Improving the Lives of Patients with Liver Diseases Corporate Presentation April 2021
Improving the Lives of Patients with Liver Diseases
Corporate Presentation
April 2021
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Safe Harbor Statement
This presentation contains "forward-looking" statements that involve risks, uncertainties and assumptions, and actual results may differ substantially from those projected or expected in the forward-looking statements. Forward-looking statements include, but are not limited to: any projections of financial information; any statements about future development, clinical or regulatory events; any statements concerning CymaBay's plans, strategies or objectives; and any other statements of expectation or belief regarding future events. These statements are based on estimates and information available to CymaBay at the time of this presentation and are not guarantees of future performance. Actual results could differ materially from CymaBay's current expectations as a result of many factors including, but not limited to: CymaBay's ability to obtain additional financing to fund its operations; unexpected delays or results in clinical trials; uncertainties regarding obtaining regulatory approvals; uncertainties regarding the ability to protect CymaBay's intellectual property; uncertainties regarding market acceptance of any products for which CymaBay is able to obtain regulatory approval; the effects of competition; and other market and general economic conditions. Additional risks relating to CymaBay are contained in CymaBay’s filings with the SEC, including without limitation its most recent Quarterly Report on form 10-Q, Annual Report on form 10-K and other documents subsequently filed or furnished to the SEC, especially under the caption “Risk Factors,” which are available on the SEC web site at http://www.sec.gov, for a fuller discussion of these and other risks relating to an investment in CymaBay’s common stock. CymaBay assumes no obligation for and does not intend to update these forward-looking statements, except as required by law.
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Improving the Lives of Patients with Liver Diseases
ENHANCE data supports potential for broad use of seladelpar in PBCAnti-cholestatic, anti-inflammatory, anti-pruritic effects offer potential to expand addressable population
Laser focus on seladelpar for PBCHighly de-risked, breakthrough therapy and PRIME status, orphan drug designation, Phase 3 start Q1 2021
Effects of seladelpar on NASH resolution and fibrosis: a versatile option for combination therapyStudy with complementary mechanisms through strategic relationships
Strong balance sheet and supportive top-tier institutional biotech investorsCash sufficient to fund current operating plan into 2022
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CymaBay PipelineNovel small molecules targeting high unmet need
PRE-CLINICAL PHASE 1 PHASE 2 PHASE 3
Seladelpar
Seladelpar
Seladelpar
MBX-2982(GPR 119 agonist)
CB-0406(PPARγ non-agonist ligand)
CB-001(GPR 120 agonist)
Primary Biliary Cholangitis
Diabetic Hypoglycemia
Non-alcoholic Steatohepatitis
Primary Sclerosing Cholangitis
Inflammation
Inflammation
| Improving the Lives of Patients with Liver Diseases • Confidential
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SeladelparDifferentiated opportunity addressing unmet needs in liver disease
1.8 Å RMSD X-ray Crystal StructureSeladelpar - PPARδLigand Binding DomainEC50 = 2 nM
First potent and selective PPARδ agonist in development for inflammatory liver diseases
Regulation of pathways important in inflammatory liver diseases; bile acids, lipid metabolism, inflammation and fibrosis
Oral, once daily with clinical activity at 10mg and clinical experience with exposures beyond two years
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Anti-Inflammatory NFκB-dependent gene activation Inflammatory cytokines hs-C-Reactive Protein
Increase Lipid Metabolism Cholesterol/LDL-C Fatty acid oxidation Insulin sensitivity
Decrease Bile Acids Cholesterol synthesis Bile acid synthesis (C4) Transport
Anti-Fibrotic Profibrotic genes Stellate cell activation Collagen synthesis/deposition
SeladelparTargets all important cell types in liver disease
