DOCSLIB.ORG

Update on Treatments for Patients with Genetic Obesity

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Update on Treatments for Patients with Genetic Obesity 5 183 C Poitou and others Treatments in genetic obesity 183:5 R149–R166 Review MECHANISMS IN ENDOCRINOLOGY Update on treatments for patients with genetic obesity C Poitou1,2, H Mosbah1 and K Clément1,2 1Assistance Publique-Hôpitaux de Paris, Reference Center for Rare Diseases (PRADORT, Prader-Willi Syndrome and Correspondence Other Rare Forms of Obesity with Eating Behavior Disorders), Nutrition Department, Pitié-Salpêtrière Hospital, Paris, should be addressed France and 2Sorbonne Université, INSERM, Nutrition and Obesity: Systemic Approaches (NutriOmics) Research Unit, to K Clément Paris, France Email [email protected] Abstract Obesity, defined by an excess of body fat impacting on health, is a complex disease resulting from the interaction between many genetic/epigenetic factors and environmental triggers. For some clinical situations with severe obesity, it has been possible to classify these obesity forms according to the molecular alterations. These include: (i) syndromic obesity, which associates severe early-onset obesity with neurodevelopmental disorders and/or polymalformative syndrome and (ii) non-syndromic monogenic obesity, due to gene variants most often located in the leptin- melanocortin pathway. In addition to severe obesity, patients affected by these diseases display complex somatic conditions, eventually including obesity comorbidities, neuropsychological and psychiatric disorders. These conditions render the clinical management of these patients particularly challenging. Patients’ early diagnosis is critical to allow specialized and multidisciplinary care, with a necessary interaction between the health and social sectors. Up to now, the management of genetic obesity was only based, above all, on controlling the patient's environment, which involves limiting access to food, ensuring a reassuring daily eating environment that limits impulsiveness, and the practice of adapted, supported, and supervised physical activity. Bariatric surgery has also been undertaken in genetic obesity European Journal of Endocrinology cases with uncertain outcomes. The context is rapidly changing, as new innovative therapies are currently being tested both for syndromic and monogenic forms of obesity. This review focuses on care management and new therapeutic opportunities in genetic obesity, including the use of the melanocortin 4 agonist, setmelanotide. The results from ongoing trials will hopefully pave the way to a future precision medicine approach for genetic obesity. European Journal of Endocrinology (2020) 183, R149–R166 Invited Author’s profile Karine Clément (MD, PhD) is a Medical Doctor and Full Professor of Nutrition at Pitié- Salpêtrière hospital and Sorbonne University, Paris. Since 2002, her research unit at INSERM (www.nutriomique.org) works on the pathophysiology of obesity and related disorders. From 2011 to 2016, she created and was the director of the Institute of CardiometAbolism and Nutrition (ICAN). Prof Clément has been primarily involved in genetics of obesity and contributed to the identification of monogenic forms of obesity. Her group is also exploring the link between environmental changes (as changes in lifestyle and nutrition), gut microbiota, immune system and tissue functional modifications (adipose tissue fibrosis and inflammation). https://eje.bioscientifica.com © 2020 European Society of Endocrinology Published by Bioscientifica Ltd. https://doi.org/10.1530/EJE-20-0363 Printed in Great Britain Downloaded from Bioscientifica.com at 09/30/2021 01:43:16PM via free access -20-0363 Review C Poitou and others Treatments in genetic obesity 183:5 R150 Introduction body composition, with increased fat mass and reduced muscle mass (4), endocrine abnormalities (growth Technological advances in recent years, such as candidate hormone deficiency, hypogonadism), intellectual gene approaches, next-generation sequencing (NGS), impairment, and learning difficulties, as well as behavioral genome-wide association studies (GWAS), and expression disorders, and dysmorphic traits (5). The evolution of studies using microarrays, have led to the discovery PWS from childhood to adulthood is often marked by of hundreds of genes involved in the development of the development of severe obesity, mostly associated with obesity. There is a proposed continuum between obesity a switch from difficulties eating