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Doxil” and Beyond

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Doxil” and Beyond The expanding role of liposome- based cancer nanomedicine : “Doxil” and beyond Alberto A. Gabizon, M.D., Ph.D. Center of Nano-oncology / Shaare Zedek MC. Hebrew University-Faculty of Medicine, Jerusalem, ISRAEL Séance: Les Nanomédicaments: d’où vient-on et où allons nous? Paris, 2019 PARIS 2010 Disclosures: - Founder & Director of Lipomedix Pharm. - Grant support form MERCK Co. - Sci.Adv.Board member of Cristal Therap. - 1964: Discovery of liposomes – Alec Bangham (Cambridge, UK) - 1971: First in vivo applications of liposomes for drug delivery - 1995: US-FDA approval of liposomal doxorubicin for cancer therapy G. Gregoriadis, D. Papahadjopoulos, A. Bangham (2001) Liposomal Anti-Cancer Agents Clinically Tested Pegylated Non-Pegylated Regional therapy Non-cytotoxic DOXIL/Caelyx, Myocet (NPLD) DepoCyt Lip. MTP-PE Lipodox (PLD) (intrathecal) (Mepact) Nano- Irinotecan DaunoXome Lip. NDDP Lip. ATRA (Onivyde) (intrapleural) PROMITIL Lip. Annamycin Lip.Camptothecin BLP25 Lip. (MMC Prodrug) (aerosol) Vaccine Lip. Eribulin Marqibo (Lip. Lip. IL2 (aerosol) Lip.Nucleotides Vincristine) Lipoplatin Lurtotecan (OSI-211) Lip. E1A SPI-077 TS inhib. (OSI-7904L) (intra-tumoral) S-CKD602 Lip. Paclitaxel FF- 10832 Dual Drug: Lip.AraC- (Gemcitabine) Dauno (Vyxeos) Targeted: αHer2-Doxil MCC-465 Consolidating Nanomedicine Challenges and Key Considerations of the EPR Effect for Nanomedicine in Oncology Prabhakar U, et al., Cancer Research, 2013 Alliance for Nanotechnology Cancer nanomedicines - crossing the in Cancer / National Cancer translational gap Institute, USA Gabizon A, et al., Lancet, 2014 Integrating Nanotechnology into Cancer NCL: Nanotech Character. Lab Care Grodzinski P, et al., ACS Nano, 2019 “Conventional” “Leaky” “Stealth” Liposomes Liposomes Liposomes -TUMORS- There is a direct correlation between liposome circulation time and tumor uptake (Gabizon & Papahadjopoulos, PNAS 1988) Nanoparticle/Liposome classification system for characterization of liposome drug products DOXIL-like liposomes From: Hsu L and Huang J, Int J Clin Pharm Therap, 2014 Pegylated Liposomal Doxorubicin (DOXIL, Caelyx) 1. PEG Coating (Stealth Effect): long circulation time 2. Ammonium sulfate drug loading gradient: stability in circulation PEG Doxorubicin Plasma Levels in Humans: DOXIL vs. doxorubicin 90 nm 90 - 80 Hours After Infusion Lipid Bilayer Phospholipid+Cholesterol DOXIL: doxorubicin remains in liposome- encapsulated form in circulation 25.0 10.0 Total Doxorubicin Total Doxorubicin 2.5 1.0 Encapsulated Doxorubicin Doxorubicin (µg/mL) Doxorubicin 0.2 0.1 0 1 2 3 4 5 6 7 Days After Infusion Gabizon et al., Cancer Res. 1994 External medium 2x DOX-NH +Cl- Liposome 3 aqueous phase 2x NH + 3 2x DOX-NH2 2x DOX-NH2 + 2x H 2x NH Ammonia + - 3 + 2x H Cl escapes Neutral form of DOX + 2 -2 2x DOX-NH3 + (NH4) SO4 crosses bilayer + -2 2 (DOX–NH3 )2SO4 + (NH4) Cryo-TEM Rod-like precipitate (reversible) “coffee bean” Remote Loading of Doxorubicin to form DOXIL Liposomes Cardiac Toxicity of Doxorubicin (Adriamycin) • Limits the cumulative dose leading to early treatment discontinuation • Irreversible, crippling and life-threatening 10/17/2019 Rationale