Creating New Opportunities for Patients

Transcription

1 Creating New Opportunities for Patients

2 Forward-Looking Statements his presentation contains certain forward-looking statements that are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of All statements, other than statements of historical or present facts, are forward-looking statements, including statements regarding our future financial condition, business strategy, and plans and objectives of management for future operations. In some cases, you can identify forward-looking statements by terminology such as believe, will, may, estimate, continue, aim, assume, anticipate, contemplate, intend, target, project, should, plan, expect, predict, could, possible, seek, goal, potential, hypothesize, likely or the negative of these terms or other similar terms or expressions that concern our expectations, strategy, plans, or intentions. hese statements are based on our intentions, beliefs, projections, outlook, analyses, or current expectations using currently available information, are not guarantees of future performance, and involve certain risks and uncertainties. Although we believe that the expectations reflected in these forward-looking statements are reasonable, we cannot assure you that our expectations will prove to be correct. herefore, actual outcomes and results could materially differ from what is expressed, implied, or forecast in these statements. Any differences could be caused by a number of factors including but not limited to: the success, cost, and timing of our product development activities and clinical trials; our ability to advance our NRF2 Activators and other technologies; our ability to obtain and maintain regulatory approval of our product candidates, and limitations and warnings in the label of an approved product candidate; our ability to obtain funding for our operations, including funding necessary to complete further development and commercialization of our product candidates; our plans to research, develop, and commercialize our product candidates; the commercialization of our product candidates, if approved; the rate and degree of market acceptance of our product candidates; the size and growth potential of the markets for our product candidates, and our ability to identify target patient populations and serve those markets, especially for diseases with small patient populations; the success of competing therapies that are or may become available; our expectations regarding our ability to obtain and maintain intellectual property protection for our product candidates; the ability to license additional intellectual property relating to our product candidates and to comply with our existing license agreements; our ability to contract with third-party suppliers and manufacturers and their ability to perform adequately; our ability to attract collaborators with development, regulatory, and commercialization expertise; our ability to attract and retain key scientific or management personnel; our ability to grow our organization and increase the size of our facilities to meet our anticipated growth; the accuracy of our estimates regarding expenses, future revenue, capital requirements, and needs for additional financing; and regulatory developments in the United States and foreign countries. Additional factors that could cause actual results to differ materially from our expectations can be found in our Securities and Exchange Commission filings. Moreover, we operate in a very competitive and rapidly changing environment. New risk factors emerge from time to time, and it is not possible for our management to predict all risk factors nor can we assess the effects of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in, or implied by, any forward-looking statements. All forward-looking statements included in this presentation are expressly qualified in their entirety by these cautionary statements. he forward-looking statements speak only as of the date made and, other than as required by law, we undertake no obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events, or otherwise. 2

3 Company Overview Developing small-molecule drugs for serious and life threatening orphan diseases Lead programs: Nrf2 activators bardoxolone methyl (Bard) and omaveloxolone (Omav) Nrf2 is a transcription factor that regulates over 200 genes that restore mitochondrial energy production, downregulate inflammation, and reduce fibrosis Mitochondrial dysfunction, chronic inflammation, and Nrf2 suppression are central to the pathogenesis of the diseases we target Bard in Phase 3 for connective tissue disease-associated pulmonary arterial hypertension (CD-PAH) with data expected 1H 2018 Omav moving to pivotal Part 2 of MOXIe trial in Friedreich s ataxia in 2H 2017 Positive Part 1 data released in June 2017 Potential to be first therapy approved for FA wo additional orphan disease programs with potential to begin pivotal trials 2H 2017 Alport syndrome: Phase 2 data 2H 2017 Mitochondrial myopathy: Part 1 data 2H 2017 Additional expansion opportunities for Bard in interstial lung disease (ILD) and renal indications, and Omav in neurology and immuno-oncology 3

