LUIGI MORO

Simposio AFI 2011
Forme farmaceutiche a rilascio modificato
nel trattamento delle malattie intestinali
Luigi Moro
Cosmo Pharmaceuticals
1
MMX - Multi Matrix System
From: AFI simposio 2001
Stomach
Duodenum
2
MMX: Proving extended release and persistence
of radioactive traces released by MMX in gut
1h 30’ duodenum
10h trasverse colon
4h 30’ ascending colon
16h descending colon
7h 30’ trasverse colon
24h rectum
3
Product pipeline
Product and Indication
Lialda ®/ Mezavant ®/Mesavancol®
Mild to moderate Ulcerative Colitis
Zacol NMX®
Intestinal Disorders (nutraceutical)
Budesonide MMX® (Cortiment MMX®)
Mild to moderate Ulcerative Colitis
Rifamycin SV MMX®
Drug
type
Phase I
Phase II
Phase III
MA
Launch
Partner
USA
Shire/Giuliani
5-ASA
EU
Dietary
supplement
ITA
Corticosteroid
2010
Antibiotic
2010
Travellers’ Diarrhoea
H2/11
EU
H1/12
USA
3 EASTERN
EUROPEAN
COUNTRIES
EU H1/12
USA H2/12
Dr. Falk
Ferring – Worldwide
Santarus - USA
Dr. Falk – Eu & Australia
Santarus - USA
LMW Heparin MMX®
2010
- Induction of remission in UC
H2/12 EU
Biologic
- Maintenance treatment for UC of all
severities
CB-17-01
Chromendoscopy
CB-01-16
Opioid Induced Constipation
H2/12
H2/11
Diagnostic
Opioids
Antagonist
Q4
11
4
2010
The dilemma of pharma companies: high costs of
developing a NCE, low probabilities of success
Biology
Chemistry
HTS
Preclinical
Screening
Optimization
Phase 0
Leads
Drug
candidates
IND
5.0%
0.00021%
50.0%
40.0%
70.0%
52.0%
65.0%
91.0%
# targets input
1,000
50.0
# compounds
input
625,000
31,250,000
32.2
12.9
9.0
4.7
3.0
Value Chain
Target
ID/val1
Target Val II
Clinical
Phase I
Phase II
FDA
Phase III
Terminology
Activity/output
Circumstantial
val
Functional val
Probability
to pass
# IDval1 exp.
run
333
# pot.
tgts/IDval1 exp.
3
64.4
# candidates
input
Running total
$m
% of total
Subtotal %
NDA
25,5
231,3
271,4
390,2
484,5
531,2
616,0
716,6
742,3
3.4%
27.7%
5.4%
16.0%
12.7%
6.3%
11.4%
13.6%
3.5%
21.4%
12.7%
31.3%
3.5%
31.2%
Source: Boston Cons. Matrix 2004
5
Cosmo strategy: go for lower risks & higher
probabilities of success
Preclinical to
market
phase I to
market
phase II to
market
phase III to
market
Post phase III
to market
Classical NCE(1)
probability of
success
9%
22%
31%
59%
91%
Gastro NCE
probability of
success
12%
31%
50%
64%
91%
Gastro ACE(2)
probability of
success
40%
50%
55%
64%
91%
Probabilities
(1)
(2)
NCE: new chemical entity
ACE: previously approved chemical entity
6
The therapeutic gap in conventional therapy: from Lialda®
to corticosteroids like Budesonide MMX®
Lialda® for active Ulcerative Colitis
• Improvement is achieved in 70% of
patients
• Remission rates @ 8 weeks
• Remission definition: DAI <1
• 517 patients, mild-moderate UC
• Placebo vs 2.4g/d vs 4.8g once daily
Sandborn et al APT 2007;26:205
100
90
80
70
60
50
40
30
20
10
0
Therapeutic gap
Placebo
MMx
MMx 4.8g
2.4g/d
od
PROVEN, PROPRIETARY, PATENTED MMX® TECHNOLOGY
Proof of concept achieved
