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Item 8.01 | Other Events. |
On June 1, 2021, BridgeBio Pharma, Inc. updated its corporate presentation. A copy of the presentation is attached hereto as Exhibit 99.1 and incorporated herein by reference.
(d) Exhibits.
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Description | |
99.1 | Corporate Presentation, dated June 1, 2021 | |
104 | Cover Page Interactive Data File (embedded within the Inline XBRL document) |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
BridgeBio Pharma, Inc. | ||||||
Date: June 1, 2021 | /s/ Brian C. Stephenson | |||||
Brian C. Stephenson | ||||||
Chief Financial Officer |
Exhibit 99.1 Corporate presentation June 2021Exhibit 99.1 Corporate presentation June 2021
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 forward-looking statements include, without limitation, statements regarding BridgeBio Pharma, Inc.’s (the “Company’s”) research and clinical development plans, expected manufacturing capabilities, commercialization and general strategy, regulatory matters, market size and opportunity, future financial position, future revenue, projected costs, prospects, plans, objectives of management, and the Company’s ability to complete certain milestones. Words such as “believe,” “anticipate,” “plan,” “expect,” “intend,” “will,” “may,” “goal,” “potential,” “should,” “could,” “aim,” “estimate,” “predict,” “continue” and similar expressions or the negative of these terms or other comparable terminology are intended to identify forward-looking statements, though not all forward-looking statements necessarily contain these identifying words. These forward-looking statements are neither forecasts, promises nor guarantees, and are based on the beliefs of the Company's management as well as assumptions made by and information currently available to the Company. Such statements reflect the current views of the Company with respect to future events and are subject to known and unknown risks, including business, regulatory, economic and competitive risks, uncertainties, contingencies and assumptions about the Company, including, without limitation, risks inherent in developing therapeutic products, the success, cost, and timing of the Company’s product candidate development activities and ongoing and planned preclinical studies and clinical trials, including for its four (4) core value driver programs, the success and timing of clinical trial results, the success of its clinical trial designs, the fact that successful preliminary clinical trial results may not result in future clinical trial successes and/or product approvals, trends in the industry, the legal and regulatory framework for the industry, the success of the Company’s engagement with the U.S. Food and Drug Administration (“FDA”) and other regulatory agencies, the Company’s ability to obtain and maintain regulatory TM TM approval for its product candidates and FDA-approved products, including NULIBRY (fosdenopterin) for the treatment of MoCD Type A and TRUSELTIQ (infigratinib) for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test, the Company’s ability to receive approval for and commercialize its product candidates and FDA-approved products, including NULIBRY and TRUSELTIQ, the success of current and future agreements with third parties in connection with the development or commercialization of the Company’s product candidates and FDA-approved products, including NULIBRY and TRUSELTIQ, the size and growth potential of the market for the Company’s product candidates and FDA-approved products, including NULIBRY and TRUSELTIQ, the accuracy of the Company’s estimates regarding expenses, future revenue, future expenditures and needs for and ability to obtain additional financing, the Company’s ability to obtain and maintain intellectual property protection for its product candidates and approved products, including NULIBRY and TRUSELTIQ, the potential for NULIBRY as the first and only FDA-approved therapy for MoCD Type A, the efficacy of each of NULIBRY and TRUSELTIQ, the safety profile of each of NULIBRY and TRUSELTIQ, plans for the supply, manufacturing and distribution of each of NULIBRY and TRUSELTIQ, the competitive environment and clinical and therapeutic potential of each of NULIBRY and TRUSELTIQ, potential adverse impacts due to the ongoing global COVID-19 pandemic such as delays in clinical trials, preclinical work, overall operations, regulatory review, manufacturing and supply chain interruptions, adverse effects on healthcare systems and disruption of the global economy, and those risks and uncertainties described under the heading “Risk Factors” in the Company’s most recent Annual Report on Form 10-K filed with the U.S. Securities and Exchange Commission (“SEC”) and in subsequent filings made by the Company with the SEC, which are available on the SEC’s website at www.sec.gov. In light of these risks and uncertainties, many of which are beyond the Company’s control, the events or circumstances referred to in the forward-looking statements, express or implied, may not occur. The actual results may vary from the anticipated results and the variations may be material. You are cautioned not to place undue reliance on these forward-looking statements, which speak to the Company’s current beliefs and expectations only as of the date this Presentation is given. Except as required by law, the Company disclaims any intention or responsibility for updating or revising any forward-looking statements contained in this Presentation in the event of new information, future developments or otherwise. No representation is made as to the safety or effectiveness of the product candidates for the therapeutic use for which such product candidates are being studied. Certain information contained in this Presentation relates to or is based on studies, publications, surveys and other data obtained from third-party sources and the Company’s own internal estimates and research. While the Company believes these third-party sources to be reliable as of the date of this Presentation, it has not independently verified, and makes no representation as to the adequacy, fairness, accuracy or completeness of, any information obtained from third-party sources. In addition, all of the market data included in this Presentation involves a number of assumptions and limitations, and there can be no guarantee as to the accuracy or reliability of such assumptions. Finally, while the Company believes its own internal research is reliable, such research has not been verified by any independent source. The Company is the owner of various trademarks, trade names and service marks. Certain other trademarks, trade names and service marks appearing in this Presentation are the property of third parties. Solely for TM convenience, the trademarks and trade names in this Presentation are referred to without the ® and symbols, but such references should not be construed as any indicator that their respective owners will not assert, to the fullest extent under applicable law, their rights thereto. 2Forward-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 forward-looking statements include, without limitation, statements regarding BridgeBio Pharma, Inc.’s (the “Company’s”) research and clinical development plans, expected manufacturing capabilities, commercialization and general strategy, regulatory matters, market size and opportunity, future financial position, future revenue, projected costs, prospects, plans, objectives of management, and the Company’s ability to complete certain milestones. Words such as “believe,” “anticipate,” “plan,” “expect,” “intend,” “will,” “may,” “goal,” “potential,” “should,” “could,” “aim,” “estimate,” “predict,” “continue” and similar expressions or the negative of these terms or other comparable terminology are intended to identify forward-looking statements, though not all forward-looking statements necessarily contain these identifying words. These forward-looking statements are neither forecasts, promises nor guarantees, and are based on the beliefs of the Company's management as well as assumptions made by and information currently available to the Company. Such statements reflect the current views of the Company with respect to future events and are subject to known and unknown risks, including business, regulatory, economic and competitive risks, uncertainties, contingencies and assumptions about the Company, including, without limitation, risks inherent in developing therapeutic products, the success, cost, and timing of the Company’s product candidate development activities and ongoing and planned preclinical studies and clinical trials, including for its four (4) core value driver programs, the success and timing of clinical trial results, the success of its clinical trial designs, the fact that successful preliminary clinical trial results may not result in future clinical trial successes and/or product approvals, trends in the industry, the legal and regulatory framework for the industry, the success of the Company’s engagement with the U.S. Food and Drug Administration (“FDA”) and other regulatory agencies, the Company’s ability to obtain and maintain regulatory TM TM approval for its product candidates and FDA-approved products, including NULIBRY (fosdenopterin) for the treatment of MoCD Type A and TRUSELTIQ (infigratinib) for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test, the Company’s ability to receive approval for and commercialize its product candidates and FDA-approved products, including NULIBRY and TRUSELTIQ, the success of current and future agreements with third parties in connection with the development or commercialization of the Company’s product candidates and FDA-approved products, including NULIBRY and TRUSELTIQ, the size and growth potential of the market for the Company’s product candidates and FDA-approved products, including NULIBRY and TRUSELTIQ, the accuracy of the Company’s estimates regarding expenses, future revenue, future expenditures and needs for and ability to obtain additional financing, the Company’s ability to obtain and maintain intellectual property protection for its product candidates and approved products, including NULIBRY and TRUSELTIQ, the potential for NULIBRY as the first and only FDA-approved therapy for MoCD Type A, the efficacy of each of NULIBRY and TRUSELTIQ, the safety profile of each of NULIBRY and TRUSELTIQ, plans for the supply, manufacturing and distribution of each of NULIBRY and TRUSELTIQ, the competitive