Bifantis

1
Bifantis(Bifidobacterium infantis 35624)

• Clinical Data In
• Irritable Bowel Syndrome
• (IBS)

2
Irritable Bowel Syndrome

• Functional GI condition characterized by
  abdominal pain associated with a change in bowel
  habits (diarrhea, constipation or alternating
  between the two)
• 2nd only to common cold in causes of workplace
  absenteeism
• Accounts for approximately 2.4 to 3.5 million
  physician visits annuallyaverage of 4 to 6
  visits per patient per year
• Total annual costs (direct and indirect) of IBS
  in the United States have been estimated to be
  approximately 30 billion, excluding prescription
  and over-the-counter drug costs

3
Diagnosis of IBS

• No diagnostic test or associated pathology
  diagnosis made primarily by exclusion
• Current standard for diagnosis is the Rome III
  criteria
• Recurrent abdominal pain or discomfort, at least
  3 days/month in the last 3 months associated with
  two or more of the following
• 1. Improved with defecation
• Onset associated with a change in frequency of
  stool
• Onset associated with a change in form
  (appearance) of stool
• Criterion fulfilled for the last 3 months with
  symptom onset at least 6 months prior to
  diagnosis

4
Establishment of the Microflora

• Digestive environment (the microflora) is
  established early in life (as an infant)
• Primarily 5 species bifidobacteria, bacteriodes,
  eubacterium, fusobacterium and peptostreptococcus
• In a healthy state, primary functions of
  microflora are
• a natural defense system
• providing nutrients and metabolic processes
  necessary for proper diet and nutrition
• Changes occur due to diet, infection, stress,
  antibiotic use, travel, etc.
• Altered flora has been documented in the
  literature associated with IBS
• In particular, decreased levels of bifidobacteria
  have been found in IBS subjects

5
Defining Probiotics

• Probiotics are living microorganisms which, upon
  ingestion in certain numbers, exert health
  benefits beyond inherent basic nutrition
• Use of probiotics can be traced to the Ancient
  Roman Historian Plinio (76 AD) who advocated the
  use of fermented milk for the treatment of GI
  infections
• Modern probiotics were first described by
  Metchnikoff in 1907 ingested bacteria, in the
  form of yogurt and other fermented foods, could
  beneficially affect the normal gut flora

6
Desirable Selection Criteria for Probiotics

• Should
• be of human origin
• be nonpathogenic
• be resistant to processing
• be resistant to gastric acidity and bile toxicity
• adhere to gut epithelial tissue
• colonize the GI tract
• produce antimicrobial substances
• modulate immune response
• influence metabolic activities
• be documented and assessed independently

Lee Salminen 1995
7
Probiotics for IBS

• All probiotics are currently marketed in the U.S.
  as dietary supplements
• A few probiotics have been demonstrated to have
  benefits in digestive disorders
• Travelers diarrhea, antibiotic-induced diarrhea
• Several probiotic products make claims of
  benefits in IBS however, they are not backed by
  solid evidence
• Scarcity of well-controlled clinical trials
  published
• Poor-quality control results and formulation in
  inability to sustain live bacteria in product
• Use of strains that are not purified

8
Bifidobacterium infantis 35624

• Only probiotic species known to be isolated from
  a healthy human colon
• Demonstrates ability to adhere to mucosal tissue
• Complete genome has been sequenced
• No regions that code for pathogenicity were found
• Formulated into a capsule that is shelf-stable at
  room temperature
• Industry-leading quality control methods being
  used in production to ensure viability and purity
  of finished product

9
Bifidobacterium infantis AH 35624
10
Initial Clinical Trial in IBS

• Double-blind, placebo-controlled, parallel
  14-week study in 77 male and female IBS
  suffererers
• 2-week run-in, 8 weeks of treatment with 4 weeks
  of follow-up
• Milk-based formulation at dosage of 1 x 1010 CFU
  per day
• Compared B. infantis 35624 to L. salivarius 43331
  and placebo
• Results indicated improvement in abdominal pain,
  bloating and bowel movement difficulty (composite
  score) with B. infantisbut not the Lactobacillus
  strain.
• Also found a marked immunologic difference
  between IBS patients and controls.

