10-Docetaxel Presentation February 2014

New Drug Delivery Platform
Dedicated to making safer and more effective cancer
therapies that are more accessible to those suffering
from cancer
LUMINUS BIOSCIENCES, INC
100 NE Loop, Suite 1090
San Antonio, TX 78216, USA
210-366-0006
2/15/2014
Confidential
Management
 James W. Simmons, PhD, PO, MBA
Chairman, Chief Executive Officer and President
 Chandra U. Singh, PhD – Founder and Director
Vice President for Drug Discovery &
New Delivery Technologies
 Jeffrey D. Kahl, PhD – Chief Scientific Advisor
Metabolic disorders, inflammation, cancer therapies
Confidential
Drug Delivery Platform …
 Offers effective ways to extend product life cycles of
existing products by enhancing therapeutic efficacy
and reducing toxicity
 Improves the therapeutic value of a drug molecule
throughout its life cycle, from discovery through
commercialization
2/15/2014
Confidential
Drug Delivery Platform
 As more challenging drug candidates are discovered
they require robust delivery systems.
 Integration of drug delivery systems in the drug
discovery process can increase the number of
potential candidates available for development
considerations.
2/15/2014
Confidential
LUMINUS’s Drug Delivery Platform
 It is a next generation drug delivery platform for
producing stable solid nanoparticles
 Delivers water insoluble drugs with less toxicity by
eliminating toxic solvents
 Significantly improves drug efficacy through “solvent
–free” delivery in an aqueous medium
 Minimizes adverse side effects due to toxic solvents
 Dosage can be increased due to “solvent-free”
formulation
2/15/2014
Confidential
Confidential
Incidence of Cancer in the US … 2010
2/15/2014
Confidential
Incidence of Cancer in the World
2/15/2014
Confidential
Global Cancer Market
2/15/2014
Confidential
Projection of Cancer Market
More than 12 Million newly diagnosed cancer cases in
2007 and the number of newly diagnosed global cancer
cases is expected to reach over 17 Million by 2020
Growing at a CAGR (Compounded Annual Growth Rate)
of 12.3% between 2007 and 2012, the global market for
cancer drugs had crossed US$78 Billion in 2012
 Drug manufactures are now focused on developing targeted
therapies. These drugs attack target cancer cells and thus limit the
severity of side effects
Chemotherapy is expected to grow as more combination
drugs are developed
2/15/2014
Confidential
Taxanes
Taxanes are plant Diterpenes with Anti-tumor activity
They include Paclitaxel and Docetaxel
 They are Microtuble Inhibitors
Pacific Yew Tree
Taxus brevifolia
2/15/2014
Confidential
Taxanes
Structure
Solubility
Paclitaxel: 0.4mg/mL
Docetaxel: 14mg/mL
Cabazitaxel: 8mg/mL
2/15/2014
Microtubule Structure

2 Main isoforms of Tubulin
protein  and 
 and  tubulins form dimers
 Protofilaments – strand
lengths of the dimers (~25 µm)
 Microtubules –
a lateral arrangement of
13 protofilaments
 They are circular in shape
2/15/2014
Confidential
Microtubules and Mitosis
 Tubulin – Structural protein that is critical for the
formation of the mitotic spindle
 Microtubules (composed of tubulin protein) form the
‘cytoskeleton’ that anchors the organelles and
provides scaffolding for cell structure
2/15/2014
Confidential
Microtubule as Drug Target
 Microtubules are in Dynamic Equilibrium –
Formation of the microtubules are in a
constant state of equilibrium
(Polymerization <-> Depolymerization)
 Two Different Mechanisms for Drug Design:
1) Inhibit polymerization
2) Inhibit depolymerization
(prevents breakdown of mitotic spindle)
 These actions lead to G2 –M phase cell cycle arrest
2/15/2014
Confidential
Tubulin Binding Agents
 Colchicines bind to tubulin dimers and prevent their
polymerization into microtubules
 Vinca alkaloids (vincristine, vinblastine) bind to
tubulin dimers at the GTP site and prevent their
polymerization. Used to treat cancers that have a high
proportion of proliferating cells
 Taxanes (paclitaxel and docetaxel) bind to tubulin dimers
and prevent depolymerization. Used in the treatment of
breast, prostate and lung cancers
2/15/2014
Confidential
Tubulin -Colchicine Complex
Binding to the Dimer
The resulting microtubule/colchicine complex does not have
the ability to assemble
2/15/2014
Confidential
Tubulin -Vincristine Complex
Binding to the GTP Site
The resulting microtubule/vincristine complex does not have
the ability to assemble
2/15/2014
Confidential
Tubulin - Paclitaxel Complex
Binding to the b-subunit
The resulting microtubule/paclitaxel complex does not have
the ability to disassemble
2/15/2014
Confidential
Docetaxel differs from Paclitaxel by
two functional groups
Paclitaxel
Docetaxel
2/15/2014
Confidential
Docetaxel Binds to Tubulin
An Anti-mitotic Cytotoxic Agent
Docetaxel is an anti-mitotic cytotoxic agent that stabilizes
microtubular networks.