environment and clinical and therapeutic potential of each of NULIBRY and TRUSELTIQ, potential adverse impacts due to the ongoing global COVID-19 pandemic such as delays in clinical trials, preclinical work, overall operations, regulatory review, manufacturing and supply chain interruptions, adverse effects on healthcare systems and disruption of the global economy, and those risks and uncertainties described under the heading “Risk Factors” in the Company’s most recent Annual Report on Form 10-K filed with the U.S. Securities and Exchange Commission (“SEC”) and in subsequent filings made by the Company with the SEC, which are available on the SEC’s website at www.sec.gov. In light of these risks and uncertainties, many of which are beyond the Company’s control, the events or circumstances referred to in the forward-looking statements, express or implied, may not occur. The actual results may vary from the anticipated results and the variations may be material. You are cautioned not to place undue reliance on these forward-looking statements, which speak to the Company’s current beliefs and expectations only as of the date this Presentation is given. Except as required by law, the Company disclaims any intention or responsibility for updating or revising any forward-looking statements contained in this Presentation in the event of new information, future developments or otherwise. No representation is made as to the safety or effectiveness of the product candidates for the therapeutic use for which such product candidates are being studied. Certain information contained in this Presentation relates to or is based on studies, publications, surveys and other data obtained from third-party sources and the Company’s own internal estimates and research. While the Company believes these third-party sources to be reliable as of the date of this Presentation, it has not independently verified, and makes no representation as to the adequacy, fairness, accuracy or completeness of, any information obtained from third-party sources. In addition, all of the market data included in this Presentation involves a number of assumptions and limitations, and there can be no guarantee as to the accuracy or reliability of such assumptions. Finally, while the Company believes its own internal research is reliable, such research has not been verified by any independent source. The Company is the owner of various trademarks, trade names and service marks. Certain other trademarks, trade names and service marks appearing in this Presentation are the property of third parties. Solely for TM convenience, the trademarks and trade names in this Presentation are referred to without the ® and symbols, but such references should not be construed as any indicator that their respective owners will not assert, to the fullest extent under applicable law, their rights thereto. 2
BridgeBio Pharma: Hope through rigorous science Our mission: To discover, create, test and deliver transformative medicines to treat patients who suffer from genetic diseases and cancers with clear genetic drivers 3BridgeBio Pharma: Hope through rigorous science Our mission: To discover, create, test and deliver transformative medicines to treat patients who suffer from genetic diseases and cancers with clear genetic drivers 3
Our 2025 vision – A leading player in genetic medicine Multiple best-in-class or first-in-class products in blockbuster markets, with a total of 4+ NDAs on file Patient-centric global commercial infrastructure World-class drug discovery and development platform Broad network of >40 university partnerships Multiple therapeutic modalities, many diseases Deep pipeline of 30+ R&D programs 4Our 2025 vision – A leading player in genetic medicine Multiple best-in-class or first-in-class products in blockbuster markets, with a total of 4+ NDAs on file Patient-centric global commercial infrastructure World-class drug discovery and development platform Broad network of >40 university partnerships Multiple therapeutic modalities, many diseases Deep pipeline of 30+ R&D programs 4
Context #1: 2021 is a critical year for BridgeBio Value to patients and investors Returns to scale 4 clinical trial readouts in $750 M+ markets: ADH1, ATTR, achondroplasia, CAH 2015 2020 2021 2022 2 NDAs accepted for priority review 8 new clinical trials initiated 4 later-stage trials fully enrolled 5 INDs submitted 12 new programs 5 5 strategic collaborations with universities or geographic partners Context #1: 2021 is a critical year for BridgeBio Value to patients and investors Returns to scale 4 clinical trial readouts in $750 M+ markets: ADH1, ATTR, achondroplasia, CAH 2015 2020 2021 2022 2 NDAs accepted for priority review 8 new clinical trials initiated 4 later-stage trials fully enrolled 5 INDs submitted 12 new programs 5 5 strategic collaborations with universities or geographic partners
Context #2: The opportunity to help patients remains large 8,000 $1B+ opportunities in 8 the pipeline 1) Acoramidis for ATTR CM and PN 2) Low-dose infigratinib for achondroplasia >50 3) AAV5 gene therapy for congenital adrenal hyperplasia 4) High-dose infigratinib for adjuvant urothelial carcinoma 5) Pan-mutant KRAS inhibitor for KRAS+ cancer Number of Number with monogenic diseases approved product(s) 6) SHP2 inhibitor for RAS and kinase mutant cancer Thousands of distinct diseases requiring novel 7) GPX4 inhibitor for multiple tumor types therapeutic options 8) GO1 inhibitor for frequent kidney stone formers 6Context #2: The opportunity to help patients remains large 8,000 $1B+ opportunities in 8 the pipeline 1) Acoramidis for ATTR CM and PN 2) Low-dose infigratinib for achondroplasia >50 3) AAV5 gene therapy for congenital adrenal hyperplasia 4) High-dose infigratinib for adjuvant urothelial carcinoma 5) Pan-mutant KRAS inhibitor for KRAS+ cancer Number of Number with monogenic diseases approved product(s) 6) SHP2 inhibitor for RAS and kinase mutant cancer Thousands of distinct diseases requiring novel 7) GPX4 inhibitor for multiple tumor types therapeutic options 8) GO1 inhibitor for frequent kidney stone formers 6
Context #3: Still Day 1 for innovation within genetic medicine New Therapeutic Macromolecules Molecular Systems Clinical Diagnosis Modalities • Whole genome sequencing of rare disease patients in UK • Antisense oligonucleotides • Mass spectrometry + DNA RNA Protein Biobank coming of age st metabolomics give us 1 snap • CryoEM • gnomAD • GTEx • Expanded sequencing led to • Gene therapy continues of purine bio-synthesis • DeepMind • ENCODE3 • Single cell novel causal variants in 28 maturing sequencing genetic disorders advances 16 FDA approvals for GTEx tissues drugs targeting rare genetic D F diseases or genetically Deconvolution of 7 cell types defined cancers in 2020 G H Interaction QTLs I 7Context #3: Still Day 1 for innovation within genetic medicine New Therapeutic Macromolecules Molecular Systems Clinical Diagnosis Modalities • Whole genome sequencing of rare disease patients in UK • Antisense oligonucleotides • Mass spectrometry + DNA RNA Protein Biobank coming of age st metabolomics give us 1 snap • CryoEM • gnomAD • GTEx • Expanded sequencing led to • Gene therapy continues of purine bio-synthesis • DeepMind • ENCODE3 • Single cell novel causal variants in 28 maturing sequencing genetic disorders advances 16 FDA approvals for GTEx tissues drugs targeting rare genetic D F diseases or genetically Deconvolution of 7 cell types defined cancers in 2020 G H Interaction QTLs I 7
Product platform: Our drug engineering platform leverages and efficiently translates innovation to therapies that matter Discover Create Test Deliver Novel genetic Medicines with industry- Our drugs through global Our products to patients through disease targets leading research capabilities development footprint commercial infrastructure Computational genomics, Molecular dynamics assisted 20 ongoing trials across >450 Global infrastructure, systemic disease mapping, chemistry, gene therapy, sites and 26 countries, central diagnostics, patient support, broad network of academic therapeutic proteins, antisense operations toolkit and analytics disease state awareness partnerships oligos 8Product platform: Our drug engineering platform leverages and efficiently translates innovation to therapies that matter Discover Create Test Deliver Novel genetic Medicines with industry- Our drugs through global Our products to patients through disease targets leading research capabilities development footprint commercial infrastructure Computational genomics, Molecular dynamics assisted 20 ongoing trials across >450 Global infrastructure, systemic disease mapping, chemistry, gene therapy, sites and 26 countries, central diagnostics, patient support, broad network of academic therapeutic proteins, antisense operations toolkit and analytics disease state awareness partnerships oligos 8
Product platform: BridgeBio is a people and a process Scientific insight and judgment from industry leaders with a proven track record Discover Charles Homcy, MD Frank McCormick, PhD Richard Scheller, PhD Len Post, PhD Phil Reilly, MD, JD Founder and Chairman of Founder and Chairman of Advisor Advisor Chairman of R&D Pharmaceuticals Oncology Experienced team of R&D operators responsible for 100+ INDs and 20+ approved products Mendelian Oncology Create Uma Sinha, PhD Robert Zamboni, PhD Eli Wallace, PhD Pedro Beltran, PhD Susan Moran, MD Chief Scientific Officer Chemistry Chief Scientific Officer, SVP, Oncology Chief Medical Officer, Oncology QED Therapeutics 9Product platform: BridgeBio is a people and a process Scientific insight and judgment from industry leaders with a proven track record Discover Charles Homcy, MD Frank McCormick, PhD Richard Scheller, PhD Len Post, PhD Phil Reilly, MD, JD Founder and Chairman of Founder and Chairman of Advisor Advisor Chairman of R&D Pharmaceuticals Oncology Experienced team of R&D operators responsible for 100+ INDs and 20+ approved products Mendelian Oncology Create Uma Sinha, PhD Robert Zamboni, PhD Eli Wallace, PhD Pedro Beltran, PhD Susan Moran, MD Chief Scientific Officer Chemistry Chief Scientific Officer, SVP, Oncology Chief Medical Officer, Oncology QED Therapeutics 9
