美国2013年开发中的阿尔茨海默氏病新药

20 13 R EPO RT Today, more than 5 million Americans are suffering from Alzheimer’s disease. The disease ravages the minds of patients, burdens families and currently costs the health care system $200 billion a year. These sobering statistics are projected to get much worse as the 76 million American baby boomers age. If no new medicines are found to prevent, delay or stop the progression of Alzheimer’s disease, the number of people affected in America will jump to 15 million by 2050, according to the Alzheimer’s Association. Cost of care for Alzheimer’s patients could increase five-fold to $1.2 trillion a year. Even modest progress can drastically change this trajectory. A medicine that delays the onset of Alzheimer’s disease by five years would lower the number of Americans suffering from the disease by nearly half in 2050 and save $447 billion in related costs, the Alzheimer’s Association projects. America’s biopharmaceutical research companies are currently developing 73 potential new treatments and diagnos- tics for Alzheimer’s. However, the path from basic research to new medicines is extremely complex with setbacks along the way, particularly in the case of Alzheimer’s. A recent analysis by PhRMA found that from 1998 through 2011, there were 101 unsuccessful attempts to develop drugs to treat Alzheimer’s—or as some call them “failures.” In that time, only three new medicines were approved to treat the symptoms of Alzheimer’s disease. In other words, for every one research project that yielded a new medicine, 34 fell short. Setbacks in Alzheimer’s research are disappointing to many—to patients, their families, healthcare providers, and the scientists carrying out the studies —but those unsuccessful attempts are critical stepping stones to advancing the understanding of this extremely complex disease. The reality is that those setbacks in the development of new medicines for Alzheimer’s are helping to redirect research by providing new information that allows science to move forward. Biopharmaceutical Research Companies Are Developing Nearly 75 Medicines for Alzheimer’s Disease MeDiCiNes iN DevelopMeNt Alzheimer’s Disease presented by america’s biopharmaceutical research companies Di ag no st ics Al zh eim er ’s D ise as e 64 9 Application Submitted Phase III Phase II Phase I Medicines and Diagnostics in Development for Alzheimer’s Disease Contents Alzheimer’s Medicines in the Pipeline ..........................................2 Preventing Alzheimer’s Disease ..........2 Challenges in Alzheimer’s Clinical Trials ...................................3 Research Breakthroughs in Alzheimer’s Disease ......................... 4 Medicines in Development ................5 Glossary ........................................11 Drug Development/ Approval Process ........................... 12 Medicines in Development alzheimer’s disease 20132 Alzheimer’s Medicines in the pipeline Medicines currently available for Alzheimer’s treat the cognitive symptoms of the disease—helping memory loss, confusion and problems with thinking—but do not address the underly- ing causes of the disease. Ongoing research is focused on treatments that may stop or slow down disease progression— disease-modifying agents. Two key hallmarks of Alzheimer’s disease are the appearance of amyloid plaques and neurofi- brillary tangles in the brain. Plaques are abnormal clusters of beta-amyloid protein fragments between nerve cells, while tangles are twisted fibers made primarily of a protein called “tau” that accumulates in the brain cells, damaging and killing them. Other areas of research are looking at the role inflammation and insulin resistance play in Alzheimer’s disease. A diagnosis of Alzheimer’s is normally based on cognitive testing, but until recently the only definitive way to diagnose the dis- ease was by conducting a biopsy of the patient’s