Active Biotech today announces that its partner Teva Pharmaceuticals, has decided not to proceed to the randomization stage of the planned Libretto trial for the treatment of Relapsing Remitting Multiple Sclerosis (RRMS), as the current design is no longer aligned with the regulatory strategy. This decision has no impact on other ongoing studies, such as CONCERTO, which are proceeding as planned, or on Teva Pharmaceuticals' plans to initiate clinical studies in Primary Progressive Multiple Sclerosis (PPMS).
About laquinimod (Nerventra(R))
Laquinimod (Nerventra(R)) is an oral, investigational, CNS-active immunomodulator with a novel mechanism of action primarily being developed for the treatment of relapsing-remitting MS (RRMS). The global Phase III clinical development program evaluating oral laquinimod in MS includes two pivotal studies, ALLEGRO and BRAVO. A third Phase III laquinimod trial, CONCERTO, is evaluating two doses of the investigational product (0.6mg and 1.2mg) in approximately 1,800 patients for up to 24 months. The primary outcome measure will be time to confirmed disability progression as measured by the EDSS. In addition to the MS clinical studies, laquinimod has concluded Phase II of development for Crohn's disease and lupus nephritis.
Source: Market Watch Copyright © 2014 MarketWatch, Inc (19/02/14)
The European Medicines Agency's (EMA's) Committee for Medicinal Products for Human Use (CHMP) has recommended against approval of a new drug for multiple sclerosis (MS).
During their monthly meeting on January 23, the CHMP panel adopted a negative opinion on granting marketing authorization for laquinimod ( Nerventra, Teva Pharma) in patients with relapsing-remitting MS.
The panel noted concerns about results from animal studies showing a higher occurrence of cancers after long-term exposure to laquinimod, noting that a similar long-term risk could not be ruled out in humans, "especially when considering that the way the medicine works in the body is unclear," the EMA noted in a press release.
There was also a possible risk from animal data on teratogenic effects in offspring of women taking the drug, the panel said. "The CHMP noted that the risk could not be excluded with current data and that animal studies suggest that any harmful effects may be delayed and only seen later on in the child's life. In addition, the Committee was not convinced about the effectiveness of the company's proposed measures to prevent pregnancies in women who would take the medicine."
The CHMP panel also pointed out that although the drug had been shown to slow the worsening of disability, its effect on relapses was "modest."
The 2 phase 3 trials of laquinimod completed to date were called ALLEGRO (Assessment of Oral Laquinimod in Preventing Progression in Multiple Sclerosis) and BRAVO. Hope was high for this agent after results of ALLEGRO were published in the New England Journal of Medicine, showing laquinimod reduced the annualized relapse rate as well as delayed progression of disability vs placebo.
In BRAVO, however, which compared oral laquinimod with an active comparator, interferon β-1a ( Avonex, Biogen Idec), the trial missed the primary endpoint of a reduction of annualized relapse rates. However, the reduction seen with laquinimod was significant after researchers adjusted for an imbalance in the volume of T2 disease between groups and the number of gadolinium-enhancing lesions on MRI.
Both trials showed a reduction in disability that was unexpected given the effect seen on relapse rates, raising the possibility that the agent might be affecting disability through some novel mechanism. A reduction in brain atrophy was also noted, which was in line with the effect on disability, another novel finding with this agent.
The upshot is that laquinimod is now being evaluated in a third phase 3 trial, CONCERTO, after a Special Protocol Assessment agreement was reached with the US Food and Drug Administration (FDA). The trial will assess 2 doses of laquinimod — 0.6 and 1.2 mg daily for up to 24 months — in about 1800 patients with relapsing-remitting MS. The primary outcome will be confirmed disability progression on the Expanded Disability Status Scale.
For its part, "the CHMP was of the view that the benefits of Nerventra in patients with relapsing-remitting MS do not outweigh the potential risks and recommended that it be refused marketing authorisation," the EMA release notes.
The CHMP opinion has is no consequences "for the time being" on any ongoing trials of laquinimod, it concludes.
Source: Medscape Multispeciality Copyright © 1994-2014 by WebMD LLC (29/01/14)
Development continues on MS drug Nerventra® (laquinimod) following the EMA’s CHMP negative opinion(24/01/14)
Teva Pharmaceutical Industries Ltd and Active Biotech announced today that both companies remain committed to the Nerventra® (laquinimod) clinical development program for multiple sclerosis (MS) following the announcement of a negative opinion for the treatment of relapsing-remitting multiple sclerosis (RRMS) by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA).
