general enquiries on this form should be made...
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General enquiries on this form should be made to:Defra, Science Directorate, Management Support and Finance Team,Telephone No. 020 7238 1612E-mail: [email protected]
SID 5 Research Project Final Report
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NoteIn line with the Freedom of Information Act 2000, Defra aims to place the results of its completed research projects in the public domain wherever possible. The SID 5 (Research Project Final Report) is designed to capture the information on the results and outputs of Defra-funded research in a format that is easily publishable through the Defra website. A SID 5 must be completed for all projects.
This form is in Word format and the boxes may be expanded or reduced, as appropriate.
ACCESS TO INFORMATIONThe information collected on this form will be stored electronically and may be sent to any part of Defra, or to individual researchers or organisations outside Defra for the purposes of reviewing the project. Defra may also disclose the information to any outside organisation acting as an agent authorised by Defra to process final research reports on its behalf. Defra intends to publish this form on its website, unless there are strong reasons not to, which fully comply with exemptions under the Environmental Information Regulations or the Freedom of Information Act 2000.Defra may be required to release information, including personal data and commercial information, on request under the Environmental Information Regulations or the Freedom of Information Act 2000. However, Defra will not permit any unwarranted breach of confidentiality or act in contravention of its obligations under the Data Protection Act 1998. Defra or its appointed agents may use the name, address or other details on your form to contact you in connection with occasional customer research aimed at improving the processes through which Defra works with its contractors.
Project identification
1. Defra Project code NF0612
2. Project title
Sustainable production of the natural product, galanthamine
3. Contractororganisation(s)
Institute of Grassland and Environmental Research Plas GogerddanAberystwythSY23 3EB
54. Total Defra project costs £ 52,274(agreed fixed price)
5. Project: start date................ 01 April 2005
end date................. 31 March 2006
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6. It is Defra’s intention to publish this form. Please confirm your agreement to do so...................................................................................YES NO (a) When preparing SID 5s contractors should bear in mind that Defra intends that they be made public. They
should be written in a clear and concise manner and represent a full account of the research project which someone not closely associated with the project can follow.Defra recognises that in a small minority of cases there may be information, such as intellectual property or commercially confidential data, used in or generated by the research project, which should not be disclosed. In these cases, such information should be detailed in a separate annex (not to be published) so that the SID 5 can be placed in the public domain. Where it is impossible to complete the Final Report without including references to any sensitive or confidential data, the information should be included and section (b) completed. NB: only in exceptional circumstances will Defra expect contractors to give a "No" answer.In all cases, reasons for withholding information must be fully in line with exemptions under the Environmental Information Regulations or the Freedom of Information Act 2000.
(b) If you have answered NO, please explain why the Final report should not be released into public domain
Executive Summary7. The executive summary must not exceed 2 sides in total of A4 and should be understandable to the
intelligent non-scientist. It should cover the main objectives, methods and findings of the research, together with any other significant events and options for new work.This project involved producing desktop review of the galanthamine supply chain and construction of a
financial model to describe the chain. Some experimental work was conducted to analyse galanthamine
in daffodil bulbs and provide baseline figures for the supply chain model. This work was described in a
technical annex to the review report. Each part of the project was reported to the National Non Food
Crops Centre(NNFCC) and Defra in free flowing text documents and (for the financial model) as a
Microsoft Excel spread sheet. What is reported in this Sid 5 form is a concise version of the original
desktop review and technical annex (both of which are provided as annex documents). The model, written
in Excel, is also submitted electronically as part of the final report.
Alzheimer’s disease is a common form of dementia with an estimated population of 15 million sufferers
worldwide and this number expected to treble by 2050. Alzheimer sufferers exhibit a gradual decline in
cognitive faculties with loss of memory, judgement and ability to comprehend the external environment.
These patients require considerable care and their inevitable disease progression can exert a heavy toll Alzheimer patients can be treated with a class of drugs, called acetylcholinesterase inhibitors. These
drugs slow the progression of the disease and alleviate many of the symptoms. One of these drugs is a
compound called galanthamine and is marketed in the UK as Reminyl by Shire Pharmaceuticals.
Galanthamine is an alkaloid compound found in plants such as daffodils and snowdrops and this natural
product was used in the original drug formulation. A synthetic route was found to produce galanthamine
which reduced the requirement for daffodil-sourced drug but the impending loss of patent protection for the
use of galanthamine as a drug treatment in Alzheimer patients may change this situation.
This report describes the current and historical UK supply chain for galanthamine production and sale for
production of the branded drug, Reminyl. The production of generic formulations of galanthamine is
discussed and a potential supply chain for a generic producer from UK-grown daffodils is outlined.
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Interviews with actual or possible suppliers for the galanthamine supply chain, the regulatory bodies and
patient organisations have been carried out and the intelligence gained incorporated into the report. Each
component of the supply chain has been considered and the commercial and legislative requirements of
the different parts of the chain reported, alongside possible hurdles and interactions between supply chain
members. Alternative routes to market, such as health supplements, are considered together with the
cost implications of related pricing strategy and legislative issues.
The technical component of this study is described in the Technical Annex to the report and used
commercially grown material from test plots supplied by Alzeim Ltd. to analyse levels of galanthamine in a
range of commercially-available daffodil varieties including the normal galanthamine stock, Carlton, from
upland and lowland sites in Wales. The level of galanthamine present in Carlton bulbs at the two sites has
also been analysed for variability, the distribution of galanthamine throughout the plant tissues determined
and the levels of compound compared with the plant growth cycle in time course experiments.
The financial feasibility of expanding the current supply chain has been modelled: particularly to consider
the effects of generic formulations on the price of galanthamine in a markets-based model. A production
and extraction-based model has also been constructed to describe the likely sensitivities of galanthamine
price with daffodil bulb price, extraction costs and extraction efficiency. These models showed that a UK
daffodil-based supply chain for the extraction and supply of galanthamine for generic drug manufacture is
feasible, that extraction efficiency has a considerable impact on the economics of the supply chain
process and that cost-effective research to increase the overall level of galanthamine in the daffodil bulb
stock would be beneficial.
Project Report to Defra8. As a guide this report should be no longer than 20 sides of A4. This report is to provide Defra with
details of the outputs of the research project for internal purposes; to meet the terms of the contract; and to allow Defra to publish details of the outputs to meet Environmental Information Regulation or Freedom of Information obligations. This short report to Defra does not preclude contractors from also seeking to publish a full, formal scientific report/paper in an appropriate scientific or other journal/publication. Indeed, Defra actively encourages such publications as part of the contract terms. The report to Defra should include: the scientific objectives as set out in the contract; the extent to which the objectives set out in the contract have been met; details of methods used and the results obtained, including statistical analysis (if appropriate); a discussion of the results and their reliability; the main implications of the findings; possible future work; and any action resulting from the research (e.g. IP, Knowledge Transfer).
Scientific Objectives (as set down in the contract)
There are three major objectives to this proposal as follows:
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1. To conduct a desktop review focusing on the economics, opportunities and constraints for developing a sustainable UK-based supply chain for the plant-derived natural product, galanthamine. Merigan Ltd will have a major role in the conduct of the review.