brain after death. In 2012, Amyvid®, a positron emission tomography (PET) imaging agent, became the first diagnostic approved for Alzheimer’s disease and other causes of cognitive decline by identifying beta-amyloid plaques in the living brain. Several others are in development. targeting Upstream pathways—A potential first-in-class disease-modifying medicine for the treatment of Alzheimer’s targets energy production in neurons. Specifically, the medicine targets bioenergetic pathways upstream from the beta-amyloid peptide production found in Alzheimer’s. In preclinical studies, the medicine demonstrated significant improved cognition. Gene therapy to Restore Neuronal Function—A gene therapy for the treatment of Alzheimer’s disease is designed to deliver nerve growth factor (NGF) to the brain. NGF is a natu- rally occurring protein important for neuron survival. The gene treatment is injected into the brain region where the cells are damaged in Alzheimer’s patients. It is thought that the resulting sustained expression of NGF in the neurons can restore their lost function, leading to memory and cognition improvement. Boosting immune Responses with vaccine treatments—A synthetic vaccine using an “affitope,” a peptide designed to mimic beta-amyloid antigens, induces antibody production against this protein without creating a systemic immune response (which would raise some safety concerns). Older vaccines carried the risk of activating specific T-cells that could lead to meningoencephalitis. preventing plaque Formation—A small molecule compound has been shown to prevent the formation and accumulation of the soluble and insoluble forms of beta-amyloid protein as well as amyloid plaques. It also appears to target and inhibit the tau protein, which plays an important role in the formation of the filaments that contribute to devastating neurofibrillary tangle formation. The presence of neurofibrillary tangles in the brain containing tau protein is an important pathological hallmark of Alzheimer’s disease. It potentially could affect both of the two major known components of Alzheimer’s disease brain lesions. inhibiting Beta-Amyloid production—A potential first-in-class medicine prevents the production of beta-amyloid by inhibiting an enzyme that is crucial in its propagation called the beta-site amyloid precursor protein cleaving enzyme (BACE1) inhibitor. It is thought that by reducing the levels of beta-amyloid entering into the brain, it can impact the progression of the disease. preventing Alzheimer’s Disease Following the research setbacks experienced over the last few years to find treatments for Alzheimer’s disease, sev- eral U.S. government grants have been awarded to study medicines that have the potential to prevent Alzheimer’s. Those preventative studies take a page from strategies used to combat other diseases, such as heart disease, by look- ing at people who are at risk for the disease and trying to prevent or delay onset. Some of the grants are part of the National Plan to Address Alzheimer’s Disease, established under the National Alzheim- er’s Project Act (NAPA) that was signed into law in January 2011. The Plan is intended to facilitate the goal of preventing and effectively treating Alzheimer’s disease by 2025. • In September 2013, a $33.2 million grant was awarded to study the effects of an Alzheimer’s medicine on people who have no symptoms of the disease, who are be- tween the ages of 60 and 75 and, while they are not symptomatic, they do have two copies of a gene known to increase the risk of getting Alzheimer’s. A separate award of $1.5 million was given to a trial that will study three anti-amyloid medicines in people with a rare gene mutation that leads to early-onset Alzheimer’s disease. • Another grant was awarded to study an anti-amyloid monoclonal antibody in people at risk for late-stage onset Key issues Medicines