Gene Activation or
Repression
PPARδ RXR
Hepatocyte
Myocyte
Adipocyte
Enterocyte
Hepatocyte
Cholangiocyte
Kupffer Cell
Macrophage
Stellate Cell
Regulates Genes That Control Pathways in Liver Health and Disease
CH3OHOOC
SO
O
CF3
CH3
7
Seladelpar
Primary Biliary Cholangitis
Orphan (FDA, EMA), Breakthrough Therapy (FDA) and Priority Medicine (EMA) designations
Seladelpar has potential to meet the needs of PBC patients with better efficacy and tolerability than current 2nd line therapy
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Primary Biliary Cholangitis (PBC)
• Orphan, cholestatic, autoimmune liver disease• Impairment of bile flow (cholestasis), portal
inflammation and destruction of bile ducts• Elevated serum markers of cholestasis including alkaline
phosphatase (ALP), gamma-glutamyl transferase (GGT) and total bilirubin
• Clinical symptoms of fatigue and pruritus (itching)• Affects 1 in 1,000 women over 40 (~130k U.S. patients)• A chronic and progressive disease
ALP below 1.67x the upper limit of normal and normal total bilirubin are clinical surrogates for slowing disease progression
Liver Transplant
Healthy liver
Inflammation
FibrosisCirrhosis
Cholestasis
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Unmet Need Remains Despite Existing TherapiesPatients need improved efficacy and better tolerability
▲ First line therapy for PBC
▼ ~40% inadequate responders: ALP >1.67x ULN
▼ Additional ~5% are intolerant to therapy
▲ Add-on therapy for UDCA inadequate responders
▲ Monotherapy for UDCA intolerant patients
▲ ALP/bilirubin as biomarkers for accelerated approval
▼ ~50% inadequate responders
▼ Can cause or worsen pruritus
Seladelpar is Being Developed as a Potential Improved 2nd Line Treatment for PBC
Ursodeoxycholic Acid (UDCA) 1st Line
Obeticholic Acid (Ocaliva)2nd Line
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ALT, alanine aminotransferase; AMA, antimitochondrial antibody; ANA, antinuclear antibody; AST, aspartate aminotransferase; ELISA, enzyme-linked immunosorbent assay; ULN, upper limit of normal.
Seladelpar was administered orally once daily. Seladelpar or placebo was administered as an add-on to UDCA therapy for patients who tolerated UDCA; for patients with UDCA intolerance, the study drug was administered as a monotherapy. The study was discontinued because of unexpected histological findings that were later determined to be pre-existing in the nonalcoholic steatohepatitis seladelpar program.
Long-Term Safety Study
ENHANCE Phase 3 Study (Original Design)
Placebo
(n=80)
(n=80)
(n=80)
Day 1 Week 52
Seladelpar 5 mgSeladelpar 10 mg
Seladelpar 5 mg
Seladelpar 10 mg
Key Inclusion Criteria
Week 26
• 18 to 75 years old, male or female with a diagnosis of PBC based on any 2 of the following criteria:– History of ALP above 1.0x ULN for at least 6 months– Positive AMA titer (>1:40 on immunofluorescence or M2 positive by ELISA) or positive PBC-specific ANA– Documented liver biopsy results consistent with PBC
• UDCA for the past 12 months (stable dose) OR intolerant to UDCA• ALP ≥1.67x ULN; ALT/AST ≤3x ULN; total bilirubin ≤2x ULN
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ENHANCE Design and Analysis Plan
* Composite responder: ALP <1.67x ULN, ≥15% decrease in ALP, total bilirubin ≤ULN.mITT, modified intention-to-treat.
Design
Enrolled Patients
Study Population
Endpoints
• Intolerance or inadequate response to UDCA• ALP ≥1.67x ULN, bilirubin ≤2x ULN• Includes patients with severe pruritus
• Seladelpar 10 mg and 5/10 mg titration vs placebo (1:1:1 randomization)• Stratified by ALP value (<350 U/L vs ≥350 U/L) and pruritus Numerical Rating Scale (NRS) (<4 vs ≥4)
Placebo Seladelpar 5 mg Seladelpar 10 mg
Safety/mITT Population 87 89 89
Month 3 56 56 55
Month 6 23 26 20
Primary Endpoint:• Composite
responder rate at Month 3*
Key Secondary Endpoints: • ALP normalization at Month 3• Change from baseline in pruritus NRS at
Month 3 (patients with baseline NRS ≥4)
Other Secondary Endpoints:• Previous 3 endpoints at
Month 6
Amended Endpoints (No dose titration prior to Month 6)
Blinded analysis after early termination. The safety analysis set included any patient who received at least 1 dose of study drug. The mITT analysis set included any patient randomized and dosed.