2. To produce a model of the supply chain to inform the industry about the potential for developing sustainable commercial production of galanthamine in the UK. Merigan Ltd will have a major role in the development of the model and contribute, under objective 1 above, to the conduct of the review.
3. To analyse the levels of galanthamine present in commercially-acceptable daffodil varieties grown on a relevant scale at upland and lowland sites using material provided from Alzeim’s trials. Data from this objective will contribute to inform the review and supply chain model described under objectives 1 and 2 above. IGER will be responsible for the design of these trials and the analysis (identification and quantification) of galanthamine.
These objectives were met and reported (in free flowing text) to the NNFCC and Defra in timely fashion. Both organisations received copies of the Desktop review, the Supply chain Model (as a Microsoft Excel spread sheet) and the Technical Annex. The results of the study were also presented to the Plant-Derived Phar5maceuticals meeting held at Rothamsted in may 2006. A fact sheet from that meeting is appended at the end of this report.
Method and research Plan
The project was conducted at IGER and included sub-contracts to two industrial partners, Merigan Research Services Ltd., and Alzeim Ltd. IGER was responsible for overall project management and the laboratory analysis of galanthamine in bulbs grown and provided by Alzeim Ltd. Merigan developed the Desktop Review and Supply Chain Model. Alzeim Ltd. also provided know how in relation to bulb growth, galanthamine extraction, purification and supply.
The project aims to acquire knowledge on the individual components of the current and proposed supply chain for galanthamine and, together with some proprietary data from Alzeim Ltd., produce a desk top review and supply chain model for the feasibility of establishing sustainable production of galanthamine in the UK.
The approaches used to achieve these deliverables relate to the three objectives described above and were as follows:
Objective 1: desktop review
1. Identify critical steps in the supply chain required for delivery of galanthamine to the end-user and consider their impact on current or prospective providers of each part of the supply chain.
2. Consider critical issues for the commercial feasibility of each of the individual steps and processes in the supply chain. These will include: (a) selection criteria for optimal germplasm, (b) agronomic characteristics of bulb yield, persistency and cultivation methodologies(c) suitability and extent of land resource (d) galanthamine yield and extraction/purification procedures for the compound, (e) routes to market and the supply chain beyond primary production (f) marketing and distribution networks and (g) consultation with pharmaceutical and nutraceutical companies, pressure groups and the National Health Service in relation to uptake and use.
3. Examine the links between the processes within the supply chain and attempt to identify likely weaknesses and possible solutions. Examine the environmental and social impact of the processes described compared with the existing supply routes.
Objective 2: supply chain model4. Construct a model with qualitative and quantitative representations of the opportunities, any weaknesses
and potential economic, environmental and social benefits of a UK-based galanthamine supply chain. Data from approach 5, below, together with data previously generated by Alzeim Ltd. and IGER will be included in a quantitative model of the supply chain. The assumptions for the quantitative component of the model will be based on intelligence gathered in approach 2 above. The descriptive component of the model will be based on the outcome of approaches 1 and 3.
Objective 3: galanthamine analysis (technical annex)5. Analyse commercially prepared plant material for the level of galanthamine within bulbs and any
variability between varieties with growing site and agronomic practice. The analysis is via HPLC in comparison with a known galanthamine standard for quantitation. For quality assurance purposes, mass spectrometric confirmation of the presence of galanthamine will be included for some samples.
Desktop Review
The desktop review is presented in annex 1 and a condensed version is presented here.
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Alzheimer’s diseaseAlzheimer’s disease is a form of dementia that accounts for approximately 50% of all dementia cases. It has an age-related incidence with only 1.1% of UK sufferers from the 45-64 age group (age group is 22.9% of the population) rising to more than 39% in the ≥85 age group (age group is 1.89% of the population). These patterns are found throughout the developed World with an estimated 15 million Alzheimer’s sufferers worldwide; a number predicted to treble by 2050 (Forman et al., 2004). An average sized health authority in the UK has 6048 dementia patients (500 000 population total, 1.2% incidence) and of these 3327 would be Alzheimer patients with 1996 falling into the mild-to-moderate definition pertinent to this study.
Alzheimer sufferers exhibit a gradual decline in cognitive faculties with loss of memory, judgement and ability to comprehend the external environment (Orgogozo et al., 2004; Aguglia et al., 2004). Behavioural difficulties and alteration of mood often result from onset of the disease with a requirement for significant hands-on care, often from family and friends, in the early to mid-stages of disease progression.
Prevalence and Size of Patient PopulationThere are several sources of recent information on prevalence of Alzheimer’s disease in the EU, US and throughout the developed World. These include the OECD report on dementia care by Moise et al (2004) the Europa and Eurostat websites, an article on the projected US populations by Hebert et al (2003) and a Delphi consensus study on estimates of incidents and World population by Ferri et al. (2005).
While symptoms and disease progression is relatively consistent between regions of the developed World, the prevalence of the disease in less developed regions and in different age group of similar regions is difficult to quantify precisely because of differences in the way that data has been gathered. All datasets show a substantial increase in prevalence with advancing age. Differences in estimates of prevalence rates can cause quite significant variation in estimates of patient populations, e.g. the OECD study (Moise et al., 2004) gives a total US Alzheimer’s population of 2.1million compared with the estimate of 4.5million from Hebert et al. (2003) and 3.4 million for the total dementia population from the Delphi consensus study (Ferri et al. 2005). All sources agree however that the population is large and growing at a considerable rate, with an interesting perspective on the shift in world pharmaceutical markets in the future considering the rapid growth in dementia in developing countries such as India and China, where numbers of dementia sufferers are expected to increase by 300% between 2001 and 2040 compared with a 100% increase in the developed world (Ferri et al. 2005).
The population dynamics of the developed world are such that despite low projected increases in overall population size, age demographics show a marked shift towards a more elderly population. For example the EU-25 group of countries had an over-65s population of 74.7million in 2003, at 16.3% of the total compared with only 14.4% total population in 1993. This would at a conservative estimate put the EU-25 over-65s population at 100M by 2050 with an even larger increase in the 85-plus age group at particular risk of Alzheimer’s disease. Hebert et al. (2003) have estimated that the number of over-85s in the US will quadruple by 2050 with Alzheimer patient populations increasing by nearly 3-fold from 4.5 to 13.2 million.
It is clear that the patient base for Alzheimer drugs will increase substantially for the foreseeable future unless new anti-Alzheimer’s drugs are found which not only alleviate the symptoms of the disease but actually prevent the occurrence and development of the illness.
Disease Pathology
The brain of Alzheimer patients change in chemistry and histology throughout the course of the disease. An abnormal protein ( amyloid protein)) is found at elevated levels in brain and cerebrospinal fluid. This amyloid protein is accumulated and deposited in plaques around nerve cells in the brain, eventually leading to cell death, and in the walls of small blood vessels within the brain. Another protein, ‘tau’, which is normally present within cells helping to organise the cytoskeletal microtubules, is also accumulated abnormally. Tau is phosphorylated abnormally in Alzheimer patients and accumulates within nerve cells as neurofibrillary tangles.