to uncontrolled eating due to polygenic inheritance, the most common form, behavior. Of note this critical period in the developmental in which the environment has a critical impact on the trajectory is markedly influenced by the nature of the phenotypic development, and the rare forms of genetic patient’s environmental care (i.e. provided by caregivers) obesity, which are often severe and show an early onset, and implemented specialized care. In other words, early with a predominant contribution of genetic factors. and closely implemented care can limit the severity of These genetic forms are now considered to represent uncontrolled eating and the development of obesity (6). approximately 5–10% of childhood severe obesity (1). PWS is linked to abnormal parental genomic imprinting As it is described elsewhere (2), we will not describe in with the physical or functional absence of chromosomal detail the clinical progression of obesity from childhood segment 15q11–q13 of paternal origin. The 15q11.2– to adulthood that may give rise to the suspicion of genetic q13 region contains a PWS domain with five paternally obesity and lead to its molecular diagnosis (2). However, it expressed protein-coding genes including MRKN3 should be noted that early-onset obesity (before 6 years of (makorin 3), MAGEL2 (MAGE-like 2), NDN (necdin), age) associated with eating disorders, endocrine anomalies NPAP1 and SNURF-SNRPN (SNRPN uptream reading (hypogonadism, growth abnormality), and/or signs specific frame-small nuclear ribonucleoprotein polypeptide N) of the syndromic form, such as neurodevelopmental and snoRNAs (7). disorders, should alert clinicians and lead to molecular The BBS phenotype is also heterogeneous with testing. Thus, after summarizing the clinical pictures, we autosomal recessive transmission. In addition to severe present the latest advances concerning new therapies that early-onset obesity, patients may show retinal dystrophy, have been developed over the past several years that have polydactyly, kidney abnormalities, hypogonadism, made it possible to propose effective solutions to patients dysmorphia, and learning disabilities. At least 19 genes with genetic obesity. are involved in BBS, all linked to functioning of the European Journal of Endocrinology primary cilium (8). Hair cells are critical for properly functioning cellular machinery and are used to transmit Clinical subtypes of genetic obesity signaling messages from the outside to the inside of cells. Hair cells are also involved in mammalian development, Syndromic obesities (ORPHANET code 240371) are contributing, in particular, to right/left symmetry. The defined as obesity starting early in childhood linked precise mechanisms involved in obesity development to eating behavior disorders and associated with a in BBS are still poorly understood. However, several neurodevelopmental disorder (intellectual impairment, hypotheses have been put forward (9, 10). One proposes a delayed walking, delayed learning, autism spectrum central origin of obesity due to hypothalamic dysfunction disorders) and/or malformative syndrome. More than 80 associated with hyperphagia. For example, the loss of syndromes have been described but not all of them have BBS proteins leads to synaptic aberrations in principal an identified genetic substratum (3). We briefly summarize neurons, especially in structures such as the hippocampus the main phenotypic traits for the most common and amygdala (11). Other hypotheses of a peripheral syndromes sharing physiopathological characteristics origin involving adipose tissue and adipocyte proliferation related to hypothalamus impairment. or other endocrine tissues (pancreas, stomach, intestine) PWS, of which the frequency is between 1/15 000 have also been proposed (10). to 1/20 000 births, is characterized by severe neonatal The 16p11.2 microdeletion syndrome is a disorder hypotonia, eating disorders evolving in several phases caused by a deletion of a small piece of chromosome (from anorexia with suckling disorders in the first months 16, detectable by chromosomal microarray analysis. of life to hyperphagia, with major food impulsivity People with 16p11.2 deletion syndrome usually have appearing at approximately 4–8 years of age), abnormal developmental delay, intellectual disability, and early-onset https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 09/30/2021 01:43:16PM via free access Review C Poitou and others Treatments in genetic obesity 183:5 R151 obesity. The prevalence is estimated to be approximately may depend in part on the environment and the influence 3 in 10 000. In a large cohort of patients with a 16p11.2 of other genes. These forms of obesity account for at least deletion syndrome, satiety was impaired in children 5% of the causes of early and severe obesity (19), but before the onset of obesity occurring in adolescence (12). this prevalence is probably underestimated and may be Among genes encompassed by this deletion, the SH2B1 higher in certain populations, especially those in which gene is involved in regulation of leptin signalization in consanguinity is frequently observed (16, 20, 21). Patients
