Adicet Bio, Inc. · NASDAQ:ACET
Adicet Bio — resTORbio — Investor Presentation (March 2019)
42 slides from Adicet Bio's investor presentation, Mar 18, 2019
Slide 1: Targeting the biology of aging to prevent and treat aging-related diseases
March 2019 Targeting the biology of aging to prevent and treat aging-related diseases 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 First-in-class and most advanced selective TORC1 program for aging-related diseases Extensive body of literature demonstrating that aging is a biology regulated by the TORC1 pathway Lead candidate, RTB101, is an orally administered, small molecule, potent TORC1 inhibitor product
Slide 4: 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 5: The TORC1 pathway
The TORC1 pathway Source: Lamming, Dudley W., et al. (2013) Journal of Clinical Investigation123 (3): 980–989. TORC1 inhibition has extended lifespan and healthspan in multiple preclinical species Mice Flies Worms Yeast TORC1 is an evolutionarily conserved pathway that regulates aging
Slide 6: 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 inhibitors extended lifespan in mice even when started late in life
TORC1 inhibitors extended lifespan in mice even when started late in life and given intermittently Daily Dosing Intermittent Dosing Once Every 5 Days Harrison et al. (2009) Nature, 460:392-396 Arriola Apelo et al. (2016) Gerontol A Biol Sci Med Sci, 71: 876–88
Slide 8: TORC1 may become dysregulated and overactive in some 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 activated TORC1 leading to in
Slide 9: 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 immune dysregulation C
Slide 10: TORC1 Pathway
TORC]1 Pathway
Slide 11: 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 decreased lifespan and caused hyperglycemia and hyperlipidemia in mice (Science, 2012; Aging Cell, 2014) S6K Ulk1 4EBP1 Atg Inhibition of TORC1 by genet
Slide 12: 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 Inhibits the phosphorylation of 1 target of TORC1 Inhibits the phosphorylation of 2 targets of TORC1 Inhibits the phosphorylation of 3 targets of TORC1 Spectrum of TOR
Slide 13: Objective: Improve immune function to decrease respiratory illness in the elderly
Objective: Improve immune function to decrease the burden of respiratory illness in the elderly
Slide 14: 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 15: RTB101: Immunotherapy targeting TORC1
RTB101: IMMUNOTHERAPY TARGETING TORC1 RTB101 offers a potential 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 pathogens det
Slide 16: Phase 2a to Phase 2b: population, endpoint and dosing modified
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 and dose for Phase 3 program
Slide 17: 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 18: Dosing regimens in Phase 2b and 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 19: RTB101 10mg QD reduced incidence of laboratory-confirmed RTIs
RTB101 10mg QD was observed to reduce the incidence of laboratory-confirmed RTIs 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 incidence1 Placebo incidence1 Odds ratio2 p-value3 1No. of subjects in cohort with one or more laboratory-con
Slide 20: 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 21: Preclinical mTOR inhibition in asthma and smoking models
In preclinical studies mTOR inhibition decreased airway inflammation in asthma models 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 intranas
Slide 22: Significant reduction in lab-confirmed RTIs in subjects 65+
A significant reduction in the incidence of laboratory-confirmed RTIs was observed in subjects 65+ (excluding smokers/COPD subjects) 1No. of subjects in cohort with one or more laboratory-confirmed RTIs/No. of subjects in cohort; 2Odds ratio represents the odds of experiencing one or more laboratory
Slide 23: End-of-Phase meeting with FDA and planned Phase 3 design
End-of-Phase 2 meeting with FDA and planned design of Phase 3 clinical trials Patient population: 65 and older excluding current smokers/COPD patients Dosing arms: RTB101 10mg QD vs. matching placebo Duration of treatment: 16 weeks during winter cold and flu season Primary endpoint: Reduction in the
Slide 24: Planned design for Phase 3 clinical trials
