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BACKGROUND & AIMS
AVX-470 is an oral, enteric-coated, bovine-derived, polyclonal
antibody designed to target TNF in the gastrointestinal (GI) tract
without significant systemic exposure. AVX-470 was evaluated in a
double-blind, placebo-controlled, first-in-human trial undertaken to
explore the pharmacodynamics (bio-markers, clinical, endoscopic
response), pharmacokinetics (tissue, stool, systemic bioavailability),
immunogenicity & safety of 4 weeks of AVX-470 administration in
patients with active ulcerative colitis (UC).
• AVX-470 was well-tolerated with no drug-
related SAEs, opportunistic infections or
allergic reactions.
• AVX-470 was stable in passage through the
GI tract and was not associated with
significant systemic exposures. No
immunogenicity was observed.
• Bovine Ig was shown to penetrate the colonic
mucosa, even in areas of normal endoscopic
activity. However, prior dietary exposures
interfered with detection of changes in tissue
levels.
• Efficacy trends were observed across multiple
parameters (clinical, endoscopic, biomarker)
of disease activity, most favoring the 3.5g/d
dose group.
• This is the first study to suggest the benefit of
an orally delivered, locally-active agent in a
moderate-severe UC population. Future
studies will examine the effects of higher
doses and longer dose duration.
1Avaxia Biologics, Lexington, MA, USA. 2Toronto Digestive Disease Associates, Toronto, ON, Canada. 3Nashville Medical Research Institute, Nashville, TN, USA 4University Hospital Gasthuisberg, Leuven, Belgium.
Pharmacokinetics, Pharmacodynamics, Immunogenicity, and Safety of AVX-470, an Oral, Bovine-Derived Anti-TNF Antibody, in Patients with Active Ulcerative Colitis (UC): Initial Human Experience
A concurrent use 36.1%; B concurrent use 30.6%
a uncontrolled UC activity during Week 1 of treatment; b Patient withdrew
before first dosing; c recurrence of nausea and dysphagia for medications,
established pre-study, precluded continued study participation
Parameter
Placebo
(n = 9)
0.2 g/d
(n = 8)
1.6 g/d
(n = 12)
3.5 g/d
(n = 7)
Pooled
Active
(n = 27)
Overall
(n = 36)
All, n (%) A 7 (77.8) 3 (37.5) 6 (50.0) 5 (71.4) 14 (51.9) 26 (72.2)
AEs (Total) B 13 (100.0) 8 (100.0) 13 (100.0) 13 (100.0) 34 (100.0) 47 (100.0)
Mild 9 (69.2) 7 (87.5) 10 (77.0) 9 (69.2) 26 (76.5) 35 (74.5)
Moderate 4 (30.8) 1 (12.5) 2 (15.9) 4 (30.8) 7 (20.6) 12 (23.4)
Severe 0 (0.0) 0 (0.0) 1 (7.7)† 0 (0.0) 1 (2.9) 1 (2.1)
SAEs, n (%) A 0 (0.0) 0 (0.0) 1 (8.3)† 0 (0.0) 1 (3.7) 1 (2.8)
AEs of Special
Interest C 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Treatment-Emergent AEs (TEAEs)
A no. of patients experiencing AEs, n (%); B no. of AEs, n (%); C allergic
reaction or opportunistic infection; † worsening UC on Day 3 of study drug
M. Scott Harris, M.D., Chief Medical Officer
Avaxia Biologics Inc.