Base for further product development and replenishment of pipeline
7
Multi-matrix System (MMX®)
• Multi-matrix system (MMX®) – a unique
technology
• Targeted drug delivery to entire colon, the site of UC
• Potential for efficacy of conventional steroid, while minimizing
systemic side effects
• MMX® technology has previously been successfully applied to
IBD (Lialda®)
8
Budesonide MMX®
• Budesonide
• Highly potent non-halogenated corticosteroid
• Low systemic bioavailability
• Established value as topical therapy in UC and targeted delivery for
CD
• Budesonide MMX®
• Gastro-resistant MMX® delivery
9
Budesonide MMX ®
PK Comparison vs. Entocort
Comparative bioavailability study:
Bioavailability profile of a new MMX™ Budesonide Extended release (6, 9 mg tablets) formulation
compared vs. A controlled ileal release formulation, Entocort® 3 x 3 mg capsules, in healthy
volunteers
Mean Plasma Budesonide concentration after single oral dose
concentration (pg/mL)
E n t o c o r t ® E C 3 m g × 3 c a p s u le s
B u d e s o n id e M M X ™ 9 m g
B u d e s o n id e M M X ™ 6 m g
200 0
150 0
100 0
500
0
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
T im e ( h )
10
% Remission
Budesonide MMX® Phase 3 Study Results
Primary Efficacy Endpoint
Remission after 8 weeks of treatment
20
18
16
14
12
10
8
6
4
2
0
N = 410
17,4 *
12,6 +
8,3
4,5
Placebo
N=89
Remission, n(%)
4
(4.5%)
MMX 9 mg MMX 6 mg Entocort EC
N=109
19
(17.4%)
N=109
9
(8.3%)
N=103
13
(12.6%)
∆ vs. Placebo
--
12.9%
3.8%
8.1%
P-value
--
0.0047*
0.2876
0.0481+
* Statistically significant (p < 0.025)
+ Statistically significant (p < 0.05)
Study not powered to show a statistical difference between budesonide MMX® and Entocort® EC treatment arms
11
Remission at Week 8
Primary Efficacy Endpoint
% Remission
N = 489
N=121
N=123
N=121
N=124
9 (7.4)
22 (17.9)
16 (13.2)
15 (12.1)
∆ vs. Placebo
--
10.4%
5.8%
4.7%
P-value
--
0.0143*
0.1393
0.2200
Remission,
n(%)
12
* Statistically significant (p < 0.025)
Not powered to show statistical difference between budesonide MMX® treatment arms and Asacol®
Morning Plasma Cortisol
Symbols indicate mean plasma cortisol level for each visit for each treatment.
13
Sviluppo internazionale: difficoltà tipiche
Livello
REGOLATORIO
Tipo
● Agenzie diverse con richieste di struttura del dossier personalizzate a livello locale
● Guidelines diverse nelle specifiche di reclutamento (histology EU, not US)
● Non accettazione di atti da altre Agenzie Regolatorie
● Advisor meetings gestiti con diverse procedure (moltiplicazione della documentazione)
● IND – CTX - Tempi di approvazione diversi (da qualche settimana a >6 mesi)
- Possibilità di rifiuto sulla stessa domanda accettata da altri Paesi in EU
(feasibility allargata e frazionamento del reclutamento come risk
management tool)
14
Logistics of Phase III budesonide-MMX (Cortiment®)
development: Example-Time to open new sites/countries
In Europe the time to
set up sites varies by
county from 12 -27 weeks.