Our pipeline spans multiple therapeutic areas with numerous upside opportunities Small molecule Topical small molecule Biologics Antisense oligo Gene therapy Preclinical Clinical Portfolio Patient pop. Program Drug mechanism Diseases Modality segment (US+EU) Discovery IND-enabling Phase1 Phase 2 Phase 3 Acoramidis TTR stabilizer ATTR-CM >400K TM NULIBRY (fosdenopterin) cPMP replacement MoCD type A 100 Approved Infigratinib Low-dose FGFR1-3i Achondroplasia 55K 1 Encaleret CaSR antagonist ADH1 / HP 12K / 200K BBP-418 Glycosylation substrate LGMD2i 7K Mendelian BBP-671 PanK activator PKAN / OA 7K BBP-711 GO1 inhibitor PH1 / FSF 5K / 1.5M BBP-472 PI3Kβi PTEN autism 120K 4 undisclosed small molecule programs >500K 4 undisclosed antisense oligonucleotide programs >300K BBP-589 Recombinant COL7 RDEB 1.5K Genetic Derm BBP-681 Topical PI3Kai VM / LM 117K BBP-561 Topical KLK 5/7i Netherton 11K TM 2 TRUSELTIQ (infigratinib) FGFR1-3i 3 FGFR+ tumor programs 37K Approved Targeted Oncology BBP-398 SHP2i Multiple tumors >500K BBP-454 Pan-mutant KRASi 3 KRAS+ tumors programs >500K BBP-954 GPX4i Multiple tumors >500K BBP-631 21-OH gene therapy CAH >75K Gene Therapy BBP-812 ASPA gene therapy Canavan 1K BBP-815 TMC1 gene therapy Genetic hearing loss 10K 4 undisclosed AAV gene therapy programs 150K 1 US carriers 2 Truseltiq approved for 2L+ CCA 10Our pipeline spans multiple therapeutic areas with numerous upside opportunities Small molecule Topical small molecule Biologics Antisense oligo Gene therapy Preclinical Clinical Portfolio Patient pop. Program Drug mechanism Diseases Modality segment (US+EU) Discovery IND-enabling Phase1 Phase 2 Phase 3 Acoramidis TTR stabilizer ATTR-CM >400K TM NULIBRY (fosdenopterin) cPMP replacement MoCD type A 100 Approved Infigratinib Low-dose FGFR1-3i Achondroplasia 55K 1 Encaleret CaSR antagonist ADH1 / HP 12K / 200K BBP-418 Glycosylation substrate LGMD2i 7K Mendelian BBP-671 PanK activator PKAN / OA 7K BBP-711 GO1 inhibitor PH1 / FSF 5K / 1.5M BBP-472 PI3Kβi PTEN autism 120K 4 undisclosed small molecule programs >500K 4 undisclosed antisense oligonucleotide programs >300K BBP-589 Recombinant COL7 RDEB 1.5K Genetic Derm BBP-681 Topical PI3Kai VM / LM 117K BBP-561 Topical KLK 5/7i Netherton 11K TM 2 TRUSELTIQ (infigratinib) FGFR1-3i 3 FGFR+ tumor programs 37K Approved Targeted Oncology BBP-398 SHP2i Multiple tumors >500K BBP-454 Pan-mutant KRASi 3 KRAS+ tumors programs >500K BBP-954 GPX4i Multiple tumors >500K BBP-631 21-OH gene therapy CAH >75K Gene Therapy BBP-812 ASPA gene therapy Canavan 1K BBP-815 TMC1 gene therapy Genetic hearing loss 10K 4 undisclosed AAV gene therapy programs 150K 1 US carriers 2 Truseltiq approved for 2L+ CCA 10
Product pipeline: Layers of de-risking and upside Future pipeline catalysts and Targeted oncology Common mendelian long-term growth (FGFR3 in UC, (LGMD2i, RDEB, SHP2, KRAS) PKAN, VM) Near-term major catalysts from Validation of asset picking 4 core value drivers and execution (ATTR, ADH1, achondroplasia, CAH) 2 FDA approvals in 2021 Proving ground and revenue 72 MoCD Type A 2L+ CCA 11 Assumes achievement of anticipated milestonesProduct pipeline: Layers of de-risking and upside Future pipeline catalysts and Targeted oncology Common mendelian long-term growth (FGFR3 in UC, (LGMD2i, RDEB, SHP2, KRAS) PKAN, VM) Near-term major catalysts from Validation of asset picking 4 core value drivers and execution (ATTR, ADH1, achondroplasia, CAH) 2 FDA approvals in 2021 Proving ground and revenue 72 MoCD Type A 2L+ CCA 11 Assumes achievement of anticipated milestones
Value to patients and shareholders Significant milestones for BridgeBio in the next 12 months Mid ‘22 Gene therapy for CAH: Ph1 data ENDO 2021 data: 1H ‘22 100% response rate Low-dose infigratinib Q4 for achon: Ph2 data ‘21 Q1 Acoramidis for ATTR: ‘21 Ph3 data Encaleret for ADH1: Ph2 data Growth potential this year:▪ Positive pivotal data in a multi-billion market ▪ Positive POC data in multiple blockbuster indications ▪ Transition to commercial-stage biopharma company 12 Assumes achievement of anticipated milestonesValue to patients and shareholders Significant milestones for BridgeBio in the next 12 months Mid ‘22 Gene therapy for CAH: Ph1 data ENDO 2021 data: 1H ‘22 100% response rate Low-dose infigratinib Q4 for achon: Ph2 data ‘21 Q1 Acoramidis for ATTR: ‘21 Ph3 data Encaleret for ADH1: Ph2 data Growth potential this year:▪ Positive pivotal data in a multi-billion market ▪ Positive POC data in multiple blockbuster indications ▪ Transition to commercial-stage biopharma company 12 Assumes achievement of anticipated milestones
Acoramidis (AG10) for transthyretin (TTR) amyloidosis (ATTR) ATTR overview Prevalence Genetic driver Pathophysiology 400,000+ worldwide, Destabilizing TTR Systemic disease most largely undiagnosed today variants or factors of commonly presenting as aging, leading to cardiomyopathy or peripheral amyloid accumulation neuropathy Features of a potential best-in-class medicine for ATTR Near-complete Preserve TTR tetramer, Oral dosing, a convenient and stabilization of TTR, which has known beneficial flexible solution for ATTR preventing the formation roles and is highly patients and their families of amyloid deposits evolutionarily conserved Art ATTR-CM patient 13Acoramidis (AG10) for transthyretin (TTR) amyloidosis (ATTR) ATTR overview Prevalence Genetic driver Pathophysiology 400,000+ worldwide, Destabilizing TTR Systemic disease most largely undiagnosed today variants or factors of commonly presenting as aging, leading to cardiomyopathy or peripheral amyloid accumulation neuropathy Features of a potential best-in-class medicine for ATTR Near-complete Preserve TTR tetramer, Oral dosing, a convenient and stabilization of TTR, which has known beneficial flexible solution for ATTR preventing the formation roles and is highly patients and their families of amyloid deposits evolutionarily conserved Art ATTR-CM patient 13
In under two years, ATTR is already a $2B+ market with major upside potential 1 Global annual ATTR market sales $B Significant potential future ATTR market growth $2.3 driven by: +71% $1.7 ▪ Increasing diagnosis in established $1.7 geographies (23.5K patients diagnosed in US is a fraction of $0.8 $0.1 >400K global prevalence) $0.7 $0.6 ▪ Patient finding in new geographies 2 2019 2020 2021 Actuals Annualized 1 ATTR market includes all approved drugs for ATTR-PN and ATTR-CM, Includes sales from Waylivra 2 First ATTR-CM sales occurred in Q2 2019 14 14In under two years, ATTR is already a $2B+ market with major upside potential 1 Global annual ATTR market sales $B Significant potential future ATTR market growth $2.3 driven by: +71% $1.7 ▪ Increasing diagnosis in established $1.7 geographies (23.5K patients diagnosed in US is a fraction of $0.8 $0.1 >400K global prevalence) $0.7 $0.6 ▪ Patient finding in new geographies 2 2019 2020 2021 Actuals Annualized 1 ATTR market includes all approved drugs for ATTR-PN and ATTR-CM, Includes sales from Waylivra 2 First ATTR-CM sales occurred in Q2 2019 14 14
Acoramidis was designed to treat ATTR at its source Native TTR circulates Monomers aggregate, Dissociation into in blood as a tetramer causing disease monomers initiates pathogenesis ~130 known destabilizing mutations Disease mechanism Protective T119M mutation Therapeutic Acoramidis was designed to mimic protective T119M mutation by stabilizing hypothesis TTR tetramers to slow or halt disease progression 15Acoramidis was designed to treat ATTR at its source Native TTR circulates Monomers aggregate, Dissociation into in blood as a tetramer causing disease monomers initiates pathogenesis ~130 known destabilizing mutations Disease mechanism Protective T119M mutation Therapeutic Acoramidis was designed to mimic protective T119M mutation by stabilizing hypothesis TTR tetramers to slow or halt disease progression 15
Acoramidis has been well-tolerated and demonstrated near-complete TTR stabilization in preclinical, Phase 1, and Phase 2 studies 1 2 Phase 2 safety summary Phase 2 TTR stabilization TTR stabilization at steady-state trough level Acoramidis Placebo %, mean ± SEM (pooled doses) N = 17 N = 32 140 Any Adverse Event 15 (88%) 21 (66%) 120 Mild 6 (35%) 11 (34%) 100 Moderate 8 (47%) 9 (28%) 80 Severe 1 (6%) 1 (3%) 60 Any Serious Adverse 2 (12%) 1 (3%) 40 Event 1 20 AF and CHF 1 (6%) 0 0 Leg cellulitis 1 (6%) 0 14 45 90 180 Dyspnea 0 1 (3%) Visit Day 1 Judge, D.P. et al., JACC Vol. 74, No. 3, 2019:285 – 95 2 Judge, D.P. et al., American Heart Association 2019 16Acoramidis has been well-tolerated and demonstrated near-complete TTR stabilization in preclinical, Phase 1, and Phase 2 studies 1 2 Phase 2 safety summary Phase 2 TTR stabilization TTR stabilization at steady-state trough level Acoramidis Placebo %, mean ± SEM (pooled doses) N = 17 N = 32 140 Any Adverse Event 15 (88%) 21 (66%) 120 Mild 6 (35%) 11 (34%) 100 Moderate 8 (47%) 9 (28%) 80 Severe 1 (6%) 1 (3%) 60 Any Serious Adverse 2 (12%) 1 (3%) 40 Event 1 20 AF and CHF 1 (6%) 0 0 Leg cellulitis 1 (6%) 0 14 45 90 180 Dyspnea 0 1 (3%) Visit Day 1 Judge, D.P. et al., JACC Vol. 74, No. 3, 2019:285 – 95 2 Judge, D.P. et al., American Heart Association 2019 16
Deaths and CV hospitalizations reported in acoramidis Phase 2 OLE were lower than in placebo-treated ATTR-ACT participants All-cause mortality at 15 months Cardiovascular hospitalizations at 15 months Participants died or receiving transplant (%) Participants with ≥1 CV hospitalization (%) -44% -39% 15.3% 41.8% 25.5% 8.5% Placebo Acoramidis Placebo Acoramidis ATTR-ACT Phase 3 Phase 2 OLE ATTR-ACT Phase 3 Phase 2 OLE 1 Based on routine adverse event reporting Note: These data are based on a cross-trial comparison and not a randomized clinical trial. As a result, the values shown may not be directly comparable 17 Source: Judge, DP et al., American Heart Association Scientific Sessions 2019Deaths and CV hospitalizations reported in acoramidis Phase 2 OLE were lower than in placebo-treated ATTR-ACT participants All-cause mortality at 15 months Cardiovascular hospitalizations at 15 months Participants died or receiving transplant (%) Participants with ≥1 CV hospitalization (%) -44% -39% 15.3% 41.8% 25.5% 8.5% Placebo Acoramidis Placebo Acoramidis ATTR-ACT Phase 3 Phase 2 OLE ATTR-ACT Phase 3 Phase 2 OLE 1 Based on routine adverse event reporting Note: These data are based on a cross-trial comparison and not a randomized clinical trial. As a result, the values shown may not be directly comparable 17 Source: Judge, DP et al., American Heart Association Scientific Sessions 2019
