ArmaGen Technologies-Enabling Biotechnology for the Brain

March 14, 2008. ArmaGen receives Notice of Allowance from the U.S. Patent and Trademark Office. The U.S. Patent and Trademark Office has granted a Notice of Allowance on Delivery of Pharmaceutical Agents Via the Human Insulin Receptor. The patent claims cover the genetic engineering of a monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb acts as a molecular Trojan horse to ferry drugs across the human blood-brain barrier (BBB). The HIRMAb BBB molecular Trojan horse, in conjunction with other platform technologies developed by the Company, can be used to deliver virtually any large molecule biopharmaceutical through the human BBB. The HIRMAb, and fusion protein technology, can deliver recombinant proteins, monoclonal antibodies, and therapeutic enzymes to the human brain from blood. The HIRMAb, and avidin biotin technology (U.S. Patent 6,287,792), can deliver siRNA across the human BBB. The HIRMAb, and Trojan horse liposome technology (U.S. Patent 6,372,250), can deliver non-viral plasmid DNA across the human BBB.

January 15, 2008. ArmaGen receives Orphan Drug Designation from the FDA for AGT-181. The U.S. Food and Drug Administration has granted ArmaGen Technologies Orphan Drug Designation for AGT-181 for the treatment of Mucopolysaccharidosis (MPS) Type I. MPS Type I is caused by an inherited defect leading to the low production of a lysosomal enzyme in the brain. The enzyme deficiency causes severe degeneration of brain cells. Enzyme replacement therapy does not treat the brain, because the enzyme does not cross the blood-brain barrier (BBB). ArmaGen has re-engineered the missing lysosomal enzyme as a fusion protein that is bi-functional, and both has lysosomal enzyme activity and crosses the human BBB via receptor-mediated transport. ArmaGen's re-engineering of lysosomal enzymes to cross the human BBB is described in the February 1, 2008 issue of Biotechnology & Bioengineering. The development of AGT-181 is the first enzyme pharmaceutical that has been specifically engineered to cross the human BBB and treat the brain in lysosomal storage disorders.

November 8, 2007. Intravenous RNAi of the brain with targeted siRNA.RNA interference (RNAi) enables the knock down of pathologic genes with short interfering RNA (siRNA) duplexes. The limiting factor in the translation of RNAi therapeutics from cultured cell systems to the in vivo state is the siRNA delivery system. Anionic siRNA molecules are generally formulated as a polyplex with a cationic molecule. ArmaGen Technologies has developed a new siRNA delivery system that does not use cationic formulations. In the December, 2007, issue of Pharmaceutical Research, Armagen Technologies achieves intravenous RNAi in intra-cranial brain cancer in vivo with the intravenous injection of targeted siRNA. The breakthrough combines RNAi technology with 2 delivery technologies: receptor-specific molecular Trojan horses and avidin-biotin technology. The mono-biotinylated siRNA is bound with very high affinity to a conjugate of streptavidin and a receptor-specific monoclonal antibody (MAb) that both crosses the blood-brain barrier (BBB) and the tumor cell membrane. Avidin, and streptavidin, bind biotinylated ligands with a dissociation half time of 3 months, and these complexes are highly stable in vivo. ArmaGen technologies has genetically engineered an avidin-MAb fusion protein, AGT-3 (see Products), for the in vivo delivery of siRNA in humans.

September 14, 2007. Neuroscene podcast on the blood-brain barrier and brain drug development. Neuroscene.com posts 20 minute podcast discussion on the role of the blood-brain barrier (BBB) in brain drug development. Discussion includes a review of the major role played by the BBB in limiting drug penetration to the brain: >98% of small molecule drugs do not cross the BBB, and ~100% of large molecule drugs do not cross the BBB. Since all Big Pharma and Big Biotech firms lack in-house BBB drug targeting technology, the majority of brain drug development programs--for small or large molecules-will be terminated. The problem is traced to a chronic under-development in infrastructure, as the number of scientist currently being trained in the BBB is minimal. No academic neuroscience program in the U.S. emphasizes BBB transport biology, much less BBB drug targeting technology. The podcast can be accessed in the Cognition section of Neuroscene.com under the date of Sept. 7, 2007.

August 23, 2007. ArmaGen Technologies completes Pre-IND meeting with FDA. ArmaGen Technologies today completes a Pre-IND meeting with the FDA for the treatment of acute ischemic stroke with intravenous AGT-120 administered within 5 hours of the brain attack. The meeting highlights included discussion of clinical trial design, GLP Pharmacology-Toxicology, and GMP manufacturing of AGT-120, a recombinant fusion protein. AGT-120 is a neuroprotective neurotrophin that was genetically engineered specifically to cross the human blood-brain barrier (BBB) following intravenous administration. The BBB is intact during the first 5 hours after a stroke, when neuroprotection and the rescue of dying brain cells is still possible. Therefore, neuroprotective drugs for stroke must be enabled to cross the BBB in order to be clinically effective in acute ischemic stroke.