Post-mortem histological analysis of brains from Alzheimer patients show a general loss of nerve cells and their synapses giving “spaces” and an atrophied appearance to areas of the brain where nerve cells would be expected. Levels of the neurotransmitters serotonin, acetylcholine, norepinephrine and somatostatin are all found to be decreased in the brains of Alzheimer patients while glutamate levels are usually elevated.
The causal mechanism of Alzheimer’s disease is not known definitively but three main hypotheses have been proposed and collectively, these have informed the direction of drug discovery in the area of Alzheimer disease.Current Therapies
Acetylcholinesterase InhibitorsThese act on the enzyme that breaks down acetylcholine in the brain as part of the normal control mechanism for brain function. Alzheimer sufferers have reduced levels of acetylcholine due to death of acetylcholine-producing
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cells in the brain. In general, reducing the breakdown of acetylcholine relieves some of the symptoms and slows progression of the disease by several months and in some cases by up to a year and a half.
Galanthamine appears to have dual action whereby it not only acts as an acetylcholinesterase inhibitor but also acts on the target brain cell to strengthen its response to available acetylcholine.
Figure 1 Chemical structures of the three anti-Alzheimer’s Disease drugs in common usage: galanthamine, rivastigmine and donepezil (respectively).
Four acetylcholinesterase inhibitors have received approval for clinical use in early- to mid-stage Alzheimer’s disease: tacrine, donepezil, rivastigmine and galanthamine (three are shown in Fig 1). Tacrine the first in class gained FDA approval in 1993 but has since been largely withdrawn due to adverse side effects. The three remaining drugs, donepezil, rivastigmine and galanthamine have fewer adverse side-effects and appear relatively safe in general use.
Dosage and FormulationGalanthamine HBr is dispensed as Reminyl or Razadyne (US) in prolonged release capsules with 8, 16 or 24 mg equivalent of free galanthamine base; in colour-coded tablets with 4, 8 or 12 mg equivalent of free galanthamine base or in 4 mg/ml oral solution. The capsules are designed for single daily dosing whereas the tablets and oral solution should be administered twice daily. The drug is given at a lower starting dose of 8 mg daily and is then increased over a period of 4 weeks to an initial maintenance dose of 16 mg daily for at least 4 weeks and then may be increased if beneficial to a final maintenance level of 24 mg daily. Rivastigmine tartrate is produced as Exelon in 1.5, 3, 4.5 and 6 mg capsule strengths plus a 2 mg/ml oral solution. The dosing is twice per day and is increased slowly with an initial daily dose of 3 mg for at least 2 weeks then similarly spaced incremental increases to 6, 9 and if tolerated 12 mg per day. Donepezil hydrochloride is produced as colour coded tablets with a once daily dosing of 5 mg which may be increased to 10 mg after 4-6 weeks if tolerated and beneficial.
NMDA Receptor AntagonistsThe 2nd class of drug approved for treatment of Alzheimer’s disease is the NMDA receptor antagonists (N-methyl-D-aspartate mimics the natural neurotransmitter glutamate). The only compound approved to date is memantine hydrochloride which is marketed as Namenda in the US, as Axura in Germany and as Ebixa in other parts of Europe including the UK.
Memantine hydrochloride was approved by the European Medicines Agency for treatment of moderate to severe Alzheimer’s disease in 2002 and by the FDA in 2003. The drug was developed by Merz Pharmaceuticals GmbH and is licensed to Forest Laboratories Inc. in the US and to Lundbeck A/S in other parts of Europe and Mexico. It has not yet received NICE approval for use within the NHS in the UK.
Dosage and FormulationMemantine is produced as 5 and 10 mg tablets and as a 2 mg/ml oral solution for twice daily dosing. The approved dosage is 10-20 mg per day but as for the compounds above the dose should be titrated with an initial dose of 5 mg once daily increasing to two 5 mg doses after 2 weeks, then 15 mg and finally a maintenance dosage of 20 mg daily if tolerated and beneficial. The costs for this drug are comparable to the acetylcholinesterase inhibitors at £74.20 for 28 days supply for the tablets and £66.25 for 25 days of the liquid format (www.alzscot.org).
Drugs in the Pipeline The market for Alzheimer treatment drugs is relatively young in comparison to more established areas such as cardiovascular disease but given the projected age demography it is not surprising that there is a substantial amount of interest in drug development. A number of new compounds are progressing through the drug discovery and development process at this time. The two anti-Alzheimer drug classes with approved drugs available, the cholinesterase inhibitors and the NMDA receptor antagonists, are represented in the drug pipeline.
Axonyx, an American biotechnology company are developing esterase inhibitors with a dual mode of action that are also considered to reduce the levels of -amyloid protein. The first of these, Phenserine, was recently (Nov 2005) withdrawn from development after failure in phase III trials. A single isomeric form of the phosphoaminoacid
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is now in phase I and a butyrlcholinesterase, BNC, is at the late pre-clinical (IND) stage. Novartis, the producers of Rivastigmine (Exelon) are planning to file an application in 2006 for an extended release formulation as part of the life cycle management of their acetylcholinesterase brand.
Forest Laboratories and Merz are developing Neramexane (phase III) for treatment of moderate to severe Alzheimer’s disease to replace Memantine within its product line when this approved first-in-class drug becomes available generically (2009-2011). They are also gathering data for approval of Memantine in mild Alzheimer’s disease in conjunction with treatment with vitamin E and/or approved esterase inhibitors.
Compounds with a primary activity against the amyloid protein are the focus of R&D by several companies. These compounds are often anti-inflammatory and alter the processing of the amyloid protein reducing its propensity to form plaques within the brain. Two of these compounds are in phase III clinical trials, Neurochem’s Alzehemed and Myriad Genetics’ Flurizan. Eli Lilly have a compound with a similar mode of action in phase II trials. It is thought that these compounds, if effective, will not only reduce the symptoms of the disease but should alter its progression by reducing the severity of plaque formation and its consequences for the disease pathology.
One drug in development is the AAB001 humanised monoclonal antibody (Elan Pharmaceuticals/ Wyeth) that appears to act as a passive immunisation against the amyloid protein products found in the plaques and removes them via a different mechanism to the compounds above. This monoclonal has replaced an earlier active immunisation programme (using peptide AN-1792) which was discontinued at phase II due to adverse safety events caused by inappropriate immune responses in some patients. Elan is also developing a new, more specialised vaccine product which is in the preclinical stage of development.
Sanofi-Aventis are developing compounds that promote the action of neural growth factors in the brain; one of these in phase III and the other in phase II trials. It has long been considered that reduction of growth factors in the brain of Alzheimer patients makes them more likely to lose neurones by cell death during the disease pathology and so it is hypothesised that these drugs would provide protection against the cell death. One of these, Xaliproden, is also thought to act as a serotonin agonist. Sanofi-Aventis have a third compound in trials for Alzheimer’s disease with a similar agonist activity.
Eli Lilly are testing one of their drugs approved for use in Attention Deficit/Hyperactivity Disorder (Strattera) to determine whether co-treatment with acetylcholinesterase inhibitors provides additional benefits in symptom relief (phase IV).
There has been an observed link between taking cholesterol-lowering statin drugs and a reduced risk of developing Alzheimer’s disease. There is also preliminary evidence for beneficial effects in patients with mild Alzheimer’s disease which is now undergoing further analysis via two phase III trials using Pfizer’s Lipitor and Merck’s Zocor (latter trial conducted by National Institute on Ageing).