Multiple steps required:
•National regulatory approval
•Site
Site contracts
•Local ethics approval
•Drug import (subject to
national approval first)
15
Sviluppo internazionale: difficoltà tipiche
Livello
Tipo
•REGOLATORIO
- Agenzie diverse con richieste di struttura del dossier personalizzate a livello locale
- Guidelines diverse nelle specifiche di reclutamento (histology EU, not US)
- Non accettazione di atti da altre Agenzie Regolatorie
- Advisor meetings gestiti con diverse procedure (moltiplicazione della documentazione)
- IND – CTX - Tempi di approvazione diversi (da qualche settimana a >6 mesi)
- Possibilità di rifiuto sulla stessa domanda accettata da altri Paesi in EU
(feasibility allargata e frazionamento del reclutamento come risk
management tool)
• CLINICO
- Richiesta di un numero di pazienti in costante aumento rendono indispensabile
coinvolgere paesi emergenti (es. Russia, India, etc.) con imprevedibili
riflessi sulla qualità dei dati
- Competizione tra diversi clinical trials nei siti più noti ed affidabili prolungano i tempi di
reclutamento (20 mesi per 8 settimane di trattamento)
16
Logistics of Phase III budesonide-MMX
(Cortiment®) development
4 Phase III trials completed
Study
design
# active
centres
# screened
patients
# treated
patients
CB-01-02/01
Countries
Randomised
double blind.8
weeks treatment
108
803
509
USA,Canada,Mexi
co, India
CB-01-02/02
Randomised
double blind.8
weeks treatment
69
613
511
Western &
Eastern
Europe,Israel,
Australia
CB-01-02/04
Randomised
double blind.Upto
12 months
treatment
60
123
123
USA, Canada,
Eastern and
Western Europe,
India
CB-01-02/06
Open Label
8 weeks treatment
15
61
61
India
17
Logistics of Phase III budesonide-MMX (Cortiment®)
development: Study site distribution
18
Sviluppo internazionale: difficoltà tipiche
Livello
•REGOLATORIO
• CLINICO
Tipo
- Agenzie diverse con richieste di struttura del dossier personalizzate a livello locale
- Guidelines diverse nelle specifiche di reclutamento (histology EU, not US)
- Non accettazione di atti da altre Agenzie Regolatorie
- Advisor meetings gestiti con diverse procedure (moltiplicazione della documentazione)
IND – CTX - Tempi di approvazione diversi (da qualche settimana a >6 mesi)
- Possibilità di rifiuto sulla stessa domanda accettata da altri Paesi in EU
(feasibility allargata e frazionamento del reclutamento come risk
management tool)
- Richiesta di un numero di pazienti in costante aumento rendono indispensabile
coinvolgere paesi emergenti (es. Russia, India, etc.) con imprevedibili
riflessi sulla qualità dei dati
- Competizione tra diversi clinical trials nei siti più noti ed affidabili prolungano i tempi di
reclutamento (20 mesi per 8 settimane di trattamento)
- Criteri sempre più severi nella definizione degli Endpoints rendono penalizzanti i
confronti con farmaci già approvati da qualche anno
19
Dates of FDA approval for Common IBD Drugs
Administrative changes in Changes in FDA since 1938
Agencies evolution and drugs approval
1962: Kefauver – Harris amendments
- products must be proven both safe and effective prior to marketing
1984: Hatch-Waxman Act (bioequivalence)
1997: FDA Modernization Act
-includes regulation of marketing for off label use
1973: Center for Biologics Evaluation and
Research
(CBER) established within FDA
2003:Responsibility for biological agents
transferred to Center for Drug Evaluation and
Research (CDER)
1938: FDA established
2005: Infliximab approved for UC
1953: 6MP and methotrexate approved
1992: Mesalamine approval for UC
1968: 6MP and methotrexate approved
1995: Cyclosporine approved
2008: Certolizumab and
Natalizumab approved for CD
1998: Infliximab approved for CD
1977: Sulfasalazine approved for UC
2002: Adalimumab approved for CD
20
Summary of different properties measured in clinical activity
indices
(1955)
(1982)
(1987)
(1989)
(1994)
(1998)
(1998)
21
Taken from Trials 2007, 8:17
Summary of activity indices used for ulcerative
