C O M P A N Y P R E S E N T A T I O N
January 2020
Forward-Looking Statements
Statements in this Presentation that are not statements of historical fact are forward-looking statements. Such forward-looking statements include, without limitation, statements regarding our research and clinical development plans, expected manufacturing capabilities, 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" and similar expressions are intended to identify forward-looking statements, though not all forward-looking statements necessarily contain these identifying words. These forward-looking statements 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, future results from the Company's ongoing and planned preclinical studies and clinical trials, the Company's ability to obtain adequate financing to fund its preclinical studies and planned clinical trials and other expenses, trends in the industry, the legal and regulatory framework for the industry and future expenditures. In light of these risks and uncertainties, the events or circumstances referred to in the forward-looking statements may not occur. The actual results may vary from the anticipated results and the variations may be material. These forward-looking statements should not be taken as forecasts or promises nor should they be taken as implying any indication, assurance or guarantee that the assumptions on which such forward-looking statements have been made are correct or exhaustive or, in the case of the assumptions, fully stated in the Presentation. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date this Presentation is given. This Presentation discusses product candidates that are under preclinical study or clinical trial and which have not yet been approved for marketing by the U.S. Food and Drug Administration (the "FDA"). No representation is made as to the safety or effectiveness of these 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.
2
We are at Day 1 in the era of genetic medicine
Advances in science and medicine (2019)
- Better context: Cryptic genetic variation and modifiers
- Better understanding heterogeneity: genetic interaction manifolds and the wonderful story of Hirschsprung's Disease
- Deeper saturation: saturation genome editing
- Faster: Rapid whole-genome sequencing in the ICU
- Developing infrastructure: NHGRI reports cost per genome at $942 this year (all time low)
- Striking new therapeutics: SCD, CF, PN, TTR, SMA, and others
Source: Science, Science Translational Medicine, Nature, NEJM, NHGRI
Vast opportunity to help patients
6,650 7,000
350
Therapies | Diseases with | Known |
today | no therapy | genetic |
diseases |
3
We are building a leading genetic disease company
Core attributes…
- Distinctive early stage asset selection
- Experienced, product-focused R&D team
- Efficient corporate structure
- The willingness and scale to fail
- Focus at the level of individual diseases and assets
…applied many times…
- 18 BridgeBio programs
…creating a pipeline of blockbusters and synthetic blockbusters
- Two $1B+ franchises in Phase 2 or later
- Two low risk NDAs being filed in this year
- Several early stage potential big franchises
- KRAS
- GPX4
- Congenital adrenal hyperplasia
- Leber's hereditary optic neuropathy
- Several low risk clinical or IND-enabling programs
- Four new programs announced in January 2020
4
BridgeBio is led by a world-class team of experienced drug developers
We rely on some of the top R&D minds in this industry to select assets…
Charles Homcy, MD
Chairman of Pharmaceuticals
Frank McCormick, PhD, FRS
Chairman of Oncology
Richard Scheller, PhD
Chairman of R&D
…and put them in the hands of one of the most productive groups of R&D operators in the industry
Uma Sinha, PhD
Chief Scientific Officer
Eli Wallace, PhD
Chief Scientific Officer in Residence, Oncology
Robert Zamboni, PhD
Chemistry
Tucatinib PT2997 (HER2i, Ph3) (HIF2αi, Ph3)
Together, our R&D team is responsible for 100+ INDs and 20+ approved products
5
Assessing BridgeBio
Criteria | Relevance | Today's Talk | |||
High probability of success | • Historically higher probability of success for genetic | Current | |||
Pipeline | |||||
disease drugs | |||||
1 | |||||
Progress | |||||
• | BridgeBio's early programs have outperformed | ||||
historical probabilities | |||||
Number of programs
2
Capital efficiency
3
- We find great science and unlock its potential for patients
- Always searching for the next PellePharm or Eidos
- Scale allows for objective assessment and failure
- Generate value by making each program ROI-positive
- Driven by judicious use of capital at the high-risk preclinical stages
New
Programs
Spend to
IND
6
Genetic disease drug discovery is lower risk, faster, and has higher returns than traditional drug discovery
>4x Higher cumulative probability of success
Probability of success from Ph1 to
launch | ||
50% | 45% | |
40% | ||
