Getting cytisine licensed for use world-wide: a call to action

Most tobacco users live in low and middle income countries where stop smoking medicines are unavailable or unaffordable. There is an urgent need for action by key stakeholders to get cytisine licensed worldwide so that its life-saving potential can be realised. Effective tobacco cessation medicines are needed in low- and middle-income countries (LMICs), where most tobacco users live, but are often unavailable or unaffordable 1. Cytisine (an alkaloid found in some plants belonging to the Leguminosae family) could be a solution to this problem. Cytisine, like varenicline, is a partial agonist at nicotinic acetylcholine receptors (nAChRs) 2 with high affinity for the alpha-4 beta-2 nAChRs subtype, and aids cessation by reducing the severity of withdrawal and the satisfaction associated with tobacco use 3. However, there are a number of key differences between the two medications (Table 1). Evidence for cytisine's efficacy and effectiveness comes from several sources. Four systematic reviews (five trials, undertaken in central/eastern Europe, n = 3250) have found cytisine to be superior to placebo for short- and long-term abstinence from smoking 7-10, with a pooled relative risk at ≥ 6 months of 3.29 (95% confidence intervals = 1.84–5.90) 8. A New Zealand non-inferiority trial (n = 1310) found that cytisine was more effective than combination nicotine replacement therapy (NRT) at increasing 6-month quit rates 11. Cytisine is well tolerated when taken according to the recommended dose: adverse events reported in trials are typically non-serious and self-limiting gastrointestinal and sleep disturbances 7-11. Cytisine is cheaper than varenicline (Table 1), nortriptyline (~US$95 for a 12-week course), NRT (~US$112–685 for an 8–10-week course) and bupropion (~US$228–521 for a 12-week course) 4. Cytisine is affordable (even in LMICs) 12, it has the lowest cost per quality-adjusted life-year of all smoking cessation medications 13 and may be more cost-effective than varenicline 14. Since the 1960s cytisine has been available as a prescription-only or non-prescription smoking cessation treatment in central/eastern Europe. Cytisine is manufactured according to the principles of European Union (EU) Good Manufacturing Practice standards by two companies: Sopharma (Bulgaria) and Aflofarm (Poland), yet cytisine is currently authorized only by regulatory authorities for smoking cessation in four EU countries (Bulgaria, Poland, Latvia, Lithuania) and 13 non-EU countries (Azerbaijan, Armenia, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Moldova, Russia, Serbia, Tajikistan, Turkmenistan, Uzbekistan, Ukraine). Many LMICs will not licence cytisine unless it is first licensed in a reference country (namely Australia, Austria, Belgium, Canada, Denmark, Germany, Finland, Iceland, France, Ireland, Luxemburg, Holland, New Zealand, Norway, Sweden, Switzerland, United States, United Kingdom, Japan, Italy, Spain, Portugal) or is on the World Health Organization (WHO) Essential Medicines List. If cytisine is effective, cost-effective, affordable and well tolerated, why is it not licensed more widely? 4, 13, 15 A key reason is that Sopharma and Aflofarm have not sought regulatory approval actively outside central/eastern Europe. This could be because regulatory authorities such as the UK Medicines and Healthcare Products Regulatory Agency (MHRA), the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) may require further placebo-controlled trials of cytisine to be undertaken in western European and/or North American populations. However, there is little incentive for pharmaceutical companies to conduct such research, as cytisine is a generic drug. Potential investors may not see the opportunity for substantial return unless a patent can be attached; this would almost certainly increase the cost to consumers 15. Interestingly, Extab has recently obtained the rights from Sopharma to market a ‘new patent-protected version of Tabex (cytisine)’ outside central and eastern Europe, and is currently seeking regulatory approval in the United States, Japan and other major markets (Archived by WebCite® at http://www.webcitation.org/6iOWMRTDu). Extab's website states: ‘Following discussions with FDA and MHRA, a further large-scale clinical trial is in planning’ (Archived by WebCite® at http://www.webcitation.org/6iOWaLk4z). If regulatory approval is obtained, it remains unknown where the new version of Tabex will be priced in the market. What can be done now to promote wider marketing authorization and availability of the existing low-cost cytisine? Without pharmaceutical industry investment, trials required by the MHRA, EMA and FDA will rely upon public good funding to progress; such funding is difficult to obtain in a highly competitive research environment and is often insufficient to cover the costs of studies that would meet regulatory standards. For many LMICs, where cytisine has the potential to have the greatest impact, there are additional barriers to accessing tobacco cessation products. For example, tobacco cessation is not listed among the WHO ‘best buys’—a priority list of cost-effective interventions to tackle non-communicable diseases (NCDs) 16—despite being a leading risk factor in the WHO target of a 25% relative reduction in NCD mortality by 2025 17. Furthermore, tobacco control is key to achieving Goal 3 (Good Health and Well-Being) of the United Nations Sustainable Development Goals (Archived by WebCite® at http://www.webcitation.org/6iOWjGvM2). To date, international