Adicet Bio, Inc. · NASDAQ:ACET
Adicet Bio — resTORbio — Investor Presentation (December 2019)
23 slides from Adicet Bio's investor presentation, Dec 3, 2019
Slide 1: Targeting the biology of aging to treat aging-related diseases
Targeting the biology of aging to treat aging-related diseases Corporate Presentation December 2019 Exhibit 99.1
Slide 2: Forward-looking statements
Forward-looking statements 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 “fo
Slide 3: resTORbio highlights
resTORbio highlights Extensive preclinical data demonstrate that TORC1 inhibition may ameliorate multiple aging related diseases, including neurodegenerative diseases TORC1 inhibition may be a promising approach for the treatment of Parkinson’s disease (PD) Induces lysosomal biogenesis and autophagy
Slide 4: Pipeline
Pipeline * For Parkinson’s disease, we may be required to file an investigational new drug application, or IND, prior to initiating Phase 2 clinical trials ** For neurodegenerative diseases and diseases associated with TORC1 hyperactivation, subject to review by the U.S. Food and Drug Administration
Slide 5: RTB101 or RTB101 + sirolimus mechanism
RTB101 OR RTB101+ sirolimus TORC1 substrates include TFEB & ULK1, regulators of autophagy and lysosomal biogenesis Decreased Lipid Synthesis Decreased Protein Synthesis SREBP 4EBP1 S6K Increased Autophagy Increased Lysosomal Biogenesis ULK1 TFEB TORC1 Decreased Protein Synthesis Key mechanism of act
Slide 6: Parkinson's Disease Neurodegenerative Diseases
Parkinson’s Disease Neurodegenerative Diseases
Slide 7: 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 8: Autophagy breaks down aggregated misfolded proteins and dysfunctional organelles
Autophagy is a mechanism by which aggregated misfolded proteins and dysfunctional organelles are broken down and recycled into nutrients in cells Defective autophagy may contribute to the accumulation of aggregated proteins in neurodegenerative diseases Protein Aggregate Autophagosome Nutrients Phag
Slide 9: Mutations in autophagy-related proteins found in multiple neurodegenerative diseases
Mutations in autophagy-related proteins are found in multiple neurodegenerative diseases Menzies et al. Neuron, 2017
Slide 10: TORC1 inhibition stimulates autophagy in preclinical models
Autophagy is a mechanism by which aggregated proteins and dysfunctional organelles are broken down and recycled into nutrients in cells TORC1 inhibition stimulates autophagy in preclinical models and therefore may have benefit in Parkinson’s disease Protein Aggregate Autophagosome Nutrients Phagopho
Slide 11: TORC1 may become dysregulated during aging
TORC1 may become dysregulated during aging and contribute to a decline in autophagy TORC1 activity (pS6 in liver) Fed Fasted Young Mice Old Mice Feeding activates TORC1 leading to increased protein and lipid synthesis In old mice, TORC1 activity remained aberrantly elevated during fasting, preventin
Slide 12: 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 13: Intermittent TORC1 inhibition is disease-modifying in a PD rat model
Intermittent TORC1 inhibition is disease-modifying in a PD rat model In an adeno-associated virus rat PD model that overexpresses a-syn in the substantia nigra, the TORC1 inhibitor CCI-779 started 3 weeks after adenoviral delivery (3w) and given every other day for 5 weeks was shown (A) to correct i
Slide 14: TORC1 inhibition is disease modifying in a mouse model of PD
TORC1 inhibition is disease modifying in a mouse model of PD Siddiqui et al. J. Neurosci. 2015 In the mutant parkin Q311X mouse model of PD, the TORC1 inhibitor rapamycin (A) increased autophagy in dopaminergic neurons (as evidenced by decreased p62 levels), (B) increased the number of dopaminergic
Slide 15: TORC1 inhibition ameliorates levodopa-induced dyskinesia in preclinical PD models
TORC1 inhibition also ameliorates levodopa-induced dyskinesia in preclinical PD models A: Administration of levodopa in a mouse model of PD (unilateral 6-OHDA lesion) activated TORC1 selectively in medium spiny neurons and led to the development of dyskinesia. B: Rapamycin inhibited TORC1 activation
Slide 16: TORC1 inhibitors under evaluation in a Phase 1b/2a trial in Parkinson's disease
TORC1 inhibitors under evaluation in a Phase 1b/2a trial in Parkinson’s disease sirolimus (rapamycin): Allosteric inhibitor of TORC1 Partial TORC1 inhibitor that does not consistently induce autophagy or activate TFEB in all cell types Approved for use in humans sirolimus (rapamycin) RTB101: ATP com
Slide 17: Potential spectrum of TORC1 inhibition with RTB101 and sirolimus
Potential spectrum of TORC1 inhibition with RTB101 and sirolimus Nyfeler et al. Molecular and Cellular Biology, 2011; Nyfeler et al. PLoS ONE, 2012; Eid et al. PNAS, 2017; Roczniak-Ferguson et al. Sci Signal, 2012 sirolimus Inhibits the phosphorylation of more targets downstream of TORC1 RTB101 RTB1
Slide 18: 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 19: resTORbio Phase 1b/2a Parkinson's disease trial
resTORbio Phase 1b/2a Parkinson’s disease trial Study initiated in 1Q19 Data expected by 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: Combination of RTB101 and a rapalog may benefit Huntington's disease
The combination of RTB101 and a rapalog may have potential benefit in other neurodegenerative diseases including Huntington’s disease Source: Novartis Data on file 250nM evero RTB evero RTB101 RTB101 Aggregated mHtt protein levels in cultured cortico-striatal slices from R6/2 Huntington’s disease mo
Slide 21: Parkinson's Disease
Parkinson’s Disease Image from Wikiwand Prevalence Second most common neurodegenerative disease Affects 1% of population over 55 years of age Pathology Characterized by loss of >50% of the neurons that produce the neurotransmitter dopamine in a specific area of the brain (substantia nigra) Clinical
Slide 22: resTORbio highlights
resTORbio highlights Extensive preclinical data demonstrate that TORC1 inhibition may ameliorate multiple aging related diseases, including neurodegenerative diseases TORC1 inhibition may be a promising approach for the treatment of Parkinson’s disease (PD) Induces lysosomal biogenesis and autophagy
Slide 23: Targeting the biology of aging to treat aging-related diseases
Targeting the biology of aging to treat aging-related diseases Corporate Presentation December 2019