30% | ||
20% | ||
10% | 10% | |
0% | Industry | Genetic |
average | average |
Sources: Hay et al., Nature Biotechnology, "Clinical Development Success Rates for Investigational Drugs", 2014
>65% Faster time to Phase 3
Time from lead optimization to Ph3
7 | 7.0y | |||||||||
6 | First 2 BridgeBio | |||||||||
5 | ||||||||||
Years | programs | |||||||||
4 | ||||||||||
2.8y | ||||||||||
3 | 2.0y | |||||||||
2 | ||||||||||
1 | ||||||||||
0 | ||||||||||
Industry | ATTR | Gorlin | ||||||||
average | (Eidos) | (Pelle) |
Sources: Paul et al., Nat Rev Drug Disc, "How to
improve R&D productivity: the pharmaceutical industry's grand challenge.", 2010
>8x | Better return on |
investment |
Total return on investment
[Enerprise value]/[APIC - cash on hand]*
35 | First 2 BridgeBio | |||||||||||
programs | ||||||||||||
30 | ||||||||||||
23.2x | ||||||||||||
25 | ||||||||||||
20 | 15.5x | |||||||||||
15 | ||||||||||||
10 | ||||||||||||
5 | 2.3x | |||||||||||
0 | ||||||||||||
NBI | ATTR | Gorlin | ||||||||||
median** | (Eidos) | (Pelle)*** |
*As of 1/10/2020 close
**Includes all NBI constituents with market value <$20bn
***Calculated as total consideration from LEO Pharma transaction divided by total burn to date
Sources: FactSet
Targeting genetic disease has higher average probability of success and BridgeBio has demonstrated higher ROI and shorter development time in its first 2 programs
7
A rapidly-advancing pipeline
Since our inception, we have actively built our pipeline through business development efforts, including the acquisition and in-licensing of assets, and advancing programs through internal stage-gates
Growth of assets in our pipeline:
20
16 | |||||||||||
Total | 9 | ||||||||||
programs | 5 | ||||||||||
1 | |||||||||||
2015 | 2016 | 2017 | 2018 | 2019 |
Advancement of product candidates through key stage-gates:
Lead-Opt | IND enabling | Ph1 | Ph2 | Ph3 | ||
2016 | ||||||
Internal | +1 | |||||
2017 | ||||||
+1 | ||||||
program | ||||||
advancement | 2018 | |||||
+1 | +1 | |||||
2019 | ||||||
+6 | +1 | +3 | ||||
8
Our pipeline of 20+ genetic medicines spans multiple therapeutic areas and drug modalities
Small molecule Topical small molecule Biologics Gene therapy
Portfolio | Patient | Pre-Clinical | Clinical | ||||||||||||||||||||||||
Program1 | Drug mechanism | Diseases | pop. | Modality | |||||||||||||||||||||||
segment | IND- | ||||||||||||||||||||||||||
(US+EU)2 | Discovery | Phase1 | Phase 2 | Phase 3 | |||||||||||||||||||||||
enabling | |||||||||||||||||||||||||||
Mendelian | AG10 | TTR stabilizer | ATTR-CM | >400K | |||||||||||||||||||||||
BBP-870 | cPMP replacement | MoCD type A | 100 | NDA | |||||||||||||||||||||||
Infigratinib | Low-doseFGFR1-3i | Achondroplasia4 | 55K | ||||||||||||||||||||||||
BBP-711 | GO1 inhibitor | PH1 / FSF | 5K / 1.5M | ||||||||||||||||||||||||
BBP-761 | Succinate prodrug | LHON | 20K | ||||||||||||||||||||||||
BBP-671 | PanK activator | PKAN / OA | 7K | ||||||||||||||||||||||||
BBP-418 | Glycosylation substrate | LGMD2i | 7K | ||||||||||||||||||||||||
Encaleret | CaSR antagonist | ADH1 / HP | 2K / 200K | ||||||||||||||||||||||||
New program | |||||||||||||||||||||||||||
BBP-551 | Synthetic retinoid | LCA / RP | 3K | ||||||||||||||||||||||||
New program | |||||||||||||||||||||||||||
BBP-472 | PI3Kβi | PTEN autism | 120K | ||||||||||||||||||||||||
New program | |||||||||||||||||||||||||||
Genetic | BBP-0093 | Topical SMOi | Gorlin / BCC | 120K | |||||||||||||||||||||||
Dermatology | BBP-589 | Recombinant COL7 | RDEB | 1.5K | |||||||||||||||||||||||
BBP-681 | Topical PI3Kαi | VM / LM | 117K | ||||||||||||||||||||||||
BBP-561 | Topical KLK 5/7i | Netherton | 11K | ||||||||||||||||||||||||
Targeted | Infigratinib | FGFR1-3i | FGFR+ tumors | 37K | |||||||||||||||||||||||
Oncology | |||||||||||||||||||||||||||
BBP-398 | SHP2i | Multiple tumors | >500K | ||||||||||||||||||||||||
BBP-454 | Pan-mutant KRASi | KRAS+ tumors | >500K | ||||||||||||||||||||||||
BBP-954 | GPX4i | Multiple tumors | >500K | ||||||||||||||||||||||||
Gene Therapy BBP-631 | 21-OH gene therapy | CAH | >75K | ||||||||||||||||||||||||
BBP-812 | ASPA gene therapy | Canavan | 1K | ||||||||||||||||||||||||
New program | BBP-815 | TMC1 gene therapy | Genetic hearing loss | 10K | |||||||||||||||||||||||
1 Each of our programs is housed in a separate subsidiary; 2 Patient population: Prevalence except for asterisked figures which represent incidence; 3We are party to an option agreement pursuant to which LEO Pharma A/S has been granted an exclusive, irrevocable option to acquire PellePharm, including the BBP-009 program. If the option is exercised by LEO Pharma A/S, we will no longer have rights to develop and commercialize BBP-009. See "Business -Our Material Agreements-BBP-009 (Patidegib): Option Agreement with LEO Pharma A/S. 4Protocol submitted to Australian local ethics committed, IND submission to FDA expected 2020.
