SelincroTM (nalmefene) is an orally administered opioid receptor ligand for the treatment of alcohol dependence. Unlike other treatments for this disease, SelincroTM is taken on an ‘as needed’ basis to reduce the desire to drink, thus offering patients a novel treatment option compared to traditional methods which are aimed at total abstinence and usually include intensive psychosocial therapy. Biotie has licensed global development and commercialization rights to nalmefene to H. Lundbeck A/S, a leader in CNS drug development.
In December 2011, Biotie?s partner Lundbeck submitted a marketing authorization application (MAA) through the centralized procedure to the European Medicines Agency (EMA) for SelincroTM. In December 2012, Lundbeck received a positive opinion from EMA’s Committee for Medicinal Products for Human Use (CHMP) recommending marketing authorization of SelincroTM for the reduction of alcohol consumption in adult patients with alcohol dependence who have a high level of alcohol consumption. (Stock Exchange Release 14 December, 2012)
About alcohol dependence
Alcohol dependence is a disease in which the afflicted person continually craves alcohol, is unable to limit his or her drinking, needs to drink greater amounts to get the same effect and has withdrawal symptoms after stopping alcohol use. Alcohol dependence also has potentially fatal consequences such as liver cirrhosis and cancer (footnote a), among others. As a result, this disease is one of the most serious health concerns in the western world, both socially and economically, with estimated associated costs to society of at least EUR 200 billion per annum. 10% of deaths and 25% of all emergency room admissions in the western world are directly alcohol related. According to the World Health Organization, there are 60 million people in Europe alone who are ‘riskful’ consumers of alcohol, which is categorized as alcohol consumption of 40–60 grams (5–6 standard drinks) by females and 60–100 grams (7–8 standard drinks) by males on a single drinking day. Despite this, alcohol dependence tends to be severely under-diagnosed with only approximately 13% of alcohol dependants receiving treatment, characterizing it as a large unmet medical need.
Currently, conventional methods of treating alcohol dependence require abstinence from drinking as a starting point - a high hurdle for an alcohol dependent patient. There are only a few pharmaceutical compounds that have received marketing approval to help alcohol dependent patients maintain abstinence. All these treatments, including psychosocial counseling measures, cannot prevent patients from relapsing and the long term prognosis remains poor. There are no approved therapies on the market yet to proactively help curb a person's urge to drink.
SelincroTM product profile
Selincro is a small molecule opioid receptor modulator that inhibits the reward pathway in the brain that reinforces the desire and craving for alcohol and other addictive substances. As a result, Selincro targets a novel principle in the treatment of alcohol dependence by removing a person’s desire to drink.
Selincro builds on a novel principle of treating alcohol dependence. Unlike existing therapies, treatment with Selincro is not aimed at keeping the patients from drinking. Instead, Selincro helps to control and limit the intake of alcohol. Selincro distinguishes itself by being available as a tablet formulation to be taken only according to need, ("as needed"), whereas existing pharmaceuticals must be taken continuously over a longer period of time and are aimed at maintaining abstinence.
Biotie has licensed global development and commercialization rights to nalmefene to Danish CNS specialist, H. Lundbeck A/S (Lundbeck). Lundbeck is an ideal partner for Biotie, as it has significant experience and a substantial track record in depression, a therapeutic area with many parallels to alcohol use disorders. Lundbeck’s specialist marketing force and its long-established relationships with prescribers in the relevant therapeutic areas will be important in driving a successful launch and maximizing the market potential for nalmefene.
Under the terms of the agreement with Lundbeck, Biotie is eligible for up to EUR 89 million in upfront and milestone payments plus royalties on sales. Further milestone payments are expected on commercial launch of nalmefene and on the product reaching certain predetermined sales.
Phase 3 program
Biotie has previously conducted three Phase 2 studies and two Phase 3 studies in alcohol dependence with nalmefene. The larger one of the previous Phase 3 studies, which investigated 400 alcoholic patients in Europe, demonstrated nalmefene's ability to significantly limit both the patient's average alcohol intake and the number of heavy drinking days (intake above 5 standard drinks of alcohol).
Based on the results of previous trials sponsored by Biotie, Lundbeck initiated three Phase 3 clinical studies in Europe in 2008. The program was completed in 2011, and results from the Phase 3 program were presented in March 2012 at the 20th European Congress of Psychiatry (EPA) in Prague, Czech Republic. Data from the three placebo-controlled Phase 3 studies (ESENSE 1, ESENSE 2 and SENSE) was discussed during the symposium. In addition, the ESENSE 1 study was presented as a poster by Prof. Dr. Karl Mann et al. Further details of the ESENSE 2 and SENSE studies will be presented at the Annual Research Society on Alcoholism (RSA) Scientific Meeting in San Francisco in June.
