Disclosures and Funding

Transcription

1 S894 A Phase 1, Open-Label Study to Determine the Safety, Tolerability, and Pharmacokinetics of Escalating Doses of LJPC-41 (Synthetic Human Hepcidin) in Patients With Iron Overload Ashutosh Lal, 1 Antonio Piga, 2 Vip Viprakasit, 3 James Maynard, 4 Antonis Kattamis, 5 Dan Yaeger, 6 Brian Byrnes, 6 Lakhmir Chawla, 6 George Tidmarsh 6 1 University of California San Francisco Benioff Children's Hospital, Oakland, CA, USA; 2 Università degli Studi di Torino, Turin, Italy; 3 Siriraj-Thalassemia Center, Mahidol University, Bangkok, Thailand; 4 CTI Clinical Research Center, Cincinnati, OH, USA; 5 National and Kapodistrian University of Athens, 'Aghia Sophia' Children's Hospital, Athens, Greece; 6 La Jolla Pharmaceutical Company, San Diego, CA, USA

2 Disclosures and Funding V. Viprakasit is a consultant for and receives research grants from La Jolla Pharmaceutical Company, Novartis, Sideris, Ferrokin, Vifor, Celgene, Protagonist, Biorad, Sanofi-Genzyme, SEBIA, Roche, Roche Diagnostics and Agios. A. Lal and A. Piga are consultants for and receives research grants from La Jolla Pharmaceutical Company D. Yaeger, B. Byrnes, L. Chawla, and G. Tidmarsh are employees of La Jolla Pharmaceutical Company Funding: This study was funded by La Jolla Pharmaceutical Company, San Diego, CA

3 Background Iron overload is a significant complication in patients with hereditary hemolytic anemias and hereditary hemochromatosis 1-3 Hepcidin Can cause damage to the liver, heart, and endocrine glands and may result in death reduced serum hepcidin levels characterize iron overload Endogenous hepcidin regulates dietary iron absorption and tissue distribution 4,5 Iron efflux to the bloodstream is restrained by hepcidin As a result, recycled iron remains in macrophages, and dietary iron absorption is inhibited 1. Porter J, Garbowski M. Hematology Am Soc Hematol Educ Program. 213;213: Leecharoenkiatx K et al. Asian Pac J Trop Med. 216;9: Gozzelino R, Arosio P. Int J Mol Sci. 216;17:E Liu J et al. Medicine (Baltimore). 216;95:e Sebastiani G et al. Front Pharmacol. 216;7:16.

4 Background (cont d) In animal models, increasing hepcidin levels by synthetic hepcidin injection or genetic induction has been shown to improve iron overload 1 A moderate increase in expression of hepcidin in β-thalassemic mice limited iron overload and improved anemia 2 Supply of exogenous hepcidin or increased expression of hepcidin ameliorated hemochromatosis and β-thalassemia in mice 3,4 These observations suggest that increasing hepcidin levels may help treat the abnormal iron absorption in individuals with β-thalassemia and related disorders 1. Ruchala P, Nemeth E. Trends Pharmacol Sci. 214;35(3): Gardenghi S et al. J Clin Invest. 21;12(12): Corradini E, et al. Gastroenterology. 21;139(5): Guo S et al. J Clin Invest. 213;123(4):

5 Potential effects of hepcidin agonists or activators on iron absorption under normal and β-thalassemic conditions Normal condition β thalassemia (NTDT) Drug treatment Gardenghi S et al. J Clin Invest. 21;12(12):

6 Background (cont d) LJPC-41, a synthetic human hepcidin, is being developed as a therapeutic intervention for iron overload Tested in 3 clinical studies to date 2 single-dose studies NHV1 in healthy volunteers (poster presentation PF47) TPP1 in patients at risk for iron overload 1 multidose study NHV2 in healthy volunteers

7 TPP1 Study Design and Objectives Population: Adult patients at risk of iron overload Design: Phase 1, open-label, dose-escalation study Study Duration: Single SC dose, 7-day observation LJPC-41 dosing at 1, 5, 1, 2, or 3 mg PRIMARY ENDPOINT Safety and tolerability TEAEs, laboratory values, ECGs, vital signs, and physical examination data SECONDARY ENDPOINT Serum iron level Eligible patients were adults with 1 of the following: Transfusion-dependent anemia and hemochromatosis Iron chelation therapy in the past 6 months Serum ferritin level >1 μg/l, or hemochromatosis* *Patients with hemochromatosis that required phlebotomy at least once every 2 months or had received iron chelation therapy in the past 6 months. ECG, electrocardiogram; SC, subcutaneous; TEAE, treatment-emergent adverse event.

