Adicet Bio, Inc. · NASDAQ:ACET
Adicet Bio — resTORbio — Guggenheim Healthcare Talks Neuro/Immunology Day 2019
22 slides from Adicet Bio's conference presentation, Nov 18, 2019
Slide 1: November 2019 Guggenheim Healthcare Talks Neuro/Immunology Day
November 2019 Guggenheim Healthcare Talks Neuro/Immunology Day Exhibit 99.1
Slide 2: Forward-looking statements disclaimer
This presentation has been prepared by resTORbio, Inc. (“we,” ”us,” “our,” “resTORbio,” or the “Company”) and is made for informational purposes only and does not constitute an offer to sell or a solicitation of an offer to buy securities. This presentation may contain “forward-looking statements” w
Slide 3: Aging is the biggest risk factor for most chronic diseases
Aging is the biggest risk factor for most chronic diseases Global Burden of Disease Collaborative Network. Global Burden of Disease Study 2017 (GBD 2017) Results Why does this happen? Aging is not just due to random wear and tear Aging is biology that may be targeted with medicines
Slide 4: Well-characterized pathways associated with aging and aging-related diseases
Well-characterized pathways associated with aging and aging-related diseases AGING Accumulation of Senescent Cells TORC1 Activity NAD Depletion Epigenetic Changes DNA Damage Mitochondrial Dysfunction Stem Cell Exhaustion
Slide 5: TORC1 inhibition extended lifespan and healthspan in multiple preclinical species
TORC1 Pathway: Lamming et al. Journal of Clinical Investigation, 2013 TORC1 inhibition extended lifespan and healthspan in multiple preclinical species Mice Flies Worms Yeast TORC1 is an evolutionarily conserved pathway that regulates aging
Slide 6: TORC1 inhibitors extend lifespan in mice even when started late in life
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) 1Harrison et al. Nature, 2009; 2Arriola Arpelo et al. Gerontol A Biol Sci Med Sci, 2016
Slide 7: TORC1 activity in fed and fasted young and old mice
TORC1 activity (pS6 in liver) Fed Fasted Young Mice Old Mice Feeding activates TORC1 and increases protein and lipid synthesis TORC1 activity remained aberrantly elevated during fasting, which may prevent upregulation of protective pathways Sengupta et al., Nature, 2010 Fed Fasted Fasting inhibits T
Slide 8: Inhibition of TORC1 may improve function of multiple aging organ systems
Inhibition of TORC1 has the potential to 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 cardiac dysfunction Fl
Slide 9: 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/
Slide 10: Protein aggregation is a common pathogenic mechanism in neurodegenerative diseases
Protein aggregation is a common pathogenic mechanism in aging-related neurodegenerative diseases Alzheimer’s Disease Huntington’s Disease Amyloid plaques Neurofibrillary tangles Lewy bodies Aggregated huntingtin Amyloid β protein Phosphorylated tau α-synuclein Mutated huntingtin Parkinson’s Disease
Slide 11: Defective autophagy may contribute to accumulation of aggregated proteins
Defective autophagy may contribute to the accumulation of aggregated proteins in neurodegenerative diseases Autophagy is a mechanism by which aggregated proteins and dysfunctional organelles are broken down and recycled into nutrients in cells Protein Aggregate Autophagosome Nutrients Phagophore Aut
Slide 12: Mutations in autophagy-related proteins are found in multiple neurodegenerative diseases
Mutations in autophagy-related proteins are found in multiple neurodegenerative diseases Menzies et al. Neuron, 2017
Slide 13: TORC1 inhibition and autophagy in neurodegenerative diseases
Defective autophagy may contribute to the accumulation of aggregated proteins in neurodegenerative diseases Autophagy is a mechanism by which aggregated proteins and dysfunctional organelles are broken down and recycled into nutrients in cells Protein Aggregate Autophagosome Nutrients Phagophore Aut
Slide 14: Parkinson's Disease
Parkinson’s Disease Prevalence: Parkinson’s disease (PD) is the second most common neurodegenerative disease and affects 1% of population over 55 years of age Pathobiology: PD is characterized by loss of >50% of the neurons that produce the neurotransmitter dopamine in a specific area of the brain (
Slide 15: TORC1 inhibitors may be of therapeutic benefit in Parkinson's disease
TORC1 inhibitors may be of therapeutic benefit in Parkinson’s disease Induction of autophagy with a TORC1 inhibitor leads to the clearance of a-synuclein aggregates in a preclinical PD model Malagelada et al. J Neurosci, 2010; Crews et al. PLoS one, 2010 # dead neurons Vehicle TOR inhibitor Vehicle
Slide 16: TORC1 inhibitors to be evaluated in a Phase 1b/2a trial in Parkinson's disease
TORC1 Inhibitors that will be evaluated in a Phase 1b/2a trial in Parkinson’s Disease SIrolimus: Allosteric inhibitor of TORC1 Consistently inhibits phosphorylation of only some targets downstream of TORC1 Approved for use in humans sirolimus (rapamycin) RTB101: ATP competitive catalytic site inhibi
Slide 17: RTB101 and sirolimus synergize to induce autophagy in neuronal cells
RTB101 and sirolimus synergize to induce autophagy in neuronal cells SK-N-SH neuroblastoma cell line assay
Slide 18: Potential mechanism underlying synergistic inhibition and autophagy activation
S6K ULK1 FKBP12 sirolimus TORC1 RTB101 Sirolimus may induce a conformation change in TORC1 that allows lower concentrations of RTB101 to inhibit TORC1 Potential Mechanism Underlying Synergistic Inhibition and Autophagy Activation by sirolimus + RTB101 Adapted from Nyfeler et al. PloS one, 2012
Slide 19: resTORbio Phase 1b/2a Parkinson's disease trial
resTORbio Phase 1b/2a Parkinson’s disease trial Study initiated in 1Q19 Data expected in mid-2020 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-moderate PD patients (mH&Y I-III) On stand
Slide 20: RTB101 plus a rapalog may benefit other neurodegenerative diseases including Huntington's
The combination of RTB101+ a rapalog may have potential benefit in other neurodegenerative diseases including Huntington’s disease Source: Novartis Data on file 250nM evero RTB evero RTB RTB Aggregated protein levels in cultured brain slices from a Huntington’s Disease mouse model 250 nM everolimus
Slide 21: Summary
Summary Protein aggregation is a common pathogenic mechanism underlying multiple neurodegenerative diseases Induction of autophagy may have therapeutic benefit in neurodegenerative diseases by clearing toxic protein aggregates In preclinical models, TORC1 inhibition with RTB101 alone or in combinati
Slide 22: November 2019 Guggenheim Healthcare Talks Neuro/Immunology Day
November 2019 Guggenheim Healthcare Talks Neuro/Immunology Day
resTORbio — Guggenheim Healthcare Talks Neuro/Immunology Day 2019 on 6ix