12GGT, gamma-glutamyl transferase.Mean (SD) unless otherwise specified.
Demographic and Baseline CharacteristicsmITT population
Placebo (n=87)
Seladelpar 5 mg (n=89)
Seladelpar 10 mg (n=89)
Female, n (%) 85 (98%) 82 (92%) 83 (93%)Age, years 56 (8) 55 (10) 56 (9)Caucasian, n (%) 80 (92%) 83 (93%) 77 (87%)Duration of PBC, years 8 (6) 8 (6) 8 (6)History of Pruritus, n (%) 57 (66%) 66 (74%) 65 (73%)Pruritus NRS ≥4 27 (31%) 27 (30%) 27 (30%)UDCA Dose, mg/kg/day 15 (3) 16 (4) 15 (4)UDCA Intolerant, n (%) 2 (2%) 6 (7%) 8 (9%)ALP ULN: 116 U/L 293 (106) 290 (104) 291 (109)ALT ULN: 41 U/L 44 (21) 48 (21) 47 (21)AST ULN: 34 U/L 37 (17) 40 (14) 40 (15)GGT ULN: 38 U/L 229 (193) 231 (212) 243 (228)Total bilirubin ULN: 1.1 mg/dL 0.71 (0.32) 0.76 (0.35) 0.72 (0.32)Immunoglobulin M ULN: 230 mg/dL 358 (264) 332 (202) 316 (181)
13 ns, not significant. P values by Cochran-Mantel-Haenszel (CMH) test.
Primary Composite Endpoint Achieved at 3 months ALP <1.67x ULN, ≥15% decrease in ALP, total bilirubin ≤ULN
10.3
47.5
64.6
0
20
40
60
80
100
Month 1
Prop
ortio
n of
Pat
ient
s (%
)
P<0.0001
P<0.0001
P<0.05
(n=78) (n=80) (n=79)
5 mgPlacebo 10 mg
12.5
57.1
78.2
0
20
40
60
80
100
Prop
ortio
n of
Pat
ient
s (%
)
P<0.0001
P<0.0001
P<0.05
Month 3
(n=56) (n=55)(n=56)
Month 6
21.7
61.570.0
0
20
40
60
80
100
Prop
ortio
n of
Pat
ient
s (%
)
P=0.0006
P=0.002
ns
(n=26) (n=20)(n=23)
78% of patients on seladelpar 10 mg achieved the primary composite endpoint with high statistical significance at 3 months
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Key Secondary Endpoint Achieved: ALP Normalization RateALP ≤1x ULN
05.0
12.7
0
10
20
30
40
50
Prop
ortio
n of
Pat
ient
s (%
)
P=0.0441
P=0.0013
ns
Month 1
(n=78) (n=80) (n=79)
0
11.5
30.0
0
10
20
30
40
50
Prop
ortio
n of
Pat
ient
s (%
)
ns
P=0.0023
ns
Month 6
(n=26) (n=20)(n=23)
Month 3
Prop
ortio
n of
Pat
ient
s (%
)
ns
P<0.0001
P<0.01
05.4
27.3
0
10
20
30
40
50
(n=56) (n=55)(n=56)
P<0.01
P values by CMH test.
27% of patients on seladelpar 10 mg normalized ALP by 3 months
5 mgPlacebo 10 mg
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ALP Relative and Absolute Change at Month 3
-3.7
-35.7
-44.2-50
-40
-30
-20
-10
0
LS M
ean
Chan
ge in
ALP
(%)
P<0.0001
P<0.0001
P=0.0013
(n=56) (n=54) (n=53)
ALP Absolute ChangeALP Relative Change
-2.3
-101
-122-140
-120
-100
-80
-60
-40
-20
0
LS M
ean
Chan
ge in
ALP
(U/L
) P<0.0001
P<0.0001
P=0.0286
(n=56) (n=54) (n=53)
Significantdose-dependent
relative and absolute reductions in ALP
were observedat 3 months
LS Mean and P values by analysis of covariance (ANCOVA). CymaBay, Data on File 2020.