8 Study Assessments Safety assessments TEAEs Physical examinations Laboratory evaluations Immunogenicity Visits/sampling on day 1 predose, day 8, and day 22 PK assessments Parameters of baselinecorrected serum LJPC-41 obtained by noncompartmental analysis Blood samples collected at predose and.5, 2, 4, 8, 24, 48, and 168 hours postdose PD assessments Effects on Serum iron level Transferrin level Transferrin saturation Ferritin level Samples collected at screening, day 1 predose, 24, 48, and 168 hours postdose PD, pharmacodynamics; PK, pharmacokinetics; TEAE, treatment-emergent adverse event.

9 Patient Baseline Characteristics LJPC-41 dose Parameter, n (%) 1 mg (n = 3) 5 mg (n = 3) 1 mg (n = 3) 2 mg (n = 6) 3 mg (n = 3) Total (N = 18) Age <65 years 65 years 3 (1) 1 (33.3) 2 (66.7) 3 (1) 6 (1) 3 (1) 16 (88.9) 2 (11.1) Gender Male Female 2 (66.7) 1 (33.3) 3 (1) 3 (1) 2 (33.3) 4 (66.7) 1 (33.3) 2 (66.7) 8 (44.4) 1 (55.6) Iron overload disease Hemochromatosis BL serum ferritin, mean (SD), 248 (592) ng/ml 1 (33.3) 3 (1) 3 (1) 3 (5.) 1 (33.3) 11 (61.1) Sickle cell disease BL serum ferritin, mean (SD), 1151 (7375) ng/ml 2 (66.7) 1 (16.7) 1 (33.3) 4 (22.2) TD β-thalassemia BL serum ferritin, mean (SD), (24) ng/ml 2 (33.3) 1 (33.3) 3 (16.7) BL, baseline; SD, standard deviation.

10 Summary of Safety Parameter, n (%) 1 mg (n = 3) 5 mg (n = 3) LJPC-41 dose 1 mg (n = 3) 2 mg (n = 6) 3 mg (n = 3) Number of TEAEs a Total (N = 18) Patients with 1 TEAEs 2 (66.7) 3 (1) 2 (66.7) 6 (1) 3 (1) 16 (88.9) Number of treatment-related b TEAEs Patients with 1 treatment-related b TEAEs 3 (1) 1 (33.3) 6 (1) 3 (1) 13 (72.2) Number of SAEs 1 c 1 Most frequently occurring TEAEs ( 2 patients) Injection site reactions 3 (1) 6 (1) 3 (1) 12 (66.7) Nausea 2 (66.7) 2 (11.1) ALT increased 1 (33.3) 1 (33.3) 2 (11.1) Decreased appetite 1 (33.3) 1 (16.7) 2 (11.1) Hypoesthesia 1 (33.3) 1 (33.3) 2 (11.1) No severe (grade 3) TEAEs, TEAEs leading to discontinuation, or deaths. Individual patient clinical labs reviewed by the study investigator suggested no clinically significant shifts. ALT, alanine aminotransferase; PD, pharmacodynamics; PK, pharmacokinetics; SAE, severe adverse event; TEAE, treatment-emergent adverse event. a 34 mild and 4 moderate in severity; b Possibly, probably, or definitely related to study drug administration; c Sickle cell pain crisis, not considered treatment-related, fully recovered.

11 Immunogenicity Assay and Results Positive Control/Assay Format Streptavidin ( ) conjugated to SulfoTag ( ) Sample or serum spiked with anti-ljpc surrogate antibody Hepcidin Species-specific anti-ig conjugated to biotin ( ) LJPC-41 coat Detection Control Species-specific anti-ig conjugated to biotin ( ) In 3 clinical trials, which included analysis of a total of 227 samples, all samples were confirmed negative for antibody to LJPC-41. Human IgG at 1 ng/ml LOD 125 ng/ml MSD High Bind assay plate Signal from positive control demonstrates the assay is properly detecting Ab to hepcidin MSD High Bind assay plate Signal generated by the detection control verifies the assay is capable of detecting at least 1 ng/ml of Ab

12 Mean Baseline-Corrected Serum LJPC Mean (SE) concentration, ng/ml Time, h Dose, mg Dose-dependent increase in exposure (except 3 mg) Peak concentrations occurred at 2-4 h Half-life ~6-13 h SE, standard error.

