Bridgebio Pharma, Inc. · NASDAQ:BBIO
Bridgebio Pharma — Investor Day (October 2021)
112 slides from Bridgebio Pharma's investor day presentation, Oct 12, 2021
Slide 1: R&D Day
hope through rigorous science R&D Day October 12, 2021
Slide 2: Today’s agenda
Today’s agenda Introduction Grace Rauh | V.P. Communications, BridgeBio Pharma Genetic Basis of Disease Richard Scheller, Ph.D. | Chairman of R&D, BridgeBio Pharma BridgeBio’s Endless Summer Neil Kumar, Ph.D. | Founder and CEO, BridgeBio Pharma Precision Cardiorenal Introduction Cameron Turtle, D. P
Slide 3: Forward-Looking Statements and Disclaimer
Forward-Looking Statements and Disclaimer Statements in this Presentation that are not statements of historical fact are forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. Such fo
Slide 4: Genetic basis of disease
Genetic basis Richard Scheller, Ph.D. of disease Chairman of R&D 4
Slide 5: DNA structure
DNA structure 3.4 billion base pairs 23 chromosomes 5
Slide 6: The human genome differs from our closest animal relatives by approximately 50M changes
The human genome differs from our closest animal relatives by approximately 50M changes 6
Slide 7: 7
7
Slide 8: We differ from each other by 4-5 million variants
We differ from each other by 4-5 million variants - African genomes are the most diverse Source: A. Auton et al. Nature 526, 68-74 (2015) doi: 10. 1038/nature15393 8
Slide 9: Investing in computational genetics and academic partnerships
Investing in computational genetics and academic partnerships for: Monogenic target Indication expansion into identification & validation common diseases 9
Slide 10: Single gene variants can cause or contribute to disease
Single gene variants can cause or contribute to disease Hundreds of monogenic disease-causing …and common disease associations are variants are discovered every year… increasing exponentially 4,000 120,000 3,500 monogenic diseases 100,000 GWAS associations Genes that cause Common disease 3,000 80,00
Slide 11: Convergence of genetic innovation driving drug development
Convergence of genetic innovation driving drug development Large-scale genotype- phenotype databases Unique opportunity for BridgeBio to efficiently translate genomic information into meaningful therapies Small Molecules Single-Cell Improving Sequencing Gene Therapy Proteins Expanding therapeutic ch
Slide 12: BridgeBio’s endless summer
BridgeBio’s Neil Kumar, Ph.D. endless summer Founder and CEO 12
Slide 13: Currently, few examples of sustainable innovation engines for genetic medicines
Currently, few examples of sustainable innovation engines for genetic medicines Big pharma R&D destroys value in aggregate Biotech companies have expectations that can’t be met Big pharma R&D IRR The biotech market requires constant and significant innovation to create long term stable ROIC ▪ Curren
Slide 14: Sustainable genetic medicine innovation ecosystem: Criteria #1
What does a sustainable genetic medicine innovation ecosystem look like? Criteria #1 Criteria #1: Need to solve for diseconomies of scale early, and economies of scale late Economies of Learning Decentralized R&D Scale and economies of enables focus at the learning drive value in a level of each ass
Slide 15: Sustainable genetic medicine innovation ecosystem: Criteria #2
What does a sustainable genetic medicine innovation ecosystem look like? Criteria #2 Criteria #2: Each program needs to be NPV positive and supported by beautiful science Realistic market size estimates Only 2.3% of brands today >$2 Bn Each program is NPV positive Capital efficient IND cost < $15 Mn
Slide 16: BridgeBio satisfies the criteria of a sustainable innovation engine
BridgeBio satisfies the criteria of a sustainable genetic medicine innovation engine Key attributes of BridgeBio ▪ The willingness and scale to fail and to re-allocate capital, within a decentralized company model Key criteria of a sustainable genetic Criteria #1 medicine innovation engine ▪ Focus a
Slide 17: The opportunity to build the next great genetic medicine company
Putting it all together: The opportunity to build the next great genetic medicine company Traditional genetic medicines players fall into 1 of 2 archetypes 1 2 Blockbuster Smaller product, limited products, large pipeline pipeline Acoramidis for ATTR as a blockbuster market opportunity Large pipelin
Slide 18: Fingerprints of hope – #1 BridgeBio’s distinctive productivity
Fingerprints of hope – #1 BridgeBio’s distinctive productivity In less than 6 years since inception, BridgeBio has delivered… Select Programs: 2 30+ ATTR APPROVED ACTIVE R&D PROGRAMS PRODUCTS ACROSS 4 MODALITIES Concept to Ph3 in ~3 years 20 460 New Program IND Cleared Ph 3 Start Ph 3 Readout 2016 2