Planned design for Phase 3 clinical trials Patient population: 65 and older excluding smokers/COPD subjects First Phase 3 Clinical Trial Second Phase 3 Clinical Trial 1:1 randomization n = 1,000 1:1 randomization n = 1,600 RTB101 10mg QD Matching placebo RTB101 10mg QD Matching placebo Duration of t
Slide 25: Planned primary and secondary endpoints
Planned primary and secondary endpoints Primary endpoint: Reduction in the percentage of subjects with clinical symptoms consistent with an RTI with or without laboratory-confirmation of a pathogen Defined as clinically symptomatic respiratory illness Consistent with the Phase 2b clinical trial, the
Slide 26: Phase 2b reduction in clinically symptomatic respiratory illness in 65+
1No. of subjects in cohort with one or more clinically symptomatic respiratory illness/No. of subjects in cohort; 2Odds ratio represents the odds of experiencing one or more clinically symptomatic respiratory illness in the active treatment group versus the placebo group; 3One-sided p-value; **p<0.0
Slide 27: Expected timeline for Phase 3 clinical trials
Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Expected timeline for Phase 3 clinical trials 2019 2020 1st Phase 3 Clinical Trial (~1,000 subjects) Top-line data from Phase 3 clinical trials expected mid-2020 Statistical power: ≥ 90% power to show a 30% reduction in the percentage of subjects with clinically symptomatic r
Slide 28: Phase 2 data support design of Phase 3 trials
QD = once daily; **p<0.01 An analysis of the Phase 2b data demonstrated a 46.6% reduction in the percentage of subjects with clinically symptomatic respiratory illness in the proposed Phase 3 population (**p=0.007) Data from two Phase 2 studies with RTB101 10mg QD support the design of Phase 3 clini
Slide 29: Market Opportunity in RTIs
Market Opportunity in RTIs
Slide 30: RTIs are a significant healthcare burden in the elderly
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 The majority of RTIs are caused by viruses for which there
Slide 31: 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 32: Ameliorating Neurodegenerative Diseases: Parkinson's Disease
Ameliorating Neurodegenerative Diseases Parkinson’s Disease
Slide 33: 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 34: 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 35: 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 36: Most advanced pipeline targeting aging-related diseases
Additional Aging-Related Target Most advanced pipeline targeting aging-related diseases RTB101 Clinical Symptomatic Respiratory Illness Parkinson’s Disease Program Indication Phase 1 Phase 2 Phase 3 Discovery Heart Failure with Preserved Ejection Fraction Preclinical Urinary Tract Infections *For he
Slide 37: Near term milestones and financials
Near term milestones and financials Q1 2019 End-of-Phase 2 meeting with the FDA Q1 2019 Initiate Phase 1b/2a study in Parkinson’s disease Q2 2019 Initiate global Phase 3 program for RTB101 Milestones Cash, cash equivalents and marketable securities were ~$115 million as of September 30, 2018 Financi
Slide 38: Targeting the biology of aging to prevent and treat aging-related diseases
March 2019 Targeting the biology of aging to prevent and treat aging-related diseases
Slide 39: Phase 2b reduction in clinically symptomatic respiratory illness in 65+
An analysis of the Phase 2b demonstrated a reduction in clinically symptomatic respiratory illness in subjects 65+ (excluding smokers/COPD subjects), the proposed Phase 3 population 11/41 16/42 0.509 0.099 8/40 16/42 0.405 0.042* 9/73 17/75 0.445 0.039* 17/113 33/117 0.428 0.007** 12/83 17/75 0.550
Slide 40: References for genetic validation of TORC1 inhibition
References for extensive genetic validation that TORC1 inhibition extends lifespan across species (slide 6) 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, Va
Slide 41: References: RTIs are a significant healthcare burden
References RTIs are a significant healthcare burden in the elderly(slide 30) 2017, NCHS, National Vital Statistics System, Mortality; 2015, American Cancer Society, Inc, Surveillance Research Pfunter, A (2013) HCUP Statistical Brief #162 BMJ, 1995, 310:1225-1228; BMJ, 1993, 307:982-986 Am J Med. 200
Slide 42: References for number of elderly people without COPD and non-smokers
References for the number of elderly people without COPD and who are non-smokers (slide 30) 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