Load more

Recommended publications
  • Efficacy and Safety of the MC4R Agonist Setmelanotide in POMC
    Efficacy and Safety of the MC4R Agonist Setmelanotide in POMC Deficiency Obesity: A Phase 3 Trial TT-P-LB-3712 Presenting Author: Karine Clément,1,2 Jesús Argente,3 Allison Bahm,4 Hillori Connors,5 Kathleen De Waele,6 Sadaf Farooqi,7 Gregory Gordon,5 James Swain,8 Guojun Yuan,5 Peter Kühnen9 Peter Kühnen 1Sorbonne Université, INSERM, Nutrition and Obesities Research Unit, Paris, France; 2Assistance Publique Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Nutrition Department, Paris, France; 3Department of Pediatrics & Pediatric Endocrinology, Universidad Autónoma de Madrid University, Madrid, Spain; 4Peel Memorial Hospital, Toronto, Ontario, Canada; 5Rhythm Pharmaceuticals, Inc., Boston, MA; [email protected] 6Ghent University Hospital, Ghent, Belgium; 7Wellcome-MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, United Kingdom; 8HonorHealth Bariatric Center, Scottsdale, AZ; 9Institute for Experimental Pediatric Endocrinology Charité Universitätsmedizin Berlin, Berlin, Germany Summary ¡ In this phase 3 trial, setmelanotide was associated with clinically meaningful weight loss and reduction in hunger scores in individuals with proopiomelanocortin (POMC) or proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency obesity ¡ No new safety concerns emerged, and setmelanotide was generally well tolerated in individuals with POMC or PCSK1 deficiency obesity ¡ Further evaluation of setmelanotide is warranted in other disorders resulting from variants in the central melanocortin pathway that cause impaired melanocortin 4 receptor (MC4R) activation ¡ Participants were instructed to not change their regular diet or exercise regimen Table 1. Baseline Participant Characteristics ¡ During the placebo withdrawal period, participants gained an average of 5.52 kg (n=8), and Introduction participants’ mean “most hunger” score (n=6) increased from 4.87 during the first open-label active Figure 2.
    [Show full text]
  • Efficacy and Safety of the MC4R Agonist Setmelanotide in POMC Deficiency Obesity: a Phase 3 Trial
    Efficacy and Safety of the MC4R Agonist Setmelanotide in POMC Deficiency Obesity: A Phase 3 Trial Karine Clément,1,2 Jesús Argente,3 Allison Bahm,4 Hillori Connors,5 Kathleen De Waele,6 Sadaf Farooqi,7 Greg Gordon,5 James Swain,8 Guojun Yuan,5 Peter Kühnen9 1Sorbonne Université, INSERM, Nutrition and Obesities Research Unit, Paris, France; 2Assistance Publique Hôpitaux de Paris, Pitié- Salpêtrière Hospital, Nutrition Department, Paris, France; 3Department of Pediatrics & Pediatric Endocrinology Universidad Autónoma de Madrid University, Madrid, Spain; 4Peel Memorial Hospital, Toronto, Canada; 5Rhythm Pharmaceuticals, Inc., Boston, MA; 6Ghent University Hospital, Ghent, Belgium; 7Wellcome-MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, United Kingdom; 8HonorHealth Bariatric Center, Scottsdale, AZ; 9Institute for Experimental Pediatric Endocrinology Charité Universitätsmedizin Berlin, Berlin, Germany Melanocortin Signaling Is Crucial for Regulation of Body Weight1,2 • Body weight is regulated by the hypothalamic central melanocortin pathway • In response to leptin signaling, POMC is produced in POMC neurons and is cleaved by protein convertase subtilisin/kexin type 1 into α-MSH and β-MSH • α-MSH and β-MSH bind to the MC4R, which decreases food intake and increases energy expenditure, thereby promoting a reduction in body weight Hypothalamus AgRP/NPY Neuron LEPR Hunger AgRP Food Intake ADIPOSE Weight TISSUE MC4R- Energy Expressing Expenditure MC4R Neuron LEPTIN PCSK1 BLOOD-BRAIN BARRIER POMC α-MSH LEPR POMC Neuron AgRP, agouti-related protein; LEPR, leptin receptor; MC4R, melanocortin 4 receptor; MSH, melanocyte-stimulating hormone; NPY, neuropeptide Y; PCSK1, proprotein convertase subtilisin/kexin type 1; POMC, proopiomelanocortin. 2 1. Yazdi et al.