Docetaxel binds to free tubulin and promotes the assembly
of tubulin into stable microtubules.
This results in the inhibition of mitosis and leads to
cell death.
Unlike most spindle poisons in clinical use, Docetaxel
does not alter the number of protofilaments in bound
microtubules.
Clinical Efficacy of Docetaxel
Over the past decade, Docetaxel has emerged as one of the
most important cytotoxic agents for chemotherapeutics, with
clinical efficacy against five different cancer indications:
 Non-small cell lung
 Breast
 Prostate
 Gastric adenocarcinoma
 Squamous Cell Cancers of the Head and neck
Market Position
The total sale of Taxotere® in the world during
2008 was around $3.5 billion
Docetaxel treatment is indicated for about 723,000
cancer patients in the US alone
Sanofi-Aventis® is the leader in the Docetaxel
market with the patented Taxotere®
2/15/2014
Confidential
Taxotere® (i.v.; Sanofi-Aventis®)
Formulation Limitations
Docetaxel is insoluble in water
Taxotere® is currently delivered in surfactant-ethanol
vehicles - producing:
– hypersensitivity reactions
– vesicular degeneration
– Dermatition
– fluid retention
– The formation of micelles in blood which inhibit tissue
distribution
This requires pretreatment desensitization of patients with
corticosteroids, diphenhydramine, H2-antagonists,
antihistamines, etc
2/15/2014
Confidential
Method for Nanoparticles Preparation
Solvent Evaporation Technique





Form oil in water nano-emulsion
Evaporate the organic phase rapidly
Filter the solution using 0.22μ filter
Fill in vials
Lyophilize the product
2/15/2014
Confidential
Lipid-Albumin Solid Nanoparticles Preparation
2/15/2014
Confidential
Lipid-Albumin Solid Nanoparticles
(LASN™) Technical Overview
 Form oil in water emulsion using high
pressure homogenization (22,000-28,000 PSI)
 Rapidly evaporate the organic phase
(less than 2 min) under high vacuum
 Sterilize the solid nanoparticles suspension
by filtration through 0.22 micron filter
 Fill the sterile filtered aqueous suspension in vials
 Lyophilize the filled vials to form cake and
reconstitute as needed
2/15/2014
Confidential
Human Serum Albumin
The protein is principally characterized by its
remarkable ability to bind a broad range of hydrophobic
small molecule ligands including fatty acids, bilirubin,
thyroxine, bile acids and steroids; it serves as a
solubilizer and transporter for these compounds
The protein is a helical monomer of 66 kD containing
three homologous domains (I-III) each of which is
composed of A and B subdomains.