in Development alzheimer’s disease 2013 3 Alzheimer’s disease. Those patients have amyloid plaques in their brains, but are not experiencing any symptoms of the disease. • In 2012, $16 million was awarded to help test an anti- amyloid monoclonal antibody on a large extended family in Colombia with a gene mutation that causes them to develop early-onset Alzheimer’s disease. Challenges in Alzheimer’s Clinical trials There are several unique challenges researchers face when recruiting patients for Alzheimer’s disease clini- cal trials, both in terms of preventative studies, which recruit patients who have not yet shown symptoms for Alzheimer’s, and treatment clinical studies, which require patient participants, many of whom are already suffer- ing from diminished decision-making skills. Some of the challenges specific to treatment trials include: • Recruiting and retaining clinical trial participants (currently the greatest obstacle to developing new Alzheimer’s treatments). • Acquiring the necessary increased funding for clinical trials—both federal and private. • Gaining informed consent from patients who are already suffering from the effects of the disease. • Involving caregivers in research trials, which can add an extra burden to their daily routine. Key issues public/private partnerships: critical to advancing science Collaboration among partners in the entire medical innovation ecosystem is critical to help advance scientific understanding of some of the most complex diseases facing patients, including Alzheimer’s disease. Federal research institutions, academia, biopharmaceutical research companies and patient communities all play an important role in furthering research in Alzheimer’s disease. Medicines in Development alzheimer’s disease 20134 Early research discoveries often fuel the drug development pathways that biopharmaceutical company scientists undertake. Those discoveries help researchers target the disease through certain biological mechanisms that may have been previously unknown. Some noteworthy recent scientific discoveries in the field of Alzheimer’s research include: • Researchers at Mount Sinai Medical Center found 10 genes that account for half of the genetic risk for Alzheimer’s. • Two separate research groups have identified a mutation on the TREM2 gene that may increase a person’s chance of de- veloping late-stage Alzheimer’s disease by three to five times. Key issues research Focus: early alzheimer’s With the obstacles and challenges in finding treatments for late-stage Alzheimer’s disease, some scientists are shifting their focus to patients in the early stages of the disease, before the onset of noticeable dementia and significant irreversible damage to the brain. By finding and studying people with very early Alzheimer’s disease, or those who are at risk of developing the disease, researchers believe that new treatments will have the best chance of providing meaningful benefit to patients. Three new studies are working toward preventing the onset of Alzheimer’s disease in people who are at high-risk of developing the disease, but are pre-symptomatic and asymptomatic. Trial participants will be selected because they either have a genetic risk or already have plaque build-up in their brains. The trials will test different therapies. Two of the studies are targeting individuals with a gene mutation that almost guarantees they will develop Alzheimer’s at a young age, while the third will study older individuals with plaque formations, but who are pre-symptomatic and asymptomatic. Research Breakthroughs in Alzheimer’s Disease Medicines in Development alzheimer’s disease 2013 5 medicines in development for alzheimer’s disease *For more information about a specific medicine or company in the report, please use the website provided. Alzheimer’s Disease, Therapeutics Product Name Sponsor Indication Development