Denosumab Compared With Zoledronic Acid for the Treatment of Bone Metastases in Patients With Castration-Resistant Prostate Cancer Karim Fizazi,1 Michael.

Slides:



Advertisements
Similar presentations
Más es posible: CPRC con Metástasis Óseas Sintomáticas Javier Puente, MD, PhD Hospital Universitario Clinico San Carlos Medical Oncology Department Complutense.
Advertisements

Adam M. Brufsky, MD, PhD Co-Director, Comprehensive Breast Cancer Center Magee-Women’s Hospital University of Pittsburgh Medical Center Pittsburgh, Pennsylvania.
TROPHY TRial Of Preventing HYpertension. High-normal BP increases CV risk Vasan RS et al. N Engl J Med. 2001;345: Incidence of CV events in women.
Herceptin® (trastuzumab) in combination with chemotherapy: pivotal metastatic breast cancer survival data 1.
Efficacy and Safety of Conatumumab Plus AMG 479 in Patients With Advanced Sarcoma S Chawla,1 AC Lockhart,2 N Azad,3 E Elez,4 F Galimi,5 N Baker,6 YJ.
Prof. Robert Coleman, MD, FRCP Cancer Research Centre
Advances in the Management of Skeletal Related Events/Bone Metastases in Prostate Cancer Robert Dreicer, M.D., M.S., FACP, FASCO Chair Dept of Solid Tumor.
19th Annual NOCR Meeting Session I: Breast Cancer
1Stopeck A et al. Proc SABCS 2010;Abstract P
Renal Safety of Zoledronic Acid in Patients With Breast Cancer.
Denosumab in bone metastasis of cancer and hypercalemia Supervisor: 趙大中 大夫 Reporter: 郭政裕 總醫師.
The Effect of Zoledronic Acid (ZOL) on Aromatase Inhibitor-Associated Bone Loss in Postmenopausal Women with Early Breast Cancer Receiving Adjuvant Letrozole:
“Fighting Cancer: It’s All We Do.” ™. Restoring Quality of Life And Managing Side Effects Ulka Vaishampayan M.D. Chair, GU Multidisciplinary team Associate.
Hormone Refractory Prostate Cancer A Regulatory Perspective of End Points to Measure Safety and Efficacy of Drugs Hormone Refractory Prostate Cancer Bhupinder.
Advances in osteoporosis treatment John C Stevenson National Heart & Lung Institute Imperial College London Royal Brompton Hospital London, UK.
Cabozantinib (XL184) in Metastatic Castration-Resistant Prostate Cancer (mCRPC): Results from a Phase II Randomized Discontinuation Trial Hussain M et.
Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study) Lambers Heerspink,
Design of Clinical Trials for Select Patients With a Rising PSA following Primary Therapy Anthony V. D’Amico, MD, PhD Professor of Radiation Oncology Harvard.
Capecitabine versus Bolus 5-FU/Leucovorin as Adjuvant Therapy for Colon Cancer: X-ACT Trial Results James Cassidy, MD Colorectal Cancer Update Think Tank.
A Phase 2 Study of Elotuzumab in Combination with Lenalidomide and Low-Dose Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma: Updated.
CC39/11-1 ZOMETA ® in Prostate Cancer and Solid Tumors Other Than Prostate Cancer and Breast Cancer: Placebo-Controlled Trials Matthew Smith, MD, PhD Massachusetts.
11 One vs Three Years of Adjuvant Imatinib for Operable Gastrointestinal Stromal Tumor A Randomized Trial Joensuu H, Eriksson M, Sundby Hall K, et al.
CC10-1 ZOMETA ® in Breast Cancer and Multiple Myeloma: Pamidronate-Controlled Trial (010) James Berenson, MD Cedars-Sinai Medical Center Los Angeles, California.
Bondronat achieves better outcomes in metastatic bone disease Ingo Diel CGG-Klinik GmbH Mannheim, Germany.
Core Benefit/Risk (CR)
Final Analysis of Overall Survival for the Phase III CONFIRM Trial: Fulvestrant 500 mg versus 250 mg Di Leo A et al. Proc SABCS 2012;Abstract S1-4.
AVADO TRIAL David Miles Mount Vernon Cancer Centre, Middlesex, United Kingdom A randomized, double-blind study of bevacizumab in combination with docetaxel.
D-1 Bisphosphonate Bone Metastases Trials Proportion of Patients With Any SRE § (12, 010) Patients, % TreatmentN 3 mo6 mo9 mo12 mo Pamidronate Study 12.
A Phase 3 Prospective, Randomized, International Study (MMY-3021) Comparing Subcutaneous and Intravenous Administration of Bortezomib in Patients with.
GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma [HCC] and Of its treatment with sorafeNib) second interim analysis in.
SNDA Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.
A Phase 2 Study with a Daily Regimen of the Oral mTOR Inhibitor RAD001 (Everolimus) in Patients with Metastatic Clear Cell Renal Cell Cancer Amato RJ et.
