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Clash between old and older ?
Some considerations

Presenter Chris Mulder
Gastroenterologist
Disclaimer
• The views and opinions expressed in the following PowerPoint
slides are those of the individual presenter and should not be
attributed to Drug Information Association, Inc. (“DIA”), its
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organization with which the presenter is employed or affiliated.
• These PowerPoint slides are the intellectual property of the
individual presenter and are protected under the copyright laws
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registered trademarks. All other trademarks are the property of
their respective owners.
2
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 6Tg, 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

1988

Nobel prize for this

Who is she?

Imuran®
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
Sorry: too much information

Lindqvist Appell and Haglund 2009
Metabolism of thiopurines

De Boer et al. 2006
Family of thiopurines
Azathioprine
6-Mercaptopurine
6-Thioguanine
Azathioprine in Europa
6-Mercaptopurine in USA

Maintenance Therapy
(ECCO-guidelines)

Escape Drug
(off label)
Drug rediscovery: Clash between old and older ?
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
Metabolism of thiopurines
®

– ®

®
only one metabolic step

?
De Boer et al. 2006
Toxicity of thiopurines
Dose dependent adverse events
–
–
–
–

General malaise
Infections
Hepatitis
Myelotoxicity

( 20 %)
11 %
7,4 %
0,3 – 1,3 %
1,4 – 5,0 %

Derijks et al. 2006

CM: In Crohn you start MAB’s ?
Toxicity of thiopurines
Dose independent adverse events
–
–
–
–

Rash
Fever
Artralgia
Pancreatitis

(2%)

1,4 – 3,3 %

Derijks et al. 2006

CM: We have alternatives
Toxicity prevention
TPMT determination ?
Too much money,
it doesn’t help you
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
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
TPMT determination ?
• Myelotoxicity may be avoided
• Dose adjustment according to
TPMT status
• Cost-effective
Winter et al. 2005

VUMC : too expensive , doesn’t protect
Toxicity prevention
Therapeutic drug monitoring ?

CM: TDM is what we prefer.
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®)

6-Mercaptopurine
(Purinethol®)

6-Thioguanine
(Lanvis®)
Leukemia

1957

1956

1950

Gertrude Elion Nobel prize1988
T6-G : only for hematologists?

Azathioprine
(Imuran®)

6-Mercaptopurine
(Purinethol®)

6-Thioguanine
(Lanvis®)
Leukemia

1957

1956

1950
Efficacy 6-TG treatment
Patients
(numbers
)

Duration
(weeks)

6-TG Dose
(mg/day)

Toxicity
(%)

Respons
e
(%)

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%

Trials
Dubinsky et al. 2001
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
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% )
Paediatric

• 2003

:

16/26 = 62% NRH
however
> 40 mg

Dubinsky et al, 2003

26 out of 111
90 % pre-6TG hepatotoxicity
Paediatric

:
th
y:
ud
St
• 2003

ox
int
is

te
ca
i

th
ry
ve
e
d

g.
in

16/26 = 62% NRH

Dubinsky et al, 2003

26 out of 111
90 % pre-6TG hepatotoxicity

however
> 40 mg
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
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
Dosages
• Azathioprine
• 2 – 2.5 mg/kg/daily

(Imuran ®)

• 6-Mercaptopurine
• 1 – 1.5 mg/kg/daily

(Purinethol ®)

• 6-TG
(Lanvis®)
• 0.3 mg/kg/daily VUMC in A’dam
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
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
TG vs
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
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
Regulatory aspects (C’tnd)
• Pharmaco-economics

• Authorisation

42
Summary

Drug rediscovery helps patients,
however is a disaster to
re-registrate and distribute

43
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%
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 NRH
Daily
dose mg

Total
dose

Tx mo

6TGNlevel

NRH 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
↑HVPG

25%

-

28

-

Def 6/60
Pro10/60

27%

Author

Teml
2007

40 → 20

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%
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
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.”
Drug rediscovery: Clash between old and older ?
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 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
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, 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
PCH Regulatory
• Victor Benjaminsen
Dir 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

•

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

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Drug rediscovery: Clash between old and older ?

