Nab Formulation Technology Platform for Small Molecule Drugs

Transcription

1 Nab Formulation Technology Platform for Small Molecule Drugs Willard Foss, PhD Director Biologics Development and Nanotechnology Celgene Corp Drug Delivery & Formulation Summit San Diego June 13, 2016

2 Outline Description of the nab technology Mechanism of action of nab-paclitaxel nanoparticles Clinical trial results, approved indications and future directions 2

3 O History and Challenges of Delivering Paclitaxel (Taxol ) NH HO O O O HO O O Paclitaxel M.W History of Paclitaxel Discovered in 1962 by NCI O OH Isolated from bark of the Pacific Yew Disrupts microtubule breakdown during mitosis O O O O Best new anticancer agent in 30 yrs Licensed to Bristol-Myers Squibb Taxol approved by FDA in Dec 1992 Delivery Challenges Low solubility and poor bioavailability Dissolved in cremophor EL (polyethoxylated castor oil) and ethanol Forms paclitaxel-containing micelles in saline Life threatening anaphylaxis and hypersensitivity reactions Patients require pre-medication Dose limited to 175 mg/m 2 Administered i.v. over 3 hours Property Mol. Wt. Crystalline solubility in water Value g/mol 0.4 µg/ml T melt 216 C LogP (Expt l) 3.4 Hydrogen acceptors 10 Hydrogen donors 4 Cremophor Pcalitaxel 3

4 Abraxane Utilizes the Nab Technology to Deliver Paclitaxel Summary of Abraxane (nab-paclitaxel) A solvent-free formulation of paclitaxel More efficacious and less toxic than Taxol Formulated only with human albumin Lyophilized drug product Room temperature stable Reconstituted to 5 mg/ml Intravenous delivery 30 minute infusion time Dosed to 260 mg/m 2 No pre-medication required 4

5 A Brief History of Abraxane 1990 s 2000 s 2010 s Early Concepts First in vivo data First FDA Meeting Phase I Initiated Phase II Initiated Phase III Initiated NDA Submission FDA Approval Breast Cancer 3 New Phase III Studies Initiated Acquisition by Celgene NSCLC study positive FDA Approval NSCLC; Melanoma, Pancreas positive phase III FDA Approval Pancreas EU Approval Pancreas EU Approval NSCLC 5

6 Structure of Nab Nanoparticles Revealed by Cryo-TEM Cross-linked albumin coating Amorphous paclitaxel core 6

7 Nab Nanoparticles in the Abraxane Drug Product Sterile suspension 20 ml Saline 7

8 Volume Distribution, % Particle Size of Abraxane Reconstituted Suspensions Allow for Sterile Filtration 15 Particle Size Distribution by Dynamic Light Scattering Abraxane Diameter, nm Sample Lots Mean ± 95% Confidence Interval Volume-weighted Particle Diameter D V50, nm Volume-weighted Span (D V90 - D V10 )/D V50 ABRAXANE ± ±

9 Isolated Nab-Paclitaxel Nanoparticles are Amorphous by X-Ray Powder Diffraction Controls: Crystalline paclitaxel hydrate Lyophilized human albumin Physical mixtures of paclitaxel and albumin Samples: Isolated nab-paclitaxel nanoparticles 9

10 Plasma PK of nab-paclitaxel and cremophor-paclitaxel Plasma bound Paclitaxel (ng/ml) Plasma free paclitaxel (ng/ml) Paclitaxel CL (L/h/m 2 ) Abraxane: 260 mg/m 2 Abraxane Taxol: 175 mg/m 2 Taxol Total Time from start of infusion (hour) Abraxane: 260 mg/m 2 Abraxane Taxol: 175 mg/m 2 Taxol Unbound Time from start of infusion (hour) mg/m 2, IV 3 hrs Abraxane 27.2 Taxol Dose (mg/m 2 ) PK Parameter Abraxane (260 mg/m 2 ), 0.5 h IV Taxol (175 mg/m 2 ), 3 h IV N Mean (CV%) N Mean (CV%) CL (L/h/m 2 ) (26.0) (37.8) Fu (%) (33.3) (37.5) Total AUC (h*ng/ml) Total C max (ng/ml)