Manufacturer: Amgen Inc FDA Approval Date: August 27, 2015
Cabozantinib (XL184) in metastatic castration- resistant prostate cancer (mCRPC): Results from a phase II randomized discontinuation.
Evaluating the Effects of Zoledronic Acid on Overall Survival in Newly Diagnosed Patients with Multiple Myeloma: Results of the Medical Research Council.
P.A. Tang 1, S. J. Cohen 1, G. Bjarnason 1, C. Kollmannsberger 1, K. Virik 1, M. J. MacKenzie 1, J. Brown 1, L. Wang 1, A. Chen 2, M. J. Moore 1 1 Princess.
REGULATORY HISTORY of ZOMETA and AREDIA JAW OSTEONECROSIS (ONJ) Oncologic Drug Advisory Committee March 4, 2005 Nancy S. Scher, M.D.
CON - 1 Conclusions C David R. Parkinson Vice President, Global Head, Clinical Research and Development Novartis Pharmaceuticals Corporation.
Long-Term Tolerability of Ticagrelor for Secondary Prevention: Insights from PEGASUS-TIMI 54 Trial Marc P. Bonaca, MD, MPH on behalf of the PEGASUS-TIMI.
C-1 Safety Results S. aureus Bacteremia and Endocarditis Study Gloria Vigliani, M.D. Vice President, Medical Strategy Cubist Pharmaceuticals.
Zometa for Prostate Cancer Bone Metastases Protocol 039 Amna Ibrahim, M.D. Oncology Drug Products FDA.
Slideset on: Terpos E, Morgan G, Dimopoulos MA, et al. International myeloma working group recommendations for the treatment of multiple myeloma-related.
Erlotinib plus Gemcitabine Compared with Gemcitabine Alone in Patients with Advanced Pancreatic Cancer: A Phase III Trial of the National Cancer Institute.
R2 민준기 / 정재헌 교수님. Introduction Patients with resected high-risk locally advanced head and neck cancer –Expect favorable outcomes after concomitant radiochemotherapy(CCRT)
CCO Independent Conference Coverage*: The 2015 Annual Meeting of the CTRC-AACR San Antonio Breast Cancer Symposium, December 8-12, 2015 San Antonio, Texas.
Julie R. Gralow, MD Professor, Medical Oncology University of Washington School of Medicine Director, Breast Medical Oncology Seattle Cancer Care Alliance.
Bone matters in lung cancer T. Brodowicz, K. O’Byrne & C. Manegold Annals of Oncology 23: 2215–2222, 2012 R3 김승민 /Prof 정재헌.
Bone Health Secondary Breast Cancer
MA.17R: Reduced Risk of Recurrence With Extending Adjuvant Letrozole Beyond 5 Yrs in Postmenopausal Women With Early-Stage Breast Cancer CCO Independent.
Everolimus for Advanced Pancreatic Neuroendocrine Tumors N Engl J Med 2011;364: R4. 박선희 / Prof. 동석호.
Matthew Raymond Smith, MD, PhD Professor of Medicine Harvard Medical School Program Director, Genitourinary Oncology Massachusetts General Hospital Cancer.
The role of bisphosphonates in the treatment of bone metastases of genitourinary tumors Nuno Gil WHAT YOU HAVE TO KNOW XIV WORKSHOP ON ONCOLOGICAL UROLOGY.
A cura di Filippo de Marinis
Alessandra Gennari, MD PhD
CCO Independent Conference Coverage
EVOLUZIONE DEL RAPPORTO COSTO/EFFICACIA DELLA
STAMPEDE: Docetaxel Significantly Improves Survival in Men With Hormone-Naive Prostate Cancer CCO Independent Conference Highlights of the 2015 ASCO Annual.
Randomized, Open-Label Phase 1/2 Study of Pomalidomide Alone or in Combination with Low-Dose Dexamethasone in Patients with Relapsed and Refractory Multiple.
Slide set on: McCarthy PL, Owzar K, Hofmeister CC, et al
Vahdat L et al. Proc SABCS 2012;Abstract P
Elotuzumab, Lenalidomide, and Low-Dose Dexamethasone in Relapsed/Refractory Myeloma Slideset on: Lonial S, Vij R, Harousseau JL, et al. Elotuzumab in combination.
Alena Kreychman Xofigo.
Final results of the phase III, randomised, double-blind AVOREN trial of first-line bevacizumab + interferon-a2a in metastatic renal cell carcinoma Escudier.
Fred Saad  European Urology Supplements 
Barrios C et al. SABCS 2009;Abstract 46.
Volume 68, Issue 1, Pages (July 2015)
Prostate-Specific Antigen Kinetics and Outcomes in Patients with Bone Metastases from Castration-Resistant Prostate Cancer Treated with or Without Zoledronic.
Bisphosphonates Can Prevent Skeletal Complications of Malignant Bone Disease from Prostate Cancer and Renal Cell Carcinoma  Fred Saad  European Urology.
1University Hospital Gasthuisberg, Leuven, Belgium;
New Research Findings on Clinical Benefits of Bisphosphonates in Patients With Advanced Prostate Cancer  Noel W. Clarke  European Urology Supplements 
Presentation transcript:

Denosumab Compared With Zoledronic Acid for the Treatment of Bone Metastases in Patients With Castration-Resistant Prostate Cancer Karim Fizazi,1 Michael Carducci,2 Matthew Smith,3 Ronaldo Damião,4 Janet Brown,5 Lawrence Karsh,6 Piotr Milecki,7 Michael Rader,8 Neal Shore,9 Sylvia Tadros,10 Huei Wang,10 Qi Jiang,10 Roger Dansey,10 Carsten Goessl10 1Institut Gustave Roussy, University of Paris, Villejuif, France 2Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA 3Massachusetts General Hospital Cancer Center, Boston, MA, USA 4Hospital Universitario Pedro Ernesto, Rio de Janeiro, Brazil 5Cancer Research UK Clinical Centre, Leeds, UK 6The Urology Center of Colorado, Denver, CO, USA 7Wielkopolskie Centrum Onkologii, Poznan, Poland 8Union State Bank Cancer Center, Nyack Hospital, Nyack, NY, USA 9Carolina Urological Research Center, Myrtle Beach, SC, USA 10Amgen Inc., Thousand Oaks, CA, USA

Disclosures This study was supported by Amgen Inc. K Fizazi has been a consultant for and received honoraria from Amgen and Novartis. M Carducci has been a consultant for and received research funding from Amgen. M Smith has been a consultant for Amgen and Novartis and received honoraria and research funding from Amgen. R Damião and Piotr Milecki have received research funding from Amgen. J Brown has been a consultant for Amgen and received honoraria from Amgen and Novartis. L Karsh has been a consultant for Amgen and received honoraria and received research funding from Amgen. M Rader has been a consultant for and received honoraria and research funding from Amgen. N Shore has been a consultant for and received honoraria from Amgen. H Wang, S Tadros, R Dansey, Q Jiang, and C Goessl are employed by and have received stocks/stock options from Amgen.

