Cellectar Fact Sheet 2009

CORPORATE FACT SHEET
Unique
Product Features
• Uptake and specific retention in 45+
malignant tumor models in proof-ofprinciple animal imaging studies
Overview
Cellectar is a radiopharmaceutical company
used in thyroid cancer therapy for many years.
that designs and develops products to detect,
For diagnosis or therapy monitoring, Cellectar
treat and monitor a wide variety of human
attaches a different iodine isotope (124I) which is
cancers. Cellectar’s product candidates combine
a PET scanning isotope. Because the molecule is
lipid-like molecules, phospholipid ether analogs
identical irrespective of the isotope chosen, all of
(PLEs), with radioisotopes that destroy or image
Cellectar’s preclinical studies and nearly all of our
• 131I-CLR1404 is terminally sterilized
malignant cells. Empirical evidence has shown
manufacturing processes are identical. The result
• Retention only by malignant cells and
tissues, not normal or non-malignant
tumor cells and tissues
that PLEs and their analogs (similar, synthetic
is that Cellectar can efficiently and simultaneously
compounds) become trapped in malignant tumor
progress through the clinical trials process in both
cell membranes because the tumor cells cannot
• Preclinical safety pharmacology &
toxicology studies (single dose and
multi-dose) completed to NDA level
with zero adverse effects
therapy and imaging.
metabolize and eliminate them. Non-
• Small molecule, development risk
low compared to large biological molecules such as monoclonal
antibodies
•Potential combination with other
treatment modalities, such as
selective chemotherapies and external beam radiotherapy, to enhance therapeutic effect
•Therapeutic doses of Iodine-131
labeled compounds are in common
clinical use for malignant conditions
malignant cells, however, metabolize
Cellectar’s lead therapy molecule, CLR1404, is in
Cellectar’s Approach
to Cancer Treatment
a Phase 1 clinical dosimetry trial. It is the intent
Cellectar’s portfolio capitalizes on the unique
of the business to progress our lead molecule on
characteristics of cancer cells to “find, treat
parallel tracks in both therapy and imaging of
and follow” malignancies through the delivery
malignancy. To treat cancer, Cellectar attaches
of radiopharmaceuticals in a novel, highly
a radioactive iodine isotope ( I) that has been
selective way.
and clear these compounds.
131
Product
Development
Status
TM
Therapeutic product
candidate: 131I-CLR1404
•Preclinical studies to date: anti-tumor
effects in the following cancers:
ovarian, breast, melanoma, renal,
glioma, colorectal and pancreatic
•IND cleared; Phase 1 underway
•Phase 1 will consist of a dosimetry
study and a subsequent maximum
tolerated dose study. In both cases,
all solid tumors will be considered
for eligibility
Diagnostic product candidate:
124
I-CLR1404
•Proof-of-principle preclinical imaging
studies completed
•Physician-sponsored IND Phase
1 clinical trial for lung cancer in 21
human subjects, including 10
normal and 11 patients, have
shown no adverse effects related to
CLR1404 and those with cancer have
shown evidence of tumor specific
retention
Highlights
Proprietary technology with potential to detect, treat
and monitor of a wide variety of cancers
Unique mechanism of action based on accumulation
and selective retention in malignant tumors, not normal cells
Preclinical therapeutic proof-of-principle studies have been
completed in ovarian, breast, melanoma, renal, glioma,
colorectal and pancreatic cancers
Preclinical safety pharmacology & toxicology studies
completed to full NDA level including single dose at
1000x the anticipated human dose and multi-dose (6x)
at ~10,000x the anticipated human dose. In both cases,
zero adverse effects were reported
Small molecule development risk is low
compared to large biological molecules
cGMP radiopharmaceutical manufacturing
facility operational and proven capable of
providing drug product into Phase 3
IND cleared by the FDA;
Phase 1 underway
Strong and expanding IP position
with low royalty commitments
CORPORATE FACT SHEET (PAGE 2)
Cellectar’s Drug Candidates
A Unique Approach to Cancer
Treatment, Detection and Monitoring
Cellectar scientists have based the development
of their proprietary PLE analog compounds
on the key discovery that selective retention by
malignant tumor cells depends on several specific
properties of PLE analog compounds. These
properties include the structure of the molecule’s
“backbone” (whether it is straight or branched),
the alkyl chain length (the number of carbon
atoms in the backbone), the structure of the
“polarhead” group (the part that protrudes out of
the cell membrane), whether it is small or large,
and if it is charged or not. By performing multiple
structure-activity relationship (SAR) experiments
in which they synthesized multiple PLEs with a
straight backbone of varying alkyl chain lengths
and with two different isotope placements, Cellectar scientists found that alkyl chain length was
a critical molecular determinant of both increased
malignant tumor uptake and selective retention.