5 mgPlacebo 10 mg
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ALT Normalization at Month 3Patients with baseline ALT >ULN
17.9
51.7 50.0
0
20
40
60
80
100
Prop
ortio
n of
Pat
ient
s (%
)
P=0.0102
P=0.0201
ns
Month 3
(n=29) (n=28)(n=28)
P values by CMH test.
In patients with elevated baseline ALT on seladelpar 10 mg
50% normalized ALT by 3 months
5 mgPlacebo 10 mg
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Improvement in Other Serum Liver TestsMonth 1, 3, and 6 treatment effects in mITT population
mITT population
Placebo Seladelpar 5 mg Seladelpar 10 mg
Month 1(n=78)
Month 3(n=56)
Month 6(n=23)
Month 1(n=78)
Month 3(n=54)
Month 6(n=24)
Month 1(n=78)
Month 3(n=53)
Month 6(n=18)
ALT % Change -2.0% -4.0% 2.4% -14% -23% -23% -6% -17% -35%
GGT % Change -6.7% -6.5% 0.1% -28% -30% -24% -34% -36% -37%
AST % Change 1.3% -0.2% 1.4% -6.6% -8.5% -15% 3.8% -4.8% -17%
Total bilirubin % Change -1.3% 0.9% 1.7% -2.8% -6.1% -3.1% -9.9% -4.0% -15%
IgM % Change -2.6% -5.7% -3.4% -5.7% -10% -8.7% -7.3% -12% -12%
IgM, immunoglobulin M.
Seladelpar demonstrated broad anti-cholestatic and anti-inflammatory effects
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Key Secondary Endpoint Achieved: Treatment Improvement in PruritusPatients with baseline NRS ≥4
-1.14 -1.22
-2.38
-5
-4
-3
-2
-1
0
LS M
ean
Chan
ge in
NRS
P=0.0111
ns
P=0.0170
(n=26) (n=26) (n=27)
Month 1
-2.47 -2.46
-4.24-5
-4
-3
-2
-1
0
LS M
ean
Chan
ge in
NRS
ns
ns
ns
Month 6(n=6) (n=9) (n=7)
-1.55-2.01
-3.14
-5
-4
-3
-2
-1
0
P=0.0164
ns
ns
Month 3(n=18) (n=17) (n=18)
LS M
ean
Chan
ge in
NRS
In patients with moderate and severe pruritus (baseline NRS of 6.2), significant improvements in pruritus were seen with seladelpar 10 mg at 3 months
LS Mean and P values by ANCOVA.
5 mgPlacebo 10 mg
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Dose-Ordered Reductions in Pruritus NRS Observed at Month 3Patients with baseline NRS ≥4
16.7
38.9 42.1
0
20
40
60
80
100
≥4-point Reduction
5.6
22.2
36.8
0
20
40
60
80
100
Prop
ortio
n of
Pat
ient
s (%
)
P=0.0183
≥2-point Reduction
33.3
50.0
68.4
0
20
40
60
80
100
Prop
ortio
n of
Pat
ient
s (%
)
P=0.0361
≥3-point Reduction
Prop
ortio
n of
Pat
ient
s (%
)
(n=18) (n=18) (n=19) (n=18) (n=19)(n=18) (n=18) (n=19)(n=18)
Dose-ordered reductions in NRS were seen at 3 months in patients with moderate and severe pruritus
P values by CMH test. Nonsignificant P values not shown.
5 mgPlacebo 10 mg
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Safety OverviewSummary of treatment-emergent adverse events
Safety Population, n (%)Placebo (n=87)
Seladelpar 5 mg (n=89)
Seladelpar 10 mg (n=89)
Patients with at least 1 AE 64 (73.6) 56 (62.9) 58 (65.2)
Any treatment-related AE 16 (18.4) 25 (28.1) 15 (16.9)
Any treatment-related AE ≥ Grade 3 (CTCAE)* 0 0 0
Any AE with outcome of death 0 0 0
Any SAE 3 (3.4) 3 (3.4) 1 (1.1)
Any treatment-related SAE 0 0 0
Any AE leading to study drug discontinuation 2 (2.3) 2 (2.2) 2 (2.2)
*No Grade 3 ALT/AST elevations.
AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; SAE, serious adverse event.
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Treatment-Emergent Adverse EventsOccurring in ≥5% of patients in any randomized treatment
Safety Population, n (%)Placebo (n=87)
Seladelpar 5 mg (n=89)
Seladelpar 10 mg (n=89)
Seladelpar Total (n=178)
Abdominal pain upper 3 (3.4) 8 (9.0) 6 (6.7) 14 (7.9)Pruritus 11 (12.6) 3 (3.4) 10 (11.2) 13 (7.3)Nausea 4 (4.6) 5 (5.6) 7 (7.9) 12 (6.7)Headache 1 (1.1) 5 (5.6) 7 (7.9) 12 (6.7)Upper respiratory tract infection 2 (2.3) 6 (6.7) 4 (4.5) 10 (5.6)Arthralgia 5 (5.7) 5 (5.6) 4 (4.5) 9 (5.1)Constipation 2 (2.3) 5 (5.6) 3 (3.4) 8 (4.5)Urinary tract infection 0 2 (2.2) 5 (5.6) 7 (3.9)Fatigue 8 (9.2) 2 (2.2) 4 (4.5) 6 (3.4)Dry mouth 0 5 (5.6) 1 (1.1) 6 (3.4)Sinusitis 5 (5.7) 2 (2.2) 1 (1.1) 3 (1.7)
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Treatment-Emergent Serious Adverse Events
Safety Population, n (%)Placebo (n=87)
Seladelpar 5 mg (n=89)
Seladelpar 10 mg (n=89)
Seladelpar Total (n=178)
Patients with at least 1 serious TEAE 3 (3.4) 3 (3.4) 1 (1.1) 4 (2.2)Any treatment-related SAE 0 0 0 0List of SAEs by preferred term:
Cellulitis 0 0 1 (1.1) 1 (0.6)Pyelonephritis acute 1 (1.1) 0 0 0Cognitive disorder 0 1 (1.1) 0 1 (0.6)Partial seizures 1 (1.1) 0 0 0Leukocytosis 0 1 (1.1) 0 1 (0.6)Adenoid cystic carcinoma 0 1 (1.1) 0 1 (0.6)Rectal polyp 1 (1.1) 0 0 0
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Safety and Efficacy of Seladelpar in Patients with PBC
• 78% of patients achieved primary endpoint with 10 mg dose• Seladelpar 10 mg had a statistically significant effect on ALP normalization• Seladelpar 10 mg had a statistically significant reduction in pruritus• 10 mg dose is optimal with consistently greater effects on all endpoints• Overall, seladelpar was generally safe and well-tolerated
A 52-week Phase 3 global registration study
(RESPONSE) to begin enrolling patients in Q1 2021
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Long-Term Safety Study
RESPONSE Phase 3 Pivotal Study in Patients with PBCSame patient population, same dose and same endpoints as ENHANCE
n=180
Seladelpar 10mg
Placebo
(n=120)
(n=60)
Day 1 Week 52
Primary Outcome: • Composite responder rate (ALP <1.67 x ULN, ≥ 15% decrease in ALP, total bilirubin ≤ULN)
Secondary Outcomes: • Proportion of patients with ALP ≤ 1.0 x ULN at 12 months• Change from baseline in pruritus in subjects with baseline Numerical Rating Scale ≥4 using e-diary at 6 months
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Seladelpar
Primary Sclerosing Cholangitis (PSC)
Seladelpar’s anti-cholestatic, anti-inflammatory and anti-fibrotic effects suggest its potential as a treatment for Primary Sclerosing Cholangitis (PSC)
26
Primary Sclerosing Cholangitis (PSC)
• Orphan, cholestatic, autoimmune liver disease• Characterized by diffuse inflammation and fibrosis of
both intra- and extra-hepatic bile ducts • May progress to end-stage liver disease• Common initial symptoms are fatigue, abdominal
pain and itching (pruritus)• ~ 70% of patients have IBD• Cholangiocarcinoma develops in 8–30% of patients• Affects men 2:1 (~40,000 patients in the U.S.)