Market Size and Future Market ProspectsThe IMS figure for annual sales of Razadyne in the US were approximately $247 for the year to April 2005 (Pharmacy choice). The sales of galanthamine appear to be increasing with royalties payable to Shire Pharmaceuticals increasing by 14% in the year with Q3 2005 royalties at $12.9M (www.shire.com). The latest data freely available puts the UK sales of Reminyl at £7.9M ($13.04 M at 1.65 $ to sterling rate) in 2003 as part of a total market of £53 m for anti-AD medication. The rate of growth in UK markets may be lower than US markets due to the uncertainties associated with the NICE recommendations.
NICE is the National Institute for Health and Clinical Excellence and it is responsible for considering the cost-effectiveness of medicines for prescription under the NHS. It has recently changed its recommendations regarding the use of anti-acetylcholinesterase drugs, such as galanthamine, in mild-to-moderate Alzheimer’s disease. The guidelines now state that patients already receiving these drugs should continue to receive them from the NHS but that in the future new patients will only receive them once the disease has progressed to the moderate stage.
These recommendations do not alter the licence terms for this drug class but reflect a decision made on economic grounds. Further dialogue is ongoing between the drug companies, patient groups such as the Alzheimer’s Society and NICE over these issues. The onset of generic forms of these drugs (see below) with the expected reduction in pricing is also likely to bring about a difference in the cost-effectiveness arguments and should increase the availability of the drugs to the widest group of patients possible. Discussions with the Alzheimer’s Society have indicated that they would welcome the widest availability of these drugs to a clinically appropriate patient population.
Galanthamine as a Generic drug
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Generic medicines are pharmaceutical products that contain an active ingredient that is not protected by patents. Generics are generally sold with little if any promotion and tend to rely on cost compared with branded competitors as a major driver for their sales.
The primary use patent for galanthamine in treatment of Alzheimer’s Disease was due to expire on 15th January 2006 but has an initial extension from the FDA until the 14th December 2008. This means that a generic competitor is likely to launch any product in early 2009 with development and registration proceeding in 2005/2006 or shortly thereafter.
An early indicator of activity in the filing of applications for marketing approvals for generic forms of a drug is the submission of Type II Drug Master Files (US FDA definitions) by companies likely to produce the API (Active Pharmaceutical Ingredient). A range of companies have filed Drug Master Files on galanthamine to the FDA since December 2004 in readiness for the ANDA application approvals for generic galanthamine. These companies are based around the World and form part of the new potential supply chain for galanthamine.
Current Supply Chain for Galanthamine
The following sections describe the historical formation of the UK daffodil-based supply chain for galanthamine, the development of an alternative supply chain from a synthetic chemical route and the possible formation of a new UK supply chain to serve a generic manufacturer.
Background and History to DevelopmentShire Pharmaceuticals approached Macfarlan Smith in the early 1990s to develop the bulk extraction and supply chain process for plant-derived cGMP (current Good Manufacturing Process) produced galanthamine for their proposed anti-Alzheimer’s drug, Reminyl.
There was at that time some history of galanthamine extraction from Turkish snowdrops in Eastern Europe, particularly Bulgaria. The supply of galanthamine from these wild-grown snowdrops was likely to be in the 300 kg per year region rather than the thousands of kilogrammes likely to be required for the new drug.
Alternative sources of galanthamine-containing biomass were tested and the agronomically more manageable daffodil was chosen as the best source of galanthamine for commercial extraction.
Macfarlan Smith developed an extraction process and assisted Johnson and Johnson (Janssen) with the preparation of the Drug Masterfile Document for submission to the FDA in preparation for Reminyl’s approval and launch in 2000. Dedicated laboratory space was built in Edinburgh for galanthamine extraction at the Macfarlan Smith site. A later approval was gained for Reminyl prepared using synthetic galanthamine from Sanochemia in 2001 in the US (see section below). The demand for naturally produced galanthamine was now not as high as initially envisaged when no chemical synthesis route was available and Macfarlan Smith withdrew from the market for supply of daffodil bulbs for galanthamine production after its contract for supply ended in 2003 (Johnson Matthey Annual Report 2003; http://www.matthey.com/AR03/phmat.html ). Galanthamine is now listed again as one of the products produced by Macfarlan Smith on their website (www.macsmith.com , March 2006).
Sanochemia Pharmazeutike AGSanochemia are an Austrian chemistry-based pharmaceutical company with a patent for the synthetic production of galanthamine; they are based in Vienna and were founded in 1990. They filed their original process patent in 1995 and gained the final approval for the synthetic route in 2000; this expires in 2014. They have recently purchased three other galanthamine patents for €6.85M.
Sanochemia have been working with Johnson and Johnson (Janssen) and Shire Pharmaceuticals since 1997 and have worked with them for successful registration of the synthetic galanthamine as a component of Reminyl in the EU in 2002.
Sanochemia have the rights to develop galanthamine derivatives in a variety of applications and are keen to develop these in the areas of stroke, epilepsy and Parkinson’s disease. They have also been involved in clinical trials for use of galanthamine in limited alternative applications, namely post-operative delirium.
Shire PharmaceuticalsShire is a successful growing business, founded in the UK in 1986 to market calcium products for the osteoporosis market. It has grown by acquisitions and in 2001 via a merger into the third largest UK- based pharmaceutical company with sites in the US, Canada and Europe. Shire’s total revenues for 2004 were $1.36 bn growing steadily from the value of $0.64 bn in financial year 2000.
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Shire has a wide ranging portfolio with interests in acquiring compounds in phase II or later for development and marketing particularly in the areas of CNS, GI tract and renal treatment. It has several products for ADHD (attention deficient hyperactivity disorder) in development and is also developing compounds in niche areas with few competitor drugs such as the metabolic diseases, Hunters and Gauchers.
Shire developed galanthamine as a treatment for mild to moderate Alzeimer’s in cooperation with Janssen (Johnson and Johnson). They originally co-marketed the product Reminyl in the UK and Ireland with Janssen-Cilag but now have sole marketing rights after agreeing $30M terms with Janssen-Cilag. Shire acquired the galanthamine use patents from Synaptech and hold rights to the compound worldwide except for North America, Japan, Korea, Taiwan, Thailand and Singapore. Johnson and Johnson pay Shire royalties on sales for North America and the rest of the World.
Potential and Current UK / EU Supply Chain
This section outlines both the current and possible future members of the galanthamine supply chain and suggests likely individual organisations that either have an interest or would be suitable partners in any future enterprise.
Daffodil Production in the UKMuch of the information on daffodil production systems in the UK was derived from a meeting with Gordon Hanks (HRI) in May 2005.
Daffodils are planted in raised ridges (similar to potatoes) in an almost continuous band by machine. Daffodil planting machines come in different sizes according to field sizes and scale of operation. Growers in the Eastern part of the UK tend to use larger scale machines due to the size of their fields compared with the Cornish and Isles of Scilly growers. An average planting rate in the UK is 15 t bulbs ha-1 but this could easily be increased to 20 t ha-1 with minimal negative impact on yield per individual bulb but with the advantage of higher planting density in terms of land use and manpower.
