Two New S1P Receptor Modulators Pass Phase 2 Test in MS

Susan Jeffrey

May 07, 2012

May 7, 2012 (New Orleans, Louisiana) — Data on 2 new investigational oral agents with a mechanism similar to that of fingolimod (Gilenya, Novartis) show the drugs were well tolerated and reduced lesions related to relapsing-remitting multiple sclerosis (MS). However, both were still associated with cardiovascular effects, such as bradycardia.

Fingolimod, the first oral agent approved for use in MS, is an effective treatment, but some concerns about cardiovascular effects, particularly bradycardia and atrioventricular (AV) block after the first dose, have led to recent label changes in the United States and Europe.

The new agents, siponimod (BAF312, under development by Novartis, makers of fingolimod) and ONO-4641 (being developed by ONO Pharmaceutical), are oral selective modulators of the sphingosine-1-phosphate (S1P) receptor subtypes 1 and 5. The goal of this increased selectivity is to maintain or improve upon the efficacy seen with fingolimod while simultaneously trying to improve the safety profile.

New phase 2 results with these agents, plus additional analysis of a dose-titration strategy to reduce cardiac effects with siponimod, were presented at the American Academy of Neurology's 64th Annual Meeting.

Aim to Improve Safety

Dr. Timothy Vollmer

In the phase 2 DreaMS trial, presented during the AAN's Emerging Science session, 407 patients with relapsing-remitting MS were randomly assigned to placebo or 1 of 3 doses of ONO-4641: 0.05 mg, 0.10 mg, or 0.15 mg once daily for 26 weeks. Patients were included if they had Expanded Disability Status Scale scores of up to 5.5, had had 2 or more relapses during the 2 years before the trial or 1 or more in the previous year, or 1 or more gadolinium-enhancing lesions within the previous 3 months.

"S1P-1 receptors are more selectively expressed in the immune system, and the goal was to try to decrease activation of other members of the S1P receptor family that are involved in cardiac, pulmonary and other functions," said lead author Timothy Vollmer, MD, from the University of Colorado, Denver.

The primary endpoint was the number of T1 gadolinium-enhancing lesions on magnetic resonance imaging (MRI); secondary endpoints included new and enlarging T2 lesions.

"All 3 treatment groups showed a rather substantial decrease in MRI disease activity as measured both by gadolinium-enhancing lesion numbers and new or enlarging T2s," Dr. Vollmer said. "The treatment effects were quite large, in the 77 to 92% range for gadolinium-enhancing lesions and 71 to 82% in the T2 measures, and all of them were highly statistically significant."

Table 1. Primary Endpoint: T1 Gadolinium-Enhancing Lesions by Treatment Group

Treatment Group Mean Gadolinium-Enhancing Lesions (Weeks 10 - 26) (n) Reduction (%) P Value
Placebo 8.3
ONO-4641, 0.05 mg 1.5 82 <.0001
ONO-4641, 0.1 mg 0.7 92 <.0001
ONO-4641, 0.15 mg 1.9 77 <.0001


Table 2. Secondary Endpoint: New or Enlarging T2 Lesions by Treatment Group

Treatment Group Mean New or Enlarging T2 Lesions (Weeks 6 - 26) (n) Reduction (%) P Value
Placebo 11.4
ONO-4641, 0.05 mg 3.1 73 <.0001
ONO-4641, 0.1 mg 2.1 82 <.0001
ONO-4641, 0.15 mg 3.3 71 <.0001


The study was not powered and was too short to assess effects on relapse rates or disability progression, but nevertheless a statistically significant decrease in relapse rate was seen with the 0.1-mg dose, Dr. Vollmer noted. "This shows us that the drug has a fairly substantial effect in the 50% range in terms of relapse reduction," he told Medscape Medical News.

Safety data showed the drug is similar to fingolimod, he said. "We did see some cardiac effects, particularly bradycardia and AV block, which we saw transiently in a few patients and then resolved. None of the patients were stopped on medication for that, and none of it was symptomatic."

Serious adverse events were mainly related to relapses. Infections increased slightly with active treatment, and there was some increase in pulmonary issues, a well-known effect of these drugs, as well as some gastrointestinal side effects.

