Adicet Bio, Inc. · NASDAQ:ACET
Adicet Bio — resTORbio — Investor Presentation (January 2019)
44 slides from Adicet Bio's investor presentation, Jan 7, 2019
Slide 1: Targeting the Biology of Aging to Restore Health
January 2019 Targeting the Biology of Aging to Restore Health Exhibit 99.1
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: resTORbio highlights
resTORbio highlights Targeting the biology of aging Lead clinical candidate, RTB101, is the most advanced selective TORC1 inhibitor TORC1 inhibition improves the function of aging organ systems including the immune, neurologic, and cardiovascular systems Positive results in Phase 2b to improve immun
Slide 4: Aging population and burden on healthcare systems
People age 65 and older are the fastest growing population globally and an increasing burden on healthcare systems1 62% of people age 65 and older have 2 or more chronic diseases which represent the greatest challenge for healthcare systems in the 21st century2 Healthcare expenditures for the elderl
Slide 5: Targeting the biology of aging
Targeting the biology of aging AGING Accumulation of Senescence Cells TORC1 Activity NAD Depletion Epigenetic Changes DNA Damage Mitochondrial Dysfunction Stem Cell Exhaustion
Slide 6: TORC1 is a conserved pathway that regulates aging
TORC1 is an evolutionarily conserved pathway that regulates aging TORC1 inhibition extended lifespan and healthspan in multiple species Mice Flies Worms Yeast Source: Lamming, Dudley W., et al. (2013) Journal of Clinical Investigation123 (3): 980–989.
Slide 7: Genetic manipulation to inhibit mTOR across species
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 8: TORC1 inhibitors extend lifespan in mice
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 9: TORC1 may become dysregulated in aging organ systems
TORC1 may become dysregulated and overactive in some aging organ systems TORC1 activity (pS6 in liver) Fed Fasted Young Mice Old Mice Decreasing TORC1 activity may upregulate protective pathways and may have benefits in aging-related diseases Fed Fasted Total S6 Feeding activates TORC1 leading to in
Slide 10: 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 11: 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 12: TORC1 Pathway
TORC]1 Pathway
Slide 13: 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 14: Spectrum of TORC1 inhibition with RTB101 and rapalog
S6K Ulk1 TORC1 everolimus or sirolimus 4EBP1 S6K Ulk1 4EBP1 TORC1 RTB101 + everolimus or sirolimus 4EBP1 S6K Ulk1 TORC1 4EBP1 RTB101 Inhibiting the phosphorylation of 1 target of TORC1 Inhibiting the phosphorylation of 2 targets of TORC1 Inhibiting the phosphorylation of 3 targets of TORC1 Spectrum
Slide 15: RTB101: First-in-class immunotherapy targeting TORC1
RTB101: First-in-class immunotherapy targeting TORC1 Best validated target for aging-related diseases Extensive body of literature that TORC1 pathway regulates aging RTB101 is a potent inhibitor of TORC1 Potential to treat multiple diseases of aging Robust safety profile Over 1,000 patients dosed Do
Slide 16: Improving Immune Function: Respiratory Tract Infections (RTIs)
Improving Immune Function Respiratory Tract Infections (RTIs)
Slide 17: Burden of RTIs in the elderly
4th Most Common Cause of Hospitalization3 RTIs are the 4th most common cause of hospitalization in people age 65+ (US); 2nd in 85+ (US) Fastest Growing Population1 The elderly is the fastest growing population across the globe No Approved Therapies6 Viruses for which there are no approved therapies
Slide 18: Results of Phase 2a trial
Results of Phase 2a trial 264 mostly healthy elderly people randomized to the following TORC1 inhibitor treatment arms (all doses were QD): Both RTB101 10mg QD and RTB101 10mg + everolimus 0.1mg QD significantly reduced the incidence of all infections as well as respiratory tract infections (RTIs) R
Slide 19: RTB101 alone or in combination with everolimus: immunotherapy
