Transcript Alvimopan - Moodle Lille 2

Alvimopan
EnteregTM
On May 20th 2008, FDA Approves Entereg to Help Restore Bowel Function
Following Surgery, after a third review cycle. Entereg has been in development
for seven years. Why did it take so long?
Regulation: insights into the risk evaluation and mitigation strategy (REMs): FDA’s decision on the
NDA for alvimopan (Entereg®) could be a good indicator of the agency’s use of newly mandated
risk management plans, as its advisory committee supported the short term benefits of the drug in
postoperative ileus, but also worried about CV risk signals in longer term use.
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Pain submarkets
Post-Op
Post-Op
Post-Op
Cancer
Cancer
+ PAR, …
Opioid-treated pain
The total market for pain
drugs is an estimated
US$7.25 billion.
Gershell and Goater Nature Reviews Drug Discovery 5, 889–890 (November 2006) | doi:10.1038/nrd2179
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Evolution of Consumption of Morphine
1980-2006 (mg/capita)
USA
Mg/capita
FRANCE
Mg/capita
1. Pain & Policy Studies Group ; Univ. Madison Wisconsin http://www.painpolicy.wisc.edu/
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1. The medical need
treatment of OBD/POI :market and
pharmacoeconomics
OBD: Opioid Bowel Dysfunction
POI : Post-Operative Ileus
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Inhibitory Effects of Opioids on
Bowel Function
1. Senagore; Supplement to Contemporary Surgery August 2007 S3
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OBD : Opioid-Induced Bowel
Dysfunction
• Common AE associated
with opioid therapy
• Add to patient discomfort
• Limits therapy or prompts
discontinuation.
Problems associated with chronic
opioid use. % of surveyed physicians
who rated the different
symptoms in order of importance.
Major limit to effective
pain management
1. Pappagallo M 2001 Nov;182(5A Suppl):11S-18S
2. Gershell and Goater Nature Reviews Drug Discovery 5, 889–890 (November 2006) | doi:10.1038/nrd2179
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POI : Post Operative Ileus
• Transient impairment
of GI function after
surgery
• May last > 5 days
• Incidence rates
reported 6-20%
• Physiopathology:
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Restoring GI function after surgery :
an unmet medical need
1. Andrew Luckey, Arch Surg (2003).
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Restoring GI function after surgery :
an unmet medical need
• Opioid-sparing regimens (NSAIDS in Europe)
• Prokinetic agents
1.
2.
3.
Peter J. S. Koo, Balancing Postoperative Analgesia and Management of Side Effects, Medscape
Expert Opin. Investig. Drugs 2008 17(9) 1365
Person & Werxner, Supplement to Contemporary Surgery n August 2007 S9
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Patients
Incidence of POI after select
procedures
1.
2.
3.
National Center For Health Statistics
Goldstein Pharm.&Therapeut. • February 2007 • Vol. 32 No. 2; 82
Saunders ASHSP , 2004, Abstract 30346
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Projected Incidence of POI with common
Abdominal-related Procedures
42.5 million inpatient surgical procedures in 2002 (45 million in 2007)
30% on digestive tract
713,628 intestinal resections
1.
National Center For Health Statistics
2.
Goldstein Pharm.&Therapeut. • February 2007 • Vol. 32 No. 2; 82
142,026 cases of POI
3.
Saunders ASHSP , 2004, Abstract 30346
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• Direct effects
–
–
–
–
–
POI effects
Increase nausea and vomiting
Increased post-operative pain
Accumulation of gas & fluids
Delayed passage of flatus & defecation
Prolonged time to regulatory diet
• Complications
– Increased risk for malnutrition/catabolism
– Prolonged time to mobilization
– Increased pulmonary complications
Prolonged hospitalisation and increased costs
1. Senagore; Supplement to Contemporary Surgery n August 2007 S3
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Associated costs
• The total direct cost of coded POI : $1.26 billion
including:
–
–
–
–
–
nasogastric intubation.
intravenous (IV) hydration.
laboratory tests.
nursing care.
increased hospital length of stay (LOS).
• The rate of readmission within 30 days
3.6% for recurrent POI, vs 0.02% for non coded POI.
1.
2.
3.
Senagore; Supplement to Contemporary Surgery n August 2007 S3
Goldstein P&T® • February 2007 • Vol. 32 No. 2; 82
Liu & Carpenter & Mackey
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Economic Burden of POI
1. Senagore; Supplement to Contemporary Surgery n August 2007 S3
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Potential annual savings
1. The Surgical Team and Outcomes Management Journal of PeriAnesthesia Nursing, Vol 21, No 2A (April), 2006: pp S2-S6
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1. The medical need
treatment of OBD/POI :market and
pharmacoeconomics
2. The drug
– A « long » pre-NDA history
– Pharmacological mode of action
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A « long » story…
• 1984: Discovery
• 1988 : Eli Lilly then Roberts Pharmaceutical
• 1998 : Exclusive worldwide license to
• 03/2001 : 1st Phase III trial
• 04/2002 : Collaboration with
• 08/2002 : Acquisition of IP rights
• 2004 : NDA filing .