Spinal Cord Compression Background Up to 75% of advanced prostate cancer patients develop bone metastasis1 Bone metastases lead to osteoclast-mediated bone destruction Clinical consequences include skeletal-related events (SREs)2 IV zoledronic acid (ZA) is the only bisphosphonate approved to delay or prevent SREs in castration-resistant prostate cancer3 Radiation to Bone Pathologic Fracture Spinal Cord Compression Surgery to Bone 1Coleman R. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 2006; 12(20 Suppl):6243s-6249s. 2Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev. 2001;27:165-76. 3Saad F, Gleason DM, Murray R. J Natl Cancer Inst. 2002;94:1458-1468.

PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT RANKL Is a Central Mediator of the “Vicious Cycle” of Bone Destruction in Metastatic Cancer RANKL RANK Tumor Cell PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT PDGF, BMPs TGF-β, IGFs FGFs Activated Osteoclast Osteoblasts Adapted from Roodman D. N Engl J Med. 2004;350:1655.

PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT Denosumab May Interrupt the “Vicious Cycle” of Cancer-Induced Bone Destruction RANKL RANK Denosumab Tumor Cell Formation Inhibited PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT PDGF, BMPs TGF-β, IGFs FGFs Apoptotic Osteoclast Osteoblasts Adapted from Roodman D. N Engl J Med. 2004;350:1655.

RANKL and OPG Expression in Osteoblasts When Co-cultured With Prostate Cancer Cells CTR OSB + 2b OSB + 2a OSB + LNCaP OSB + PC3 CTR OPG RANKL Fizazi et al. Clin Cancer Res 2003;9:2587–2597

Denosumab: Properties and Clinical Program Properties of Denosumab Fully human monoclonal antibody with high affinity and specificity for human RANKL Advanced cancer dose: subcutaneous 120 mg monthly In clinical trials No requirement for renal monitoring or dose adjustment1 No acute phase reactions attributed to denosumab1,2 Pivotal Studies in Patients With Bone Metastases Denosumab superior to ZA for preventing/delaying SREs in breast cancer (N=2046; HR=0.82; P<0.0001, non-inferiority endpoint; adjusted P=0.01, superiority endpoint)3 Denosumab non-inferior (trend to superior) to ZA for preventing/delaying SREs in solid tumors and multiple myeloma (N=1776; HR= 0.84; P=0.0007, non-inferiority endpoint; adjusted P=0.06, superiority endpoint)4 To date, approximately 11,000 patients have been exposed to denosumab in clinical trials of patients with cancer or bone loss 1Fizazi K et al. J Clin Oncol. 2009;27:1564-1571 2Ellis et al. J Clin Oncol. 2008;26:4875-4882 3Stopeck A et al. Eur J Cancer Suppl. 2009;7:2(Abs 2LBA) 4Henry D, et al. Eur J Cancer Suppl. 2009;7:11(Abs 20LBA)

Study Design: International, Randomized, Double-Blind, Active-Controlled Study Key Inclusion Hormone-refractory (castration resistant) prostate cancer and bone metastases Key Exclusion Current or prior IV bisphosphonate treatment Denosumab 120 mg SC and Placebo IV* every 4 weeks (N = 950) Zoledronic acid 4 mg IV* and Placebo SC every 4 weeks (N = 951) Calcium and Vitamin D supplemented in both treatment groups Accrual period from May 2006 to December 2008 Analysis cut-off date October 2009 *Per protocol and Zometa® label, IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine. No SC dose adjustments made due to increased serum creatinine. 8

Sequential Testing of Primary and Secondary Endpoints Primary Efficacy Endpoint (Non-inferiority) Time to first on-study SRE Only if P<0.05 Secondary Efficacy Endpoints (Superiority) Time to first on-study SRE Time to first-and-subsequent on-study SRE (multiple events) Hochberg adjustment for multiplicity between the two secondary endpoints Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 1998;75:800-802.