"There was 1 patient who developed a maculopathy, a retinal problem, but we don't know if it was related to the drug or not," Dr. Vollmer noted. "He was in the lowest dosing group and that was the only case out of the entire study, which is encouraging because as you know with fingolimod, macular edema is one of the potential side effects."

Table 3. Reported Adverse Events by Treatment Group

Adverse Event Placebo ONO-4641, 0.05 mg ONO-4641, 0.1 mg ONO-4641, 0.15 mg
Infections and infestations 41 (40.6) 40 (39.6) 46 (45.1) 40 (40.0)
Cardiac disorders 10 (9.9) 7 (6.9) 10 (9.8) 11 (11.0)
First-degree AV block 1 (1.0) 0 5 (4.9) 3 (3.0)
Second-degree AV block 0 0 1 (1.0) 3 (3.0)
Bradycardia 1 (1.0) 1 (1.0) 0 1 (1.0)
Sinus bradycardia 4 (4.0) 2 (2.0) 1 (1.0) 4 (4.0)
Gastrointestinal disorders 11 (10.9) 20 (19.8) 23 (22.5) 23 (23.0)
Respiratory disorders 8 (7.9) 7 (6.9) 12 (11.8) 10 (10.0)
Eye disorders 8 (7.9) 12 (11.9) 10 (9.8) 8 (8.0)
Maculopathy 0 1 (1.0) 0 0

Values are number (percentage) of patients.

The major reason for discontinuation of therapy was elevation in liver enzymes, although the rate of discontinuation for this reason did not differ between groups. Liver enzyme elevations greater than 5 times the upper limit of normal were seen in 10 patients in the placebo group, 7 in the low-dose ONO-4641 group, 10 in the 0.1-mg group, and 11 in the 0.15-mg group.

Overall, the safety profile was, "remarkably clean in this study of 400 patients," Dr. Vollmer said.

"Most of these patients have gone on to open label safety extension phase and we'll be gathering more safety data over this next year or so as that past study continues," he added. There are plans now to go into phase 3 investigation. "It looks like we've got a pretty good drug that deserves further development."

Siponimod (BAF312)

In a separate presentation, researchers lead by Olaf Stuve, MD, PhD, associate professor of neurology and neurotherapeutics at University of Texas Southwestern in Dallas, reported data from a phase 2 dose-finding study of siponimod, also known as BAF312. Also a selective S1P receptor modulator, siponimod has a relatively short half-life, with complete wash-out in approximately 6 days.

The trial was an "adaptive" design: Patients were randomly assigned to 1 of 3 doses of siponimod, and then, after an interim 3-month analysis, 2 additional doses were added in a second cohort of patients, with a small placebo group for the second cohort. Cohort 1, 188 patients, received placebo or once-daily siponimod in doses of 10 mg, 2 mg, or 0.5 mg for 6 months. Cohort 2 included 109 patients who were given 1 of 2 additional intermediate doses of 1.25 mg or 0.25 mg, selected on the basis of an interim analysis, for 3 months. Patients completing the core study were eligible for a 3-month extension.

Patients had relapsing-remitting MS; about half were treatment-naive, and half had gadolinium-enhancing lesions at baseline. MRI was performed monthly. Annualized relapse rate was analyzed post hoc for cohort 1 (6-month core data) and cohort 2 (3-month core data plus 3-month extension data).

At 6 months, the adjusted proportion of relapse-free patients was highest for the 2-mg dose: 84% for the 10-mg group, 92% for the 2-mg group, and 77% for the 0.5-mg group vs 72% for the placebo group (P = .014 for 2 mg siponimod vs placebo).

In the 6-month post hoc analysis, the annualized relapse rate was lower with the 3 higher doses than the 2 lower doses and placebo. The reduction with the 2-mg dose reached statistical significance vs placebo (P = .044).

Table 4. Cohort 2: 6-Month Annualized Relapse Rate by Treatment Group

Endpoint Siponimod, 10 mg Siponimod, 2 mg Siponimod, 1.25 mg Siponimod, 0.5 mg Siponimod, 0.25 mg Placebo
Annualized relapse rate 0.30 0.20 0.23 0.61 0.55 0.58


MRI findings were reported separately in a paper with lead author David Li, MD, from the University of British Columbia, Vancouver, Canada.