13 Mean Serum Iron Concentration at 8 Hours Postdose Mean Serum Iron Change From Baseline (SD), % Dose Response P= mg (n=3) 5 mg (n=3) 1 mg (n=3) 2 mg (n=6) 3 mg (n=3) LJPC-41 dosing cohorts Note: For analyses excluding the 3-mg dose group, a dose-dependent, statistically significant reduction in serum iron level was observed (P=.8 for dose response; not adjusted for multiple comparisons). SD, standard deviation.

14 Percent Changes in Iron Parameters in Individual Subjects (2- and 3-mg Dose Groups) 5 Ferritin Serum Iron TSAT% 2 mg (n=6) 3 mg (n=3) Percent change from baseline Time, h Ferritin Serum Iron TSAT% Time, h * * *One outlier patient in the 3-mg group had an exchange transfusion 2 days prior to study entry that may have altered iron homeostasis. SD, standard deviation; TSAT%, transferrin saturation.

15 Mean Serum Iron Concentration at 8 Hours Postdose Post Hoc Analysis, Excluding 1 Subject Outlier Mean Serum Iron Change From Baseline (SD), % Dose Response P= mg (n=3) 5 mg (n=3) 1 mg (n=3) 2 mg (n=6) 3 mg (n=2) LJPC-41 dosing cohorts SD, standard deviation.

16 Sustained Iron-Lowering Effect With Comparable PK Exposures Between Healthy Subjects and Patients Mean (SE) value Hepcidin Exposures AUC, (ng.h/ml) ng h/ml Dose, mg Healthy Subjects Patients C max, ng/ml 1 2 Heathy subjects (1 mg: n=6; 2 mg: n=6) Patients (1 mg: n=3; 2 mg: n=6) Mean (SE) iron %change Iron-Lowering Effect Healthy Subjects (NHV1) Time, h Mean (SE) iron %change Dose, mg 1 2 Patients (TPP1) Time, h PK exposures (AUC and C max ) are generally comparable between healthy subjects and patients Longer and sustained iron-lowering effect observed in patients returning toward baseline after 1 week PD effect likely due to difference in iron hemostasis and regulation between the 2 populations AUC, Area under the curve; C max, maximum drug concentration.

17 Improved Hepcidin Production Human hepcidin is difficult to manufacture, with challenges around stability and aggregate formation The original methods for synthesis of hepcidin resulted in ~15% higher molecular weight hepcidin aggregate that was prone to further aggregation under in-use conditions The updated proprietary process for producing hepcidin results in <1% aggregate that is stable under in-use conditions HPLC Trace Red: Original process Black: Improved process High-order aggregate HPLC, high-performace liquid chromatography.

18 Improved Formulation Enhanced Bioavailability 4 AUC, ng.h/ml 4 2 C max ng.h/ml Dose, mg Dose, mg Formulation Improved (NHV2) Original (NHV1) Original (TPP1) A new improved formulation increased subcutaneous bioavailability (AUC and C max ) up to 3-fold.

19 Improved Formulation- Enhanced Iron-Lowering Effect Mean (SE) Iron %Change at Hour Dose, mg Formulation Improved (NHV2) Original (NHV1) Original (TPP1) Enhanced bioavailability resulted in greater iron reduction at the same dose.

20 Conclusions LJPC-41 was well tolerated at doses between 1 mg and 3 mg, with the maximum iron-lowering effect observed at 2 mg LJPC-41 showed significant decreases in serum iron levels compared with baseline, which were sustained in most patients for up to 8 days In comparison to healthy adults, in whom LJPC-41 caused a decrease in serum iron levels that returned to baseline levels within 48 hours, 1 the iron-lowering effect in iron overload patients was more sustained 1. Yaeger D et al. Presented at the 23rd Congress of the European Hematology Association; June 14-17, 218; Stockholm, Sweden; poster PF47.

21 Conclusions (cont d) New formulation has improved PK exposure and PD effect with no corresponding increase of injection site reaction severity or duration Additional studies are ongling to further explore the iron-regulating effects of LJPC-41 in patients with iron-overload disorders 1. Pivotal study in patients with transfusion-dependent beta thalassemia (HELIOS) 1 patient, 12 mo., parallel group study, evaluating the effects of LJPC-41 on myocardial iron 2. Phase 2 study in patients with hereditary hemochromatosis (HERCULES Study) 6 patient, 4 mo., single-blind, placebo-controlled study evaluating the effects of LJPC-41 on TSAT and phlebotomy requirements