colitis
Index
Year
Also known as
Clinical/ biomedical
Truelove & Witts’
Powell Tuck
Rachmilewitz
Lichtiger
Walmsley
Feagan
1978
1988
1990
1992
1998
2005
St. Mark’s Index
Clinical Activity Index (CAI)
Modified Truelove & Witts’
Activity Index (AI)
Simple Clinical Colitis Index (SCCAI)
Ulcerative Colitis Clinical Score (UCCS)
1987
1987
Mayo score, Disease Activity Index (DAI)
UC Disease Activity Index (UCDAI)
1993
1998
2002
2005
PGA assessment score
Composite (clinical and endoscopic)
Schroeder
Sutherland
Evaluation
Physician’s Global Evaluation
Investigator’s Global Evaluation
Individual Symptom Score
Patient Defined Remission
Taken from Trials 2007, 8:17
22
Indices and endpoints used in recent clinical trials with
patients in active disease
Drug/Study
Index/Score system
Endpoint Definition of Remission
ASCEND II [20]
Mayo Clinic Index (DAI)
Overall improvement from baseline
( treatment success)
Complete remission:
A normal stool frequency and normal endoscopy findings
No rectal bleeding
PGA score of 0 and PFA score of 0
MEZAVANT [21]
Modified UC Disease Activity Index
(UCDAI) including
Clinical and endoscopic evaluation
Modified UC-DAI ≤ 1
Stool frequency – score 0 and
Rectal bleeding – score 0 and
Combined PGA score and sigmoidoscopy
score ≤ 1 ( no friability) and
≤ 1 point reduction from baseline in sigmoidoscopy score
PINCE [16]
UCDAI including
Clinical and endoscopic evaluation
UC-DAI <2
Sum of stool frequency and rectal bleeding and mucosal
appearance and PGA is 0 or 1
SALOFALK [14]
CAI
Only Clinical evaluation
CAI≤ 4
Number of stools; percentage of bloody stools; abdominal pain
and general well being in last 7 days; temperature due to
colitis; presence of EIMs; laboratory findings (ESR and Hb)
ACT I/II [18]
Mayo Clinical Index (DAI) )
including Clinical and endoscopic
evaluation
Score ≤ 2; no individual subscore >1
Sum of stool frequency; rectal bleeding;
Mucosal appearance; PGA
23
Impact of different definitions of remission
threshold on clinical trial outcomes
ASCEND I/II
[5, 20, 23]
Study
Mayo Score/DAI
Index
Criteria included
Remission indicated by score
Remission rate
Stool frequency compared to normal
Rectal bleeding
Sigmoidoscopy
PFA
PGA
0
≤1
≤2
22%
28%
50%
24
Sviluppo internazionale: difficoltà tipiche
Livello
•REGOLATORIO
• CLINICO
Tipo
- Agenzie diverse con richieste di struttura del dossier personalizzate a livello locale
- Guidelines diverse nelle specifiche di reclutamento (histology EU, not US)
- Non accettazione di atti da altre Agenzie Regolatorie
- Advisor meetings gestiti con diverse procedure (moltiplicazione della documentazione)
IND – CTX - Tempi di approvazione diversi (da qualche settimana a >6 mesi)
- Possibilità di rifiuto sulla stessa domanda accettata da altri Paesi in EU
(feasibility allargata e frazionamento del reclutamento come risk
management tool)
- Richiesta di un numero di pazienti in costante aumento rendono indispensabile
coinvolgere paesi emergenti (es. Russia, India, etc.) con imprevedibili
riflessi sulla qualità dei dati
- Competizione tra diversi clinical trials nei siti più noti ed affidabili prolungano i tempi di
reclutamento (20 mesi per 8 settimane di trattamento)
- Criteri sempre più severi nella definizione degli Endpoints rendono penalizzanti i
confronti con farmaci già approvati da qualche anno
- Problemi di confezionamento (etichette, IC e CRF multilingua) e distribuzione degli
IMPs
- Comitati Etici locali con richieste diverse nella struttura dai contratti (220 contratti da
proporre, negoziare e firmare)
25
Logistics of Phase III budesonide-MMX (Cortiment®)
development: Bio sample and drug distribution
(*) Gary Lichtenstein. Gastroenterology 2007; 132: 516-26
26
Logistics of Phase III budesonide-MMX (Cortiment®)
development: Some other cost drivers
Item
Count
Approx. number of laboratory blood,
urine, stool and histology samples
analysed during PIII Cortiment®
studies.