ATTRibute-CM will provide 12-month functional outcome data and 30-month mortality and CV hospitalization data 12-month endpoints: 30-month endpoints: Primary: Change in 6MWD Primary: Hierarchical composite Key Key secondary: Change in KCCQ Key secondary: Change in 6MWD, KCCQ inclusion criteria 800 mg acoramidis twice daily ▪ Subjects with diagnosed ATTR-CM N ~ 421 (WT or mutant) 800 mg ▪ NYHA Class I-III acoramidis twice daily ▪ ATTR-positive biopsy or Placebo twice daily 99m Tc scan N ~ 211 ▪ Light chain amyloidosis excluded if 99m diagnosis by Tc Screening and randomization Part A Part B Open-label extension Tafamidis usage allowed 6MWD = Six-minute walk distance KCCQ = Kansas City Cardiomyopathy Questionnaire NYHA = New York Heart Association 99m Tc = Technetium labeled pyrophosphate (PYP) or bisphosphonate (e.g., DPD) 18 CV = cardiovascular-relatedATTRibute-CM will provide 12-month functional outcome data and 30-month mortality and CV hospitalization data 12-month endpoints: 30-month endpoints: Primary: Change in 6MWD Primary: Hierarchical composite Key Key secondary: Change in KCCQ Key secondary: Change in 6MWD, KCCQ inclusion criteria 800 mg acoramidis twice daily ▪ Subjects with diagnosed ATTR-CM N ~ 421 (WT or mutant) 800 mg ▪ NYHA Class I-III acoramidis twice daily ▪ ATTR-positive biopsy or Placebo twice daily 99m Tc scan N ~ 211 ▪ Light chain amyloidosis excluded if 99m diagnosis by Tc Screening and randomization Part A Part B Open-label extension Tafamidis usage allowed 6MWD = Six-minute walk distance KCCQ = Kansas City Cardiomyopathy Questionnaire NYHA = New York Heart Association 99m Tc = Technetium labeled pyrophosphate (PYP) or bisphosphonate (e.g., DPD) 18 CV = cardiovascular-related
Higher dose of tafamidis demonstrated increased TTR stabilization and greater clinical benefit in ATTR-ACT + LTE Phase 3 ATTR-ACT study tested two doses of tafamidis (20 mg & 80 mg) vs. placebo ▪ In an analysis of ATTR-ACT combined with long-term extension (LTE), benefit of tafamidis 1 80 mg vs. 20 mg was evident on all-cause mortality ▪ At baseline, ATTR-ACT participants treated with 80 mg of tafamidis were older and had more severe evidence of 1 disease than those treated with 20 mg of tafamidis 2 ▪ Participants receiving 80 mg of tafamidis (vs. 20 mg) exhibited greater TTR stabilization Increased levels of TTR 2 1 TTR stabilization All-cause mortality stabilization may translate to improved clinical outcomes in ATTR-CM 1. Damy, T., ESC Heart Failure Association Discoveries 2020. “The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial” 2. FDA CDER Clinical Pharmacology and Biopharmaceutics, Clinical Review (Vyndaqel/Vyndamax), 2019; Fourfold increase in tafamidis dose did not lead to a fourfold 19 increase in TTR stabilization due to non-linear pharmacokineticsHigher dose of tafamidis demonstrated increased TTR stabilization and greater clinical benefit in ATTR-ACT + LTE Phase 3 ATTR-ACT study tested two doses of tafamidis (20 mg & 80 mg) vs. placebo ▪ In an analysis of ATTR-ACT combined with long-term extension (LTE), benefit of tafamidis 1 80 mg vs. 20 mg was evident on all-cause mortality ▪ At baseline, ATTR-ACT participants treated with 80 mg of tafamidis were older and had more severe evidence of 1 disease than those treated with 20 mg of tafamidis 2 ▪ Participants receiving 80 mg of tafamidis (vs. 20 mg) exhibited greater TTR stabilization Increased levels of TTR 2 1 TTR stabilization All-cause mortality stabilization may translate to improved clinical outcomes in ATTR-CM 1. Damy, T., ESC Heart Failure Association Discoveries 2020. “The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial” 2. FDA CDER Clinical Pharmacology and Biopharmaceutics, Clinical Review (Vyndaqel/Vyndamax), 2019; Fourfold increase in tafamidis dose did not lead to a fourfold 19 increase in TTR stabilization due to non-linear pharmacokinetics
Ongoing and planned studies of acoramidis aim to continually expand clinical evidence and addressable patient population 2025+ Prevention in high risk populations ATTRibute-CM Phase 3 study enrolled 2024 632 participants and is on track for Head-to-head comparisons topline data in 4Q 2021 2023 ATTR-PN ATTR-PN Hereditary Hereditary Functional outcomes Functional outcomes 2021 ATTR-CM ATTR-CM ATTR-CM WT and hereditary WT and hereditary WT and hereditary Functional outcomes Functional outcomes Functional outcomes + + + Composite mortality and Composite mortality and Composite mortality and ATTR-CM morbidity morbidity morbidity WT and hereditary Functional outcomes 20Ongoing and planned studies of acoramidis aim to continually expand clinical evidence and addressable patient population 2025+ Prevention in high risk populations ATTRibute-CM Phase 3 study enrolled 2024 632 participants and is on track for Head-to-head comparisons topline data in 4Q 2021 2023 ATTR-PN ATTR-PN Hereditary Hereditary Functional outcomes Functional outcomes 2021 ATTR-CM ATTR-CM ATTR-CM WT and hereditary WT and hereditary WT and hereditary Functional outcomes Functional outcomes Functional outcomes + + + Composite mortality and Composite mortality and Composite mortality and ATTR-CM morbidity morbidity morbidity WT and hereditary Functional outcomes 20
Encaleret for autosomal dominant hypocalcemia type 1 (ADH1) overview ADH1 overview Prevalence Genetic driver Pathophysiology 12K individuals harboring Calcium-sensing receptor Decreased blood calcium, 1 variants in US (CaSR) hyperactivation elevated urine calcium, and lower 2 parathyroid hormone secretion Features of a potential best-in-class medicine for ADH1 Direct targeting of CaSR Potential to address most Oral dosing, the first targeted therapy for ADH1 in a convenient common symptoms Normalization of all form for patients and families arising from altered calcium downstream effects of CaSR and parathyroid hormone hyperactivity Alexis and Jackson dysregulation 21 21 ADH1 patients 1 Dershem et al., Amer Jour of Hum Genetics, 2020; 2 Lienhardt, et al., JCEM, 2001Encaleret for autosomal dominant hypocalcemia type 1 (ADH1) overview ADH1 overview Prevalence Genetic driver Pathophysiology 12K individuals harboring Calcium-sensing receptor Decreased blood calcium, 1 variants in US (CaSR) hyperactivation elevated urine calcium, and lower 2 parathyroid hormone secretion Features of a potential best-in-class medicine for ADH1 Direct targeting of CaSR Potential to address most Oral dosing, the first targeted therapy for ADH1 in a convenient common symptoms Normalization of all form for patients and families arising from altered calcium downstream effects of CaSR and parathyroid hormone hyperactivity Alexis and Jackson dysregulation 21 21 ADH1 patients 1 Dershem et al., Amer Jour of Hum Genetics, 2020; 2 Lienhardt, et al., JCEM, 2001
Encaleret is designed to treat ADH1 at its source by normalizing CaSR sensitivity CaSR senses and regulates Hyperactive CaSR causes Acute symptoms and serum Ca levels dysregulation of Ca homeostasis long-term complications Presenting symptoms 2+ Increased urinary calcium Ca Hypocalcemic seizures ADH1 disease 2+ Ca Paresthesia mechanism Tetany ADH1-causing mutations 2+ Decreased serum calcium Ca Muscle cramps hyperactivate CaSR Long-term complications Nephrocalcinosis Decreased parathyroid PTH hormone secretion Nephrolithiasis Chronic kidney disease Therapeutic Encaleret is a CaSR inhibitor designed to normalize PTH, serum Ca and 2+ Ca hypothesis urine Ca levels, potentially resolving key symptoms of disease 22Encaleret is designed to treat ADH1 at its source by normalizing CaSR sensitivity CaSR senses and regulates Hyperactive CaSR causes Acute symptoms and serum Ca levels dysregulation of Ca homeostasis long-term complications Presenting symptoms 2+ Increased urinary calcium Ca Hypocalcemic seizures ADH1 disease 2+ Ca Paresthesia mechanism Tetany ADH1-causing mutations 2+ Decreased serum calcium Ca Muscle cramps hyperactivate CaSR Long-term complications Nephrocalcinosis Decreased parathyroid PTH hormone secretion Nephrolithiasis Chronic kidney disease Therapeutic Encaleret is a CaSR inhibitor designed to normalize PTH, serum Ca and 2+ Ca hypothesis urine Ca levels, potentially resolving key symptoms of disease 22
Majority of ADH1 patients are symptomatic including one third with severe symptoms Meta-analysis of published ADH1 case reports Size proportional to study sample number 100% Pagan, 2004 Mancilla, 1997 Hendy, 2003 80% Pearce, 1996 Watanabe, 1998 Uckun-Kitapci, 2005 Tan, 2003 60% Hirai, 2001 Livadariu, 2011 In aggregate, ~60% of familial ADH1 Burren, 2005 cases experienced hypocalcemia- Baran, 2015 Alvarez-Hernandez, 2003 Schouten, 2011 40% Baron, related symptoms with one-third Chikatsu, 2003 Kim, 2010 1996 experiencing severe symptoms Gomes, 2020 Garcia-Castano, 2019 Raue, 2011 20% Kwan, 2018 Nagase, 2002 Lienhardt, 2001 Gorvin, Okazaki, Schoutteten, 2017 Obermannova, 2016 Conley, 2000 2018 1999 Lazarus, 2011 0% Pollak, 1994 Park, 2013 Lovlie, 1996 Lienhardt, 2000 Poppe, 2002 Rasmussen, 2018 Kamiyoshi, 2015 0% 20% 40% 60% 80% 100% % Symptomatic of all cases 23 Source: 31 published reports, cumulatively 252 confirmed ADH1 cases over 24 years % Severe of all casesMajority of ADH1 patients are symptomatic including one third with severe symptoms Meta-analysis of published ADH1 case reports Size proportional to study sample number 100% Pagan, 2004 Mancilla, 1997 Hendy, 2003 80% Pearce, 1996 Watanabe, 1998 Uckun-Kitapci, 2005 Tan, 2003 60% Hirai, 2001 Livadariu, 2011 In aggregate, ~60% of familial ADH1 Burren, 2005 cases experienced hypocalcemia- Baran, 2015 Alvarez-Hernandez, 2003 Schouten, 2011 40% Baron, related symptoms with one-third Chikatsu, 2003 Kim, 2010 1996 experiencing severe symptoms Gomes, 2020 Garcia-Castano, 2019 Raue, 2011 20% Kwan, 2018 Nagase, 2002 Lienhardt, 2001 Gorvin, Okazaki, Schoutteten, 2017 Obermannova, 2016 Conley, 2000 2018 1999 Lazarus, 2011 0% Pollak, 1994 Park, 2013 Lovlie, 1996 Lienhardt, 2000 Poppe, 2002 Rasmussen, 2018 Kamiyoshi, 2015 0% 20% 40% 60% 80% 100% % Symptomatic of all cases 23 Source: 31 published reports, cumulatively 252 confirmed ADH1 cases over 24 years % Severe of all cases
Current therapy for ADH1 (oral calcium, activated Vitamin D) raises blood Ca but does not address disease mechanism; increases UCa, suppresses PTH Without supplementation Summary of key disease measures in ADH1 patients with and without supplementation With supplementation Blood calcium Urine calcium Blood parathyroid hormone mg/dL, mean Calcium:Creatinine ratio, mean pg/mL, mean ULN 1.0 65 ULN Normal Normal 10 60 range range 55 0.8 9 50 45 LLN Encaleret 8 40 0.6 target 35 7 30 0.4 25 Encaleret 6 20 target ULN 15 0.2 Normal 5 10 LLN range 5 Encaleret 4 0.0 0 target N = 19 19 10 10 8 8 ULN = upper limit of normal, LLN = lower limit of normal 24 Source: Pearce et al., Clin Endocrinol (Oxf).1996. PTH values reported as below detection limit or undetectable were recorded as “0”Current therapy for ADH1 (oral calcium, activated Vitamin D) raises blood Ca but does not address disease mechanism; increases UCa, suppresses PTH Without supplementation Summary of key disease measures in ADH1 patients with and without supplementation With supplementation Blood calcium Urine calcium Blood parathyroid hormone mg/dL, mean Calcium:Creatinine ratio, mean pg/mL, mean ULN 1.0 65 ULN Normal Normal 10 60 range range 55 0.8 9 50 45 LLN Encaleret 8 40 0.6 target 35 7 30 0.4 25 Encaleret 6 20 target ULN 15 0.2 Normal 5 10 LLN range 5 Encaleret 4 0.0 0 target N = 19 19 10 10 8 8 ULN = upper limit of normal, LLN = lower limit of normal 24 Source: Pearce et al., Clin Endocrinol (Oxf).1996. PTH values reported as below detection limit or undetectable were recorded as “0”
