Adicet Bio, Inc. · NASDAQ:ACET
Adicet Bio — resTORbio — Investor Presentation (February 2019)
48 slides from Adicet Bio's investor presentation, Feb 7, 2019
Slide 1: Targeting the biology of aging to prevent and treat aging-related diseases
February 7, 2019 Targeting the biology of aging to prevent and treat aging-related diseases Exhibit 99.2
Slide 2: Forward-looking statements
This presentation may contain “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding the safety, efficacy and regulatory and clinical progress of our product candidates, including RTB101 alone and i
Slide 3: Aging is the biggest risk factor for most chronic diseases
Aging is the biggest risk factor for most chronic diseases Why does this happen? Aging is not just due to random wear and tear Aging is biology that may be targeted with medicines Global Burden of Disease Collaborative Network. Global Burden of Disease Study 2017 (GBD 2017) Results
Slide 4: resTORbio is targeting the biology of aging
resTORbio is targeting the biology of aging AGING NAD Depletion Mitochondrial Dysfunction TORC1 Activity DNA Damage Accumulation of Senescence Cells Stem Cell Exhaustion Epigenetic Changes
Slide 5: The TORC1 pathway
The TORC1 pathway Source: Lamming, Dudley W., et al. (2013) Journal of Clinical Investigation123 (3): 980–989. TORC1 inhibition extended lifespan and healthspan in multiple species Mice Flies Worms Yeast TORC1 is an evolutionarily conserved pathway that regulates aging
Slide 6: Extensive genetic validation that TORC1 inhibition extends lifespan
Species Genetic Manipulation to Inhibit mTOR Yeast SCH9 (Akt/S6K homolog) insertional mutant 1 SCH9 (Akt/S6K homolog) deletion 1 SCH9 (Akt/S6K homolog) insertional mutant 2 SCH9 (Akt/S6K homolog) deletion 2 TOR1 deletion 3 TOR1 deletion 4 C. elegans TOR (let-363) RNAi 5 Raptor (daf-15) heterozygous
Slide 7: TORC1 inhibition may improve function of multiple aging organ systems
TORC1 inhibition may improve the function of multiple aging organ systems Improvement in physical activity Selman et al., Science, 2011 Harrison et al., Nature, 2009 Wilkinson et al., Aging Cell, 2014 Flynn et al., Aging Cell, 2013 Reversal of aging-related immune dysregulation Chen et al., Science
Slide 8: Most advanced pipeline targeting aging-related diseases
Additional Aging-Related Target Most advanced pipeline targeting aging-related diseases RTB101 Respiratory Tract Infections Parkinson’s Disease Program Indication Phase 1 Phase 2 Phase 3 Discovery Heart Failure with Preserved Ejection Fraction Preclinical Urinary Tract Infections *For heart failure
Slide 9: TORC1: A Compelling Target for Neurodegenerative Diseases
TORC1: A Compelling Target for Neurodegenerative Diseases Matt Kaeberlein, PhD Department of Pathology University of Washington 9
Slide 10: Age is the greatest risk factor for neurodegenerative disease
Age is the greatest risk factor for neurodegenerative disease Age Risk of Death (per 100,000) http://www.spring.org.uk/ 10
Slide 11: The biology of aging drives neurodegenerative disease
The biology of aging drives neurodegenerative disease AGING Vascular dementia ALS Lewy body disease Alzheimer’s Parkinson’s Frontotemporal dementia 11
Slide 12: We now better understand the biology of aging
We now better understand the biology of aging 12
Slide 13: TORC1 connects aging with neurodegenerative disease