The main sites for daffodil production within the UK are East Anglia, Cornwall (and Scilly Isles) and Angus with an estimated 4500 ha of commercial acreage.
In the past, the Eastern regions were predominantly bulb suppliers with the cut flower market being quite separate but that distinction is now blurred with many producers supplying both bulbs and cut flowers.
Part of the reason for this changing market perspective is the decrease in market price for bulbs; on average daffodil bulbs were fetching £500 per tonne 8-11 years ago whereas the 2004 price was £150-200 per tonne and the current price is around £300-350 per tonne (Farm gate price, 3 separate grower telephone reports). The UK market is estimated at 20-30 000 tonnes p.a.
The UK method of growing daffodil bulbs differs from other countries in that we adopt a 2-year down approach. For example, bulbs planted in August 2005 would not be lifted until June 2007. This has advantages for the grower in terms of land utilisation and labour costs plus it overcomes a major hurdle for combining the cut flower and bulb production process into one. Before planting, bulbs are routinely treated with hot water to reduce the pathogen load on the bulb, in particular the stem nematode, Ditylenclius dispaci . Bulbs are soaked at 46ºC for 3h which is sufficiently close to the lethal temperature of 50ºC, for this length of incubation, to damage flower developing within the bulb. So in our example of a bulb planted in Aug 2005, after heat treatment the flower produced in Spring 2006 would be poor but this would be reversed by Spring 2007.
A disadvantage with the 2-year down method is that crops can become prone to diseases such as fungal or bacterial rots which would be largely avoided with a one-year cycle. This is particular important during times of market depression where bulbs may be left for more than 2 years. The merging of cut flower and bulb production provides flexibility and has allowed larger companies to manage their portfolio more easily by balancing income with the two products according to the state of the market.
The economics and logistics of daffodil growing requires intensive input on three occasions during the growing season(s) once the bulbs are set: (1) flower picking, (2) bulb lifting and finally after lifting (3) cleaning and grading of the bulbs for resale or replanting. These processes are semi-mechanised but still require considerable amounts of labour for short periods of time. There are small lifting machines that usually are accompanied by workers removing clods of earth and breaking up clumps of bulbs to minimise the downstream processing required. Alternatively if fields are of sufficient size then there are large machines requiring considerably less labour which will be less discriminating in the removal of earth and bulb clumps from the harvested material. The sorting and cleaning of bulbs will still be required but can be done at a central yard which may be more efficient for larger organisations.
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The yield of bulbs from daffodils is at least 100%, i.e. bulbs planted at 20 t ha-1 will yield bulbs at lifting at 40 t ha-1, but this would be considered a poor return with 150% representing a more reasonable yield.
The grower would routinely treat the bulbs with 3 applications of herbicide and 5 of fungicides per season. The grower may occasionally treat with an insecticide to try and combat the large narcissus fly although there are no really effective compounds available. Good practice would recommend “rogueing” removal of poor or aberrant forms from the daffodil plots during the flower picking season.
The most vigorous cultivars suited for growing in the UK are the widely available commercial varieties. Golden Harvest and Carlton make up 40% of the UK stock with 20-30 other main varieties covering the remaining stock. There are several hundred types of daffodils available but not usually at commercially relevant levels. This would be an important factor when choosing galanthamine-rich varieties outside of these varieties as daffodils are slow to multiply.
GrowersThere are many small producers of bulbs and flowers but many of these have formed cooperative organisations or entered into marketing deals with the larger companies. In Cornwall there are 1750 ha daffodils grown with a market size of £2.4 M for bulbs and £10.7 M for cut flowers annually (www.chenet.org.uk/horticulture/industry.php). Major names in Cornwall are Fentongollan (www.flowerfarm.co.uk), Cornish Bulbgrowers Ltd. and Winchester Growers (see below). In East Anglia, Nocton Ltd provide up to 20% of the UK cut flower supply, together with Winchester growers and ex-Angloflora which is now part of Grampian Growers (see below)
Winchester Growers are based in Spalding, Lincolnshire with an additional major site near Penzance, Cornwall. They farm approximately 400 ha of daffodils producing 120 M stems and approximately 5000 tonnes bulbs annually. www.winchestergrowers.com
Grampian Growers are based at Logie, Montrose in Angus and are a cooperative of 18 bulb growers that produce between four and five thousand tonnes of bulbs annually. They actively export their bulbs, in particular to North America and have certified virus-free stock. www.grampiangrowers.co.uk
Extraction FacilitiesThe UK industry has sufficient expertise and available facilities to make commercial extraction of galanthamine of the appropriate scale and quality feasible. A possible European player has been added due to their known interest in galanthamine.
Macfarlan SmithMacfarlan Smith is based in Edinburgh and is now part of the Johnson Matthey group. The company has a long history in the extraction of pharmaceutical agents from botanicals and is particularly renowned for its work on extraction of opiates. Macfarlan Smith was the original providers of daffodil-extracted galanthamine for Reminyl and contributed to the original drug master file submitted to the FDA by Johnson and Johnson. They are one of the eight companies that have filed a drug master file with the FDA for production of generic galanthamine (filed Feb 2005) together with Omnichem from Belgium and Ivax Pharmaceuticals from the Czech Republic. There are also files submitted from two Chinese and two Indian manufacturers.
BotanixBotanix is an extraction specialist with headquarters in Kent. This company has grown from a background of hop extract supply to the brewing industry. It has broadened its product range to include a wide variety of natural products such as essential oils and has contract extraction facilities. Botanix has particular skills in the use of liquid and supercritical carbon dioxide as an extraction solvent. Extraction of galanthamine from daffodils using carbon dioxide has not been reported to date but may be applicable and commercially feasible.
Wilde and Co.Wilde and Co specialise in extraction of oils from plant material using hydrofluorocarbons at low temperatures. They have a large extraction plant in Thailand but have a product development facility at Thirsk and are a possible UK extractor for galanthamine from daffodils.
OmnichemOmnichem is based in Belgium with a manufacturing capability in Wetteren. It has a long history in the production of active ingredients from botanicals and has provided active pharmaceutical ingredients, APIs, particularly alkaloids (galanthamine is an alkaloid) from natural sources for several decades. It is now part of the Japanese Ajinomoto Company group and is known to have investigated the production of galanthamine both by submission to the FDA and also by negotiations with UK-based daffodil growers.
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Within the EU there are several companies with considerable experience in extraction of natural products from plants in commercially relevant quantities, e.g. Pierre Fabre in France and Indena in Italy.
Marketing AgentsUnited Farmaceuticals is a wholly-owned subsidiary of the UK marketing cooperative United Oilseeds. It was formed in 2003 to exploit the markets for pharmaceutically active ingredients from crops. A major focus is the supply of morphine poppies to Macfarlan Smith for opiate production. United Farmaceuticals have purchased daffodils for galanthamine production and have recently reported that they have doubled their hectarage for the Summer 2006 harvest. The majority of their galanthamine supply comes from the daffodil variety Carlton, with most of the bulbs destined for export to the EU for extraction (Annual report United Oilseeds, Autumn 2005; notes from meeting with John Manners, 2005).