9
Low-dose FGFR inhibitor (infigratinib) for achondroplasia
Achondroplasia overview:
- Prevalence: 55,000 (US+EU) - one of the most common genetic conditions
- Genetic driver: FGFR3 activation
- Pathophysiology: Up regulation of STAT1 and MAPK in the growth plate cause cranial, spinal, and stature symptoms
Features of a best-in-class medicine for achondroplasia:
- Direct targeting of FGFR3 and normalization both STAT1 and MAPK signaling pathways
- Potential to address all drivers of symptoms, including cranial, spinal and stature issues
- Oral dosing, the most convenient solution for children with achondroplasia and their families
Claudia, child with achondroplasia
10
Best-in-class approach to treating achondroplasia directly at its genetic source
ACH FGFR3 gain-of-function mutation causes:
- 2-3xover activation of the receptor
- Up-regulationof downstream pathways STAT1 and MAPK
- Aberrant growth plate development causes cranial, spinal, and stature symptoms
Low-dose infigratinib is able to:
- Directly inhibit the causal gain-of-function mutation in FGFR3
- Normalize both the STAT1 and MAPK signaling pathways
- Demonstrate clear macro and microscopic improvements on foramen magnum, intervertebral discs, and long bones in validated preclinical model
FGF | ||||||||
FGFR3 | ||||||||
G380R | ||||||||
mutation | Growth plate chondrocyte | |||||||
Low-dose | CNP analogues indirectly | |||||||
infigratinib | ||||||||
block MAPK | ||||||||
On target, selective | ||||||||
inhibition of FGFR3 directly | ||||||||
blocking both STAT1 and | ||||||||
MAPK | STAT1 | MAPK |
Misregulated growth plate development
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
11
Low-dose infigratinib improves all the key drivers of clinical symptomology in the validated ACH mouse model
1 Cranial bone issues
17% | 6% |
increase in | increase in AP |
FM area | skull length |
May lead to decrease in foramen
magnum stenosis and fewer surgeries
FGFR3 WT | FGFR3Y367C/+ | FGFR3Y367C/+ |
No treatment | No treatment | Infigratinib tx |
2 Disorders of the spine
12% | 73% |
increase in | increase in |
L4-L6 length | disc width |
May lead to decrease in spinal stenosis,
possibly reducing need for surgery
3 Disproportionate short stature
21% | 33% |
increase in | increase in |
femur length | tibia length |
May lead to increased stature
and proportionality
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
12
Low-dose infigratinib showed best in-class preclinical profile in the validated achondroplasia mouse model
Preclinical data from infigratinib and other investigational achondroplasia therapies
Percent increase compared to non-treated mouse
Company/ | MOA | Route | ||
Asset | ||||
Selective
Infigratinib FGFR1-3i Oral
Vosoritide | CNP analogue Daily SQ |
(BMN111) |
TransCon | CNP analogue Weekly SQ |
CNP1 |
FGFR3 decoy Weekly SQ
Reifercept
(TA-46)
Status
Ph2 lead-in
ongoing2
Pivotal
Ph2 lead-in
ongoing
Ph1
Mouse model
FGFR3Y367C/+
FGFR3Y367C/+
FGFR3Y367C/+
FGFR3ACH/+
Tibia length | Femur length | |
33% 21%
7%5%
12%*
9%*7%*
Foramen
magnum area
16%
No
known
publically available data
L4-L6 height
12%
3%
Source: Komla-Ebri et al. J Clin In2v 2016, Lorget et al. Am J Hum Genet 2012, Garcia et al. Science Trans Med 2013, Breinholt ENDO 2017
Note: subcutaneous doses, percent increase compared to vehicle treated FGFR3Y367C/+, FGFR3ACH/+ mouse as noted in "Mouse model" columns Infigratinib treatment with 2mg/kg subcutaneous dose
1Based on vosoritide continuous infusion; *Value estimated using DigitizeIt. 2Protocol submitted to Australian local ethics committed, IND submission to FDA expected 2020.