TORC1 connects aging with neurodegenerative disease TORC1 = mTOR Complex 1 (Adapted from Oncogene 36:2191 2017) mTOR Inhibitor 13
Slide 14: TORC1 is critical when we are young
TORC1 is critical when we are young ↓ Autophagy TORC1 ↑ Protein synthesis ↑ Lipid Synthesis Environmental and Hormonal Growth signals ↑ Inflammation 14
Slide 15: TORC1 becomes hyperactivated as we get old
TORC1 becomes hyperactivated as we get old ↓ Autophagy ↑ Protein synthesis ↑ Lipid Synthesis Environmental and Hormonal Growth signals ↑ Inflammation Proteo-toxicity Immune-senescence Metabolic dysfunction TORC1 TORC1 Inhibitor TORC1 inhibition may delay aging X X 15
Slide 16: TORC1 inhibition improves aging organ function in multiple mammalian species
TORC1 inhibition improves the function of aging organ systems in multiple mammalian species Inhibition of TORC1 increases lifespan and improves immunologic, neurologic and cardiac function in aging mice Inhibition of TORC1 reverses age-related decline in cardiac function in pet dogs Inhibition of TO
Slide 17: TORC1 inhibition has benefit in multiple neurodegenerative diseases
TORC1 inhibition has therapeutic benefit in multiple neurodegenerative diseases TORC1 inhibition delays or reverses Alzheimer’s disease in multiple mouse models TORC1 inhibition effective in multiple mouse and fly models of Parkinson’s disease Enhanced autophagy leading to clearance of aggregated su
Slide 18: TORC1 is a Master Negative Regulator of Autophagy
TORC1 is a Master Negative Regulator of Autophagy TORC1 TORC1 TFEB P ULK1 TFEB P Nucleus TFEB Autophagy and Lysosomal Genes ULK1 Vps34 complex Immature/Inactive Phagophore Atg complexes LC3-II Phagophore a-syn aggregate Autophagosome (Figure adapted from Neuron 93:1015, 2017) Lysosome Autolysosome 1
Slide 19: TORC1 inhibition may be of particular benefit in Parkinson's Disease
TORC1 inhibition may be of particular benefit in Parkinson’s Disease Nearly 200 papers published with “TORC1” (or “mTOR”) and “Parkinson’s” in the title/abstract Activation of autophagy is the favored mechanism of action Protects against a-synuclein toxicity Prevents neuron loss Improves motor funct
Slide 20: Classes of TORC1 Inhibitors
Classes of TORC1 Inhibitors Rapalogs: Allosteric inhibitors of TORC1 Chronic inhibition can also suppress TORC2 Inhibit only some targets downstream of TORC1 Approved for use in oncology indications and to prevent organ transplant rejection The class of TORC inhibitors used in most PD models Sirolim
Slide 21: Rapamycin is an imperfect TORC1 inhibitor
Rapamycin is an imperfect TORC1 inhibitor ↑ Autophagy TORC1 ↓ Protein synthesis ↓ Inflammation Neuroprotection Rapamycin RTB101 + Rapamycin does not consistently induce autophagy Chronic rapamycin treatment also inhibits TORC2 leading to side effects RTB101 induces autophagy at high concentrations t
Slide 22: Targeting Autophagy in Parkinson's Disease
Targeting Autophagy in Parkinson’s Disease Roy Alcalay, MD, MS Florence Irving Assistant Professor of Neurology Division of Movement Disorders Columbia University Medical Center
Slide 23: Disclosures
Disclosures Funding: Dr. Alcalay is funded by the Parkinson’s Foundation, the National Institutes of Health (NS080915, NS094607), the Smart Foundation and the Michael J. Fox Foundation. Dr. Alcalay receives consultation fees from Genzyme/Sanofi, Denali, Biogen and Roche.
Slide 24: What is Parkinson's Disease?
