Research: Fingolimod in Volunteers

Epub: Boulton C et al. Pharmacodynamic Effects of Steady-State Fingolimod on Antibody Response in Healthy Volunteers: A 4-Week, Randomized, Placebo-Controlled, Parallel-Group, Multiple-Dose Study. J Clin. Pharmacol 2011 Dec.

Fingolimod (Gilenya) , a first-in-class oral sphingosine 1-phosphate receptor (S1PR) modulator, is approved in many countries for relapsing-remitting multiple sclerosis, at a once-daily 0.5-mg dose. A reduction in peripheral lymphocyte count is an expected consequence of the fingolimod mechanism of S1PR modulation.

This study investigated if this pharmacodynamic effect impacts humoral (antibodies and B cells) and cellular (T cell) immunogenicity. In this double-blind, parallel-group, 4-week study, 72 healthy volunteers were randomized to steady state, fingolimod 0.5 mg, 1.25 mg, or to placebo.

The authors compared T-cell dependent and independent responses to the neoantigens, keyhole limpet hemocyanin (KLH. Limpet blood protien), and pneumococcal (pneumonia bacteria) polysaccharides vaccine (PPV-23), respectively, and additionally recall antigen response (tetanus (lockjaw) toxoid [TT]) and delayed-type hypersensitivity (DTH) to KLH, TT, and Candida albicans (Thrust, yeast).

Fingolimod caused mild to moderate decreases in antibody response to anti-KLH and anti-PPV-23 IgG and IgM antibody levels versus placebo. Responder rates were identical between placebo and 0.5-mg groups for anti-KLH IgG (both greater than 90%) and comparable for anti-PPV-23 IgG (55% and 41%, respectively). Fingolimod did not affect anti-TT immunogenicity, and DTH response did not differ between placebo and fingolimod 0.5-mg groups. Expectedly, lymphocyte count reduced substantially in the fingolimod groups versus placebo but reversed by study end. Fingolimod was well tolerated, and the observed safety profile was consistent with previous reports.

DTH Skin Test (Reddening and swelling)

Generalised immunosuppression results in inhibtion of T cell and cell immune responses that could leave you succeptible to infections and tumours and may inhibit your response to infections that you have been vaccinated against. Gilenya traps immune cells in lymph glands and prevents them entering the blood. Whilst this may be good for stopping MS, it may not be good for fighting infections. However Gilenya is not supposed to cause a blanket inhibition of cell function and leaves some white blood cell subsets unaffected. These subsets are thought to deal with infection and so the hope is that you can deal with MS, whilst still having the capacity to fight infection.

The study indicated that there was a modest reduction in antibody responses, which would equate to some reduced capacity to deal with infections but T cell responses as tested using DTH skin swelling response to infections to which we have immunity was unaffected. This is good because it means Gilenya is not completely removing our protective immunity, however we should expect some infection issues as there were some in clinical trials.

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