The CHMP has concluded that the risk-benefit profile of Nerventra is not favourable at this time. In accordance with European regulations, Teva and Active Biotech intend to request a re-examination of the CHMP opinion. Teva and Active Biotech are focusing on evaluating the CHMP’s review and will continue to liaise closely with the EMA in working to make Nerventra available as a new treatment option for patients with RRMS in Europe.
NERVENTRA is a once-daily oral, investigational, CNS-active immunomodulator with a novel mechanism of action being developed for the treatment of relapsing-remitting MS (RRMS) and progressive MS (PMS). In extensive non-clinical and clinical studies Nerventra has demonstrated both anti-inflammatory and neuroprotective properties and effects that have been shown to provide clinically meaningful results. The global Phase III clinical development program evaluating Nerventra in MS includes two pivotal studies, ALLEGRO and BRAVO. A third Phase III Nerventra trial, CONCERTO, is evaluating two doses of the investigational product (0.6mg and 1.2mg) in approximately 1,800 patients for up to 24 months. The primary outcome measure will be time to confirmed disability progression as measured by the EDSS.
The safety profile of Nerventra is based on 2645 MS patients that have been exposed to Nerventra for a total duration of 7490.8 subject years, with a maximal duration of seven years. Very common or important adverse reactions include headache, abdominal pain, back and neck pain, appendicitis, and mild, asymptomatic laboratory abnormalities, including liver enzyme elevations, hematological changes, and elevation of CRP or fibrinogen levels. Potential risks include teratogenicity and carcinogenicity, both related to findings in rats, which are based on non-clinical data and have not been encountered in patients.
In addition to the MS clinical studies, Nerventra is currently in clinical development for Crohn's disease. Studies are also planned to study the efficacy, safety and tolerability of Nerventra in other neurodegenerative diseases, including Huntington’s disease.
Source: MarketWatch Copyright © 2014 MarketWatch, Inc (24/01/14)
The Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) decided on Friday to defer a decision on Laquinimod, an oral treatment for relapsing-remitting multiple sclerosis (RRMS). Laquinimod is being developed jointly by Teva Pharmaceutical Industries Ltd, and Swedish company Active Biotech. According to Active Biotech, the EMA will issue an opinion at its January, 2014 meeting.
Press reports overseas state that the EMA spokesperson refused to provide further details, but said that the agency's experts were entitled to decide on a postponement of a decision of this kind if they saw a necessity to do so.
The future of Laquinimod is uncertain, since it failed to achieve the main endpoints in a clinical trial in 2011. The US Food and Drug Administration (FDA) has requested an additional Phase III trial before it will consider the companies' application to approve the product for sale.
Teva hopes that the drug will be launched in Europe in 2014. There are already several orally administered treatments for multiple sclerosis on the market, among them Biogene's Tecfidera, which analysts see becoming a blockbuster drug, with annual sales of $3 billion.
Source: Globes © Globes 2013 (23/12/13)
Teva Pharmaceutical Industries Ltd. and Active Biotech have announced the publication of a pre-planned analysis of the Phase III ALLEGRO study demonstrating that once-daily oral laquinimod provides a beneficial impact on brain tissue damage, one of the most destructive aspects of multiple sclerosis. These data, "Placebo-controlled trial of oral laquinimod in multiple sclerosis: MRI evidence of an effect on brain tissue damage," published online in September by the Journal of Neurology, Neurosurgery & Psychiatry (JNNP), along with an accompanying editorial titled, "Oral laquinimod for multiple sclerosis: beyond the anti-inflammatory effect," can be found on the JNNP website at www.jnnp.bmj.com.
"This Phase III sub-study was pre-planned to explore the ability of laquinimod to act on mechanisms leading to irreversible brain tissue damage," said Professor Massimo Filippi, Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University. "This study indicates that laquinimod likely exerts a favourable effect on several MRI metrics of neurodegeneration, which in turn might explain the previously observed ability of the drug to significantly slow down progression of locomotor disability in relapsing-remitting multiple sclerosis."
The results showed that when compared with placebo, patients treated with laquinimod experienced decreased rates in brain tissue damage shown by various MRI markers. Specifically, patients receiving laquinimod showed decreased rates of white matter (WM), grey matter (GM) and thalamic atrophy; developed fewer permanent black holes (PBH); and accumulated less damage in normal appearing brain tissue (NABT), WM and GM, when compared to patients receiving placebo.
