AMT-101, a gut selective oral IL-10 fusion: Results from a ...
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AMT-101, a gut selective oral IL-10 fusion: Results from a Phase 1b study in patients with active Ulcerative Colitis Maximillian Posch 1 , Raisa Tanase 2 , Konstantine Maisaia 3 , Alina Jucov 4 , Christian Geier 5 , Drew Hotson 6 , Omar Hamdy 6 , J. Andrew Whitney 6 , Marvin Garovoy 6 , Bittoo Kanwar 6 , and Stefan Schreiber 5 BACKGROUND METHODS RESULTS CONT’D CONCLUSIONS 1 mg N = 3 3 mg N = 3 10 mg N = 3 30 mg N = 3 Randomized, placebo-controlled, multiple ascending dose study to assess safety and guide dose selection for Phase 2 Placebo N = 4 Ulcerative Colitis Patients - Active symptoms - Biologic naïve patients - 14 days of once daily oral treatment 16 patients: 3 active, 1 placebo per cohort Endpoints: - Standard safety assessments - Objective measures of disease activity (e.g., fecal calprotectin, CRP, central read histology) Biomarker Assessments - Extensive blood collection for PK and serum biomarkers - Tissue and stool collected pre-treatment and end of treatment - FACS, RNAseq, IHC, microbiome analysis RESULTS • Disease severity was balanced through groups with a mean Mayo Score of 7.2. • AMT-101 was safe and well tolerated (Table 1). • By design, no systemic PK was observed confirming gut-selectivity. • Objective markers of disease activity revealed early signs of clinical activity (Figures 1 and 2). • Biomarker assessments revealed favorable changes in microbiome. No clear changes in immune compartment were detected. Bacteroidetes Firmicutes Proteobacteria Actinobacteria Other 1 2 0.0 0.5 1.0 3 4 5 6 1 2 0.0 0.5 1.0 3 4 1 2 0.0 0.2 0.4 0.6 0.8 1.0 3 4 5 6 1 2 0.0 0.5 1.0 3 4 1mg 3mg 30mg Placebo Baseline Week 2 Baseline Week 2 Baseline Week 2 Baseline Week 2 Baseline Week 2 Baseline Week 2 Baseline Week 2 Baseline Week 2 Baseline Week 2 Baseline Week 2 Faecalibacterium prausnitzii 20% 10% 0% Relative Abundance Baseline Week 2 Baseline Week 2 Baseline Week 2 Week 2 Baseline • AMT-101 is an oral, gut-selective, fusion protein of IL-10 and a carrier protein (Chx386) that mediates transcytosis through intestinal enterocytes into the lamina propria (LP). 1 • IL-10 is a pleiotropic immunomodulatory cytokine that restores mucosal homeostasis. • Subcutaneous use of recombinant human IL-10 treatment in patients with Crohn’s Disease led to symptomatic and endoscopic improvement, but dose limiting systemic toxicities (anemia and thrombocytopenia) were observed with systemic treatment. 2 • Pre-clinical studies demonstrated that AMT-101 efficiently transits the epithelial cell barrier, targets mucosal immune cells in the LP, and results in improved colitis disease severity without systemic exposure. 1. Fay NC, et al. A Novel Fusion of IL-10 Engineered to Traffic across Intestinal Epithelium to Treat Colitis. J Immunol. 2020. 205(11):3191-3204 2. Stefan et al. Safety and efficacy of recombinant human interleukin 10 in chronic active Crohn's disease. Schreiber, Gastroenterology, 2000, Volume 119, Issue 6, 1461 - 1472 • Once daily, oral AMT-101 was safe and well tolerated: • AEs previously observed with systemic IL-10 (anemia and thrombocytopenia) were not detected. • No systemic PK was detected, as expected with gut-selective therapy. • After only 14 days of treatment, potential clinical efficacy observed at doses 10 mg or less: • Reduction in average CRP and calprotectin levels • Enhancement of favorable enteric commensal bacteria • Histological improvements in 6/10 active vs 0/2 placebo • These findings support AMT-101 as actively exerting an immunomodulatory effect by targeting LP immune cells resulting in local and systemic benefit. • Data support ongoing Ph2 trials of AMT-101 in UC (monotherapy and combination), pouchitis, and rheumatoid arthritis. A) Change in FCP B) Change in CRP Placebo adjusted mean reductions of 44% and 27% in the 1 mg and 3 mg dose groups Local gut delivery of IL-10 may result in localized as well as systemic immunomodulatory effects Figure 2. Histopathology Improvement in UC Patients After 14 Days of Treatment with AMT-101 Figure 1. Changes in A) patients with > 150 ug/g Fecal Calprotectin (FCP) and B) in patients