Enzyme Replacement Therapies that Cross the Blood-Brain Barrier. June 2016

Transcription

1 Enzyme Replacement Therapies that Cross the Blood-Brain Barrier June 2016

2 Plethora of validated neurodegeneration & neuroinflammation targets for biologics Abeta Phospho-Tau Alpha-synuclein TNF-alpha EPO GDNF NGF BDNF TGF-beta IL-1 PrP Why virtually no Biologics approved for CNS therapy? Blood-brain Barrier 2

3 The Blood-Brain Barrier brain spinal cord Whole body autoradiogram of mouse shows histamine, a small molecule, penetrates all organs of the body, except for the brain and spinal cord ~100% of all large molecule drugs do not cross the BBB 98% of all small molecule drugs do not cross the BBB

4 Barriers of the CNS Saunders NR, et al. Trends Neurosci. 2008;31:

5 Alternatives Intraventricular injections Intrathecal delivery By-pass BBB Disruption Intranasal Receptor mediated transcytosis Ligand Antibody-based

6 Intraventricular Intrathecal 6

7 Flow of Cerebrospinal Fluid 1,2 1. Eklund A, et al. 2007; Available at: 2. Internalize Medicine Available at:

8 Microvasculature of the Brain: Anatomical Site of the Blood-Brain Barrier There are >100 billion capillaries in the human brain The total length of brain capillaries is 400 miles The surface area of the brain endothelium is 20 M 2 8

9 Isolated Brain Capillaries: Blood-Brain Barrier in vitro 9

10 Transport Pathways Across the Blood Brain Barrier Herda LM, et al. Eur J Nanomed. 2014;6:

11 RMT Targets Cholesterol/Lipid Transporters 5 Transferrin Receptor mab 1 Receptor mab 3 Transferrin Receptor 2 Insulin Receptor 4 1. Zhang Y, et al Available at: 2. NLM Available at: 3. Deperalta G, et al. MAbs. 2013;5: Structural Biology and Diabetes Available at: 5. Emonard H, Marbaix E. Metalloproteinases in Medicine. 2015;2:9-18.

12 Antibodies: BBB Carrier + Therapeutic Antibody domain Binding receptor Therapeutic enzyme alone Therapeutic enzyme fusion Blood Brain

13 Neurovascular Unit CONFIDENTIAL

14 Pre-Clinical

15 AGT-182 Distributed Extensively to All Regions of Brain within 2 Hours of IV Injection in Rhesus Monkey MAb against mouse TfR IDS CONCLUSION Elaprase Alone AGT-182 Autoradiograph of AGT-182 versus Elaprase (approved recombinant form of IDS, the enzyme domain of the AGT-182 IgG-enzyme fusion protein) Re-engineering of IDS can deliver therapeutic levels of medical important enzymes across the Boado MJ, et al. Bioconjugate BBB Chem. 2013;24:

16 Enzyme Delivery to Rhesus Monkey Brain: Comparison of AGT-182 vs Elaprase alone Organ Uptake (%ID/100g) % injected dose brain Organ AGT-182 Elaprase Ratio Frontal cortex white matter 0.99 ± ± Lung 2.97 ± ± Skeletal muscle 0.23 ± ± Fat 0.25 ± ± [ 125 I]- AGT [ 125 I]- Elaprase Heart 1.32 ± ± Kidney 14.0 ± 0.69 Spleen Liver ± ± ± ± ±

17 AGT-m181 Validated in Mouse Model of Hurler Syndrome DISEASE DEFICIENT ENZYME STANDARD OF CARE Hurler Syndrome (MPS I) a-l-iduronidase (IDUA) Aldurazyme enzyme replacement therapy (ERT) administered weekly by IV STUDY DESIGN DOSE CONCLUSION Mouse with MPS I (age: 6 months) AGT-m181 (1 mg/kg) administered 2 times per week by IV for 8 weeks Reductions in: Lysosomal inclusion bodies in brain Glycosoaminoglycans in peripheral organs Immune response Adult Hurler mouse Boado MJ, et al. Molecular Pharmaceutics 2011;8:

18 AGT-m181 Reduced Lysosomal Inclusion Bodies in Mouse Model of Hurler Syndrome 73% reduction in lysosomal bodies in brain with 8 weeks of AGT-m181 treatment in adult Hurler mice Electron microscopy of brain of Hurler mouse treated with saline (A) or AGT-m181 (B). AGT-m181 targets the transferrin receptor, whereas AGT-181 targets the insulin receptor. TREATMENT Saline 18.5 ± 1.1 AGT-m ± 1.6* # of multi-vacuolated brain cells per 100 nucleoli *Statistically significant reduction. p<0.005 Boado MJ, et al. Molecular Pharmaceutics 2011;8:

19 HIRMAb-TNFR2 fusion protein: High affinity binding to HIR Binding to HIR extracellular domain

20 TfRMAb-TNFR fusion protein (AGT-m110): Neuroprotection in mouse model of Stroke Reversible middle cerebral artery occlusion (MCAO) stroke model saline etanercept Intravenous etanercept (1 mg/kg) had no effect in stroke, because etanercept does not cross the BBB, and the BBB is intact in the early hours after stroke when neuroprotection is still possible Intravenous AGT-m110 (1 mg/kg) reduced stroke volume by 48%, which was associated with a 54% reduction in neural deficit Sumbria RK, et al. Molecular Pharmaceutics 2011;8: Sumbria RK, et. al. Brain Research 2013; 1507; AGT-m110