health donors have shown limited interest in tobacco cessation. If cytisine became available more widely, the presence of an in-class competitor to varenicline (which comes off patent in 2020) could exert a downward pressure on the price of both drugs. There is urgent need for action by key stakeholders to get cytisine licensed worldwide so that its life saving potential can be realized. The editorial was drafted initially by N.W., with input from all co-authors on subsequent versions. N.W. will act as guarantor. N.W., C.B. and J.B. have been involved in a clinical trial in which cytisine was supplied at no cost by the manufacturer, Sopharma/Extab Ltd, Bulgaria. N.W., C.B. and J.S. have also accessed cytisine tablets for pharmacokinetic/pharmacodynamic studies, which have been provided free of charge from Aflofarm, Poland and/or Sopharma/Extab Ltd, Bulgaria. In all instances the companies have had no role in the study design, data collection, analysis and writing and interpretation of the study findings. N.W. has had funding for her research in the past 3 years from the University of Auckland, the Health Research Council of New Zealand, the National Health and Medical Research Council of Australia, the Auckland Medical Research Foundation, the University of Malaya, Social Code Ltd, Waitemata District Health Board, the Heart Foundation of New Zealand and the New Zealand Ministry of Health. She has also received support for travel, accommodation, conference fees, honoraria and/or expenses from the Heart Foundation of New Zealand, the Society for Research into Nicotine and Tobacco and the University of Malaya. C.B. has had funding for his research, consultancy or travel as a speaker in the past 3 years from the Health Research Council of New Zealand, Moffit Cancer Centre, Commonwealth University of Virginia, University of Hong Kong, National University of Taiwan, University of Malaya and the New Zealand Ministry of Health. J.B. has undertaken fee-paid work commissioned for the University of Otago, Curtin University, University of Queensland, University of Sydney and the Pharmaceutical Society of New Zealand. She has been a paid speaker for the Pharmaceutical Society of New Zealand and received funding from the University of Auckland and University of Auckland UniServices. She has also received support for travel and conference fees and/or expenses from the Auckland Medical Research Foundation, the Maurice and Phyllis Paykel Trust, the University of Otago/International Scientific Acupuncture and Meridian Symposium, the Pharmaceutical Society of New Zealand and the National Institute of Complementary Medicine (Australia). She has also received royalties from Elsevier/Churchill Livingstone and the Authors’ Licensing and Copyright Association. H.M.R. has received investigator-led research funding and honoraria for speaking at educational meetings from Pfizer Inc. He has also received honoraria from Johnson and Johnson for speaking at educational meetings and an advisory board meeting. P.T. has undertaken paid consultancy for Aflofarm, a manufacturer of cytisine. M.R. has no conflicts of interest to declare. J.-F.E. has no conflicts of interest to declare. K.S. has received research funding from Pfizer (GRAND 2014) to conduct a smoking cessation trial. R.J.C. has had funding for his research in the past 3 years from the National Health and Medical Research Council of Australia and is supported by a Cancer Institute New South Wales Early Career Research Fellowship (GNT14/ECF/1-46). J.M.C.M. has been awarded a Pfizer Independent Grant for Learning and Change (IGLC), managed by Global Bridges (Healthcare Alliance for Tobacco Dependence Treatment) and hosted at the Mayo Clinic, to support free smoking cessation treatment training in addiction/mental health care units in Brazil (grant IGLC 13513957). P.S. has no conflicts of interest to declare. J.S. has had funding for her research in the past 3 years from the University of Auckland, Auckland Medical Research Foundation and the New Zealand Education and Research Foundation. She received research funding from Britannia Pharmaceuticals in 1997 to undertake research. She has also attended CME dinners sponsored by Reckitt Benckiser, Sanofi, Janssen Cilag, AlphaPharm and Invidior and was supported to travel to the International Harm Reduction Association conference in 2005 by Schering Plough. She has co-supervised a PhD student who had received funding from Janssen-Cilag, Eli Lilly, Astra Zeneca, Roche Diagnostics and Douglas Pharmaceuticals, but was not named on any of these grant applications. Her personal investments may include shares in pharmaceutical companies as part of a managed portfolio. She was awarded a University of Auckland Hood Fellowship in 2007. The Lion Foundation http://www.lionfoundation.org.nz/, a gambling charity which derives its money from gambling machines, is one of the major donors to this fund. She has received funding from the Alcohol Advisory Council (ALAC) of New Zealand to conduct a literature review. A.L.A.C. received a hypothecated levy on the consumption of alcohol. She is a Co-Principle Investigator on an investigator-initiated project funded by the Health Promotion Agency (NZ) which is a Crown Agency (http://www.hpa.org.nz/who-we-are). The HPA is funded from Vote Health, the levy on alcohol produced or imported for sale in New Zealand (hypothecated funding) and part of the problem gambling levy. N.A.R. has received a research grant and been a consultant (accepting no honorarium) to Pfizer.

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