Nanotechnology in clinical trials final
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Nanotechnology in clinical trials final

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Nanotechnology essentially restructures molecules to make materials lighter, stronger, more penetrating or absorbant, among many innovative qualities. In cancer research, it offers a unique ...

Nanotechnology essentially restructures molecules to make materials lighter, stronger, more penetrating or absorbant, among many innovative qualities. In cancer research, it offers a unique opportunity to study and interact with normal and cancer cells in real time, at the molecular and cellular scales, and during the various stages of the cancer process. For cancer researchers, a special interest lies in ligand-targeted therapeutic nanoparticles (TNP), which are expected to selectively deliver drugs and especially cytotoxic agents specifically to tumor cells and enhance intracellular drug accumulation. Targeting can be achieved by various mechanisms. For example, nanoparticles with numerous targeting ligands can provide multi-valent binding to the surface of tumor cells with high receptor density (as opposed to low receptor density on normal cells) or nanoparticle agents can enhance permeability and retention (EPR) effect to exit blood vessels in the tumor, to target surface receptors on tumor cells, and to enter tumor cells by endocytosis before releasing their drug payloads.

In this presentation we shall look at nanotechnology in drug development with a focus on anticancers and the advantages of nanoparticles as therapeutic platform technology. Approved nanotech based drugs and their clinical trials will be discussed. Two specific clinical trial case studies will be focused on along at some length with a mention of some ongoing clinical trials of nanotherapeutics. We shall also take a look at the future direction of nanotechnology based therapeutics.

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  • The use of materials in nanoscale provides unparallel freedom to modify fundamental properties such as solubility, diffusivity, blood circulation half-life, drug release characteristics, and immunogenicity. In the last two decades, a number of nanoparticle-based therapeutic and diagnostic agents have been developed for the treatment of cancer, diabetes, pain, asthma, allergy, infections, and so on.3,4 These nanoscale agents may provide more effective and/or more convenient routes of administration, lower therapeutic toxicity, extend the product life cycle, and ultimately reduce health-care costs. As therapeutic delivery systems, nanoparticles allow targeted delivery and controlled release. For diagnostic applications, nanoparticles allow detection on the molecular scale: they help identify abnormalities such as fragments of viruses, precancerous cells, and disease markers that cannot be detected with traditional diagnostics. Nanoparticle-based imaging contrast agents have also been shown to improve the sensitivity and specificity of magnetic resonance imaging. Given the vast scope of nanomedicine, we will focus on the therapeutic applications, in particular, drug delivery applications, of nanoparticles. Many advantages of nanoparticle-based drug delivery have been recognized.5,6 It improves the solubility of poorlywater-soluble drugs, prolongs the half-life of drug systemic circulation by reducing immunogenicity, releases drugs at a sustained rate or in an environmentally responsive manner and thus lowers the frequency of administration, delivers drugs in a target manner to minimize systemic side effects, and delivers two or more drugs simultaneously for combination therapy to generate a synergistic effect and suppress drug resistance. As a result, a few pioneering nanoparticle-based therapeutic products have been introduced into the pharmaceutical market, and numerous ensuing products are currently under clinical testing or are entering the pipeline.
  • A global survey conducted by the European Science and Technology Observatory in 2006 showed that more than 150 companies are developing nanoscale ther apeutics. 7 So far, 24 nanotechn ology-ba sed therapeutic products have been approved for clinical use, with total sales exceeding $5.4 billion.7 Among these products, liposomal drugs and polymer–drug conjugates are two dominant classes, accounting for more than 80% of the total amount.
  • A global survey conducted by the European Science and Technology Observatory in 2006 showed that more than 150 companies are developing nanoscale ther apeutics. 7 So far, 24 nanotechn ology-ba sed therapeutic products have been approved for clinical use, with total sales exceeding $5.4 billion.7 Among these products, liposomal drugs and polymer–drug conjugates are two dominant classes, accounting for more than 80% of the total amount.
  • A global survey conducted by the European Science and Technology Observatory in 2006 showed that more than 150 companies are developing nanoscale ther apeutics. 7 So far, 24 nanotechn ology-ba sed therapeutic products have been approved for clinical use, with total sales exceeding $5.4 billion.7 Among these products, liposomal drugs and polymer–drug conjugates are two dominant classes, accounting for more than 80% of the total amount.