IMMUNOTHERAPY: RTB101 alone or in combination with everolimus RTB101 offers new approach to harnessing the immune system to target multiple pathogens Source: S. Jain et al., NEJM 2015 Indicates the annual number of pathogen-specific pneumonia hospitalizations per 10,000 adults ≥ 80 The majority of p
Slide 20: Phase 2a to Phase 2b modifications
Phase 2a to Phase 2b: Population, primary endpoint and dosing duration were modified Self-reported RTIs Laboratory-Confirmed RTIs 6 weeks 16 weeks Healthy, 65 and older POPULATION: PRIMARY ENDPOINT: DOSING DURATION: Phase 2a Phase 2b Goal: Define patient population for Phase 3 program
Slide 21: Phase 2b design
Phase 2b design Primary Endpoint: Reduction in the percentage of patients with laboratory-confirmed RTIs through week 16 Population: Elderly subjects at increased risk of RTI-associated morbidity and mortality, defined as: ≥ 85 years of age 65-84 years of age with one or more comorbidities including
Slide 22: Dosing regimens and duration of TORC1 inhibition
Dosing regimens in Phase 2b estimated to result in different duration and spectrum of TORC1 inhibition S6K Ulk1 4EBP1 TORC1 4EBP1 RTB101 5mg QD Intermittent inhibition of two TORC1 targets RTB101 10mg QD 0 12 24 Estimated duration of TORC1 inhibition (hrs) RTB101 10mg BID Persistent inhibition of tw
Slide 23: Odds ratio supports dose selection of RTB101 10mg QD
Odds ratio supports dose selection and potential efficacy of RTB101 10mg QD 21/61 26/60 0.618 0.109 34/176 50/180 0.601 0.025* 25/120 24/120 1.050 0.560 25/115 24/120 1.187 0.700 Active rate1 Placebo rate1 Odds ratio2 p-value3 1No. of patients in cohort with one or more laboratory-confirmed RTIs/No.
Slide 24: Consistent benefit in multiple pre-specified analyses
RTB101 10mg QD showed consistent benefit in multiple pre-specified analyses of lab-confirmed RTIs Odds ratio of experiencing lab-confirmed RTIs through Week 16 – primary endpoint Odds ratio of experiencing severe lab-confirmed RTI symptoms through Week 16 Odds ratio of experiencing lab-confirmed RTI
Slide 25: COPD and smokers were non-responding subgroups
COPD and smokers were non-responding subgroups (pre-specified analyses) 85+: % subjects with 1 or more laboratory-confirmed RTIs Asthma T2DM COPD Smokers 65+: % subjects with 1 or more laboratory-confirmed RTIs Southern Hemisphere Northern Hemisphere Southern & Northern Hemispheres (%) (%) (%) (%) (
Slide 26: mTOR inhibition in asthma and smoking models
mTOR inhibition decreased airway inflammation in asthma and increased airway inflammation due to smoking Asthma Smoking mTOR inhibition with rapamycin (Rapa) significantly decreased airway inflammation in a preclinical asthma model in which mice were exposed to intranasal house dust mites (HDM)1 Dis
Slide 27: Reduction in incidence of RTIs in subjects 65+ excluding smokers/COPD
A significant reduction in the incidence of laboratory-confirmed RTIs was observed in subjects 65+ (excluding smokers/COPD patients) 1No. of patients in cohort with one or more laboratory-confirmed RTIs/No. of patients in cohort; 2Odds ratio represents the odds of experiencing one or more laboratory
Slide 28: Reduction in rate of RTIs in subjects 65+ excluding smokers/COPD
RTB101 5mg QD RTB101 10mg QD RTB101 10mg BID RTB101 10mg + everolimus 0.1mg A significant reduction in the rate of laboratory-confirmed RTIs was observed in subjects 65+ (excluding smokers/COPD patients) 1Rate ratio represents the rate of experiencing one or more laboratory-confirmed RTIs in the act
Slide 29: Summary of RTB101 10mg QD data from two Phase 2 studies
Summary of RTB101 10mg QD data from two Phase 2 clinical studies enrolling > 900 elderly subjects 42% reduction in the rate of RTIs (p=0.006) Phase 2a 264 healthy elderly (23% with comorbidities) Phase 2b 652 elderly (100% with comorbidities) 30.6% reduction in the percent of patients with laborator
Slide 30: RTB101 was well-tolerated in high-risk elderly patients
RTB101 was well-tolerated in high-risk elderly patients through Week 24 Adverse events (AEs) were balanced between the RTB101 10mg QD and placebo cohorts 1 unrelated death occurred in the RTB101 10mg QD cohort (patient was hit by car while riding a bicycle), 1 unrelated death occurred in the RTB101