July 12, 2007. ArmaGen engineers neurotrophin fusion protein for neural repair.ArmaGen Technologies describes the genetic engineering, expression, activity, and blood-brain barrier transport in the primate of a bi-functional fusion protein. The work is published in the August 15, 2007 issue of Biotechnology and Bioengineering. The work shows that ArmaGen's molecular Trojan horse can deliver across the human and primate blood-brain barrier (BBB) a neurotrophin that is one of the most potent inducers of neural repair. The fusion protein is a bi-functional molecule that both binds a human BBB receptor, to trigger transport into brain from blood, and binds a neuronal tyrosine kinase receptor, to trigger neuroprotection. The fusion protein binds the human BBB with high activity, and induces neuroprotection in human neural cells. The fusion protein crosses the Rhesus monkey BBB in vivo, and increases by many-fold the neurotrophin concentration in primate brain.

March 21, 2007. ArmaGen engineers therapeutic antibody for Alzheimer's disease. ArmaGen Technologies describes the genetic engineering, expression, activity, and transport in the primate of a tri-functional fusion antibody therapeutic for Alzheimer's disease (AD). The work is published today in Bioconjugate Chemistry by the American Chemical Society (http://pubs.acs.org/journals/bcches/index.html). The work shows that ArmaGen's molecular Trojan horse can deliver across the human and primate blood-brain barrier (BBB) a monoclonal antibody therapeutic that binds and disaggregates the Abeta amyloid of AD. This is the first anti-Abeta antibody that has been specifically engineered to cross the BBB in both directions: from blood-to-brain, and brain-to-blood. Therapeutic antibodies for AD in the blood must have a mechanism to access the Abeta amyloid plaque in brain behind the BBB. Moreover, once in brain, there must be a mechanism for the Abeta/antibody complex to exit the brain and return to blood for final degradation in liver and spleen. These functions are all incorporated in this new tri-functional fusion antibody therapeutic for AD. A single injection of the antibody fusion protein in the brains of AD transgenic mice caused a nearly 40% reduction in the brain amyloid burden within 48 hours. The fusion antibody was rapidly transported in the blood to brain direction via the BBB insulin receptor and was rapidly transported in the brain to blood direction via the BBB Fc receptor.

September 20 , 2006. ArmaGen receives funding for clinical trial of AGT-120 in acute stroke. ArmaGen Technologies receives a Type 2 Small Business Innovation Research (SBIR) grant from the National Institutes of Health (NIH) to fund the phase I-IIA clinical trial of AGT-120 in acute stroke. The award will fund GLP Pharmacology-Toxicology in primates, submission of the Investigational New Drug (IND) application to the FDA, the GMP manufacturing of AGT-120, and the phase I-IIA clinical trial. The trial is multi-center, randomized, double-blind, placebo-controlled, ascending dose study. Patients will be treated up to 5 hours after stroke. The primary endpoints are the safety, tolerability, and pharmacokinetics of a single intravenous administration of AGT-120, and the secondary endpoints will explore drug effect on clinical outcome scales in stroke. AGT-120 is a fusion protein comprised of a highly neuroprotective neurotrophin, which is fused to a genetically engineered molecular Trojan horse. The Trojan horse part of the fusion protein triggers receptor-mediated transport across the blood-brain barrier (BBB), so that the neurotrophin part can then activate its cognate receptor on brain cells to halt the neuronal death cycle in stroke. Neurotrophins, which are strongly neuroprotective in stroke, must be injected directly into the brain, because these molecules do not cross the BBB. Moreover, the BBB is intact after stroke when neuroprotection is still possible. Since it is not possible to treat acute stroke by direct injection into the brain--neuroprotective agents, such as neurotrophins, must be engineered to cross an intact human BBB. AGT-120 is the first neuroprotective agent ever engineered specifically to cross the BBB.

September 19, 2006. ArmaGen expands exclusive patent estate licensed from the University of California. ArmaGen Technologies and the University of California (UC) amend the Exclusive Patent License granted by the UC to ArmaGen to include new technology for the blood-brain barrier (BBB) delivery of a wide range of pharmaceuticals. The expanded license now includes the delivery of certain neurotrophins across the BBB for the treatment of stroke, and the delivery of lysosomal enzymes across the BBB for the treatment of lysosomal storage disorders. The amended license also includes the exclusive use of avidin-biotin technology in drug delivery.

September 18 , 2006. ArmaGen develops AGT-185 for the treatment of nerve gas exposure. ArmaGen Technologies initiates a new program on the development of AGT-185, a treatment for acute nerve gas exposure of the central nervous system (CNS). AGT-185 is a genetically engineered recombinant fusion protein, which is comprised of 2 parts: (a) a human enzyme that is the most potent agent causing degradation of chemical nerve gas agents, and (b) a molecular Trojan horse. The latter is able to cross the blood-brain barrier (BBB) and deliver the nerve gas degrading enzyme into the CNS. Nerve gas agents cause death by the action of these agents within the CNS behind the BBB. Therefore, it is crucial that nerve gas antidotes are engineered to cross the human BBB to degrade the chemical nerve gas molecules within the CNS.