Baseline Characteristics Characteristic, n (%) or median Zoledronic Acid (N = 951) Denosumab (N = 950) Age (years) 71.0 ECOG performance status of 0 or 1 886 (93) 882 (93) Stratification factors: Proportion of subjects with PSA ≥ 10 ng/mL 806 (85) 805 (85) Chemotherapy (≤ 6 weeks before randomization) 132 (14) Previous SRE 231 (24) 232 (24) Time from first bone metastasis to randomization (months): median (Q1, Q3) 5.2 (1.3, 16.1) 3.9 (1.2, 15.7)

IV Zoledronic Acid (N = 946) Drug Exposure and Adjustments for Renal Function Overall Exposure IV Zoledronic Acid (N = 946) SC Denosumab (N = 942) Median number of doses (Q1, Q3) 10.5 (5.0, 17.0) 13.0 (6.0, 19.0) Cumulative exposure (patient-years) 913.6 991.3 Adjustments for Renal Function Subjects with dose adjustments for creatinine clearance at baseline, n (%) 213 (22.5) NA Subjects with doses withheld for serum creatinine increases on study, n (%) 143 (15.1) Total number of doses withheld due to serum creatinine increases on study 592 NA = Not applicable per protocol

Patient Disposition Randomized Subjects: 1901* Zoledronic Acid Subjects: 951 Denosumab Subjects: 950 Discontinued: 743 (78.1%) Discontinued: 722 (76.0%) Reasons for Discontinuation Death 269 (28.3%) Consent Withdrawn 164 (17.2%) Disease Progression 113 (11.9%) Adverse Event 43 (4.5%) Other 154 (16.2%) Reasons for Discontinuation Death 294 (30.9%) Consent Withdrawn 147 (15.5%) Disease Progression 117 (12.3%) Adverse Event 56 (5.9%) Other 108 (11.4%) *Does not include three subjects with insufficient IRB oversight

Time to First On-Study SRE HR 0.82 (95% CI: 0.71, 0.95) P = 0.0002 (Non-inferiority) P = 0.008 (Superiority) Risk Reduction 18% 1.00 0.75 Proportion of Subjects Without SRE 0.50 KM Estimate of Median Months 0.25 Denosumab 20.7 Zoledronic acid 17.1 3 6 9 12 15 18 21 24 27 Study Month Subjects at risk: Zoledronic Acid 951 733 544 407 299 207 140 93 64 47 Denosumab 950 758 582 472 361 259 168 115 70 39

Time to First and Subsequent On-Study SRE* (Multiple Event Analysis) 2.0 Rate Ratio = 0.82 (95% CI: 0.71, 0.94) Risk Reduction 18% 1.8 P = 0.008 1.6 1.4 1.2 Cumulative Mean Number of SREs per Patient 1.0 0.8 0.6 Events 0.4 Denosumab 494 0.2 Zoledronic acid 584 0.0 3 6 9 12 15 18 21 24 27 30 33 36 Study Month *Events occurring at least 21 days apart

Percent of Subjects With First SRE Spinal Cord Compression First On-study SRE by Type 30 All subjects 25 20.0 20 14.7 15 Percent of Subjects With First SRE 10 3.3 5 0.3 Radiation to Bone Spinal Cord Compression Surgery to Bone Fracture

Prostate-Specific Antigen (PSA) 600 Zoledronic acid (N = 951) Denosumab (N = 950) 500 400 Median (Q1, Q3) PSA (ng/mL) 300 200 100 3 6 9 12 15 18 21 24 27 30 33 Study Month

Without Disease Progression Proportion of Subjects Overall Disease Progression HR = 1.06 (95% CI: 0.95, 1.18) 1.00 P = 0.30 0.75 Without Disease Progression Proportion of Subjects 0.50 0.25 Denosumab Zoledronic acid 3 6 9 12 15 18 21 24 27 Study Month Subjects at risk: Zoledronic Acid 951 708 507 356 246 168 108 74 50 33 Denosumab 950 715 518 370 273 180 111 71 51 32

Proportion of Subjects Survived Overall Survival HR = 1.03 (95% CI: 0.91, 1.17) 1.00 P = 0.65 0.75 Proportion of Subjects Survived 0.50 0.25 Denosumab Zoledronic acid 3 6 9 12 15 18 21 24 27 30 Study Month Subjects at risk: Zoledronic Acid 951 864 745 635 519 401 297 207 143 98 55 Denosumab 950 872 746 645 552 427 310 233 156 99 54

