volume.

The comparison with interferon beta‐1a 30µg weekly included 1292 patients treated for one year. The annualised relapse rate with fingolimod (0.16 at 0.5mg daily; 0.20 at 1.25mg daily) was significantly lower than that with interferon beta‐1a (0.33). This was consistent with MRI endpoints, with fewer new or enlarged lesions (but no difference in lesion volume) and less reduction in brain volume. There was no difference in progression of disability.

Adverse effects associated with fingolimod included lower respiratory tract infections, abnormal liver function tests, mild hypertension and, with the first dose, bradycardia and AV block. A total of seven cases of macular oedema were associated with the higher dose of fingolimod; these resolved within six months of discontinuation in all but one patient.

The third trial randomised 1326 patients to placebo or treatment with Merck Serono's cytotoxic agent cladribine (New Engl J Med 2010;362:416‐26). This drug preferentially targets lymphocytes where it disrupts cellular metabolism, inhibits DNA syntheses and promotes apoptosis. Compared with the fingolimod trials, these patients had slightly worse disability scores (mean EDSS 2.8‐3) and marginally longer duration of disease (an average of eight to nine years).

Cladribine was administered as 10mg tablets to achieve cumulative doses of 3.5 or 5.25mg per kg body weight per day given as two or four short courses per 28 days for 96 weeks. As with fingolimod, the annualised relapse rate was significantly reduced to 0.14 and 0.15 with 3.5mg and 5.25mg per kg cladribine respectively compared with 0.33 with placebo; it also reduced the risk of disability progression by about 30 per cent. Cladribine also significantly reduced brain lesion count on MRI.

The commonest adverse effects were headache and lymphocytopenia. The severity of lympho cytopenia correlated with the risk of infection; serious infections were slightly more frequent with cladribine (2.3‐2.9 vs 1.6 per cent with placebo). Cladribine was associated with 20 cases of herpes zoster infection, three of which were reported as serious adverse events. Copyright © 2010 Wiley Interface Ltd