Only Effective Therapy is Liver Transplant
Hirschfield, et al; The Lancet. 2013
27
Mechanism that decreases:• Metabolic load – reduces bile acids,
cholesterol & lipids• Cell stress and injury – reverses
hepatocellular ballooning• Inflammation and fibrosis – lowers
macrophages & collagen
Non-alcoholic Steatohepatitis (NASH)
Seladelpar
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Nonalcoholic Steatohepatitis (NASH)
Pathological Progression from NAFLD to NASH:
Up to 25% of U.S. suffers from NAFLD with 20% progressing to NASH
Liver Transplant
• ER stress/ROS• Inflammatory
mediators
• Activation & recruitment (Kupffer cells, macrophages, neutrophils)
• Cell death• Stellate cell activation
• Extracellular matrix deposition & remodeling
• Steatosis• Insulin resistance• Bile acids• Free Cholesterol• Lipotoxic lipids
Metabolic Load
Cell Stress & Injury Inflammation Fibrosis
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Seladelpar Phase 2b Study in NASHPaired-liver biopsy 52-week study design
Seladelpar 20 mg PO QD (n=50)
Placebo PO QD (n=25)
Seladelpar 50 mg PO QD (n=50)
Seladelpar 10 mg PO QD (n=50)
Primary EndpointChange in Liver Fat Content
by MRI-PDFF
Secondary EndpointsResolution of NASH
1-Stage Decrease in Fibrosis
Week 12 Week 52Day 1
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Population 12-Week Outcome Measures
Other Key Outcome Measures
Histologically confirmed NASH
Liver fat content (LFC) ≥10%
by MRI-PDFF
F1 to F3, NAS > 4; 1 point in each component
Includes diabetics and non-diabetics
12-week relative change in LFC
Liver biochemistry: ALT, AST, GGT, ALP
Lipid markers: LDL-C, triglycerides
Other inflammatory markers:hs-CRP
Safety and tolerability
52-week histological improvement in NAS and fibrosis
LFC and cT1 by LMS
Liver stiffness by MRE and Fibroscan
Biochemical fibrosis markers and Histoindex® quantitative
digital pathology
Seladelpar Phase 2b Study in NASHEnrolled patients reflective of Phase 3 population
Study Remained Blinded to 52 Weeks
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Seladelpar Phase 2b Study in NASHBaseline demographics and patient characteristics (mITT)
Parameter (Mean ± SD)Placebo(n=26)
10 mg(n=50)
20 mg(n=47)
50 mg(n=48)
Age (Years) 54 (10.5) 53 (12.6) 57 (12.0) 53 (11.3)
Male/Female (%) 30.8/69.2 30.0/70.0 31.9/68.1 33.3/66.7
Body Weight (kg) 104.4 (19.9) 95.3 (21.6) 100.7 (22.9) 99.9 (19.9)
MRI-PDFF (%) 22.3 (9.5) 22.0 (7.8) 20.8 (6.1) 20.5 (6.8)
ALT (U/L) 61.0 (34.7) 60.4 (29.6) 57.4 (26.3) 67.6 (40.2)
AST (U/L) 43.5 (24.5) 45.2 (24.9) 46.0 (21.1) 46.3(27.9)
GGT (U/L) 99.3 (177.5) 84.7 (124.4) 97.4 (80.6) 66.5 (45.2)
ALP (U/L) 82.1 (34.1) 83.9 (25.1) 81.1 (28.0) 76.5 (21.6)
NAS 5.3 (1.1) 5.2 (1.0) 5.1 (1.0) 5.1 (1.0)
Fibrosis Stage 2.1 (0.65) 2.1 (0.70) 2.3 (0.72) 2.1 (0.65)
LDL-C (mg/dL) 114.2 (45.5) 103.8 (33.0) 111.0 (47.6) 106.7 (40.0)
Triglycerides (mg/dL) 151.2 (51.3) 166.4 (79.5) 173.4 (72.8) 154.2 (93.8)
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Seladelpar Phase 2b Study in NASHChanges in relative liver fat content by MRI-PDFF at 12 weeks
Patients with Reduction in LFC by 30%Comparative Relative Change from Baseline
Placebo 10 mg 20 mg 50 mg
-30
-20
-10
0
Mea
n R
elat
ive
Cha
nge
in L
FC (%
)
p=NS
p=NSp=NS
p-values relative to placeboPlacebo 10 mg 20 mg 50 mg
0
10
20
30
40
Prop
ortio
n of
Sub
ject
s (%
)
33
Seladelpar Phase 2b Study in NASHALT and AST levels over 52 weeks