  • A global survey conducted by the European Science and Technology Observatory in 2006 showed that more than 150 companies are developing nanoscale ther apeutics. 7 So far, 24 nanotechn ology-ba sed therapeutic products have been approved for clinical use, with total sales exceeding $5.4 billion.7 Among these products, liposomal drugs and polymer–drug conjugates are two dominant classes, accounting for more than 80% of the total amount.
  • Fig 1. Lifetime dose of doxorubicin to a cardiac event.
  • Fig 3. Time to treatment failure.
  • Fig 4. Time to progression.
  • Fig 5. Overall survival.
  • Abraxane is a novel formulation of paclitaxel in which paclitaxel is complexed only with albumin to form stable, 130 nm particles. Each 50 mL vial of Abraxane contains 100 mg of paclitaxel and approximately 900 mg of human albumin as a sterile, lyophilized cake. Each vial is reconstituted with 20 mL of 0.9% Sodium Chloride Injection, USP to produce a suspension containing 5 mg/mL of albumin-bound particles. Reconstituted Abraxane suspension is infused at a recommended dose of 260 mg/m2 intravenously over 30 minutes. Cremophore ADRs: Its use has been associated with severe anaphylactoid hypersensitivity reactions, hyperlipidaemia, abnormal lipoprotein patterns, aggregation of erythrocytes and peripheral neuropathy.
  • In other words, zeta potential is the potential difference between the dispersion medium and the stationary layer of fluid attached to the dispersed particle . A value of 25 mV (positive or negative) can be taken as the arbitrary value that separates low-charged surfaces from highly-charged surfaces.

Nanotechnology in clinical trials final Nanotechnology in clinical trials final Presentation Transcript

  • NANOTECHNOLOGYIN CLINICALTRIALS Dr. Bhaswat S. Chakraborty Sr. VP & Chair, R&D Core Committee Cadila Pharmaceuticals Ltd., Ahmedabad
  • CONTENTS Nanotechnology in drug development Advantage of nanoparticles as therapeutic platform technology Approved nanotech based drugs Clinical trials of nanotech based drugs Case Study 1: Myocet (liposome-encapsulated doxorubicin) Case Study 2: Abraxane (Albumin bound Paclitaxel) Some ongoing CTs of nanotherapeutics Future directions Concluding remarks
  • Comparing a nanoparticle to anant is like comparing that ant toa four-kilometer strip of a 12-lane highway!
  • SO SMALL!! ANY RISKS?WHAT BENEFITS? Essentially, nanotechnology restructures molecules make materials lighter, stronger or more penetrating or absorbant, among many innovative qualities; thus:  Are they toxic? Are we poisoning ourselves (since they are foreign to the body)?  Have there been extensive basic research of “nano- toxicity”?  True estimation of benefits  Do the benefits outweigh the risks?  How would one regulate the nanotherapeutics?  Etc.
