Core set

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Safety Efficacy of Alosetron
Allen Mangel, M.D., Ph.D.International
DirectorGastroenterology International Product
Development Leader, Alosetron
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Alosetron

• Potent and Selective 5HT3 receptor antagonist
• 5HT3 receptors participate in motor and sensory
  processes in the gut

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Study Design (S3BA3001/S3BA3002)
2 weeks
4 weeks
12 weeks
Screening
Follow-up (No treatment)
Treatment (BID)Placebo Alosetron 1 mg
Diarrhea-predominant Alternating bowel pattern
Female Only
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Primary Endpoint

• Adequate relief of IBS pain and discomfort
• In the past seven days have you had adequate
  relief of your irritable bowel syndrome pain and
  discomfort?

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In the Past Seven Days Have You Had Adequate
Relief of Your Irritable Bowel Syndrome Pain and
Discomfort?
(Diarrhea-Predominant)
S3BA3001
S3BA3002
Treatment
Treatment
Follow-up
Follow-up





















With Adequate Relief
Week
Week
placebo alosetron
plt0.05
LOCF
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Have You Felt or Experienced a Sense of Urgency
Today?
(Diarrhea-Predominant)
S3BA3001
S3BA3002
Follow-up
Treatment
Treatment
Follow-up

Days






















Week
Week
placebo alosetron
plt0.05
LOCF
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Please Enter the Number of Times You Have Passed
Stool Today
(Diarrhea-Predominant)
S3BA3001
S3BA3002
Follow-up
Treatment
Treatment
Follow-up
Stools/Day
























Week
Week
placebo alosetron
plt0.05
LOCF
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Please Rate the Consistency OfYour Stool Today
(Diarrhea-Predominant)
S3BA3001
S3BA3002
Follow-up
Treatment
Treatment
Follow-up
Firmer Consistency Score
























Week
Week
placebo alosetron
plt0.05
LOCF
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Efficacy Update
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International Comparator

• Two studies 600 patients each
• Compare alosetron to mebeverine (antispasmodic)
  or trimebutine (opioid acting agent)

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In the past seven days have you had adequate
relief of your irritable bowel syndrome pain and
discomfort? (Diarrhea-Predominant)
S3BB3001
S3BB3002
Treatment
Follow-up
Treatment
Follow-up
With Adequate Relief
With Adequate Relief
Week
Week
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S3B30011

• Recently completed
• 783 female diarrhea predominant IBS patients
• Twelve week treatment phase
• 21 (alosetron placebo) randomization

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IBS Global Improvement Question

• Compared to the way you usually felt during the
  3 months before you entered the study, are your
  IBS symptoms over the past 4 weeks
• Substantially worse
• Moderately worse
• Slightly worse
• No change
• Slightly improved
• Moderately improved
• Substantially improved

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Global Improvement Responder





Responders
plt0.05
Month
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Efficacy Conclusion

• IBS is a multidimensional disorder
• In diarrhea-predominant female patients alosetron
  produces robust improvement on multiple endpoints

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Safety
Constipation
Ischemic Colitis
Hepatic Function
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Agreements With FDA Prior To June 27, 2000

• No change in frequency and/or severity of
  ischemic colitis since approval of alosetron
• Number of cases of ischemic colitis and serious
  constipation reconciled
• At the November 16, 1999 Advisory Committee
  meeting alternative etiologies for some of the
  cases for ischemic colitis were presented.
  However, at the request of the FDA, pathology of
  ischemic colitis would not be discussed.