13
The PROPEL clinical program is enrolling and will provide POC in 2021
Observational run-in | Ph2 Dose-finding (n=40) | Expansion (n=20) |
Children are followed
for a minimum of 6 months to establish baseline annualized growth velocity (AGV)
Dose level 4
n=10
Dose level 3
n=10
Dose level 2
n=10
Dose level 1
n=10
Select dose
12 month long-term extension
20 new subjects for expansion
Key inclusion criteria
• Children 2.5 - 10 years old
• Clinical and molecular ACH diagnosis
Primary objectives | Primary objectives | |
• Baseline annualized growth velocity | • Identify safe therapeutic dose for | |
(AGV) | expansion / pivotal study | |
• | Safety and tolerability | |
• | Change from baseline in AGV |
Primary objectives
- Long-termsafety and efficacy
14
Recombinant Collagen 7 for recessive dystrophic epidermolysis bullosa (RDEB)
RDEB overview:
- Prevalence: 1,500 (US + EU)
- Genetic driver: Collagen 7 (COL7) deficiency
- Pathophysiology: Systemic impairment of dermal- epithelial cohesion throughout various tissues leading to painful blistering on the skin, GI tract, and oral cavity
Features of a best-in-class medicine for RDEB:
- Treating RDEB at its genetic source, by replacing missing COL7 protein via a simple IV infusion
- Potential to address burden of RDEB beyond the skin, including systemic manifestations
- Proactively address wound formation and healing, rather than reactively treat lesions
Bardy, child with
RDEB
15
Recombinant collagen 7 for recessive dystrophic epidermolysis bullosa (RDEB)
RDEB COL7 loss-of-function mutations cause:
- Near complete loss of COL7 at epithelial junctions on the skin and throughout the body
- Painful erosions and blistering on the skin, GI tract, and oral cavity
- Failure to thrive, decreased life span, high risk for squamous cell carcinoma
Our systemic COL7 replacement is designed to:
- Replace COL7 at epithelial junctions throughout the body
- Address the systemic burden of RDEB including on the skin, GI tract and oral cavity
- Proactively address wound formation and healing globally rather than reactively treat lesions
16
Recombinant COL7 distributes systemically, leading to survival benefits in the RDEB mouse model
A single intravenous injection of recombinant COL7 distributed to epithelial barriers throughout the body (skin, oral cavity, GI tract), in a dose-dependentmanner
This led to a significant survival benefit in COL7-treatedanimals
Intravenous | Vehicle | 25 | 23 | |||||||||
COL7 | (%intensity | |||||||||||
Skin (abdomen) | 15 | 13 | ||||||||||
stainingCOL7 | 20 | |||||||||||
Tongue | positive) | 10 | 6 | |||||||||
5 | 0 | |||||||||||
0 | ||||||||||||
COL7 is stained green in images above | Vehicle | 5ug | 16ug | 28ug | ||||||||
e = epiderma |
d = dermal
COL7
Source: Hou & Chen, Journal of Investigative Dermatology 2015
Probability of survival (%)
100 | Vehicle | |||||||||||||
80 | ||||||||||||||
COL7 (IV) | ||||||||||||||
60 | ||||||||||||||
40 | ||||||||||||||
20 | ||||||||||||||
0
0 20 40 60 80 100 120 140 Days
17
Ongoing randomized, dose-escalation Phase 1/2 proof-of-concept clinical study in adults with RDEB
- First patient dosed in 1Q19
- Anticipate clinical POC in 1H20
Six doses
Patient
enrollment
Recombinant
COL7 (BBP-589)
8-week
(adults with
RDEB
diagnosis)
Randomization 1:1
Cross overfollow up
period
Saline
Day 0 wk2 wk4 wk6 wk8 wk10
Cohort 1: 0.1 mg/Kg | Cohort 2:0.3 mg/Kg | Cohort 3:1 mg/Kg |
N=2 | N=4 | N=8 |
KEY INCLUSION CRITERIA | PRIMARY ENDPOINT | |
▪ Adult with RDEB diagnosis | ▪ Safety and tolerability | |
▪ Deficiency but not total loss of COL7 protein |
▪ At least 1 wound >20cm2 for ≥6 weeks
KEY SECONDARY ENDPOINTS
KEY EXCLUSION CRITERIA
- Known hypersensitivity to BBP-589
- Received investigational RDEB agent in last 6 months
- Pharmacokinetics
- COL7 deposition in skin biopsies
- Change in healing of up to 5 chronic wounds
- Patient reported outcomes (itch, QoL)
18
Targeted Oncology Portfolio
Andrea, CCA patient
World-class oncology team drives our discovery and development
- Eli Wallace: CSO Oncology
- Frank McCormick, Chairman of Oncology
- Richard Scheller, Chairman of R&D
We target driver mutations in genetically defined cancers…
- FGFR1-3i for FGFR+ cancer: Near-term revenue in CCA, multiple expansion indications
- Pan-mutantKRASi for KRAS+ cancer: Platform approach in partnership with NCI RAS initiative
…while also focusing on novel targets with extensive academic validation
- SHP2i for multiple tumors (10+ recent papers in Nature, Science, Nature Medicine)
- GPX4i for multiple tumors (10+ recent papers in Nature, Cell, Cancer Cell)
Program | MOA | Disease | Stage | Next update |
Infigratinib | FGFR1-3 inhibitor | FGFR+ cancer | Ph3 | Pivotal CCA data 2020, NDA 2020 |