28,784
Number of data items captured in
eCRF during PIII studies
CB-01-02/06
CB-01-02/04
CB-01-02/01
CB-01-02/02
– 110,728
– 151,729
– 1,112,340
– 785,110
Total: 2,159,907
Logistic costs to distribute IMPs
worldwide
85,500 €
27
Sviluppo internazionale: difficoltà tipiche
Livello
Tipo
•REGOLATORIO
- Agenzie diverse con richieste di struttura del dossier personalizzate a livello locale
- Guidelines diverse nelle specifiche di reclutamento (histology EU, not US)
- Non accettazione di atti da altre Agenzie Regolatorie
- Advisor meetings gestiti con diverse procedure (moltiplicazione della documentazione)
IND – CTX - Tempi di approvazione diversi (da qualche settimana a >6 mesi)
- Possibilità di rifiuto sulla stessa domanda accettata da altri Paesi in EU
(feasibility allargata e frazionamento del reclutamento come risk
management tool)
• CLINICO
- Richiesta di un numero di pazienti in costante aumento rendono indispensabile
coinvolgere paesi emergenti (es. Russia, India, etc.) con imprevedibili
riflessi sulla qualità dei dati
- Competizione tra diversi clinical trials nei siti più noti ed affidabili prolungano i tempi di
reclutamento (20 mesi per 8 settimane di trattamento)
- Criteri sempre più severi nella definizione degli Endpoints rendono penalizzanti i
confronti con farmaci già approvati da qualche anno
- Problemi di confezionamento (etichette, IC e CRF multilingua) e distribuzione degli
IMPs
- Coinvolgimento obbligato di CRO multistrutturate (impatto sui costi)
28
Main costs of Phase III Budesonide-MMX (Cortiment®)
development due to clinical organizations
CRO costs mainly driven by:
•
•
•
•
Number of countries and sites initiated.
Number of patients screened and randomised
Duration of studies
Complexity of studies
• Number of data points collected
• Sites required pre-study visits, interim monitoring visits and close-out visits
• Investigator fees, variable depending on region (Some US investigators charge up to
$9,000 per completed patient)
• Protocol Local Approval (e.g. central IRB in the USA, national competent authority in EU
member states)
• Local site ethics committee approval required for many sites (particularly in Europe).
29
Main costs of Phase III Budesonide-MMX (Cortiment®)
development due to Study complexity
- Studies included up to 2 colonoscopies (with biopsies for histology confirmation)
- Microbiology, haematology, chemistry, urinalysis testing: all samples required
transport and analysis.
- Statistical analysis, medical writing
•
Each patient required : blinded drug treatment kits. Laboratory testing kits.
Translated patient diaries, signed informed consent, travel expenses
rembursement.
•
Drug kits required temperature recording during transit and insulated
(expensive) packaging in some cases (e.g winter months, tropical climates).
•
Multiple warehouses with temperature controlled storage were established and
integrated with the randomisation (IVRS) and drug distribution process.
•
Data collection via online electronic CRF system (contracted supplier).
•
Comparator drugs Entocort and Asacol required purchase, over-encapsulation,
release and re-packaging/labelling to maintain blinded treatment allocation.
30
Sviluppo internazionale: difficoltà tipiche
Livello
Tipo
•TECNICO - ANALITICO
- Specifiche diverse in funzione delle varie Farmacopee richiedono SOPs
analitiche multiple in funzione del Paese di destinazione o
gestione separata dei prodotti/IMPs.
- La distribuzione del prodotto in vari Paesi impone presentazioni diverse con
materiali di confezionamento personalizzati (lingua, dimensioni)
- Possibilità di ispezioni dell’unità produttiva da Paesi non Europei (Korea,
Brasile,etc.)
- L’invio del prodotto in paesi a clima diversificato impone studi di stabilità
in diverse condizioni aggiuntive
• GESTIONALE
- Creazione di Teams dedicati per le diverse tipologie di problemi (risorse
umane specialistiche?)
- Creazione di unità di controllo costi/investimenti con conoscenza dei mercati
internazionali e delle loro regole
- Reperimento di Problem Solving Units in diverse parti del mondo per la
risoluzione dei problemi locali
31
Budesonide –MMX
Project timelines & costs
•
•
•
•
•
•
•
•
•
•
•
Ph I PS + PK studies
Ph II POC study
Pre-IND meeting with FDA
Tox. Bridging study
New Ph. I comparative study
FDA Special Protocol Assess.