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2 Databases (June 1, 2000)

• Clinical Trials
• 3000 subjects at approval
• 6852 subjects as of June 1, 2000
• Post-Marketing Spontaneous
• 130,000 prescriptions

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Constipation

• Potential Complications
• Impaction
• Obstruction
• Ileus
• Megacolon
• Perforation

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Constipation (Phase II/III)

• 27 of patients developed constipation (5
  placebo patients)
• Of the patients who became constipated, 65
  reported mild to moderate constipation
• 75 of constipated patients had only one episode
• 10 of patients in Phase II/III withdrew
  secondary to constipation

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Constipation (Phase III)Management

• Four consecutive days without a bowel movement
• Brief (up to 4 days) interruption of alosetron
• Occurred in 9 of alosetron treated patients
• 88 of patients resumed bowel movement during the
  interruption

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Constipation

• At approval
• No serious events
• June 1, 2000
• 2 reports in clinical development
• 4 reports in spontaneous database
• No deaths

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Constipation - Clinical Trials (Hospitalized)

• Duration of AlosetronEvent Age (Days) Other
  Factors
• Impaction 54 7 Previously disimpacted
• Constipation
• Colectomy 56 27 Constipation
• (Obstruction, Dense abdominal
• megacolon, 2o ischemia) adhesions

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Constipation - Spontaneous Reports (Hospitalized)

• Duration of AlosetronEvent Age (Days) Other
  Factors
• Stercoral ulcer 48 7 History of idiopathic
  constipation
• Impaction/SBO 50 21
• Loop colostomy 68 2 Sigmoid stricture (18 days
  after d/c colitis
• Alosetron)
• Sigmoid perforation 72 17 Hydrocodone
• No report of constipation before surgery

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Constipation Conclusion

• Most frequent adverse event
• Rare reports of complications of constipation
  have been reported since approval
• Pre-existing constipation was reported
• No deaths

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Ischemic Colitis
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Ischemic Colitis - Clinical Trials

• At approval (clinical development)
• 4 reports/3000 subjects (1750)
• June 1, 2000
• 3 New reports
• 7 Total reports/6852 subjects (1979)
• Acute, transient ischemic colitis
• No sequelae/no change in severity
• No deaths

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Ischemic Colitis - Spontaneous(June 1, 2000)

• 130,000 prescriptions dispensed
• Spontaneous Reports 5
• Acute, transient and self limiting
• No sequelae
• No deaths

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Chronic Colitis

• ColonicSurgeryDate Unknown

InitiateAlosetron3/16/00
StopAlosetron3/22/00
InitiatePrednisone4/00
ColonicSurgery6/4/00
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Ischemic Colitis

• Three large private GI practices(5/95-5/2000)
• 110,000 patients
• 188 cases of ischemic colitis
• Duke Database (7/93-11/99)
• 14,478 colonoscopies
• 130 cases of ischemic colitis

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Ischemic Colitis Conclusion

• No change in frequency and/or severity of
  ischemic colitis
• All cases represented acute, transient ischemic
  colitis
• No sequelae noted
• No deaths

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Hepatic Function
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ALT (gt3x Normal)

• Time Placebo Alosetron
• Pre-approval 0.4 0.5
• Post-approval 0.9 0.4
• Total 0.43 0.42

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Alkaline Phosphatase/Bilirubin

• Parameter Placebo Alosetron
• Alk Phos 0.07 0.09
• (2X Normal)
• Bilirubin 0.29 0.12
• (2X Normal)
• No alosetron treated subjects had ALT gt3X and
  Bili gt2X

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Elevated Liver Enzymes

• One patient with hepatitis (without jaundice) in
  label at time of approval
• Two additional narratives from spontaneous
  reports in briefing document one case with
  multiple confounding factors

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Hepatic Function Conclusions

• No signal
• Rates similar to placebo

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Other Serious Events(21 Total - 11
Reviewed)(130,000 Prescriptions)

• Abdominal Pain (n2)
• Overdose Other Medications (n2)
• Syncope (n1)
• CVA (n1)
• Bloody Diarrhea (n1)
• Chest Pain (n1)
• Acute Enteritis (n1)
• Viral Meningitis (n1)

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Overall Conclusion

• IBS is a significant disease with a large burden
  of illness for the individual patient
• Alosetron produces robust multidimensional
  improvement (pain, urgency, frequency,
  consistency), in the treatment of female
  diarrhea-predominant IBS patients

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Overall Conclusion (continued)

• No change in the frequency and/or severity of
  ischemic colitis since approval
• Rare complications of constipation have been
  observed
• Overall risk-benefit shows clear benefits of
  alosetron

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