![]() Cowen Health Care Conference March 4, 2015 Boston, MA Harold Van Wart, Ph.D. President and CEO Exhibit 99.1 |
![]() 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. You should read CymaBay's Quarterly Report on Form 10-Q filed with the SEC on November 14, 2014, especially under the caption “Risk Factors,” which is 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 CymaBay Highlights • Arhalofenate is the first drug in the Urate Lowering Anti-Flare Therapy (ULAFT) class for the treatment of gout Reduces gout flares and lowers serum uric acid (sUA) Refined product profile established in recently completed Phase 2 studies Good overall and renal safety data in over 1,000 subjects • MBX-8025 is a potential novel treatment for rare or serious lipid and liver disorders, including homozygous familial hypercholesterolemia (HoFH) Positive effects on lipids and markers of liver health demonstrated in mixed dyslipidemia Phase 2 trial Focusing further development in rare or orphan diseases • Near-term, value-driving catalysts Arhalofenate End-of-Phase 2 meeting with FDA in 3Q 2015 Phase 2 trial initiation for MBX-8025 in HoFH expected in 1H 2015 |
![]() Key Features of Gout Hyperuricemia, urate crystal deposits and flares Hyperuricemia Serum Uric Acid (sUA) Mono Sodium Urate (MSU) crystal deposits Inflammatory response IL-1 Painful flare Therapeutic targets Joint erosion 4 |
![]() 5 Current Treatment of Gout Uric acid Lowering Therapies (ULTs) and anti-inflammatories – Treatment paradigm (ACR Guidelines) – Anti-inflammatory to treat the flare – ULT is initiated to address the hyperuricemia with a goal of sUA < 6 mg/dL to debulk offending MSU burden – Initiation of ULT increases flare risk, requiring dose titration and colchicine prophylaxis – Anti-inflammatory drugs – Colchicine (Colcrys) – NSAIDs, steroids – Ilaris (anti-IL-1 biologic) approved in EU • ULTs – Xanthine oxidase (XO) inhibitors (allopurinol, febuxostat) – Uricosurics (probenecid, lesinurad in development) – Pegloticase (for severe treatment failure gout) |
![]() 6 Gout Patients Are Poorly Served by Available Drugs Need for more sUA lowering and better control of flares • More sUA lowering – ~2 million patients do not reach their sUA goal on their current ULT • <6 mg/dL for patients without tophi • <5 mg/dL for patients with tophi – ~300 thousand patients are allopurinol intolerant – Inadequate responders to ULT continue to increase their MSU burden and the disease continues to progress • Better flare control – ~1 million patients experience 3 flares/year – Patients care about the pain, suffering and medical costs of flares – Colchicine, NSAIDs and steroids are “strongly contraindicated” in >40% of gout patients due to their comorbidities – Colchicine non-compliance is estimated to be ~40% |
![]() 7 Arhalofenate The First Urate Lowering Anti-Flare Therapy (ULAFT) • Lowers sUA by improving uric acid excretion in the kidney (uricosuric effect) – Blocks urate reabsorption by URAT1 – Same target as lesinurad – Very favorable PK for a uricosuric drug • 50 hour half-life produces gradual changes in serum and urinary UA with small intraday fluctuations • Avoids “hyperuricosuria” • Reduces flares through anti-inflammatory properties and long plasma half-life – Suppresses MSU crystal-induced IL-1 in gouty joints – No systemic suppression of IL-1 and no infection risk Human URAT1 Arhalofenate Acid (M) 10 -6 10 -5 10 -4 10 -3 0 20 40 60 80 100 IC 50 = 92 M |
![]() * NHANES 2008 ** Source Healthcare 2012 Gout Population Segregated by sUA Status Treating inadequate responders with a uricosuric drug Uricosuric drug Uricosuric drug Uricosurics in Development: Lesinurad (ULT) Arhalofenate (ULAFT) The original positioning of arhalofenate was for the ~1M patients flaring >3 times/year Allopurinol Intolerant ~300 K Diagnosed Gout* 8.3 M ULT Treated** >90% Allopurinol ~3.3 M Inadequate Responders ~2 M Responders ~1.3 M 8 |