Treatment with radioactive isotopes has been
used as a fundamental cancer therapeutic for
decades. Goals of novel therapies include selective delivery of effective doses of isotopes that
destroy tumor tissue, spare surrounding normal
tissue, do not accumulate in and damage vital
organs, particularly liver and kidneys; and can
be rapidly eliminated from the body. Cellectar’s
isotope delivery technology achieves these goals.
Empirical evidence has shown that PLEs and their
analogs (similar synthetic compounds) become
trapped in malignant tumor cells because the
tumor cells cannot metabolize and eliminate
them. Normal cells, however, metabolize and
clear these compounds.
Preclinical studies confirmed this
selective retention hypothesis:
analysis of malignant tumors following administration of radioiodinated
PLEs showed the presence of the
intact compound, whereas analysis
of normal tissues (liver and muscle)
and urine revealed only metabolites.
These differential clearance rates of
PLE analogs from normal cells versus
tumor cells form the conceptual basis
of Cellectar’s anti-tumor agents.
Polarhead Group
The Structure of CLR1404
Iodine-131
or Iodine-124
Oxygen
in
n Cha
Carbo
Phosphorous
(18)
Phosphate group
Nitrogen
Carbon
Iodophenyl Group
Hydrogen
One factor in malignant cell retention of Cellectar’s proprietary
is the length of the alkyl chains, which determines their
hydrophobic (fat-like) properties. Decreasing chain length
from 12 carbon atoms to 7 carbon atoms results in little or no
tumor accumulation, accompanied by rapid clearance of the
compound in tumor-bearing rats within 24 hours of administration. Increasing the chain length has the opposite effect, with
C15 and C18 analogs displaying delayed plasma clearance and
enhanced tumor uptake and retention.
Quaternary Ammonium
Cellectar chose the linear C18 analog with a quarternary amine,
CLR1404, for initial clinical evaluation in human lung cancer
patients based on preclinical imaging and tissue distribution
studies and on the recognized need to develop candidates that
do not cause unacceptable levels of radioactivity localization in
the liver and kidneys.
Selected references
Pinchuk, A.N., et al. Synthesis and structure-activity relationship effects on the tumor avidity of radioiodinated phospholipid ether analogues. J. Med. Chem. 2006: 49, 2155-2165.
Gajate, C and Mollinedo, F. Biological activities, mechanisms of action and biomedical prospect of the antitumor ether phospholipid ET-18-OCH3 (edelfosine), a propaptotic agent
in tumor cells. Curr. Drug Metab. 2002:3, 491-525.
Rampy, M.A., et al. Synthesis and biological evaluation of radioiodinated phospholipid ether analogs. Nucl. Med. Biol. 1995:22, 502-512.
CORPORATE FACT SHEET (PAGE 3)
Survival Analysis of Ovcar-3
Percent Survival
Tumor volume mm3
Ovcar-3 (Ovarian Adenocarcinoma)
Time (days)
Time (days)
Therapeutic studies with 131I-CLR1404 in
tumor-bearing mouse models (human tumors)
established that Cellectar’s therapy candidate
slowed the growth of malignant tumors. Results
in multiple cancer types also confirm the breadth
of the molecule from both an imaging and treatment perspective. Each of the graphs shown to
the left reflect experiments with the following
characteristics:
5-6 control subjects treated with
non-radioactive (“cold”) 127I-CLR1404
Survival Analysis of Caki-2
(represented in red)
5-6 treatment subjects treated with a single injection of~100µCi of 131I-CLR1404
(represented in blue)
Percent Survival
Tumor volume mm3
Caki-2 - Clear Cell Carcinoma (Renal)
Preclinical
Therapeutic Studies
Injections given when tumors reached
approximately 200mm3
Tumors are measured using a commonly
accepted 2 dimensional measuring
technique (RECIST)
Time (days)
Time (days)
HCT 116 (Colorectal Carcinoma)
Survival Analysis of HCT 116
Preclinical MTD Studies
Percent Survival
Tumor volume mm3
Maximum tolerated does studies with
131
I-CLR1404 in tumor-bearing mouse
models (human tumors) were performed.