Slide 19: Fingerprints of hope – #2 BridgeBio’s unique product platform
Fingerprints of hope – #2 BridgeBio’s unique product platform ▪ 4 new databases ▪ NMR spectroscopy for ▪ 4 new clinical trials ▪ Two commercial launches ▪ Bayesian methods for new drug targets ▪ Activated 62 new sites in (MoCD Type A, 2L CCA) Recent Additions precise disease ▪ AI for deciphering new
Slide 20: Fingerprints of hope – #3 BridgeBio’s great drug developers
Fingerprints of hope – #3 BridgeBio’s great drug developers Scientific insight and judgment from industry leaders with a proven track record Charles Homcy, MD Frank McCormick, PhD Richard Scheller, PhD Len Post, PhD Phil Reilly, MD, JD Founder and Chairman of Founder and Chairman of Chairman of R&D
Slide 21: Fingerprints of hope – #4 BridgeBio’s pipeline
Fingerprints of hope – #4 BridgeBio’s pipeline, including potential best- in-class candidates Pt. pop. Indication Drug Mechanism Discovery Pre-IND Phase 1 Phase 2 Phase 3 Approved Partner (US+EU) MoCD type A NULIBRYTM (Synthetic cPMP, fosdenopterin) 100 Achondroplasia Low-dose FGFRi (infigratinib) 5
Slide 22: BridgeBio’s endless summer
BridgeBio’s endless summer MoCD Type A ATTR-CM/PN PKAN/OA KRAS 2L CCA ADH1 PH1/FSF, VM ALS, Autism Achon SHP2, UC, RDEB CF, A1AT, GALT CAH LGMD2i, Canavan TMC1, TSC1/2 22
Slide 23: Presentations to come
Presentations to come ■ Precision Cardiorenal: ■ Introduction – Cameron Turtle ■ Acoramidis, a TTR stabilizer, for ATTR – Jonathan Fox ■ Encaleret, a CaSRi, for ADH1 – Mary Scott Roberts ■ Gene therapy platform – Eric David ■ Wave 3 Mendelian programs – Uma Sinha ■ Precision Oncology – Eli Wallace ■
Slide 24: Precision cardiorenal
Precision Cameron Turtle, D. Phil. cardiorenal Chief Strategy Officer 24
Slide 25: Genetic drivers of cardiac disease are unlocking precision medicine targets
Genetic drivers of cardiac disease are unlocking precision medicine targets Diagnosis by phenotype Diagnosis by mechanism – genetic associations Amyloid – TTR HFrEF HFpEF Contractile – MYH7, MYBPC3, TNNT2 Other Structural/signaling – TTN, LAMP2, BAG3 Hyperlipidemia – PCSK9, LDLR HFrEF = heart failur
Slide 26: Precision medicines have delivered increased treatment effect sizes
Precision medicines have delivered increased treatment effect sizes Mendelian disease High genetic risk in broader diseases % reduction in mortality % reduction in mortality 37% 30% 13% 5% RAAS Inhibitor in TTR Stabilizer in Alirocumab in low Alirocumab in high hypertensive patients1 ATTR-CM patient
Slide 27: Cardiorenal pipeline overview
Cardiorenal pipeline overview Pt. pop. Indication Drug Mechanism Discovery Pre-IND Phase 1 Phase 2 Phase 3 (US+EU) ATTR amyloidosis TTR stabilizer (acoramidis) >400k Precision Cardiorenal ADH1 CaSR antagonist (encaleret) 12k1 PH1 / frequent stone formers GO1 inhibitor (BBP-711) 5k / 1.5m Undisclosed
Slide 28: Acoramidis: TTR stabilizer for ATTR
Precision cardiorenal Acoramidis: Jonathan Fox, M.D., Ph.D. TTR stabilizer Chief Medical Officer, Cardiorenal for ATTR Acoramidis is an investigational drug. Its safety and efficacy have not been full evaluated by any regulatory authority. 28
Slide 29: Acoramidis for transthyretin (TTR) amyloidosis (ATTR)
Acoramidis for transthyretin (TTR) amyloidosis (ATTR) Prevalence Pathophysiology 400k+ Worldwide Systemic disease most commonly presenting as cardiomyopathy or peripheral neuropathy Genetic Driver Therapeutic Hypothesis Destabilized TTR leading TTR stabilizer designed to mimic to amyloid accumulatio
Slide 30: ATTR is a systemic disease with multiple manifestations
ATTR is a systemic disease with multiple manifestations Central nervous system Ocular Clinical Presentation Cardiomyopathy (ATTRwt-CM or ATTRv-CM) • Deposition of wild-type or variant (e.g., V122I) TTR amyloid in the heart, leading to predominantly diastolic Diagnostic Approach heart failure • Likel
Slide 31: Rapid increase in patient finding driven by non-invasive diagnosis techniques
Rapid increase in patient finding driven by non-invasive diagnosis techniques New ATTR-CM diagnoses per year at single site Invasive heart biopsies Clinical Presentation Diagnostic Approach Therapeutic Approach Published Data Non-invasive technetium scans Pivotal Trial Design 6MWD Importance Upcomin
Slide 32: TTR plays a physiological role in the body
TTR plays a physiological role in the body Healthy TTR Clinical Presentation metabolism Diagnostic Approach “Leaky pipe” Therapeutic Approach Published Data Pivotal Trial Design 6MWD Importance Upcoming Milestones 32
Slide 33: Targeting diseases at their source optimizes safety and efficacy