![]() 9 Arhalofenate Phase 2 Clinical Program for Gout • Five Phase 2 studies completed – Monotherapy with and without colchicine – Combination with febuxostat and allopurinol – Arhalofenate doses of 400, 600 and 800 mg • Summary of results – Very effective sUA lowering in combination with febuxostat (40 or 80 mg) – Arhalofenate monotherapy is an alternative for the XOI intolerant patients – Arhalofenate has anti-flare activity • Provides the symptomatic relief that patients really want • Helps patients in which colchicine is contraindicated or not tolerated – Does not require dose titration • Refined product positioning – Recent arhalofenate Phase 2 data and lesinurad news has shifted positioning to address the larger sUA inadequate responder segment |
![]() 10 Arhalofenate Febuxostat Phase 2 Study • Objectives – Assess sUA reductions of different dose combinations – Measure the interday and intraday fractional excretion of UA (FEUA) – Assess if there is a drug-drug interaction – Additional safety data for arhalofenate/febuxostat combination N = 16 per cohort ; PK from cohort 2 at Weeks 2, 4 and 6 All patients received colchicine for flare prophylaxis Cohort 1 Cohort 2 Weeks 1-2 Week 3 Week 4 Weeks 5-6 Arhalofenate 600 Febuxostat 80 + Arhalofenate 600 Febuxostat 40 + Arhalofenate 600 Febuxostat 40 Arhalofenate 800 Febuxostat 40 + Arhalofenate 800 Febuxostat 80 + Arhalofenate 800 Febuxostat 80 |
![]() Arhalofenate Febuxostat Phase 2 Study Changes in sUA for treatment phases sUA = -33% RR = 43% sUA = -24% RR = 100% Arhalofenate decrease sUA by an additional 24% and increases the Responder Rate from 43 to 100% Baseline Fbx (40 mg) Fbx (40 mg) + Arhalo (800 mg) 0 2 4 6 8 10 12 11 |
![]() 12 Arhalofenate Febuxostat Phase 2 PK/PD Study sUA responder rate for febuxostat 40 mg treatments < 6.0 mg/dL < 5.0 mg/dL < 4.0 mg/dL < 3.0 mg/dL Febuxostat (40 mg) + Arhalofenate (800 mg) Febuxostat (40 mg) + Arhalofenate (600 mg) Febuxostat (40 mg) N 15 14 15 p-values reflect comparisons vs. febuxostat 40 mg. McNemar’s exact test and Fischer’s exact test were used for comparisons within and between cohorts, respectively. * p < .05 ** p < .01 *** p < .001 * ** *** 0 20 40 60 80 100 |
![]() 13 < 6.0 mg/dL < 5.0 mg/dL < 4.0 mg/dL < 3.0 mg/dL Febuxostat (80 mg) + Arhalofenate (800 mg) Febuxostat (80 mg) + Arhalofenate (600 mg) Febuxostat (80 mg) N 14 16 14 Arhalofenate Febuxostat Phase 2 PK/PD Study sUA responder rate for febuxostat 80 mg treatments * * p < .05 for comparison vs. febuxostat 80 mg; McNemar’s exact test 0 20 40 60 80 100 |
![]() 14 Time Period *** p < 0.001 Matched pairs t-test Fractional Excretion of Uric Acid (FEUA) Normal Range* * Perez-Ruiz et al., Arthr. Rheum. 47, 610 (2002) Day 0 (n = 8) Day 14 (n = 8) Mean ± SE 9 am to 3 pm 3 pm to 9 pm 9 pm to 9 am *** *** *** 2 3 4 5 6 7 8 9 10 Arhalofenate Febuxostat Phase 2 PK/PD Study Intraday and interday variation in FEUA for arhalofenate (800 mg) 14 |
![]() • Design – Randomized double blind placebo- and active-controlled study – 12-week duration – 248 gout patients who had >3 flares in prior year • Goal for arhalofenate – Establish statistically significant reduction in gout flares – Show anti-flare effect in the absence of colchicine • Primary end point – Mean flares/patient • Secondary end point – Reduction in sUA Arhalofenate Phase 2b Flare Study Arhalofenate flare study Electronic diary for patient flare reporting |
![]() 16 Arhalofenate Phase 2b Study Design Primary Endpoint: Reduction in flare rate for arhalofenate compared to allopurinol n = 25 n = 50 n = 50 n = 50 n = 50 Allopurinol 300 mg + Colchicine Allopurinol 300 mg Arhalofenate 600 mg Placebo Flare Rescue 3 Month Treatment Phase 2 Week Follw-up Arhalofenate 800 mg |