The bulb industry contains several strong grower cooperatives to market and supply their produce. One of these, Lingarden, has demutualised and adopted a slightly different business model with the original members now holding shares in the trading company. Since July 2005 Lingarden has been part of Flamingo Holdings which also controls a range of cut flower suppliers and growers throughout the EU and Africa. (http://www.lingarden.com/ ). Lingarden provided contract-grown daffodil bulbs to Macfarlan Smith during the 1990s, when Macfarlan Smith were under contract for Reminyl production
Contract ManufacturersThere is a wide range of pharmaceutical manufacturing capability in the UK, a few of the possible solid oral dose and liquid oral dose suppliers are described below. Almac Pharmaceutical Development and Manufacturing Services have a MHRA licensed and FDA approved manufacturing facility in Northern Ireland. Ashton Pharmaceuticals, near Manchester, is part of the Inyx group and has a cGMP manufacturing plant (14 000 m2) which is compliant with MHRA, EU and Asia regulatory requirements. Penn Pharmaceuticals based in Tredegar, Wales have a small manufacturing capability of 40 m2 suitable for galanthamine tablet or capsule production. Pharmapac UK have a well-respected manufacturing operation at the ex-Bristol-Myers Squibb site on the Wirral.
Generic Companies with UK Manufacturing CapabilityAlpharma, now part of the Actavis group of companies, have a large manufacturing plant in Barnstaple, Devon which is capable of producing up to 5 bn tablets p.a. Johnson and Johnson instigated legal action against Alpharma regarding Alpharma’s challenge to their protected galanthamine production as outlined above in the Generics section.
There are a range of other UK-based generics companies some with manufacturing capabilities in the UK, others acting as sales and marketing organisations for their parent companies. Some of the available manufacturing space within this sector is accessible as contract manufacturing facilities. The British Generics Manufacturer’s Association is a useful starting point for information on this sector (http://www.britishgenerics.co.uk ). Two of these manufacturing plants are part of the Teva group and another is a representative of Dr Reddy’s Laboratories, both companies have filed ANDA applications for galanthamine.
Branded Manufacture of ReminylThe production of Reminyl by Janssen for supply to Shire Pharmaceuticals or other Johnson and Johnson partners takes place at the Janssen Pharmaceutica Pharmaceuticals plant in Geel, Belgium (http://www.pharmaceutical-technology.com/projects/geel/ ).
Reminyl® supplied to UK pharmacies comes from Shire Pharmaceuticals if bought directly. The advent of a free market within the EU means that wholesalers will sometimes import medicines from other EU states into the UK. This process called parallel import requires a licence from the MHRA. Many wholesalers have applied and been granted such licences for the parallel import of Reminyl®. Parallel importers buy medicines from another EU country where the price of the product has been set by the government to be lower than in the UK. The medicines are often repackaged in the UK and sold into the usual supply chain. The Association of the British Pharmaceutical Industry estimates that more than one in eight prescriptions is serviced from parallel imports into the UK.
Drug Wholesalers The drug wholesalers known to be used by Shire include AAH Pharmaceuticals, Unichem, Phoenix Healthcare Distribution and Boots.
The wholesale market in the UK is dominated by AAH Pharmaceuticals and Unichem who control over sixty percent of total sales. Boots occupies an unusual position in that it is a major wholesaler within the sector by virtue of its very large share of the total prescription market (11% of NHS scripts dispensed) serviced by its retail pharmacies. The sector is one that is predominantly a logistics-driven business with regular, reliable supply of products necessary for the hospital and independent pharmacies.
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AAH Pharmaceuticals is the UK’s largest pharmaceutical wholesaler with over thirty percent of the total market for high street pharmacies and hospital dispensaries. Their business is a large logistics operation with 19 depots and over 600 vehicles distributing 27000 different products.
Unichem plc is part of the Alliance Unichem group formed in 1997 to encompass the broad aspiration of supply of medicines, surgicals and support services for pharmacies in the UK and since 2000 throughout the EU. Another member of Alliance Unichem, Alliance Pharmacy, is the third largest pharmacy group in the UK. Unichem was formed in 1938 and are based in Surrey with eleven regional distribution centres to provide the twice daily deliveries to their 5700-strong client base.
Phoenix UK is part of the large Phoenix Group headquartered in Mannheim, Germany. It was formed by the acquisition of several UK-based wholesalers in the late 90s and early 00s and the major East Anglian acquisition in Feb 2005. Phoenix UK is based in Runcorn in Cheshire with good GB-wide geographical coverage supplied by its 14 depots. Phoenix UK has a close association with the over the counter (OTC) supplier, Numark plc, which is owned by the independent pharmacies and is an equal partner in a joint venture marketing Numark products.
Health Food/Supplement Route to MarketAn alternative route to market that could be adopted by a galanthamine producer would be a food supplement marketed through the internet or via health food outlets. Two major players in this market, Holland and Barrett and Boots were approached but neither was prepared to discuss this option for the UK market. A spokesperson for the MHRA indicated that galanthamine would not be covered by the Herbal Medicines Directorate and that any product produced using daffodil-produced galanthamine could not be marketed with any health claims unless it underwent the appropriate licensing procedure.
Galantamind is a capsule formulation of galanthamine produced from a natural source which is available on the internet from US sources. It claims to support memory function but does not specifically mention Alzheimer’s disease. The capsules contain 8mg galanthamine and the dosing information is as for the branded product. This product is available for $66.14 for 90 capsules with further discounts available for bulk purchases, a comparable amount of branded galanthamine would cost £175.50 (using an exchange rate of $1.75:£1 correct March 2006) approximately 4.6 times more expensive.
Alternatives to Daffodils as Natural Sources of GalanthamineDaffodils are the natural choice for galanthamine-containing biomass for UK suppliers but alternative crops are available outside of the UK. In Eastern Europe the Bulgarian Pharmaceutical Group Ltd. produce Nivalin which is galanthamine extracted from the snowdrop Leucojum aestivum (www.bpg.bg/nivalin ). The Chinese pharmaceutical company Yixin Pharmaceuticals use a range of spider lily plants from the genus Lycoris, in particular Lycoris radiata and trade through a Czech site (www.galantamine.cn ).
Critical Analysis of Galanthamine Supply Chain
Factors affecting Galanthamine Levels in Daffodil Bulbs (from information derived via the technical part of the contract)The data used in this section of the report for levels of galanthamine in bulbs and information on changes to the levels throughout the growing season were derived from the technical part of the project which is outlined in full in the Technical Annex (annex 2) and presented in abbreviate format below.
The aims of the technical part of this project were as follows:
To analyse the levels of galanthamine present in a range of commercially acceptable daffodil varieties grown on a relevant scale at upland and lowland sites using material provided from Alzeim’s trials.
To determine the optimum harvesting time to maximize galanthamine accumulation at upland and lowland sites.
To analyse commercially prepared plant material for the level of galanthamine within bulbs.
The technical component of the this study used commercially grown material from test plots supplied by Alzeim Ltd. to analyse levels of galanthamine in a range of commercially available daffodil varieties including the normal galanthamine stock, Carlton, from an upland and a lowland site in Wales. The level of galanthamine present in Carlton bulbs at the two sites was analysed for consistency and level of accumulation across the season and within the plant growth cycle in time course experiments.