Targeting diseases at their source optimizes safety and efficacy Two ways to stop a leaky pipe Clinical Presentation Diagnostic Approach 1 2 Therapeutic Approach Published Data Pivotal Trial Design 6MWD Importance Shut down the entire water line Fix the leak (Target upstream) (Target the source) Upc
Slide 34: Acoramidis was designed to treat ATTR at its source
Acoramidis was designed to treat ATTR at its source Clinical Presentation Native TTR circulates in Dissociation into Monomers aggregate, blood as a tetramer monomers initiates causing disease pathogenesis Diagnostic Approach ~130 known destabilizing variants Disease Therapeutic Approach mechanism Pr
Slide 35: Human genetics suggest TTR instability is associated with disease severity
Human genetics suggest TTR instability is associated with disease severity Relative TTR tetramer stability Clinical Presentation kdiss, WT / kdiss, mutant 0.0 0.2 0.4 0.6 0.8 1.0 37.2 Disease severity Diagnostic Approach Carriers nearly 100% likely to develop ATTR, highly L55P 0.1 pathogenic form of
Slide 36: Higher dose of tafamidis increased stabilization and improved clinical benefit
Higher dose of tafamidis increased stabilization and improved clinical benefit Phase 3 ATTR-ACT study tested two doses of tafamidis (20 mg & 80 mg) vs. placebo Clinical Presentation ▪ Participants receiving 80 mg of tafamidis (vs. 20 mg) exhibited greater TTR stabilization1 ▪ Benefit of tafamidis 80
Slide 37: Acoramidis demonstrates near-complete stabilization of TTR
Acoramidis demonstrates near-complete stabilization of TTR TTR target site occupancy by FPE assay1 Clinical Presentation %, mean +/- SD 100 Diagnostic Approach 80 Therapeutic Approach 60 40 Published Data 20 Pivotal Trial Design 0 Tafamidis 16 µM * Tafamidis 26 µM* Acoramidis 10 µM 6MWD Importance A
Slide 38: Phase 2 ATTR-CM trial provided randomized 28-day and 15-month OLE data
Phase 2 ATTR-CM trial provided randomized 28-day and 15-month OLE data Schematic of acoramidis Phase 2 studies4 Outcomes Clinical Presentation 49 Patients underwent randomization Secondary and Primary Exploratory Diagnostic Approach Randomized portion Acoramidis Acoramidis Safety and tolerability Ph
Slide 39: Acoramidis well-tolerated with near-complete TTR stabilization
Acoramidis has been well-tolerated and demonstrated near-complete TTR stabilization in preclinical, Ph 1, and Ph 2 studies Clinical Presentation Phase 2 safety summary1 Phase 2 OLE TTR stabilization2 Acoramidis TTR stabilization at steady-state trough level Placebo Randomized portion (pooled doses)
Slide 40: Acoramidis increased serum TTR concentrations in a dose-dependent manner
Acoramidis increased serum TTR concentrations in a dose-dependent manner Serum TTR concentration ATTRwt-CM ATTRv-CM Δ from baseline to day 28 (%) Clinical Presentation Below normal TTR at Day 281 150% 1.5 Diagnostic Approach 120% 1.2 90% 0.9 Therapeutic Approach 60% 0.6 30% 0.3 Published Data 0% 0 -
Slide 41: NT-proBNP and TnI remained stable throughout OLE
NT-proBNP and TnI remained stable in acoramidis-treated participants throughout OLE Clinical Presentation NT-proBNP1 TnI1 pg/mL; 95% confidence interval, quartiles, median ng/mL; 95% confidence interval, quartiles, median Diagnostic Approach Therapeutic Approach Published Data Pivotal Trial Design 6
Slide 42: Echocardiography parameters remained stable throughout OLE
Echocardiography parameters remained stable in acoramidis-treated participants throughout OLE Clinical Presentation Left ventricular mass1 Left ventricular stroke volume index1 g; 95% confidence interval, quartiles, median mL/m2; 95% confidence interval, quartiles, median Diagnostic Approach Therape
Slide 43: Embedded Ph3 design includes 12-month and 30-month primary endpoints
Embedded Ph3 design includes 12-month and 30-month primary endpoints 12-month primary endpoint: 30-month primary endpoint: Key Change in 6MWD Hierarchical composite Clinical Presentation inclusion criteria Diagnostic Approach 800 mg acoramidis HCl twice daily ▪ Subjects with diagnosed ATTR- CM (WT o
Slide 44: 6-Minute Walk Test is a clinically meaningful, treatment-responsive endpoint
6-Minute Walk Test is a clinically meaningful, treatment-responsive endpoint Clinical Presentation Simple, sub-maximal exercise test to Diagnostic Approach assess aerobic capacity and endurance Therapeutic Approach “The 6-minute walk test (6MWT), a Demonstrated to measure treatment measure of functi
Slide 45: Rapid functional decline in untreated ATTR-CM patients
Rapid functional decline in untreated ATTR-CM patients provides opportunity to demonstrate robust clinical benefit Clinical Presentation Summary of 6MWD data in ATTR and healthy cohorts 6MWD Healthy elderly adults1 Diagnostic Approach Meters Tafamidis (ATTR-ACT)2 12-month decline: Placebo (ATTR-ACT)
