Oral fingolimod (FTY720) for relapsing multiple sclerosis
Kappos L, Antel J, Comi G, Montalban X, O'Connor P, Polman CH, et al.;
Commented by , 26 Oct 2006
Background
Several new MS disease-modifying drugs are currently under investigation, and one of the more interesting ones is fingolimod (FTY720). Fingolimod is an oral sphingosine-1 receptor modulator, exerting its action by sequestering lymphocytes in lymphoid tissue. This leads to a reduction in peripheral lymphocyte counts and following recirculation of lymphocytes to the central nervous system.
Aim
To evaluate the efficacy and safety of fingolimod for the treatment of relapsing remitting MS (RRMS).
Methods
The authors included 281 relapsing-remitting MS (RRMS) patients in this double blind, placebo-controlled phase 2 proof-of-concept study. Patients were randomized to receive oral fingolimod at a dose of 1.25 mg or 5.0 mg or placebo once daily. MRI was conducted monthly for 6 months and number of gadolinium enhancing (Gd+) lesions on T1 weighted images was used as primary end point.
In an extension study (months 7-12), patients who received placebo were randomized to one of the fingolimod doses. A number of clinical end points were also collected, although the study was not designed to detect these changes.
Results
The core study was completed by 255 patients.
Median number of Gd+ lesions was 5 in the placebo group, 1 in the fingolimod 1.25 group (p<0.001) and 3 in the fingolimod 5.0 group (p=0.006).
Annualized relapse rate was 0.77 in the placebo group, 0.35 in the fingolimod 1.25 group (p=0.009; 55% reduction) and 0.36 in the fingolimod 5.0 group (p=0.01; 53% reduction).
Number of Gd+ lesions and relapse rate remained low in the fingolimod groups of the extension study, and both measures also decreased in patients switching from placebo to fingolimod.
Adverse events were increased in the high dose group. Clinically asymptomatic elevations of alanine aminotransferase (10-12% of fingolimod cases) and initial reduction of heart rate was seen in both groups. Symptomatic brachycardia was detected in the 5.0 group, where a case of posterior reversible encephalopathy syndrome also was diagnosed.
Dr Blinkenberg's comments
The study shows that fingolimod reduce MRI measurements of cerebral inflammatory activity and relapse rate in MS patients substantially. There was no gain of the higher (5.0 mg) fingolimod dose, which is not recommended since serious adverse events were increased in this group. This must give rise to concern and thorough evaluation of the risk-profile for future fingolimod use.
Adverse events were generally acceptable in the fingolimod 1,25 mg group and the authors suggest that doses lower than 1,25 mg should be explored in future trials.
The basic pharmacological principle of fingolimod is interesting, since it indirectly interacts with T-cell CNS migration by sequestering encephalitogenic T-cells in the lymphoid tissues. This effect is potentially reversible, since the natural pool of lymphocytes is still alive, and can be recruited by cessation of treatment.
Another mode of action is direct modulation of sphingosine-1 receptors in the CNS, although this effect is still poorly understood and will need further investigation.
The dark horse in novel therapeutic approaches interfering with T-cell function is the risk of harmful side effects associated with long-term treatment, exemplified by the development of PML in patients treated with natalizumab.
The critical limit for immunomodulation/suppression with these drugs has not been characterized yet, and the question is if highly efficacious treatment in MS can be maintained without inducing potentially lethal conditions.