    [Show full text]
  • Obesity Pharmacotherapy: Options and Applications in Clinical Practice
    Obesity Pharmacotherapy: Options and Applications in Clinical Practice Scott Kahan, MD, MPH Obesity Pharmacotherapy • Few providers prescribe pharmacotherapy. • Few patients use pharmacotherapy. • Pharmacotherapy can be extremely effective but also misused, overused, or underused. • Patients respond differently to each medication. • Combining therapeutic options significantly improves weight loss and other outcomes. • Pharmacotherapy can be effective for weight maintenance, not just weight loss. Few Eligible Patients Use Obesity Pharmacotherapy 2 1.8 1.6 1.4 1.3 1.2 1 0.9 0.8 0.7 0.6 0.6 0.4 12 months after the index date, % 0.2 0.2 Use of pharmacotherapy for weight loss within 0 >27‐<30 >30‐<35 >35‐<40 >40 Overall Body mass index at index (kg m2) Zhang S, et al. Obesity Science & Practice.2016;2:104-114. FDA-approved Pharmacotherapy Options for the Treatment of Obesity • Phentermine and other noradrenergic agents • Orlistat • Phentermine/topiramate ER • Lorcaserin • Naltrexone SR/bupropion SR • Liraglutide 3.0mg ER = extended release; SR = sustained release. Phentermine • Sympathomimetic amine, NE release • Blunts appetite • Approved in 1959 for short-term use, schedule IV • Dosing: 8 to 37.5 mg qAM; use lowest effective dose • Contraindications: pregnancy, nursing, MAOIs, glaucoma, drug abuse history, hyperthyroidism • Relative contraindications: uncontrolled hypertension, tachycardia, history of CAD, CHF, stroke, arrhythmia • Warnings: primary pulmonary hypertension, valvular heart disease, tolerance, risk of abuse, concomitant use with alcohol CAD = coronary artery disease; CHF = congestive heart failure; HTN = hypertension; MAOIs = monoamine oxidase inhibitors; NE = norepinephrine. Phentermine [package insert]. Cranford, NJ: Alpex Pharma SA; 2011; Munro JF, et al. Br Med J.
    [Show full text]
  • MC4R) Agonist (Setmelanotide) in MC4R Deficiency
    Brief Communication Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency Tinh-Hai Collet 1,2,12, Béatrice Dubern 3,4,12, Jacek Mokrosinski 1,12, Hillori Connors 5,12, Julia M. Keogh 1, Edson Mendes de Oliveira 1, Elana Henning 1, Christine Poitou-Bernert 3,4, Jean-Michel Oppert 3,4, Patrick Tounian 3,4, Florence Marchelli 3, Rohia Alili 3,4, Johanne Le Beyec 6,7,8, Dominique Pépin 6, Jean-Marc Lacorte 3,4,6, Andrew Gottesdiener 5, Rebecca Bounds 1, Shubh Sharma 5, Cathy Folster 5, Bart Henderson 5, Stephen O’Rahilly 1, Elizabeth Stoner 5, Keith Gottesdiener 5, Brandon L. Panaro 9,10, Roger D. Cone 10,11, Karine Clément 3,4,***,12, I. Sadaf Farooqi 1,*,12, Lex H.T. Van der Ploeg 5,**,12 ABSTRACT Objective: Pro-opiomelanocortin (POMC)-derived peptides act on neurons expressing the Melanocortin 4 receptor (MC4R) to reduce body weight. Setmelanotide is a highly potent MC4R agonist that leads to weight loss in diet-induced obese animals and in obese individuals with complete POMC deficiency. While POMC deficiency is very rare, 1e5% of severely obese individuals harbor heterozygous mutations in MC4R.We sought to assess the efficacy of Setmelanotide in human MC4R deficiency. Methods: We studied the effects of Setmelanotide on mutant MC4Rs in cells and the weight loss response to Setmelanotide administration in rodent studies and a human clinical trial. We annotated the functional status of 369 published MC4R variants. Results: In cells, we showed that Setmelanotide is significantly more potent at MC4R than the endogenous ligand alpha-melanocyte stimulating hormone and can disproportionally rescue signaling by a subset of severely impaired MC4R mutants.