21 Clinical

22 Lysosomal Storage Diseases: Large unmet need Potential to revolutionize treatment of devastating neurological disorders CNS sequelae in majority of patients Intellectual disability Severe behavioral issues Premature mortality MPS II Patient vs Normal Enlarged peri-ventricular space Axial T2 22

23 Antibody Directed Receptor-Mediated Transcytosis Therapies Entered Clinical Proof-of-Concept in 2016 Multiple Clinical Trials Ongoing Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 U.S. only AGT-181 Phase 1/2a Adult 9 pts, weekly IV dosing (8 weeks) Brazil only Phase 1 Adult Single dose 6 pts AGT-181 Phase 2 POC Pediatric 10 pts, weekly IV dosing (6 months) U.S. Europe Philippines AGT-182 Phase 1/2a Adult 12 pts, weekly IV dosing (8 weeks) 23

24 Clinical Data from MPS I & II Phase 1/2a and Phase 2 Studies Safety (Ongoing) Peripheral Pharmacodynamics: ugag (Ongoing) Liver and spleen size (Ongoing) CNS Pharmacodynamics: CSF GAG (Q Q1 2017) MRI (Hurler only) (Q Q1 2017) Behavioral (Hurler only) (Q Q1 2017) Cognitive (Hurler only) (Q Q1 2017) 24

25 Clinical Summary Pharmacokinetic data consistent with modeling of monkey data Projects to 1% injected dose entering CNS Safety confirmed Transient glucose depression during infusion o Managed with dextrose and snacking o Up to 3 mg/kg in adult Phase 1 (Brazil) Somatic pharmacodynamic impact confirmed Effect seen at lowest dose tested (1 mg/kg) Significant decrease in ugag/liver/spleen after washout 25

26 ArmaGen Pipeline PRODUCT INDICATIONS ENZYME REPLACED STATUS PARTNER AGT-181 Hurler syndrome (MPS I) Iduronadase (IDUA) Initiate Phase 2 in Q AGT-182 Hunter syndrome (MPS II) Iduronate-2-sulfatase (IDS) Phase 1/2a ongoing AGT-683 Metachromatic leukodystrophy Arylsulfatase A (ASA) Lead entering Pre-IND studies AGT-184 Sanfilippo A Sulfamidase (SGSH) Lead entering Pre-IND studies AGT-187 Sanfilippo B N-acetyl-alpha-D-glucosaminidase Lead entering Pre-IND studies Future Pipeline Opportunities: LSDs and Beyond Lysosomal Storage Disease CNS disease Targets Canavan leukodystrophy Alzheimer s Disease Anti-Abeta Battens CLN1 &CLN 2 Anti-tau Krabbe disease Anti-BACE Gangliosidosis GM1 & GM2 (Sandhoff) Parkinson s Disease Anti-alpha synuclein Niemann-Pick A Parkin Tay-Sachs disease CJD Anti-PrP Gaucher Neuroinflammation Anti-pro-inflammatory cytokine Alpha mannosidosis Stroke EPO Schindler type I-III Anti-TNF 26

27 ArmaGen Focuses on Multiple Receptors Based on Broad, Dominant Intellectual Property Ossianix Roche & Genentech Angiochem bioasis Vect-Horus Biogen Medimmune Dominant intellectual property Exclusive license for UCLA patent estate <500 claims for recombinant fusion proteins Claims cover receptors for insulin, transferrin, LRP-1 and any future receptor not yet identified 13 U.S. Patents issued or allowed covering lysosomal enzymes, neurotrophins, and therapeutic antibodies Recent allowance in Japan CONFIDENTIAL 27

28 Partnerships with Industry Leaders Validate Clinical and Commercial Potential of ArmaGen s Therapies Worldwide licensing and collaboration agreement with Shire plc to develop AGT-182 for Hunter syndrome $225 million in payments, including: o o o $15 million upfront in cash and equity Additional equity investment, R&D funding Development/sales milestones and tiered royalties up to double digits ArmaGen responsible for Phase 1 study; Shire responsible for further clinical development, registration and worldwide commercialization Research collaboration with Janssen (neuroscience target) Deals signed December 2015 Constructs under development at ArmaGen Research collaboration with Amgen and Janssen (neuroscience target) Deals signed December 2015 Constructs under development at ArmaGen CONFIDENTIAL 28

29 Conclusion High value clinical stage pipeline Two orphan clinical programs targeting high-unmet need o Hurler Syndrome (MPS I) fully owned by ArmaGen o Hunter Syndrome (MPS II) partnered with Shire Deep pipeline, potential for numerous transactions o Comparables transacting for high valuations Transformational platform technology Securing the biotech revolution access to the CNS Dominant IP & leader in the field Near-term value inflections Pharmacodynamic measures of somatic and CNS effects Validating pharma partnerships 29

30 Engineering Biotechnology for the Brain June 2016