BBP-398 | SHP2 inhibitor | Multiple tumor types | Pre-IND | IND submission in 2020 |
BBP-454 | Pan-mutant KRAS | KRAS+ cancer | Discovery | Clinical candidate nomination |
inhibitor | ||||
BBP-954 | GPX4 inhibitor | Multiple tumor types | Discovery | Clinical candidate nomination |
19
KRAS: multiple shots on goal with our pan-mutant inhibitor programs - each with a unique MOA targeting a novel pocket
KRAS activation in cancer is a multistep process
Receptor tyrosine kinase signals (EGFR, FGFR, etc)
Our programs target different steps of the KRAS activation process
Program 1: C185 targeting | Program 2: H95 targeting | |
• Blocks KRAS from tethering | • Directly binds activated KRAS | |
• Blocks conversion of inactive | • Inhibits KRAS from signaling | |
KRAS GDP to active KRAS GTP | through effectors |
KRAS | KRAS | |
GTP | ||
GDP | ||
2 | KRAS is | |
activated by | ||
KRAS | RTK signaling | |
GDP | 3 | |
KRAS GDP
KRAS GTP
Effector
1 KRAS must tether to the cell membrane to be activated
Active KRAS drives cancer proliferation and survival
KRAS tethering is blocked - cancer growth is inhibited
Activated KRAS signaling is inhibited
20
SHP2: Compounds from the BBP-398 series appear to restore sensitivity to osimertinib in resistant NSCLC models
MOA | Key data | |
Receptor tyrosine kinase signals (EGFR, ALK, etc)
pY | ||
pY | KRAS | |
pY SHP2 | SOS | |
GTP | ||
BBP-398 |
- Growth factor signaling through mutant or wild- type receptors causes pathway activation
- SHP2 connects RTK signaling to downstream SOS/RAS activation
- Our compound potently traps SHP2 in an inactive state, thereby blocking downstream oncogenic signaling
Source: AACR-NCI-EORTC meeting 2019
21
GPX4: Potential first-in-class therapy for a novel cancer target
MOA
Altered cancer | Treatment | |
metabolism | resistant state | |
Key data
In vivo monotherapy activity in a renal cell carcinoma mouse model
Model: 786-O RCC xenograft (VHL LOF, p53 LOF)
Lipid peroxidation and
ROS accumulation
GPX4 GPX4i
Ferroptosis and cancer cell death
▪ GPX4 was recently identified as a key tumor |
dependency in multiple CRISPR screens and |
)
3
T u m o r V o lu m e (m m
6 0 0 | B B IO G P X 4 i 4 m p k B ID s u b Q |
V e h ic le | |
4 0 0 |
2 0 0
0
0 | 2 | 4 | 6 |
D a y s o f tre a tm e n t
Rapid tumor regression after only 7 days of dosing
8
mechanistic studies | |
▪ | GPX4 allows tumor cells to survive by |
neutralizing toxic lipid peroxides | |
▪ | Our approach is to directly inhibit GPX4, thereby |
triggering cancer death through ferroptosis |
Synergy with targeted therapies and immunotherapy using in vitro models
22
Infigratinib (FGFRi): Near term revenue in CCA and multiple large expansion opportunities
Indication
FGFR2+ cholangiocarcinoma
FGFR3+ urothelial carcinoma
FGFR fusion- positive tumor agnostic
Key Data
39% ORR
in patients with ≤1 previous
line of treatment
25% ORR
in metastatic relapsed refractory setting suggests clear activity in this tumor
5 tumor types
Showed response to infigratinib in Ph1/2
Status | Next Update | ||
▪ Enrollment complete in | ▪ | Updated pivotal data | |
2L Ph2 pivotal cohort | 2H20 | ||
▪ Ph3 in 1L study enrolling | ▪ | NDA submission 2H20 | |
▪ | 2021 launch |
▪ FPI for Ph3 in adjuvant | ▪ Complete enrollment in |
setting in 1H20 | Ph3 adjuvant study |
▪ FPI for Ph2 signal | ▪ Potential Ph2 data 2021 |
optimization study in 1H20 |
SOURCE: Javle M et al. ESMO 2018, Pal S et al. Cancer Discovery 2018, data on file
23
Gene Therapy Portfolio
Experienced team with track record in gene therapy
Partnered with top academics in the gene therapy space
- Guangping Gao, Ph.D (UMass)
- Pierre Bougneres, M.D., Ph.D. (INSERM)
- Jeff Holt, Ph.D (Boston Children's)
Congenital adrenal hyperplasia (BBP-631)
- One of the largest known AAV gene therapy markets (prevalence 75K US+EU)
- Low threshold to correct phenotype, validated by human genetics
- Durable transgene delivery and expression for 6m in NHP study
Canavan disease (BBP-812)
- Lethal, degenerative, neuromuscular disease
- Precedented AAV9 serotype with safety shown in compassionate use case
TMC1-driven hearing loss (BBP-815)
- Delivers functional copy of TMC1 gene allowing transmission of auditory stimuli
- Nature Communications publication shows significant rescue of hearing function in diseased mice
Program | MOA | Disease | Stage | Next update |
Vayle, child with Canavan
BBP-631 | 21-OHase gene therapy | Congenital adrenal |
hyperplasia | ||
BBP-812 | ASPA gene therapy | Canavan disease |
BBP-815 | TMC1 gene therapy | Genetic hearing loss |
Pre-IND | IND submission in 2020 |
Pre-IND | IND submission in 2020 |
Discovery | Clinical candidate nomination |