Summary of Adverse Events Subject incidence, n (%) Zoledronic Acid (N = 945) n (%) Denosumab (N = 943) n (%) Adverse events (AEs) 918 (97) 916 (97) Most common AEs in either arm Anemia 341 (36) 337 (36) Back Pain 287 (30) 304 (32) Decreased appetite 274 (29) 267 (28) Nausea 245 (26) 272 (29) Fatigue 222 (24) 257 (27) CTC Grade 3, 4, or 5 AEs 672 (71) 718 (76) Serious AEs 568 (60) 594 (63) AEs leading to treatment discontinuation 138 (15) 164 (17)

Forest Plot of Adverse Events With Unadjusted P < 0.05 Zoledronic Acid Denosumab (N = 945) (N = 943) n (%) n (%) Pyrexia 133 (14.1) 100 (10.6) Influenza like illness 33 (3.5) 11 (1.2) Myalgia 57 (6.0) 37 (3.9) Chills 28 (3.0) 11 (1.2) Cholelithiasis 10 (1.1) (0.0) Cognitive disorder 11 (1.2) 1 (0.1) Blood glucose increased 15 (1.6) 5 (0.5) Drug hypersensitivity 1 (0.1) 7 (0.7) Ilium fracture 1 (0.1) 7 (0.7) Hypercalcemia 2 (0.2) 9 (1.0) Blood alkaline phosphatase 1 (0.1) 9 (1.0) Oral herpes 1 (0.1) 10 (1.1) Tooth abscess 2 (0.2) 11 (1.2) Cerebrovascular accident 5 (0.5) 15 (1.6) Sinusitis 5 (0.5) 16 (1.7) Osteonecrosis 10 (1.1) 21 (2.2) Toothache 12 (1.3) 26 (2.8) Hypophosphatemia 13 (1.4) 28 (3.0) Influenza 24 (2.5) 40 (4.2) Prostatic specific antigen increased 19 (2.0) 36 (3.8) Thoracic vertebral fracture 30 (3.2) 47 (5.0) Hyperhidrosis 11 (1.2) 31 (3.3) Muscle spasms 27 (2.9) 51 (5.4) Hypocalcemia 51 (5.4) 116 (12.3) -15 -10 -5 5 10 15 Risk Difference (% in Denosumab - % in Zoledronic Acid) Risk greater with Zoledronic Acid Risk greater with Denosumab

Adverse Events of Interest Subject incidence, n (%) Zoledronic Acid (N = 945) Denosumab (N = 943) Infectious AEs 375 (39.7) 402 (42.6) Infectious serious AEs 108 (11.4) 130 (13.8) Acute phase reactions (first 3 days) 168 (17.8) 79 (8.4) Renal AEs* 153 (16.2) 139 (14.7) Cumulative rate of osteonecrosis of the jaw (ONJ)† 12 (1.3) 22 (2.3) Year 1 5 (0.5) 10 (1.1) Year 2 8 (0.8) Hypocalcemia 55 (5.8) 121 (12.8) New primary malignancy 18 (1.9) *Includes renal failure, increased blood creatinine, acute renal failure, renal impairment, increased blood urea, chronic renal failure, oliguria, hypercreatininemia, anuria, azotemia, decreased creatinine renal clearance, decreased urine output, abnormal blood creatinine, proteinuria, decreased glomerular filtration rate, and nephritis. †P = 0.09

ONJ Subjects with positively adjudicated ONJ, n (%) Zoledronic Acid N = 12 (1.3%) Denosumab N = 22 (2.3%) Risk factors Tooth extraction, dental appliance, or poor oral hygiene 10 (83) 17 (77) Chemotherapy 9 (75) 14 (64) Treatment* Limited surgery (eg, debridement) 3 (25) 10 (45) Bone resection 1 (8) 2 (9) Outcome* Resolution (mucosal coverage) 4 (18) *As of April 2010

Summary Denosumab was superior to zoledronic acid in preventing/delaying: First SREs Multiple SREs Notable adverse events occurring in both treatment groups included hypocalcemia and ONJ Denosumab continues to be studied as a potential treatment option for bone metastases Administered as a monthly SC injection No need for renal monitoring or dose adjustment No need to manage acute phase reactions

Acknowledgements We thank all patients, their families, investigators, and study site staff who participated in the 20050103 study for their contributions.