![]() Arhalofenate Phase 2b Flare Study Most frequent adverse events and safety summary Placebo Arhalofenate 600 mg Arhalofenate 800 mg Allopurinol 300 mg + COL Allopurinol 300 mg N 28 53 51 53 54 AEs 17 (60.7%) 24 (45.3%) 21 (41.2%) 24 (45.3%) 22 (40.7%) SAEs 0 1 0 1 3 Discon due to AE or Lab 1 1 1 5 3 CK increased 0 3 (5.7%) 2 (3.9%) 3 (5.7%) 3 (5.6%) URT Infection 2 (7.1%) 3 (5.7%) 2 (3.9%) 2 (3.8%) 0 Headache 1 (3.6%) 3 (5.7%) 2 (3.9%) 0 2 (3.7%) Hypertension 2 (7.1%) 1 (1.9%) 2 (3.9%) 2 (3.8%) 1 (1.9%) Creatinine >1.5X and >ULN 0 0 0 0 0 17 |
![]() Arhalofenate Phase 2b Flare Study Arhaolfenate 800 mg dose met the primary flare end point Arhalofenate (800 mg) vs. allopurinol (300 mg) + colchicine were not statistically different (p = .091) -46% p= 0.0056 Arhalofenate (600 mg) Allopurinol (300 mg) Placebo Allopurinol (300 mg) + Colchicine Arhalofenate (800 mg) -68% p < 0.0001 -41% p = 0.049 0.00 0.25 0.50 0.75 1.00 1.25 1.50 N 53 51 53 54 28 1.13 1.04 0.66 1.24 0.40 18 |
![]() Arhalofenate Phase 2b Flare Study Mean lowering of serum uric acid 8 weeks p < .01 vs. Pbo for all changes 12 weeks Arhalofenate (600 mg) Allopurinol (300 mg) Placebo Allopurinol (300 mg) + Colchicine Arhalofenate (800 mg) Baseline sUA 9.1 9.0 9.1 9.2 9.1 16-20% drop in sUA projected to give RR = 100% in combo with Fbx (40 mg) -30 -20 -10 0 19 N 28 53 51 53 54 |
![]() 20 Allopurinol Intolerant ~300 K Inadequate Responders ~2 M Arhalofenate (800 mg) + Febuxostat (80 mg) Arhalofenate (800 mg) Arhalofenate Target Population Major target is inadequate responders on current ULT Patients w/o Tophi ~1.6 M Patients with Tophi ~ 0.4 M Arhalofenate (800 mg) + Febuxostat (40 mg) Great majority reach their sUA goal Experience fewer flares Don’t need colchicine prophylaxis No need for dose titration A fixed dose combination pill is in development for patient convenience Benefits to Patient |
![]() 21 Comparison of Arhalofenate with Lesinurad Arhalofenate (800 mg) Lesinurad (200 mg) sUA lowering 16-24% (Ph 2) Monotherapy for allopurinol intolerant Responder Rate (< 6 mg/dL) increase with XOI On top of Allo (300 mg) On top of Fbx (40 mg) Flare benefit Colchicine Prophylaxis needed Renal safety * Ardea presentation materials **ACR presentation, 2014 No signal No Yes 57% (Ph 2) Yes No** 38% (Ph 2)*; 25% (Ph 3)** No** 16% (Ph 2)* |
![]() 22 Arhalofenate Clinical Studies Safety summary • Completed 9 Phase 2 clinical studies (200-800 mg) – More than 1,000 subjects exposed to arhalofenate for up to 6 months • General safety – Adverse events similar to placebo and balanced across dose groups – Low incidence of asymptomatic liver transaminase elevations – No change in neutrophils or increase in infections • Renal safety – No kidney stones or decrease in urine pH – No creatinine signal • No dose-limiting toxicity has been identified |
![]() 23 Arhalofenate Nonclinical Studies Non-clinical development status • Drug materials – Economical, proprietary synthesis – Tablet formulations developed – Fixed dose formulation with febuxostat in development • Completed preclinical safety package – Sub-chronic and chronic toxicology – Safety pharmacology and reproductive toxicology – Two-year carcinogenicity studies – Carcinogenicity and CV safety review by FDA completed • All results support further development |
