drug rediscovery: clash between old and older ?
TRANSCRIPT
Clash between old and older ?Some considerations
Presenter Chris MulderGastroenterologist
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Agenda• Introduction• Drug rediscovery Model Case IBD
– Current therapy and pharmaceutical needs– Safety – Efficacy– Availability
• Regulatory aspects– Clinical Research
– Investment
– Pharmaco-economics
– Authorisation
• Summary
Introduction VUmc
• Prof. dr. C.J.J. Mulder• Gastroenterologist• Head of departement
• Expertise Coeliac disease, IBD, GI-malignancies, Auto-immune Liver diseases, drug rediscovery 6-Tg, 2-CDA
• Drug rediscovery: 2-CDA, 6-Tg, Dapson, Budesonide
• Chairman Dutch Society of Gastroenterology
Introduction
•The concept of Drug Rediscovery:
Don't throw away old shoes, before you have new ones
5
Introduction (Ctn’d)
• Knowledge + Experience + Curiosity lead to new applications of old “drugs”
• Just Off-label use of old drugs or Creating evidence base
• Example: the use of 6-Tg in IBD
6
Thiopurine family
1950 Thioguanine / Lanvis®
1951 Mercaptopurine / Purinethol®
1957 Azathioprine Imuran®
1988 Nobel prize for this
Who is she?
Her name is Gertrude Elion:
Nobel Prize 1998
Thiopurines in IBD
State of the art therapy - L Derijks 2005 :
• Thiopurines have proven efficacy in IBD. • Initial response efficacy is reasonably well sustained with remission
rates of 95%, 69% and 55% after 1, 3 and 5 years respectively.• AZA and 6-MP efficacy in induction of remission in active Crohn’s
with OR : 3.5. • Thiopurines have steroidsparing effect. • Combination of AZA with prednisolone is superior to prednisolone alone [2,
7].
PhD 2005
Lindqvist Appell and Haglund 2009
Sorry: too much information
Metabolism of thiopurines
De Boer et al. 2006
Family of thiopurines
Azathioprine
6-Mercaptopurine
6-Thioguanine Escape Drug
(off label)
Azathioprine in Europa
6-Mercaptopurine in USA
Maintenance Therapy
(ECCO-guidelines)
Failure of thiopurines(AZA / 6-MP)
30-40 % of IBD patients
discontinues the use
due to therapeutic failure or the
development of adverse events
CM: << 5 yrs 50 % stops Jahrap et al IBD 2010
Metabolism of thiopurines
– ®
De Boer et al. 2006only one metabolic step
?
®
®
Toxicity of thiopurines
Dose dependent adverse events ( 20 %)
– General malaise 11 %
– Infections 7,4 %
– Hepatitis 0,3 – 1,3 %– Myelotoxicity 1,4 – 5,0 %
Derijks et al. 2006
CM: In Crohn you start MAB’s ?
Toxicity of thiopurines
Dose independent adverse events (2%)
– Rash – Fever – Artralgia – Pancreatitis 1,4 – 3,3 %
Derijks et al. 2006
CM: We have alternatives
TPMT determination ?
Too much money,
it doesn’t help you
Toxicity prevention
TPMT and metabolism
TPMT: a key enzyme
High TPMT activity:• High concentration of 6-MMP =Liverproblems• Low concentration of 6-TGN = Ineffective
treatment
Low TPMT activity :• Low concentration of 6-MMP• High concentration 6-TGN
.
• N=262 AZA treated adult IBD patients• Leucopenia in 4,6 %• Frequency of mutant TPMT alleles was significantly
higher in the myelotoxic group (20,8 % versus 4 %)
• N=72 AZA treated paediatric IBD patients• Leucopenia in 2,8 %• TPMT status did not explain adverse events
Myelotoxicity and TPMT
Zelinkova et al. 2006 de Ridder et al 2006
Does is prevent to
xicity?
TPMT determination ?
• Myelotoxicity may be avoided• Dose adjustment according to
TPMT status• Cost-effective
Winter et al. 2005
VUMC : too expensive , doesn’t protect
Therapeutic drug monitoring ?
CM: TDM is what we prefer.
Toxicity prevention
Literature 6-TGN > 490 Increased risk on
myelotoxicity
6-TGN < 235 Less efficacy
6-MMP > 5700 Hepatotoxicity
Dubinsky 2000, Al Hadithi 2004, Jahrap IBD 2010
TDM conclusions
• Dose adjustment according to metabolites
• Evaluation of compliance
• Role in clinical practice needs to be established
We can’t work without in VUMC
Toxicity yes : “what to do?”
When to start 6-TG ?
Azathioprine (Imuran®)
1957
6-Mercaptopurine (Purinethol®)
1956
6-Thioguanine (Lanvis®)Leukemia
1950 Gertrude Elion Nobel prize1988
Azathioprine (Imuran®)
1957
6-Mercaptopurine (Purinethol®)
1956
6-Thioguanine (Lanvis®)Leukemia
1950
T6-G : only for hematologists?
