Customized Phage Therapies To Eradicate Harmful Bacteria In Chronic Diseases. Europe Microbiome Congress London, 14 Nov., 2018

Transcription

1 Customized Phage Therapies To Eradicate Harmful Bacteria In Chronic Diseases Europe Microbiome Congress London, 14 Nov., 2018

2 Biomx At A Glance We are a microbiome drug discovery company developing customized phage therapies that target and destroy harmful bacteria in chronic diseases such as IBD and cancer Global Cosmetic Big Pharma Scientific Founders Investors Prof. Eran Elinav MD, PhD WIS Microbiome Prof. Rotem Sorek PhD WIS Phage-bacteria Defense Systems Prof. Timothy K Lu PhD MIT Synthetic Biology 8VC

3 Growing Evidence Of Harmful Bacteria Role In Chronic Diseases Gastric Cancer H. Pylori IBD Kleibsiella Colon Cancer Fuso Proven to be directly linked to gastric cancer Oct Jan Disease State Oct Induce Inflammation

4 Phage Evolved Naturally to Target and Destroy Specific Bacteria Engineered by Nature: Specific to targeted bacterial strains Amplifying at target Self-limiting - replication dependent on host existence History of safety in humans Key takeaways from FDA Workshop, DC, July 2017 Safety relies on phage attributes; GLP healthy animal safety studies considered non-informative Phase 1 can move straight to patients or carriers of target bacteria Phage have been approved in the past as GRAS Images adopted from multiple web sites

5 BiomX Technology Platform License Target Discovery Platform Acquisition - Target Discovery Platform License - Phage Discovery Platform License Phage SynBio Methods Target Discovery Phage Discovery Pre-Clinical /Clinical Confirmed Target - Identify bacterial target + functional validation Customized Phage Cocktail Cocktail optimization, in-vivo efficacy

6 A Robust, Cloud based Big Data Microbiome Analysis Platform for Target Discovery PROPRIETARY APPROACHES/ALGORITHMS Founded by Israeli IT entrepreneurs building a robust, cloud based discovery platform BACTERIA GROWTH DYNAMICS BACTERIA RNA RESPONSE - MOA RAW DATA Metagenomics DATABASE Metatranscriptome Data Integration Genes Pathways 10K s of strains Mining Target Bacterial Strains Metadata Growth Dynamics 6

7 Phage Discovery Target Target Discovery Phage Discovery Pre-Clinical /Clinical Considerations Designing Customized Phage Cocktails Resistance Host Range Lysogenic/Lytic Harmful Genes Study Bacterial Mutations Structure/function of bacteria and phage Expand Host Range A. Phage Combinations B. Synthetic Biology Bacteria Phage Database Biofilm Degradation Formulation Other Evaluate Biofilm Degradation Capacity Biofilm Growth (white circles) Left Antibiotic Right Phage Cocktail Customized Phage Cocktail Long Term Stability Studies Developing formulations stable at room temp. for >1 year

8 Density (OD) Phage Discovery Synthetic Biology Target Target Discovery Phage Discovery Pre-Clinical /Clinical Example 1 Convert Lysogenic to Lytic Why - Lysogenic phage insert DNA into target bacteria, without killing it. Lytic phage kill the bacteria Commercial Application (example) Colorectal Cancer Only lysogenic Fuso. Nucleatum phage are found. We need lytic phage Phage sequence Integrase Gene Repressor Repressor deletion => Lysogenic to Lytic Example 2 Add Genes/Features to phage Why - Add specific genes to provide improved phage performance Commercial Application (example) Show fluorescence upon infection for diagnostics Expand host range Add additional payload Synthetic phage - Fluorescently glowing upon infection of KP bacteria (IBD target bacteria) Time (hrs) Repressor-less synthetic phage (green) = Known model lytic phage (blue) Original wild type lysogenic phage (red) KP Bacteria + synthetic infecting phage KP Bacteria + WT infecting phage Only KP Bacteria

9 Pipeline Focus On Chronic Diseases TARGET DISCOVERY PHAGE DISCOVERY PRE-CLINICAL DEVELOPMENT CLINICAL DEVELOPMENT Acne BX001 IBD (Inflammatory Bowel Disease) BX002 Liver (PSC) Colorectal Cancer

10 BX001 Acne Candidate to Enter Clinic H Product Attributes Clinical Trial H A topical gel containing natural phage against P. acnes to modulate skin microbiome cocktail against P. acnes Objectives: Safety P. acnes modulation (efficacy) Skin microbiome evaluation Skin appearance (lesions) Active on antibiotic resistant strains Penetrates biofilm Cohorts 2 doses + vehicle Duration 4 weeks of application Self-amplifying ( phage per bacteria) Does not affect other bacteria Under collaboration with leading multinational cosmetic company

11 % Relative Abundance IFN-g IFN-g IBD Novel Pro-inflammatory Targets Addressing Disease Triggers Pro-inflammatory Kleibsiella Strains Oct Inflammatory Induction in GF Mice GF + 7 Other Mix GF + Target Strain TH1 Disease State Higher Abundance in IBD Patients Abundance of Klebsiella Pneumoniae strains Induce Inflammation Science (Atarashi et al. 358 (6361), )

12 % %IFN-g IFN g of CD4+ T cells %IFN-g of CD4+ T cells IBD Novel Pro-inflammatory Target Addressing Disease Triggers Klebsiella Bacterial Target Oct Disease State Induce Inflammation Science (Atarashi et al. 358 (6361), ) Confirmation of Target effect In-Vivo Gut Th1 Cell Population KI2 females in GF Mice Placebo GF Target Strain Klebsiella+ Female C57black infected with KP2-R for 3 weeks High Prevalence in IBD Patients Prevalence (%) of Target Bacteria in IBD Cohorts baselines (>250 C57black patients) males 20 Israeli Patients 15 French 10 Patients 5 US Patients 0 isolator GF SPF UC CD 8 weeks old Germ free mice, fresh from the isolators versus 8 weeks C57 SPF mice

13 C F U /g r s to o l IBD BX002 Phage Therapy (in-vivo Results) Target Bacteria Eradication Administration Schedules dosing Use of luminescent tag to detect phage eradication (model bacteria) n o tre a tm e n t c o c k ta il, s in g le d o s e c o c k ta il, th re e d o s e s Applied Phage Limit of detection d a y s Control Planned IND in H2 2019

14 BX002 Clinical Development Phase 1 Study Phase 1a/b Study objectives Primary: Safety and tolerability of orally administered BX002 Secondary: Reduction of target bacteria levels in stool Evaluation of microbial composition in stool Exploratory: Clinical response parameters Population Target bacteria carriers mild IBD or healthy individuals Patient A Stool Test Specific qpcr companion diagnostic Target Bacteria Cohorts Three cohorts: 2 dose levels + placebo (vehicle) 10-15/cohort Treatment route, duration Oral route 4 weeks, daily administration Phage treatment BX002

15 Thank you.