Phase* AAB-003/PF-05236812 (beta-amyloid protein inhibitor mAb) Janssen Alzheimer Immunotherapy South San Francisco, CA Pfizer New York, NY Alzheimer’s disease Phase I www.janssenrnd.com www.pfizer.com ABT-126 (alpha-7-NNR antagonist) AbbVie North Chicago, IL Alzheimer’s disease Phase II www.abbvie.com ABT-354 (serotinin 5-HT6 receptor antagonist) AbbVie North Chicago, IL Alzheimer’s disease Phase I www.abbvie.com ABT-957 (calpain inhibitor) AbbVie North Chicago, IL Alzheimer’s disease Phase I www.abbvie.com AC-1204 (glucose stimulant) Accera Broomfield, CO mild to moderate Alzheimer’s disease Phase II/III www.accerapharma.com AD02 vaccine (amyloid-beta protein inhibitor) Affiris Vienna, Austria GlaxoSmithKline Rsch. Triangle Park, NC Alzheimer’s disease Phase II www.affiris.com www.gsk.com AD03 vaccine (amyloid-beta protein inhibitor) Affiris Vienna, Austria GlaxoSmithKline Rsch. Triangle Park, NC Alzheimer's disease Phase I www.affiris.com www.gsk.com APH-0703 (protein kinase C stimulant) Aphios Woburn, MA Alzheimer’s disease Phase II www.aphios.com ARC029 (nilvadipine) Archer Pharmaceuticals Sarasota, FL Alzheimer’s disease Phase I/II www.archerpharma.com ARC031 (soluble amyloid reducing/clearing agent) Archer Pharmaceuticals Sarasota, FL Alzheimer’s disease Phase I www.archerpharma.com AVN 101 (serotonin 5-HT6 receptor antagonist) Avineuro Pharmaceuticals San Diego, CA Alzheimer’s disease Phase II www.avineuro.com AVN 322 (serotonin 6 receptor antagonist) Avineuro Pharmaceuticals San Diego, CA Alzheimer’s disease Phase I www.avineuro.com Medicines in Development alzheimer’s disease 20136 medicines in development for alzheimer’s disease Alzheimer’s Disease, Therapeutics Product Name Sponsor Indication Development Phase AVP-923 (dextromethorphan/quinidine fixed-dose combination) Avanir Pharmaceuticals Aliso Viejo, CA agitation in Alzheimer’s disease Phase II www.avanir.com AZD3293 (beta secretase) Astex Pharmaceuticals Dublin, CA AstraZeneca Wilmington, DE Alzheimer’s disease Phase I www.astx.com www.astrazeneca.com BACE inhibitor Janssen Pharmaceuticals Titusville, NJ Shionogi Florham Park, NJ Alzheimer’s disease Phase I www.janssenpharmaceuticalsinc.com www.shionogi.com BAN2401 (amyloid beta-protein inhibitor) Eisai Woodcliff Lake, NJ early stage Alzheimer’s disease Phase II www.eisai.com BIIB037 (human anti-amyloid beta mAb) Biogen Idec Weston, MA Alzheimer’s disease Phase I www.biogenidec.com bisnorcymserine (BNC) QR Pharma Berwyn, PA moderate to severe Alzheimer’s disease Phase I www.qrpharma.com BMS-241027 (microtubule stabilizer) Bristol-Myers Squibb Princeton, NJ Alzheimer’s disease Phase I www.bms.com CAD106 (amyloid beta-protein inhibitor) Novartis Pharmaceuticals East Hanover, NJ Alzheimer’s disease Phase II www.novartis.com CERE-110 (AAV-NGF) Ceregene San Diego, CA Sangamo BioSciences Richmond, VA Alzheimer’s disease Phase II www.ceregene.com www.sangamo.com crenezumab (anti-amyloid-beta mAb) Genentech South San Francisco, CA Alzheimer’s disease Phase II www.gene.com donepezil/memantine extended release (fixed-dose combination) Adamas Pharmaceuticals Emeryville, CA Forest Laboratories New York, NY moderate to severe Alzheimer’s disease Phase III www.adamaspharma.com www.frx.com DSP-8658 (PPAR alpha/gamma agonist) Sunovion Pharmaceuticals Marlborough, MA Alzheimer’s disease Phase I www.sunovion.com Medicines in Development alzheimer’s disease 2013 7 Alzheimer’s Disease, Therapeutics Product Name Sponsor Indication Development Phase E2212 (amyloid precursor protein secretase modulator) Eisai Woodcliff Lake, NJ Alzheimer’s disease Phase I completed www.eisai.com E2609 (BACE1 protein inhibitor) Eisai Woodcliff Lake, NJ Alzheimer’s disease Phase I completed www.eisai.com ELND005 Speranza Therapeutics Dublin, Ireland neuropsychiatric symptoms in Alzheimer’s disease (Fast Track) Phase II EVP-0962 (gamma secretase modulator) EnVivo Pharmaceuticals Watertown, MA Alzheimer’s disease Phase I www.envivopharma.com EVP-6124 (alpha7 nicotinic acetylcholine receptor agonist) EnVivo Pharmaceuticals Watertown, MA Alzheimer’s disease Phase II www.envivopharma.com Exebryl-1® (amyloid-beta-protein/tau protein inhibitor) ProteoTech Kirkland, WA Alzheimer’s disease Phase I www.proteotech.com gantenerumab (RG1450) Roche Nutley, NJ early stage Alzheimer’s disease Phase II/III www.roche.com GM6 (peptide therapeutic) Genervon Biopharmaceuticals Pasadena, CA Alzheimer’s disease Phase I www.genervon.com GSK2647544 (Lp-PLA2 inhibitor) GlaxoSmithKline Rsch. Triangle Park, NC Alzheimer’s disease Phase I www.gsk.com HPP854 (BACE1 inhibitor) Transtech Pharma High Point, NC Alzheimer’s disease Phase I www.ttpharma.com JNJ-54861911 Janssen Research & Development Raritan, NJ Alzheimer’s disease Phase I www.janssenrnd.com KU-046 (amyloid beta-protein modulator) Kareus Therapeutics La Chaux-de-Fonds, Switzerland Alzheimer’s disease Phase I www.kareustherapeutics.com LMTX™ tau aggregation inhibitor TauRx Pharmaceuticals Singapore Alzheimer’s disease, frontotemporal dementia Phase III www.taurx.com Lu AE58054 (5-HT6 receptor antagonist) Lundbeck Deerfield, IL Otsuka America Pharmaceutical Rockville, MD Alzheimer’s disease (cognition) Phase II www.lundbeck.com www.otsuka.com medicines in development for alzheimer’s disease Medicines in Development alzheimer’s disease 20138 Alzheimer’s Disease, Therapeutics Product Name Sponsor Indication Development Phase LY2886721 (beta secretase inhibitor) Eli Lilly Indianapolis, IN Alzheimer’s disease (slow disease progression) Phase II www.lilly.com LY3002813 (N3pG-AB mAb) Eli Lilly Indianapolis, IN Alzheimer’s disease Phase I www.lilly.com MK-8931 (BACE1 protein inhibitor) Merck Whitehouse Station, NJ Alzheimer’s disease Phase II/III www.merck.com MSDC-0160 (mTOT modulator insulin sensitizer) Metabolic Solutions Development Company Kalamazoo, MI Alzheimer’s disease Phase II www.msdrx.com NIC5-15 (amyloid precursor protein secretase inhibitor) Humanetics Minneapolis, MN Alzheimer’s disease Phase II www.humaneticscorp.com PF-05212377 (SAM-760) Pfizer New York, NY Alzheimer’s disease Phase II www.pfizer.com pioglitazone low-dose Takeda Pharmaceuticals U.S.A. Deerfield, IL Zinfandel Pharmaceuticals Chapel Hill, NC mild cognitive impairment due to Alzheimer’s disease Phase III www.takeda.com Posiphen® R-phenserine QR Pharma Berwyn, PA early Alzheimer’s disease Phase II www.qrpharma.com RG1577 (MAO-B inhibitor) Roche Nutley, NJ Alzheimer’s disease Phase II www.roche.com RG7129 (BACE1 protein inhibitor) Roche Nutley, NJ Alzheimer’s disease Phase I www.roche.com rilapladib (Lp-PLA2 inhibitor) GlaxoSmithKline Rsch. Triangle Park, NC Alzheimer’s disease Phase II www.gsk.com RVX-208 (BET protein inhibitor) Resverlogix Calgary, Canada Alzheimer’s disease Phase I www.resverlogix.com SAR110894 (H3 antagonist) Sanofi US Bridgewater, NJ Alzheimer’s disease Phase II www.sanofi.com SAR228810 (anti-protofibrillar AB mAb) Sanofi US Bridgewater, NJ Alzheimer’s disease Phase I www.sanofi.com medicines in development for alzheimer’s disease Medicines in Development alzheimer’s disease 2013 9 Alzheimer’s Disease, Therapeutics Product Name Sponsor Indication Development Phase sGC-1061 (nomethiazole) sGC Pharma Wellesley, MA Alzheimer’s disease Phase I www.sgcpharma.com solanezumab (amyloid-beta protein inhibitor) Eli Lilly Indianapolis, IN mild Alzheimer’s disease Phase III www.lilly.com ST101 Sonexa Therapeutics San Diego, CA Alzheimer’s disease Phase II completed www.sonexa.com T3D-959 (dual PPAR agonist) T3D Therapeutics Rsch. Triangle Park, NC Alzheimer’s disease Phase I completed www.t3dtherapeutics.com T-817MA Toyama Chemical Tokyo, Japan Alzheimer’s disease Phase II www.toyama-chemical.co.jp TC-1734 (ispronicline) Targacept Winston-Salem, NC Alzheimer’s disease Phase II www.targ