Ligand Pharmaceuticals Incorporated · NASDAQ:LGND
Ligand Pharmaceuticals — Technical Presentation (August 2005)
42 slides from Ligand Pharmaceuticals's technical presentation, August 2005
Slide 1: SPIRIT II Trial: Bexarotene/Carboplatin/Paclitaxel in NSCLC
A Randomized Phase III Trial Comparing Bexarotene/Carboplatin/Paclitaxel vs. Carboplatin/Paclitaxel in Chemotherapy-Naive Patients with Advanced or Metastatic NSCLC (SPIRIT II Trial) George R. Blumenschein, Jr., M.D. The University of Texas MD Anderson Cancer Center For The SPIRIT II Trial Group 1
Slide 2: Study Rationale
Study Rationale z Bexarotene (Targretin®) is an RXR-selective rexinoid. z High RXR-β expression in NSCLC correlates with longer patient survival. (Brabender, Clin. Canc. Res. 2002) z Disease stabilization and improved survival with bexarotene in NSCLC patients in Phase I and II trials. (Khuri, JCO 2
Slide 3: Bexarotene Molecular Activity
Bexarotene Molecular Activity Bexarotene RXR Regulation P Transcription Regulation α of β of Gene GeneNetworks Networks γ RXR Partners (P) THERAPEUTICS BIOMARKERS •RAR (α,β,γ) •Cell Cycle Control •Triglycerides ↑ •LXR (α, β) •Apoptosis (LXR/FXR/RAR) •FXR •Differentiation •Thyroid Stimulating •PPAR (
Slide 4: SPIRIT II Trial Design
SPIRIT II Trial Design Stage IIIB with pleural effusions, IV ECOG =0, 1 No prior Chemo Chemotherapy* observation R A N D O Chemotherapy* Option to M continue I + Bexarotene Bexarotene Z E until disease progression * Carboplatin/paclitaxel Sample size: 612 patients 4
Slide 5: Treatments
Treatments z Carboplatin AUC 6, Paclitaxel 200mg/m2 infusion every 3 weeks z Restaging every 2 cycles z Bexarotene was dosed at 400 mg/m2 orally daily z Patients on Bexarotene arm allowed to continue with maintenance therapy until progression. z Anti-lipid therapy started on day one of the Bexaroten
Slide 6: Study Endpoints
Study Endpoints z Primary: ¾ Overall survival z Secondary: ¾ Two-year survival z Other Outcomes: ¾ Progression-Free Survival ¾ Time to Progression ¾ Safety ¾ Population pharmacokinetics ¾ Biochemical and genetic biomarkers 6
Slide 7: Patient Demographics
Patient Demographics Carboplatin/ Carboplatin/Paclitaxel Paclitaxel + Bexarotene (N = 306) (N = 306) % % Male 66 66 Gender Female 34 34 Stage of NSCLC Stage IIIB + 13 13 effusion Stage IV 87 87 ECOG 0 34 34 1 65 65 Median Age 63 yrs 63 yrs Histopathology Adenocarcinoma 50 55 Squamous 21 20 Large cel
Slide 8: Patient Demographics
Patient Demographics Carboplatin/ Carboplatin/Paclitaxel Paclitaxel + Bexarotene (N = 306) (N = 306) % % Tobacco Smoking Ever 91 90 Never 8 9 Weight Loss - 6 mos < 5% 53 50 5% - 10% 20 18 >10% 18 22 Ethnicity Caucasian 89 88 Black 7 8 Hispanic 3 1 8
Slide 9: Overall ITT Population Survival
Overall ITT Population Survival 100% Median Survival 2 yr survival 90% Control 9.2 mo. 16.3% SURVIVAL RATE 80% Bexarotene 8.5 mo. 12.4% 70% p=0.2 p=0.2 60% 50% N = 306 40% N = 306 30% 20% 10% 0% 0 100 200 300 400 500 600 700 800 900 1000 1100 1 Yr 2 Yr SURVIVAL (Days) 9
Slide 10: Survival Hazard Ratio for Spirit II
Survival Hazard Ratio for Spirit II Gender Male No Significant Differences Female Stage III B + Effus. IV x ECOG 0 1 x Histology Adeno CA x Squamous CA Large Cell Undiff. CA Weight >10% Loss – 6 5%-10% mos prior <5% x Smoking Never Ever x 0.5 1.0 1.5 2.0 Favors no bexarotene Favors adding bexarotene