Slide 31: RTB101 may reduce incidence of total infections
RTB101 may also reduce the incidence of total infections of any kind Odds ratio of experiencing any infection (lab-confirmed RTI and all other infections) through Week 16 Odds ratio of experiencing urinary tract infections through Week 16 OR = Odds ratio represents the odds of experiencing one or mo
Slide 32: Market Opportunity in RTIs
Market Opportunity in RTIs
Slide 33: RTIs in the elderly represent a significant healthcare burden
Mortality from RTIs is higher than mortality from colorectal, pancreatic, breast or prostate cancer1 RTIs are the 4th most common cause for hospitalization in 65+ (2nd in 85+)2 RTIs cause the majority of asthma exacerbations in the elderly3 RTIs in the elderly represent a significant healthcare burd
Slide 34: Estimated number of elderly that may benefit from RTB101
US EU5 JP CN # Elderly People without COPD and who are non-smokers* 40M 53M 29M 77M Elderly (65-84 years old) with asthma: 3.2M 3.3M1 2.1M2 2.5M3 Very elderly (85+ years old): 6.5M 9.3M 5.5M 8.9M Estimated number of elderly that may benefit from RTB101 in key geographies *Based on references provide
Slide 35: Physician survey: expected use in target populations
% Reduction in RTI Estimated % prescribed in patients (patient-weighted means) ≥85 65-84 with asthma 65-84 with comorbidities 25% 33% 36% 36% 33% 41% 44% 47% 40% 46% 48% 51% Survey of 100 physicians to determine potential usage in the target patient populations Medical Specialty Geriatrics 25 Primar
Slide 36: Ameliorating Neurodegenerative Diseases: GBA Parkinson's Disease
Ameliorating Neurodegenerative Diseases GBA Parkinson’s Disease
Slide 37: GBA mutation in Parkinson's disease leads to a-synuclein aggregation
GBA mutation in Parkinson’s disease (PD) leads to a-synuclein aggregation and neuronal cell death Disease cascade: GBA is a gene encoding the lysosomal enzyme glucocerebrosidase (GCase) Mutant GCase may contribute to PD pathogenesis through a loss or gain of function: Loss of function: Decreased GCa
Slide 38: resTORbio GBA PD program potential benefits
resTORbio GBA PD program potential benefits to GBA PD patients (both loss or gain of function GBA mutations) Gain of Function 1Guri, Y., et al. (2017). Cancer Cell 32(6): 807-823; 2Decressac, M., et al. (2013). Proc Natl Acad Sci USA 110(19): E1817-1826; 3 Cullen,V., et al. (2011). Ann Neurol 69(6):
Slide 39: Phase 2a Parkinson's disease trial design
Phase 2a Parkinson’s disease trial design Phase 2a 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 2a Study (12-week dosing) Mild-to-moderate PD patients (mH&Y I-III) with confirmed GBA mutatio
Slide 40: Near term milestones and financials
Near term milestones and financials Q1 2019 End of Phase 2 meeting with the FDA Q1 2019 Initiate Phase 2a study in Parkinson’s disease H1 2019 Initiate Phase 3 program for reducing the incidence of RTIs Milestones Cash, cash equivalents and marketable securities were ~$115 million as of September 30
Slide 41: resTORbio highlights
resTORbio highlights Targeting the biology of aging Lead clinical candidate, RTB101, is the most advanced selective TORC1 inhibitor TORC1 inhibition improves the function of aging organ systems including the immune, neurologic, and cardiovascular systems Positive results in Phase 2b to improve immun
Slide 42: Targeting the Biology of Aging to Restore Health
January 2019 Targeting the Biology of Aging to Restore Health
Slide 43: 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
Slide 44: References for number of elderly people without COPD and non-smokers
References for number of elderly people without COPD and who are non-smokers US: 4,038,000 elderly people estimated to be smokers in the US. U.S. NHIS 2017, https://www.cdc.gov/nchs/nhis/SHS/tables.htm (accessed Jan 5, 2019), Table A-12b. Prevalence of COPD in the elderly estimated at 14.2%. Hanania