with > 5mg/L C-Reactive Protein (CRP) Were Observed After 14 Days of Oral Treatment with AMT-101 Figure 3. Microbiome Changes Observed in AMT-101 Treatment Groups • Modulation of microbiome observed in lower doses of AMT-101 (1mg and 3mg cohorts; 14-day treatment) • Increase in Bacteroidetes:Actinobacteria ratio • Increase in butyrate-producing F prausnitzii observed • A decrease in F. prausnitzii is associated with IBD 3 ACKNOWLEDGEMENTS We thank the patients and clinical sites for participating in this study. NCT04224857 1 Charité Research Organisation GmbH, Charitéplatz 1, 10117 Berlin, Germany 2 ARENSIA Exploratory Medicine, Republican Clinical Hospital ‘Nicolae Testemitanu’, Chisinau, Moldova 3 ARENSIA Exploratory Medicine LLC, Tbilisi, Georgia 4 ARENSIA Exploratory Medicine, Republican Clinical Hospital and Nicolae Testemitanu State University of Medicine and Pharmacy, Chisinau, Moldova 5 University Hospital Schleswig-Holstein, Dep. Medicine, Kiel, Germany 6 Applied Molecular Transport, 1 Tower Place, Suite 850, South San Francisco, CA 94080 USA Transcytosis Function (Carrier Protein) AMT-101 AMT-101 Table 1. Ph1b 14 day safety data 3) Lopez-Siles M, Duncan SH, Garcia-Gil LJ, Martinez-Medina M. Faecalibacterium prausnitzii: from microbiology to diagnostics and prognostics. ISME J. 2017 Apr;11(4):841-852. doi: 10.1038/ismej.2016.176. Epub 2017 Jan 3. 1mg 3mg 30mg Placebo
Transcript of AMT-101, a gut selective oral IL-10 fusion: Results from a ...
AMT-101, a gut selective oral IL-10 fusion: Results from a Phase 1b study in patients with active Ulcerative ColitisMaximillian Posch1, Raisa Tanase2, Konstantine Maisaia3, Alina Jucov4, Christian Geier5, Drew Hotson6, Omar Hamdy6, J. Andrew Whitney6, Marvin Garovoy6, Bittoo Kanwar6, and Stefan Schreiber5
BACKGROUND
METHODS
RESULTS CONT’D
CONCLUSIONS
1 mgN = 3
3 mgN = 3
10 mgN = 3
30 mgN = 3
Randomized, placebo-controlled, multiple ascending dose study to assess safety and guide dose selection for Phase 2
PlaceboN = 4
Ulcerative Colitis Patients- Active symptoms- Biologic naïve patients- 14 days of once daily oral treatment
16 patients: 3 active, 1 placebo per cohort
Endpoints:- Standard safety assessments- Objective measures of disease activity (e.g.,
fecal calprotectin, CRP, central read histology)
Biomarker Assessments- Extensive blood collection for PK and serum biomarkers- Tissue and stool collected pre-treatment and end of treatment
- FACS, RNAseq, IHC, microbiome analysis
RESULTS• Disease severity was balanced through groups with a mean Mayo Score of 7.2.• AMT-101 was safe and well tolerated (Table 1).• By design, no systemic PK was observed confirming gut-selectivity.• Objective markers of disease activity revealed early signs of clinical activity
(Figures 1 and 2).• Biomarker assessments revealed favorable changes in microbiome. No clear
changes in immune compartment were detected.
1 2 3 40.0
0.5
1.0
Placebo
Bacteroidetes
Firmicutes
Proteobacteria
Actinobacteria
Other
1 2 3 4 5 60.0
0.5
1.0
1mg
Bacteroidetes
Firmicutes
Proteobacteria
Actinobacteria
Other
1 2 3 4 5 60.0
0.5
1.0
1mg
Bacteroidetes
Firmicutes
Proteobacteria
Actinobacteria
Other
1 2 3 4 5 60.0
0.5
1.0
1mg
Bacteroidetes
Firmicutes
Proteobacteria
Actinobacteria
Other
1 2 3 40.0
0.5
1.0
Placebo
Bacteroidetes
Firmicutes
Proteobacteria
Actinobacteria
Other
1 2 3 40.0
0.5
1.0
Placebo
Bacteroidetes
Firmicutes
Proteobacteria
Actinobacteria
Other
1 2 3 4 5 60.0
0.2
0.4
0.6
0.8
1.0
3mg
Bacteroidetes
Firmicutes
Proteobacteria
Actinobacteria
Other
1 2 3 4 5 60.0
0.2
0.4
0.6
0.8
1.0
3mg
Bacteroidetes
Firmicutes
Proteobacteria
Actinobacteria
Other
1 2 3 4 5 60.0
0.2
0.4
0.6
0.8
1.0
3mg
Bacteroidetes
Firmicutes
Proteobacteria
Actinobacteria
Other
1 2 3 40.0
0.5
1.0
30mg
Bacteroidetes
Firmicutes
Proteobacteria
Actinobacteria
Other
1 2 3 40.0
0.5
1.0
30mg
Bacteroidetes
Firmicutes
Proteobacteria
Actinobacteria
Other
1mg 3mg 30mg Placebo
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• AMT-101 is an oral, gut-selective, fusion protein of IL-10 and a carrier protein (Chx386) that mediates transcytosis through intestinal enterocytes into the lamina propria (LP). 1
• IL-10 is a pleiotropic immunomodulatory cytokine that restores mucosal homeostasis.