mITT Population with Biopsy
-60
-50
-40
-30
-20
-10
0
10ALT
% A
LT C
hang
e
LS M
ean
(SE)
4 8 12 26 390 52 (Weeks)-60
-50
-40
-30
-20
-10
0
10AST
% A
ST C
hang
e
LS M
ean
(SE)
(Weeks)
Placebo
10mg
20mg
50mg
0 4 8 12 26 39 52
34
Liver Histology Response at Week 52/ET* mITT population with biopsy
* * Effects not statistically significant versus placeboone of the treatment effects were statistically significant vs placebo (threshold p < 0.05)
Placebo 10mg 20mg 50mg0
10
20
30
Prop
ortio
n of
Sub
ject
s
8.0%10.3%
19.0%
26.1%
Placebo 10mg 20mg 50mg0
10
20
30
40
Prop
ortio
n of
Sub
ject
s
20.0%23.1% 23.8%
37.0%
Placebo 10mg 20mg 50mg0
5
10
15
20
25
Prop
ortio
n of
Sub
ject
s
8.3%
5.1%
11.9%
19.6%
NASH Resolution
Fibrosis Improvement
NASH Resolution and Fibrosis Improvement
35
MBX-2982
Prevention of Hypoglycemia in Type 1 Diabetes
36
MBX-2982: Oral GPR119 AgonistEmerging science for a role in glucagon regulation
* Xiaoyan et al. Diabetes 2018;67:1401–1413
Clinical-stage Asset
GPR119 Mechanism
Opportunity
• Once daily oral drug• Clinical activity in 5 clinical studies in > 200 pts up to 4 weeks• Clean profile in 6-month rat and dog studies
• Lipid activated GPCR in intestine, pancreas and liver• Stimulates release of insulin (𝛽𝛽 cells) and incretin (L-cells) hormones• New*: Stimulates glucose-regulated release of glucagon from 𝛼𝛼 cells
• Prevention of hypoglycemia in T1D with glucagon dysregulation• Estimated 3M individuals in US and EU are at risk of hypoglycemia
associated with T1D • Proof-of-pharmacology clamp study
37
Hypoglycemia in Diabetes• Glucagon is a hormone secreted by the pancreas, that
naturally reverses hypoglycemia by signaling the liver to release stored glucose
• Glucagon secretion is dysregulated in diabetes and can result in hypoglycemia
• Hypoglycemia in diabetes is a significant limiting factor in achieving the desired glucose control and is the cause of significant morbidity
• Global HAT study (n=27,000)– 4 out of 5 individuals with T1D reported hypoglycemia– Rate of severe hypoglycemia (requiring assistance of another
person) of approximately 5 events per patient-year
No approved therapy for prevention, only rescue therapy
38
GPR119 Agonists Stimulate Glucose-regulated Release of Glucagon from 𝛼𝛼 cells
Cmpd A – Merck GPR119 agonist
Cmpd B – Merck GPR119 agonist
Nina Xiaoyan Li et al. Diabetes 2018;67:1401-1413
0
2
4
6
8
10
12
14 2mM Glucose 16mM Glucose
Insulin from Human Islets
Insu
lin R
elea
se (n
g/m
l)
DMSO Cmpd A 5 µM
Cmpd B 5 µM
A
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GPR119 Agonist Provide Durable Glucagon Response under Hypoglycemic Conditions
Cmpd A – Merck GPR119 agonist Cmpd B – Merck GPR119 agonist Nina Xiaoyan Li et al. Diabetes 2018;67:1401-1413
40
MBX-2982 Phase 2a Proof of Pharmacology Study
Design:• Randomized, double-blind, placebo-controlled within subject cross-over study• MBX-2982 or placebo, 14-day dosing• Hypoglycemic clamp after 14-day dosing• 29 participants; Type 1 diabetes and healthy volunteers
Proposed Design and Objectives
Objectives:Maximal glucagon concentration during hypoglycemia versus baseline and versus placebo
MBX-2982
Placebo
Double-blind treatment Double-blind treatmentWashout
1 14 42217 3528DAYS
Clamp 1 Clamp 2
Study funded by The Leona M. and Harry B. Helmsley Charitable TrustSponsor: Translational Research Institute for Metabolism and Diabetes, Floridahttps://clinicaltrials.gov/ct2/show/NCT04432090