for DOXIL: Heart vs Tumor: Liposome Tissue Access is the Key! Tumor Heart Muscle Extracellular space Cardiomyocytes and intercalated disks Enhanced Permeability and Retention (EPR) Extravasation and Release of Liposomal Drug in Tumor Interstitial Fluid Tumor compartment: Interstitial fluid Tumor Cells 5 Vascular space No Functional Lymphatics Blood Vessels: The Achyless Heel of Cancer Extravasation of liposomes across tumor vessel: Skin-fold window in vivo model (R. Jain et al.) 111In-PLA Mice bearing MDA-MB- 231 triple-negative Liposomes can be breast cancer tumors (10-90 mg) imaged with PET-imaged to select In111–labeled Doxil-like patients for therapy Liposomes with good targeting to in tumors. Median tumor uptake: F. Man, A. Gabizon, ~25% ID/gram R.TM de Rosales et al. Marked Drug Deposition in Subcutaneous Tumor Implants After i.v. DOXIL Dox concentration: ~22% ID/gram tumor 30- fold increase in AUC M109 8 Human Tumor Model Skin = 0.5 µg/g 6 Tumor Halo 40 µg/g 4 86 µg/g DOXIL 2 µg Drug/gm Tumor Drug/gm µg Doxorubicin 0 50 100 150 200 Hours Dose=20 mg/kg, i.v., 48h Gabizon et al., Vaage et al. Anti-Tumor Effect of DOXIL is >4-fold than doxorubicin (DXR)* Values inside bars: • M109 mouse tumor % Tumor-Free Mice 800 (also observed in mouse 3LL and human N87 models) 700 600 P<0.05 Treatment given i.v. on 500 day 15 as indicated doses (mg/kg). 400 On day 36, mice 0% 17% sacrificed, tumors 300 11% dissected and weighed. 29% 200 100 Median Tumor Weight (% (% Weight Cures) Median Tumor 27% 0 Control DXR DXR DOXIL DOXIL 2.5 10 2.5 10 Gabizon et al, 2002 DOXIL Clinical Proofs of Added Value • Cardiac function: Major reduction of cardiotoxicity as compared to free doxorubicin in all settings. (2000) • AIDS-related Kaposi’s Sarcoma: Superior efficacy over former conventional therapy (1995) • Recurrent Ovarian Cancer: Superior efficacy and improved safety profile over comparator drug (topotecan) (1998) • Metastatic Breast Cancer: Equivalent efficacy and reduced cardiotoxicity compared to free doxorubicin (2003) • Multiple Myeloma: Equivalent efficacy and improved safety profile compared to free doxorubicin combo. Superior efficacy in combination with bortezomib over single agent bortezomib. (2007) Reduced rate of cardiac events with DOXIL (vs doxorubicin) PLD Doxorubicin, Hazard Ratio 50 mg/m2 q4w 60 mg/m2 q3w (95% CI) Cardiac 6.6% 25.7% 3.16 Events (1.58-6.31) CHF 0 5.3% O’Brien M E R et al. Ann Oncol 2004;15:440-449 DOXIL (PLD) vs Doxorubicin: Change of toxicity profile Side Effect Effect of liposome delivery Vesicant effect Absent (irritation only) Nausea/Vomiting Reduced Myelosuppression Reduced (no neutropenic fever) Stomatitis/Mucositis Increased Hand-Foot (PPE) Increased Cardiotoxicity Reduced or Absent Alopecia Reduced or Absent Slightly decreased Maximal Single Dose (50mg/m2 q4w) Maximal Cumulative Greatly increased Dose (>900mg/m2) Doxil in Ovarian Ca: Major Improvement in Survival in “Pt-Sensitive” Patients* 100 DOXIL (n=109) 90 Topotecan (n=111) 80 P=.008 DOXIL 70 25.2 mths 60 50 40 30 20 Topotecan 10 15.6 mths 0 0 20 40 60 80 100 120 140 * Median survival for all patients: Weeks Since First Dose DOXIL=15mth; Topotecan=13mth (p=0.025) Gordon AN, et al. J Clin Oncol. 2001;19:3312-3322. 