• Subcutaneous use of recombinant human IL-10 treatment in patients with Crohn’s Disease led to symptomatic and endoscopic improvement, but dose limiting systemic toxicities (anemia and thrombocytopenia) were observed with systemic treatment.2
• Pre-clinical studies demonstrated that AMT-101 efficiently transits the epithelial cell barrier, targets mucosal immune cells in the LP, and results in improved colitis disease severity without systemic exposure.
1. Fay NC, et al. A Novel Fusion of IL-10 Engineered to Traffic across Intestinal Epithelium to Treat Colitis. J Immunol. 2020. 205(11):3191-32042. Stefan et al. Safety and efficacy of recombinant human interleukin 10 in chronic active Crohn's disease. Schreiber, Gastroenterology, 2000, Volume 119, Issue 6, 1461 - 1472
• Once daily, oral AMT-101 was safe and well tolerated:• AEs previously observed with systemic IL-10 (anemia and thrombocytopenia)
were not detected.• No systemic PK was detected, as expected with gut-selective therapy.
• After only 14 days of treatment, potential clinical efficacy observed at doses 10 mg or less:
• Reduction in average CRP and calprotectin levels • Enhancement of favorable enteric commensal bacteria • Histological improvements in 6/10 active vs 0/2 placebo
• These findings support AMT-101 as actively exerting an immunomodulatory effect by targeting LP immune cells resulting in local and systemic benefit.
• Data support ongoing Ph2 trials of AMT-101 in UC (monotherapy and combination), pouchitis, and rheumatoid arthritis.
A) Change in FCP B) Change in CRP
Placebo adjusted mean reductions of 44% and 27% in the 1 mg and 3 mg dose groups
Local gut delivery of IL-10 may result in localizedas well as systemic immunomodulatory effects
Figure 2. Histopathology Improvement in UC Patients After 14 Days of Treatment with AMT-101
Figure 1. Changes in A) patients with > 150 ug/g Fecal Calprotectin (FCP) and B) in patients with > 5mg/L C-Reactive Protein (CRP) Were Observed After 14 Days of Oral Treatment with AMT-101
Figure 3. Microbiome Changes Observed in AMT-101 Treatment Groups
• Modulation of microbiome observed in lower doses of AMT-101 (1mg and 3mg cohorts; 14-day treatment)
• Increase in Bacteroidetes:Actinobacteria ratio• Increase in butyrate-producing F prausnitzii observed
• A decrease in F. prausnitzii is associated with IBD3
ACKNOWLEDGEMENTSWe thank the patients and clinical sites for participating in this study.NCT04224857
1 Charité Research Organisation GmbH, Charitéplatz 1, 10117 Berlin, Germany 2ARENSIA Exploratory Medicine, Republican Clinical Hospital ‘Nicolae Testemitanu’, Chisinau, Moldova3 ARENSIA Exploratory Medicine LLC, Tbilisi, Georgia4 ARENSIA Exploratory Medicine, Republican Clinical Hospital and Nicolae Testemitanu State University of Medicine and Pharmacy, Chisinau, Moldova5 University Hospital Schleswig-Holstein, Dep. Medicine, Kiel, Germany6 Applied Molecular Transport, 1 Tower Place, Suite 850, South San Francisco, CA 94080 USA
Transcytosis Function(Carrier Protein)
AMT-101
AMT-101
Table 1. Ph1b 14 day safety data
3) Lopez-Siles M, Duncan SH, Garcia-Gil LJ, Martinez-Medina M. Faecalibacterium prausnitzii: from microbiology to diagnostics and prognostics. ISME J. 2017 Apr;11(4):841-852. doi: 10.1038/ismej.2016.176. Epub 2017 Jan 3.
1mg 3mg 30mg Placebo