    [Show full text]
  • Medical Treatment of Obesity: the Past, the Present and the Future
    Best Practice & Research Clinical Gastroenterology 28 (2014) 665e684 Contents lists available at ScienceDirect Best Practice & Research Clinical Gastroenterology 11 Medical treatment of obesity: The past, the present and the future * George A. Bray, MD, MACP, MACE, Boyd Professor 6400 Perkins Road, Baton Rouge, LA 70808, USA abstract Keywords: Medications for the treatment of obesity began to appear in the Orlistat late 19th and early 20th century. Amphetamine-addiction led to Serotonergic drugs the search for similar drugs without addictive properties. Four Sympathomimetic drugs sympathomimetic drugs currently approved in the US arose from Glucagon-like peptide-1 agonists this search, but may not be approved elsewhere. When norad- Combination therapy renergic drugs were combined with serotonergic drugs, additional weight loss was induced. At present there are three drugs (orlistat, phentermine/topiramate and lorcaserin) approved for long-term use and four sympathomimetic drugs approved by the US FDA for short-term treatment of obesity. Leptin produced in fat cells and glucagon-like peptide-1, a gastrointestinal hormone, provide a new molecular basis for treatment of obesity. New classes of agents acting on the melanocortin system in the brain or mimicking GLP-1 have been tried with variable success. Combi- nation therapy can substantially increase weight loss; a promising approach for the future. © 2014 Elsevier Ltd. All rights reserved. Introduction ‘A desire to take medicine is, perhaps, the great feature which distinguishes man from other animals.’ Sir William Osler [1] * Tel.: þ1 (225) 763 3176; fax: þ1 (225) 763 3045. E-mail addresses: [email protected], [email protected], [email protected].
    [Show full text]
  • Anti-Obesity Therapy: from Rainbow Pills to Polyagonists
    1521-0081/70/4/712–746$35.00 https://doi.org/10.1124/pr.117.014803 PHARMACOLOGICAL REVIEWS Pharmacol Rev 70:712–746, October 2018 Copyright © 2018 The Author(s). This is an open access article distributed under the CC BY Attribution 4.0 International license. ASSOCIATE EDITOR: BIRGITTE HOLST Anti-Obesity Therapy: from Rainbow Pills to Polyagonists T. D. Müller, C. Clemmensen, B. Finan, R. D. DiMarchi, and M. H. Tschöp Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (T.D.M., C.C., M.H.T.); German Center for Diabetes Research, Neuherberg, Germany (T.D.M., C.C., M.H.T.); Department of Chemistry, Indiana University, Bloomington, Indiana (B.F., R.D.D.); and Division of Metabolic Diseases, Technische Universität München, Munich, Germany (M.H.T.) Abstract ....................................................................................713 I. Introduction . ..............................................................................713 II. Bariatric Surgery: A Benchmark for Efficacy ................................................714 III. The Chronology of Modern Weight-Loss Pharmacology . .....................................715 A. Thyroid Hormones ......................................................................716 B. 2,4-Dinitrophenol .......................................................................716 C. Amphetamines. ........................................................................717 Downloaded from 1. Methamphetamine
    [Show full text]
  • Pharmacotherapy in the Treatment of Obesity
    © 2016 ILEX PUBLISHING HOUSE, Bucharest, Roumania http://www.jrdiabet.ro Rom J Diabetes Nutr Metab Dis. 23(4):415-422 doi: 10.1515/rjdnmd-2016-0048 PHARMACOTHERAPY IN THE TREATMENT OF OBESITY Floriana Elvira Ionică 1, Simona Negreș 2, Oana Cristina Șeremet 2, , Cornel Chiriță 2 1 University of Medicine and Pharmacy, Faculty of Pharmacy, Craiova, Romania 2 “Carol Davila” University of Medicine and Pharmacy, Faculty of Pharmacy, Bucharest, Romania received: September 17, 2016 accepted: December 02, 2016 available online: December 15, 2016 Abstract Background and Aims: In the last three decades, obesity and its related co morbidities has quickly increased. Sometime, obesity was viewed as a serious health issue in developed countries alone, but now is recognized as a worldwide epidemic, and its associated costs are enormous. Obesity is related with various diseases, like hypertension, type 2 diabetes mellitus (T2DM), dyslipidemia, chronic cardiovascular diseases, respiratory conditions, alongside chronic liver diseases, including non- alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). This review purpose is to provide data on the current anti-obesity drugs, also available and in the development. Material and Methods: We searched MEDLINE from 2006 to the present to collect information on the anti-obesity pharmacotherapy. Results and Conclusions: In the patients with obesity related comorbidities, there may be an adaptation of the anti-obesity pharmacotherapy to the patients’ needs, in respect to the improvements of the cardiometabolic parameters. Although their efficacy was proven, the anti-obesity pharmacotherapies have presented adverse events that require a careful monitoring during treatment. The main obstacle for approve new drugs seems to be the ratio between the risks and the benefits, because of a long-time background of perilous anti-obesity drugs.