What is Parkinson’s Disease? Clinical manifestations: Four cardinal motor symptoms: Resting tremor Bradykinesia (slowed movements) Muscle rigidity Postural instability Pathobiology: Loss of >50% of the neurons that produce the neurotransmitter dopamine in a specific area of the brain (substantia nig
Slide 25: PD: Non Motor Symptoms
PD: Non Motor Symptoms Many patients develop non-motor symptoms including: Autonomic dysfunction Sleep problems (RBD) Psychiatric symptoms: anxiety, depression Impaired sense of smell Over 80% of affected individuals develop cognitive impairment over time. There are a variety of symptomatic treatmen
Slide 26: PD Biology
PD Biology PD is defined by neuronal degeneration with protein (alpha-synuclein, a-syn) aggregation Multiple genes have been linked to PD Many of them are in the auto-phagosome pathway
Slide 27: Impaired Autophagy Genes in Neurodegenerative Diseases
Impaired Autophagy Genes in Neurodegenerative Diseases (Neuron 93:1015, 2017)
Slide 28: GBA/PD: A Genetically-linked form of PD
GBA/PD: A Genetically-linked form of PD A single GBA mutation (heterozygous mutation) is the most common genetic risk for PD 5-10% of PD patients carry a GBA mutation or variant (Gan-Or, 2015) Two mutations (homozygous mutations) in the GBA gene cause Gaucher disease, a lysosomal storage disorder Ga
Slide 29: GBA: An Accelerated form of Idiopathic PD
GBA: An Accelerated form of Idiopathic PD Clinical Similarities Motor signs are similar to idiopathic PD (iPD), but progress faster than idiopathic PD Cognitive impairment, loss of sense of smell, sleep disturbances and autonomic dysfunction are more common than in patients with idiopathic PD Good s
Slide 30: GBA: An Accelerated form of iPD
GBA: An Accelerated form of iPD Histologic and Biochemical Similarities GBA/PD associated with higher amounts of a-syn deposition (Lewy bodies) in brain (an accelerated form of PD) GCase (the GBA protein product) expression and activity decreases in human brains with age (Ann Clin Transl Neurol 2:43
Slide 31: TORC1 Inhibition Increases Autophagosomes and Decreases a-syn
TORC1 Inhibition Increases Autophagosomes and Decreases a-syn (PLoS one 5:e9313, 2010) LCE autophagosome marker staining (brown) Control Vehicle a-syn Transgenic Vehicle Mouse: Treatment: a-syn Transgenic mTOR inhibitor a-synuclein staining (brown)
Slide 32: Why GBA/PD may be a good target for proof of concept trials
TORC1 inhibitor/PD Clinical Trials: Why GBA/PD may be a good target for proof of concept/efficacy trials All disease modification strategies for PD to date have failed. Glucosylceramide (GCase substrate) is reduced by mTOR inhibition1 GBA/PD is more homogenous. Strongly associated with a-syn patholo
Slide 33: Targeting the biology of aging to prevent and treat aging-related diseases
Targeting the biology of aging to prevent and treat aging-related diseases
Slide 34: The TORC1 pathway
The TORC1 pathway Source: Lamming, Dudley W., et al. (2013) Journal of Clinical Investigation123 (3): 980–989. TORC1 inhibition extended lifespan and healthspan in multiple species Mice Flies Worms Yeast TORC1 is an evolutionarily conserved pathway that regulates aging
Slide 35: TORC1 inhibition may improve function of multiple aging organ systems
TORC1 inhibition may improve the function of multiple aging organ systems Improvement in physical activity Selman et al., Science, 2011 Harrison et al., Nature, 2009 Wilkinson et al., Aging Cell, 2014 Flynn et al., Aging Cell, 2013 Reversal of aging-related immune dysregulation Chen et al., Science
Slide 36: TORC1 inhibitors extend lifespan in mice even when started late
TORC1 inhibitors extend lifespan in mice even when started late in life and given intermittently Daily Dosing Intermittent Dosing Once Every 5 Days (1) (2) Harrison et al. (2009) Nature, 460:392-396 Arriola Apelo et al. (2016) Gerontol A Biol Sci Med Sci, 71: 876–88