Slide 46: Timeline of upcoming milestones
Timeline of upcoming milestones Clinical Presentation Diagnostic Approach YE 2021 Acoramidis Part A topline data Therapeutic Approach Mid-2022 NDA and MAA filings Published Data Pivotal Trial Design 2023 Acoramidis Part B topline data 6MWD Importance Upcoming Milestones 46 Note: NDA/MAA filings to o
Slide 47: Encaleret: CaSR inhibitor for ADH1
Precision cardiorenal Encaleret: Mary Scott Roberts, M.D. CaSR inhibitor Sr. Director, Clinical Development, for ADH1 Cardiorenal Encaleret is an investigational drug. Its safety and efficacy have not been full evaluated by any regulatory authority. 47
Slide 48: Encaleret for autosomal dominant hypocalcemia type 1 (ADH1)
Encaleret for autosomal dominant hypocalcemia type 1 (ADH1) Prevalence Pathophysiology 12k+ US Decreased blood calcium, elevated urine calcium, and lower parathyroid hormone secretion Genetic Driver Therapeutic Hypothesis Hyperactivation of calcium- Selectively antagonize CaSR to sensing receptor (C
Slide 49: ADH1-causing variants hyperactivate the CaSR and disrupt calcium homeostasis
ADH1-causing variants hyperactivate the CaSR and disrupt calcium homeostasis leading to potentially life-threatening symptoms Disease Overview Disease Mechanism Clinical Manifestation Normal CaSR senses and regulates serum Ca Presenting symptoms Therapeutic Approach • Hypocalcemic seizures • Tetany
Slide 50: ADH1 symptom severity and inadequacy of current treatment
ADH1 symptom severity is associated with blood calcium levels and current treatment inadequately addresses symptom burden Disease Overview Blood calcium at clinical presentation ADH1 medical intervention Blood corrected calcium Individuals on calcium and/or active vitamin D Therapeutic Approach mg/d
Slide 51: Successful CaSR antagonism would increase PTH secretion and renal calcium reabsorption
Successful CaSR antagonism would increase PTH secretion and renal calcium reabsorption Disease Overview Parathyroid and renal CaSR antagonist action Parathyroid cell Renal tubule Therapeutic Approach Ca2+ Urine Blood PTH Phase 2 Design CaSR PTH Gaq + Gai Phase 2 Clinical Data Ca2+ Summary & Next Ste
Slide 52: Encaleret designed to normalize blood calcium and urine calcium
Encaleret is designed to address the underlying disease mechanism and simultaneously normalize blood calcium and urine calcium Disease Overview Summary of key disease measures in ADH1 patients with and without supplementation Without supplementation With supplementation Therapeutic Approach Blood pa
Slide 53: Encaleret Phase 2 study design
Encaleret Phase 2 study design Program Overview Disease Overview Complete Period 1 Period 2 Period 3 LTE Therapeutic Approach Individualized dose Individualized dose Outpatient Long-term escalation titration extension extension Phase 2 Design 5 days, inpatient (N=6) 5 days, inpatient (N=13) 6 months
Slide 54: Period 2 individualized dose titration resulted in lower Day 5 mean dose
Period 2 individualized dose titration phase resulted in a lower Day 5 mean encaleret dose as compared to Period 1 Disease Overview Period 1 and Period 2 encaleret dosing summary Therapeutic Approach Period 1 Dosing Period 2 Dosing Defined dose escalation Individualized dose titration Day 5 Mean: 35
Slide 55: Baseline characteristics of study participants
Study participants exhibited hypocalcemia, elevated urine calcium, suppressed PTH, and elevated phosphate at baseline Disease Overview Baseline characteristics Study Population Characteristic Normal Range Therapeutic Approach N = 13 Age, mean, yr (range) 39 (22-60) Female, n (%) 8 (62%) Phase 2 Desi
Slide 56: Encaleret generally well-tolerated with no serious adverse events
Encaleret continues to be generally well-tolerated with no serious adverse events reported1 Disease Overview Summary of Period 1 and Period 2 safety measures Period 1 Period 2 Therapeutic Approach N=6 N=13 Number of subjects experiencing any Serious Adverse Event 0 (0%) 0 (0%) Number of subjects exp
Slide 57: Encaleret increased blood calcium and PTH and decreased urine calcium in Period 1
Encaleret treatment increased blood calcium and parathyroid hormone and decreased urine calcium in ADH1 participants during Period 1 Disease Overview Individual and mean responses on Day 1 and 5 of Period 1 (N=6) Baseline Value (Day 1) Mean Value (Day 5) on encaleret 180 mg BID§ Therapeutic Approach
Slide 58: Encaleret normalized mean blood and urine calcium during Period 2
