Fingolimod and MS

Fingolimod (FTY720) has the option of being the first orally available drug against MS. In 1994, an immunosuppressive natural product, ISP-I (myriocin), was isolated from the culture broth of Isaria sinclairii, a type of vegetative wasp. The chemical modification of ISP-I yielded a new compound, FTY720, which has more potent immunosuppressive activity and less toxicity [4]. This synthetic sphingosine analog that becomes phosphorylated in vivo and acts as a sphingosine-1-phosphate (S1P) receptor agonist [1] - which may be clear to a few specialists. To the rest of the World, it is perhaps better  understandable that the drug has been shown to reduce inflammatory activity by an effect on the macrophages. A striking feature of Fingolimod is also the induction of a marked decrease in peripheral blood T- and B-cells [4].

As an immunosuppressive, the drug is being tested on a number of clinical indications, such as transplantion surgery and a variety of autoimmune diseases. It does not impair T and B lymphocytes but interferes with the re-circulation of lymphocytes between lymphoid organs and blood [1]. This action has established S1P receptors as key targets for future drug development.

We have, since the introduction of the beta-interferonn [ns, witnessed a large number of therapies with some effect upon MS - and still the long-term results have largely been disappointing. We have learned to be cautious with our euphoria. What justifies new hopes related to this drug is first of all the experimental efficacy. Again, the experimental autoimmune encephalomyelitis (EAE) seems to be a condition in which mice may profit from anything, starting with cheese. In such a placebo-controlled study [2], however, the FTY720-treated animals displayed no signs of inflammatory activity or neurological impairment - 100% vs 0% effect.

In the first study on humans [3], involving 281 patients (of whom 255 completed 6 months and 227 one year), the number of gadolinium-enhanced lesions and relapse rates remained low in the therapy groups. The low-dose (1,25 mg daily) group was slightly favorable to the high dose (5 mg daily) group. In a study of oral vs. IV administration, the mean lymphocyte nadir was 35% lower after oral than after IV administration of 1.25 mg orally and 1 mg IV [5].

As usual, the therapy was compared to placebo and not to the other substances that neurologists have previously claimed to be effective  the treatment of MS (A Conflict to Come). Despite this ethical problem, I share the hope for this substance in the coming years.

Status 2010
Brinkmann [6] reported that the drug may act through immune-based and central mechanisms to reduce inflammation and support structural restoration of the central nervous system parenchyma," and  thus not be confined simply to reduce relapse rates. The mode of action was further described by Chun and Hartung [7], who reported that "Fingolimod-phosphate initially activates lymphocyte S1P1 via high-affinity receptor binding yet subsequently induces S1P1 down-regulation that prevents lymphocyte egress from lymphoid tissues, thereby reducing autoaggressivelymphocyte infiltration into the central nervous system."

The clinical studies remained positve in their conclusions. In a large (>1000 patients for 24 months) study, Kappos et al. [8] found that, “As compared with placebo, both [0.5 and 1.25 mg] doses of oral fingolimod improved the relapse rate, the risk of disability progression, and end points on MRI.”  In a 12-months study of more than 1000 patients (and comparatively many aurthors and "collaborators"), the drug was finally tested towards another classical MS drug. The authors [9] found “superior efficacy of oral fingolimod with respect to relapse rates and MRI outcomes in patients with multiple sclerosis, as compared with intramuscular interferon beta-1a.“ However, “Two fatal infections occurred in the group that received the 1.25-mg dose of fingolimod,” a dose now abandoned while it probably increases the risk of adverse effects without essentially offering more success than 0.5 mg. Other adverse effects include bradycardia and atrioventricular block, increased liver enzyme levels, hypertension and macular edema [10].

Status 2011

Fingolimod has convinced further in 2011. Simultaneously, one must regret that this is one of the most expensive oral therapies available. So far (June 2011), I found no new studies addressing comparative efficacy of fingolimod this year. Johnson et al. [11] found that time for lymphocyte reconstitution after prolonged FTY720 therapy can be significantly greater than predicted by shorter-term studies. Our current knowledge of the drug’s metabolism  was summarized by Zollinger et al. [12]. Mehling et al. [13] found that fingolimod-treated individuals can mount vaccine-specific adaptive immune responses comparable to healthy controls. Kowarik et al. [14] found that fingolimod exerts a differential effect on various WCB cells of importance in MS

 

 
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  1. Dumont FJ. Fingolimod. Mitsubishi Pharma/Novartis. IDrugs. 2005;8:236-53.
  2. Rausch M, Hiestand P, Foster CA, Baumann DR, Cannet C, Rudin M. Predictability of FTY720 efficacy in experimental autoimmune encephalomyelitis by in vivo macrophage tracking: clinical implications for ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging. J Magn Reson Imaging. 2004;20:16-24
  3. Kappos L, Antel J, Comi G, Montalban X, O'Connor P, Polman CH, Haas T, Korn AA, Karlsson G, Radue EW; FTY720 D2201 Study Group. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 2006;355:1124-40.
  4. Chiba K. FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors. Pharmacol Ther 2005;108:308-19.
  5. Kovarik JM, Hartmann S, Bartlett M, Riviere GJ, Neddermann D, Wang Y, Port A, Schmouder RL. Oral-intravenous crossover study of fingolimod pharmacokinetics, lymphocyte responses and cardiac effects. Biopharm Drug Dispos. 2007;28:97-104
  6. Brinkmann V. FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system. Br J Pharmacol. 2009;158:1173-82.
  7. Chun J, Hartung HP. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin Neuropharmacol. 2010;33:91-101.
  8. Kappos L. et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362:387-401
  9. Cohen JA et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. . N Engl J Med. 2010;362:402-15.
  10. Horga et al. Fingolimod for relapsing multiple sclerosis: an update. . Expert Opin Pharmacother. 2010 Apr 5. [Epub ahead of print]
  11. Johnson TA et al. Reconstitution of circulating lymphocyte counts in FTY720-treated MS patients. Clin Immunol 2010;137:15-20.
  12. Zollinger M, Gschwind HP, Jin Y, Sayer C, Zécri F, Hartmann S. Absorption and disposition of the sphingosine 1-phosphate receptor modulator fingolimod (FTY720) in healthy volunteers: a case of xenobiotic biotransformation following endogenous metabolic pathways. Drug Metab Dispos 2011;39:199 -207.
  13. Mehling M et al. Antigen-specific adaptive immune responses in fingolimod-treated multiple sclerosis patients. Ann Neurol 2011;69:408-13.
  14. Kowarik MC et al. Differential effects of fingolimod (FTY720) on immune cells in the CSF and blood of patients with MS. Neurology 2011;76:1214-21.

Inserted
November 1, 2006
Revised June 21, 2010