Encaleret Phase 2 study design Complete Ongoing Phase 2 Period 2 Phase 2 Period 3 Phase 2 Period 1 Individualized dose adjustment Outpatient extension Individualized dose escalation 5 days, inpatient 5 days, inpatient 6 months, outpatient (N=6) (N=11-16) (N=11-16) Program Overview March 2021: 2H 2021: Proof-of-concept Planned interaction early results with FDA Key study objectives: Additional measures ▪ Safety and tolerability▪ Blood 1,25-(OH) Vitamin D, magnesium, and phosphate 2 ▪ Blood calcium concentration▪ Urine creatinine, cAMP, citrate, phosphate, sodium, magnesium ▪ Urine calcium concentration▪ Bone turnover markers (serum collagen C-telopeptide, serum procollagen Type 1 N-propeptide) ▪ Intact parathyroid hormone concentration 25Encaleret Phase 2 study design Complete Ongoing Phase 2 Period 2 Phase 2 Period 3 Phase 2 Period 1 Individualized dose adjustment Outpatient extension Individualized dose escalation 5 days, inpatient 5 days, inpatient 6 months, outpatient (N=6) (N=11-16) (N=11-16) Program Overview March 2021: 2H 2021: Proof-of-concept Planned interaction early results with FDA Key study objectives: Additional measures ▪ Safety and tolerability▪ Blood 1,25-(OH) Vitamin D, magnesium, and phosphate 2 ▪ Blood calcium concentration▪ Urine creatinine, cAMP, citrate, phosphate, sodium, magnesium ▪ Urine calcium concentration▪ Bone turnover markers (serum collagen C-telopeptide, serum procollagen Type 1 N-propeptide) ▪ Intact parathyroid hormone concentration 25
All trial participants had normal blood and urine calcium by Day 5 Baseline Value (Day 1) Mean Value (Day 5) Blood calcium Urine calcium Blood parathyroid hormone mg/dL mg/day pg/mL 1000 11 120 800 10 90 600 9 60 400 8 30 200 7 0 0 6 † * * All Subjects Average All Subjects Average Average All Subjects *Values below limit of assay quantitation recorded as “0” † Day 4 values used in two subjects given Day 5 values unavailable 26 † Dashed lines reflect normal rangesAll trial participants had normal blood and urine calcium by Day 5 Baseline Value (Day 1) Mean Value (Day 5) Blood calcium Urine calcium Blood parathyroid hormone mg/dL mg/day pg/mL 1000 11 120 800 10 90 600 9 60 400 8 30 200 7 0 0 6 † * * All Subjects Average All Subjects Average Average All Subjects *Values below limit of assay quantitation recorded as “0” † Day 4 values used in two subjects given Day 5 values unavailable 26 † Dashed lines reflect normal ranges
Encaleret Ph baseline characteristics Encaleret Characteristic Normal Range N = 6 Age, mean (range) 40 (22-60) Female, n (%) 3 (50%) Nephrocalcinosis, n (%) 4 (67%) ECG QT B (msec) 452 ± 9 < 440 c Corrected Calcium (mg/dL)* 7.6 ± 0.6 8.4 –10.2 Intact PTH (pg/mL)* 3.4 ± 4.5 15 – 65 Phosphate (mg/dL)* 4.5 ± 0.7 2.5 – 4.5 Magnesium (mg/dL)* 1.6 ± 0.4 1.6 – 2.6 24h Urine Calcium (mg/24h) 436 ± 255 < 250-300 Supplements Elemental Calcium (mg/day) [mean (range)] 2317 (800-4000) Calcitriol (µg/day) [mean (range)] 0.9 (0.5-2.0) CASR Variants C131Y (2), P221L (2), E604K (1), A840V (1) ECG QT B = electrocardiogram Bazett-corrected Q-T interval c 27 *Measurements taken pre-dose Day 1 (mean ± SD)Encaleret Ph baseline characteristics Encaleret Characteristic Normal Range N = 6 Age, mean (range) 40 (22-60) Female, n (%) 3 (50%) Nephrocalcinosis, n (%) 4 (67%) ECG QT B (msec) 452 ± 9 < 440 c Corrected Calcium (mg/dL)* 7.6 ± 0.6 8.4 –10.2 Intact PTH (pg/mL)* 3.4 ± 4.5 15 – 65 Phosphate (mg/dL)* 4.5 ± 0.7 2.5 – 4.5 Magnesium (mg/dL)* 1.6 ± 0.4 1.6 – 2.6 24h Urine Calcium (mg/24h) 436 ± 255 < 250-300 Supplements Elemental Calcium (mg/day) [mean (range)] 2317 (800-4000) Calcitriol (µg/day) [mean (range)] 0.9 (0.5-2.0) CASR Variants C131Y (2), P221L (2), E604K (1), A840V (1) ECG QT B = electrocardiogram Bazett-corrected Q-T interval c 27 *Measurements taken pre-dose Day 1 (mean ± SD)
Encaleret was generally well-tolerated with no serious adverse events reported after 5 days N = 6 Number of subjects experiencing any Serious Adverse Event 0 (0%) Number of subjects experiencing any Adverse Event 5 (83%) Mild 5 (83%) Moderate 0 (0%) Severe 0 (0%) Number of Adverse Events Reported 9 Mild 9 (100%) Moderate 0 (0%) Severe 0 (0%) Only treatment-related AE was mild, transient, asymptomatic hypophosphatemia (<2 mg/dL) in 2 subjects 28Encaleret was generally well-tolerated with no serious adverse events reported after 5 days N = 6 Number of subjects experiencing any Serious Adverse Event 0 (0%) Number of subjects experiencing any Adverse Event 5 (83%) Mild 5 (83%) Moderate 0 (0%) Severe 0 (0%) Number of Adverse Events Reported 9 Mild 9 (100%) Moderate 0 (0%) Severe 0 (0%) Only treatment-related AE was mild, transient, asymptomatic hypophosphatemia (<2 mg/dL) in 2 subjects 28
Dose dependent-increases in PTH mirrored encaleret levels * 90 180 180 180 180 180 30 8 mg mg mg mg mg mg mg 6 4 2 0 250 200 150 100 50 0 Day 1 Day 2 Day 3 Day 4 Day 5 29 Data shown as mean ± SD *One subject reduced second dose on Day 5 to 120 mg *Dashed line reflects normal range of PTH 15-65 pg/mL iPTH (pg/mL) Plasma Encaleret (μm)Dose dependent-increases in PTH mirrored encaleret levels * 90 180 180 180 180 180 30 8 mg mg mg mg mg mg mg 6 4 2 0 250 200 150 100 50 0 Day 1 Day 2 Day 3 Day 4 Day 5 29 Data shown as mean ± SD *One subject reduced second dose on Day 5 to 120 mg *Dashed line reflects normal range of PTH 15-65 pg/mL iPTH (pg/mL) Plasma Encaleret (μm)
Encaleret normalized blood and urine calcium * 30 90 180 180 180 180 180 11 mg mg mg mg mg mg mg ULN 10 9 LLN 8 7 6 1200 800 400 ULN 0 Day 1 Day 2 Day 3 Day 4 Day 5 Data shown as mean ± SD *Values below limit of assay quantitation were marked as “0” *One subject reduced second dose on Day 5 to 120 mg *Dashed line 30 reflects normal ranges: calcium, 8.4-10.2 mg/dL; 24-hr urine calcium, < 250-300 mg/day . Urine Ca (mg/24 h) Blood cCa (mg/dL)Encaleret normalized blood and urine calcium * 30 90 180 180 180 180 180 11 mg mg mg mg mg mg mg ULN 10 9 LLN 8 7 6 1200 800 400 ULN 0 Day 1 Day 2 Day 3 Day 4 Day 5 Data shown as mean ± SD *Values below limit of assay quantitation were marked as “0” *One subject reduced second dose on Day 5 to 120 mg *Dashed line 30 reflects normal ranges: calcium, 8.4-10.2 mg/dL; 24-hr urine calcium, < 250-300 mg/day . Urine Ca (mg/24 h) Blood cCa (mg/dL)
Conclusions ▪ Encaleret was well-tolerated when administered in escalating oral doses once or twice daily over 5 days, with no serious adverse events reported and no adverse events of moderate or severe intensity ▪ Blood calcium, PTH, and phosphate were normalized and maintained within the normal range on average by day 5 ▪ Urinary calcium excretion was reduced to below the upper limit of normal or undetectable in all participants while on encaleret and eucalcemic ▪ Consistent changes from baseline in blood and urine mineral measurements provide proof-of-concept data that encaleret may be an effective treatment option for ADH1 ▪ Data support further development of encaleret in ADH1 31Conclusions ▪ Encaleret was well-tolerated when administered in escalating oral doses once or twice daily over 5 days, with no serious adverse events reported and no adverse events of moderate or severe intensity ▪ Blood calcium, PTH, and phosphate were normalized and maintained within the normal range on average by day 5 ▪ Urinary calcium excretion was reduced to below the upper limit of normal or undetectable in all participants while on encaleret and eucalcemic ▪ Consistent changes from baseline in blood and urine mineral measurements provide proof-of-concept data that encaleret may be an effective treatment option for ADH1 ▪ Data support further development of encaleret in ADH1 31
Next steps for encaleret include generating further evidence in ongoing Phase 2 study Planned activities ✓ Initiate Phase 2 study in ADH1 2020 ▪ Phase 3 registrational study in ADH1 ✓ Receive ODD from FDA for ADH ▪ Pediatric development program in ADH1 ▪ Evaluation of encaleret in non-genetic ✓ Report Phase 2 proof-of-concept results hypoparathyroidism ❑ Complete enrollment of Cohort 2 in Phase 2 2021 study ❑ Interaction with FDA 32Next steps for encaleret include generating further evidence in ongoing Phase 2 study Planned activities ✓ Initiate Phase 2 study in ADH1 2020 ▪ Phase 3 registrational study in ADH1 ✓ Receive ODD from FDA for ADH ▪ Pediatric development program in ADH1 ▪ Evaluation of encaleret in non-genetic ✓ Report Phase 2 proof-of-concept results hypoparathyroidism ❑ Complete enrollment of Cohort 2 in Phase 2 2021 study ❑ Interaction with FDA 32
Low-dose FGFR inhibitor (infigratinib) for achondroplasia Achondroplasia overview Prevalence Genetic driver Pathophysiology 55,000 (US+EU) – FGFR3 activation Up-regulation of STAT1 and MAPK one of the most common in the growth plate cause cranial, genetic conditions spinal, and stature symptoms Features of a potential best-in-class medicine for achondroplasia Direct targeting of FGFR3 Potential to address all Oral dosing, the most and normalization of both convenient solution for drivers of symptoms, STAT1 and MAPK children with achondroplasia including cranial, spinal signaling pathways and their families and stature issues Claudia, child with achondroplasia 33Low-dose FGFR inhibitor (infigratinib) for achondroplasia Achondroplasia overview Prevalence Genetic driver Pathophysiology 55,000 (US+EU) – FGFR3 activation Up-regulation of STAT1 and MAPK one of the most common in the growth plate cause cranial, genetic conditions spinal, and stature symptoms Features of a potential best-in-class medicine for achondroplasia Direct targeting of FGFR3 Potential to address all Oral dosing, the most and normalization of both convenient solution for drivers of symptoms, STAT1 and MAPK children with achondroplasia including cranial, spinal signaling pathways and their families and stature issues Claudia, child with achondroplasia 33
