nanotechnology in clinical trials final

NANOTECHNOLOGY IN CLINICAL TRIALS

Dr. Bhaswat S. ChakrabortySr. VP & Chair, R&D Core CommitteeCadila 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 an ant is like comparing that ant to a 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

APPROVED NANOTHERAPEUTICS 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

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Examples of nanotechnologies and targeting nanocarriers

NANOTHERAPEUTICS IN CLINICAL 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

It is 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.

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CASE STUDY 1: ELAN’S MYOCET (LIPOSOME-ENCAPSULATED DOXORUBICIN) 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.

Liposomes contain an internal aqueous core surrounded by a phospholipid bilayer. The internal aqueous core, which is used for drug encapsulation, is suited for the delivery of hydrophilic drugs, and the phospholipid bilayer allows for the delivery of hydrophobic drugs

Phospholipid bilayer

Aqueous core(hydrophilic)

EXTRAVASATION AND RELEASE OF LIPOSOMAL DRUG CARGO IN TUMOR INTERSTITIAL FLUID

CLINICAL TRIAL: MYOCET + CYCLOPHOSPHAMIDE

(MC) VS CONVENTIONAL DOXORUBICIN +

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: cardiotoxicity in 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

©2001 by American Society of Clinical Oncology

MC=Myocet in combination with cyclophosphamideAC=Conventional doxorubicin with cyclophosphamide

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 – AC)

1

95% CI for difference (–10, 12)

OBJECTIVE RESPONSE TO TREATMENT

TIME TO TREATMENT FAILURE

Batist G et al. JCO 2001;19:1444-1454



Batist G et al. JCO 2001;19:1444-1454


TIME TO PROGRESSION


Batist G et al. JCO 2001;19:1444-1454


OVERALL SURVIVAL

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: objective response 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 months

Conclusion: Myocet reduces cardiotoxicity and grade 4 neutropenia of doxorubicin and provides comparable antitumor efficacy, when used in combination 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 TRIAL STUDY DESIGN Randomized, Phase 3, open label Designed to show non-inferiority in RR

If the 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)

Abraxane260 mg/m2

Taxol175 mg/m2

All randomized patients

Response Rate95% CI

50/233 (21.5%)(16.19%-26.73%)

25/227 (11.1%)(6.94%-15.09%)

P-value 0.003

Taxol Indication: Patients who failed combination chemotherapy or relapsed within 6 months of adjuvant chemotherapy

Response Rate95% CI

20/129 (15.5%)(9.26%-21.75%)

12/143 (8.4%)(3.85%-12.94%)

RATIO OF RESPONSE (ABRAXANE/TAXOL) + 95% CI

TIME TO TUMOUR PROGRESSION


PROGRESSION FREE SURVIVAL


OVERALL SURVIVAL


Not Significant

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 asthenia

Conclusion: In the metastatic breast cancer RCT, Abraxane has a higher tumor 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.

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.

THANK YOU VERY MUCH

Acknowledgement:

nanotechnology in clinical trials final

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