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agate
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 Posted: Sun May 06, 2012 4:56 pm Post subject: New oral drug, ONO-4641, shows promise in trial |
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From the MS Foundation's MSFYi Newsletter, May 1, 2012:
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Another Oral Drug Shows Promise in Trial
A study of an experimental oral drug called ONO-4641 reduced the number of lesions in people with relapsing-remitting MS by as much as 92 percent, Colorado researchers have reported. However, the drug must undergo a larger clinical trial before it can be submitted for FDA approval for general use.
ONO-4641, developed by Ono Pharmaceutical Co. Ltd. of Osaka, Japan, works differently than existing MS drugs. It traps destructive lymphocytes (white blood cells) in the lymph nodes, preventing them from reaching myelin and damaging it.
Dr. Timothy Vollmer and his colleagues at the University of Colorado in Denver studied 407 adults with relapsing-remitting MS, giving them one of three different diseases of the drug daily for 26 weeks. All of them had had either two relapses in the previous two years or at least one in the year prior to the onset of the study.
Vollmer reported at a New Orleans meeting of the American Academy of Neurology that 92 percent of participants receiving the most-effective dose of the drug, 0.1 mg, had 92 percent fewer lesions at the end of the study as measured by a MRI.
Side effects included slower heartbeat, blood pressure changes, and a block in electrical conduction between the atria and ventricles of the heart. About 1 percent of the people receiving the most-effective dose developed abnormally low levels of lymphocytes in the blood.
Merck KGaA has the license to develop the medicine globally, excluding Japan, South Korea, and Taiwan.
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agate
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| Posted: Thu Jul 26, 2012 12:56 pm Post subject: |
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This article was chosen among the "editor's picks" by the American Academy of Neurology, July 25, 2012:
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News from the AAN Annual Meeting: Novel Agent Reduces MS. Lesions in Early Trial
Neurology Today7 June 2012; Volume 12(11); p 40
Goodman, Alice
ARTICLE IN BRIEF
In a double-blind, placebo-controlled trial, fewer Gd-enhancing lesions were observed in relapsing-remitting MS patients taking an experimental drug, ONO-441.
NEW ORLEANS—ONO-4641, an investigational oral drug, reduced the number of lesions detected by MRI in people with relapsing remitting multiple sclerosis (RRMS) — the primary outcome for the phase 2b Drug Research EvaluAtion for MS (DreaMS) trial. And while the investigators hope the drug will be safer and more effective than other drugs with similar mechanisms, they noted that the current trial did not measure clinical efficacy. Ono Pharmaceuticals funded the trial.
ONO-4641 is a potent selective sphingosine-1-phosphate (S1P) receptor agonist, stimulating primarily the S1P1 and S1P5 receptors, thus inhibiting the infiltration of lymphocytes into MS lesions. Fingolimod is an approved oral drug for MS that also exerts its effect on the S1P receptor. Another S1P inhibitor potentially useful in MS called BAF is being developed by Novartis.
“In that this new compound is somewhat more selective in its S1P activation pattern than fingolimod, it is our hope that it will have good efficacy with improved safety. We will see if this is borne out in future research,” Timothy Vollmer, MD, professor of neurology at the University of Colorado Health Sciences Center, and medical director of the Rocky Mountain MS Center at Anschutz Medical Center, said. He reported the findings of the double-blind, placebo-controlled trial here at the AAN annual meeting in April.
STUDY PROTOCOLS
The dose-ranging trial enrolled 407 RRMS patients between the ages of 18 and 55 years from 11 different countries, including the US. They were randomized to three daily doses of ONO-4641 —.05 mg, .10 mg, or .15 mg — or placebo, and treated for 26 weeks. To be eligible to participate, they had to have had two or more relapses in the previous two years; one or more relapses within the previous year; or one or more new T1 gadolinium (Gd)-enhancing lesions on MRI within the previous three months. Patients were evaluated with MRI scans every four weeks from week 10 to week 26.
The primary endpoint was the cumulative number of T1 Gd-enhancing lesions, not clinical efficacy. At week 26, fewer Gd-enhancing lesions were observed in 82 percent of the .05 mg group; 92 percent of the .10 mg group; and 77 percent in the .15 mg group versus placebo. All three doses of ONO-4641 were significantly superior to placebo for the secondary endpoint of cumulative number of new or enlarged T2 lesions (p<.0001).