All studies were multi-centre, randomized, double-blind, placebo controlled, parallel group studies of 18 mg Selincro taken as needed in patients with alcohol dependence according to DSM-IV criteria. Patients were instructed to take one tablet on each day they perceived a risk of drinking alcohol, preferably one to two hours prior to the anticipated time of drinking. Medical advice and support to enhance motivation and adherence were included in all treatment arms in the studies. No abstinence treatment goal was imposed.
A total of 1,997 patients were randomized in the three studies, 604 patients in ESENSE 1 (298 on placebo, 306 on Selincro), 718 in ESENSE 2 (360 on placebo, 358 on Selincro), and 675 in SENSE (166 on placebo, 509 on Selincro).
The primary objective of the two identical six month studies ESENSE 1 and ESENSE 2 was to evaluate the efficacy of as-needed use of Selincro versus placebo in reducing the number of heavy drinking days (HDD) and the monthly total alcohol consumption (TAC) over a period of six months in alcohol-dependent patients. A heavy drinking day is defined as a day with a consumption of at least 60g alcohol for men and at least 40g alcohol for women. The primary objective of SENSE was to evaluate the long-term safety and tolerability of Selincro versus placebo over a period of 52 weeks in patients with alcohol dependence, as well as to evaluate the efficacy of Selincro versus placebo at six months. In all studies a wide range of secondary endpoints were assessed, including the proportion of responders based on drinking measures, alcohol dependence symptoms and clinical status, liver function, other laboratory tests and pharmaco-economic outcomes.
In ESENSE 1 and ESENSE 2, Selincro was superior to placebo in reducing the number of HDDs (p <0.05 in both studies) and TAC (ESENSE 1, p <0.05; ESENSE 2, p = 0.088) at month 6. In SENSE, Selincro was more effective than placebo (p<0.05) in reducing the number of HDDs and TAC at the majority of the time points studied, including 52 weeks, although not at month 6. In all the studies, the effect of Selincro as measured by HDD and TAC was evident already at month one and was maintained throughout the treatment period.
In ESENSE 1, the mean number of HDDs decreased from 19 to 7 days/month and the mean TAC decreased from 84 to 30g/day in the Selincro group at month 6. In the placebo group, the mean number of HDDs decreased from 20 to 10 days/month and the mean TAC decreased from 85 to 43g/day at month 6. Further, improvements in the secondary endpoints Clinical Global Impression and the liver enzymes GGT and ALAT were larger (p<0.05) in the Selincro group than in the placebo group at month 6.
In ESENSE 2, the mean number of HDDs decreased from 20 to 7 days/month and the mean TAC decreased from 93 to 30g/day in the Selincro group at month 6. In the placebo group, the mean number of HDDs decreased from 18 to 7 days/month and the mean TAC decreased from 89 to 33g/day at month 6.
In SENSE, the mean number of HDDs decreased from 15 days/month at baseline to 5 days/month at month 6, and further to 3 days/month at one year in the Selincro group. While the mean TAC decreased from 75g/day at baseline to 22g/day at month 6, and to 16g/day at one year. In the placebo group, the mean number of HDDs decreased from 15 days/month at baseline to 6 days/month at month 6, while the mean TAC decreased from 75g/day at baseline to 27g/day at Month 6, with essentially no further decreases for both endpoints at one year.
In all three clinical studies the overall safety profile of Selincro was consistent with observations and data provided in previous studies, resulting in a total clinical database of more than 3,000 individuals. The most frequent adverse events included dizziness, insomnia and nausea and these were mild and transient. The majority of these events had an onset within the first days after the initial dose, and then decreased with treatment continuation.
In December 2011, Biotie’s partner Lundbeck submitted a marketing authorization application through the centralized procedure to the EMA for Selincro. In December 2012, Lundbeck received a positive opinion from the CHMP, recommending marketing authorization of Selincro for the reduction of alcohol consumption in adult patients with alcohol dependence who have a high level of alcohol consumption.
Once approved, Lundbeck will provide Selincro as part of a new treatment concept that includes continuous psychosocial support focused on the reduction of alcohol consumption and treatment adherence.
The European Commission usually delivers its final decision on approval within 2-3 months of the CHMP recommendation. The decision will be applicable to all 27 European Union member states plus Iceland and Norway. Subject to the Commission's final approval and completion of pricing and reimbursement discussions, Lundbeck expects to launch Selincro in a number of European markets by mid-2013.