Slide 11: Progression-Free Survival (ITT)
Progression-Free Survival (ITT) 100% Median P-F Survival 90% Control 4.9 mo. SURVIVAL RATE 80% Bexarotene 4.1 mo. 70% p=0.061 60% N = 306 50% 40% 30% 20% N = 306 10% 0% 0 100 200 300 400 500 600 700 800 900 1000 1 Yr 2 Yr SURVIVAL (Days) 11
Slide 12: Investigator-Reported Grade 3/4 Adverse Events
Investigator-Reported Grade 3/4 Adverse Events ≥5% with p≤.05 Difference Between Treatment Arms Adverse Event Carboplatin/ Carboplatin/Paclitaxel Paclitaxel (%) +Bexarotene (%) Grade 3/4 Grade 3/4 Hypertriglyceridemia 0 32 Neutropenia 13 28 Asthenia 2 7 Leukopenia 1 6 Dehydration 1 5 12
Slide 13: Subgroup Analysis
Subgroup Analysis z We performed a retrospective analysis to identify subgroups who may have benefited from Bexarotene z Hypertriglyceridemia correlated with improved outcome. 13
Slide 14: Hypothesis
Hypothesis Bexarotene’s impact on triglyceride metabolism is a surrogate for its anti- tumor effect. 14
Slide 15: Serum Levels of Triglycerides and Bexarotene Dose
Serum Levels of Triglycerides and Bexarotene Dose A. Triglycerides as a potential biomarker of bexarotene activity Substantial elevations ≥ 5 fold ULN (NCI Gr 3) Rapid increases usually within first 3-4 weeks B. Bexarotene mean daily dose: 315 mg/m2 60% of pts. above the mean 40% of pts. below the m
Slide 16: Triglyceride Biomarker Differentiates Two Distinct Patient Populations
Triglyceride Biomarker Differentiates Two Distinct Patient Populations High Sensitivity (≥ Grade 3) Low / No Sensitivity (≤ Grade 2) N = 117 1000 N = 172 Dose 1000 400 400 Dose Bexarotene Dose (mg/m2/d) Bexarotene Dose (mg/m2/d) 800 800 Triglyceride (mg/dl) Triglyceride (mg/dl) 300 300 600 600 200 N
Slide 17: Survival for Patients Sorted by Triglyceride Responses in Spirit II
Survival for Patients Sorted by Triglyceride Responses in Spirit II NCI Grade 0+1+2 n = 172 HR = .82 (.74, .91) Triglycerides in Bexarotene Arm NCI Grade 3+4 HR = 1.36 (1.1, 1.7) n = 117 From Multivariate Survival Analysis: Triglycerides NCI Grade 0-4 Bexarotene Arm: p=0.0002 Chemo/Control: p=0.44 0
Slide 18: Survival of Control vs Bexarotene Subgroups
Survival of Control vs Bexarotene Subgroups with Grade 0-2 or Grade 3-4 Triglycerides 100% Median Survival 90% Bexarotene Hi Trigs 12.4 mo. p=0.014 SURVIVAL RATE 80% Chemo/Control 9.2 mo. N = 117 Bexarotene Lo Trigs 6.6 mo. p=0.001 70% 60% N = 306 50% Median Survival 40% 30% Bexarotene 1.9 mos 20% N
Slide 19: Survival Hazard Ratio – SPIRIT II Bexarotene (TGs Gr3+4) vs Control
Survival Hazard Ratio – SPIRIT II Bexarotene (TGs Gr3+4) vs Control Gender Male * Female Stage III B + Effus. IV * ECOG 0* 1 Histology Adeno CA * Squamous CA Large Cell Undiff. CA Weight >10% Loss – 6 5%-10% mos prior <5% Smoking Never Ever * 0.5 1.0 1.5 2.0 2.5 * Significant Differences Favors Cont
Slide 20: Summary and Conclusions
Summary and Conclusions ¾ In the intent to treat population, Bexarotene added to carboplatin/paclitaxel in a first line setting did not improve overall survival. ¾ A retrospective subset analysis suggests that elevation in triglyceride levels in patients treated with Bexarotene correlates with impro
Slide 21: Acknowledgments