Encaleret treatment normalized mean blood and urine calcium during Period 2 Mean responses on Day 1 through Day 5 in Period 2 (N=13) Disease Overview Blood cCa (mg/dL) 11 10 Therapeutic Approach 9 8 Phase 2 Design 7 6 Day 1 Day 2 Day 3 Day 4 Day 5 N=13 Phase 2 Clinical Data Urine Ca (mg/24 h) 800 60
Slide 59: Encaleret increased PTH and decreased blood phosphate during Period 2
Encaleret increased PTH and decreased mean blood phosphate during Period 2 Mean responses on Day 1 through Day 5 in Period 2 (N=13) Disease Overview 210 Therapeutic Approach iPTH (pg/mL) 175 140 105 Phase 2 Design 70 35 0 Phase 2 Clinical Data Day 1 Day 2 Day 3 Day 4 Day 5 N=13 Phosphate (mg/dL) 6 S
Slide 60: Summary reported Phase 2 data and next steps
Summary reported Phase 2 data and next steps Summary of encaleret development program Disease Overview ■ In 13 participants, encaleret normalized mean blood calcium and 24-hour urine calcium excretion, increased PTH, and decreased phosphate into the normal range during both Periods 1 and 2 Therapeut
Slide 61: BridgeBio Gene Therapy
BridgeBio Gene Eric David, M.D., J.D. Therapy CEO, BBGT 61
Slide 62: Gene therapy pipeline overview
Gene therapy pipeline overview Pt. pop. Indication Drug Mechanism Discovery Pre-IND Phase 1 Phase 2 Phase 3 (US+EU) CAH AAV5 gene therapy (BBP-631) >75k Canavan AAV9 gene therapy (BBP-812) 1k TMC1 hearing loss AAV gene therapy (BBP-815) 2k Gene Therapy Galactosemia AAV gene therapy (BBP-818) >7k Tub
Slide 63: Research and manufacturing capabilities
Research and manufacturing capabilities Facility | 20,000 sq ft lab space in Raleigh, NC People | 60+ gene therapy employees (>50% in research or CMC) Capabilities | Vector development, optimization, analytical development, and production (200L) External Manufacturing | Dedicated GMP manufacturing s
Slide 64: BBGT program updates
BBGT program updates Program Status Update Next Catalyst Congenital Adrenal Hyperplasia (CAH) Trial enrollment underway Initial Phase 1/2 data Canavan Trial enrollment underway Initial Phase 1 biomarker data Proof-of-concept established in Transmembrane Channel Protein 1 (TMC1) multiple disease mode
Slide 65: BBP-631: AAV5 gene therapy for congenital adrenal hyperplasia
BBP-631: AAV5 gene therapy for congenital adrenal hyperplasia (CAH) Prevalence Pathophysiology >75k US & EU Inability to produce cortisol causes need for supraphysiologic doses of synthetic steroids, 3-4x increase in mortality risk, hirsutism, Cushingoid symptoms Genetic Driver Therapeutic Hypothesi
Slide 66: 5-10% of WT enzyme may be sufficient for clinical impact
5-10% of WT enzyme may be sufficient for clinical impact Genotype-phenotype studies NHP protein data suggests show that >5-10% of enzyme potentially therapeutic levels of Preclinical Data activity results in nonclassical CAH 21-hydroxylase enzyme Human 21-hydroxylase protein as a % of NHP 21- Stimul
Slide 67: Phase 1/2 first-in-human trial design
Phase 1/2 first-in-human trial design Status Eligibility Preclinical Data ■ Trial enrollment underway ■ Age >18 years with classic CAH (simple virilizing or salt-wasting) due to 21-Hydroxylase Deficiency (21-OHD) ■ Screening/baseline 17-OHP levels > 5-10 × ULN Phase 1/2 Design FIH Trial Design Dose
Slide 68: BBP-812: AAV9 gene therapy for Canavan disease
BBP-812: AAV9 gene therapy for Canavan disease Prevalence Pathophysiology Dysregulated amino acid metabolism ~1kUS & EU leads to neurodegeneration and loss of motor function. Most children do not live past age 10 Genetic Driver Therapeutic Hypothesis Loss of function of AAV9 gene therapy aspartoacyl
Slide 69: CANAspire FIH trial for BBP-812 will assess two doses
CANAspire, our FIH trial for BBP-812, will assess two doses before expanding Status Eligibility Phase 1/2 Design ■ Trial enrollment underway ■ Age ≤ 30 months with Canavan disease ■ Stable health with no acute or chronic renal and liver disease ■ Negative for AAV9 total antibodies FIH Trial Design D
Slide 70: BBP-815: AAV gene therapy for TMC1 genetic hearing loss
BBP-815: AAV gene therapy for TMC1 genetic hearing loss Addressable Prevalence Pathophysiology ~2kUS & EU Lack of functional TMC1 protein in the inner and outer hair cells of the cochlea leads to severe-to-profound bilateral hearing loss Genetic Driver Therapeutic Hypothesis Loss of function of Intr
Slide 71: Gene therapy is the only modality designed to address TMC1 hearing loss at its source
Gene therapy is the only modality designed to address TMC1 hearing loss at its source and allow for endogenous production of the TMC1 protein Therapeutic Approach BBP-815 is the only intervention designed to enable natural hearing TMC1 = transmembrane channel protein 1 Preclinical Data Sound-evoked
Slide 72: BBP-815 durably rescues hearing in profoundly-deaf mice