Methods for the extraction and analysis of galanthamine in leaves and bulbs of snowdrop, snowflake and daffodils were established in previous studies using widely accepted methodologies and a high purity analytical standard from Sigma Chemical Co. A compound indistinguishable from the galanthamine standard in terms of its
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chromatographic properties by normal–phase thin layer chromatography (relative mobility, fluorescence and response to alkaloid reagents) and by high performance reverse-phase liquid chromatography (HPLC) (retention time and ultra-violet + visible spectra), was identified and quantified (against the galanthamine standard) in plant extracts from different tissues of the three species. The structure of galanthamine in bulb extracts of daffodils var Carlton was confirmed by mass spectroscopy following HPLC, by comparison with the authentic standard.
Four experiments were performed. In experiments 1 and 2, a comparison was made of galanthamine accumulation in up to seven commercial daffodil varieties grown at up to three sites in Wales differing in altitude and soil type. The third experiment considered galanthamine accumulation in relation to the developmental stage of the bulb. The fourth experiment quantified galanthamine accumulation in different parts of the plant (flower bud and scape, upper and lower leaf portions, outer, middle and inner bulb scales, bulb base plate and roots) of variety Carlton. ) the variety, Carlton,
The level of galanthamine found in individual bulbs was highest in the variety, Carlton (as previously determined), but varies considerably with replicate bulb samples from both sites analysed showing three-fold differences at some time points. However, the variability did not appear to show any particular phasing nor was it confined to one sampling site or time-point and presumably reflects the inherent variability often seen in levels of plant secondary products (see Technical Annex)
The level of galanthamine in the daffodil bulbs grown at the two sites analysed in the technical study appears to be highest before flowering. The time-course data suggests that the maximum levels may be attained soon after germination of the bulb.
Harvesting of bulbs at this point, before flower formation, while providing the highest concentration of galanthamine in the bulbs, would have logistical and economic consequences for daffodil production. These factors and the possible advantages or disadvantages that may arise from such a change in harvest date are outlined below:
Higher levels of galanthamine are likely to improve extraction efficiency Bulbs lifted early would have low mass so growers would expect premium Increased drying costs for early-lift bulbs Additional machine and labour costs of separate harvest Inclement weather more likely to hinder early harvest Growers lose flower income from bulbs harvested pre-flowering
Factors affecting Choice of Supplier by Supply Chain MembersThe branded or generic manufacturer (i.e. the ultimate industrial customer in the supply chain) will probably look to the supplier of extracted galanthamine to ensure maintenance of high standards in the chain below them, from middleman and/or directly to the grower. Factors likely to influence choice of supplier for the extracted product and the raw bulb material are outlined below.
The bulb growers need to be able to provide Carlton stock in sufficient quantities, hundreds and not tens of tonnes, to supply most or all of the galanthamine extractor’s requirements. They are unlikely to wish to deal with many bulb suppliers and so may choose to buy from a small number of large growers or deal with a single agent for their entire annual purchase. In either case the provenance of the bulbs is important both for extraction efficacy and for quality assurance and traceability of the medicinal product. The galanthamine extractor may wish to secure their supply of bulbs for future years and require a guaranteed growth and delivery contract at a predetermined price from chosen bulb growers.
The company responsible for extraction of the galanthamine should ideally be familiar with the principles and practice of medical grade natural product extractions, if possible with experience of cGMP. Their facilities should have been inspected by the medicines agency, MHRA, or be suitable for such inspection. The extractor needs to be technically capable of developing an efficient extraction process at a reasonable cost. Experience in the support of regulatory submissions would also be a useful attribute.
Critical Points in Financial Feasibility of Supply Chain An understanding of the financial sensitivities of the supply chain is necessary to be able to comment on the factors influencing the likelihood of maintaining or increasing the current UK daffodil-derived production of galanthamine for drug use. Two simple financial models have been constructed using a ‘top-down’, market-led approach to determine galanthamine price and an extraction and raw materials cost based ‘bottom-up’ model to determine the cost of galanthamine production. The models are available as an Excel spreadsheet and show all assumptions made during their construction.
The market model has been subjected to sensitivities consistent with price deflation and altered gross margins for pharmaceutical producers in generic manufacture whereas the extraction model has been analysed to determine
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the effect of changes in bulb price, extraction efficiency, extraction costs and galanthamine levels in the starting material.
Market Model (with values derived from the supply chain model developed as part of the contract)The key drivers for this model are likely to be changes in drug pricing and expected margins of generic manufacturers compared with current branded product. Galanthamine is an expensive API and would be expected to contribute a significant cost to the total for the formulated product, particularly for simple tablet formulation, making the 30-90% figures modelled for this parameter sensible. Similarly it is normal for the market price of drugs to fall by up to 30% with generic competition; thus the market model analysis below considers a 10-40% reduction in cover price.
The gross margin expected by a branded pharmaceutical manufacturer is at least 75% which is reflected in the market model, whereas generic producers would consider 55% or 65% gross margin to be desirable as their overall gross margins are more likely to be in the range of 45-50%, for example the generics manufacturer Teva Pharmaceuticals reported an overall gross margin of 47% in 2005 whereas Shire Pharmaceuticals’ margin was 87% for 2004.
Figure 1 Galathamine Cost Comparsion
Galanthamine price vs. total price for all market costs and gross margins
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http://www.tevapharm.com/pdf/12909ACL.PDF , http://www.shire.com/shire/uploads/reports/Annual_Report_2004.pdfFigure 1 shows some examples of the maximum price payable for galanthamine from the market model sensitivity analysis. The permissible costs for a branded-manufacturer level of gross margin (75%) at full price and discounted by 30% is shown together with the comparable figures at a more normal generic manufacturer’s gross margin of 55% Clearly the proportion of total manufacturing costs derived from the galanthamine price is an important factor in this calculation of affordability, however as stated previously above in a simple formulation such as tablets the cost of the active pharmaceutical ingredient (API) would account for the vast majority of the total costs (70-90% are reasonable figures).
This analysis shows that there is considerable opportunity for a normal market adjustment to take place in the price of a generic galanthamine drug but still maintain a profitable market sector for galanthamine producers. For example, under the conditions assumed by the model, a reduction in current drug cover price by 30% at a generic-type gross margin of 55% and a moderate 70% figure for the galanthamine proportion of total drug production costs gives a top level of figure of £17800 per kg galanthamine.
Extraction ModelModelling of the cost of galanthamine production shows that efficiency of extraction is a key driver when considering the economic feasibility of the process. The parameters varied in the sensitivity analysis have been adjusted to give the most accurate picture possible considering the relative lack of available published data on these parameters (Figure 2).
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The bulb price has been considered both at its current level of £300-350 per tonne, a slight premium for Carlton at this time due to market demand, up to an elevated level which could be envisaged if harvesting practices were changed to reflect the maximum temporal concentration of galanthamine in the bulbs and the associated premium required by growers.
Figure 2 Production Costs in Relation to Extraction Efficiency
Production costs vs extraction efficiency
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Figure 2 shows data for £550 per tonne extraction costs. The data points are for bulb costs £350 or £700 per tonne with data from both the high and low galanthamine level assumptions.
