A Novel Class of Living Medicines
Synthetic BioticTM medicines to perform and deliver critical therapeutic functions to treat diseases throughout the body
NPKUA Conference
July 2018 Bacteria and the Microbiome
10-100 trillion Growing list of bacteria live in the diseases associated human body with microbiome
10x more non-human > 20 companies cells than human cells developing new treatments
> 10,000 different 4M US adults (2%) species described take a daily probiotic
2 How the Microbiome Influences Health
Digestion & Diet and Non-Digested Uptake of Food Food Food Components
Secretion Human Microbiome Body
Metabolic Products and Interactions with Immune System
Adapted from: http://selfcarejournal.com/article/human-microbiota-in-health-and-disease/
3 Synthetic Biotic Medicines: A Novel Approach
Synthetic Biotic: E. coli Nissle as chassis: • Engineered bacteria • Widely-used oral probiotic • With designed genetic circuits • Leverage the safety of probiotic • To degrade metabolites that • Found within natural human induce disease or synthesize microbiome substances to treat disease
Synthetic Biology + Bacteria = Synthetic Biotic Medicine
Therapeutic delivered locally to treat systemic diseases
4 Synlogic: Therapies Under Development
Lead Lead IND-Enabling Phase I Phase II Discovery Optimization Studies
Hyperammonemia - SYNB1020 Urea Cycle Disorder
Phenylketonuria SYNB1618
Maple Syrup Urine Disease
Organic Acidemias
Hyperammonemia - SYNB1020 Hepatic Encephalopathy
Inflammatory Bowel Disease Immuno Oncology 1: STING A/Kyn Consumer Inborn Errors of Metabolism Immuno Oncology 2 Metabolic Disease Immunomodulation Immuno Oncology 3 No Programs are approved as medicines by the FDA or other Regulatory Authority
5 PKU
Why a Synthetic Biotic for PKU? −Diet is major source of phe −Phe present in the gut even in fasting state −Bacteria can consume phe as amino acid as well as small peptides −Bacteria can live in the gut and evade digestion −Feedback from patient advisory board supported development of new treatments
• Goals of the Program: − Normalize phe − Increase protein intake to >25g − Oral dosing without systemic toxicity
This program is investigative and has not been approved as a medicine by the FDA or other Regulatory Authority
6 How it Works
When PAH Enzyme is Missing or Not Bacteria Engineered to Consume Phe Effective
Amino acids from Hippuric acid Dietary proteins Phenylalanine t-Cinnamic Acid (TCA) Healthy Phe PKU High-Affinity Uptke Phenylalanine Phenylalanine t-Cinnamic Hydroxylase Acid (PAH) Impaired PAH PAL + LAAD ! Accumulation Enzyme Converts Phe of Phe to toxic into tyrosine levels Synthetic Genetic Circuit SYNB1618 Probiotic bacteria: E. Coli Nissle
Normalized levels of Phe
7 PKU Mouse Studies
Water, control SYNB or Blood Phe Phe SYNBPKU Test blood Levels
PKU Mouse
8 SYNB1618 in Healthy Non-Human Primates: Phe Metabolism is Dose Responsive
Bacteria degrade phe. The higher the Phe metabolites can also be detected in dose, the more phe broken down urine
300
hrs 0.04
200 ) moles
0.02 µ 100 HA ( dose period post - dose
Plasma TCA AUC AUC 6 Plasma TCA 0.00 0
Dose Dose
9 SYNB1618 in the Clinic: Phase 1 Single and Multiple Dose Study in Healthy Volunteers and People with PKU
2017 2018 2019 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Pre-clinical / IND enabling studies
Manufacturing
IND submission SAD / MAD HV
SAD/MAD PKU cohort
Goal: assess safety, tolerability and kinetics in healthy volunteers and PKU patients across a range of doses • Once dose is found to be well-tolerated in healthy volunteers, a group of volunteers with PKU will be enrolled • Up to 7 days of dosing in multi dose group
10 Study Sites + Clinicaltrials.gov link
HV SAD, HV MAD, PKU SAD, PKU MAD Enrollment:
Dr. Searle/PRA Health Sciences Phase 1 Unit, Salt Lake City, UT (HVs) Dr. Nicola Longo/University of Utah Health, Salt Lake City, UT (PKU referrals)
PKU MAD Enrollment:
Additional sites are planned for Boston, Pittsburgh and Portland, OR
Clinicaltrials.gov: https://clinicaltrials.gov/ct2/show/NCT03516487
11 Thank You