Ph III - First Patient In
Ph III - Last Patient Out
Final Ph. III CSRs
MA submission
MA Approval
• Total development time
• Total development costs
2002 - 2004
2005
2006
2007
2007 - 2008
2008
2008
2010
2011
2011
? (2012)
10 years
several milions
€
32
Top issues impacting pharmaceutical market access in 2011
The two main challenges faced by the pharmaceutical industry with regard to market access in 2011 are likely to be
the end of free-pricing and the continued importance of innovative contracting and patient access schemes.
Budget driven reform may end free-pricing
The end of free-pricing in 2011 has been signalled by two of the traditional free-pricing markets changing their
reimbursement systems.
Germany – demonstrated incremental benefit required for 12 months of free-pricing
The Act on the restructuring of the German pharmaceutical market (Arzneimittelmarkt-Neuordnungsgesetz; AMNOG)
came into force in January. Under the new Act, the Federal Joint Committee (G-BA) will assess value dossiers
submitted by the pharmaceutical company, to establish if a new product demonstrates incremental benefit against an
appropriate comparator. If a drug does not offer incremental benefit over the comparator, then its reimbursement
price will be based on the comparator, if appropriate, as part of the reference pricing (Festbetrage) system. However,
if incremental benefit over the comparator is demonstrated, then the company's launch price will be reimbursed for a
period of 12 months. For such a product, longer-term reimbursement figures will be negotiated with the price agreed
by the GKV-Spitzenverband (the statutory health insurance umbrella organisation) or an arbitration board.
UK – White Paper changes lead to uncertainly over market access, and the promise (threat?) of a new
pricing system
…. The Government claims that these changes will help them to reduce National Health Service (NHS) administration
costs, make the service more responsive to patient needs and improve services, as they maintain their commitment
to preserve NHS spending levels.
Currently free pricing is allowed for all new medicines at launch and all licensed medicines are automatically
reimbursed by the NHS; but free-pricing is irrelevant if a pharmaceutical company can not gain effective market
access. Even under the existing system, restrictions are placed on patient access and prescribing, for example with
National Institute for Health and Clinical Excellence (NICE) denying access to some medicines or issuing guidelines
restricting use. At a more regional level, SHAs and PCTs in England were responsible for enacting such guidelines
within their budgets.
33
L’incubo dei prezzi
• L’innovazione dovrebbe essere premiata da un Premium Price a supporto degli
investimenti a rischio effettuati
• La variabile prezzo condiziona per i farmaci innovativi:
- il tempo di arrivo nel mercato del singolo Paese
- la possibilità che in qualche Paese non entri affatto nel repertorio farmacetico
34
Innovazione: Premium price ?
Market
Lialda/Mezavant
ITALY
59,43€ (60 tab)
1 tab= 0,99 €
USA
204.73 USD (30 tab)
1 tab= 6.82USD (4,66 €)
NETHERLANDS
150€ (120 tab)
1 tab= 1,25 €
CANADA
213€ (120 tab)
1 tab= 1,77 €
IRELAND
109,11€ ( 60 tab)
1 tab=1,81 €
UK
54,64£ (60 tab)
1 tab= 1,018 €
Currency US dollar :1.46 €
Currency GBP: 1,12 €
35
MMX: innovazione tecnologica al servizio del
paziente
36
Conclusioni
L’innovazione è un processo che contempla anni di investimenti rischiosi, che richiede
competenze complesse, risorse e organizzazioni efficienti dedicate.
A fronte di questi impegni le società farmaceutiche non si augurano di trovare, oltre alle
difficoltà tecniche prevedibili, altri ostacoli di non facile previsione, quali
- Incertezza e variabilità nei meccanismi regolatori e autorizzativi
- impossibilità di svolgere un Mktg efficace attraverso confronti con farmaci già sul mercato
- negoziazioni critiche con gli enti predisposti al riconoscimento del prezzo di vendita
L’innovazione porta vantaggi prima di tutto al paziente: in una società che guarda al
futuro essa va incentivata e sostenuta da tutte le componenti del mondo del farmaco.
To be successfull in drug research & development….
-
Geschick
Geduld
Glück
Geld
4 G are needed :
(Ability)
(Patience)
(Luck)
(Money)
[Paul Ehrlich]
37