Most adverse events in the group of patients treated with ONO-4641 were dose-related, including cardiovascular events. Asymptomatic, transient first- and second-degree atrioventricular block and bradycardia were associated with initiation of dosing; no cases required discontinuation and all resolved with no need for treatment. Maximum mean reduction in heart rate was 8.4 bpm, with the highest dose of ONO-4641. Liver enzyme elevations of varying degrees were seen in slightly less than half of all treated patients compared with 27 percent of placebo patients. Gastrointestinal disorders were slightly less common. Grade 4 lymphopenia was reported in 4 percent of the group receiving the highest dose (0.15 mg) and 1 percent of those on the 0.10 mg dose. Most serious adverse events were related to MS itself.
“ONO-4641 was well tolerated by the study population with no unexpected adverse events,” Dr. Vollmer commented.
IS IT SAFER?
“Both ONO-4641 and BAF have undergone dose-ranging studies with the goal of finding the effective dose with the fewest side effects. These drugs differ from fingolimod in that fingolimod is a prodrug, while these two drugs are active once ingested. The hope is that these drugs can avoid the first-dose effect seen with fingolimod, including cardiovascular and lymphopenia, but it appears that this won't happen. The phase 2b study [of ONO-441] shows that lower doses will be safer,” said Mark S. Freedman, MD, professor of medicine (Neurology) at the University of Ottawa and director of the Multiple Sclerosis Research Unit at the Ottawa Hospital, Ontario, Canada.
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agate
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| Posted: Wed Mar 27, 2013 1:18 pm Post subject: |
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Presented at the AAN conference in San Diego, March 16-23, 2013:
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[S31.005] An Exploratory Analysis of Magnetic Resonance Imaging Outcomes in the DreaMS Trial: A Double-Blind, Placebo-Controlled, Phase 2, 26-Week Trial of a Selective Sphingosine 1-Phosphate Receptor Agonist ONO-4641 in Patients with Relapsing–Remitting Multiple Sclerosis
Krzysztof Selmaj, Lodz, Poland, Frauke Zipp, Mainz, Germany, Timothy Vollmer, Aurora, CO, Amit Bar-Or, Montreal, QC, Canada, Bryan Due, Lawrenceville, NJ, Johan Van Beek, Geneva, Switzerland, Kathinathan Thangavelu, Geneva, Switzerland
OBJECTIVE:
To prospectively analyze magnetic resonance imaging (MRI) outcomes in the Phase 2 DreaMS (Drug Research and EvaluAtion in Multiple Sclerosis) study using a more sensitive statistical method than that specified in the original study protocol.
BACKGROUND: The DreaMS study assessed the efficacy and safety of ONO-4641, a selective sphingosine 1-phosphate (S1P) receptor-1 and -5 agonist, in patients with relapsing–remitting multiple sclerosis (RRMS). MRI outcomes were primarily lesion counts, analyzed using the Wilcoxon rank sum test.
A further sensitivity analysis using a negative binomial (NB) model was prospectively planned. The NB model is better suited for the analysis of such zero-inflated but highly skewed data, and it provides an estimate of the treatment effect and also allows for adjustment for covariates.
DESIGN/METHODS:
MRI outcomes were analyzed by an NB model adjusting for the number of lesions per patient at baseline.
RESULTS:
Using NB analysis, the cumulative number of T1 gadolinium-enhancing lesions from Week 10 to 26 (primary endpoint) was significantly lower (p<0.0001) in all three active-treatment groups versus placebo (adjusted means: placebo, 5.65; 0.05 mg, 1.41; 0.10 mg, 0.57; 0.15 mg, 0.63; relative reduction [95% confidence interval {CI}] vs placebo: 0.05 mg 75% [57–85]; 0.10 mg, 90% [82–94]; 0.15 mg, 89% [80–94]).
The cumulative number of new/enlarging T2 lesions was also significantly reduced (p<0.0001) with all three doses of ONO-4641 versus placebo (adjusted means: placebo, 8.01; 0.05 mg, 2.37; 0.10 mg, 1.68; 0.15 mg, 1.44; relative reduction [95% CI] vs placebo: 0.05 mg, 70% [54–81]; 0.10 mg, 79% [67–87]; 0.15 mg, 82% [72–89]).
CONCLUSIONS:
These findings confirm the robust, positive effect of ONO-4641 on MRI outcomes in patients with RRMS, as initially observed using the per-protocol planned primary analysis, and better characterize the dose-dependent effect of ONO-4641 on MRI outcomes.
_______________________
Supported by: Ono Pharmaceutical Co. Ltd, Osaka, Japan.
Category - MS and Related Diseases: Clinical Science
Wednesday, March 20, 2013 4:52 PM
Moderated Platform Session S31: Multiple Sclerosis: Novel Treatments |
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