05/20/05
Confidential
Human Serum Albumin
 The most abundant plasma
protein (~640 μM)
 Structure
– 578 amino acids,
– 9 b-strands,
– 31 a-helix,
– 17 disulfides,
– 1 free sulfhydral group
(SH)
– b-barrel domain
– hydrophobic pocket
2/15/2014
Confidential
Critical Factors in Nanoparticles Preparation
 Particle size
Less than 150 nm
 Method of manufacture
Need to produce amorphous particles
 Stability of the suspension
At least 3 days for commercial manufacturing
 Steric stabilization
Prevents Aggregation in Solution
 Sterilization by Filtration
2/15/2014
Confidential
Safety Concerns
Toxicity (RBC lysis)
 Type and Concentration
Residual solvent
Overload of reticuloendothelial system (RES)
Particle size
 (tail above 1 um) - Blockage of capillaries
 Size affects RES uptake and tissue targeting
 Stability: shelf-life and in vivo
 Dose dumping (via protein binding)
 Sterility
2/15/2014
Confidential
Nanoparticles Instability …
Causes of Instability
 Creaming
 Flocculation
 Coalescence
 Ostwald Ripening
 Creaming:
The separation caused by upwards
motion of nanoparticles that have lower density than the
surrounding medium. May be described by Stokes law.
2/15/2014
Confidential
Nanoparticles Instability …
Flocculation: Is an aggregation of particles. Flocculation
occurs when the kinetic energy released during collisions
bring the particles over the repulsive force barrier and into
a region where attractive forces operate and the particles
attach to each other
Coalescence: Coalescence occurs when two particles
collide and lose their identity with the formation of a
single larger particle
2/15/2014
Confidential
Nanoparticle Instability
Oswald Ripening (OR): Results from the diffusional
transport of matter from small particles into larger ones.
The driving force is the decrease in chemical potential of
the matter in particles of greater radius
Nanoparticles of Docetaxel is not stable in solution
because of OR due to its high solubility in water
(~14 mg/L of Docetaxel vs 0.4 mg/L of Paclitaxel)
2/15/2014
Confidential
The Innovation …
 Luminus has developed stable solid nanoparticles of
microtubule inhibitors dispersed in aqueous medium
 The technology to produce such nanoparticles is
called Lipid-Albumin Solid Nanoparticles (LASN™)
platform
 LASN™ is a patented drug delivery platform for
microtubule inhibitors
 LASN™-Docetaxel is the first drug candidate using
this delivery platform
2/15/2014
The Innovation
LASN™-Docetaxel can be delivered in water or saline
and is therefore free of ethanol and Tween 80®
LASN™-Docetaxel is likely to lead to improved safety,
efficacy and market share compared to Taxotere® --similar to the displacement of Paclitaxel by
ABRAXANE®
2/15/2014
Confidential
Advantages of LASN™ Delivery Platform

First in the world to produce stable amorphous
nanoparticles of Docetaxel dispersed in aqueous
medium
 Solid nanoparticles of Docetaxel produced by the
LASN™ delivery platform are stable up to 1 week in
solution (Critical for manufacturing)
 Ostwald Ripening is inhibited by suitable lipids
 Nanoparticles of Docetaxel can be prepared containing
up to 10 mg/mL
2/15/2014
Confidential
LASN™-Docetaxel Formulations are Stable
for 4 Years as Lyophylized Powder and
for up to 5 Days in Solution
 LBI formulated different Docetaxel-containing nanoparticles
using different lipids.
 Three different LASN™ suspensions contain either:
(1) cholesteryl stearate and cholesterol (DCSC)
(2) hexadecyldexadecanoate and cholesterol (DHC)
(3) glyceryl tristearate and cholesterol (DGTC).
 The average size of the formed lipid nanoparticles is between 70
and 100 nm, under the endothelial fenestration gap of 100nm.
 The LASNs have been found to be stable for at least 4 years as
lyophylized powder at -20 °C.
2/15/2014
Confidential
Particle Size Analysis Containing
Hexadecyldexadecanoate and Cholesterol
After reconstitution
After Storing at 25C for 3 Days
2/15/2014
Confidential
Particle Size Analysis of LASN-Docetaxel
Containing
Glyceryl Tristearate and Cholesterol
After reconstitution
After Storing at 25C for 3 Days
2/15/2014
Confidential
Particle Size Analysis of LASN-Docetaxel
Containing Cholesteryl Stearate and
Cholesterol
After reconstitution
After Storing at 25C for 40 Hours
2/15/2014
Confidential
Particle Size Analysis of Docetaxel without
Ostwald Ripening Inhibitors
After 30 mins kept at 24 C
2/15/2014
Confidential
After 60 mins kept at
24 C
LASN™-Docetaxel Drug Candidate (LBI-1103)
 LBI-1103 is stable in aqueous medium and free
from Ostwald Ripening
 The particles are complexed with human serum
albumin and lipids:
– Hexadecyldexadecanoate (Cetyl Palmitate)
– Cholesterol
2/15/2014
Confidential
LBI-1103
The average size of the LBI-1103 is 70 nm, under the
100nm endothelial fenestration gap.