BBP-815 durably rescues hearing in profoundly-deaf mice Durability of Auditory Brainstem Response (ABR) in TMC1-N193I Therapeutic Approach mice dosed with BBP-815 Preclinical Data Source: BridgeBio Gene Therapy data on file 72
Slide 73: BBP-818: AAV gene therapy for classic galactosemia type I
BBP-818: AAV gene therapy for classic galactosemia type I Prevalence Pathophysiology 7k+US & EU Inability to metabolize galactose leads to impaired speech, developmental delays, impaired motor function, primary ovarian insufficiency, and osteopenia Genetic Driver Therapeutic Hypothesis Loss of funct
Slide 74: Classic galactosemia is a slowly progressive disease
Classic galactosemia is a slowly progressive disease that impacts development of the CNS, ovaries, and bone despite strict dietary restrictions Unmet Need Therapeutic Approach Toddlers/Children Teens Adults ■ Speech/ language ■ Puberty and fertility ■ Tremor Preclinical Data disorders problems (fema
Slide 75: Gene therapy designed to treat galactosemia at its source
Gene therapy is the only therapy designed to treat galactosemia at its source and allow for endogenous production of the GALT enzyme Functional galactose Dysregulation of galactose metabolism in Unmet Need metabolism (Leloir Pathway) type I galactosemia Alternate Dietary & endogenous pathway Therape
Slide 76: BBP-818 achieves dose-dependent production of GALT enzyme in mouse brain
BBP-818 achieves significant, dose-dependent production of the GALT enzyme in GALT-KO mouse brain; these levels may be sufficient for clinical impact Genotype-phenotype studies show patients Unmet Need with >10% of GALT activity tend to be GALT-KO mouse data suggests asymptomatic, and those with >1%
Slide 77: BridgeBio Gene Therapy
BridgeBio Gene Therapy EXPERIENCED GENE FLEXIBLE MANUFACTURING GROWING THERAPY TEAM MODEL PIPELINE Senior leadership team of In-house capabilities & Robust pipeline with clinical industry veterans flexible facility build-out readouts in 2022 2 clinical programs 2 pre-IND programs 4 discovery program
Slide 78: Mendelian Wave 3 Programs
Mendelian Uma Sinha, Ph.D. Wave 3 Programs Chief Scientific Officer 78
Slide 79: Mendelian pipeline overview
Mendelian pipeline overview Pt. pop. Indication Drug Mechanism Discovery Pre-IND Phase 1 Phase 2 Phase 3 Approved (US+EU) NULIBRYTM (synthetic cPMP, MoCD type A 100 fosdenopterin) Achondroplasia Low-dose FGFRi (infigratinib) 55k LGMD2i Glycosylation substrate (ribitol) 7k RDEB Recombinant COL7 (BBP-
Slide 80: Primary Hyperoxaluria Type 1 (PH1)
Primary Hyperoxaluria Type 1 (PH1) Prevalence Pathophysiology 5k US & EU Excess oxalate result in the buildup of oxalate stones in the kidneys, urinary tract, and other vital organ Genetic Driver Therapeutic Hypothesis Loss of function of AGXT GO1 inhibitor to reduce gene causing excess oxalate oxal
Slide 81: GO1 inhibitor (BBP-711) is designed to treat PH1 at its genetic source
GO1 inhibitor (BBP-711) is designed to treat PH1 at its genetic source Disease Mechanism Therapeutic Approach PH1 Program Overview Functional AGXT metabolizes glyoxylate into glycine resulting in normal oxalate production Inhibition of GO reduces the precursor substrate (glyoxylate) for oxalate prod
Slide 82: Well tolerated in Phase 1 with dose-dependent increases in plasma glycolate
Well tolerated in Phase 1 with dose-dependent increases in plasma glycolate Oral doses in healthy adult volunteers Timeline PH1 Program Overview Mean maximal plasma glycolate concentration Mean ± SD (µM) Preliminary and interim data 2022 Phase 1 Clinical Data Phase 1 data 250 & Phase 2/3 start 200 E
Slide 83: Expansion opportunity in recurrent stone formers with hyperoxaluria
Expansion opportunity in recurrent stone formers with hyperoxaluria Disease Mechanism PH1 Program Overview Prevalence Epigenomic changes in AGXT results in excess oxalate Phase 1 Clinical Data production, causing oxalate stone formation ~1.5M US & EU GO AGT Glycine Expansion opportunity Glycolate Gl
Slide 84: Limb-Girdle Muscular Dystrophy Type 2i (LGMD2i)
Limb-Girdle Muscular Dystrophy Type 2i (LGMD2i) Prevalence1 Pathophysiology 7k US & EU Progressive muscle weakness resulting in the loss of ability to perform routine daily functions Genetic Driver Therapeutic Hypothesis Loss of function of Add glycosylation substrate to FKRP gene drive residual enz
Slide 85: Ribitol (BBP-418) as upstream substrate to drive residual FKRP activity
Ribitol (BBP-418) is being investigated as an upstream substrate to drive residual activity of the mutant FKRP enzyme LGMD2i Program Disease Mechanism Therapeutic Approach Overview Functional FKRP fully glycosylates alpha-dystroglycan Supply supraphysiological levels of ribitol upstream to Update /