    [Show full text]
  • Pharmacological Interventions for Obesity Issues Document Updated: April 21, 2021
    EMERGINGTHERAPEUTICS Pharmacological Interventions for Obesity Issues Document Updated: April 21, 2021 Summary Obesity is a chronic health condition that should be managed long-term. Over the past few decades, obesity has steadily increased in the U.S. and it continues to be a health concern for children, adolescents and adults. Increased weight is a risk factor for many conditions including diabetes, high cholesterol and high blood pressure. Studies have shown that even a moderate weight loss (5% to 10% from baseline) can decrease the severity of these obesity-associated conditions when it is sustained. Historically, weight-management drugs and supplements have been plagued by low effectiveness, rebounding weight gain, undesirable side effects and/or safety concerns. However, some recent FDA approved and near-term pipeline agents will challenge this narrative and require a closer look. This document provides an overview of currently available obesity drugs and highlights therapies under development that could enter this market over the next several years. Take-Aways The obesity epidemic continues to grow in the U.S. Current estimates are that 42.5% of U.S. adults age 20 years and older were obese in 2018 and 31.1% more were overweight, with no significant difference seen between genders. Also, for children and adolescents between two years and 19 years of age, approximately 19.3% were obese and another 16.1% were overweight. Obesity is a chronic disease, which commonly, incorrectly and insensitively is stigmatized. Actually, underlying causes can include genetic, social, economic and environmental circumstances. Obesity is a risk factor for many conditions, including diabetes, high cholesterol and high blood pressure.
    [Show full text]
  • Rxoutlook® 1St Quarter 2019
    ® RxOutlook 1st Quarter 2020 optum.com/optumrx a RxOutlook 1st Quarter 2020 Orphan drugs continue to feature prominently in the drug development pipeline In 1983 the Orphan Drug Act was signed into law. Thirty seven years later, what was initially envisioned as a minor category of drugs has become a major part of the drug development pipeline. The Orphan Drug Act was passed by the United States Congress in 1983 in order to spur drug development for rare conditions with high unmet need. The legislation provided financial incentives to manufacturers if they could demonstrate that the target population for their drug consisted of fewer than 200,000 persons in the United States, or that there was no reasonable expectation that commercial sales would be sufficient to recoup the developmental costs associated with the drug. These “Orphan Drug” approvals have become increasingly common over the last two decades. In 2000, two of the 27 (7%) new drugs approved by the FDA had Orphan Designation, whereas in 2019, 20 of the 48 new drugs (42%) approved by the FDA had Orphan Designation. Since the passage of the Orphan Drug Act, 37 years ago, additional regulations and FDA designations have been implemented in an attempt to further expedite drug development for certain serious and life threatening conditions. Drugs with a Fast Track designation can use Phase 2 clinical trials to support FDA approval. Drugs with Breakthrough Therapy designation can use alternative clinical trial designs instead of the traditional randomized, double-blind, placebo-controlled trial. Additionally, drugs may be approved via the Accelerated Approval pathway using surrogate endpoints in clinical trials rather than clinical outcomes.