June 26, 2006. ArmaGen develops AGT-140, a neurotrophin neuroprotective therapy for stroke. ArmaGen Technologies begins development of AGT-140, a novel recombinant neurotrophin fusion protein that is able to both cross the blood-brain barrier (BBB) and to induce neuroprotection in acute stroke. ArmaGen will develop AGT-120 (see above) and AGT-140 in parallel for the acute treatment and neuroprotection in stroke. The pharmacological effect of the 2 drugs in stroke will be additive, as AGT-120 and AGT-140 cause neuroprotection in different regions of the brain via different neurotrophin receptors. The drug development of AGT-140, in parallel with AGT-120, is designed to enable combination therapy for neuroprotection in stroke.

February 6, 2006. ArmaGen develops AGT-180, a lysosomal enzyme replacement therapy of the brain. ArmaGen Technologies initiates a program in Lysosomal Enzyme Replacement Therapy of the Brain. The work will produce a new genetically engineered form of a lysosomal enzyme that is enabled to cross the blood-brain barrier (BBB) following intravenous administration. With this new form of therapy, a lysosomal enzyme may be delivered to virtually all cells in the brain following an intravenous infusion, because the enzyme is delivered across the vascular wall of the brain, which forms the BBB. The lysosomal enzyme is fused to ArmaGen's molecular Trojan horse, which ferries the lysosomal enzyme from blood into the brain.

September 28, 2005. ArmaGen receives Notice of Allowance on U.S. Patent, "Non-invasive gene targeting to ocular cells." ArmaGen Technologies receives Notice of Allowance on U.S. Patent, "Non-Invasive Gene Targeting to Ocular Cells." This technology uses Trojan Horse Liposomes to deliver non-viral gene therapies to the retina and other structures of the eye in humans. The gene therapy is administered by a simple intravenous injection and without viruses. The exogenous gene is distributed and expressed in the entire retina.

February 17, 2005. ArmaGen publishes pre-clinical validation of lysosomal enzyme delivery to the brain . ArmaGen Technologies pre-clinical validation of lysosomal enzyme delivery to brain is published today in the Fast Forward section of the Journal of Pharmacology and Experimental Therapeutics (http://jpet.aspetjournals.org/). The work shows that ArmaGen's molecular Trojan horse can deliver a 116,000 Dalton enzyme across the blood-brain barrier (BBB) of adult mice following an intravenous administration. Without the molecular Trojan horse, there is no brain uptake of the blood-borne enzyme, because the protein does not cross the BBB. Following enzyme attachment to the molecular Trojan horse, which carries the enzyme into brain via endogenous peptide receptor transporters within the BBB, the brain enzyme activity is increased 1000% above basal levels. The study provides the basis for future lysosomal enzyme therapy of the brain using genetically engineered fusion proteins of lysosomal enzymes and BBB molecular Trojan horses.

September 30, 2004. ArmaGen gene delivery technology reviewed in Nature. Nature magazine reviews non-viral gene delivery technology developed by ArmaGen Technologies, Inc., in the Express Delivery box of the article entitled RNA Interference: the Silent Treatment.

April 27, 2004. ArmaGen brain delivery technology highlighted in Wall Street Journal. New Treatments for Brain Cancer article in Wall Street Journal highlights brain drug and gene delivey technology developed by ArmaGen Technologies, Inc.

April 2, 2004. ArmaGen signs exclusive patent agreement for technology platform with the University of California. ArmaGen Technologies signs Exclusive Patent and Bailment Agreement for 'Mediated Delivery Systems' with the University of California. The agreement gives ArmaGen exclusive, world-wide license rights to pending and world-wide issued patents comprising a broad patent estate covering multiple technology platforms for the delivery to brain, and other organs, of drugs, recombinant proteins, and non-viral gene medicines. Some areas covered by the exclusive license include:

technology platform for the use of molecular Trojan horses to ferry drugs across the blood-brain barrier
technology platform for the delivery of non-viral gene therapies to brain, as well as non-brain organs
delivery of non-viral gene therapies to the retina and other structures of the eye
genetically engineered molecular Trojan horse for drug and gene delivery across the human blood-brain barrier
antisense gene therapy for human brain cancer

March 18, 2004. ArmaGen develops AGT-2000, a non-viral gene therapy of brain cancer. ArmaGen Technologies announces program to develop AGT-2000, a non-viral gene therapy for primary and metastatic brain cancer. AGT-2000 is a new form of gene therapy for brain cancer that is active following an intravenous administration without viruses. The gene therapy knocks down an oncogenic gene common to both primary and metastatic brain cancer. The gene is delivered across the blood-brain barrier of brain cancer with the same molecular Trojan horses which are used to deliver ArmaGen's protein based therapeutics. Since the gene target is expressed in both primary and metastatic cancer of the brain, the potential market for AGT-2000 is > 100,000 cases per year in the U.S.

March 11, 2004. Company incorporated as ArmaGen Technologies, Inc. Company changes its name and status from Neurogene Technologies LLC to ArmaGen Technologies, Inc., a Delaware corporation.

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