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Main Category: Multiple Sclerosis
Article Date: 23 Apr 2012 - 12:00 PDT
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At the 64th annual meeting of the American Academy of Neurology (AAN), Novartis will present new data that supports Gilenya's (fingolimod) efficacy and safety profile and introduce new data of its investigational compound BAF312 (siponimod), a selective modulator of the S1P receptor subtypes 1 and 5 (S1P1, -5R modulator) in its multiple sclerosis portfolio3.
Gilenya (fingolimod) is the only oral therapy approved to treat relapsing forms of multiple sclerosis (MS)1,2. It is the first in a new class of sphingosine 1-phosphate receptor (S1PR) modulating compounds and has demonstrated superior efficacy over Avonex (interferon-beta-1a IM), a commonly prescribed treatment.
In a pivotal head-to-head trial in patients with relapsing- remitting multiple sclerosis at one year, Gilenya achieved both its primary and secondary endpoints, i.e. a 52% relative reduction of the yearly relapse rate and a 40% relative reduction in the rate of brain atrophy. A recent sub-analysis at one year revealed that in comparison to interferon-beta-1a (IM), Gilenya achieved a 61% relative reduction in the rate of yearly relapses in patient subgroups with highly active relapsing-remitting MS patients who previously received interferon therapy.
Gilenya has no label restrictions specific to treatment duration and was generally well tolerated during clinical trials with a manageable safety profile. Since February 2012, over 36,000 patients have been treated with Gilenya in clinical trials and in the post-marketing setting, which confirms Gilenya's long- term effectiveness and safety profile. 2,400 patients have been taking the drug for longer than two years.
The most common adverse events reported were cough, diarrhea, headache, liver enzyme elevations and back pain, whilst other side effects included a mild increase in blood pressure, transient, generally asymptomatic, heart rate reduction and atrioventricular block upon treatment initiation, macular edema, and mild bronchoconstriction.
Overall, the rates of infections including serious events were similar in all treatment groups. However, patients treated with Gilenya reported a slightly higher rate of respiratory tract infections that consisted mainly of bronchitis. There were only a small number of reported malignancies in the clinical trial, with similar rates between the Gilenya and control groups.
David Epstein, Head of the Pharmaceuticals Division of Novartis Pharma AG said:
"The data being presented reinforce our confidence in the sustained efficacy and safety profile of Gilenya. We also are pleased to present encouraging data for our investigational compound BAF312 (siponimod). The clinical development of BAF312 demonstrates our commitment to developing new therapeutic options for the MS community."
New data presented on long-term efficacy and safety profile of Gilenya
According to new results from the phase III FREEDOMS extension study, patients who received placebo during the 2-year core study and then switched to Gilenya during the extension study demonstrated considerable improvements in clinical and MRI measures.The double blind, two-year FREEDOMS 24 core study involved a total of 1,033 patients, of which 90% completed 3 years of monitoring and 45% who were followed up for 4 years before being transferred to the umbrella follow-up study (LONGTERMS).
The annual relapse rate (ARR) of patients who switched from placebo in the core phase to Gilenya in the extension phase was 0.29, compared with 0.13 (p
Whilst Gilenya reduced the brain atrophy by 38% in the core FREEDOMS study at 2 years compared with placebo, the extension study demonstrated that MRI measures continued to show substantially better effects in fingolimod. At the end of the observation, the lower rate of brain atrophy in in continuously treated patients compared with those who switched from placebo was -1.67%, compared with -2.24% in the average change in percentage in brain volume (p = 0.001).
The safety profile of the phase III FREEDOMS extension was consistent to that of the pivotal phase III trials, with the most common adverse events reported as nasopharyngitis, low lymphocyte counts, which was to be expected from the mode of action, upper respiratory tract infections and influenza.
Ludwig Kappos from the Department of Neurology at the University of Basel in Switzerland said:
"This extension study confirms the efficacy shown in the published phase III studies and supports positive long term impact of continuous treatment. The favorable longer-term safety profile is consistent with results from the phase III studies. These observations in a large group of patients, now for four and more years, confirm that fingolimod is a valuable treatment option for patients with relapsing remitting MS."
Furthermore, new data for up to 7 years of treatment from the phase II extension study demonstrated that 122 patients who were treated with Gilenya had sustained low MRI and clinical disease activity. The overall ARR for the continuous Gilenya therapy group was 0.16, which translates to 1 relapse every 6 years. At completion of the long-term extension, more than 50% of those who were in the continuous Gilenya treatment since the start of the study remained free of relapses throughout the study.
The phase III registration program for Gilenya included the two-year FREEDOMS study, as well as a parallel study in which Gilenya achieved a 52% relative reduction in annualized relapse rate at the 1-year primary endpoint, as compared with Avonex (interferon-beta-1a IM), a commonly prescribed treatment.
Low incidence of ECG abnormalities and symptomatic heart rate reduction at treatment initiation in 2,400 patient FIRST Study
According to new data from the large, 4-month, open-label, single-arm multi-center FIRST study, the overall incidence of important first dose slowing of heart rate (bradycardia) and heart rate abnormalities at initiation of the Gilenya treatment was low, i.e. 1.3% of patients had bradycardia of less than 45 bmp, with no patient experiencing a heart rate of less than 30 bpm and conduction abnormalities.The study also provides data on continuous ECG monitoring by ambulatory Holter Electrocardiogram (ECG) for six hours after the first dose of Gilenya was given, in order to identify any heart rate or ECG abnormalities. The results of over 2,400 patients was a 1.4% incidence of Mobitz I second degree atrioventricular blocks (AVBs) as per Holter ECG 6 hours after administration of the dose, whilst the incidence of Mobitz II second degree or AVBs was 0.5%.
Gilenya's short-term safety profile in the FIRST study generally proved consistent with that in the phase III studies, including the low incidence of known cardiac effects of fingolimod at treatment initiation, i.e. commonly transient decreases in heart rate and generally asymptomatic atrioventricular blocks.
Positive phase IIb data for BAF312 (siponimod)
At the 64th annual meeting of the AAN, Novartis will also present key results from a phase II dose finding study of its investigational compound BAF312 (siponimod), which is a selective modulator of the S1P receptor subtypes 1 and 5 (S1P1, 5-R modulator) in MS.The double blind, placebo-controlled study utilized a newly adapted trial design and established a statistically important dose response relationship.
The study also demonstrated that in comparison with placebo, BAF312 reduced brain MRI lesions by almost 80%, with infrequent relapses that seemed to be reduced in BAF312 with an ARR of 0.20 for 2 mg, as compared with 0.58 in placebo (p=0.044).
BAF312 was generally well tolerated with an initial dose titration, with the most common adverse events consisting of headache, dizziness, bradycardia, and nasopharyngitis.
Novartis is planning to start a phase III MS program later this year.
Written By Petra Rattue
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today
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