Acknowledgments z F. R. Khuri, Winship Cancer Inst., Emory Univesity, Atlanta, USA z U. Gatzemeier, Hospital Grosshansdorf, Grosshansdorf, Germany z W.H. Miller, McGill University, Montreal, Canada z J. von Pawel, Asklepios Fachklinken, Munich, Germany z J.R. Rigas, Dartmouth Medical School, Lebanon
Slide 22: THANK YOU to All of the Spirit II Clinical Sites and Patients
THANK YOU to All of the Spirit II Clinical Sites and Patients, Worldwide! Germany Canada: United States Spain France Austria 22
Slide 23: Bexarotene/Cisplatin/Vinorelbine vs. Cisplatin/Vinorelbine (Spirit I trial)
A randomized phase III trial comparing bexarotene/cisplatin/vinorelbine vs. cisplatin/vinorelbine in advanced or metastatic NSCLC (Spirit I trial) Jacek Jassem, M.D., Ph.D. Medical University of Gdańsk, Poland For the Spirit I Trial Group 23
Slide 24: Study rationale
Study rationale Bexarotene (Targretin®) is an RXR-selective rexinoid High RXR-β expression in NSCLC correlates with longer survival (Clin. Canc. Res., 2002) Bexarotene: − modulates multiple gene regulatory pathways (apoptosis, differentiation, metastasis, angiogenesis) − decreases EGFR, multi-drug r
Slide 25: SPIRIT I trial design
SPIRIT I trial design S Cisplatin –Vinorelbine Stage IIIB T with pleural R R A A Cisplatin – 100 mg/m2 IV Q 4-wks effusion, IV T Vinorelbine – 25 mg/m2 IV weekly N I ECOG 0, 1 D F Y O No prior M 1:1 chemo S I T Z No prior Cisplatin-Vinorelbine A A cancer G T +Bexarotene E I Adequate O Cisplatin-Vino
Slide 26: Study endpoints
Study endpoints Primary: - Overall survival Secondary: - Two-year survival Other outcomes: - Progression-free survival - Time to progression - Safety - Population pharmacokinetics - Biochemical and genetic biomarkers 26
Slide 27: Patient demographics (n=623)
Patient demographics (n=623) Cis-Vin (%) Cis-Vin-Bex (%) N = 312 N = 311 Sex Male 72 72 Female 28 28 Stage IIIB 19 17 IV 81 83 ECOG O 23 26 1 77 74 Median age (yrs) 61 61 Histopathology Adenocarcinoma 42 42 Squamous 36 38 Large cell 3 5 Other 19 15 27
Slide 28: Patient demographics cont’d
Patient demographics cont’d Cis-Vin (%) Cis-Vin-Bex (%) Tobacco smoking Ever 80 80 Never 17 17 Weight loss (6 mos) <5% 63 54 5-10% 14 18 >10% 17 21 Race Caucasian (%) 92 89 Black (%) 4 5 Hispanic (%) 3 2 28
Slide 29: Safety analysis: Serious adverse events
Safety analysis: Study drug related serious adverse events >1% with p≤.05 difference between treatment arms Adverse event Cis-Vin Cis-Vin+Bex (%) (%) Febrile neutropenia 6.1* 2.6 Neutropenia 1.0 3.5* * p ≤ 0.05 29
Slide 30: NCI grade 3-4 adverse events
NCI grade 3-4 adverse events ≥5% with p≤.05 difference between treatment arms Adverse event Cis-Vin (%) Cis-Vin+Bex (%) Hypertriglycerid. 0 30 Leukopenia 16 10 Dyspnea 4 10 Hypercholesterol. 0 6 30
Slide 31: Overall ITT population survival
Overall ITT population survival 100% Median 2 year 90% survival survival 80% Bexarotene 8.7 mo. 13.2% SURVIVAL RATE 70% Control 9.9 mo. 15.7% 60% N = 311 p=0.3 p=0.4 50% 40% N = 312 30% 20% 10% 0% 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1 Yr 2 Yr Days 31
Slide 32: Survival hazard ratios
Survival hazard ratios No significant differences Sex Male Female Stage III B+ effusions IV ECOG 0 x 1 Histology Adeno CA Squamous CA Large Cell CA Other Weight Loss – >10% 6 mos prior 5%-10% <5% Smoking Never Ever 0.0 0.5 1.0 1.5 2.0 Favors Cis-Vin Arm Favors Bexarotene Arm 32