10/17/2019 3SP2# nozibaG tpp.37 23 Example of Response and Prolonged Remission on CAELYX™ Maintenance 1000 Relapse 6 months from ABMT 800 E.Q. 45 y.o. papillary serous Diagnosis 2/1/94 Cumulative dose=880 mg/m2 600 (U/mL) 125 400 CA CA New LLQ mass & liver mets 200 CAELYX™ 0 Oct Dec Jun Dec Jun Dec Jun Oct 96 96 97 97 98 98 99 99 115 cycles of PLD (40mg/m2) during 9 years with stable disease: No Cardiac Toxicity! This is >10 times more than the maximal recommended dose of free Doxorubicin Caelyx in 1st Line Ovarian Cancer No significant advantage of Doxil-based combo over Paclitaxel based combo! Doxil® (PLD) vs free doxorubicin (1st line) in Metastatic Breast Cancer No sig efficacy advantage of Doxil over free doxorubicin! Progression-free Survival Overall Survival O’Brien et al., Ann Oncol 2004 The DOXIL-Nanomedicine Efficacy Gap: Preclinical Results Clinical results • EPR in human cancer limited or even insignificant. • Dose translation from animals to humans may differ for nanomeds. • Liposomes activate macrophages to enhance tumor growth and blunting the therapeutic advantage in humans. • Drug release rate from liposomes in the tumor bed is suboptimal in humans. • Poor clinical study design. Despite its great safety, DOXIL has not been approved for 1st Line or Adjuvant/Curative Settings EPR in human cancer: present but variable iGamma Scintigraphy after Injection of [DTPA-In111] Stealth Liposomes Kaposi Sarcoma Lung Tumor Liver, Spleen Spleen Bone Marrow Harrington et al., Clin. Cancer Res. 2001 Posterior view 48h Controlling for the variability of EPR effect in Human Cancer: Real time imaging for Patient Selection Grozinski et al., ACS Nano 2019 Imaging of EPR to predict Efficacy (X-ray enhancement = measure of EPR) Control Low tumor Treatment enhancement with DOXIL High tumor enhancement Karathanasis et al., Radiology 2009 EPR imaging in pancreas tumor patients Tumor MRI signal and liposomal drug activity correlate! Patient EPR effect stratification possible: Higher PET/CT signal corresponds with more favorable treatment outcome. Muco-cutaneous toxicity of DOXIL is the result of slower clearance upon retreatment with DOXIL Clearance (Dose/AUC) 27.5 n.s. (p=0.56) p=0.0003 25.0 AUC Increase of 40% from 1st SEM) 22.5 rd to 3 cycle 20.0 17.5 15.0 12.5 10.0 7.5 5.0 Clearance, mL/hourClearance, (Mean 2.5 0.0 30 mg/m2 60 mg/m2 1st Cycle 2nd Cycle 3rd Cycle Gabizon et al., CCP 2007 Grenader and Gabizon, J Clin Oncol 2010 Effect of Dose: Increase in tumor accumulation of Doxil and saturation of liver uptake Liver M109 Tumor 20 160 140 15 120 Free DXR 100 DOXIL 10 80 60 5 DOXIL 40 g doxorubicin-equiv. / g doxorubicin-equiv. g g doxorubicin-equiv. / g doxorubicin-equiv. g 20 Free DXR 0 0 0 5 10 15 20 0 5 10 15 20 Dose mg/kg Dose mg/kg Hypothesis: Giving a high initial loading dose followed by a lower maintenance dose will increase efficacy without increase of toxicity Liposome-induced tumor growth enhancement is macrophage-dependent and can be abrogated by liposomal Alendronate (PLA) but not by free Alen. 1 2 0 0 L IP O ) 3 1 0 0 0 L IP O + A le n m m V e h ic le ( 8 0 0 e P L A m u l 6 0 0 * ** o V r 4 0 0 o m u 2 0 0 T 0 3 6 9 2 5 7 9 3 6 8 1 1 1 1 2 2 2 T im e P o s t T u m o r Im p la n t (d a y s ) La-Beck NM, Rajan R, Wood LM, Gabizon AA, et al.
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