    [Show full text]
  • Targeting Energy Expenditure—Drugs for Obesity Treatment
    pharmaceuticals Review Targeting Energy Expenditure—Drugs for Obesity Treatment Carlos M. Jimenez-Munoz 1 , Marta López 1 , Fernando Albericio 2,3,4,* and Kamil Makowski 2,3,* 1 School of Chemical Sciences and Engineering Yachay Tech University, San Miguel de Urcuquí 100119, Ecuador; [email protected] (C.M.J.-M.); [email protected] (M.L.) 2 Department of Surfactants and Biotechnology, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain 3 CIBER-BBN, Networking Centre of Bioengineering, Biomaterials, and Nanomedicine, and Department of Organic Chemistry, University of Barcelona, 08028 Barcelona, Spain 4 School of Chemistry and Physics, University of KwaZulu-Natal, Durban 4001, South Africa * Correspondence: [email protected] (F.A.); [email protected] or [email protected] (K.M.) Abstract: Obesity and overweight are associated with lethal diseases. In this context, obese and overweight individuals infected by COVID-19 are at greater risk of dying. Obesity is treated by three main pharmaceutical approaches, namely suppressing appetite, reducing energy intake by impairing absorption, and increasing energy expenditure. Most compounds used for the latter were first envisaged for other medical uses. However, several candidates are now being developed explicitly for targeting obesity by increasing energy expenditure. This review analyzes the compounds that show anti-obesity activity exerted through the energy expenditure pathway. They are classified on the basis of their development status: FDA-approved, Withdrawn, Clinical Trials, and Under Citation: Jimenez-Munoz, C.M.; Development. The chemical nature, target, mechanisms of action, and description of the current López, M.; Albericio, F.; Makowski, K.
    [Show full text]
  • 2016 Medicines in Development for Rare Diseases a LIST of ORPHAN DRUGS in the PIPELINE
    2016 Medicines in Development for Rare Diseases A LIST OF ORPHAN DRUGS IN THE PIPELINE Autoimmune Diseases Product Name Sponsor Official FDA Designation* Development Status Actemra® Genentech treatment of systemic sclerosis Phase III tocilizumab South San Francisco, CA www.gene.com Adempas® Bayer HealthCare Pharmaceuticals treatment of systemic sclerosis Phase II riociguat Whippany, NJ www.pharma.bayer.com ARA 290 Araim Pharmaceuticals treatment of neuropathic pain in patients Phase II Tarrytown, NY with sarcoidosis www.ariampharma.com ARG201 arGentis Pharmaceuticals treatment of diffuse systemic sclerosis Phase II (type 1 native bovine skin Collierville, TN www.argentisrx.com collagen) BYM338 Novartis Pharmaceuticals treatment of inclusion body myositis Phase III (bimagrumab) East Hanover, NJ www.novartis.com CCX168 ChemoCentryx treatment of anti-neutrophil cytoplasmic Phase II (5a receptor antagonist) Mountain View, CA auto-antibodies associated vasculitides www.chemocentryx.com (granulomatosis with polyangitis or Wegener's granulomatosis), microscopic polyangitis, and Churg-Strauss syndrome * This designation is issued by the FDA's Office of Orphan Products Development while the drug is still in development. The designation makes the sponsor of the drug eligible for entitlements under the Orphan Drug Act of 1983. The entitlements include seven years of marketing exclusivity following FDA approval of the drug for the designated use. Medicines in Development: Rare Diseases | 2016 1 Autoimmune Diseases Product Name Sponsor Official FDA
    [Show full text]
  • Setmelanotide for Pro-Opiomelanocortin Deficiency Obesity NIHRIO (HSRIC) ID: 8496 NICE ID: 9505
    NIHR Innovation Observatory Evidence Briefing: September 2017 Setmelanotide for pro-opiomelanocortin deficiency obesity NIHRIO (HSRIC) ID: 8496 NICE ID: 9505 LAY SUMMARY Body fat and food intake are regulated by signals from the brain to the gut. One of the important hormones that is responsible for this is pro-opiomelanocortin (POMC). In a very small group of people there is a lack of this hormone (due to a genetic mutation), referred to as POMC deficiency. This causes severe overeating which leads to obesity and high blood sugar in children. Very few adults have been observed with this condition, which may be due to high death rates in adolescence. Pale skin that does not tan and red hair are common signs of POMC deficiency obesity. Currently there are no licensed treatment options for POMC deficiency obesity, however weight loss medicines orlistat and methylcellulose are the only treatment options offered. Setmelanotide is being developed to treat pro-opiomelanocortin (POMC) deficiency obesity. If marketed setmelanotide could be the first effective treatment option aimed specifically at this patient group as it replaces one of the key hormones that is lacking in POMC deficiency patients (melanocyte- stimulating hormone). It has been shown to reduce hunger and has resulted in substantial weight loss in previous patients. This briefing is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commerc ial purposes or commissioning without additional information.
    [Show full text]