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Strategies for antagonizing opioid
induced adverse GI effects
1. Peter J. S. Koo, Balancing Postoperative Analgesia and Management of Side Effects, Medscape
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Strategies for antagonizing opioid
induced adverse GI effects
• Limit systemic absorption
– Naloxone (oral : 1st pass metabolism)
• Limit BBB penetration
– Methylnaltrexone
• Both
– Alvimopan
1. Peter J. S. Koo, Balancing Postoperative Analgesia and Management of Side Effects, Medscape
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Limit BBB penetration
• Quaternary amines:
N-Methylnaltrexone
bromine MNTX
• Zwitterions :
Alvimopan
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Alvimopan : the 1st PAM-OR
a Peripherally Acting MuOpioid Receptor antagonist
• ED50 1mpk
• Duration of action 8hrs
• Induces Diarrhea in
morphine dependent mice
1. ChemMedChem 2007, 2, 1552 – 1570
2. J. Med. Chem. 1994,37, 2262-2265
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1. The medical need
treatment of OBD/POI :market and
pharmacoeconomics
2. The drug
– A « long » pre-NDA history
– Pharmacological mode of action
3. Key Clinical results & Regulation Timeline
– The timeline
– Clinical trials
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Entereg regulatory timeline
•
•
•
•
1999 : beginning of clinical development
Mar 2001 : 1st Phase III trial
Fev 2004 : Pre NDA meeting
May 2005 : FDA wants results from GSK001
Phase III study (failed)
• Jul 2005 : FDA requires additional efficacy data
• Sept 2005 : Concern about optimal dosing
• May 2006 : Complete response to FDA. PDFUA
sets to Nov 2006
1. Biocentury 2008, VOL16, 5
Prescription Drug User Fee Act (PDFUA)
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Clinical Programs
Randomized, double-blind, placebo-controlled, multicentered trials
OBD
•
•
•
patients on chronic
opioids
< 0,5 mg, BID
outpatient
POI
•
•
•
patients undergoing
partial large or small
bowel resection (BR) or
total abdominal
hysterectomy (TAH)
surgery
6 or 12 mg, BID
only in hospital
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Endpoints in POI
•
GI Recovery
–
–
•
•
GI-3 = toleration of solid food + first bowel
movement or flatus
GI-2
Length of hospital stay
Post Operative Morbidity =
readmission, NG tube, ...
1. Advisory Panel Briefing Document, Adolor Corp.
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First results
• 12 mg = better consistency in
benefit/response without ↑ risk of AEs
• not significant in TAH
• treatment only in BR :
– 1 dose prior to surgery
– then BID
– until hospital discharge or POD 7
• 5 studies to prove efficacy
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Time to Upper and Lower GI Recovery
Standard of Care Evaluation and Treatment of Post-Operative Ileus
Widmann, CUMC: Department of Surgery; October 11th, 2007
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Patients Remaining in Hosp.
POD ≥7
1. Advisory Panel Briefing Document, Adolor Corp.
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Patients with Post-Op Morbidity
Dec 06.
May 2006 : Complete response to FDA
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CV-Risk in OBD
May 06
May 2006 : imbalance in MIs
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Nov 06
Entereg regulatory timeline
• Nov 2006 : FDA requires OBD results, safety
(Study GSK014)
1. Biocentury 2008, VOL16, 5
Prescription Drug User Fee Act (PDFUA)
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Safety
OBD
• imbalance in MIs
• imbalance in
neoplasms
• bone fractures↑
POI
• nausea and
vomiting ↓
• other adverse
events =
• mortality =
CLINICAL HOLD in Jun. 2007
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CV-Risk
•
•
•
GSK014 isolated observation
• preexisting CV risk
• 5/7 MIs were enrolled at 2/230 sites
no numerical imbalances in the Worldwide POI
Safety Database
timeframe
• 5/7 MIs occurred within 90 days and no MIs
beyond 111 days
• not relevant in POI
Unexpected
No causal relationship to alvimopan
1. Advisory Panel Briefing Document, Adolor Corp.
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Entereg regulatory timeline
• Aug 2007 : FDA sets PDFUA for POI to
Fev 2008
• Fev 2008 : Approval but need of a REMS
for POI
• May 2008 : Response with REMS,
Approved for POI
• Aug 2008 : End of clinical hold
1. Biocentury 2008, VOL16, 5
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The medical need
treatment of OBD/POI :market and
pharmacoeconomics
2. The drug
– A « long » pre-NDA history
– Pharmacological mode of action
3. Key Clinical results & Regulation Timeline
– The timeline
– Clinical trials
4. RiskMAP & REMS
– First propositions
– Final REMS
1.