24
21-OH gene therapy for CAH: NHP study showed durable transgene expression; 5-10% of WT enzyme may be sufficient for clinical impact
Genotype-phenotype studies show that >5-10% of enzyme activity results in nonclassical
CAH
- Due to the high enzymatic efficiency/selectivity of 21- OHase, only a small amount of enzyme is required to rescue the phenotype
Source: ESGCT 2019
Mouse studies show a VGC of
only 0.13 at 18 wks was sufficient for phenotypic reversal
VGC from the whole adrenal gland was
0.13 at wk 18
- At 15 weeks in treated mice, progesterone (the key substrate of 21OHase in mice) was significantly reduced vs untreated mice
NHP studies show sustained VGC and RNA out to at least 6 months
BBP-631 vector levels in the adrenal gland
- Mean vector genome copies per cell appear stable at 24 wks
BBP-631 mRNA expression in the adrenal gland
- Transgene expression is dose- dependent and stable out at 24 wks
25
ASPA gene therapy for Canavan: Phenotypic correction in a lethal mouse model and broad CNS transduction in NHPs
Mouse studies show a VGC of only 0.13 at 18 wks was sufficient for phenotypic reversal
Effect of BBP-812 on rotarod and
balance beam, ASPA KO mice (untreated
vs 3 different doses) and WT mice
- ASPA KO mice treated with at least 2.6e13 vg/kg had survival and performance on motor function tests fully rescued. Mice treated at 2.6e14 vg/kg outperformed WT mice.
Source: ESGCT 2019
NHP studies show broad CNS distribution with
IV delivery
Vector copies per diplome in various
CNS regions in NHPs
- IV delivery of BBP-812 showed superior transduction of several CNS regions compared to ICV and IT delivery
26
AG10 for TTR Amyloidosis (Eidos)
- Addressing large and growing need in ATTR, a fatal disease affecting >400K patients
- Targeting the disease at its source by stabilizing TTR, a genetic and clinically validated mechanism
- Advancing AG10, a potential best-in-classdrug that mimics naturally occurring rescue mutation
- Phase 2 open label extension study suggests potential to reduce mortality and cardiovascular hospitalizations at 15 months
- Executing Phase 3 study in ATTR-CMwith top- line data 2021
Art, ATTR-CM patient
27
AG10 structurally mimics disease-protective mutation by hyper-stabilizing TTR
Disease-protective T119M mutation | AG10-bound TTR | ||||
Strong inter-monomerH-bonds observed via X-ray crystallography
Unique binding mode vs other stabilizers
28
Serum TTR levels, a prognostic indicator of survival, increased upon AG10 treatment and were maintained throughout Ph 2 study
Serum TTR concentration
mg/dL, mean ± SEM
AG10 WT1
35 | +39% | AG10 Variant1 | ||||||
30 | OLE baseline | +56% | Placebo WT | |||||
25 | Placebo Variant | |||||||
20 | ||||||||
15 | Lower limit of | |||||||
10 | OLE baseline | normal = 20 mg/dL2 | ||||||
5 | ||||||||
0 | ||||||||
1 | 14 | 28 | 1 | 14 | 45 | 90 | 180 |
N WT | 35 | 35 | 34 | 35 | 35 | 33 | 33 | 32 | ||||
N Variant | 13 | 14 | 13 | 12 | 11 | 12 | 12 | 10 | ||||
AG10-201 (R) | Rollover | AG10-202 (OLE) | ||||||||||
AG10-202 (OLE) Visit Day
1 400mg and 800mg BID AG10 groups pooled during randomized portion
2 Defined as the lower limit of the reference interval for the serum prealbumin (TTR) clinical laboratory assay
29
Deaths and CV hospitalizations reported in AG10 Phase 2 OLE were lower than in placebo-treatedATTR-ACT participants
All-cause mortality at 15 months
Participants died or receiving transplant (%)
-44%
15.3%
8.5%
Cardiovascular hospitalizations at 15 months Participants with ≥1 CV hospitalization (%)
-39%
41.8%
25.5%
Placebo | AG10 | Placebo | AG10 |
ATTR-ACT Phase 3 | Phase 2 OLE | ATTR-ACT Phase 3 | Phase 2 OLE |
Phase 3 ATTRibute study expected to complete enrollment in 2H20
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
30
Fosdenopterin (cPMP replacement) for MoCD type A
Genetic driver: MOCS1 / cPMP depletion
Prevalence (US + EU): 100
- Addressing an extreme unmet medical need in molybdenum cofactor deficiency (MoCD) type A, a progressive and rapidly fatal CNS disorder (median survival <4 years)
- Targeting the disease at its source by directly replacing cPMP, the missing metabolite that causes CNS toxicity
Elliott, child with MoCD type A
- Potentially life saving therapy with compelling pivotal data showing prolonged survival, seizure control and ambulation vs natural history
- Rolling NDA submission initiated in 4Q19, under FDA Breakthrough Therapy Designation
31
We presented data from our natural history study in MoCD type A at SSIEM 2019
- Median survival time of <4y highlights urgent need for a new medicine
- Data will play an important role in our NDA data package
32