Efficacy 6-TG treatmentTrials
Patients(numbers
)
Duration(weeks)
6-TG Dose(mg/day)
Toxicity(%)
Response
(%)
Dubinsky et al. 2001
10 16 20 0 70%
Herrlinger et al. 2003a 16 26 20-40 50 88%
Herrlinger et al. 2003b 37 26 40-80 16 57%
Bonaz et al. 2003 49 52 20 10 79%
Qasim et al. 2007 40 34 40 33 73%
Efficacy 6-TG treatmentTrials
Patients(numbers
)
Duration(weeks)
6-TG Dose(mg/day)
Toxicity(%)
Response
(%)
Dubinsky et al. 2001
10 16 20 0 70%
Herrlinger et al. 2003a 16 26 20-40 50 88%
Herrlinger et al. 2003b 37 26 40-80 16 57%
Bonaz et al. 2003 49 52 20 10 79%
Qasim et al. 2007 40 34 40 33 73%
Is good!
Tolerability 6-TG treatment
40
8
05
10152025303540
Median t reat ment durat ion(months)
6-TG cont inuat ion6-TG w it hdraw al
31 (27% )
82 (73% )
P<0.001
n=113 ; Mean daily dose: 0.25 – 0,35 mg/kg
245 treatment years
• 2003 : 16/26 = 62% NRH however
> 40 mg
26 out of 111
90 % pre-6TG hepatotoxicity
Paediatric
Dubinsky et al, 2003
• 2003 : 16/26 = 62% NRH however
> 40 mg
26 out of 111
90 % pre-6TG hepatotoxicity
Paediatric
Dubinsky et al, 2003Study: th
is intoxicated everything.
• Azathiopurine is sufficient in 50%
• 6-MP has 20 % less side-effects
• 6TG = Lanvis is good in 90 % of
AZA/6MP intolerant patients
Read: M.L. Seinen etc in 2010
Journal of Digestive Liver Diseases
Clinical recommendations
CM: Money issue 1 year 6-Tg: < $ 1.000
• Azathiopurine is sufficient in 50%
• 6-MP has 20 % less side-effects
• 6TG=Lanvis is good in 90 % of
AZA/6MP intolerant patients
Read M.L. Seinen etc in the next issue of
Journal of Digestive Liver Diseases
Clinical recommendations
Cheaper than MAB’s MABS : > $ 20.000 year
Dosages• Azathioprine (Imuran ®)
• 2 – 2.5 mg/kg/daily
• 6-Mercaptopurine (Purinethol ®)• 1 – 1.5 mg/kg/daily
• 6-TG (Lanvis®)
• 0.3 mg/kg/daily VUMC in A’dam
Dosages• Azathioprine (Imuran ®)
• 2 – 2.5 mg/kg/daily
• 6-Mercaptopurine (Purinethol ®)• 1 – 1.5 mg/kg/daily
• 6-TG (Lanvis®)
• 0.3 mg/kg/daily VUMC in A’dam
2012 N > 800 patients on 6-TG in the Netherlands
Toxicity on classic thiopurines: 6-Thioguanine (Lanvis®)Lanvis®)
Option after adverse events due
to classical thiopurines
Less toxic metabolites, more 6-TGN
At 1 year: > 80% continued 6-TG use
Less than $ 1.000 per year
TG vs AZA/6MP
• Therapeutic drug monitoring:– Compliance control– During toxicity or exacerbation of disease– 6-Tg is useful
Clinical recommendations
CM: At least once a year
This will help you a lot in the United States
Seinen ML et al JGLD 2010 september
Regulatory aspects
• Clinical Research– Combination of treatment with clinical research– Recue medication
• Investment – Drug rediscovery is not sponsored by
pharmaceutical industry– Drug rediscovery is not enthusiastically
absorbed in academic setting (not easy to come in Lancet)
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Regulatory aspects (C’tnd)
• Pharmaco-economics
• Authorisation
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Summary
Drug rediscovery helps patients, however is a disaster to
re-registrate and distribute
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none presentNRH 94 % 6%
de Boer et al. 2008
Prevalence of NRH in IBD ( Non AZA users )
• Non-thiopurine users
• IBD surgery
• Biopsy during operation
• N=130
6-TG 2008 N de Boer
• Absence of nodular regenerative hyperplasia after low-dose 6 thioguanine maintenance therapy in inflammatory bowel disease patients N.K.H. de Boer, P.E. Zondervan, L.P.L. Gilissen, G. den Hartog, B.D. Westerveld, L.J.J. Derijks, E. Bloemena, L.G.J.B. Engels, A.A. van Bodegraven, C.J.J. Mulder
• Gepubliceerd in Digestive & Liver Disease 40 (2008) 108–113
6-TG 2008 N de Boer
• Conclusion:“We have demonstrated that low-dose 6-thioguanine maintenance therapy in inflammatory bowel disease patients is not likely to be associated with induction of nodular regenerative hyperplasia. The induction of nodular regenerative hyperplasia appears to be 6-thioguanine dose or 6-thioguaninenucleotides level dependent.”