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Dec 07
14th Dec. 2007
• « A risk management plan has been
proposed that will communicate the
possible CV risk of longer-term alvimopan
exposure as well as minimize off-label
use »
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Scientific Communication &
Promotion
• Professional labeling :
– MI (GSK014)
– Contraindications (7-day consecutive Opioid treatment)
– Hospital use only
– Approved dosing regimen (15 max)
• Patient Counseling Info. via healthcare professionals
• Limited Promotion
• No samples
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Distribution/pharmacists
• Wholesale Distribution Agreement.
• An electronic notice in retail pharmacy
drug information systems.
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DRG payment
• Cost for Entereg 12 mg covered under the
DRG payment for BR surgery.
• Not for outpatient
DRG :diagnosis related group
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Sep.07
Entereg regulatory timeline
Sept 2007: FDAAA
FDA Amendments Act
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RiskMAP vs REMS
• Under the FDAAA* a Risk Evaluation and Mitigation
Strategy (REMS) is the new legal framework for
risk management plans, specifying timelines and
procedures for submission and review.
• RiskMAP is a tool of REMS. (safety studies,
targeted education and outreach, reminder systems
and performance-linked access systems)
1. 2009 Pharmaceutical Product Development, Inc.
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Feb 08.
Entereg regulatory timeline
Feb 2008:
• « If alvimopan is approved for the POI
indication, do you believe Adolor’s
proposed risk management plan is
adequate to adress the potential risks? »
15/15 Experts answered NO !!!
1. Biocentury 2008, VOL16, 5
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May 08.
20th May. 2008
• In approving Entereg, FDA determined that a REMS is necessary
to ensure that the benefits of Entereg outweigh its risks. The REMS
will include restricting Entereg to inpatient use only, requiring that
hospitals be specially certified, distribution of educational materials
to health care professionals, and regular assessments of the
effectiveness of the REMS.
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Risk Evaluation and Mitigation Strategy
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• Drug Dispensed in Specially Certified
Hospitals
• Direct control over who purchases Entereg
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REMS assessment
• Survey Program (phone, mail, email)
• Questions and Quizz
• Response to surgeon with the right message if errors
were done
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REMS assessment
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1.
Nature Reviews Drug Discovery 7, 963 (December 2008); FDA website
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Different levels of REMS
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1. The medical need
treatment of OBD/POI :market and
pharmacoeconomics
2. The drug
– A « long » pre-NDA history
– Pharmacological mode of action
3. Key Clinical results & Regulation
Timeline
– The timeline
– Clinical trials
4. RiskMAP & REMS
– First propositions
– Final REMS
5. Consequences of delay and perspective
• IP matter
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Data exclusivity/Patent protection
6451806
2020
combinations of alvimopan, methylnaltrexone with a variety of opioid
analgesics for the treatment of pain.
Patent term extension filed
Fda
Orange
Book
1.
FDA orange book october 2008
2.
Drugs R D. 2006 ;7 (4):245-53 16784249
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Competition
• 2004 : Big winners from this delay with Entereg are
Progenics Pharmaceuticals and Wyeth
• Mar 2008 :
• RELISTOR (MTNX) subcutaneous injection was
approved in Canada in April 2008 for the treatment of
opioid-induced constipation in patients with advanced
illness, receiving palliative care
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Key elements for Alvimopan
• 900 hospitals registered
• Net shipments of Entereg were $0.6
million (09/30/08)
• Adolor begins a Phase 4 study of Entereg
in patients undergoing radical cystectomy
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Dec 08.
19th December 2008
• In September, GSK returned to Adolor
worldwide rights to alvimopan for OBD. GSK
retains rights for postoperative ileus (POI).
• Adolor announces it will discontinue
development of Entereg to treat OBD
Adolor (NASDAQ:ADLR) fell $0.73
(33%) to $1.47 on the12/19/08
1. Adolor Press release
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Pain submarkets vs potential
market for alvimopan
Post-Op
Post-Op
Post-Op
Cancer
Cancer
Opioid-treated pain
Gershell and Goater Nature Reviews Drug Discovery 5, 889–890 (November 2006) | doi:10.1038/nrd2179
57
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Why did it take so long?
• Complex project management
– 2 industrial actors
– complex IP situation
– 2 pathologies targeted
• Clinical Facts :
– Efficacy/Dosing concerns initially
– Lethal MIs during OBD clinical trial
• Change in the legal environment during clinical
development :
– RiskMAP → REMS
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