Download BEYOND THE BLOOD BRAIN BARRIER

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CREATING BREAKTHROUGH DRUGS
TO TREAT BRAIN DISEASES
ASENT Annual Meeting 2009
New Peptide Engineered Compounds able to cross the
blood-brain barrier to treat brain diseases
rd 2009
February
March
6,232009
Confidential
Many drug candidates (mostly biologics) have
been identified BUT they do not cross the BBB
• Angiochem’s technology platform allows for the synthesis of
novel drug candidates which are designed to cross the
BBB;
• Using this platform AngioChem has developed a portfolio of
drug candidates reaching therapeutic concentration in the
brain which have been validated in animal models and in
human clinical trials
March 6, 2009
Confidential
AngioChem’s Solution
for Crossing the BBB
• We identified the consensus sequence of amino acid responsible for
binding to the LRP receptor, which naturally transports proteins to
the brain
• We design new chemical entities incorporating that sequence
which have the ability to bind to LRP and cross the BBB
physiologically
March 6, 2009
Confidential
LRP Receptor and Major Ligands
TPA
Angiopep
(tissue plasminogen activator)
2-Macroglobulin
•
RAP
•

Thyroglobulin
•
Lactoferrin
•
LRP transport small and large
molecules
LRP is highly expressed at the
surface of the BBB
LRP has a very fast endocytosis
rate t1/2 (~30 sec)
LRP is robust and has a high
capacity
ß
March 6, 2009
Confidential
Development Pipeline
DISCOV.
ANG-Cytotoxic
PRECLIN.
PHASE 1/2
PHASE 2
Primary (glioma) ANG 1005 : Antimicrotubule
and metastatic
DNA intercalation
brain tumors
ANG-Peptide
STATUS
Internal
Program
Topoisomerase II inhibitor
Metabolic diseases GLP-1 receptor agonist
ANG-MAb
Neurodegenerative
diseases
Internal
Program
ANG Leptin Peptide
Undisclosed MAb
Joint
Research
Collaboration
Undisclosed siRNA
Joint
Research
Collaboration
ANG-siRNA
Neurodegenerative
diseases
Internal Program
Joint Research Collaboration with Partner Leader in the Field
Situation in 12 months from now
March 6, 2009
Confidential
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CREATING BREAKTHROUGH DRUGS
TO TREAT BRAIN DISEASES
Proof of concept
Brain Uptake
rd 2009
February
March
6,232009
Confidential
Brain Uptake of Engineered
Peptides Compounds
 ENGINEERED PEPTIDES
WITH CY5.5
 CAPILLARIES STAINED
WITH VESSEL GREEN
(FITC-LECTIN)
 NUCLEI OF BRAIN
CELLS STAINED WITH
DAPI BLUE
March 6, 2009
Confidential
Homogenous Uptake of
ANG1005 in the Brain
22.8 nCi/g
28.6 nCi/g
37.2 nCi/g
22.36 nCi/g
28.6 nCi/g
March 6, 2009
20.9 nCi/g
Confidential
Angiochem products Shows
Superior Brain Uptake
Drug
Glucose
Brain Kin (mL/s/g)
9.5 x 10-3
Reference
Mandula et al.(2006)
ANG1005
8.8± 0.6 x 10-3
Q. Smith, present work
Ang-GLP-1 receptor agonist
8.8±1.1 x 10-4
Internal work
Morphine
Ang-siRNA
Insulin Rec Antibody
Paclitaxel and Doxorubicin
RAP
Etoposide
1.6 x 10-4
1.1 ± 0.1 x 10-4
1 ± 0.3 x 10-4
~5 x 10-5
1.0 ± 0.1 x 10-5
~4 x 10-6
Seelbach et al. (2007)
Internal work
Pardridge (1997)
Muldoon et al. (2007)
Pan (2004)
Muldoon et al. (2007)
TNF-α
4.3 ± 0.1 x 10-6
Pan (2002)
Vasopressin
2.5 ± 0.1 x 10-6
Tanabe (1999)
March 6, 2009
Confidential
ANG1005 : Activity in Glioblastoma
compared to Paclitaxel
Vehicle
Paclitaxel
ANG1005
Day 10
Day 17
Day 24
Rat Brain MRI
March 6, 2009
Confidential
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CREATING BREAKTHROUGH DRUGS
TO TREAT BRAIN DISEASES
Proof of concept
Clinical
rd 2009
February
March
6,232009
Confidential
ANG1005
Phase 1 Clinical Program
Two Protocols Conducted in Parallel in 9 centers in
the USA
 ANG1005-CLN-01: A Phase I, Open-Label, dose escalation study of
ANG1005 in patients with Malignant Glioma and a surgical sub-study
where patients are dosed prior to surgical debulking (level of
product is measured in the extracted tumor)
 ANG1005-CLN-02: A Phase I, Open-Label, dose escalation study of
ANG1005 in patients with Solid Tumors and Metastatic Brain Cancer
March 6, 2009
Confidential
Clinical Highlights
Limiting toxicity
• Bone marrow (mostly neutropenia)
No CNS Toxicity
• Neurocognitive results are negative to date (n=18)
Immunogenicity
• Results are negative for antibodies to date (n=31)
Validation in Humans
• Data collected from the clinical trial confirm preclinical data and
strongly validate the platform technology. These data will be
published in a peer reviewed journal.
March 6, 2009
Confidential
Beyond the Blood Brain Barrier
BBB
CROSSING
AHEAD
March 6, 2009
Confidential