Our current pipeline has the potential to treat nearly 3 million patients in the US and EU alone
Patient population by development | Breakdown of clinical-stage | |
stage | assets | |
'000s) | 3,000 | 2,690 | |||
2,500 | |||||
+ EU, | |||||
2,000 | 1,168 | ||||
(US | |||||
1,500 | |||||
population | |||||
1,000 | 705 | ||||
Patient | 500 | 817 | |||
0 | |||||
Clinical | IND- | Discovery | Total | ||
enabling |
Indication | Population | |
ATTR | 400,000 | |
Hypoparathyroidism | 200,000 | |
Basal cell carcinoma | 120,000 | |
Achondroplasia | 55,000 | |
FGFR+ cancer | 37,000 | |
Inherited retinal dystrophy | 3,000 | |
RDEB | 1,500 | |
MoCD type A | 100 | |
Total: | 817,000 |
Our product platform has the potential to deliver diversified and sustainable
revenue growth beginning in 2021
33
Assessing BridgeBio
Criteria
High probability of success
1
Relevance
- Historically higher probability of success for genetic disease drugs
- BridgeBio's early programs have outperformed historical probabilities
Today's Talk
Current
Pipeline
Progress
Number of programs | • We find great science and unlock its potential for | |
2 | patients | |
• Always searching for the next PellePharm or Eidos | ||
• Scale allows for objective assessment and failure | ||
New
Programs
Capital efficiency | • | Generate value by making each program ROI-positive | Spend to | |
IND | ||||
3 | • | Driven by judicious use of capital at the high-risk | ||
preclinical stages
34
We are announcing four new programs today including two entering Phase 2 trials
Mechanism: Ca sensing receptor antagonist | Mechanism: Synthetic retinoid | ||||||
Diseases and prevalence: | Diseases and prevalence: | ||||||
Autosomal dominant | Hypoparathyroidism | Leber's congenital amaurosis | |||||
/ retinitis pigmentosa (RPE65 | |||||||
hypocalcemia type 1 | 200,000 | ||||||
and LRAT) | |||||||
2,000 | US + EU | ||||||
2,000 | |||||||
US + EU | |||||||
US + EU | |||||||
Modality: Small molecule | Modality: Small molecule | ||||||
Phase 2 ready | Phase 2 ready | ||||||
Mechanism: PI3Kβ inhibitor | Mechanism: TMC1 gene therapy |
Diseases and prevalence: | Diseases and prevalence: |
PTEN autism | Genetic hearing loss |
120,000 | 10,000 |
US + EU | US + EU |
Modality: Small molecule | Modality: Gene therapy |
Discovery | Discovery |
We plan to announce multiple additional new programs in 2020
35
Encaleret (CaSR antagonist) for hypoparathyroidism
Encaleret targets disease at its source by selectively antagonizing the CaSR, a key regulator of calcium homeostasis
- Opportunity to develop encaleret was identified in collaboration with global experts at the NIH
- Being prosecuted by the BridgeBio cardiorenal group
Encaleret is a potential 1st in class CaSR antagonist with differentiated profile for hypoparathyroidism
- Initial genetically-defined population of autosomal dominant hypocalcemia type 1 (ADH1), provides high probability of success
- Potential for expansion into broader hypoparathyroidism indication (~200K patients in US & EU)
Prior clinical experience with encaleret enables accelerated clinical development
- Well tolerated in >1,300 human subjects and increased serum calcium in a dose-dependent manner
- IND application submitted in late 2019 with Phase 2b study in ADH1 planned to initiate in 1H20
- Proof-of-conceptdata in ADH1 expected in 2021
36
Assessing BridgeBio
Criteria
High probability of success
1
Relevance
- Historically higher probability of success for genetic disease drugs
- BridgeBio's early programs have outperformed historical probabilities
Today's Talk
Current
Pipeline
Progress
Number of programs | • We find great science and unlock its potential for | |
2 | patients | |
• Always searching for the next PellePharm or Eidos | ||
• Scale allows for objective assessment and failure | ||
New
Programs
Capital efficiency | • | Generate value by making each program ROI-positive | Spend to | ||
IND | |||||
3 | • | Driven by judicious use of capital at the high-risk | |||
preclinical stages | |||||
37
We have brought assets forward more efficiently than industry average
Operationally Efficient Platform
- Our track record to date is ~$6mm to IND and is ~$23mm IND to POC
- We aim to rapidly and decisively advance our product candidates to objective critical decision points
- We field a minimum viable team for each asset, with the goal of ensuring that each program has sufficient personnel to fit its purpose while reducing excess overhead cost
Spend to IND ($mm)
15.0 | |||||
-63% | |||||
8.2 | |||||
6.0 | 5.5 | ||||
4.2 | 3.6 | ||||
Industry | ATTR | Gorlin | RDEB | ADH1 | BBIO |
Average | (Eidos) | /BCC | (PTR) | (Calcilytix) | Average |
(Pelle) |
Note: BBIO values exclude license and acquisition costs.