4 Nrf2 Activator Mechanism Disease riggers Autoimmunity, Mutations, Cellular damage (DAMPs), Infection (PAMPs), Cytokines Mitochondrial Dysfunction Insufficient energy (AP) High ROS levels Inflammatory metabolic shift Oxidative Stress Cellular damage Inflammatory signaling Increased Energy Production Increased AP,NADH, FADH 2, production Mitochondrial biogenesis Anti-inflammatory metabolic shift Antioxidant activity Glutathione & NADPH SOD, RX, GRX, PRX, GPX Redox homeostasis Inflammation NF-κB transcription activity NLRP3 activation Cytokine Production NFα, IL-1β, IL-6 MCP1, GFβ Anti-inflammatory activity IκBα/NF-κB & NLRP3 inhibition Cytokine suppression: NFα, IL- 1β, IL-6, MCP1, GFβ Resolution of inflammation Potential Amelioration of Acute and Chronic Disease Deficits Acute Fatigue Decreased egfr Impaired Coordination Disease Deficits Chronic Abnormal proliferation issue remodeling Fibrosis (GFβ) Physiological May acutely improve organ function May chronically reduce fibrosis and remodeling Clinical May improve 6MWD (PAH; PH-ILD) May increase kidney function (Alport Syndrome) May increase neurological function (FA) May increase muscular function (MM) May restore normal immune surveillance (Oncology) 4

5 Overview of CD-PAH CD-PAH Pathophysiology PAH that occurs in patients with connective tissue diseases such as scleroderma and lupus erythematosus Impaired mitochondrial function, inflammation, fibrosis, and tissue remodeling implicated as prime drivers of PAH Patient Statistics 10% to 15% of scleroderma and lupus patients have CD-PAH CD-PAH is the leading cause of death for scleroderma and lupus patients 5-year survival of scleroderma patients with PAH is 10% versus 85% without PAH Estimated prevalence: 12,000 in US; 50,000 worldwide; and 30% of all PAH Disease Management Vasodilators are the only current treatment options: PDE-5 inhibitors, endothelin receptor antagonists (ERAs), and prostacyclins Vasodilators have lower benefit in CD-PAH versus idiopathic PAH (I-PAH) Side effects include syncope, headache, flushing, and jaw pain Poor risk-benefit for vasodilators in CD-PAH given minimal treatment effect and adverse events resulting from systemic vasodilation 5

6 CD-PAH is Distinct from Idiopathic PAH CD-PAH is a more severe disease than I-PAH Lower baseline six-minute walk distance (6MWD) Median survival in U.S. is 4 years for CD-PAH versus 7 years for I-PAH patients Compared to I-PAH, CD-PAH is driven more by fibrosis than by impaired hemodynamics, reducing the impact of vasodilators Fibrosis limits the ability of arteries to vasodilate, limiting vasodilator efficacy Vasodilators produce one-third the impact on 6MWD in CD-PAH versus I-PAH Explains lower survival rate in CD-PAH versus I-PAH Rhee Meta-Analysis Hemodynamics and 6MWD Change for CD vs Idiopathic PAH Patients CD-PAH I-PAH Baseline Characteristics RAP, mmhg mpap, mmhg PVR, WU MWD (m) Response to Vasodilator herapy 6MWD (m) Survival in CD vs Idiopathic PAH Patients 6

7 LARIA: Phase 2 rial of Bard Combined with Approved herapies US-only, Phase 2, double-blind, randomized, placebo-controlled trial in I-PAH and CD-PAH patients PAH patients required to be on 1 to 2 background therapies Change in 6MWD from baseline through 16 weeks Safety and tolerability through 16 weeks Initially tested fixed doses of 2.5, 5, and 10 mg once daily (n=8 per dose group) Screening Part 1 Extension E E E E Scr A Scr B D1 D3 W1 D10 W2 W3 W4 W8 W12 W16 6-Minute Walk est E Echocardiogram elephone Contact R 3:1 Bardoxolone Methyl Placebo Bardoxolone Methyl Primary efficacy analysis of initial cohorts presented at CHES 2015 showed a placebo-corrected 6MWD of 21 m (p=0.037) at doses of 2.5, 5, and 10 mg Observed large treatment effect in subset of CD-PAH patients (~ 30 m 6MWD) Expanded LARIA to enroll additional CD-PAH patients ested titration design of 5 10 mg once daily 7