Slide 86: Strong safety profile in Phase 1 with first LGMD2i patient dosed
Strong safety profile in Phase 1 with first LGMD2i patient dosed in 1Q21 Phase 1 findings: Exposure by total LGMD2i Program daily dose for healthy volunteers Timeline Overview 900 Update / Next Steps 800 700 SAD MAD1 2022 Phase 2 Data AUC (ug*h/ml) 600 500 400 300 Key Endpoints 200 100 • Safety and
Slide 87: Recessive Dystrophic Epidermolysis Bullosa (RDEB)
Recessive Dystrophic Epidermolysis Bullosa (RDEB) Prevalence Pathophysiology 2k US & EU Loss of structural adhesion causes debilitating blistering, tearing and scarring of the skin and impacts oral and GI Genetic Driver Therapeutic Hypothesis Loss of function of collagen Systemic treatment by provid
Slide 88: PTR-01 is currently the only systemic treatment targeting RDEB at its source
PTR-01 is currently the only systemic treatment targeting RDEB at its source Disease Mechanism Therapeutic Approach RDEB Program Overview Epidermis Functional C7 forms layer anchoring fibrils (AFs) to Blistering secure the epidermis to Update / Next Steps the dermis in healthy skin Dermis RDEB Patie
Slide 89: Well tolerated in Phase 1 with dose-dependent increase in C7 skin deposition
Well tolerated in Phase 1 with dose-dependent increase in C7 skin deposition RDEB Program Overview Phase 1: Immunofluorescence C7 Deposition Timeline Treatment window: Pts received 3 doses 3 mg/kg 0.3 mg/kg of BBP-589 (3mg/kg) during this time Update / Next Steps Patient 1 Patient 2 Patient 3 1H22 1
Slide 90: Mendelian program summary
Mendelian program summary 15+ Mendelian Disease Programs 1 FDA approval MoCD Type A 5 mid/late-stage programs ATTR, Achondroplasia, ADH1, RDEB, LGMD2i 3 early clinical programs PH1, PKAN, VM/LM 10+ preclinical programs Catalysts (YE21 / 2022) Acoramidis – Part A readout 4Q 2021 Achondroplasia, RDEB,
Slide 91: Precision Oncology: Program Updates
Precision Eli Wallace, Ph.D. Oncology: Chief Scientific Officer, Oncology Program Updates 91
Slide 92: Precision oncology pipeline overview
Precision oncology pipeline overview Pt. pop. Indication Drug Mechanism Discovery Pre-IND Phase 1 Phase 2 Phase 3 Approved (US+EU) FGFR2+ cholangiocarcinoma (2L) TRUSELTIQTM (FGFRi, infigratinib) 4k FGFR2+ cholangiocarcinoma (1L) FGFRi (infigratinib) FGFR3+ adjuvant urothelial FGFRi (infigratinib) 2
Slide 93: KRAS mutant-driven cancers
KRAS mutant-driven cancers Prevalence Pathophysiology >500k US & EU RAS is the most frequently mutated oncogene, leading to abnormal cell proliferation and survival Program Highlights G12C dual inhibitor PI3Ka:RAS Breaker MOA: first to directly bind and inhibit MOA: first to block RAS-driven PI3Kα b
Slide 94: Partnerships afford us exceptional collaborators and resources
Partnerships afford us exceptional collaborators and resources Research Capabilities G12C Dual Inhibitor PI3Ka:RAS Breaker ■ Partnership with the National RAS Initiative, ■ Home to Sierra: the world’s 3rd fastest including 60 of the world’s foremost academic computing system RAS researchers ■ Enable
Slide 95: Dual GTP/GDP inhibitor hypothesis for KRAS G12C
We hypothesize that a compound that inhibits both GTP (active) and GDP (inactive) forms of KRASG12C will be superior to one that only inhibits the latter Research Capabilities G12C Dual Inhibitor Ras “OFF” PI3Ka:RAS Breaker Ras BBP “ON” AMG510 BBP MRTX849 Newly made RASGTP GTP (active) / GDP (inacti
Slide 96: BridgeBio G12C inhibitors modify both GTP and GDP forms of KRAS G12C
BridgeBio G12C inhibitors modify both GTP (active) and GDP (inactive) forms of KRASG12C Research Capabilities G12C Dual Inhibitor BBP AMG510 MRTX849 15’ 100 0 0 PI3Ka:RAS Breaker KRASG12C GTP (active) 120’ 100 0 0 % modified 15’ 100 80 73 KRASG12C GDP (inactive) 120’ 100 83 80 KRASG12C : RAF1 35 >10
Slide 97: RAS-GTP locked mutant A59G provides evidence for GTP-state inhibitor activity
RAS-GTP “locked” mutant A59G, provides strong evidence for cellular GTP- state inhibitor activity Impact of KRAS Mutations on KRASG12C/A59G Research Capabilities Nucleotide Turnover AMG-510 (µM) BBP (µM) DMSO 0.3 1 3 10 0.3 1 3 10 G12C Dual Inhibitor KRAS G12C pAKT PI3Ka:RAS Breaker (S473) GDP GTP A
Slide 98: G12C dual inhibitors engage KRAS G12C more quickly and potently
BridgeBio G12C dual inhibitors engage KRASG12C more quickly and potently than inhibitors that only target the GDP (inactive) form Research Capabilities KRASG12C homozygous, p53 mutant CRC 30 min 2h 6h 24 h G12C Dual Inhibitor DMSO AMG MRTX BBP1 BBP2 DMSO AMG MRTX BBP1 BBP2 DMSO AMG MRTX BBP1 BBP2 DM
Slide 99: G12C dual inhibitors are more potent and retain activity