Spend IND to POC ($mm)
55.0 | |||
36.6 | -58% | ||
22.9 | |||
9.3 | |||
Industry | ATTR | Gorlin | BBIO |
Average | (Eidos) | /BCC | Average |
(Pelle) |
38
2019 included a range of accomplishments across our development programs and operations
Clinical, regulatory, and scientific
- ATTR: initiated Ph3 trial, presented Ph2 open-label extension data
- Achondroplasia: initiated Ph2 lead-in, established therapeutic window between human safety database and projected efficacious achondroplasia doses
- RDEB: initiated Ph2 POC trial
- MOCD Type A: initiated rolling NDA
- BCC: completed Gorlin Ph3 enrollment; initiated Ph2 high frequency BCC
- Oncology: SHP2 combination data w/ MEK, EGFR, KRAS augmenting inhibition; GPX4 demonstrated monotherapy activity in mouse model
- CCA: fast track designation, completed second line efficacy cohort
- CAH: demonstrated 6-month durability in adrenal cortex
- Canavan: demonstrated broad CNS distribution using IV route of administration
Operations and finance
- Building commercial organization: Jennifer Cook, BOD member and commercial advisor; appointed Matt Outten as CCO
- Financing: raised over $650M in IPO and crossover
BridgeBio: Commercial build out
Top talent makes a | Building awareness | Gearing up for genetic | |||||||||
difference | disease launches | ||||||||||
• | Critical patient identification | ||||||||||
• CCO: Matt Outten | capabilities expanded in rare | ||||||||||
diseases with multiple data | |||||||||||
• 20+ years pharma/biotech | sources | ||||||||||
• Multiple commercial leadership | • | Allows better target planning, | |||||||||
positions across sales, marketing, | asset review, and appropriate | ||||||||||
market access | resource allocation | ||||||||||
• Led the successful launch of | • | Developing best in class HUB | |||||||||
Imbruvica for 6 indications | and patient assistance | ||||||||||
• 25 BBIO leadership roles: | programs in prep for commercial | ||||||||||
launches | |||||||||||
• VPs of Marketing, Market Access, | • | Developing tailored launch | |||||||||
Distribution, Commercial Operations, | |||||||||||
plans for each sub, from brand | |||||||||||
Directors of Marketing and Training, | |||||||||||
development to promotional | |||||||||||
Data Analytics and Operations | |||||||||||
material and in-field team training | |||||||||||
• In-field teams established: Clinical | |||||||||||
Trial Liaisons, Professional Services | |||||||||||
We are building a leading integrated pharma company
Fully
integrated PharmCo
Mendelian | Somatic |
rare disease | cancers |
Commercial capabilities
Late-stageEarly-stage
clinical drug discovery
Oligo- | Small | Therapeutic | Gene therapy | |||||||||||||||
nucleotide | molecule | proteins | ||||||||||||||||
Asset finding | Experienced | Optimal | Preferred | Academic | ||||||||||||||
R&D | corporate | partnerships | ||||||||||||||||
& selection | partnerships | |||||||||||||||||
leadership | structure | w/CRO & mfg. | ||||||||||||||||
41
Multiple catalysts in 2020-2021
2020
ESTIMATED
2021
1H
- Recombinant COL7 for RDEB: Topline Ph1/2 data
- FGFRi for cancer: FPI Ph3 adjuvant urothelial carcinoma study
- FGFRi for cancer: FPI Ph2 FGFR fusion tumor agnostic Ph2 study
- New program announcements
2H
- FGFRi for cancer: Pivotal 2L CCA data
- Low-doseFGFRi for achondroplasia: Begin dosing Ph2
- TTR stabilizer for ATTR: Complete enrollment of ATTR- CM Ph3
- FGFRi for cancer: Submit NDA for 2L CCA
- cPMP for MoCD type A: Complete rolling NDA submission
- CAH gene therapy: Complete IND submission
FY
-
TTR stabilizer for ATTR: Topline data Ph3 Part A in
ATTR-CM - Topical SMOi for Gorlin: Topline Ph3 data
- Low-doseFGFRi for achondroplasia: Ph2 PoC data
- CAH gene therapy: Ph1/2 PoC data
- FGFRi for cancer: 2L CCA approval and launch
- cPMP for MoCD type A: Approval and launch
$612mn cash balance as of 9/30/19 provides runway through 2021
42
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BridgeBio Pharma Inc. published this content on 13 January 2020 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 13 January 2020 15:02:09 UTC