1. Clash between old and older ?
Some considerations
Presenter Chris Mulder
Gastroenterologist
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2
3. Agenda
• Introduction
• Drug rediscovery Model Case IBD
–
–
–
–
Current therapy and pharmaceutical needs
Safety
Efficacy
Availability
• Regulatory aspects
–
–
–
–
Clinical Research
Investment
Pharmaco-economics
Authorisation
• Summary
4. Introduction VUmc
• Prof. dr. C.J.J. Mulder
• Gastroenterologist
• Head of departement
• Expertise Coeliac disease, IBD, GI-malignancies,
Auto-immune Liver diseases, drug rediscovery 6Tg, 2-CDA
• Drug rediscovery: 2-CDA, 6-Tg, Dapson,
Budesonide
• Chairman Dutch Society of Gastroenterology
6. 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
9. 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
10. Sorry: too much information
Lindqvist Appell and Haglund 2009
14. Failure of thiopurines
(AZA / 6-MP)
30-40 % of IBD patients
discontinues the use
due to therapeutic failure or the
development of adverse events
Jahrap et al IBD
2010
CM: << 5 yrs 50 % stops
20. 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
21. Myelotoxicity and TPMT
•
•
•
•
•
•
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 %)
y?
it
ic
x
to
nt IBD patients
N=72 AZA treated paediatric
ve
re
Leucopenia in 2,8 %
p
s
idid not explain adverse events
TPMT status
es
Do
Zelinkova et al. 2006
de Ridder et al 2006
22. TPMT determination ?
• Myelotoxicity may be avoided
• Dose adjustment according to
TPMT status
• Cost-effective
Winter et al. 2005
VUMC : too expensive , doesn’t protect
24. 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
25. 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
30. Efficacy 6-TG treatment
Patients
(numbers
)
Duration
(weeks)
6-TG Dose
(mg/day)
Toxicity
(%)
Respons
e
(%)
10
16
20
70%
16
!
d
o
o
0
26
20-40
50
88%
37
26
40-80
16
57%
Bonaz et al. 2003
49
52
20
10
79%
Qasim et al. 2007
40
34
40
33
73%
Trials
Dubinsky et al. 2001
Herrlinger et al. 2003a
Herrlinger et al. 2003b
g
Is
31. Tolerability 6-TG treatment
n=113 ; Mean daily dose: 0.25 – 0,35 mg/kg
P<0.001
40
35
30
25
20
15
10
5
0
245 treatment years
31
40
( 27% )
6-TG cont inuat ion
6-TG w it hdraw al
8
Median t reat m ent durat ion
( m ont hs)
82
( 73% )
32. Paediatric
• 2003
:
16/26 = 62% NRH
however
> 40 mg
Dubinsky et al, 2003
26 out of 111
90 % pre-6TG hepatotoxicity
34. Clinical recommendations
•
•
•
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
CM: Money
issue 6-Tg: < $ 1.000
1 year
35. Clinical recommendations
•
•
•
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
Cheaper than MAB’s
MABS : > $ 20.000 year
37. Dosages
• Azathioprine
• 2 – 2.5 mg/kg/daily
• 6-Mercaptopurine
the
• 1 – 1.5 mg/kg/daily in
G
6- T
on
nts
ti e
pa
(Imuran ®)
s
nd
rla
he
et
N
(Purinethol ®)
• 6-TG
(Lanvis®)
0.3
8•00 mg/kg/daily VUMC in A’dam
201
N>
2
38. Toxicity on classic thiopurines:
6-Thioguanine (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
40. Clinical recommendations
•
Therapeutic drug monitoring:
– Compliance control
– During toxicity or exacerbation of disease
– 6-Tg is useful
CM: At least once a year
This will help you a lot in the United States
Seinen ML et al JGLD 2010 september
41. 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)
41
44. Prevalence of NRH in IBD
( Non AZA users )
•
•
•
•
Non-thiopurine users
IBD surgery
Biopsy during operation
N=130
none
NRH
de Boer et al. 2008
present
94 %
6%
45. 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
46. 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.”
48. Conventional thiopurines and NRH
2
%
H
R
N
f
o
k
s
r
e
v
i
t
a
l
m
u
C
1
0
0
• 37 Cases / 36 centres
(France, Austria)
Conclusies:
• 1994 and 2005
1. IBD is een risico factor mbt NRH time AZA :
– Median
48 mo
2. 6-TG, azathioprine (thiopurine (6-187)
– Cumulative risk
months after starting
derivatives) ookAZAeen, dosis
afhankelijke, risico factor • 0.5% at 5 years
• 1.25% at 10
3. Groot aantal andere risicofactoren
years
12
24
at risk : 1874
36
48
60
833
72
84
96
108 120
322
(leeftijd, geneesmiddelen gebruik)
Vernier-Massouille, 2007
49. 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
conventional
therapies including mesalamine, AZA/6-MP, MTX and
infliximab, and in whom surgery is thought to be
inappropriate”
• “Application has to be restricted to a clinical
research setting.”
51. 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 “
52. 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
53. 6-TG RA voorstel
• Well established use
voor ong 1000 patienten in de laatste 7 jaren
via 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
55. 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, Groningen
Sittard, 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
57. 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
•
Veiligheid
onderzoek 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