6-Thioguanine and NRHAuthor Daily
dose mgTotal dose Tx mo 6TGN-
levelNRH on biopsy NRH %
Dubinsky 2003 ? >40 14 gram 9-12 ≈1250 16/26 62%
Seiderer 2005 40-80 - - -
8/45 ? 16/45
18% / ? 36%
Ferlitsch 2007 40 → 10 27 gram 38 -
6/24
↑HVPG25%
Teml 2007
40 → 20- 28 -
Def 6/60Pro10/60
27%
Gilissen 2007 20 - 36 705 0/13 0%
De Boer 2008 20 22.5 gram 38 564
0/28?2/28
0%
Ansari 2008 40 - 44 807 0/11 0%
Cumulative risk of NRH %
months after starting AZA833 3221874at risk :
0
1
2
0 12 24 36 48 60 72 84 96 108 120
Conventional thiopurines and NRH
• 37 Cases / 36 centres (France, Austria)
• 1994 and 2005
– Median time AZA : 48 mo (6-187)
– Cumulative risk • 0.5% at 5 years• 1.25% at 10
years
Vernier-Massouille, 2007
Conclusies:
1. IBD is een risico factor mbt NRH
2.6-TG, azathioprine (thiopurine derivatives) ook een, dosis afhankelijke, risico factor
3.Groot aantal andere risicofactoren (leeftijd, geneesmiddelen gebruik)
6-TG EU Working Party• 2005 de Boer 6 TG WP Ref [17]
• “Low-dose 6-thioguanine may still be considered as a rescue drug for maintenance of remission in IBD patients failing and/or intolerant to all evidence-based conventionaltherapies including mesalamine, AZA/6-MP, MTX and infliximab, and in whom surgery is thought to be inappropriate”
• “Application has to be restricted to a clinicalresearch setting.”
6-TG 2010 van Asseldonk• Prolonged thioguanine therapy is well tolerated and safe in the
treatment of ulcerative colitis Dirk P.van Asseldonk, BindiaJharap , DirkJ.Kuik , Nanne K.H.de Boer , Barend D.Westerveld , Maurice G.V.M.Russel, FrankJ.G.M.Kubben, Ad A.vanBodegraven, ChrisJ.Mulder Gepubliceerd in Digestive and Liver Disease Received 18 September 2009 - Accepted 23 July 2010
• Cohort IBD patienten die 6-TG gebruiken van 2001 – 2009
• Conclusie: “Long-term use of thioguanine appears to be well tolerated and relatively safe in ulcerative colitis patients who failed conventional thiopurine therapy”
• Onderbouwing voor “well established use “
6-TG RA voorstel• 6-TG PCH 10 mg en 20 mg tablet• Proposed indication: Treatment of patients with
Inflammatory Bowel Disease (IBD), including Crohn’s disease and colitis ulcerosa, resistant to standard Thiopurine therapy, with medication control management as proposed by the European 6-TG working party.
• Nationale indiening • Legal basis of application: Article 10.3 (Hybrid)• Intended filling date: 4 Q 2011 / 1 Q 2012
6-TG RA voorstel
• Well established usevoor ong 1000 patienten in de laatste 7 jarenvia off label toepassing & magistrale bereiding
• Bioequivalentie studie voorstel – 6-TG PCH 20 mg ten opzichte van halve
tablet Lanvis 40 mg– Biowaiver voor de 6-TG PCH 10 mg
• In overleg met de Nederlandse Inspectie, levering op artsenverklaring
Continuation in UC
Van Asseldonk et al. submitted
6-TG Samenvatting• 6-TG structuur is variant van azathioprine en 6 – mercaptopurine• Metabolitisch gezien dichter bij werkzame metaboliet 6TGN
• Effectief en veilig voor de behandeling van azathioprine en 6 mercaptopurine resistente IBD patienten, incl ziekte van Crohn & CU
• Ondersteund door beroepsgroep– NL 6-TG WG
• Amsterdam VU, Maastricht UMC, Rotterdam, GroningenSittard, Utrecht Arnhem, Zwolle, Heerlen, Amersfoort,Nijmegen, Veldhoven
– EU 6-TG WG• NL. Austria, Germany, Czech Sweden, New Zealand,
Australia• Well established use
– Jaarlijks 900 – 1000 patienten op ½ Lanvis of magistrale capsule– Diverse promoties
– Uitgebreide bibliografie
PCH Regulatory
• Victor BenjaminsenDir RA R&D Pharmachemie Haarlem
6-TG werkzaamheid en tolerantie• Werkzaamheid van 6-TG
diverse studies sinds 2001 response 57 % – 88 %
• Tolerantie voor 6-TG in patienten AZA-6 MP intolerantie diverse studies range 44 % - 87 %aanbevolen dosis < 25 mg per dag
• Veiligheidonderzoek de Boer 2008 en Asseldonk 2010- NRH bij 6-TG dosisafhankelijk, niet bij lage dosering
6-TG
• “Well established use” - in kliniek laatste 6 jaren jaarlijks ong 900 – 1000 patienten
behandeld- diverse publicaties en proefschriften