128 Spring St, Lexington, MA, USA
email: [email protected]
CONTACT
Study Enrollment and Disposition
Demographics
METHODS
BACKGROUND & AIMS
RESULTS
CONCLUSIONS
Screening F/U Double-blind treatment
Colonoscopy-Biopsy
Biomarkers
Colonoscopy-Biopsy
Biomarkers
Week -3 0 4
- 36 patients with active UC - 13 centers in US, Canada, Belgium and Hungary - 4 weeks treatment, 3 ascending-dose cohorts - 0.2 g/d BID, 1.6 g/d BID, and 3.5 g/d TID in divided doses -Within each cohort, patients randomized 3:1 to AVX-470 or placebo
- Colonoscopy with central reading at Baseline and Week 4 - biopsy from cecum/ascending, transverse, descending, sigmoid, & rectum
Barbara S. Fox1, Deborah S. Hartman1, Sharon Spence1, Sally Kennedy1, Theodore Ptak2, Ron Pruitt3, Séverine Vermeire4, M. Scott Harris1
Advantages of Oral Gut-Targeted Anti-TNF Antibodies
Pla
ceb
o
0.2
g/d
ay
1.6
g/d
ay
3.5
g/d
ay
-3 0
-2 0
-1 0
0
1 0
2 0
p = 0.047
† Fold Change
IHC staining index
Changes in TNF Levels in Colon
Tissue Across Treatment Arms
AVX-470 Reduces TNF in Colon:
Direct Effect on Therapeutic Target
TNF immunohistochemistry (IHC) staining in sigmoid colon (A, B) and
rectum (C, D) at baseline (A, C) and Week 4 (B, D) in AVX-470 3.5 g/d
group. Brown staining indicates TNF protein. Magnification 400x.
Lack of Immunogenicity
Competition ELISA
Pharmacokinetics
Bovine immunoglobulin (Ig)
in stool by ELISA analysis
Bovine Ig in colon tissue
by IHC staining
Calculated levels of
TNF binding antibodies
Stool Tissue Serum
0
20
40
60
80
Placebo 0.2 1.6 3.5
AVX-470 (g/d)
% p
ositiv
e s
am
ple
s
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Se
rum
le
ve
ls (
μg
/mL
)
Literature values
SUMMARY: AVX-470 is confined to the GI tract
Parameter
Placebo
(n = 9)
0.2 g/d
(n = 8)
1.6 g/d
(n = 12)
3.5 g/d
(n = 7)
Pooled
Active
(n = 27)
Clinical Response 1/9 (11.1) 3/8 (37.5) 2/12 (16.7) 2/7 (28.6) 7/25 (25.9)
Clinical Remission 0 0 0 1/7 (14.3) 1/27 (3.7)
Endoscopic Response 0 0 1/12 (8.3) 1/7 (14.3) 2/27 (7.4)
Endoscopic Remission 0 0 1/12 (8.3) 1/7 (14.3) 2/27 (7.4)
† expressed as n/N (%)
Clinical & Endoscopic Remission†
Clinical Response Reduction of ≥ 3 points on the total Mayo score and an overall decrease of at least 30%, plus a decrease in the rectal bleeding subscore of at least 1-point or an absolute rectal bleeding score of 1 or less
Clinical Remission: Total Mayo score of 2 or lower and no subscores higher than 1
Endoscopic Response: 1-point decrease in Mayo endoscopic subscore
Endoscopic Remission: Mayo endoscopic subscore of 0-1
5
†3.5 g/day vs placebo;
two-tailed, unpaired t-
test of geometric means
of changes across five
colon segments No change from Baseline in serum levels of HABA (human anti-bovine
antibody) in AVX-470 or placebo treatment arms.
The authors would like to acknowledge Daniel E. Tracey, Brenda Lemos, Emma Erlich, Dave Keane & Rutvij Patel (current and former employees of Avaxia Biologics) for their contributions to the biomarker analysis.
ACKNOWLEDGEMENTS
p = 0.015
Ch
ange
in S
eru
m I
L-6
pg/
ml
Pla
ceb
o
0.2
g/d
ay
1.6
g/d
ay
3.5
g/d
ay
-1 5
-1 0
-5
0
5
1 0
1 5
* *Change in IL-6
compared by ANCOVA
as a function of
treatment adjusting for
baseline: AVX-470 3.5 g
vs. placebo (p = 0.015).
Changes in Serum IL-6 Levels
Across Treatment Arms
Changes in Serum CRP Levels
Across Treatment Arms & Duration
Ch
ange
in S
eru
m C
RP
ug/
ml
Week 1
Week 2
Week 3
Week 4
-3 0
-2 0
-1 0
0
1 0
2 0
p = 0.052
†
p = 0.058
††
† 3.5 g/day vs placebo – two-sided, two-sample paired t-tests †† Week 4 vs baseline CRP, paired analysis
Change over 4 weeks Time course of change (3.5 g/d)
Change over 4 weeks
Change over 4 weeks
Stool, tissue, and serum samples collected at Week 4