11 Increased Tumor Accumulation with nabpaclitaxel Concentration (ug paclitaxel/g) Tumor ABI-007 nab-paclitaxel Taxol (cremophor-paclitaxel) p< Time (hr) 33-50% higher tumor accumulation of paclitaxel over 24 hr confirmed with radiolabelled nab-paclitaxel as compared to Taxol (p<0.0001) Desai N, et al. Clin Cancer Res 2006;12(4),

12 Concentration ratio: nab-paclitaxel to CrEL paclitaxel Greater Selectivity to Tumor vs Other Tissue nab-paclitaxel vs cremophor-paclitaxel Greater selectivity to tumor vs normal tissues at equal paclitaxel dose 26% Higher tumor uptake at 1 hour after administration 33% Higher tumor accumulation over 24 hours (p<0.0001) Equal concentrations Comparative tissue distribution (ratio) of radiolabeled drug in mice bearing human breast tumor xenografts 1 hour after dose 1,2,3. 1. Hawkins et al. AACR Poster 1189; 2. Celgene Corporation. Data on file; 3. Desai et al. Clin Cancer Res. 2006; 12:

13 Dissolution and Receptor-Mediated Transport of Nab Nanoparticles 13

14 Large Differences in Tumor Tissue Distribution Due to Nanoparticle Delivery IV Dose 3 Drug with vehicle Q1 1 Drug with vehicle Q3 Q3 4 Drug Q2 2 Drug Clearance Chen N, et al. J Clin. Pharmacol. (2014) Li Y, et al. Molecular Pharmaceutics (2015)

15 nab-paclitaxel Shows Enhanced Tissue Penetration and Causes More Extensive Mitotic Arrest in Tumors Identical amounts of paclitaxel micro-injected into tumors (validated by mass spec) Near-infrared dye delineates injection site (green) Nuclei stained with DAPI (blue) Mitotically arrested cells stained with phh3 antibody (white) Chen N. et al. Cancer Chemother Pharmacol

16 Tumor volume (mm 3 ) Greater antitumour activity of ABRAXANE vs paclitaxel (Taxol) Tumor volume (mm 3 ) Tumor volume (mm 3 ) Athymic Mice With Human Xenografts (n=10 per group; daily administration for 5 days) Breast MX-1 (equidose comparison) Lung H522 (equitoxic dose comparison) Tumor volume (mm 3 ) 2000 Control ABI-007 Abraxane mg/kg/dose Taxol 30 mg/kg/dose Days postimplant Ovarian SKOV3 (equitoxic dose comparison) 1200 Control 1000 Abraxane 30 mg/kg/dose Taxol 13.4 mg/kg/dose Days postimplant Prostate PC3 (equitoxic dose comparison) Control Abraxane 30 mg/kg/dose Taxol 13.4 mg/kg/dose Control Abraxane 30 mg/kg Taxol 20 mg/kg Days postimplant Days postimplant Desai et al. Clin Cancer Res 2006;12(4),

17 ORR (± 95% CI) ORR (± 95% CI) Breast Cancer Phase III Trial 60 P = P = P = P = P = nab-paclitaxel vs cremophor-paclitaxel (N=454) % Efficacy: Improved 33.2% 34.1% overall response rate (33% vs. 19%, p=0.001) 33.5% and time to % 26.5% progression (23.0 vs weeks, p=0.006) 18.7% Improved 20overall survival in patients treated for 2 nd 18.3% 18.7% 13.2% line therapy (56.4 vs weeks, p=0.024) 10 Safety: significantly 0 lower rate of neutropenia; faster resolving neuropathy, All First-line Second-line Anthracycline Visceral requires no pre-medication for hypersensitivity patients therapy therapy exposed disease ABRAXANE : Solvent-based paclitaxel: P = % P = % 27.0% P = % Increased OS in 2 nd -line patients P = P = Doubling of ORR was confirmed by an independent review committee 34.1% 33.5% % 13.2% 18.3% 18.7% 0 All First-line Second-line Anthracycline Visceral patients therapy therapy exposed disease Gradishar WJ, et al. J Clin Oncol. 2005;23 (31):