"These analyses reinforce our faith in the potential of laquinimod and we are proud to announce that we plan to initiate a clinical trial of the drug in PPMS to gather even more evidence of this novel mechanism of action," said Dr. Michael Hayden, President of Global R&D and Chief Scientific Officer for Teva Pharmaceutical Industries Ltd. " We also believe the potential neuroprotective benefits of laquinimod could have significant application in the treatment of other diseases like Crohn's disease, lupus nephritis, Huntington's disease and Alzheimer's."
A third Phase III laquinimod trial, CONCERTO, is evaluating two doses of the investigational product (0.6mg and 1.2mg) in approximately 1,800 patients for up to 24 months. The primary outcome measure is the time to confirmed disability progression as measured by the EDSS. The study will also examine the impact of laquinimod on endpoints such as percent change in brain volume, as well as other clinical and MRI markers of disease activity.
ABOUT THE ALLEGRO STUDY
ALLEGRO was a two-year multi-national, multi-center randomized, double blind, placebo-controlled study designed to evaluate the efficacy, safety and tolerability of laquinimod in MS patients. The study was conducted at 139 sites in 24 countries and enrolled 1,106 MS patients. Patients were randomized to receive a once-daily oral dose of 0.6 mg laquinimod or matching placebo. The primary outcome measure was the number of confirmed relapses; secondary measures included confirmed disability progression and changes in MRI active lesions.
In the ALLEGRO study, laquinimod showed a statistically significant 23 percent reduction in annualized relapse rate (p=0.0024), the primary endpoint, along with a significant 36 percent reduction in the risk of confirmed disability progression, as measured by Expanded Disability Status Scale (EDSS) (p=0.0122). Treatment with laquinimod was also associated with a significant reduction in brain tissue loss, as measured by a 32.8 percent reduction in progression of brain atrophy (p<0.0001).
In these MRI analyses, white matter (WM), grey matter (GM) and thalamic fractions were derived at baseline, and months 12 and 24. Also assessed were evolution of gadolinium enhancing and/or new T2 lesions into permanent black holes (PBH); magnetization transfer ratio (MTR) of normal-appearing brain tissue (NABT), WM, GM and T2 lesions as assessed by magnetization transfer (MT) MRI; and changes in n-acetylaspartate/creatinine (NAA/Cr) levels.
Eighty percent of laquinimod and 77 percent of placebo patients completed the two-year study. Patients who completed the ALLEGRO study were offered to join an open-label extension phase, in which they are being treated with laquinimod 0.6 mg daily.
The safety and tolerability profile of laqunimod observed in the ALLEGRO and BRAVO studies was favorable. The overall frequencies of adverse events, including incidence of infections, were similar to those observed in the placebo group. The most commonly reported adverse events were headaches, nasopharyngitis and back pain. The incidence of liver enzyme elevation was higher in laquinimod treated patients; however, these elevations were transient, asymptomatic and reversible.
Laquinimod is an oral, investigational, CNS-active immunomodulator with a novel mechanism of action being developed for the treatment of relapsing-remitting MS (RRMS). The global Phase III clinical development program evaluating oral laquinimod in MS includes two pivotal studies, ALLEGRO and BRAVO. A third Phase III laquinimod trial, CONCERTO, is evaluating two doses of the investigational product (0.6mg and 1.2mg) in approximately 1,800 patients for up to 24 months. The primary outcome measure is the time to confirmed disability progression as measured by the EDSS.
In addition to the MS clinical studies, laquinimod is currently in Phase II of development for Crohn's disease and lupus nephritis. Because of the neuroprotective findings, Teva is evaluating further studies to determine the effectiveness of laquinimod in treating patients with primary progressive multiple sclerosis, Huntington's disease and Alzheimer's disease.
Source: The Wall Street Journal ©2013 Dow Jones & Company, Inc (01/10/13)
Teva Pharmaceutical and Active Biotech announced top-line results from an open-label extension of the Phase 3 ALLEGRO study, which assessed the progression of disability and safety of oral laquinimod in early vs. delayed-start relapsing remitting multiple sclerosis (RRMS) patients. Laquinimod is an oral, once-daily CNS-active immunomodulator with a novel mechanism of action being developed for the treatment of MS.
The study compared the effectiveness of laquinimod in patients who received 36 months (early-start) vs. those who received 24 months of laquinimod treatment (delayed-start). Out of the 864 RRMS patients who participated in the original double-blind ALLEGRO trial, 97% enrolled in the open-label extension and 87% completed one year of the open-label phase.