8 Phase 2 Data Suggest Robust reatment Effect in CD-PAH Performed analysis of expanded dataset of all CD-PAH patients dosed up to 10 mg that completed Week 16 Included all patients and those who are CAALYS-eligible Included analysis of time-averaged (Weeks 4, 8, 12, and 16) and Week 16 changes ime-averaged change in Bard patients of ~ 27 m consistent with earlier data Dataset reatment N All CAALYS Eligible Placebo 7 BARD 15 Placebo 5 BARD p< p= p< P= p=0.009 Week 16 Δ6MWD (m) Change from Baseline 9.8 p= p< p= p<0.001 ime-averaged Δ6MWD (m) Change from Placebocorrected Baseline 0.6 p= Placebocorrected p= p=0.005 Patients with moderate to severe anemia are excluded from CAALYS because anemia treatments can affect 6MWD independent of study drug Noticed placebo responders received post-randomization anemia treatments CAALYS-eligible patients showed change of 48.5 m (p=0.005) at Week 16 Pooled standard deviation was 37 m, lower than estimated for CAALYS (50 m) 8

9 CAALYS: Phase 3 rial in CD-PAH Underway FDA concurred with proposed Phase 3 trial in CD-PAH International, double-blind, randomized, placebo-controlled trial Will enroll 130 to 200 patients on 0-2 background therapies Randomized 1:1 to receive Bard (5 10 mg) or placebo for 24 weeks Primary endpoint: 6MWD at week 24 Screening Dose-itration Period Maintenance 6-Minute Walk est elephone Contact Scr D1 D3 W1 D10 W2 W3 W4 D31 W5 W6 W7 W8 W16 W24 Placebo R 1:1 Randomization Bardoxolone Methyl (5 mg) Bardoxolone Methyl (10 mg) Data confirm that power calculations for CAALYS are appropriate LARIA end-of-treatment analysis shows placebo-corrected change in 6MWD of 48.5 m (p=0.005) at week 16 CAALYS powered to detect 12.5 m change at 24 weeks with p<0.05 Pre-specified adaptive component will assess baseline characteristics and variability, as well as potentially modify the sample size to maintain power Study enrolling, data expected 1H

10 Friedreich s Ataxia (FA): A Brief Summary FA Pathophysiology Caused by mutations that result in hypo-expression of frataxin Frataxin is responsible for biosynthesis of iron-sulfur complexes in the mitochondria used by OXPHOS complexes Nrf2 is suppressed in FA due to frataxin deficiency, which leads to increased oxidative stress and impaired energy production ypically thought of as a neurodegenerative disease; however FA is a multi-system disease that includes cardiomyopathy, diabetes, and fatigue Patient Statistics On average, patients are diagnosed in their early teens, wheelchair-bound in their 20s, and die in their 30s Cardiomyopathy is the most common cause of death Prevalence is approximately 6,000 in the U.S. and approximately 22,000 globally Disease Management No treatments are currently approved Patients routinely take vitamin cocktails and antioxidants which have shown no reproducible activity 10

11 Omav May Address Mitochondrial Dysfunction in FA Nrf2 is suppressed in FA and contributes to mitochondrial dysfunction and reduced AP production which inversely correlates with neurologic function In cultured muscle and FA cells, Omav induces Nrf2 target genes and increases mitochondrial AP production Dose-response shows dose-dependent increases with plateau and then a decline Nrf2 Activation Status NQO1 Induction AP Levels in Muscle Cells Mitochondrial Function 11 Shan Y et al., Antioxidant Redox Signal (2013); D Oria V et al., Int J Mol Sci (2013); V Paupe et al, PLoS One (2009); Drinkard BE et al., Arch Phys Med Rehabil (2010)