Potential best-in-class approach targeting achondroplasia directly at its genetic source ACH FGFR3 gain-of-function mutation causes: FGF ▪ 2-3x over-activation of the receptor FGFR3 G380R ▪ Up-regulation of downstream pathways STAT1 mutation Growth plate chondrocyte and MAPK ▪ Aberrant growth plate development, which causes cranial, spinal, Low-dose and stature symptoms infigratinib CNP analogues indirectly On target, selective block MAPK inhibition of FGFR3 directly blocking both Low-dose infigratinib has the potential to: STAT1 and MAPK STAT1 MAPK ▪ Directly inhibit the causal gain-of-function mutation in FGFR3 ▪ Normalize both the STAT1 and MAPK signaling pathways Misregulated growth plate development ▪ Reverse all key drivers of symptoms Source: Ornitz DM et al., Developmental Dynamic 2017, Richette Joint Bone Spine 2007, Unger Curr Osteoporos Rep 2017, Hoover-Fong Am J Gen Med 2017 34Potential best-in-class approach targeting achondroplasia directly at its genetic source ACH FGFR3 gain-of-function mutation causes: FGF ▪ 2-3x over-activation of the receptor FGFR3 G380R ▪ Up-regulation of downstream pathways STAT1 mutation Growth plate chondrocyte and MAPK ▪ Aberrant growth plate development, which causes cranial, spinal, Low-dose and stature symptoms infigratinib CNP analogues indirectly On target, selective block MAPK inhibition of FGFR3 directly blocking both Low-dose infigratinib has the potential to: STAT1 and MAPK STAT1 MAPK ▪ Directly inhibit the causal gain-of-function mutation in FGFR3 ▪ Normalize both the STAT1 and MAPK signaling pathways Misregulated growth plate development ▪ Reverse all key drivers of symptoms Source: Ornitz DM et al., Developmental Dynamic 2017, Richette Joint Bone Spine 2007, Unger Curr Osteoporos Rep 2017, Hoover-Fong Am J Gen Med 2017 34
Low-dose infigratinib improves all the key drivers of clinical symptomology in validated ACH mouse model Y367C/+ Y367C/+ FGFR3 WT FGFR3 FGFR3 No treatment No treatment Infigratinib tx Cranial bone issues 1 May lead to decrease 17% 6% in foramen magnum increase in increase in AP stenosis and fewer FM area skull length surgeries 2 Disorders of the spine May lead to decrease 12% 73% in spinal stenosis, increase in increase in possibly reducing L4-L6 length disc width need for surgery 3 Disproportionate short stature 21% 33% May lead to increased stature increase in increase in and proportionality femur length tibia length Source: Komla-Ebri et al., J Clin Inv 2016 Note: percent increase compared to vehicle treated FGFR3Y367C/+ mouse, infigratinib treatment with 2mg/kg subcutaneous dose 35Low-dose infigratinib improves all the key drivers of clinical symptomology in validated ACH mouse model Y367C/+ Y367C/+ FGFR3 WT FGFR3 FGFR3 No treatment No treatment Infigratinib tx Cranial bone issues 1 May lead to decrease 17% 6% in foramen magnum increase in increase in AP stenosis and fewer FM area skull length surgeries 2 Disorders of the spine May lead to decrease 12% 73% in spinal stenosis, increase in increase in possibly reducing L4-L6 length disc width need for surgery 3 Disproportionate short stature 21% 33% May lead to increased stature increase in increase in and proportionality femur length tibia length Source: Komla-Ebri et al., J Clin Inv 2016 Note: percent increase compared to vehicle treated FGFR3Y367C/+ mouse, infigratinib treatment with 2mg/kg subcutaneous dose 35
Low-dose infigratinib showed potential best in-class preclinical profile in validated achondroplasia mouse model Company/ Foramen MOA Route Status Mouse model Tibia length Femur L4-L6 height Asset magnum area Selective Y367C/+ 32.6% 20.9% 17.0% 12.1% Oral Ph2 FGFR3 FGFR1-3i Infigratinib Pivotal Y367C/+ 6.6% 5.2% 3.3% CNP analogue Daily SQ FGFR3 Vosoritide (NDA filed) (BMN111) No known publicly Y367C/+ 12.3% CNP analogue Weekly SQ Ph2 FGFR3 available 1 TransCon CNP data ACH 8.6% 6.2% FGFR3 decoy Weekly SQ Ph2 FGFR3 Reifercept (TA-46) Preclinical data from infigratinib and other investigational achondroplasia therapies Percent increase compared to non-treated mouse Source: Komla-Ebri et al., J Clin Inv 2016, Lorget et al., Am J Hum Genet 2012, Garcia et al., Science Trans Med 2013, Breinholt ENDO 2017 Y367C/+ ACH/+ Note: subcutaneous doses, percent increase compared to vehicle treated FGFR3 , FGFR3 mouse as noted in “Mouse model” columns 36 1 Infigratinib treatment with 2mg/kg subcutaneous dose Based on vosoritide continuous infusion; *Value estimated using DigitizeIt. Low-dose infigratinib showed potential best in-class preclinical profile in validated achondroplasia mouse model Company/ Foramen MOA Route Status Mouse model Tibia length Femur L4-L6 height Asset magnum area Selective Y367C/+ 32.6% 20.9% 17.0% 12.1% Oral Ph2 FGFR3 FGFR1-3i Infigratinib Pivotal Y367C/+ 6.6% 5.2% 3.3% CNP analogue Daily SQ FGFR3 Vosoritide (NDA filed) (BMN111) No known publicly Y367C/+ 12.3% CNP analogue Weekly SQ Ph2 FGFR3 available 1 TransCon CNP data ACH 8.6% 6.2% FGFR3 decoy Weekly SQ Ph2 FGFR3 Reifercept (TA-46) Preclinical data from infigratinib and other investigational achondroplasia therapies Percent increase compared to non-treated mouse Source: Komla-Ebri et al., J Clin Inv 2016, Lorget et al., Am J Hum Genet 2012, Garcia et al., Science Trans Med 2013, Breinholt ENDO 2017 Y367C/+ ACH/+ Note: subcutaneous doses, percent increase compared to vehicle treated FGFR3 , FGFR3 mouse as noted in “Mouse model” columns 36 1 Infigratinib treatment with 2mg/kg subcutaneous dose Based on vosoritide continuous infusion; *Value estimated using DigitizeIt.
We have a wide anticipated therapeutic index in achondroplasia Infigratinib has been tested in >700 humans in our oncology program, providing significant data on PK, tolerability and safety Most common and dose-limiting side effect is phosphorus elevation (on-target through FGFR1 inhibition), which occurs significantly above our planned achondroplasia doses 2.2 1 Oncology dose 2.0 1.8 1.6 Starting ACH dose 130x below 1.4 oncology dose 1.2 1.0 0.8 On-target 2 0.6 adverse events 0.4 Expected therapeutic window Anticipated 0.2 0.128 0.064 0.032 0.016 minimum 0.0 3 efficacious dose Cohort 1 Cohort 2 Cohort 3 Cohort 4 ACH Ph2 doses 1 2 3 Based on 125mg dose and 60kg adult; Based on estimated TD at 40mg and 60kg adult; Based on PK modeling and allometric scaling from animal 50 models 37 Infigratinib dose (mg/kg)We have a wide anticipated therapeutic index in achondroplasia Infigratinib has been tested in >700 humans in our oncology program, providing significant data on PK, tolerability and safety Most common and dose-limiting side effect is phosphorus elevation (on-target through FGFR1 inhibition), which occurs significantly above our planned achondroplasia doses 2.2 1 Oncology dose 2.0 1.8 1.6 Starting ACH dose 130x below 1.4 oncology dose 1.2 1.0 0.8 On-target 2 0.6 adverse events 0.4 Expected therapeutic window Anticipated 0.2 0.128 0.064 0.032 0.016 minimum 0.0 3 efficacious dose Cohort 1 Cohort 2 Cohort 3 Cohort 4 ACH Ph2 doses 1 2 3 Based on 125mg dose and 60kg adult; Based on estimated TD at 40mg and 60kg adult; Based on PK modeling and allometric scaling from animal 50 models 37 Infigratinib dose (mg/kg)
The PROPEL clinical program is enrolling with data expected in 2H 2021 Ph2 Dose-finding (n=40) Long-term extension Observational run-in Children are followed for a minimum of 6 months to establish baseline 0.128 mg/kg annualized growth velocity (AGV) n=10 0.064 mg/kg n=10 12 month Select dose long-term extension 0.032 mg/kg n=10 Potential to enroll 20 additional subjects at selected dose 0.016 mg/kg n=10 Key inclusion criteria Primary objectives Primary objectives ▪ Children 2.5 – 10 years old▪ Identify safe therapeutic dose for expansion ▪ Long-term safety and efficacy ▪ Clinical and molecular ACH diagnosis / pivotal study ▪ Safety and tolerability Primary objectives ▪ Change from baseline in AGV ▪ Baseline annualized growth velocity (AGV) 38The PROPEL clinical program is enrolling with data expected in 2H 2021 Ph2 Dose-finding (n=40) Long-term extension Observational run-in Children are followed for a minimum of 6 months to establish baseline 0.128 mg/kg annualized growth velocity (AGV) n=10 0.064 mg/kg n=10 12 month Select dose long-term extension 0.032 mg/kg n=10 Potential to enroll 20 additional subjects at selected dose 0.016 mg/kg n=10 Key inclusion criteria Primary objectives Primary objectives ▪ Children 2.5 – 10 years old▪ Identify safe therapeutic dose for expansion ▪ Long-term safety and efficacy ▪ Clinical and molecular ACH diagnosis / pivotal study ▪ Safety and tolerability Primary objectives ▪ Change from baseline in AGV ▪ Baseline annualized growth velocity (AGV) 38
BBP-631: AAV5 gene therapy for congenital adrenal hyperplasia (CAH) Program overview Prevalence Genetic driver Pathophysiology 75,000 (US+EU) – One of 21-hydroxylase Inability to produce cortisol causes need the largest known AAV inactivation for supraphysiologic doses of synthetic gene therapy markets steroids, 3x increase in mortality risk, hirsutism, Cushingoid symptoms We believe CAH is an ideal indication for AAV gene therapy: ▪ Low threshold to correct phenotype, validated by human clinical genetics (~5-10% of WT enzyme activity) ▪ Only approach designed to induce endogenous cortisol and mineralocorticoid production, potentially allowing steroid withdrawal ▪ Durable transgene delivery to the adrenal gland of NHPs with IV dosing of our construct ▪ Next catalyst: initial data from first-in-human study Maris, child with CAH 39BBP-631: AAV5 gene therapy for congenital adrenal hyperplasia (CAH) Program overview Prevalence Genetic driver Pathophysiology 75,000 (US+EU) – One of 21-hydroxylase Inability to produce cortisol causes need the largest known AAV inactivation for supraphysiologic doses of synthetic gene therapy markets steroids, 3x increase in mortality risk, hirsutism, Cushingoid symptoms We believe CAH is an ideal indication for AAV gene therapy: ▪ Low threshold to correct phenotype, validated by human clinical genetics (~5-10% of WT enzyme activity) ▪ Only approach designed to induce endogenous cortisol and mineralocorticoid production, potentially allowing steroid withdrawal ▪ Durable transgene delivery to the adrenal gland of NHPs with IV dosing of our construct ▪ Next catalyst: initial data from first-in-human study Maris, child with CAH 39
