ANG1005-Taxol derivative crosses BBB

[Rich66]

ANG1005 Crosses the Blood-Brain Barrier to Reduce Tumor Size and is Effective in Resistant Tumors

Montreal, Canada, and Chicago, IL, October 19, 2009 – Angiochem, Inc. a clinical-stage biotechnology company developing drugs that are uniquely capable of crossing the blood-brain barrier to treat brain diseases, announced today that its lead drug candidate, ANG1005, has demonstrated a favorable safety and efficacy profile in more than 100 patients with brain cancer from two separate Phase 1 /2 clinical studies in patients with progressive gliomas, including recurrent glioblastoma, and in patients with progressive brain metastases. These data, which validates in humans Angiochem's peptide-based platform technology (EPiC), were presented at the Society for Neuroscience Annual Meeting in Chicago on October 18, 2009.

In the recently completed Phase 1/2 brain metastases clinical trial, greater than 70% of patients receiving therapeutic doses experienced disease control (stable disease or better) with more than half of them showing clear reduction in tumor size. Furthermore, 78% of patients with taxane resistant tumors showed responses, indicating ANG1005 has the potential to be effective against resistant tumors. Of significance, therapeutic doses of ANG1005 were present in patient brain tumor samples, indicating that the drug successfully crosses the blood-brain barrier (BBB) and concentrates in the tumor, without showing central nervous system (CNS) toxicity or immunogenicity. Similar trends in patient responses have been observed to-date in the on-going Phase 1/2 recurrent glioblastoma clinical trial with approximately 65% of patients experiencing disease control.

"It is highly encouraging to see that ANG1005 has shown the potential to be effective in metastatic brain cancers and against drug resistant tumors, that are highly aggressive and have few treatment options," commented Jan Drappatz, MD, Center for Neuro-Oncology at Dana-Farber Cancer Institute, Department of Neurology at Brigham and Women's Hospital, and, Harvard Medical School, and lead investigator for Boston-area study centers. "Furthermore, significant reductions in tumor size and reversal of neurological deficits were observed in several cases of patients with high-grade gliomas in the on-going clinical trial. We are very encouraged by these efficacy signals and look forward to learning more about the effects of ANG1005 in recurrent glioblastoma as the study progresses."

ANG1005 is a novel, next-generation taxane derivative, targeting the LRP pathway to cross the blood-brain barrier and reach therapeutic concentrations in the brain. The drug was created with Angiochem's Engineered Peptide Compound (EPiC) platform technology. Key findings to date from the clinical studies include:

71% of patients (15/ 21) demonstrated disease control at therapeutic doses including seven partial responses (PR), four minor responses (MR) and four with stable disease (SD).
78% of patients with taxane resistant tumors (7/9) demonstrated responses indicating ANG1005 is effective in resistant tumors, including three PRs and four MRs.
Similar responses were observed in metastases located in other organs such as liver, lung, lymph nodes and bone including two complete responses (CR), one in liver and one in bone.
Therapeutic concentrations of ANG1005 were present in patient brain tumor samples, indicating the drug successfully crosses the BBB and enters the tumor.
No CNS toxicity as measured by neurocognitive testing was observed.
No immunogenicity or antibody response was observed, even after repeated dosing.
Superior side-effect profile compared to other taxanes was observed based on literature references.
Similar trends in patient responses have been observed to date in the on-going recurrent glioblastoma trial with 65% of patients experiencing disease control.
In addition to the ANG1005 clinical findings, Angiochem's EPiC technology was also highlighted at the Neurosciences meeting. In a presentation entitled "Development of a New Engineered Peptide Compound (EPiC) Platform for the Transport of Small and Large Therapeutics to the CNS", Jean-Paul Castaigne, MD, discussed the science underlying the EPiC technology and disclosed evidence of its ability to increase the amount of a variety of different therapeutics to reach the brain, highlighting the potential neurological applications of this technology and speed at which new drugs could be developed.

"We are excited by our positive results to date with ANG1005, which strongly validate our platform technology in humans," commented Jean-Paul Castaigne, MD, MBA, President and CEO of Angiochem. "Through our peptide-based platform technology, called EPiC, Angiochem creates new chemical entities that can cross the human blood-brain barrier to reach therapeutic concentration in the brain. By harnessing naturally-occurring receptors at the surface of the BBB, our EPiC drugs have the potential to treat a variety of CNS diseases, including neurodegenerative and metabolic diseases, brain cancer, psychiatric disorders and many others."

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About ANG1005 // ANG1005 is a novel, next-generation taxane derivative targeting the LRP pathway. ANG1005 was engineered with the EPiC platform which was designed to cross the BBB. Studies have shown that ANG1005 gains entry into the brain compartment by targeting the low-density lipoprotein receptor-related protein (LRP) which is one of the most highly expressed receptors on the surface of the BBB. Once inside the brain, ANG1005 enters tumor cells using the same receptor-mediated pathway through LRP, which is upregulated in various cancer cells including gliomas and metastatic brain cancers.

