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Devil is in the dosing

Following Gilenya: How follow-on S1P agonists could mitigate CV effects in MS

Data released in April suggest the theory behind second-generation sphingosine 1-phosphate receptor agonists in development for multiple sclerosis was wrong. However, two companies are finding that improved pharmacokinetics and/or dose titration could achieve the original goal of improving safety compared with first-generation S1P receptor agonist Gilenya fingolimod from Novartis AG.

Gilenya, the first oral drug for relapsing-remitting multiple sclerosis (RRMS), was approved in September 2010, but has struggled to gain a foothold in first-line use due to concerns over cardiovascular safety (see BioCentury, Sept. 27, 2010).

In April, Novartis updated the drug's U.S. and EU labels to recommend additional cardiac testing before treating patients and additional cardiac monitoring once dosing begins.

Gilenya's therapeutic effect in MS is mediated by its interaction with S1PR1 on lymphocytes. But it binds with high affinity to all of the five known S1P receptors except S1PR2.

According to Gordon Francis, VP of Novartis' neurosciences and ophthalmology clinical science unit, rodent data had suggested Gilenya's interaction with S1PR3 was responsible for reductions in heart rate and atrioventricular (AV) block.

The idea behind second-generation S1P receptor agonists thus was to dial in specificity for S1PR1, while dialing out interaction with S1PR3.

However, Phase II data reported in April for ONO-4641 from Ono Pharmaceutical Co. Ltd. and Merck KGaA, show cardiovascular signals similar to Gilenya's.

ONO-4641 is selective for S1PR1 and S1PR5.

Meanwhile, preclinical data on second-generation compounds from Novartis and Receptos Inc., as well as additional studies of Gilenya have negated the S1PR3 hypothesis.

"The rodent lied,"

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