Gene therapy is the only modality designed to treat CAH at its source and allow for production of endogenous cortisol Hormonal dysregulation with 21OHD; no cortisol “brake” on Healthy Hypothalamic-Pituitary-Adrenal Axis ACTH, shunting of 17OHP to androgens CRF Hypothalamus CRF Hypothalamus ACTH ACTH Pituitary gland Pituitary gland Adrenal gland Adrenal gland 17a hydroxy- 17a hydroxy- Progesterone Androgens Progesterone Androgens progesterone progesterone 21-hydroxylase 21-hydroxylase Aldosterone Cortisol Aldosterone Cortisol In a functional HPA system, cortisol and aldosterone are produced In CAH, cortisol and aldosterone are not able to be produced. The lack of a as needed by the body. Cortisol serves as a “brake” on the “cortisol brake” results in buildup of progesterone and 17OHP, leading to CRF/ACTH system an excess of androgen production CAH patients have 3-4X higher mortality than the general population, and suffer significant morbidity ranging across cardiovascular and metabolic disease, bone disease, infertility, chronic fatigue, and other disorders. 40Gene therapy is the only modality designed to treat CAH at its source and allow for production of endogenous cortisol Hormonal dysregulation with 21OHD; no cortisol “brake” on Healthy Hypothalamic-Pituitary-Adrenal Axis ACTH, shunting of 17OHP to androgens CRF Hypothalamus CRF Hypothalamus ACTH ACTH Pituitary gland Pituitary gland Adrenal gland Adrenal gland 17a hydroxy- 17a hydroxy- Progesterone Androgens Progesterone Androgens progesterone progesterone 21-hydroxylase 21-hydroxylase Aldosterone Cortisol Aldosterone Cortisol In a functional HPA system, cortisol and aldosterone are produced In CAH, cortisol and aldosterone are not able to be produced. The lack of a as needed by the body. Cortisol serves as a “brake” on the “cortisol brake” results in buildup of progesterone and 17OHP, leading to CRF/ACTH system an excess of androgen production CAH patients have 3-4X higher mortality than the general population, and suffer significant morbidity ranging across cardiovascular and metabolic disease, bone disease, infertility, chronic fatigue, and other disorders. 40
CAH: NHP study showed durable transgene expression; 5-10% of WT enzyme may be sufficient for clinical impact Genotype-phenotype studies show that Mouse studies show a VGC of only 0.13 NHP studies show sustained VGC and RNA >5-10% of enzyme activity results in at 18 wks was sufficient for phenotypic out to 6 months nonclassical CAH correction Stimulated cortisol (ug/dl) Progesterone levels in Cyp 21-/-mice VG Copies per Cell (DNA) hCYP21A2/Ywhaz (RNA) • Due to the high enzymatic efficiency/selectivity • At 15 weeks in treated mice, progesterone (the of 21-OHase, only a small amount of enzyme is key substrate of 21OHase in mice) was required to rescue the phenotype significantly reduced vs untreated mice • Transgene expression is dose-dependent and stable out at 24 wks • We can durably transduce the NHP adrenal gland with our construct at >20x the vector required to correct the CAH phenotype in mice Source: Perdomini, Gene Therapy 2017; ESGCT 2019 41CAH: NHP study showed durable transgene expression; 5-10% of WT enzyme may be sufficient for clinical impact Genotype-phenotype studies show that Mouse studies show a VGC of only 0.13 NHP studies show sustained VGC and RNA >5-10% of enzyme activity results in at 18 wks was sufficient for phenotypic out to 6 months nonclassical CAH correction Stimulated cortisol (ug/dl) Progesterone levels in Cyp 21-/-mice VG Copies per Cell (DNA) hCYP21A2/Ywhaz (RNA) • Due to the high enzymatic efficiency/selectivity • At 15 weeks in treated mice, progesterone (the of 21-OHase, only a small amount of enzyme is key substrate of 21OHase in mice) was required to rescue the phenotype significantly reduced vs untreated mice • Transgene expression is dose-dependent and stable out at 24 wks • We can durably transduce the NHP adrenal gland with our construct at >20x the vector required to correct the CAH phenotype in mice Source: Perdomini, Gene Therapy 2017; ESGCT 2019 41
NHP protein data using mass spec methods suggests potentially therapeutic levels of 21-hydroxylase enzyme Human 21-hydroxylase protein as a % of NHP 21-hydroxylase protein (Mass Spec quantification) ▪ We have developed mass- 24% spec methods to quantify protein expression by identifying differential peptides between human and NHP 21-OH 13% ▪ These data suggest dose- dependent enzyme 9% expression in the adrenal cortex from 9%-24% of WT levels Mild or asymptomatic ▪ Genotype-phenotype (non-classic relationship suggests as little CAH) as 5% of WT enzyme activity is associated with the 5e12 vg/kg 1.5e13 vg/kg 4.5e13 vg/kg mild/asymptomatic non- classic form of CAH Dose Source: Data on file 42NHP protein data using mass spec methods suggests potentially therapeutic levels of 21-hydroxylase enzyme Human 21-hydroxylase protein as a % of NHP 21-hydroxylase protein (Mass Spec quantification) ▪ We have developed mass- 24% spec methods to quantify protein expression by identifying differential peptides between human and NHP 21-OH 13% ▪ These data suggest dose- dependent enzyme 9% expression in the adrenal cortex from 9%-24% of WT levels Mild or asymptomatic ▪ Genotype-phenotype (non-classic relationship suggests as little CAH) as 5% of WT enzyme activity is associated with the 5e12 vg/kg 1.5e13 vg/kg 4.5e13 vg/kg mild/asymptomatic non- classic form of CAH Dose Source: Data on file 42
BridgeBio oncology research World-class oncology team drives our discovery and development Eli Wallace CSO Oncology Research Pedro Beltran SVP Oncology Frank McCormick Chairman of Oncology Richard Scheller Chairman of R&D Basia, pancreatic cancer patient (>90% KRAS-driven) 43BridgeBio oncology research World-class oncology team drives our discovery and development Eli Wallace CSO Oncology Research Pedro Beltran SVP Oncology Frank McCormick Chairman of Oncology Richard Scheller Chairman of R&D Basia, pancreatic cancer patient (>90% KRAS-driven) 43
Three disclosed oncology research targets SHP2 (BBP-398) KRAS GPX4 Receptor tyrosine kinase signals Receptor tyrosine kinase signals (EGFR, ALK, TRK, RET) (EGFR, ALK, TRK, RET) Cell membrane damage Cancer cell membrane Cancer mutations lock Cancer mutations lock KRAS in its active state KRAS in its active state Lipid oxy- Prenylation radicals SHP2 SHP2 C185 Death by Detoxification of GPX4 GPX4 ferroptosis lipid free radicals, cell survival KRAS GTP KRAS GTP RAS(ON) RAS(ON) KRAS KRAS GDP GDP H95 RAS(OFF) RAS(OFF) RAS effectors RAS effectors Tumor cell Tumor cell RAF PI3K RAF PI3K proliferation proliferation and survival and survival ▪ Potential best-in-class oral compound▪ Multiple unexploited sites▪ Potential first in class compound for novel – Optimized safety, PK and PD profile▪ Comprehensive pan-mutant targeting cancer target – Maximizes combination therapy potential approaches▪ In vivo monotherapy activity and combo ▪ First-in-human study initiated 4Q20 potential 44Three disclosed oncology research targets SHP2 (BBP-398) KRAS GPX4 Receptor tyrosine kinase signals Receptor tyrosine kinase signals (EGFR, ALK, TRK, RET) (EGFR, ALK, TRK, RET) Cell membrane damage Cancer cell membrane Cancer mutations lock Cancer mutations lock KRAS in its active state KRAS in its active state Lipid oxy- Prenylation radicals SHP2 SHP2 C185 Death by Detoxification of GPX4 GPX4 ferroptosis lipid free radicals, cell survival KRAS GTP KRAS GTP RAS(ON) RAS(ON) KRAS KRAS GDP GDP H95 RAS(OFF) RAS(OFF) RAS effectors RAS effectors Tumor cell Tumor cell RAF PI3K RAF PI3K proliferation proliferation and survival and survival ▪ Potential best-in-class oral compound▪ Multiple unexploited sites▪ Potential first in class compound for novel – Optimized safety, PK and PD profile▪ Comprehensive pan-mutant targeting cancer target – Maximizes combination therapy potential approaches▪ In vivo monotherapy activity and combo ▪ First-in-human study initiated 4Q20 potential 44
Partnerships afford us exceptional collaborators and resources rd ▪ Partnership with the National RAS Initiative, ▪ Home to Sierra: the world’s 3 fastest computing including 60 of the world’s foremost academic RAS system researchers ▪ Enables multi-microsecond molecular dynamics ▪ Cutting edge RAS structural biology expertise simulations of protein complexes, and highly efficient in silico docking simulations ▪ Utilization of cutting-edge instrumentation and techniques, as well as the expertise to lead ▪ This computing power, combined with RAS structural experiments biology expertise at the NCI, delivers unique insights that fuel our drug design 45Partnerships afford us exceptional collaborators and resources rd ▪ Partnership with the National RAS Initiative, ▪ Home to Sierra: the world’s 3 fastest computing including 60 of the world’s foremost academic RAS system researchers ▪ Enables multi-microsecond molecular dynamics ▪ Cutting edge RAS structural biology expertise simulations of protein complexes, and highly efficient in silico docking simulations ▪ Utilization of cutting-edge instrumentation and techniques, as well as the expertise to lead ▪ This computing power, combined with RAS structural experiments biology expertise at the NCI, delivers unique insights that fuel our drug design 45
Crystal structure enables a static understanding of the target … KRAS4b model based on crystal One therapeutic approach is to inhibit KRAS4b membrane localization by targeting hypervariable region Static model reveals only a subset of potential binding sites for pharmacological compounds G-domain switch II G-domain Hypervariable region G-domain switch I 46Crystal structure enables a static understanding of the target … KRAS4b model based on crystal One therapeutic approach is to inhibit KRAS4b membrane localization by targeting hypervariable region Static model reveals only a subset of potential binding sites for pharmacological compounds G-domain switch II G-domain Hypervariable region G-domain switch I 46
… whereas molecular dynamics simulation reveals transient conformations and interactions KRAS4b simulation Reveals possible KRAS4b HVR transient localization to G-domain Elucidates potential transient druggable pocket where compounds could react covalently with C185 Enables in silico SAR to inhibit KRAS4b membrane localization G-domain switch II G-domain Hypervariable region G-domain switch I 47… whereas molecular dynamics simulation reveals transient conformations and interactions KRAS4b simulation Reveals possible KRAS4b HVR transient localization to G-domain Elucidates potential transient druggable pocket where compounds could react covalently with C185 Enables in silico SAR to inhibit KRAS4b membrane localization G-domain switch II G-domain Hypervariable region G-domain switch I 47