Slide 33: ITT progression-free survival
ITT progression-free survival 100% Median P-F Survival 90% PROGRESSION-FREE Bexarotene 4.3 mo. 80% Control 5.0 mo. 70% N = 312 SURVIVAL p=0.095 60% 50% 40% 30% 20% N = 311 10% 0% 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1 Yr 2 Yr Days 33
Slide 34: Subgroup analysis: Impact of bexarotene dose and biomarker response
Subgroup analysis: Impact of bexarotene dose and biomarker response on survival 34
Slide 35: Triglyceride biomarker differentiates two distinct patient populations
Triglyceride biomarker differentiates two distinct patient populations Trigs. Grade ≥ 3 Trigs. Grade ≤ 2 1000 1000 N = 98 N = 208 Dose 400 Dose 400 Bexarotene Dose (mg/m2/d) Bexarotene Dose (mg/m2/d) 800 800 Triglyceride (mg/dl) Triglyceride (mg/dl) 300 300 600 600 200 NCI Gr 2 200 NCI Gr 2 400 400
Slide 36: Survival for patients sorted by elevated triglyceride responses in Spirit I
Survival for patients sorted by elevated triglyceride responses in Spirit I NCI Grade 0+1+2 HR = .88 (.80, .97) Triglycerides in n = 208 Bexarotene Arm NCI Grade 3+4 HR = 1.25 (.97, 1.61) n = 98 From Multivariate Survival Analysis: Triglycerides NCI Grade 0-4 Bexarotene Arm: p=0.0004 Chemo/Control:
Slide 37: Survival of control vs bexarotene subgroups
Survival of control vs bexarotene subgroups with Grade 0-2 or Grade 3-4 triglycerides 100% Median Survival 90% Bexarotene Hi Trigs 12.3 mo. p=0.08 Chemo/Control 9.9 mo. 80% Bexarotene Lo Trigs 7.5 mo. p=0.009 SURVIVAL RATE 70% N = 98 60% N = 312 50% 40% Median Survival N = 208 30% Bexarotene 1.9 mos
Slide 38: Survival for pooled patients from Spirit I + Spirit II
Survival for pooled patients sorted by elevated triglyceride responses from Spirit I + Spirit II NCI Grade 0+1+2 HR = .85 (.79, .91) p<0.0001 n = 380 MS = 6.9 mo. Triglycerides in Bexarotene arm NCI Grade 3+4 HR = 1.31 (1.1, 1.57) p = 0.0025 n = 215 MS = 12.3 mo. 0.5 1.0 1.5 2.0 2.5 Favors control a
Slide 39: Survival Hazard Ratio (Pooled Spirit I & II)
Survival Hazard Ratio (Pooled Spirit I & II) Bexarotene (TGs Gr3+4) vs Control Sex Male* Female Stage III B + Effus. IV* ECOG 0* 1 Histology Adeno CA Squamous CA Large Cell Other Weight >10%* Loss – 6 5%-10%* mos prior <5% Smoking Never Ever* 0.5 1.0 1.5 2.0 2.5 *Significant Differences 39 Favors Co
Slide 40: Conclusions
Conclusions Addition of Bexarotene to Cisplatin-Vinorelbine chemotherapy does not increase overall survival nor progression free survival compared with chemotherapy alone in the ITT population Results are consistent between both Spirit trials despite different chemotherapy and geographical study sit
Slide 41: Acknowledgments
Acknowledgments P. Zatloukal, Charles University, Prague, Czech Republic R. Ramlau, Great Poland Lung Diseases Center, Poznan, Poland P. Schwarzenberger, Louisiana State University, USA S. Orlov, Pavlov State Medical University, St. Petersburg, Russia J. Rodrigues-Pereira, Inst. Vieira-Carvalho, Sao
Slide 42: THANK YOU to all Spirit I Patients and Investigators, Worldwide!
THANK YOU to all Spirit I Patients and Investigators, Worldwide! Poland UK Hungary Canada United States France Czech Rep Russia Argentina Brazil Greece Israel Australia 42
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