  • NANOTHERAPEUTICS Nanotechnology is knowledge and control of material particles in ~1–100 nm range Nanotherapeutics (applied nanotechnology to therapeutics) is the use of precisely engineered materials at nanoscale to develop novel therapeutics and diagnostics Nanomaterials have unique physicochemical properties  e.g.,ultra small size, large surface area / mass ratio, and high reactivity  different from bulk materials of the same composition  can be used to overcome limitations found in traditional therapeutic and diagnostic agents
  • MANY ADVANTAGES &APPLICATIONS Nanotechnology allows improvement in basic properties  e.g solubility, diffusivity, t1/2, drug release characteristics, immunogenicity Nano-therapeutics and -diagnostics in last 2 decades:  developed for cancer, diabetes, pain, asthma, allergy, infections, and so on Often provide more effective and/or more convenient RoA, lower therapeutic toxicity, maximize product life cycle, & reduce costs Allow targeted delivery and controlled release (In diagnostic applications) allow detection on the molecular scale:  fragments of viruses, precancerous cells, & disease markers that cannot be detected with traditional diagnostics
  • APPROVEDNANOTHERAPEUTICS Currently >150 companies are developing nanoscale therapeutics Internationally >36 nano-therapeutic products have been approved for clinical use Total sales exceeding $12 billion Liposomal drugs and polymer–drug conjugates  are the two dominant classes, accounting for more than 80% of total Other platforms include:  nanoemulsions, dendrimers, and inorganic nanoparticles  Polymerosomes, micelles, gold nano particles  Nano-shells (gold-silica) Personal research and Zhang et al (2008) Clin Pharmacol Therap 83, 761-769
  • Zhang et al (2008) Clin Pharmacol Therap 83, 761-769
  • Examples of nanotechnologies and targeting nanocarriers
  • NANOTHERAPEUTICS INCLINICAL TRIALS Drug-encapsulated liposomes and polymer–drug conjugates (such as PEGylated drugs) were/are also the main candidates in clinical trials PEG-ylated products  PEG enhances the PK of many nanoparticle formulations  It is highly hydrated flexible polymer chain & reduces plasma protein adsorption and biofouling of nanoparticles  It reduces renal clearance of relatively smaller drug molecules, and thus prolongs drug circulation t1/2  Itis non-toxic and non-immunogenic  Examples:  PEG–naloxol for treating opioid-induced constipation, PEG– arginine deaminase for hepatocellular carcinoma, PEG–uricase) for hyperuricemia & PEG-GCSF for neutropenia. Personal research and Zhang et al (2008) Clin Pharmacol Therap 83, 761-769
  • Zhang et al (2008) Clin Pharmacol Therap 83, 761-769
  • CASE STUDY 1: ELAN’S MYOCET(LIPOSOME-ENCAPSULATEDDOXORUBICIN) Myocet (liposome-encapsulated doxorubicin) was developed to obtain an effective but less cardiotoxic parenteral dosage form of doxorubicin  using liposome nanotechnology Presented as a three-vial system; Myocet doxorubicin HCl, Myocet liposomes and Myocet buffer Constituted liposomes are:  stable pluri-lamellar liposomes  with an aqueous core  comprised of egg phosphatidylcholine (EPC) and cholesterol  drug is entrapped into liposomes during the constitution of the ready to use liposomal formulation.
  • Phospholipid bilayer Aqueous core (hydrophilic) EXTRAVASATION AND RELEASE OFLiposomes contain an LIPOSOMAL DRUG CARGO IN TUMORinternal aqueous coresurrounded by a INTERSTITIAL FLUIDphospholipid bilayer. Theinternal aqueous core, whichis used for drugencapsulation, is suited forthe delivery of hydrophilicdrugs, and the phospholipidbilayer allows for thedelivery of hydrophobicdrugs
  • CLINICAL TRIAL: MYOCET +CYCLOPHOSPHAMIDE (MC) VS CONVENTIONALDOXORUBICIN + CYCLOPHOSPHAMIDE (AC) RCT, two arms 297 patients with metastatic breast cancer  no prior chemotherapy for advanced disease  48 centers  142 patients were randomized to receive MC  155 patients were randomized to receive AC Primary end point:  cardiotoxicityin all treated patients & objective tumor response rate (primary efficacy parameter) Secondary end point:  time to disease progression, time to treatment failure, and overall survival Batist G et al. JCO 2001;19:1444-1454
  • LIFETIME DOSE OF DOXORUBICIN TO A CARDIAC EVENT Batist G et al. JCO 2001;19:1444-1454 MC=Myocet in combination with cyclophosphamide AC=Conventional doxorubicin with cyclophosphamide©2001 by American Society of Clinical Oncology
  • OBJECTIVE RESPONSE TO TREATMENT MC ACNo. % No. %Total randomized 142 155Objective responseComplete response 7 5 9 6Partial response 54 38 57 37Stable disease 41 29 38 25Progressive disease 28 20 37 24Not assessable 12 8 14 9Response rate (CR + PR) 61/142 43 66/155 4395% CI 35-52 35-51No prior doxorubicin 54/128 42 63/140 45Prior doxorubicin 7/14 50 3/15 20Cochran-Mantel-Haenszel statisticGeneral association χ2 P value .95Relative risk (MC/AC) 1.0195% one-sided lower bound 0.81Stratified difference in response rate (MC 1– AC)95% CI for difference (–10, 12)