OMahony et al. Gastroenterology 2005
(128)541-551.
11
Figure 1. Comparison of the effects of placebo,
L. salivarius UCC43331 and B. infantis 35624 on
a composite score of IBS symptoms.
12
Figure 5. Comparison of PBMC IL-10/IL-12 ratios
at baseline and following therapy with placebo,
L. salivarius UCC43331 and B. infantis 35624 with
that of a normal control period.
300
300
p0.001
p0.001
Pre
treatment
Pre
treatment
Post
treatment
Post
treatment
250
250
200
200
ratio
ratio
12
12
-
-
150
150
10IL
10IL
-
-
IL
IL
100
100
50
50
0
0
Healthy
Healthy
B. infantis 35624
L. salvarius 4331
Placebo
B. infantis 35624
L. salvarius 4331
Placebo
Volunteers
Volunteers


13
Second Clinical Trial in IBS

• Double-blind, placebo-controlled, parallel 8-week
  study in 362 female IBS suffererers
• 2-week run-in, 4 weeks of treatment with 2 weeks
  of follow-up
• Capsule formulation at 3 dose levels of B.
  infantis 35624
• 1 x 1010 CFU per day
• 1 x 108 CFU per day
• 1 x 106 CFU per day
• Compared B. infantis 35624 to placebo
• Results indicated improvement for all the
  cardinal symptoms of IBS pain, bloating and
  bowel movement difficulty with B. infantis 35624.
• Also found benefits for normalization of bowel
  movement frequency across all IBS subtypes.

14
Figure 2. Comparison of effects of placebo and
Bifidobacterium infantis 35624 on abdominal
pain/discomfort.
Whorwell et al. Am J Gastroenterol
20061011581-1590.
15
Figure 4. Comparison of effects of placebo and
Bifidobacterium infantis 35624 on IBS composite
score.
Whorwell et al. Am J Gastroenterol
20061011581-1590.
16
Figure 5. Comparison of effects of placebo and
Bifidobacterium infantis 35624 on Subjects
Global Assessment (SGA) of IBS symptoms. Positive
response rates recorded at wk 4 at the end of
therapyyes or no response Please
consider how you felt in the past week in regard
to your IBS, in particular your general
well-being, and symptoms of abdominal discomfort
or pain, bloating or distension and altered bowel
habit. Compared to the way you felt before
beginning the medication, have you had adequate
relief of your IBS symptoms?
Whorwell et al. Am J Gastroenterol
20061011581-1590.
17
Distribution by IBS Subtype
Quigley et al. Presentation at ACG, 2005.
Honolulu, Hawaii.
18
Normalization Analysis

• For analysis, normalization defined as movement
  toward 1-2 BM/day (25th to 75th percentile)
• 2-week baseline data (actual number of daily BMs)
  used to determine distribution across study

Quigley et al. Presentation at ACG, 2005.
Honolulu, Hawaii.
19
Response RateNormalization Effect
Percent of subjects outside 25th-75th percentile
at baseline (1-2.29 BM/day) that moved to
normal range at Week 4Treatment difference of
23
P0.05
Bifantis 1 x 108
Placebo
Note There was no significant change among
subjects who began study in 25th to 75th
percentile for either Bifido or Placebo.
Quigley et al. Presentation at ACG, 2005.
Honolulu, Hawaii.
20
Tolerability of B. infantis 35624

• In the second study of 362 total subjects
• 17 subjects withdrew due to adverse events (AEs)
• 9 from the placebo group
• 8 from the three treatment groups combined
• The majority were occasioned by worsening of IBS
  symptoms.
• The overall incidence of all AEs was similar in
  the four groups
• with IBS-like symptoms
• 48 placebo 29
• 37 1 x 106 37
• 52 1 x 108 28
• 43 1 x 1010 24
• The incidence of severe AEs adjudged as
  treatment related was highest in the placebo
  group at 9 rates for the three treatment groups
  were 0, 1 and 2, respectively

Quigley et al. Gastroenterology 2006130
(S2)A493.
21
Conclusions

• Two well-controlled, properly powered studies
  have demonstrated effectiveness of B. infantis
  35624 in the management of IBS.
• Benefits of B. infantis 35624 are evident
  regardless of IBS subtype
• B. infantis 35624 results in a normalization
  effect.
• Increases frequency of BMs in subjects with less
  than one BM daily (constipation)
• Decreases frequency of BMs in subjects with more
  than 2.5 BMs daily (diarrhea)