18 Non-Small Cell Lung Cancer Phase III trial: nab-paclitaxel/carboplatin vs paclitaxel/carboplatin (N=1050) Subset patients 70 years Overall response rate (ORR) was significantly improved Patients with squamous histology showed marked improvement in ORR Overall survival was significantly improved in patients 70 years (subset analysis) Socinski MA, (2012), J Clin Oncol; Socinski MA, (2011), J Clin Oncol 29 (15), abstr 7551; Socinski MA (2011), J Thorac Oncol 6 (6), abst#o

19 Pancreatic Cancer - A Desperate Need for Novel Strategies Five year survival rate is <5%. 4 th leading cause of cancer mortality worldwide 217,000 new cases and 213,000 deaths in % patients unresectable at diagnosis Overall survival ~ 5-6 months with Gemcitabine (standard of care) HPB 2008; 10: 58-62; 19

20 Proportion of Survival Metastatic Pancreatic Cancer Phase III trial: nab-paclitaxel/gemcitabine vs gemcitabine (N=861) nab-p + Gem Gem OS, months Events/n (%) Median (95% CI) 75th Percentile /431 (88) 8.7 ( ) /430 (92) 6.6 ( ) Time (months) Patients at Risk nab-p + Gem: Gem: Von Hoff DD, et al. N Engl J Med. 2013;369: Hidalgo M, Plaza C, Illei PB, et al. SPARC analysis in the phase III MPACT trial of nab-paclitaxel plus gemcitabine vs Gem alone for patients with metastatic pancreatic cancer. Oral presentation at: 16th World Congress on Gastrointestinal Cancer; June 25-28, 2014; Barcelona, Spain [abstract O-0004]. 20

21 Combinations with Immune Checkpoint Inhibitors: Pre-clinical and Early Clinical Results Pre-clinical study showing synergism of nabpaclitaxel plus atezolizumab (anti-pd-l1) in MC38 mouse tumor model Phase 1 study of nivolumab (anti-pd1) + nab-paclitaxel + carboplatin in advanced nonsmall cell lung cancer Nab-paclitaxel was used as can be administered without steroids The ability to avoid any potential immunosuppressive effects from steroids may make nab-paclitaxel a preferred chemotherapy partner for atezolizumab No added toxicity or new safety/tolerability concerns Preliminary assessments of antitumor activity were encouraging Adams S, et al., San Antonio Breast Cancer Symposium, Dec 8-12, 2015, San Antonio, TX Waterhouse D, et al., AACR Annual Meeting; April 16-20, 2016; New Orleans, LA 21

22 Highlights of the Nab Technology A unique nanoparticle-based platform for the intravenous delivery of poorly soluble small molecule drugs Nab-paclitaxel shows superior efficacy over alternate formulations Improved safety profile by use of albumin rather than solvents and surfactants Distinct mechanisms of transport and distribution of drug Now a blockbuster product approved in three indications Promising as a preferred chemotherapy in combination with immune checkpoint inhibitors 22

23 Acknowledgements Clinical Collaborations Daniel D. Von Hoff, Ramesh K. Ramanathan, Mitesh Borad (TGen/Virginia G. Piper Cancer Ctr, Scottsdale, AZ) Daniel Laheru (The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD) Lon S. Smith (South Texas Oncology/Hematology, San Antonio, TX) Tina E. Wood (University of Alabama at Birmingham, Birmingham, AL) Ronald L. Korn (Scottsdale Medical Imaging, Ltd., Scottsdale, AZ) Manuel Hidalgo (CNIO, Madrid, Spain) Celgene Neil Desai, Viktor Peykov, Tapas De, Abhijit Bhatia, Jon Cordia, Simon Zhou, Daniel Pierce, Carla Kuhner 23