The extraction costs have been modelled for between £250 and £950 per tonne with wide ranging differences in the extraction efficiencies between 20 and 80% Figure 8 shows the production costs for a process running at 40% extraction efficiency. Again this analysis shows that the relationship with the variable parameter, extraction costs, is linear and that increasing the overall galanthamine level in the bulbs would greatly increase the economic attractiveness of the process. More complex possibilities such as changes in relative extraction efficiency, which are likely to occur with an elevated galanthamine starting level, have not been included in the modelling process although it is possible to account for such changes manually in the model.
The cost of bulbs, extraction costs and amount of galanthamine present in the bulb raw material all show substantial effects on the final cost of galanthamine production but do so in a linear, or close to linear, fashion. However the extraction efficiency as would perhaps be expected shows a non-linear relationship with cost and it is clear that of any single factor the extraction efficiency is crucial for an economical process (Figure 7).
Figure 3 Production Costs in Relation to Extraction Costs
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Production costs vs extraction costs
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Figure 3 shows data for 40% extraction efficiency. The data points are for bulb costs £350 or £700 per tonne with data from both the high and low galanthamine level assumptions.
Figures 3 – 4 (above and below respectively) show that given a reasonable extraction efficiency (40% used in the model) the production costs for galanthamine can be managed with substantial variation in extraction and bulb costs. However it is also clear that the economics of the process would be considerably enhanced if the levels of galanthamine were consistently at the higher level modelled (450 g per tonne)
Increasing the basal level by cultivar selection does not seem to be feasible at this point unless a hitherto untested daffodil type shows itself to be a higher producer than Carlton. If a variety was found to be a high producer it would not really be beneficial in the short to medium term unless it was already grown on a considerable scale due to the very slow multiplying times of daffodils, or alternative lab-based methods for the multiplication were viable. Alternative agronomic approaches may be worth considering, such as the early lifting regime suggested above and modelled here or completely different approaches to daffodil propagation, such as abiotic or biotic post harvest stress or hydroponics to optimise galanthamine accumulation.
Figure 3 Production Costs in Relation to Bulb Price
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Figure 4 shows data for £550 per tonne extraction costs. The data points are for extraction efficiencies of 30 and 60% with data from both the high and low galanthamine level assumptions.
The process is clearly feasible at a commercial level at this time hence the interest from a variety of generic manufacturers in the UK, other EU states and countries outside of the EU, in filing for abbreviated drug approvals once Reminyl is out of patent. A Chinese manufacturer offered medical grade galanthamine at $40 000 per kg
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which is approximately £25 000 per kg and the ‘rule-of-thumb’ within the industry states that a good estimate of EU-based manufacturing costs can be gained by the price offered by Chinese pharmaceutical suppliers.
In Summary Extraction efficiency is key to the process Increase in galanthamine levels is highly desirable
Minimal parameters to produce galanthamine at £10 000 per kg given assumptions from model High galanthamine – efficiency ≥30% and bulb price ≤ £700 per tonne Low galanthamine – efficiency ≥50% and bulb price ≤ £400 per tonne.
Factors altering the Market in the Future There are a variety of factors that may alter the dynamics of this supply chain in the near and mid-term, these have been discussed above but are also summarised below:
New anti-Alzheimer’s drugs replacing galanthamine Use of daffodil alkaloids as a route to semi-synthetic drugs in this or other applications Wider prescribing of galanthamine recommended by NICE due to improved cost-benefit data Development of new cultivation or post cultivation methodologies to increase the level of galanthamine in
bulbs
Future ResearchThe supply chain study and descriptive model of the feasibility of establishing commercially grown daffodil bulbs as raw material for the production of galanthamine, indicates that a major impact on the economics of galanthamine production could be made by increasing the levels of galanthamine from current maximum levels of 0.2%, towards the 2% level found for total alkaloids.
Total alkaloid levels in the bulbs of all the varieties tested ranged from 1-2% dry weight whereas galanthamine levels varied from zero (in the majority of varieties) to no more than 0.2% in Carlton. It is evident therefore that while daffodils as a species have the potential biosynthetic capacity for high levels of galanthamine synthesis, currently in the majority of varieties the endogenous biochemical pathway is towards the accumulation of intermediates such as haemanthamine or non–galanthamine type alkaloid end products, such as tazettine, or lycorine (illustrated in Fig 1). It can also been seen that many minor structural alterations (epimerisations, isomerisations, demethylations ect) to the galanthamine core structure can occur giving rise to at least 10 galanthamine type derivatives which accumulate to different extents in different varieties.
In order to increase galanthamine levels and decrease the accumulation of other alkaloids, a major research gaol must be to understand the developmental, environmental and nutritional factors which direct the biochemical pathway towards galanthamine and away from non-galanthamine structures or galanthamine derivatives. This will require both a fuller understanding of the relationships between galanthamine biosynthesis, metabolism and degradation, and the accumulation of structurally related and structurally non-related alkaloids, both during dormancy break in spring and during galanthamine accumulation at the end of the growth cycle, as well as the ability to manipulate both he nutritional and environmental growth conditions of the bulbs. This latter requirement can be met by conducting controlled experiments in hydroponic culture where the environmental and nutritional stresses can be applied and linked to detailed analysis of the alkaloid spectrum of the bulbs.
References to published material9. This section should be used to record links (hypertext links where possible) or references to other
published material generated by, or relating to this project.
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Aguglia, E., Onor, M. L., Saina, M. and Maso, E. (2004) An open-label, comparative study of rivastigmine, donepezil and galantamine in a real-worldSetting. Current Medical Research and Opinion, 20, 1747–1752.
Ferri, C., Prince, M. et al. (2005) Global prevalence of dementia: a Delphi consensus study. The Lancet, 366, 2112-2117.
Forman, M.S., Trojanowski, J.Q. and Lee, V.M-Y. (2004) Neurodegenerative diseases: a decade of discoveries paves the way for therapeutic breakthroughs. Nature Medicine, 10, 1055-1058.
Grundman, M., Petersen, R.C., et al.(2004) Mild cognitive impairment can be distinguished from Alzheimer disease and normal aging for clinical trials.Arch Neurol, 61, 59-66
Hebert, L.E., Scherr, P.A., Bienias, J.L., Bennett, D.A. and Evans, D.A. (2003) Alzheimer disease in the US population. Arch Neurol. 60 1119-1122.
Loy C., Schneider L. (2004) Galantamine for Alzheimer's disease. The Cochrane Database of Systematic Reviews, Issue 4. Art. No.:CD001747.pub2. DOI: 10.1002/14651858.CD001747.pub2.
Moise, P., Schwarzinger, M., Um, M-Y. and the Dementia Experts’ Group (2004) Dementia Care in 9 OECD Countries: A Comparative Analysis. OECD Health Working Papers. http://www.oecd.org/dataoecd/10/52/33661491.pdf
Orgogozo, J-M., Small, G.W., Hammond, G., Van Baelen, B. and Schwalen, S (2004) Effects of galantamine in patients with mild Alzheimer’s disease. Current Medical Research and Opinion 20, 1815–1820
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