About Angiochem // Angiochem is a clinical-stage biotechnology company discovering and developing new breakthrough drugs that are uniquely capable of crossing the blood-brain barrier (BBB) to treat brain diseases. The company's proprietary Engineered Peptide Compounds (EPiC) technology creates drugs that cross the BBB and reach therapeutic concentration in the brain, by harnessing naturally-occurring receptors on the surface of the BBB. Angiochem's lead product candidate, ANG1005 is in two separate Phase 1/2 clinical studies in patients with brain cancers and cancer metastases. Additionally, Angiochem is developing a deep and broad product pipeline, including small and large molecules, for the potential treatment of a wide range of CNS diseases, including neurodegenerative and metabolic diseases, brain cancer, psychiatric disorders and many others. Founded in 2006, Angiochem maintains headquarters in Montreal, Canada. For additional information about the Company, please visit http://www.angiochem.com.

1: Pharm Res. 2009 Sep 23. [Epub ahead of print] Links

Uptake of ANG1005, A Novel Paclitaxel Derivative, Through the Blood-Brain Barrier into Brain and Experimental Brain Metastases of Breast Cancer.

Thomas FC, Taskar K, Rudraraju V, Goda S, Thorsheim HR, Gaasch JA, Mittapalli RK, Palmieri D, Steeg PS, Lockman PR, Smith QR.
Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, 1300 South Coulter Drive, Suite 400, Amarillo, TX, 79106, USA.
PURPOSE: We evaluated the uptake of angiopep-2 paclitaxel conjugate, ANG1005, into brain and brain metastases of breast cancer in rodents. Most anticancer drugs show poor delivery to brain tumors due to limited transport across the blood-brain barrier (BBB). To overcome this, a 19-amino acid peptide (angiopep-2) was developed that binds to low density lipoprotein receptor-related protein (LRP) receptors at the BBB and has the potential to deliver drugs to brain by receptor-mediated transport. METHODS: The transfer coefficient (K(in)) for brain influx was measured by in situ rat brain perfusion. Drug distribution was determined at 30 min after i.v. injection in mice bearing intracerebral MDA-MB-231BR metastases of breast cancer. RESULTS: The BBB K(in) for (125)I-ANG1005 uptake (7.3 +/- 0.2 x 10(-3) mL/s/g) exceeded that for (3)H-paclitaxel (8.5 +/- 0.5 x 10(-5)) by 86-fold. Over 70% of (125)I-ANG1005 tracer stayed in brain after capillary depletion or vascular washout. Brain (125)I-ANG1005 uptake was reduced by unlabeled angiopep-2 vector and by LRP ligands, consistent with receptor transport. In vivo uptake of (125)I-ANG1005 into vascularly corrected brain and brain metastases exceeded that of (14)C-paclitaxel by 4-54-fold. CONCLUSIONS: The results demonstrate that ANG1005 shows significantly improved delivery to brain and brain metastases of breast cancer compared to free paclitaxel.
PMID: 19774344 [PubMed - as supplied by publisher

1: Br J Pharmacol. 2008 Sep;155(2):185-97. Epub 2008 Jun 23. Links

Antitumour activity of ANG1005, a conjugate between paclitaxel and the new brain delivery vector Angiopep-2.

Régina A, Demeule M, Ché C, Lavallée I, Poirier J, Gabathuler R, Béliveau R, Castaigne JP.
Chemistry Department, Université du Québec Ã* Montréal, Montréal, Québec, Canada.
BACKGROUND AND PURPOSE: Paclitaxel is highly efficacious in the treatment of breast, head and neck, non-small cell lung cancers and ovarian carcinoma. For malignant gliomas, paclitaxel is prevented from reaching its target by the presence of the efflux pump P-glycoprotein (P-gp) at the blood-brain barrier. We investigated the utilization of a new drug delivery system to increase brain delivery of paclitaxel. EXPERIMENTAL APPROACH:Paclitaxel molecules were conjugated to a brain peptide vector, Angiopep-2, to provide a paclitaxel-Angiopep-2 conjugate named ANG1005. We determined the brain uptake capacity, intracellular effects and antitumour properties of ANG1005 in vitro against human tumour cell lines and in vivo in human xenografts. We then determined ANG1005 activity on brain tumours with intracerebral human tumour models in nude mice. KEY RESULTS:We show by in situ brain perfusion that ANG1005 enters the brain to a greater extent than paclitaxel and bypasses the P-gp. ANG1005 has an antineoplastic potency similar to that of paclitaxel against human cancer cell lines. We also demonstrate that ANG1005 caused a more potent inhibition of human tumour xenografts than paclitaxel. Finally, ANG1005 administration led to a significant increase in the survival of mice with intracerebral implantation of U87 MG glioblastoma cells or NCI-H460 lung carcinoma cells.CONCLUSIONS AND IMPLICATIONS: These results demonstrate the antitumour potential of a new drug, ANG1005, and establish that conjugation of anticancer agents with the Angiopep-2 peptide vector could increase their efficacy in the treatment of brain cancer.
PMID: 18574456 [PubMed - indexed for MEDLINE]