Slide 37: Selective inhibition of TORC1 may have therapeutic benefit
mTOR Selective inhibition of TORC1 may have therapeutic benefit for the treatment of aging-related diseases Inhibition of TORC2 by genetic mutation decreases lifespan and causes hyperglycemia and hyperlipidemia in mice (Science, 2012; Aging Cell, 2014) S6K Ulk1 4EBP1 Atg Inhibition of TORC1 by genet
Slide 38: Rapalogs lower the concentration of RTB101 needed to inhibit TORC1
TORC1 S6K 4EBP1 ULK1 TFEB Lipin1 Rapalogs lower the concentration of RTB101 needed to inhibit TORC1 in the brain and induce autophagy in animal models Rapalog sirolimus/ everolimus S6K High dose RTB101 4EBP1 ULK1 TFEB Lipin1 S6K TORC1 Lower dose RTB101 + sirolimus 4EBP1 ULK1 TFEB Lipin1 S6K TORC1 In
Slide 39: Potential mechanism of synergistic inhibition by sirolimus + RTB101
Potential mechanism underlying synergistic inhibition and autophagy activation by sirolimus + RTB101 Sirolimus may induce a conformation change in TORC1 that allows lower concentrations of RTB101 to inhibit TORC S6K 4EBP1 Sirolimus FKBP12 TORC RTB101
Slide 40: RTB101 and sirolimus synergize to induce autophagy at low concentrations
RTB101 and sirolimus synergize to induce autophagy at low concentrations RTB101 (nM) 87.5 130.58 114.37 156.80 170.61 173.28 181.56 196.15 174.61 158.67 216.07 43.8 91.48 71.47 123.06 118.25 166.88 154.73 189.63 194.12 190.70 214.89 21.9 31.89 25.16 81.50 100.98 125.12 137.82 212.58 197.37 166.87 21
Slide 41: RTB101 synergizes with everolimus to clear mHtt protein aggregates
RTB101 synergizes with everolimus to clear mHtt protein aggregates and rescue striatal neurons 250nM Everolimus Green = Neurofilaments Red = Neuron cell bodies (DARPP-32) 50nM RTB101 300nM RTB101 10nM RTB101 + 250 nM Everolimus 30nM RTB101 + 250 nM Everolimus 50nM RTB101 + 250 nM Everolimus Days in
Slide 42: Intermittent dosing of TORC1 inhibitors may have better safety and efficacy
Intermittent dosing of TORC1 inhibitors may have better safety and efficacy than daily dosing Beneficial effects of rapamycin on lifespan can be achieved with dosing once every 5-7 days with reduced side effects1 Rapamycin administered 3x/week (intermittent mTOR inhibition) is required for autophagi
Slide 43: Ameliorating Neurodegenerative Diseases: Parkinson's Disease
Ameliorating Neurodegenerative Diseases Parkinson’s Disease
Slide 44: Phase 1b/2a Parkinson's disease trial design
Phase 1b/2a Parkinson’s disease trial design Study initiation planned for 1Q19 Cohort RTB 101 dose (mg) Sirolimus dose (mg) 1 300 0 2 0 2 3 300 2 4 300 4 5 300 6 Design Randomized, Placebo-Controlled Phase 1b/2a Study (4-week dosing) Mild PD patients (mH&Y I-II) with or without GBA mutations On stan
Slide 45: Summary
Summary TORC1 may be an important therapeutic target for several neurodegenerative diseases in which misfolded proteins aggregate and cause neuronal toxicity TORC1 inhibition has shown therapeutic benefit in multiple preclinical PD models TORC1 inhibition may be of benefit in PD by inducing autophag
Slide 46: Targeting the biology of aging with TORC1 Inhibitors
Targeting the biology of aging with TORC1 Inhibitors TORC1 inhibition extended lifespan and improved: Immune Function Neurologic Function ü Clinical trials enrolling > 900 subjects Initiation of Phase 1a/2b planned in 1Q19 Translation to humans with RTB101 Mice Flies Worms Yeast
Slide 47: Targeting the biology of aging to prevent and treat aging-related diseases
February 7, 2019 Targeting the biology of aging to prevent and treat aging-related diseases
Slide 48: Extensive genetic validation that TORC1 Inhibition extends lifespan across species
Extensive genetic validation that TORC1 Inhibition extends lifespan across species 1 Fabrizio P, Pozza F, Pletcher SD, Gendron CM, Longo VD. Regulation of longevity and stress resistance by Sch9 in yeast. Science. 2001;292(5515):288–290. Fabrizio P, Pletcher SD, Minois N, Vaupel JW, Longo VD. Chrono