12 MOXIe Study Design and Patient Disposition MOXIe designed as a two-part study Part 1 designed as first trial to test wide range of doses in humans Part 2 designed to confirm efficacy and safety Part 1: Phase 2, double-blind, randomized, placebo-controlled, dose-ranging, multi-center, international trial 69 total patients randomized 3:1 to Omav or placebo across 7 dose levels 12 week treatment duration Safety overseen by data safety monitoring board Not powered for efficacy; assessing dose-dependent activity and separation from placebo Multiple clinical assessments of muscular and neurological function assessed in Part I Muscular: peak work during exercise testing (primary endpoint) Neurological: mfars (key secondary endpoint) and timed 25 foot walk test Omav was well-tolerated with one Omav and one placebo discontinuation Baseline characteristics were generally balanced across treatment groups 12

13 Omav Dose-Dependently Increases Nrf2 argets and Markers of Mitochondrial Function Robust changes in several Nrf2 targets, including ferritin and GG at mg Aspartate transaminase (AS) and creatine kinase (CK) are regulated by Nrf2 and indicate improved metabolism and mitochondrial function AS/CK changes maximal at 160 mg with reduced activity at 300 mg Nrf2 argets Bioenergetics Ferritin AS GG CK a Change from baseline comparison to zero and LSMEAN estimates at Week 4 using mixed-model repeated measures b Median change from baseline versus zero tested at Week 12 using a 1-way ANOVA 13

14 Pharmacodynamic Changes Associated with Efficacy Improvements Omav significantly improved mfars from baseline across all doses (p<0.0001) mfars changes mirrored AS induction PD and efficacy responses more robust and maximal at doses of mg Placebo-corrected change at 160 mg (-2.3) neared statistical significance (p=0.06) and equivalent to ~1 year of progression Mean mfars Change a N ΔWeek 12 b PBO-Corrected c All Placebo p = AS All Omav p < p = mg p = p = mg p = p = mg p = p = mg p = p = 0.53 mfars 80 mg p = p = mg p = p = mg p = p = 0.65 a Values are LS means from MMRM analysis b Change from baseline at Week 12 compared to zero c Change from baseline at Week 12 in Omav patients compared to placebo patients 14

15 mfars Change More Robust in Patients without Musculoskeletal Foot Deformity Patients who present with FA while growing can develop a musculoskeletal foot deformity that causes high arched feet and is called pes cavus Presence of foot deformity impairs patients ability to stand and coordinate their legs independent of neurological function Presence of foot deformity does not affect placebo change in mfars Placebo-corrected change in mfars in patients without foot deformity is -4.4 points (p=0.01) at Omav 160 mg All Placebo 7 All Omav mg mg 4 Mean mfars Change a Without Foot Deformity N Week 12 b PBO-Corrected c -1.6 p = p < p = p < p = p = p = 0.01 mfars a Values are LS means from MMRM analysis b Change from baseline at Week 12 compared to zero c Change from baseline at Week 12 in Omav patients compared to placebo patients d Change from baseline comparison to zero and LSMEAN estimates at Week 12 using mixed-model repeated measures 15

16 MOXIe Part 2 Study Design Assessing multiple efficacy endpoints Multiple design elements incorporated to limit variability and improve sensitivity Conservatively powered to detect a smaller effect than observed in Part 1 Endpoints Dose Key Design Elements of Part 2 Primary: mfars Secondary: peak work Exploratory: activities of daily living (ADL), 25-foot timed walk test, 9-hole peg test, frequency of falls, SF-36 Patients randomized 1:1 (150 mg Omav : PBO) Stratification by presence or absence of musculoskeletal foot deformity Eligibility mfars (Screening and Day 1 within ± 4.5) Ability to complete exercise test Duration 24 week treatment duration Size 100 patients (80 patients without musculoskeletal foot deformity) Stats Study is powered to detect a placebo-corrected difference in mfars of (p<0.05) to -1.7 (p<0.01) 16

