Date: 2014-05-23
Type of information: Negative opinion for the granting of a Market Authorisation in the EU
Product name: Nerventra®
Compound: laquinimod
Therapeutic area: Neurodegenerative diseases
Action mechanism: 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.
Company: Active Biotech (Sweden)
Disease: relapsing-remitting multiple sclerosis (RRMS)
Latest news: * On May 23, 2014, Teva Pharmaceutical Industries and Active Biotech announced that the Committee for Medicinal Products for Human Use's (CHMP) confirmed its January 23, 2014 opinion to recommend against Nerventra® (laquinimod) approval for the treatment of relapsing-remitting multiple sclerosis (RRMS) in the European Union (EU) at this time. Both companies remain committed to the Nerventra® (laquinimod) clinical development program for multiple sclerosis (MS) and are focused on evaluating the CHMP feedback to determine potential next steps. To further confirm the benefits of Nerventra® on disability progression, Teva is conducting the CONCERTO trial, the largest MS trial with disability progression as the primary endpoint. The ongoing CONCERTO trial is the third Phase III study in RRMS and explores daily doses of NERVENTRA 0.6 mg and 1.2 mg. In addition, Teva is investigating the potential of Nerventra® in progressive forms of MS. The first trial for this indication is planned to be initiated soon. In addition to the MS clinical studies, studies are planned to evaluate the efficacy, safety and tolerability of Nerventra® in other neurodegenerative diseases including Huntington's disease. At the time of the initial recommendation, the CHMP had concerns about results from animal studies showing a higher occurrence of cancers after long-term exposure to the medicine and noted that a similar long-term cancer risk could not be excluded in humans, especially when considering that the way the medicine works in the body is unclear. There was also a possible risk (again from animal studies) of effects on the unborn baby when the medicine is taken by pregnant women. The CHMP noted that the risk could not be excluded with current data and that animal studies suggest that some of the 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. During the re-examination, the CHMP considered advice from an expert group in neurology. The expert group advised that the risks seen in animal studies could have been acceptable if a clear benefit was seen in clinical studies, although a strict pregnancy prevention scheme would have been required. The CHMP noted that the effect of the medicine in preventing relapses was modest, and though its effect in slowing the worsening of disability was encouraging it still needed to be confirmed. Therefore the Committee concluded that the benefits of Nerventra at the dose studied were not sufficient to outweigh the potential risks in patients with relapsing remitting MS and maintained its recommendation that the medicine be refused marketing authorisation. * On February 13, 2014, Active Biotech has confirmed that Teva has requested a re-examination of the CHMP's opinion on laquinimod. The company has explained that the CHMP's opinion was based on the view that laquinimod's positive effect on reducing relapses did not outweigh the potential risks. Although the CHMP found that laquinimod has a positive effect on slowing disability in MS patients, this finding had no impact on the decision. In the risk assessment, the CHMP focused on findings in animal studies, performed in parallel with the pivotal clinical trials, relating to the potential risk of fetal damage and the potential increased risk of cancer. None of these effects have been observed in the comprehensive patient material, comprising 7,490 patient years in total, with some patients being exposed for more than seven years and tolerated treatment well. The ongoing pivotal Phase III study CONCERTO continues according to plan. Results are expected 2016. Teva plans to initiate clinical trials in primary progressive multiple sclerosis (PPMS). At this time, Teva has decided to postpone further clinical development of laquinimod for the treatment of Crohn's disease until a clearer clinical strategy has been defined. * On 23 January 2014, the Committee for Medicinal Products for Human Use (CHMP) has adopted a negative opinion, recommending the refusal of the marketing authorisation for Nerventra® (laquinimod)intended for the treatment of multiple sclerosis. The exact way Nerventra® works is not known, but it is believed to act as a modulator of the immune system. By modulating the immune system it is expected to help control the inflammation and the damage to nerves, thus helping to reduce symptoms and the worsening of disability in patients with MS. The effects of Nerventra® were first tested in experimental models before being studied in humans. Teva also provided results of two main studies in patients with relapsing-remitting MS. One of the studies involving 1,106 patients compared Nerventra® with placebo (a dummy treatment), while the second study in 1,331 patients compared Nerventra® with placebo and another medicine used to treat MS, interferon-beta 1a. Both studies lasted two years and the main measure of effectiveness was based on the reduction in the number of relapses per patient per year (what is known as the ‘annualised relapse rate’). The CHMP has concluded that the risk-benefit profile of Nerventra® is not favorable at this time.The CHMP had concerns about results from animal studies showing a higher occurrence of cancers after long-term exposure to the medicine and noted that a similar long-term cancer risk could not be excluded in humans, especially when considering that the way the medicine works in the body is unclear. There was also a possible risk (again from animal studies) of effects on the unborn baby when the medicine is taken by pregnant women. 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. Although the medicine was shown to slow the worsening of disability, the medicine’s effect on relapses was modest. 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. Teva Pharmaceutical Industries and Active Biotech have announced that they 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. 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. * On December 20, 2013, Active Biotech has announced that its collaboration partner Teva Pharmaceutical Industries has been notified that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has not reached a final decision for laquinimod for the treatment of relapsing-remitting multiple sclerosis (RRMS). It is anticipated that the CHMP will issue an opinion at its January, 2014 meeting. * On July 17, 2012, Active Biotech has announced that the European Medicines Agency (EMA) has completed the validation process for the marketing authorization application (MAA) of laquinimod for the treatment of relapsing-remitting multiple sclerosis (RRMS). The completion of the MAA validation process and acceptance for review now leads to the formal scientific review process by EMA's Committee for Medicinal Products for Human Use (CHMP). The MAA submission is supported by a pooled analysis of data from the two global Phase III clinical trials in RRMS involving more than 2,400 patients treated for two years, the ALLEGRO and BRAVO trials. Teva and Active Biotech have already presented several series of data on the results of these two pivotal studies and results from the Phase III ALLEGRO study have been recently published in the March 15 issue of The New England Journal of Medicine. The acceptance of the EMA filing for review triggers a milestone payment of $ 5 million to Active Biotech from its partner Teva Pharmaceuticals. Additionally, Active Biotech and Teva continue to work with the FDA to determine the regulatory path forward for laquinimod in the U.S.
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Pediatric exclusivity UE: OTC status: Other news:
