DOCSLIB.ORG

Diabetic Macular Edema (DME): High Unmet Medical Need Significant Global Burden Due to Vision Loss

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Diabetic Macular Edema (DME): High Unmet Medical Need Significant Global Burden Due to Vision Loss 15th Angiogenesis meeting 2018, Miami Roche virtual pipeline event Tuesday, 13 February 2018 Agenda Welcome Karl Mahler, Head of Investor Relations Roche in ophthalmology - overview Jason S. Ehrlich, M.D. Ph.D., Global Head, Clinical Ophthalmology – Product Development BOULEVARD: Phase 2 results of the bispecific VEGF/Ang2 antibody in diabetic macula edema Sascha Fauser, M.D., Head pRED Ophthalmology Q&A Karl Mahler, Head of Investor Relations 2 Introduction Karl Mahler Head of Investor Relations 2018: Roche off to a good start Record number of pipeline assets at pivotal stage in multiple disease areas Hemlibra polatuzumab vedotin Venclexta idasanutlin Alecensa Alecensa ipatasertib Venclexta Tecentriq Tecentriq taselisib Alecensa Hemlibra Hemlibra VEGF-ANG2 biMAb Tecentriq idasanutlin idasanutlin SMN2 splicer Cotellic taselisib taselisib V1a receptor ant. - autism lampalizumab lampalizumab lampalizumab anti-myostatin adnectin NMEs gantenerumab gantenerumab satralizumab (IL-6R MAb) gantenerumab Ocrevus Ocrevus gantenerumab crenezumab satralizumab satralizumab crenezumab Ocrevus lebrikizumab lebrikizumab Ocrevus CapEndo etrolizumab etrolizumab etrolizumab etrolizumab 2014 2015 2016 2017 2 5 5 4 1 27 1 1 21 33 31 line extensions line Oncology Ophthalmology Neuroscience Immunology 4 Diabetic macular edema (DME): High unmet medical need Significant global burden due to vision loss • Rate of T2D continues to grow; 40-45% will develop diabetic retinopathy (DR)1 • DME – is the most common diabetic eye disease and the leading cause of irreversible blindness in working age Americans1 Increased risk of DME with longer duration of diabetes and increase HbA1c levels3 PDR Proliferative Diabetic Retinopathy Severe NPDR DME 1c Occurrence (~10% of DR will HbA Moderate NPDR 1 Stages of DR of Stages develop DME ) Mild NPDR Non-proliferative diabetic retinopathy Duration of Diabetes 1 National Eye Institute. Facts About Diabetic Eye Disease. Available at: https://nei.nih.gov/health/diabetic/retinopathy. 2 NIH National Eye institute-https://nei.nih.gov/health/macular-edema/fact_sheet. 5 3 Varma et al. Prevalence of and Risk Factors for Diabetic Macular Edema in the United States:JAMA Ophthalmol. 2014 Nov; 132(11): 1334–1340. Roche in ophthalmology - overview Jason S. Ehrlich, M.D., Ph.D. Global Head, Clinical Ophthalmology - Product Development Roche in ophthalmology Taking on the leading causes of vision loss through pioneering therapies Unmet Need Breakthrough Science Patient-Focused Innovation People and Partnerships Innovative treatment We are pioneers striving for Through our smart We hire the best people to options are needed to transformative therapies innovations in molecular advance science and improve address the leading causes that leverage cutting edge engineering, biomarkers people’s lives. We foster of vision loss affecting 253 science for diseases with and sustained drug delivery, extensive collaborative million people worldwide1 high unmet medical need we strive to design the partnerships with researchers, right therapies for the clinicians and patient groups right patients 1 WHO Fact Sheet, October 2017. Accessed 6 Feb 2018, http://www.who.int/mediacentre/factsheets/fs282/en/ 7 Ophthalmology pipeline Indication Phase I Phase II Phase III In Submission Approved ranibizumab Port Delivery System Neovascular AMD Lucentis 0.5 mg PFS anti-VEGF/ANG2 biMAb (RG7716) anti-VEGF/ANG2 Lucentis 0.3 mg Lucentis 0.3 mg Diabetic Eye Disease biMAb (RG7716) PFS (DME, DR) (DME, DR) Lucentis 0.5 mg Retinal Vein Occlusion PFS NME Geographic Atrophy (RG6417) Lucentis 0.5 mg Myopic CNV PFS Actemra/RoActemra Giant Cell Arteritis Multiple Sclerosis Ocrevus anti-IL6R Neuromyelitis Optica (RG6168/SA237) Glaucoma NME (RG7945) Status as of February 1, 2018. Lucentis in collaboration with Forsight and Novartis 8 DME=diabetic macular edema; DR=diabetic retinopathy; PFS=prefilled syringe; biMAb=bispecific monoclonal antibody; NME=new molecular entity Retinal vascular diseases remain leading causes of vision loss • Leading causes of vision loss in… – working-age people in US, Europe: Diabetic eye disease (DME, PDR) – elderly people in US, Europe: Neovascular AMD 2017 Ophthalmology market Neovascular AMD & DME market outlook AMD DME 8% nAMD, DME, RVO 5.7 5% USD bn 5.3 Glaucoma 4.2 US 16% Dry Eye 53% 2.8 Ocular inflammation/infections 18% Others EU5 Japan 2016 2026 2015 2025 Market size: CHF 18.6bn Wet AMD & DME: High growth disease areas Source: Evaluate Pharma (January 2018) Source: Decision Resources (January 2018) Note: Figures for 2017 involve forecast values for Q4 2017 as investor reports of all companies are not yet released 9 DME=diabetic macular edema; PDR=proliferative diabetic retinopathy; AMD=age-related macular degeneration Vision can be recovered in neovascular AMD and DME Anti-VEGF therapy can improve outcomes and has become SOC DME phase III studies: Aflibercept vs laser; DME phase III studies: Lucentis vs sham; mean change from baseline in VA during 52-wks1 mean change from baseline in VA during 24-months2 * VISTA VIVID *with censoring of values after additional treatment was given (LOCF) 1 Ophthalmology 2014; 121: 2247-2254; 2 RIDE/RISE: Ophthalmology 2011;118:1594-1602 10 AMD=age-related macular degeneration; DME=diabetic macular edema; VA=visual acuity Still, many patients remain visually impaired Improved efficacy is a major unmet need in retinal vascular disease RIDE and RISE phase III trials – DME1 Sham injection 0.3 mg ranibizumab 0.5 mg ranibizumab (n=130; 127) (n=125; 125) (n=127; 125) or better (%) better or Snellen equivalent of 20/40 equivalent Snellen 24 months 24 months Ranibizumab versus sham-injection: Change from baseline in percentage of patients with a Snellen equivalent of 20/40 or better at 24 months Despite significant improvements, many people do not achieve a visual acuity score of 20/40 or better 1 RIDE/RISE: Ophthalmology 2011;118:1594-1602; DME=diabetic macular edema 11 Snellen (eye chart to measure visual acuity) equivalent of 20/40: a person needs to approach to a distance of 6 metres (20 ft) to read letters that a person with normal acuity could read at 12m (40 feet). In an even more approximate manner, this person could be said to have "half" the normal acuity of 6/6 or 20/20. DME is underdiagnosed and undertreated today • Rate of type 2 diabetes continues to grow Treatment received during the first year following diagnosis • 40-45% of people with diabetes will develop diabetic retinopathy1,2 • DME is a type of DR that is a leading cause of vision loss for people 10000 75% of all patients receive no treatment in first 28 days with diabetes3 8000 5.4 mn DME prevalent cases (major markets) in 2015* Ranibizumab Aflibercept 6000 number Bevacizumab Patient 4000 39% 52% Drug- Diagnosed Treated 2000 Number of Patients 0 28 365 28 365 28 365 28 365 28 365 Days 4 ~Only 50% of people diagnosed today Observation anti-VEGF Laser Corticosteroid Combination J.R. Willis et al., AAO 2017 *Source: Decision Resources (January 2018) 1 National Eye Institute. Facts About Diabetic Eye Disease. Available at: https://nei.nih.gov/health/diabetic/retinopathy. 2 NIH National Eye institute-https://nei.nih.gov/health/macular- edema/fact_sheet. 3 American Academy of Ophthalmology. What is Diabetic Retinopathy? Available at: http://www.geteyesmart.org/eyesmart/diseases/diabetic-retinopathy/index.cfm. Accessed October 2, 2015. 4 Bressler NM, Varma R, Doan Q, et al. Prevalence of Visual Impairment from Diabetic Macular Edema and Relationship to Eye Care from the 2005 − 2008 12 National Health and Nutrition Examination Survey (NHANES)[abstract]. The Retina Society 45th Annual Scientific Meetings, Washington, DC; October 4−7, 2012 (accepted for presentation). DME is underdiagnosed and undertreated today • Rate of type 2 diabetes continues to grow Treatment received during the first year following diagnosis • 40-45% of people with diabetes will develop diabetic retinopathy1,2 • DME is a type of DR that is a leading cause of vision loss for people 10000 with diabetes3 60% of all patients receive no treatment in 1st year 8000 5.4 mn DME prevalent cases (major markets) in 2015* Ranibizumab Aflibercept 6000 number Bevacizumab Patient 4000 39% 52% Drug- Diagnosed Treated 2000 Number of Patients 0 28 365 28 365 28 365 28 365 28 365 Days 4 ~Only 50% of people diagnosed today Observation anti-VEGF Laser Corticosteroid Combination J.R. Willis et al., AAO 2017 *Source: Decision Resources (January 2018) 1 National Eye Institute. Facts About Diabetic Eye Disease. Available at: https://nei.nih.gov/health/diabetic/retinopathy. 2 NIH National Eye institute-https://nei.nih.gov/health/macular- edema/fact_sheet. 3 American Academy of Ophthalmology. What is Diabetic Retinopathy? Available at: http://www.geteyesmart.org/eyesmart/diseases/diabetic-retinopathy/index.cfm. Accessed October 2, 2015. 4 Bressler NM, Varma R, Doan Q, et al. Prevalence of Visual Impairment from Diabetic Macular Edema and Relationship to Eye Care from the 2005 − 2008 13 National Health and Nutrition Examination Survey (NHANES)[abstract]. The Retina Society 45th Annual Scientific Meetings, Washington, DC; October 4−7, 2012 (accepted for presentation). Real world outcomes in nAMD, DME limited by treatment burden Potentially addressed by extending durability of anti-VEGF, targeting additional MOAs, or both Anti-VEGF injections* in 1st year of treatment in patients provided 1 2 Mean change in visual acuity from baseline over time for patients with AMD anti-VEGF within 28 days of initial DME diagnosis Germany (n=420) Italy (n=365) 20% 19.3% 8 France (n=398) The Netherlands (n=350) United Kingdom (n=410) Total (n=2227) 16.4% a 6 15% 14.1% MORE VISITS & INJECTIONS 4 10.2% 9.6% 10% 7.7% 2 7.3% 5.9% Patients (%) Patients 5.4% 5% 4.0% 0 FEWER Mean VA MeanVA difference 0 90 180 270 360 450 540 630 720 -2 0% from baseline country by (LOCF) 1 2 3 4 5 6 7 8 9 10+ -4 Days Number of Anti-VEGF Injections • Patients received a mean of 5.0 and 2.2 injections in the first and second year, • Almost 50% of patients receiving anti-VEGF treatment within 28 days of initial respectively.
Load more

Recommended publications
  • WO 2015/120233 Al 13 August 2015 (13.08.2015) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/120233 Al 13 August 2015 (13.08.2015) P O P C T (51) International Patent Classification: (72) Inventors: CHO, William; c/o Genentech, Inc., 1 DNA A61K 39/00 (2006.01) C07K 16/18 (2006.01) Way, South San Francisco, California 94080 (US). A61P 25/28 (2006.01) FRIESENHAHN, Michel; c/o Genentech, Inc., 1 DNA Way, South San Francisco, California 94080 (US). PAUL, (21) International Application Number: Robert; c/o Genentech, Inc., 1 DNA Way, South San Fran PCT/US2015/014758 cisco, California 94080 (US). WARD, Michael; c/o Gen (22) International Filing Date: entech, Inc., 1 DNA Way, South San Francisco, California 6 February 2015 (06.02.2015) 94080 (US). (25) Filing Language: English (74) Agents: WAIS, Rebecca J. et al; Genentech, Inc., 1 DNA Way, Mail Stop 49, South San Francisco, California 94080 (26) Publication Language: English (US). (30) Priority Data: (81) Designated States (unless otherwise indicated, for every 61/937,472 8 February 2014 (08.02.2014) US kind of national protection available): AE, AG, AL, AM, 61/971,479 27 March 2014 (27.03.2014) US AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 62/010,259 10 June 2014 (10.06.2014) us BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, 62/081,992 19 November 2014 (19. 11.2014) us DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (71) Applicant (for all designated States except AL, AT, BE, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, BG, CH, CN, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, HR, HU, IE, IN, IS, IT, LT, LU, LV, MC, MK, MT, NL, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, NO, PL, FT, RO, RS, SE, SI, SK, SM, TR) : GENENTECH, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, INC.
    [Show full text]
  • Treatment of Alzheimer's Disease and Blood–Brain Barrier Drug Delivery
    pharmaceuticals Review Treatment of Alzheimer’s Disease and Blood–Brain Barrier Drug Delivery William M. Pardridge Department of Medicine, University of California, Los Angeles, CA 90024, USA; [email protected] Received: 24 October 2020; Accepted: 13 November 2020; Published: 16 November 2020 Abstract: Despite the enormity of the societal and health burdens caused by Alzheimer’s disease (AD), there have been no FDA approvals for new therapeutics for AD since 2003. This profound lack of progress in treatment of AD is due to dual problems, both related to the blood–brain barrier (BBB). First, 98% of small molecule drugs do not cross the BBB, and ~100% of biologic drugs do not cross the BBB, so BBB drug delivery technology is needed in AD drug development. Second, the pharmaceutical industry has not developed BBB drug delivery technology, which would enable industry to invent new therapeutics for AD that actually penetrate into brain parenchyma from blood. In 2020, less than 1% of all AD drug development projects use a BBB drug delivery technology. The pathogenesis of AD involves chronic neuro-inflammation, the progressive deposition of insoluble amyloid-beta or tau aggregates, and neural degeneration. New drugs that both attack these multiple sites in AD, and that have been coupled with BBB drug delivery technology, can lead to new and effective treatments of this serious disorder. Keywords: blood–brain barrier; brain drug delivery; drug targeting; endothelium; Alzheimer’s disease; therapeutic antibodies; neurotrophins; TNF inhibitors 1. Introduction Alzheimer’s Disease (AD) afflicts over 50 million people world-wide, and this health burden costs over 1% of global GDP [1].
    [Show full text]
  • Passive Immunotherapy for Alzheimer's Disease: What Have We
    The Journal of Nutrition, Health & Aging© Volume 17, Number 1, 2013 EDITORIAL Passive immunotheraPy for alzheimer’s disease: what have we learned, and where are we headed? 1 2 P.s. aisen , B. vellas 1. university of California in san-diego, alzheimer’s disease Collaborative study: usa; 2. Gerontopole, univeristy of toulouse, umr inserm 1027 university toulouse 3, Chu toulouse, france from the development of the first transgenic mouse model primary efficacy goals were not met, though pooled analyses of brain amyloidosis (1), and the remarkable report on the suggest cognitive benefits. dramatic effect of active immunization against aggregated Crenezumab also binds to a mid-sequence epitope, but amyloid peptide on this model (2), anti-amyloid differs from solenazumab in that it possesses an igG4 (rather immunotherapy has been the leading strategy for disease- than igG1) backbone, so that it triggers less cytokine modifying drug development. But progress has been production from microglia while maintaining phagocytosis devastatingly slow. development of the active vaccine for towards amyloid (8). in vitro studies indicate that crenezumab human ad was halted because of meningoencephalitis in a binds to aβ fibrils and oligomers, and to some extent small percentage of treated individuals (3). while efforts monomers. Crenezumab treatment reduces brain amyloid turned to the development of safer active vaccines, using short plaque burden in transgenic mice. Phase 1 studies suggest that sequence antigens to minimize toxicity mediated by cellular crenezumab may not cause vasogenic edema, though sample immunity, many companies sought development of passive sizes were small. Crenezumab has been selected for the immunotherapy. this approach affords much greater control- a coming trial in familial autosomal dominant ad conducted by monoclonal antibody, free of risk of cellular immune response, the alzheimer’s Prevention initiative group (9).
    [Show full text]
  • Tables-Of-Phase-3-Mabs.Pdf
    Table 3. Monoclonal antibodies in Phase 2/3 or 3 clinical studies for cancer indications Most advanced Primary sponsoring company INN or code name Molecular format Target(s) phase Phase 3 indications Therapeutic area Janssen Research & Development, LLC JNJ-56022473 Humanized mAb CD123 Phase 2/3 Acute myeloid leukemia Cancer Murine IgG1, Actinium Pharmaceuticals Iomab-B radiolabeled CD45 Phase 3 Acute myeloid leukemia Cancer Humanized IgG1, Seattle Genetics Vadastuximab talirine ADC CD33 Phase 3 Acute myeloid leukemia Cancer TG Therapeutics Ublituximab Chimeric IgG1 CD20 Phase 3 Chronic lymphocytic leukemia Cancer Xencor XMAB-5574, MOR208 Humanized IgG1 CD19 Phase 2/3 Diffuse large B-cell lymphoma Cancer Moxetumomab Murine IgG1 dsFv, AstraZeneca/MedImmune LLC pasudotox immunotoxin CD22 Phase 3 Hairy cell leukemia Cancer Humanized scFv, Viventia Bio Oportuzumab monatox immunotoxin EpCAM Phase 3 Bladder cancer Cancer scFv-targeted liposome containing Merrimack Pharmaceuticals MM-302 doxorubicin HER2 Phase 2/3 Breast cancer Cancer MacroGenics Margetuximab Chimeric IgG1 HER2 Phase 3 Breast cancer Cancer Gastric cancer or gastroesophageal junction Gilead Sciences GS-5745 Humanized IgG4 MMP9 Phase 3 adenocarcinoma; ulcerative colitis (Phase 2/3) Cancer; Immune-mediated disorders Depatuxizumab Humanized IgG1, AbbVie mafodotin ADC EGFR Phase 2/3 Glioblastoma Cancer AstraZeneca/MedImmune LLC Tremelimumab Human IgG2 CTLA4 Phase 3 NSCLC, head & neck cancer, bladder cancer Cancer NSCLC, head & neck cancer, bladder cancer, breast AstraZeneca/MedImmune
    [Show full text]
  • Structure of Crenezumab Complex with Aβ Shows Loss of Β-Hairpin
    www.nature.com/scientificreports OPEN Structure of Crenezumab Complex with Aβ Shows Loss of β-Hairpin Mark Ultsch1, Bing Li1, Till Maurer1, Mary Mathieu1, Oskar Adolfsson2, Andreas Muhs2, Andrea Pfeifer2, Maria Pihlgren2, Travis W. Bainbridge1, Mike Reichelt1, James A. Ernst1, 1 1 1 1 1 Received: 20 May 2016 Charles Eigenbrot , Germaine Fuh , Jasvinder K. Atwal , Ryan J. Watts & Weiru Wang Accepted: 21 November 2016 Accumulation of amyloid-β (Aβ) peptides and amyloid plaque deposition in brain is postulated as a Published: 20 December 2016 cause of Alzheimer’s disease (AD). The precise pathological species of Aβ remains elusive although evidence suggests soluble oligomers may be primarily responsible for neurotoxicity. Crenezumab is a humanized anti-Aβ monoclonal IgG4 that binds multiple forms of Aβ, with higher affinity for aggregated forms, and that blocks Aβ aggregation, and promotes disaggregation. To understand the structural basis for this binding profile and activity, we determined the crystal structure of crenezumab in complex with Aβ. The structure reveals a sequential epitope and conformational requirements for epitope recognition, which include a subtle but critical element that is likely the basis for crenezumab’s versatile binding profile. We find interactions consistent with high affinity for multiple forms βof A , particularly oligomers. Of note, crenezumab also sequesters the hydrophobic core of Aβ and breaks an essential salt-bridge characteristic of the β-hairpin conformation, eliminating features characteristic of the basic organization in Aβ oligomers and fibrils, and explains crenezumab’s inhibition of aggregation and promotion of disaggregation. These insights highlight crenezumab’s unique mechanism of action, particularly regarding Aβ oligomers, and provide a strong rationale for the evaluation of crenezumab as a potential AD therapy.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2017/0172932 A1 Peyman (43) Pub
    US 20170172932A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0172932 A1 Peyman (43) Pub. Date: Jun. 22, 2017 (54) EARLY CANCER DETECTION AND A 6LX 39/395 (2006.01) ENHANCED IMMUNOTHERAPY A61R 4I/00 (2006.01) (52) U.S. Cl. (71) Applicant: Gholam A. Peyman, Sun City, AZ CPC .......... A61K 9/50 (2013.01); A61K 39/39558 (US) (2013.01); A61K 4I/0052 (2013.01); A61 K 48/00 (2013.01); A61K 35/17 (2013.01); A61 K (72) Inventor: sham A. Peyman, Sun City, AZ 35/15 (2013.01); A61K 2035/124 (2013.01) (21) Appl. No.: 15/143,981 (57) ABSTRACT (22) Filed: May 2, 2016 A method of therapy for a tumor or other pathology by administering a combination of thermotherapy and immu Related U.S. Application Data notherapy optionally combined with gene delivery. The combination therapy beneficially treats the tumor and pre (63) Continuation-in-part of application No. 14/976,321, vents tumor recurrence, either locally or at a different site, by filed on Dec. 21, 2015. boosting the patient’s immune response both at the time or original therapy and/or for later therapy. With respect to Publication Classification gene delivery, the inventive method may be used in cancer (51) Int. Cl. therapy, but is not limited to such use; it will be appreciated A 6LX 9/50 (2006.01) that the inventive method may be used for gene delivery in A6 IK 35/5 (2006.01) general. The controlled and precise application of thermal A6 IK 4.8/00 (2006.01) energy enhances gene transfer to any cell, whether the cell A 6LX 35/7 (2006.01) is a neoplastic cell, a pre-neoplastic cell, or a normal cell.
    [Show full text]
  • Monoclonal Antibodies As Neurological Therapeutics
    pharmaceuticals Review Monoclonal Antibodies as Neurological Therapeutics Panagiotis Gklinos 1 , Miranta Papadopoulou 2, Vid Stanulovic 3, Dimos D. Mitsikostas 4 and Dimitrios Papadopoulos 5,6,* 1 Department of Neurology, KAT General Hospital of Attica, 14561 Athens, Greece; [email protected] 2 Center for Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 11527 Athens, Greece; [email protected] 3 Global Pharmacovigilance, R&D Sanofi, 91385 Chilly-Mazarin, France; vid.stanulovic@sanofi.com 4 1st Neurology Department, Aeginition Hospital, National and Kapodistrian University of Athens, 11521 Athens, Greece; [email protected] 5 Laboratory of Molecular Genetics, Hellenic Pasteur Institute, 129 Vasilissis Sophias Avenue, 11521 Athens, Greece 6 Salpetriere Neuropsychiatric Clinic, 149 Papandreou Street, Metamorphosi, 14452 Athens, Greece * Correspondence: [email protected] Abstract: Over the last 30 years the role of monoclonal antibodies in therapeutics has increased enormously, revolutionizing treatment in most medical specialties, including neurology. Monoclonal antibodies are key therapeutic agents for several neurological conditions with diverse pathophysio- logical mechanisms, including multiple sclerosis, migraines and neuromuscular disease. In addition, a great number of monoclonal antibodies against several targets are being investigated for many more neurological diseases, which reflects our advances in understanding the pathogenesis of these
    [Show full text]
  • ALZHEIMER's DISEASE UPDATE on CURRENT RESEARCH Lawrence S
    ALZHEIMER'S DISEASE UPDATE ON CURRENT RESEARCH Lawrence S. Honig, MD, PhD, FAAN Department of Neurology, Taub Institute for Research on Alzheimer’s Disease & the Aging Brain, Gertrude H. Sergievsky Center, and New York State Center of Excellence for Alzheimer’s Disease Columbia University Irving Medical Center / New York Presbyterian Hospital DISCLOSURES Consultant: Eisai, Miller Communications Recent Research Funding: Abbvie, Axovant, Biogen, Bristol-Myer Squibb, Eisai, Eli Lilly, Genentech, Roche, TauRx Share Holder: none I will discuss investigational drugs, and off-label usage of drugs. 2 ALZHEIMER’S DISEASE Research in Epidemiology ALZHEIMER’S RISK FACTORS AGE Education Gender Head Trauma? Diet? Exercise? Hypertension? Hyperlipidemia? Diabetes? Evans DA JAMA 1989; 262:2551-6 Cardiovascular or Cerebrovascular Disease? GENETICS ALZHEIMER’S GENETIC FACTORS Early-onset autosomal dominant disorders APP, PS1, PS2 : (<0.1% of patients) Late-onset risk factors AD Neuropathology Change (ADNC) % e4neg %e4pos N APOE-e4 Low ADNC 73% 27% 367 Intermediate ADNC 57% 43% 429 High ADNC 39% 61% 1097 SORL1, CLU, CR1, BIN1, PICALM, EXOC3L2, ABCA7, CD2AP, EPHA1, TREM2 + >20 others! Late onset protective factors APP Icelandic mutation (A673T) ALZHEIMER’S DISEASE Research in Diagnostics EXAMINATION: General, Neurological, Cognitive, Lab, MRI Consciousness Attention and concentration Language: expression, comprehension, naming, repetition Orientation to time, place, and person Memory functions: immediate, short-term, long-term Visuospatial abilities: drawing Analytic abilities Judgment and Insight Positron Emission Tomography-FDG AMYLOID IMAGING CC Rowe & VL Villemagne. J Nuc Med 2011; 52:1733-1740 TAU SYNAPTIC IMAGING IMAGING Normal MCI/AD UCB1017 Chen et al. JAMA Neurol 2018 Villemagne VL et al. Sem Nuc Med 2017;47:75-88 CEREBROSPINAL FLUID JR Steinerman & LS Honig.
    [Show full text]
  • Development of the Clinical Candidate PBD-C06, a Humanized Pglu3-Aβ-Specific Antibody Against Alzheimer's Disease with Reduced Complement Activation
    www.nature.com/scientificreports OPEN Development of the clinical candidate PBD-C06, a humanized pGlu3-Aβ-specifc antibody against Alzheimer’s disease with reduced complement activation Thore Hettmann1, Stephen D. Gillies2, Martin Kleinschmidt3, Anke Piechotta3, Koki Makioka4, Cynthia A. Lemere 4, Stephan Schilling1,3, Jens-Ulrich Rahfeld1,3* & Inge Lues1 In clinical trials with early Alzheimer’s patients, administration of anti-amyloid antibodies reduced amyloid deposits, suggesting that immunotherapies may be promising disease-modifying interventions against Alzheimer’s disease (AD). Specifc forms of amyloid beta (Aβ) peptides, for example post- translationally modifed Aβ peptides with a pyroglutamate at the N-terminus (pGlu3, pE3), are attractive antibody targets, due to pGlu3-Aβ’s neo-epitope character and its propensity to form neurotoxic oligomeric aggregates. We have generated a novel anti-pGlu3-Aβ antibody, PBD-C06, which is based on a murine precursor antibody that binds with high specifcity to pGlu3-Aβ monomers, oligomers and fbrils, including mixed aggregates of unmodifed Aβ and pGlu3-Aβ peptides. PBD-C06 was generated by frst grafting the murine antigen binding sequences onto suitable human variable light and heavy chains. Subsequently, the humanized antibody was de-immunized and site-specifc mutations were introduced to restore original target binding, to eliminate complement activation and to improve protein stability. PBD-C06 binds with the same specifcity and avidity as its murine precursor antibody and elimination of C1q binding did not compromise Fcγ-receptor binding or in vitro phagocytosis. Thus, PBD-C06 was specifcally designed to target neurotoxic aggregates and to avoid complement-mediated infammatory responses, in order to lower the risk for vasogenic edemas in the clinic.
    [Show full text]
  • INN Working Document 05.179 Update 2011
    INN Working Document 05.179 Update 2011 International Nonproprietary Names (INN) for biological and biotechnological substances (a review) INN Working Document 05.179 Distr.: GENERAL ENGLISH ONLY 2011 International Nonproprietary Names (INN) for biological and biotechnological substances (a review) Programme on International Nonproprietary Names (INN) Quality Assurance and Safety: Medicines Essential Medicines and Pharmaceutical Policies (EMP) International Nonproprietary Names (INN) for biological and biotechnological substances (a review) © World Health Organization 2011 All rights reserved. Publications of the World Health Organization are available on the WHO web site (www.who.int) or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; email: [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press through the WHO web site (http://www.who.int/about/licensing/copyright_form/en/index.html). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned.
    [Show full text]
  • A Abacavir Abacavirum Abakaviiri Abagovomab Abagovomabum
    A abacavir abacavirum abakaviiri abagovomab abagovomabum abagovomabi abamectin abamectinum abamektiini abametapir abametapirum abametapiiri abanoquil abanoquilum abanokiili abaperidone abaperidonum abaperidoni abarelix abarelixum abareliksi abatacept abataceptum abatasepti abciximab abciximabum absiksimabi abecarnil abecarnilum abekarniili abediterol abediterolum abediteroli abetimus abetimusum abetimuusi abexinostat abexinostatum abeksinostaatti abicipar pegol abiciparum pegolum abisipaaripegoli abiraterone abirateronum abirateroni abitesartan abitesartanum abitesartaani ablukast ablukastum ablukasti abrilumab abrilumabum abrilumabi abrineurin abrineurinum abrineuriini abunidazol abunidazolum abunidatsoli acadesine acadesinum akadesiini acamprosate acamprosatum akamprosaatti acarbose acarbosum akarboosi acebrochol acebrocholum asebrokoli aceburic acid acidum aceburicum asebuurihappo acebutolol acebutololum asebutololi acecainide acecainidum asekainidi acecarbromal acecarbromalum asekarbromaali aceclidine aceclidinum aseklidiini aceclofenac aceclofenacum aseklofenaakki acedapsone acedapsonum asedapsoni acediasulfone sodium acediasulfonum natricum asediasulfoninatrium acefluranol acefluranolum asefluranoli acefurtiamine acefurtiaminum asefurtiamiini acefylline clofibrol acefyllinum clofibrolum asefylliiniklofibroli acefylline piperazine acefyllinum piperazinum asefylliinipiperatsiini aceglatone aceglatonum aseglatoni aceglutamide aceglutamidum aseglutamidi acemannan acemannanum asemannaani acemetacin acemetacinum asemetasiini aceneuramic
    [Show full text]
  • What Have We Learned from Aducanumab?
    What have we learned from aducanumab? Samantha Budd Haeberlein, PhD Biogen, Cambridge, MA, USA October 25, 2018 1 Disclaimer • Aducanumab, is an investigational medicine and the benefit/risk profile has not been fully established. It has not received any marketing authorization and there is no guarantee that it will obtain such authorization in the future • The information and any data presented is early interim data from ongoing clinical trials and it is made available for scientific discussion only, in consideration of the general interest of the scientific community with respect to any progress in the research and development of possible treatments for Alzheimer disease • The information and any data presented are developed from scientific research and are not intended to predict the availability of any particular drug or therapy Biogen licensed the worldwide rights to aducanumab from Neurimmune Holding AG in 2007 and is responsible for its development and the commercialization. As of October 22, 2017, Biogen and Eisai are collaborating on the development and commercialization of aducanumab globally. 2 Accumulation of Aβ is a core pathology in Alzheimer’s disease (AD) Aβ, amyloid beta; APP, amyloid precursor protein. 2017 Alzheimer’s Disease Facts and Figures. http://www.alz.org/documents_custom/2017-facts-and-figures.pdf. Accessed June 4, 2018; Dubois B, et al. Alzheimer’s & Dementia. 2016;12:292–323; Jack CR, et al. Brain. 2009;132:1355-1364. 3 Our understanding of the amyloid pathway today Soluble Insoluble Aggregated Monomer Oligomer Fibril Amyloid plaque Altered neuronal and synaptic morphology1,2 Structural and functional disruption of neuronal networks2-5 Postulated as causative of Alzheimer’s disease6,7 • The relevant pathological form of Aβ remains elusive • Soluble oligomers &/or insoluble fibrils may play important roles in disease 1.
    [Show full text]