KRAS: multiple shots on goal with our pan-mutant inhibitor programs – each with a unique MOA targeting a novel pocket Targets Crystal Molecular KRAS pathway in cancer Program MOA KRAS GTP Pan-mutant structure Dynamics ▪ Directly binds activated KRAS Program 1: H95 Receptor tyrosine kinase signals (EGFR, ALK, TRK, RET) through H95 targeting ▪ Inhibits KRAS from signaling Cancer mutations lock through effectors KRAS in its active state Prenylation SHP2 ▪ Blocks specific interaction Program 2: PI3K C185 between KRAS and PI3Ka effector blocking KRAS GTP ▪ Blocks PI3K / AKT effector KRAS RAS(ON) signaling GDP H95 RAS(OFF) RAS effectors Program 3: C185 ▪ Blocks KRAS from tethering targeting RAF PI3K ▪ Blocks conversion of inactive KRAS GDP to active KRAS GTP Tumor cell proliferation and survival Our programs are designed to address all KRAS driver mutations, which occur in >30% of all cancers 48KRAS: multiple shots on goal with our pan-mutant inhibitor programs – each with a unique MOA targeting a novel pocket Targets Crystal Molecular KRAS pathway in cancer Program MOA KRAS GTP Pan-mutant structure Dynamics ▪ Directly binds activated KRAS Program 1: H95 Receptor tyrosine kinase signals (EGFR, ALK, TRK, RET) through H95 targeting ▪ Inhibits KRAS from signaling Cancer mutations lock through effectors KRAS in its active state Prenylation SHP2 ▪ Blocks specific interaction Program 2: PI3K C185 between KRAS and PI3Ka effector blocking KRAS GTP ▪ Blocks PI3K / AKT effector KRAS RAS(ON) signaling GDP H95 RAS(OFF) RAS effectors Program 3: C185 ▪ Blocks KRAS from tethering targeting RAF PI3K ▪ Blocks conversion of inactive KRAS GDP to active KRAS GTP Tumor cell proliferation and survival Our programs are designed to address all KRAS driver mutations, which occur in >30% of all cancers 48
SHP2: Our compound shows best-in-class potential in a large cancer market Our SHP2i blocks downstream MAPK signaling We believe BBP-398 has the ideal properties for combination and abrogates T cell exhaustion with a multitude of other therapeutic classes 1 Human half life: ~10-15 hours Potentially differentiated safety profile for Receptor tyrosine kinase signals ▪ Allows for recovery above EC50 and reduced combination therapy (EGFR, ALK, TRK, RET) ▪ hERG IC50 (µM)*: >100: No QT prolongation MAPK-driven tox 2 SHP2i combination potential Supporting evidence SHP2 US + EU incidence, ‘000s Preclinical data: KRAS BBIO SHP2i Other SHP2i GTP KRAS GDP ALKi 30 RAS(ON) RAS(OFF) KRASG12C 90 RAS effectors BRAFi Tumor cell proliferation and survival 120 (BRAF mutant) Programmed death-ligand 1 (PD-L1) CDK4/6 120 EGFRi 135 Programmed death -1 (PD-1) receptor MEK 180 (NF1 LOF) T cell exhaustion SHP2 300 PD-1 Downstream signaling ~1 million patients annually 1 Human PK predictions; 2 Preclinical data of combination efficacy with SHP2i 49 SOURCE: US incidence estimated from SEER, TCGA and Kiuru & Busam The NF1 gene in tumor syndromes and melanoma”; all scaled for WW incidenceSHP2: Our compound shows best-in-class potential in a large cancer market Our SHP2i blocks downstream MAPK signaling We believe BBP-398 has the ideal properties for combination and abrogates T cell exhaustion with a multitude of other therapeutic classes 1 Human half life: ~10-15 hours Potentially differentiated safety profile for Receptor tyrosine kinase signals ▪ Allows for recovery above EC50 and reduced combination therapy (EGFR, ALK, TRK, RET) ▪ hERG IC50 (µM)*: >100: No QT prolongation MAPK-driven tox 2 SHP2i combination potential Supporting evidence SHP2 US + EU incidence, ‘000s Preclinical data: KRAS BBIO SHP2i Other SHP2i GTP KRAS GDP ALKi 30 RAS(ON) RAS(OFF) KRASG12C 90 RAS effectors BRAFi Tumor cell proliferation and survival 120 (BRAF mutant) Programmed death-ligand 1 (PD-L1) CDK4/6 120 EGFRi 135 Programmed death -1 (PD-1) receptor MEK 180 (NF1 LOF) T cell exhaustion SHP2 300 PD-1 Downstream signaling ~1 million patients annually 1 Human PK predictions; 2 Preclinical data of combination efficacy with SHP2i 49 SOURCE: US incidence estimated from SEER, TCGA and Kiuru & Busam The NF1 gene in tumor syndromes and melanoma”; all scaled for WW incidence
DUSP6 mRNA (Fold Change) DUSP6 mRNA (Fold Change) BBP-398 displays a PK/PD profile that may allow for daily pathway recovery and 100 1.5 improve SHP2 inhibitor tolerability 1 BBP-398 PK/PD data BBP-398 steady state PK simulation 10 1.0 BBP-398 predictions are based on allometric scaling and preclinical data 1 0.5 10.0 BBP-398 MAPK pathway MAPK pathway recovery Predicted RP2D inhibition >16h minimizes on-target 0.1 0.0 maximizes efficacy toxicity 4 8 12 16 20 24 Time post dose (hours) Plasma PK BBP-398 100 mg/kg DUSP6 mRNA BBP-398 100 mg/kg BBP-398 IC 50 3 1.5 mM 100 Pathway inhibition 1.0 BBP-398 plasma 2 DUSP6 mRNA conc. mM (Fold Change) 1.0 10 BBP-398 IC * 2 50 50% DUSP6 0.5 ~1.5 mM 1 inhibition 0.1 0.0 0.1 0 20 40 60 80 100 120 140 160 180 4 8 12 16 20 24 Time (hr) Time post dose (hours) Maximal efficacy achieved with IC coverage >16h Plasma PK BBP-398 100 mg/kg BBP-398 PK profile is consistent with tolerable daily dosing 50 • At maximum efficacious dose BBP-398 >1.5 mM for the majority of • Daily dosing allows for efficient titration in combination studies DUSP6 mRNA BBP-398 100 mg/kg the interval 1 PKPD data from mouse KYSE-520 xenografts following a single dose of BBP-398 2 DUSPs are negative feedback regulators of the MAPK pathway; DUSP6 expression is correlated with high pERK activity 3 IC50 based on DUSP6 mRNA fold change in mouse KYSE-520 and MiaPaCa-2 xenografts Plasma conc.,mM Plasma conc.,mM BBP-398 plasma concentration (mM)DUSP6 mRNA (Fold Change) DUSP6 mRNA (Fold Change) BBP-398 displays a PK/PD profile that may allow for daily pathway recovery and 100 1.5 improve SHP2 inhibitor tolerability 1 BBP-398 PK/PD data BBP-398 steady state PK simulation 10 1.0 BBP-398 predictions are based on allometric scaling and preclinical data 1 0.5 10.0 BBP-398 MAPK pathway MAPK pathway recovery Predicted RP2D inhibition >16h minimizes on-target 0.1 0.0 maximizes efficacy toxicity 4 8 12 16 20 24 Time post dose (hours) Plasma PK BBP-398 100 mg/kg DUSP6 mRNA BBP-398 100 mg/kg BBP-398 IC 50 3 1.5 mM 100 Pathway inhibition 1.0 BBP-398 plasma 2 DUSP6 mRNA conc. mM (Fold Change) 1.0 10 BBP-398 IC * 2 50 50% DUSP6 0.5 ~1.5 mM 1 inhibition 0.1 0.0 0.1 0 20 40 60 80 100 120 140 160 180 4 8 12 16 20 24 Time (hr) Time post dose (hours) Maximal efficacy achieved with IC coverage >16h Plasma PK BBP-398 100 mg/kg BBP-398 PK profile is consistent with tolerable daily dosing 50 • At maximum efficacious dose BBP-398 >1.5 mM for the majority of • Daily dosing allows for efficient titration in combination studies DUSP6 mRNA BBP-398 100 mg/kg the interval 1 PKPD data from mouse KYSE-520 xenografts following a single dose of BBP-398 2 DUSPs are negative feedback regulators of the MAPK pathway; DUSP6 expression is correlated with high pERK activity 3 IC50 based on DUSP6 mRNA fold change in mouse KYSE-520 and MiaPaCa-2 xenografts Plasma conc.,mM Plasma conc.,mM BBP-398 plasma concentration (mM)
SHP2: BBP-398 monotherapy study initiated in 2020; combo trials to follow Clinical development timeline First patient treated 4Q20 2020 2021 2022+ Monotherapy Combo Therapy ▪ Monotherapy study initiated 2H 2020▪ Partnered with Perceptive-backed LianBio in China to expand exploration of potential combo therapies ▪ Dose escalation followed by dose expansion ▪ Dose escalation followed by dose expansion ▪ Starting dose 80mg ▪ Priority combinations include osimertinib, and G12Ci in NSCLC Initial clinical combinations of focus based on SHP2i preclinical data SHP2i Combination Partner Tumor growth inhibition KRAS G12Ci AMG 510 ~130% EGFRi Osimertinib ~125% PD-1 Anti-mouse PD-1 ~90% MEK Trametinib ~80% CDK4/6 and MEK Trametinib + palbociclib ~110% 51SHP2: BBP-398 monotherapy study initiated in 2020; combo trials to follow Clinical development timeline First patient treated 4Q20 2020 2021 2022+ Monotherapy Combo Therapy ▪ Monotherapy study initiated 2H 2020▪ Partnered with Perceptive-backed LianBio in China to expand exploration of potential combo therapies ▪ Dose escalation followed by dose expansion ▪ Dose escalation followed by dose expansion ▪ Starting dose 80mg ▪ Priority combinations include osimertinib, and G12Ci in NSCLC Initial clinical combinations of focus based on SHP2i preclinical data SHP2i Combination Partner Tumor growth inhibition KRAS G12Ci AMG 510 ~130% EGFRi Osimertinib ~125% PD-1 Anti-mouse PD-1 ~90% MEK Trametinib ~80% CDK4/6 and MEK Trametinib + palbociclib ~110% 51
Major catalysts across the pipeline anticipated over the next 12 months ANTICIPATED Execution in 2021 4 core value drivers Pipeline upside BBIO / EIDX merger closure: Encaleret (CaSRi) for ADH1: Ph2 COL7 replacement for RDEB: Data th Completed January 26 proof-of-concept data (March ’21) from Ph2 study (late ’21 / early ’22) Four new INDs cleared Acoramidis (ATTR stabilizer) for SHP2 inhibitor for RAS and RTK ATTR-CM: Ph3 topline data (4Q21) driven cancer: Monotherapy Phase 2 TM NULIBRY (fosdenopterin) for dose selection (2022) MoCD type A: FDA approval Low-dose infigratinib (FGFRi) for achondroplasia: Ph2 proof-of- Ribitol for LGMD2i: Ph2 proof-of- TM TRUSELTIQ (high-dose concept data (1H22) concept data (2022) infigratinib) for second-line cholangiocarcinoma: FDA approval AAV5 gene therapy for CAH: Initial KRAS inhibitor program: Clinical data from Ph1/2 study (mid-22) candidate selection (2022) Acoramidis (ATTR stabilizer) for ATTR-CM: NDA submission (1H22) $1bn+ in cash and equivalents as of March 2021 anticipated to provide runway into 2023 52Major catalysts across the pipeline anticipated over the next 12 months ANTICIPATED Execution in 2021 4 core value drivers Pipeline upside BBIO / EIDX merger closure: Encaleret (CaSRi) for ADH1: Ph2 COL7 replacement for RDEB: Data th Completed January 26 proof-of-concept data (March ’21) from Ph2 study (late ’21 / early ’22) Four new INDs cleared Acoramidis (ATTR stabilizer) for SHP2 inhibitor for RAS and RTK ATTR-CM: Ph3 topline data (4Q21) driven cancer: Monotherapy Phase 2 TM NULIBRY (fosdenopterin) for dose selection (2022) MoCD type A: FDA approval Low-dose infigratinib (FGFRi) for achondroplasia: Ph2 proof-of- Ribitol for LGMD2i: Ph2 proof-of- TM TRUSELTIQ (high-dose concept data (1H22) concept data (2022) infigratinib) for second-line cholangiocarcinoma: FDA approval AAV5 gene therapy for CAH: Initial KRAS inhibitor program: Clinical data from Ph1/2 study (mid-22) candidate selection (2022) Acoramidis (ATTR stabilizer) for ATTR-CM: NDA submission (1H22) $1bn+ in cash and equivalents as of March 2021 anticipated to provide runway into 2023 52