During the entire duration of the study (double blind and open label phase), early start patients were less likely to experience disease progression than those with a delayed start of laquinimod (11.8% risk of confirmed disability progression vs. 16.7%, HR = 0.62, P< 0.0038).
Source: Monthly Prescribing Reference Copyright © 2013 Haymarket Media, Inc (22/03/13)
Teva Pharmaceutical Industries Ltd. will test its experimental multiple-sclerosis pill in combination therapies as the company mounts a response to oral competitors to its best-selling injection Copaxone.
The Israeli company is likely to start two clinical trials next year combining laquinimod with other drugs, President of Global Research and Development and Chief Scientific Officer Michael Hayden said in an interview at an MS conference in Lyon, France. One of the trials may seek to combine laquinimod with Copaxone, Hayden said.
“We haven’t pulled the trigger on it but we are getting very close,” Hayden said, referring to the possible combination with Copaxone. In multiple sclerosis, “nobody uses combination therapy. It’s really strange.” Combining another treatment to laquinimod would mean a “paradigm change” in the the care of multiple sclerosis, Hayden said.
“With the dual mechanisms, we have a chance to do that,” he said.
Teva is searching for a new approach to MS treatments as Copaxone’s dominance begins to be threatened by pills such as Novartis AG’s Gilenya and Biogen Idec Inc’s BG-12, which is awaiting a decision from U.S. regulators. Teva also said today that it’s submitting its three-times weekly version of Copaxone for approval in the beginning of 2013.
Slowing Deterioration While laquinimod failed to beat competing products in clinical trials on reducing the rates at which patients experience relapses, Teva is continuing development because studies suggest it slows the deterioration in physical ability caused by the disease. Teva is separately testing the pill in a final round of human trials at a higher dose as it seeks to verify that the drug effectively delays loss of muscle control and balance.
A U.S. federal judge in New York handed Teva a ruling in June that may keep generic versions of Copaxone off the market until 2015. The victory may give Teva more time to switch patients to a new, higher-dose version of the drug. Teva said yesterday that a late-stage trial of a longer-acting formulation reduced MS relapses more than a placebo and showed a ‘‘favourable” safety profile.
With a three times a week dose, patients on Copaxone “can focus on having the week-end without it,” Hayden said. “Weekends are times for different things, to be able to put your medication away, have a weekend without having to worry about it. For me, that would be an advantage.”
Source: Bloomberg Business Week @ 2012 BLOOMBERG L.P (11/10/12)
Teva Pharmaceutical Industries Ltd. and Active Biotech have provided an update on the clinical development program of once-daily oral laquinimod for the treatment of relapsing-remitting multiple sclerosis (RRMS). The companies are to initiate a third Phase III study of laquinimod, following the written agreement reached with the U.S. Food and Drug Administration (FDA) on the Special Protocol Assessment (SPA).
The third Phase III laquinimod trial CONCERTO will evaluate two doses of the investigational product (0.6mg and 1.2mg) in approximately 1,800 patients for up to 24 months. The primary outcome measure will be confirmed disability progression as measured by the Expanded Disability Status Scale (EDSS).
"The results achieved in the previous Phase III trials of laquinimod support the clinical utility of this compound as a unique treatment option for multiple sclerosis," said Dr. Michael Hayden, President of Global R&D and Chief Scientific Officer, Teva Pharmaceutical Industries Ltd. "We are encouraged by the FDA's agreement on the trial design and planned analysis, and look forward to further developing laquinimod as a potential treatment option for RRMS patients."
Laquinimod is an oral, once-daily CNS-active immunomodulator with a novel mechanism of action being developed for the treatment of MS. In animal models laquinimod crosses the blood brain barrier to potentially have a direct effect on resident CNS inflammation and neurodegeneration. The global Phase III clinical development program evaluating oral laquinimod in MS includes two pivotal studies, ALLEGRO and BRAVO.
In addition to the MS clinical studies, laquinimod is currently in Phase II of development for Crohn's disease and Lupus.
About Special Protocol Assessment (SPA)
A SPA is a written agreement between the FDA (Food and Drug Administration) and a drug sponsor intended to confirm that the clinical trial protocol is adequate to meet current scientific and regulatory requirements for a potential new drug application.
Source: Reuters (c) Thomson Reuters 2012 (09/08/12)