  • TIME TO TREATMENT FAILURE MC=Myocet in combination with cyclophosphamide AC=Conventional doxorubicin with cyclophosphamide Batist G et al. JCO 2001;19:1444-1454©2001 by American Society of Clinical Oncology
  • TIME TO PROGRESSION MC=Myocet in combination with cyclophosphamide AC=Conventional doxorubicin with cyclophosphamide Batist G et al. JCO 2001;19:1444-1454©2001 by American Society of Clinical Oncology
  • OVERALL SURVIVAL Batist G et al. JCO 2001;19:1444-1454©2001 by American Society of Clinical Oncology
  • OVERALL RESULTS (CASE STUDY 1) Six percent of MC patients versus 21% (including five cases of CHF) of AC patients developed cardiotoxicity (P = .0002). MC patients also experienced less grade 4 neutropenia. Antitumor efficacy of MC versus AC was comparable:  objectiveresponse rates, 43% versus 43%  median time to progression, 5.1% versus 5.5 months  median time to treatment failure, 4.6 versus 4.4 months  and median survival, 19 versus 16 monthsConclusion: Myocet reduces cardiotoxicity and grade 4 neutropenia ofdoxorubicin and provides comparable antitumor efficacy, when used incombination with cyclophosphamide as first-line therapy for MBC.
  • CASE STUDY 2: ABRAXIS’ ABRAXANE(ALBUMIN BOUND PACLITAXEL) Abraxane contains paclitaxel complexed with albumin to form stable; developed to avoid toxic solvent Cremophor® Presented as vials containing paclitaxel and human albumin  as a sterile, lyophilized cake, reconstituted with Sodium Chloride Injection, USP  to produce a suspension of 5 mg/mL of albumin-bound particles Reconstituted Abraxane is infused @ 260 mg/m2 IV/0.5 hr Constituted liposomes are:  130 nm particles  stable at high concentrations due to the negative zeta potential imparted by the albumin moiety with an aqueous core  In blood, albumin particles disassociate into individual albumin molecules and then circulate with the paclitaxel still attached
  •  Some (claimed) advantages of Abraxane over Taxol:  Allows a higher dose of paclitaxel to be administered with = toxicity  Increases intratumor paclitaxel concentrations by 33%  Eliminates solvent-related severe hypersensitivity reactions, including  anaphylactic reactions and death, permitting administration of paclitaxel over 30 minutes without premedication;  Eliminates need for specialized IV tubing required for Cremophor- containing products (to prevent leaching of plasticizers)  Results in more rapid clearance from the plasma and predictable, linear PK  Reduces neutropenia (demonstrated clinically);
  • ABRAXANE: CLINICAL TRIALSTUDY DESIGN Randomized, Phase 3, open label Designed to show non-inferiority in RR  Ifthe primary endpoint of non-inferiority was met, an analysis for superiority in all patients or in first-line patients was prospectively planned. Sample size: 460 women with metastatic breast cancer 70 sites: Russia (77%), UK (15%), Canada and US (9%) 2 Arms: Abraxane 260 mg/m2 as a 30-minute infusion and Taxol 175 mg/m2 as a 3-hour infusion Efficacy outcome:  1° Endpoint:Response Rate  2° Endpoints: TTP & Survival Source: Abraxane® ODAC Briefing Package
  • RESPONSE RATE (ITT) Abraxane Taxol 260 mg/m2 175 mg/m2 All randomized patientsResponse Rate 50/233 (21.5%) 25/227 (11.1%)95% CI (16.19%-26.73%) (6.94%-15.09%)P-value 0.003Taxol Indication: Patients who failed combination chemotherapy orrelapsed within 6 months of adjuvant chemotherapyResponse Rate 20/129 (15.5%) 12/143 (8.4%)95% CI (9.26%-21.75%) (3.85%-12.94%)
  • RATIO OF RESPONSE(ABRAXANE/TAXOL) + 95% CI
  • TIME TO TUMOURPROGRESSION Source: Abraxane® ODAC Briefing Package
  • PROGRESSION FREESURVIVAL Source: Abraxane® ODAC Briefing Package
  • OVERALL SURVIVAL Not Significant Source: Abraxane® ODAC Briefing Package
  • OVERALL RESULTS (CASE STUDY 2) Response rates in the Abraxane group were statistically significantly higher than those in the Taxol group (21.5% vs. 11.3%; P = 0.003) Time to tumor progression for all patients was significantly longer for patients treated with Abraxane (p = 0.002, log rank) An ad hoc analysis of PFS for all patients revealed results that were similar to TTP The median survival for patients treated with Abraxane was 10 weeks longer than for patients treated with Taxol but the survival curves were not statistically different. The overall toxicity of Abraxane was comparable to that of Taxol in some aspects but was lower in neutropenia and hypersensitivity reactions; however Abraxane has a higher incidence of peripheral neuropathy, nausea, vomiting, diarrhea and astheniaConclusion: In the metastatic breast cancer RCT, Abraxane has a highertumor response than Taxol but no other conclusive advantages.