17 Overview of Alport Syndrome Alport Syndrome Pathophysiology ype IV collagen mutations cause defects in the glomerular basement membrane (GBM) Patients present with hematuria, and then develop proteinuria and deterioration of kidney function, leading to end-stage renal disease (ESRD) Deafness and ocular abnormalities are also common Like diabetic chronic kidney disease (CKD), inflammation, fibrosis, and oxidative stress are known to promote disease and drive progressive loss of kidney function Patient Statistics Prevalence of approximately 12,000 patients in the US and 40,000 globally Median age at initiation of ESRD for males with most common form is 25 Median survival of approximately 55 years Current Disease Management No approved therapies ACE inhibitors and ARBs are commonly used off-label Dialysis or renal transplant is needed in most patients 17

18 Rationale for Bard in Alport Syndrome Reata conducted comprehensive development program of Bard in diabetic CKD In clinical trials of more than 2,800 patients, Bard improved markers of renal function such as estimated GFR (egfr) and inulin and creatinine clearance Reata s partner recently demonstrated that Bard improves renal function in humans using the gold standard inulin clearance method of measuring GFR Reata produced strong evidence that extended use of Bard is disease modifying in diabetic CKD by measuring egfr after withdrawal of Bard Reata terminated its diabetic CKD program in 2012 when it detected an increase in risk of fluid overload related heart failure hospitalizations Reata identified the mechanism of increased fluid retention and implemented screening and monitoring procedures to mitigate fluid retention risk he Alport development program leverages the large body of preclinical and clinical data for Bard in diabetic CKD he pathophysiology underlying CKD caused by Alport syndrome is very similar to CKD caused by ype 2 diabetes 18

19 Bard has Consistently Improved Renal Function in Clinical rials Bard significantly increased markers of renal function such as egfr, inulin clearance, and creatinine clearance across 10 clinical trials enrolling over 2,800 patients Study Phase/ Country Patient Population N egfr (ml/min/1.73m 2 ) 402-C-0903 (BEACON) 3/Global CKD/Diabetes (p<0.001 vs PBO) 402-C-0804 (BEAM) 2/US CKD/Diabetes (p<0.001 vs PBO) RA (SUBAKI) 2/Japan CKD/Diabetes 40 Data not yet publicly disclosed 402-C /US CKD/Diabetes (p<0.001) 402-C-0801 (Stratum 1) 2a/US CKD/Diabetes (p<0.001) 402-C-0801 (Stratum 2) 2b/US CKD/Diabetes (p<0.001) 402-C /US CKD/Diabetes (p<0.05) 402-C /US Cancer (p<0.0001) 402-C /2/US Cancer (p=0.001) 402-C-1302 (LARIA) 2/US Pulmonary Hypertension (p<0.001 vs PBO) 19

20 Patients with CKD and ype 2 Diabetes Show Sustained Renal Function Improvement Bard significantly increased egfr (p<0.0001) in BEAM and BEACON Change was durable through one year, the longest duration tested Changes were associated with fewer renal SAEs and ESRD events BEAM BEACON Mean egfr Change (ml/min/1.73 m 2 ) Week 150 mg (n = 14) 75 mg (n = 42) 25 mg (n = 69) Placebo (n=51) Mean egfr ± SE (ml/min/1.73 m2) PBO BARD reatment Week Number of Patients PBO BARD Pergola et al., NEJM (2011); De Zeeuw et al., NEJM (2013) 20

21 Improvements in Renal Function are Partially Retained After Withdrawal of Bard In BEAM and BEACON, a significant, placebo-corrected improvement in egfr was retained after withdrawal of drug for four weeks egfr assessed after sub-therapeutic concentrations reached End-of-treatment and withdrawal egfr changes correlate he larger the effect on-treatment, the larger the retained benefit Data suggest Bard affects chronic remodeling and fibrosis BEAM (n=172) Withdrawal Analysis Baseline egfr Placebo- Corrected egfr Post- Withdrawal P-value Low Dose p>0.05 Mid Dose p<0.05 High Dose p<0.05 BEACON (n=498) 20 mg p<