Dr. Li and colleagues report that treatment with siponimod was associated with a reduction in Combined Unique Active Lesions (CUAL) on MRI. Maximal efficacy was seen with the 2 mg group, which showed an approximately 80% reduction in active lesions.

Treatment also reduced the number of new and enlarging T2 lesions and the number of new gadolinium-enhancing lesions in patients with high baseline disease activity, defined as 2 or more gadolinium-enhancing lesions at baseline.

The most frequent adverse events were headache, bradycardia, dizziness, and nasopharyngitis, occurring most frequently in the 10-mg dose group.

Novartis confirmed in a press release that on the strength of these data, a phase 3 program looking at siponimod will begin later in 2012.

Minimizing Cardiac Issues

In a separate paper using the same cohort 1 and cohort 2 described above, researchers introduced a dose titration regimen with the aim of minimizing the cardiac conduction issues, particularly bradycardia, that are typical of the S1P receptor modulators. In cohort 1, no dose titration was used. However, after a protocol amendment, all patients in cohort 2 and the extension study had an initial 10-day dose titration with enhanced cardiac monitoring.

John DiMarco, MD, from the University of Virginia in Charlottesville, and colleagues, report that in cohort 1, there was a dose-dependent reduction in mean heart rate, and 5 patients had transient symptomatic second-degree AV blocks; 3 of these patients were receiving the 2-mg dose, and 2 were receiving the 10-mg dose. Two received treatment for these events, but all resolved within 24 hours. In addition, 13 asymptomatic AV blocks in 12 patients were seen on 24-hour ambulatory electrocardiograms over the first week of treatment, distributed across doses.

In cohort 2, the reduction in mean heart rate was less pronounced after dose titration. There was no symptomatic second-degree AV block. Two patients receiving placebo and 1 in the 2-mg group had an asymptomatic second-degree AV block, all during sleeping hours. "No episodes of syncope, Mobitz Type II or third degree heart block occurred during the study," authors conclude.

The ONO-4641 study was supported by Ono Pharmaceutical Company. Dr. Vollmer reports being a consultant or advisory board member to Biogen Idec, Consortium of MS Centers, Daiichi Sankyo, Elan Pharma, Eli Lilly and Co., Global Prairie, Guidepoint Global, Hoffman-LaRoche Pharmaceuticals, Medical Logix, MSDx, Prime Education, Projects in Knowledge, Teva Pharmaceuticals, Xenoport. He has received research support from Biogen Idec, BioMS, EMD Serono, Genzyme Pharmaceuticals, Novartis Pharmaceuticals, Ono Pharma, sanofi-aventis, and Teva Pharmaceuticals. The siponimod studies were supported by Novartis. Dr. Stuve reports he has received personal compensation for activities with Biogen Idec, Teva Neuroscience, Novartis, Roche, Genzyme, EMD Serono, and sanofi-aventis, and has received personal compensation in an editorial capacity for Archives of Neurology and Therapeutic Advances in Neurological Disorders. Dr. Li reports he has received personal compensation for activities with Genzyme, Novartis and Nuron as a consultant; he has received research support from Angiotech, Bayer, Berlex-Schering, Bio-MS, Boehringer-Ingelheim, Centocor, Daiichi Sankyo, Genentech, Hoffmann-LaRoche, Merck-Serono, Perceptives, Schering-Plough, Teva Neurosciences, sanofi-aventis, Transition Therapeutics, and Novartis. Dr. DiMarco reports he has received personal compensation for activities with Sanofi, Astellas, Novartis, Medtronic, St. Jude, Tau Therapeutics, Sequel, and Biotronik as a consultant; personal compensation in an editorial capacity for Elsevier; and research support from Boston Scientific.

American Academy of Neurology's 64th Annual Meeting. Emerging Science Abstract# 005. Presented April 25, 2012. Abstract #S30.001. Presented April 25, 2012. Abstract #S11.005. Presented April 24, 2012. Abstract #P01.131. Presented April 23, 2012.


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