BridgeBio G12C dual inhibitors are more potent and retain activity compared to inhibitors that only target the GDP (inactive) form Clonogenic Assay Research Capabilities 80 Day 6 Day 13 120 Day 34 120 100 AMG510 100 60 MRTX849 % Confluence % Confluence % Confluence G12C Dual Inhibitor 80 80 BBP 40 6
Slide 100: Dual GTP/GDP inhibitors show sustained inhibition of pERK in vivo
BridgeBio dual GTP/GDP inhibitors show potent and sustained inhibition of pERK in vivo Research Capabilities Dose Response Time Response MIA PaCa-2 MIA PaCa-2 (4 hours post BBP dose) (100 mg/kg BBP time course) G12C Dual Inhibitor %pERK (Normalized to Veh) %pERK (Normalized to Veh) 120 120 100 100 P
Slide 101: BBP induces tumor regressions and is well tolerated in MIA PaCa-2 CDX model
BBP induces tumor regressions and is well tolerated in the MIA PaCa-2 CDX model Research Capabilities MIA PaCa-2 pancreatic CDX (KRASG12C) G12C Dual Inhibitor Tumor volume Body weight % change Body Weight Change (%) 800 40 Tumor volume (mm3) PI3Ka:RAS Breaker 600 20 400 0 200 -20 0 -40 0 7 14 0 7 14
Slide 102: Novel approach to target PI3Ka is tumor cell specific
Novel approach to target PI3Ka is tumor cell specific and differentiates from kinase inhibitors Research Capabilities ■ PI3Ka kinase inhibitors block normal cell signaling as well as RAS-driven PI3Ka pathway activation in tumor cells, resulting in dose-limiting hyperglycemia and insulin-driven resis
Slide 103: Impairing PI3Ka:RAS interaction blocks oncogene-driven NSCLC tumor growth
Impairing the PI3Ka:RAS interaction blocks oncogene-driven NSCLC tumor growth in vivo Research Capabilities KRASG12D-driven tumor growth is Mutating the RBD of PIK3CA in inhibited in mice with T208D and the EGFRT790M/L858R mutant NSCLC G12C Dual Inhibitor K227A mutations in the RAS- model H1975 abro
Slide 104: BridgeBio has discovered potent and selective PI3Ka:RAS breakers
BridgeBio has discovered potent and selective PI3Ka:RAS breakers Tumor Cells Research Capabilities ▪ Structural insights provide a novel approach to RTK BBP develop PI3Kα:RAS breakers G12C Dual Inhibitor Breaker ▪ PI3Kα:RAS breakers selectively bind to PI3Kα Often mutated in cancer ̶ PI3Kα amino aci
Slide 105: Only PI3Ka breaker differentiates between RAS and IRS-driven pAKT activation
Cellular experiments show that only PI3Ka breaker differentiates between RAS and IRS-driven pAKT activation Research Capabilities IRS-dependent RAS-dependent Cells Cells % AKT inhibition in cells treated with IGF G12C Dual Inhibitor IGF-1 IGF-1 IGF Stimulation IGF-1R Ras-dependent Ras-dependant IRS-
Slide 106: BBP-398: SHP2 inhibitor for treatment resistant cancer
BBP-398: SHP2 inhibitor for treatment resistant cancer Prevalence Pathophysiology EGFR >500k US & EU SHP2 acts upstream of RAS/ERK in RTK and cytokine signaling to regulate cell proliferation, survival, adhesion, and migration Program Highlights EGFR Mutation BBP-398 is a selective, Potential to be
Slide 107: BBP-398 shows best-in-class potential in a large cancer market
BBP-398 shows best-in-class potential in a large cancer market Our SHP2i blocks downstream We believe BBP-398 has the ideal MAPK signaling and abrogates properties for combination with a Overview T cell exhaustion multitude of other therapeutic classes Preclinical Data Receptor tyrosine kinase signa
Slide 108: Predicted BBP-398 pharmacokinetics support once daily oral administration
Predicted BBP-398 pharmacokinetics support once daily oral administration to achieve target coverage Overview HCC827 (EGFRex19del & EGFRamp) BBP-398 steady-state PK - NSCLC CDX simulation for optimal efficacy Preclinical Data 1200 Tumor volume (mm3) ED50 ED90 1000 (mg/kg) (mg/kg) 800 3.99 10.1 Phase
Slide 109: Phase 1 dose escalation with BBP-398 is ongoing
Phase 1 dose escalation with BBP-398 is ongoing: Observed PK/PD is in- line with preclinical predictions Overview Dose escalation cohorts Dose expansion (at RP2D) Key enrollment criteria: Patients with MAPK-pathway alterations (e.g., KRASG12C, EGFR-mutant, but excluding BRAFV600X mutations). Preclin
Slide 110: Precision oncology summary
Precision oncology summary BridgeBio Oncology ■ Infigratinib approved for 2nd line FGFR2 fusion cholangiocarcinoma with multiple late-stage studies ongoing ■ Identified multiple series of differentiated novel KRASG12C GTP/GDP inhibitors ■ Identified multiple series of differentiated novel PI3Ka:RAS
Slide 111: BridgeBioX
Charles Homcy, M.D. BridgeBioX Chairman of Pharmaceuticals 111
Slide 112: BridgeBioX lab at Stanford
BridgeBioX lab at Stanford Our discovery lab is located in the Stanford Life Sciences District – we aim to create an academic/industry hybrid environment, and foster a culture driven by intellectual curiosity and a dedication to patient impact 112