Clash between old and older ?Some considerations

Presenter Chris MulderGastroenterologist

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

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)

41

Regulatory aspects (C’tnd)

• Pharmaco-economics

• Authorisation

42

Summary

Drug rediscovery helps patients, however is a disaster to

re-registrate and distribute

43

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