Time (days)
The MTD was at least 50% more
than the injected dose in the studies
described above
This implies that the tumor growth
suppression shown (above) is not
reflective of the maximum therapeutic
effect of the molecule
Time (days)
Mechanism of Action
Cellectar therapeutic
and diagnostic agents
PLE analog moiety selectively retained in
malignant tumor cells
Confirmed in multiple preclinical in vivo
models via direct nuclear imaging
Not metabolized by or eliminated from
malignant tumor cells
Alkyl chain length critical: Structureactivity relationships and other structural
requirements well understood and patented
Radioisotope moiety images and destroys
tumor cells (preclinical results)
rolonged, selective retention in
P
malignant tumors versus normal tissue
Substantial elimination from normal
tissues within 96 hours
Malignant tumor uptake continues
to increase for at least two days with
increasing delineation as healthy
tissues clear
131
I & 124I half lives complement the
biological half life of CLR1404
Mechanism of Action research underway
The “cold” version of the compound
(CLR1401) appears to be an AKT inhibitor
which would potentiate anti-tumor effects and
be synergistic with the radioactive compound
Global lipidomic analysis, indicates that
polyphosphatidylinositols (PIPn) and
phosphatidic acid levels are affected by
CLR1401 in malignant cells. There are
substantial increases in PIPn (esp. PIP2)
and PA levels as a consequence of CLR1401
Internal and company sponsored research in
this area is ongoing
CORPORATE FACT SHEET (PAGE 4)
Market
Opportunity
Preclinical
Proof-of-Principle Studies
Cancer Therapeutics
Imaging studies conducted using Cellectar’s diagnostic
PET compound, 124 I‑CLR1404, in more than 45 cancer
models established that:
•Therapeutic radiopharmaceutical
market opportunity projected to
be $1.9 billion by 2012 (Biotech
Systems, Inc. March 2006)
•Initial target cancers are yet to be
determined, but candidates being
considered include Ovarian, Melanoma, Glioma, Pancreatic and Lung
•The broad range of preclinical
therapy success indicates a substantial clinical opportunity
•Favorable reimbursement chang-
LR1404 accumulated and was retained
C
in more than 45 tumor models tested;
issue distribution of CLR1404 in tumor-bearing
T
mice (nude-A549) shows tumor activity peaks at
more than 6% of injected dose per gram after 2-4
days following injection with slow elimination of
t1/2 of ~12 days. In contrast, blood clearance of
CLR1404 shows t1/2 of <4 days during
elimination phase;
LR1404 demonstrated blood clearance with
C
relatively low liver, kidney, bladder and
abdominal background radioactivity,
as well as no thyroid activity.
es for therapeutic radiopharma-
I-CLR1404 and 124I-CLR1404 have been
131
studied in investigator sponsored Phase 1 clinical
trials. A total of 21 individuals received radiolabled CLR1404, ten without disease and eleven
with lung cancer, to evaluate the compounds’
safety, dosimetry and pharmacokinetics. Eight patients received 131I-CLR1404, and three received
I-CLR1404. 10 normal volunteers received un-
124
labled CLR1404 with no adverse effects. Cellectar
has initiated a Phase 1 clinical trial.
IP Overview
Exclusive license to all original PLE composition
of matter and use patents from University of
Michigan (latest from 2002)
>20 pending/allowed US and foreign patents
ceuticals are expected to take
effect on January 1, 2010
Human Clinical Studies
covering other uses
Metastasis
Exclusive license to recent and future PLE
patents originating from the University of
Wisconsin (WARF)
Management Team
•Bill Clarke, M.D., M.Sc., President
Primary
& CEO Formerly EVP and Chief
Active ongoing patent generation and filing
Technology and Medical Officer,
Upcoming Milestones
GE Healthcare; EVP of R&D, Amersham; Director of Biological Sciences, GlaxoWellcome
•Jamey Weichert, Ph.D., CSO
Associate
Professor,
I-CLR1404 in mouse with PC-3
prostate tumor allograft.
Note: no bladder activity seen
124
Development & Manufacturing
Pharmaceutics
Cellectar produces its small molecule
compounds by chemical organic synthesis
member
of the Comprehensive Cancer
Center, University of Wisconsin,
Madison. Weichert is an inventor
and primary founder of Cellectar
Cellectar has invested in, completed and
commissioned a GMP radiopharmaceutical
manufacturing facility with strong quality
systems infrastructure
•Neal J. Sandy, COO
Formerly
Strategic
Marketing
Executive, GE Healthcare
Phase 1 dosimetry trial initiated
Q4 2009
Phase 1 dosimetry trial complete
Q2 2010
Phase 1 MTD trial initiated
TBD
Phase 2 trial initiated in 1st cancer
TBD
Phase 2 trial initiated in 2nd cancer
Depts.
of Radiology, Medical Physics,
and
Q2 2009
Cellectar is exploring additional applications for
CLR1404 including unique imaging applications and
therapy that combines 131I-CLR1404 with external
beam radiation therapy. We also continue to investigate the mechanism of action for our lead molecule.
Contact
Neal J. Sandy, COO
608 441 8120 x8123
[email protected]
Cellectar, Inc.
3301 Agriculture Drive
Madison, WI 53716