  • SOME ONGOING TRIALS At the Center of Nanotechnology for Treatment, (University of California, San Diego CCNE), Dr. Thomas Kipps has developed a chemically engineered adenovirus nanoparticle to deliver a molecule that stimulates the immune system.  Phase I trial in patients with chronic lymphocytic leukemia (CLL) Calando Pharmaceuticals, founded by Dr. Mark Davis at the Caltech/UCLA CCNE, is conducting clinical trials with a cyclodextrin-based nanoparticle that safely encapsulates a small- interfering RNA (siRNA) agent that shuts down a key enzyme in cancer cells.  Phase I trial in patients who have become resistant to other chemotherapies. Cerulean Pharma, Inc. is conducting clinical trials of a cyclodextrin-based polymer conjugated to camptothecin.  Phase I open-label, dose-escalation study of CRLX101 (formerly named IT- 101)in patients with solid tumor malignancies.
  • SOME ONGOING TRIALS At the Center of Nanotechnology for Treatment, (University of California, San Diego CCNE), Dr. Thomas Kipps has developed a chemically engineered adenovirus nanoparticle to deliver a molecule that stimulates the immune system.  Phase I trial in patients with chronic lymphocytic leukemia (CLL) Calando Pharmaceuticals, founded by Dr. Mark Davis at the Caltech/UCLA CCNE, is conducting clinical trials with a cyclodextrin-based nanoparticle that safely encapsulates a small- interfering RNA (siRNA) agent that shuts down a key enzyme in cancer cells.  Phase I trial in patients who have become resistant to other chemotherapies. Cerulean Pharma, Inc. is conducting clinical trials of a cyclodextrin-based polymer conjugated to camptothecin.  Phase I open-label, dose-escalation study of CRLX101 (formerly named IT- 101)in patients with solid tumor malignancies.
  • FUTURE DIRECTIONS Approved nanotherapeutic agents have in some cases improved the therapeutic index of drugs by increasing drug efficacy &/or reducing drug toxicity. In future, nanoparticle systems may have targeting ligands such as antibodies, peptides, or receptors which may further improve their efficacy or reduce their toxicities. More complex systems such as multifunctional nanoparticles that are concurrently capable of targeting, imaging, and therapy are subject of future research. Optimally designed nanoparticles with the physicochemical and biological properties to achieve each of the desired functions can be a steady focus. Systemic therapies using nanocarriers will require methods that can overcome non-specific uptake by mononuclear phagocytic cells and by non-targeted cells. ….
  • CONCLUDING REMARKS Nanotechnology has had a discernible impact on therapeutics for last 20 years or so. Nano-therapeutics and -diagnostics have been proven highly successful in cancer, diabetes, pain, asthma, allergy, infections, and so on. Numerous other nano-therapeutivc products are currently under various stages of clinical development, including various liposomes, polymeric micelles, dendrimers, quantum dots, gold nanoparticles, and ceramic nanoparticles. Clinical trials of these agents often show “non- inferiority” rather than superiority but that is not a bad news… Future seems to be very bright.
  • Acknowledgement:THANK YOU VERY MUCH