22 Alport Syndrome Phase 2/3 rial Design Received guidance from FDA that retained egfr after withdrawal of drug for four weeks would support approval Significant effect on retained egfr after one year on drug could serve as the basis for accelerated approval Significant effect on retained egfr after two years on drug could serve as the basis for full approval rial designed with input from international key opinion leaders and the Alport Syndrome Foundation Will enroll patients from 12 to 60 years old Will enroll a broad range of kidney function (egfr between ml/min/1.73 m 2 ) Patients with stage 4 CKD, cardiovascular disease, or fluid retention will be excluded itration to be used to reach goal dose of 20 or 30 mg given orally, once daily Phase 2 Cohort enrollment underway Open-label cohort enrolling a total of 30 patients: 15 with microalbuminuria and 15 with macroalbuminuria Measuring change in egfr following 12 weeks of treatment Data not included in analysis of primary and secondary endpoints for Phase 3 Phase 3 will be initiated if pre-specified efficacy threshold met in Phase 2 cohort 22

23 Alport Syndrome Phase 2/3 rial Design Phase 3 Cohort Placebo-controlled, double-blind trial with 1:1 randomization Will enroll up to 180 patients with two years of follow-up Primary endpoint of on-treatment egfr change at Week 48 Key secondary endpoint of egfr change after 4 weeks of drug withdrawal (Week 52) Additional secondary endpoints of egfr change at Week 100 and after 4 weeks of drug withdrawal (Week 104) Phase 3 Cohort Screening Dose-itration Period Maintenance W/D Maintenance F/U ScrA ScrB D1 D3 W1 D10 W2 W3 W4 D31 W5 W6 W7 W8 W12 W24 W36 W48 W52 W64 W76 W88 W100 W104 R Baseline ACR 300 mg/g Placebo* Off Study Drug Placebo Off Study Drug 1:1 Randomization BARD (5 mg)* Baseline ACR > 300 mg/g BARD (5 mg)* BARD (10 mg) BARD (20 mg) BARD (20 mg) BARD (10 mg) BARD (20 mg) BARD (30 mg) BARD (30 mg) 23

24 Design Implications From Previous rials Statistical design of Cardinal Powered based on efficacy observed in BEAM (4.7 ml/min/1.73 m2 difference) Enrolling twice as many patients 99% and 90% power to achieve primary and secondary endpoints Study could be successful with effect that is approximately 50% less than BEAM N BL egfr Placebo-Corrected egfr Week 12 One Year Withdrawal BEAM: Mid Dose (p<0.001) 4.7 (p=0.02) CARDINAL Modeling Replicate BEAM with more patients (p<0.001) 4.7 (p<0.001) Minimal detectable difference 2.5 (p<0.05) Data from Phase 2 study expected H If Phase 2 positive, plan to initiate Phase 3 study during H

25 Upcoming Key Events and iming Stage Disease Drug Event iming Alport Syndrome (1) Bard P2 data 2H17 Lead Programs Mitochondrial Myopathies (3) Omav Part 1 data 2H17 CD-PAH (1,2) Bard P3 data 1H18 Friedreich s ataxia (3) Omav Part 2 initiation 2H17 Pulmonary Hypertension (ILD) (1) Bard P2 data 2H17 Earlier Stage Programs Melanoma (3) Omav P1b data 2H17 Orphan Neurological Indications RA 901 P1 data 2H17 (1) Bard is currently being developed unilaterally by Reata, and AbbVie retains the right to opt back into development. Reata retains commercial rights in US market; KHK has rights in certain Asian markets; AbbVie has rights in non-khk markets outside the US. (2) Reata s next milestone is data from the Phase 3 trial in CD-PAH. Reata began enrolling patients in October (3) Reata retains US commercialization; Omaveloxolone is currently being developed unilaterally by Reata, and AbbVie retains certain rights to opt back into development and commercialization. 25