Lyophilized LBI-1103 is stable for more than 4 years
and once reconstituted are stable for up to 5 days and are
compatible with standard delivery devices.
2/15/2014
Confidential
Probable Nanoparticles Composition
of Docetaxel-Lipid-Albumin Complex
Lipid 386.65354 g/mol
Docetaxel molecule 807.879 g/mol
Albumin 69,000 g/mol
Cell membrane
2/15/2014
The conjugation of lipid-Docetaxel and soluble
albumin form stable complexes
Albumin will Facilitate LBI-1103 uptake into
Tumor Cells Similar to ABRAXANE®
Secreted Protein, Acidic and Rich in Cysteine (SPARC)
ABRAXANE® (Paclitaxel; Celgene)
vs
LBI-1103 (Docetaxel; Luminus)
ABRAXANE® is an albumin-bound form of paclitaxel with a mean
particle size of approximately 130 nanometers
No premedication to prevent hypersensitivity reactions is
required prior to administration of ABRAXANE®
ABRAXANE® is reconstituted with 0.9% Sodium Chloride Injection
LBI-1103 WILL DISPLACE ITS PROTOTYPE TAXOTERE®
THE MARKETING PATTERN OF LBI-1103 WILL BE SIMILAR
TO THAT OF ABRAXANE® IN ITS DISPLACEMENT OF
PACLITAXEL
Docetaxel Assay Results of
LBI-1103 Long-Term Stability Samples
No.
1.
2.
3.
4.
2/15/2014
Description
Lot 800.008.016
Zero Time
Lot 800.008.016
Stored at Refrigerated
Condition for 2 years 4
months and then at -20C
for 2 months
Lot 800.008.013
Zero Time
Lot 800.008.013
(lyophilized)
Stored at Refrigerated
Condition for 2 years 5
months and then at -20C
for 2 months
Confidential
Docetaxel Assay
(mg/Vial)
% Zero Time
9.67 mg/Vial
100.0%
9.38 mg/Vial
97.0%
14.06 mg/Vial
100.0%
13.67 mg/Vial
97.2%
Studies for the Development of LBI-1103
 Assessment of entrapment efficiency of Docetaxel in LASN™Docetaxel Formulations
 Evaluation of in vitro cytotoxicity
 Establish a maximum tolerated dose in mouse
 Comparison of LBI-1103 and Taxotere® pharmacokinetics in
rats
 Efficacy studies in human xenograft models of PANC-1 and
MDA-MB-468 in BALB/c nude mice
 Assess biodistribution characteristics of LBI-1103 in tumor and
other tissues in tumor-bearing mice
 Preclinical Toxicology Package
2/15/2014
Confidential
Maximum Tolerated Dose for LBI-1103
MTD for Taxotere®
MTD for LBI-1103
34.3 mg/m2
100.3 mg/m2 2.9 fold
2/15/2014
Confidential
Confidential
Pilot PK Study for LBI-1103 in Rats
Plasma Concentration increases linearly with concentration
AUC is 2-2.5 fold as compared to Taxotere®
Confidential
Pilot PK Study for LBI-1103 in Rats
Plasma Concentration increases linearly with concentration
AUC is 2-2.5 fold as compared to Taxotere®
Confidential
MDA-MB-468 Xenograft Study for LBI-1103

In animals treated with Taxotere® (12mg/kg), tumor re-growth was observed 2 weeks
after the completion of dosing.

No tumor regrowth was observed in any animals two weeks after the completion of
dosing in LBI-1103 treated animals
Confidential
PANC-1 Xenograft Study for LBI-1103

In animals treated with Taxotere® (12mg/kg), tumor re-growth was observed 2 weeks
after the completion of dosing.

