corporate presentation · enterocyte. hepatocyte. cholangiocyte. kupffer cell. macrophage. stellate...

Improving the Lives of Patients with Liver Diseases

Corporate Presentation

April 2021

2

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.

3

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

4

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

5

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

6

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

8

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

9

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

10

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)


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

14

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

15

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

16

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

17

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

18

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

19

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


33.3

50.0

68.4

0

20

40

60

80

100

Prop

ortio

n of

Pat

ient

s (%

)

P=0.0361


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

20

Safety OverviewSummary of treatment-emergent adverse events

Safety Population, n (%)Placebo (n=87)



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.

21

Treatment-Emergent Adverse EventsOccurring in ≥5% of patients in any randomized treatment




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)

22

Treatment-Emergent Serious Adverse Events




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

23

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

24

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

25

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

28

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

29

Seladelpar Phase 2b Study in NASHPaired-liver biopsy 52-week study design

Seladelpar 20 mg PO QD (n=50)

Placebo PO QD (n=25)



Primary EndpointChange in Liver Fat Content

by MRI-PDFF

Secondary EndpointsResolution of NASH

1-Stage Decrease in Fibrosis

Week 12 Week 52Day 1

30

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

31

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)

32

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%


10

20

30

40

Prop

ortio

n of

Sub

ject

s

20.0%23.1% 23.8%

37.0%


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

39

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

https://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

corporate presentation · enterocyte. hepatocyte. cholangiocyte. kupffer cell. macrophage. stellate...

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