  • 1. Clash between old and older ? Some considerations Presenter Chris Mulder Gastroenterologist
  • 2. Disclaimer • The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Drug Information Association, Inc. (“DIA”), its directors, officers, employees, volunteers, members, chapters, councils, Special Interest Area Communities or affiliates, or any organization with which the presenter is employed or affiliated. • These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. Drug Information Association, Drug Information Association Inc., DIA and DIA logo are registered trademarks. All other trademarks are the property of their respective owners. 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
  • 5. Introduction •The concept of Drug Rediscovery: Don't throw away old shoes, before you have new ones 5
  • 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
  • 8. Her name is Gertrude Elion: Nobel Prize 1998
  • 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
  • 11. Metabolism of thiopurines De Boer et al. 2006
  • 12. Family of thiopurines Azathioprine 6-Mercaptopurine 6-Thioguanine Azathioprine in Europa 6-Mercaptopurine in USA Maintenance Therapy (ECCO-guidelines) Escape Drug (off label)
  • 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
  • 15. Metabolism of thiopurines ® – ® ® only one metabolic step ? De Boer et al. 2006
  • 16. Toxicity of thiopurines Dose dependent adverse events – – – – General malaise Infections Hepatitis Myelotoxicity ( 20 %) 11 % 7,4 % 0,3 – 1,3 % 1,4 – 5,0 % Derijks et al. 2006 CM: In Crohn you start MAB’s ?
  • 17. Toxicity of thiopurines Dose independent adverse events – – – – Rash Fever Artralgia Pancreatitis (2%) 1,4 – 3,3 % Derijks et al. 2006 CM: We have alternatives
  • 18. Toxicity prevention TPMT determination ? Too much money, it doesn’t help you
  • 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
  • 23. Toxicity prevention Therapeutic drug monitoring ? CM: TDM is what we prefer.
  • 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
  • 26. Toxicity yes : “what to do?” When to start 6-TG ?
  • 28. T6-G : only for hematologists? Azathioprine (Imuran®) 6-Mercaptopurine (Purinethol®) 6-Thioguanine (Lanvis®) Leukemia 1957 1956 1950
  • 29. Efficacy 6-TG treatment Patients (numbers ) Duration (weeks) 6-TG Dose (mg/day) Toxicity (%) Respons e (%) 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% Trials Dubinsky et al. 2001
  • 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
  • 33. Paediatric : th y: ud St • 2003 ox int is te ca i th ry ve e d g. in 16/26 = 62% NRH Dubinsky et al, 2003 26 out of 111 90 % pre-6TG hepatotoxicity however > 40 mg
  • 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
  • 36. Dosages • Azathioprine • 2 – 2.5 mg/kg/daily (Imuran ®) • 6-Mercaptopurine • 1 – 1.5 mg/kg/daily (Purinethol ®) • 6-TG (Lanvis®) • 0.3 mg/kg/daily VUMC in A’dam
  • 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
  • 39. TG vs
  • 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
  • 42. Regulatory aspects (C’tnd) • Pharmaco-economics • Authorisation 42
  • 43. Summary Drug rediscovery helps patients, however is a disaster to re-registrate and distribute 43
  • 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.”
  • 47. 6-Thioguanine and NRH Daily dose mg Total dose Tx mo 6TGNlevel NRH 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 ↑HVPG 25% - 28 - Def 6/60 Pro10/60 27% Author Teml 2007 40 → 20 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%
  • 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
  • 54. Continuation in UC Van Asseldonk et al. submitted
  • 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
  • 56. PCH Regulatory • Victor Benjaminsen Dir RA R&D Pharmachemie Haarlem
  • 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