No tumor regrowth was observed in any animals two weeks after the completion of
dosing in LBI-1103 treated animals
Confidential
Intellectual Property
Solid Nanoparticle Formulation of
Water Insoluble Pharmaceutical Substances with
Reduced Ostwald Ripening
(PCT WO2008013785)
(US20090238878)
2/15/2014
Confidential
IP Status
 The patent is allowed in the US
 It will be published in Q1 2014
 The patent is pending in EU and JAPAN
2/15/2014
Market Potential for LUMINUS’s Products
Worldwide
LBI Product
Competitors
Sales in
Product
millions
(2009)
LBI-1103
(LASN™
Docetaxel)
LBI-0424
(Generic
ABRAXANE®)
Sanofi-Aventis
(TAXOTERE®)
Celgene
(ABRAXANE®)
US Sales in
millions
(2009)
Projected Market
Share (US)
Projected Net
Sales in
millions (US)
$ 2,900
$ 1,100
20 %
$ 200
$750
$315
20c %
$ 60
a) Expressed in million of $. b) Based upon 30% pricing discount compared to branded drug c) Based upon
25% pricing discount compared to branded drug
Confidential
Product Competition for LBI-1103
Company
Technology
Active Ingredient
Paclitatxel (ABRAXANE®)
Abraxis Biosciences
NAB – Albumin
Azaya Therapeutics
Neopharm
PEG Liposomes
Docetaxel
LysoLiposomes
Docetaxel
Nektar
Samyang
Peg grafted
Doctaxel
Polymeric micelle
Doctaxel
Lecithin
Folate targeted
Taxanes
Taxanes
Thermo sensitive miscelles
Taxanes
Polylactides
PLGA-PEG copolymer
Taxanes
Docetaxel
Tf-congugated PLA-TPGS
Docetaxel
Oleic acid OH-apatit
Docetaxel
Liquid crystals nanoparticle
Docetaxel
mPEG-polycaprolactone
Docetaxel
Block copolymer micelles
PLA/PLGA sustain release
Taxanes
Docetaxel
Literature
2/15/2014
Confidential
Docetaxel
Confidential
Development Overview for LBI-1103
Regulatory Activity
Timelines
Notes
Formulation Development
(Preclinical development)
6 – 10 months
Finalizing product formulation parameters and conduct supporting
preclinical studies in mice
Pilot Scale Manufacturing (CMC
and product specifications)
4 – 6 months
Establish manufacturing process on multi liter scale to support
Phase I clinical study
Pre IND Package
2 – 4 months
Request for guidance from FDA for clinical development
6 – 8 months
Toxicology and pharmacokinetic studies to establish starting dose
for Phase I clinical study
IND submission
2 – 4 months
2 months to prepare application and 1 moth for FDA response
Phase I clinical Study
12 – 16 months
Phase I clinical study – determine drug safety (MTD) and
pharmacokinetics in 24 – 32 patients
Scale-up Manufacturing
12 – 18 months
Validate manufacturing process and preparing technical package for
commercial manufacturing
Phase II Clinical Studies
18 – 24 months
Multi dose safety study in selected indications
Establish Commercial
Manufacturing
18 – 24 months
Identify commercial manufacturing plan (CMO with capabilities to
support commercial manufacturing)
Phase III Clinical Studies
24 – 36 months
Pivotal clinical study to determine product label and indications
GLLP Toxicology
(Two species)
NDA Submission
2/15/2014
2 – 4 to prepare application
6 – 10 months
6 months FDA review – Market Approval
Confidential
Confidential
Path for NDA Submission
Clinical Devleopment
Formulation
Development
Pre IND
Meeting
Proof of Principle
Studies
Year 1
Phase I Clinical
Study
GLP Toxicology
Studies
Pilot Scale
Manufacturing
Year 2
IND
Submission
Year 3
Phase II Clinical Study
Scale-up
Manufacturing
Phase III Clinical Study
NDA
Submission
Commercial Manufacturing
Year 4
Year 5
2/15/2014
Confidential
Year 6
Year 7
Year 8
Confidential
Development Overview for ANDA Submission
LBI-0424
Regulatory Activity
Submit Info Package to FDA
Timelines
LBI is requesting a meeting with the FDA to
