Adicet Bio, Inc. · NASDAQ:ACET
Adicet Bio — resTORbio — Investor Presentation (February 2020)
27 slides from Adicet Bio's investor presentation, Feb 19, 2020
Slide 1: Targeting the biology of aging to treat aging-related diseases
Targeting the biology of aging to treat aging-related diseases Corporate Presentation February 2020 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) Ameliorates levodopa-induced dyskinesia in
Slide 4: Pipeline
Pipeline * For Parkinson’s disease, we may be required to file an investigational new drug application, or IND, with the U.S. Food and Drug Administration, prior to initiating Phase 2 clinical trials ** For neurodegenerative diseases and diseases associated with TORC1 hyperactivation, subject to rev
Slide 5: Broad TORC1 inhibition with RTB101 may ameliorate levodopa-induced dyskinesia and be neuroprotective
Broad TORC1 inhibition with RTB101 has the potential to ameliorate levodopa-induced dyskinesia and to be neuroprotective in Parkinson’s disease patients Decreased Lipid Synthesis Decreased Protein Synthesis SREBP 4EBP1 S6K Increased Autophagy Increased Lysosomal Biogenesis ULK1 TFEB TORC1 Decreased
Slide 6: Parkinson's Disease: Disease modification
Parkinson’s Disease: Disease modification 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: Parkinson's Disease
Parkinson’s Disease Image from Wikiwand Prevalence Second most common neurodegenerative disease Affects 1% of population over 55 years of age in the U.S. Pathology Accumulation of Lewy body protein aggregates containing a-synuclein and death of the neurons that produce the neurotransmitter dopamine
Slide 9: Autophagy breaks down and recycles aggregated misfolded proteins
Autophagy is a mechanism by which aggregated misfolded proteins and dysfunctional organelles are broken down and recycled in cells Defective autophagy may contribute to the accumulation of aggregated proteins in PD and other neurodegenerative diseases Toxic protein Aggregate Autophagosome Phagophore
Slide 10: Mutations in autophagy-related proteins found in PD and other neurodegenerative diseases
Mutations in autophagy-related proteins are found in PD and other neurodegenerative diseases suggesting that deficient autophagy contributes to neurodegenerative disease pathogenesis Menzies et al. Neuron, 2017
Slide 11: TORC1 inhibitors may be disease modifying by upregulating autophagy and lysosomal biogenesis
TORC1 inhibitors have the potential to be disease modifying in neurodegenerative diseases by upregulating autophagy and lysosomal biogenesis Toxic protein Aggregate Autophagosome Phagophore Autophagolysosome Lysosome TORC1 inhibition Menzies et al. Neuron, 2017; Roczniak-Ferguson et al. Sci Signal,
Slide 12: TORC1 inhibition is neuroprotective in PD pre-clinical models
TORC1 inhibition is neuroprotective in PD pre-clinical models In a rat PD model that overexpresses a-syn in the substantia nigra, the TORC1 inhibitor CCI-779 started 3 weeks after adenoviral delivery of a-syn (3w) and given every other day for 5 weeks was shown (A) to correct impaired TFEB function
Slide 13: 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: only consistently inhibits S6K downstream of TORC1 Approved for use in humans sirolimus (rapamycin) RTB101: ATP competitive catalytic site inh
Slide 14: 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 High Concentration of RTB101 or Low Concentrations of RTB101+ sirolimus ULK1
Slide 15: RTB101 and sirolimus synergize to inhibit TORC1 and may lower brain exposure required
The combination of RTB101 and sirolimus synergize to inhibit TORC1 and may lower the RTB101 brain exposure required to induce autophagy Total Free (5%) 87.50 4.38 130.58 114.37 156.80 170.61 173.28 181.56 196.15 174.61 158.67 216.07 43.75 2.19 91.48 71.47 123.06 118.25 166.88 154.73 189.63 194.12 19
Slide 16: Parkinson's Disease: Levodopa-induced dyskinesia
Parkinson’s Disease: Levodopa-induced dyskinesia Neurodegenerative Diseases
Slide 17: Advantage of PD as a clinical indication: levodopa-induced dyskinesia
Advantage of PD as a clinical indication for TORC1 inhibitors: levodopa-induced dyskinesia (LID) is a potential clinical endpoint that can be assessed in a shorter time frame than disease progression LID is a disabling side effect of chronic levodopa treatment associated with significantly impaired
Slide 18: Multiple LID pathways converge on ERK and TORC1 hyperactivation
Multiple pathways implicated in levodopa-induced dyskinesia (LID) pathogenesis converge on ERK and downstream TORC1 hyperactivation TSC TORC1 Dyskinesia Adapted from Calabrisi P et al., Lancet Neurol, 2010 Santini et al. Sci Signaling, 2009 Medium Spiny Neuron 4EBP1 S6K
Slide 19: TORC1 is hyperactivated in preclinical LID models and inhibition alleviates LID
TORC1 is hyperactivated in medium spiny neurons in preclinical PD models of LID and TORC1 inhibition alleviates LID A: Administration of levodopa in a mouse model of PD (unilateral 6-OHDA lesion) led to hyperactivation of TORC1(as assessed by pS6 levels) in medium spiny neurons and development of dy
Slide 20: 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 21: RTB101 CSF Concentrations in PD patients dosed with RTB101 300 mg once weekly
RTB101 CSF Concentrations in 6 PD patients dosed with RTB101 300 mg once weekly
Slide 22: RTB101 and sirolimus synergize to inhibit TORC1, lowering brain exposure predicted for clinical benefit
The combination of RTB101 and sirolimus synergize to inhibit TORC1 and may lower the RTB101 brain exposure predicted to be required for clinical benefit in PD Total Free (5%) 87.50 4.38 100 99 104 99 101 104 102 101 105 99 43.75 2.19 97 101 100 102 95 102 104 104 102 103 21.88 1.09 84 86 99 98 100 1
Slide 23: Huntington's disease
Huntington’s disease Neurodegenerative Diseases
Slide 24: Autophagy induction with TORC1 inhibitors may benefit multiple neurodegenerative diseases
Induction of autophagy with TORC1 inhibitors may have potential benefit in multiple neurodegenerative diseases in which protein aggregation contributes to disease pathogenesis Alzheimer’s Disease Huntington’s Disease Amyloid plaques Neurofibrillary tangles Lewy bodies Aggregated huntingtin Amyloid β
Slide 25: Preclinical Huntington's disease model: RTB101 and everolimus cleared protein aggregates
In a preclinical model of Huntington’s disease, the combination of RTB101 and everolimus (an analog of sirolimus) cleared protein aggregates and was neuroprotective Source: Novartis Data on file 250nM evero RTB evero RTB101 RTB101 Aggregated mHtt protein levels in cultured cortico-striatal slices fr
Slide 26: 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) Ameliorates levodopa-induced dyskinesia in
Slide 27: Targeting the biology of aging to treat aging-related diseases
Targeting the biology of aging to treat aging-related diseases Corporate Presentation February 2020