![]() 24 • Non-tophaceous gout (n = 1,000) in allopurinol inadequate responders – Febuxostat (40 mg) + colchicine vs. febuxostat (40 mg) + arhalofenate (800 mg) for 6 months + 6 month safety extension – Primary endpoint: sUA responder rate (< 6 mg/dL) at 6 months – Secondary end point: average flares/patient at 6 months • Tophaceous gout (n = 300) in allopurinol inadequate responders – Febuxostat (80 mg) + colchicine vs. febuxostat (80 mg) + arhalofenate (800 mg) for 6 months – Primary endpoint: sUA responder rate (< 5 mg/dL) at 6 months – Secondary endpoints: flare rate and tophi resolution at 12 months • Patients intolerant to allopurinol (n = 200) – Placebo and arhalofenate (800 mg) for 6 months with 6-month safety extension – Primary endpoint: average flares per patient at 6 months – Secondary end point: sUA responder rate (< 6 mg/dL) at 6 months Phase 3 Program for Arhalofenate Preliminary study design |
![]() 25 MBX-8025 • MBX-8025 – Potent selective PPAR- agonist – Once daily orally administered • Status – Originally in development for mixed dyslipidemia – Phase 2 study demonstrated favorable effects on lipids and liver biomarkers – FDA now requiring a preapproval CV outcome study for this indication • Redirecting program to higher unmet need indications – Homozygous familial hypercholesterolemia (HoFH) – Primary biliary cirrhosis (PBC) – Severe refractory hypertriglyceridemia (SHTG) – Nonalcoholic steatohepatitis (NASH) O HO O S O O CF 3 (R) |
![]() 26 • Orphan disease affecting 1 in 1 million – Markedly elevated LDL-C (>500 mg/dL) caused by loss-of-function mutations in LDL receptor (LDL-R) – Cardiovascular disease (MI, stroke, CAD) before the age of 20 – Mean age of death is in the 30s – Current therapy is focused on lowering LDL-C • Therapies that raise LDL-R activity are minimally effective – Statins, bile acid sequestrants, cholesterol absorption inhibitors, PCSK9 inhibitors • Current therapeutic options – LDL apheresis – Juxtapid (lomitapide) – Kynamro (mipomersen) 28 year-old female with cutaneous xanthoma Homozygous Familial Hypercholesterolemia (HoFH) Rare disease of impaired cholesterol metabolism |
![]() 27 Unmet Medical Need in HoFH Remains High Patients need more effective and better tolerated therapies • LDL apheresis is inconvenient and has many complications • Juxtapid (Microsomal Transfer Protein Inhibitor) – Only 28% of patients achieve LDL < 100 mg/dL – Dose limiting GI tolerability – Risk of hepatotoxicity due to increase in hepatic fat – Black box and REMs requiring monthly liver testing • Kynamro (oligonucleotide inhibitor of apo-B synthesis) – Risk of hepatotoxicity due to increase in hepatic fat – Black box and REMs requiring monthly liver testing – Flu-like symptoms and injection site reactions |
![]() 28 MBX-8025 Phase 2 Mixed Dyslipidemia Study Change in LDL-C as a function of baseline LDL-C -60 -50 -40 -30 -20 -10 0 Placebo MBX-8025 (50 mg) MBX-8025 (100 mg) LDL-C range 83-242 175 180 190 195 Mean LDL-C 159-169 186-197 189-205 195-207 197-215 N 28,27,32 8,10,11 6,9,10 3,7,9 2,5,6 |
![]() 29 Effect of MBX-8025 in the WHHL Rabbit Model of HoFH Significant and sustained reductions in LDL-C The Watanabe Heritable Hyperlipidemic (WHHL) rabbit has low (<5%) LDL-R activity LDL-C (Mean ± SD, n = 5) 1 2 3 4 5 6 7 -60 -40 -20 0 20 MBX-8025 Time (weeks) Washout |
![]() 30 MBX-8025 for the Treatment of HoFH Rationale and pilot study design • Rationale – MBX-8025 exhibited a strong anti-atherogenic profile in patients with mixed dyslipidemia including reductions in LDL-C – Data from the WHHL rabbit model suggest that the decreases in LDL-C would be retained in the setting of low LDL-R activity characteristic of HoFH • Pilot study design – Open label dose escalation study in up to 8 patients – Doses are 50, 100 and 200 mg – Study duration of 3 months – Study to be conducted in 2-3 countries in Europe – Start of study planned for 1H 2015 |
![]() 31 CymaBay Projected Milestones • Arhalofenate – Dose first patient in Phase 2b study 1H 2014 – Phase 2 febuxostat combo headline data 1Q 2015 – Phase 2b flare study headline data 2Q 2015 – End-of-Phase 2 meeting 2H 2015 – Start Phase 3 1H 2016 • MBX-8025 – Select indication for proof-of-concept 2H 2014 – Start pilot study in HoFH 1H 2015 |