2 – 4 months comply with regulatory requirements suggest
form the review committee
Conduct Human Bio-
6 – 10
equivalency Study
months
Commercial Manufacturing
Submit ANDA
Notes
Double crossover study in 24 – 26 patients
12 – 18
Establish commercial scale manufacturing,
months
product specification and CMC
18 – 24
months
2 moths to prepare ANDA application
18 – 24 months for FDA review
Confidential
Path for ANDA Submission for LBI-0424
Formulation
Development
IND
Meeting
Submit
Bio-IND
Pilot Scale
Manufacturing
Year 1
Phase I Clinical Study
ANDA Submission
Commercial Manufacturing
Year 2
Year 3
Confidential
Development Cost for
Generic Abraxane® - LBI-0424
Generic Abraxane® Manufacturing
Capital Equipment
Facility
Operational expense
Supplies
Projected Cost
$600,000
$250,000
$200,000
$300,000
$1,350,000
GLP Bioequivalence Study
Bioequivalence Material Manufacturing
Bioequivalence Study in 2 Species
Clinical Development
Clinical Material Manufacturing
Human Bioequivalence study
$50,000
$100,000
$150,000
$200,000
$400,000
$600,000
Total
$2,100,000
Confidential
Strengths, Weaknesses, Opportunities, and Threats
SWOT Analysis 1
Strengths
•
•
•
Developing products in large multi billion dollar
markets
Weaknesses
Experienced scientific team with 60+ years experience •
product manufacturing and development of complex
•
therapeutic agents
•
Diverse product pipeline utilizing scientific expertise –
•
lipid and emulsion based products
Limited financial resources
A high investment cost
Lengthy development timelines – clinical studies
Regulatory expertise
•
Strong IP enabling development of a number of
unique products
•
Unknown competition – development of generic
products are not typically reported
•
Generic products – product synergy – rapid
monetization
•
Existing patents that you can not infringe upon
•
Potential for high returns on investment
Confidential
SWOT Analysis 2
Opportunities
•
Threats
Reduce medical cost and create more accessible
products for those who suffer from acute and
chronic diseases
•
•
•
Changing economy and government policies
will enhance drug development
•
Competition from generic companies e.g. Teva
Develop unique therapeutic agents with a
•
Large Pharma with unlimited financial
Develop a disruptive technology platform that
proprietary delivery platform
•
Expedited approval for generic products
•
Large pharma is looking for new innovative
resources beginning to focus effort on generic
products
products to fill product pipelines
Confidential
Funding Requirement
LBI-1103 Clinical Development
Projected Cost
Capital Equipment (Homogenizer, Evaporator, Freeze Dryer,
etc.)
$1,400,000
Laboratory and Clean Room Facility
Operational expense
$950,000
and Legal Fees
$900,000
Supplies
-
Personnel
$500,000
-
$1,200,000
Total
$4,750,000
GLP Toxicology Study
90 Day Repeat Dose Toxicology
$1,200,000
Pharmacokinetics & Toxicokinetics Study
$280,000
Total
$1,280,000
Clinical Development
Clinical Material Manufacturing
$400,000
Clinical Trial
$1,500,000
Total
2/15/2014
Confidential
$1,900,000
Return on Investment
Return on Investment
Cost of Development (5-6 years)
1 Through Phase I Clinical Trial
2 Phase II Clinical Trial
3 Phase III Clinical Trial
8,330,000
12,000,000
30,000,000
4 NDA Submission
3,000,000
Total Cost
Projected Revenue (After NDA approval)
2/15/2014
53,330,000
Market Value
Year 1
Year 2
Year 3
$300,000,000
$450,000,000
$550,000,000
$1,800,000,000
$2,700,000,000
$3,300,000,000
Year 4
$1,000,000,000
$6,000,000,000
Return on Investment
Confidential
Over 100 Fold
THE END
2/15/2014
The Lipids
Cetyl Palmitate
Nn-hexadecanoate
2/15/2014

Download Report