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CB-0406: A PPAR𝛾𝛾Non-agonist Ligand
Inhibitor of NLRP3 Inflammasome Pathway
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CB-0406: Oral Antagonist of Innate Inflammation
Clinical-stage Asset
CB-0406 Mechanism
Opportunity
• Once daily oral drug• Active metabolite of arhalofenate projected to have greater exposure • Proof-of-concept: Blocks gout flares (IL-1β mechanism)• > 1700 patients exposed; Non-clinical tox and Carc complete
• PPARγ non-agonist ligand• Suppression of NLRP3 pathway and inflammation• Potential advantages from NLRP3 due to upstream mechanism
• Burgeoning interest in NLRP3 pathway in disease• Innate immune system plays a pivotal role in numerous diseases• Evaluating potential utility in various inflammatory diseases
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0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
N 28 51 53 54 53
1.13
0.660.66
1.041.04
0.40.4
1.241.24
-41% -46% -68%p = 0.049 p = 0.0056 p < 0.0001
-16%p = 0.37
• Arhalofenate is not detected in circulation
• CB-0406 is the only significant metabolite
Arhalofenate Attenuates Gout FlaresGout flares are driven by activation of NLRP3 inflammasome
Poiley, J., et al. (2016). "A Randomized, Double-Blind, Active- and Placebo-Controlled Efficacy and Safety Study of Arhalofenate for Reducing Flare in Patients With Gout." Arthritis Rheumatol 68(8): 2027-2034.
Flare incidence in the 4 treatment arms and in the placebo arm over 12 weeks
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Inflammasome Pathway
InflammationNF-𝛋𝛋B NLRP3 Caspase-1 IL-1𝛃𝛃
Tissue Damage & Pathogens
Biologics >$700M salesCB-0406 Companies targeting NLRP3
Pro-Caspase-1 Pro-IL-1𝛃𝛃
Increasing Infection Risk
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CB-0406 Binds to But Does Not Activate PPAR𝛾𝛾Genes
A Human PPARγ Reporter Assay
.01 .1 1 10 100 1000
35302520151050
Gregoire. Mol Endo. 2009 Jul;23(7):975-99 PMID 19389808
B Human PPARγ Regulated Genes
012348
10
12
14
***
***
******
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CB-0406 Phase 1 StudySequential SAD/MAD design
Blinded, sequential dosing of groups with 2 placebo in each cohort
100 mg
100 mg
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NLRP3 Inflammasome Pathway
• Growing body of research shows that inhibition of the NLRP3 inflammasome pathway can significantly attenuate inflammatory processes
• NLRP3 Inflammasome pathway implicated in a broad range of diseases • CymaBay exploring the potential utility of CB-0406 in numerous inflammatory
diseases
Broad Opportunity for Potential Therapeutic Intervention
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Many Milestones to Drive Value Driving seladelpar through Phase 3 to NDA and into the hands of patients
Laser focus on seladelpar for PBCENHANCE data support potential for broad use of seladelpar in PBC
Effects of seladelpar on NASH resolution: a versatile option for combination therapyStrong balance sheet and supportive top-tier institutional biotech investors
2020 2021 Late 2022/ Early 2023
Clinical Holds Lifted ENHANCE top-line data
Phase 3 PBC study start-up
Initiate Phase 3 PBC study
Complete Phase 3 PBC study enrollment
Phase 2a POC data MBX-2982
Phase 1 data CB-0406
Top-line Phase 3 PBC Data
Thank You