Development of a Long-Acting Growth Hormone Antagonist for the Treatment of Acromegaly ECE 2016.

Slides:

Advertisements

Similar presentations

Results Insulin Treatment of BBDP Rats Results (cont) Optimization of Insulin Treatment for Spontaneous Type 1 Diabetes (T1D) in BBDP/Wor Rats Barak Yahalom,

Advertisements

MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.

MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY

Adult Medical-Surgical Nursing

Elonva in poor responders

Morbidity and Mortality Conference Ann Marie Lam, PGY-2 Emory University School of Medicine Family Medicine Residency Program October 14 th, 2010.

Study by: Granger et al. NEJM, September 2011,Vol No. 11 Presented by: Amelia Crawford PA-S2 Apixaban versus Warfarin in Patients with Atrial Fibrillation.

MiRNA-drug resistance mechanisms Summary Hypothesis: The interplay between miRNAs, signaling pathways and epigenetic and genetic alterations are responsible.

analysis from the SHIFT study

Pituitary and hypothalamic diseases Dr.Malith Kumarasinghe MBBS( Colombo)

Medication Assisted Therapy for Opioid Addiction: Methadone and Buprenorphine Andrew J. Saxon, M.D. Veterans Affairs Puget Sound Health Care System and.

Medical options in the treatment of acromegaly I M Holdaway June

Application of PK/PD modeling for optimization of linezolid therapy Julia Zayezdnaya Zack.

Extended duration of injection interval. 2 Lucas et al. Efficacy of lanreotide Autogel ® administered every 4–8 weeks in patients with acromegaly previously.

Acknowledgement of funding Regulator of G-protein signaling 5 blunts cellular viability mediated by a stabilized lysophosphatidic acid analogue (2S-OMPT)

EVALUATION OF CONVENTIONAL V. INTENSIVE BLOOD GLUCOSE CONTROL Glycemic Control in Critically Ill Patients DANELLE BLUME UNIVERSITY OF GEORGIA COLLEGE OF.

Carla Chieffo, VMD, PhD, 1 Lawrence A. Frohman, MD, 2 Harry Quandt, BS, 1 Stefanie Decker, MS, 1 Mônica R. Gadelha, MD, PhD 3 1 Endo Pharmaceuticals Inc.,

Acromegaly. Very rare Prevalence in the order of 1 in 200,000 Usually diagnosed between age 40 and 60 No difference in gender susceptibility Insidious.

ACROMEGALY Ilan Shimon, MD Rabin Medical Center, Petach-Tiqva.

Prevention of Renal Injury by Nitric Oxide in Prolonged Cardiopulmonary Bypass A Double Blind Randomized Controlled Trial. Chong Lei & Lorenzo Berra Emanuele.

Defining Insulin-Like Growth Factor-I Deficiency

Prevention of Renal Injury by Nitric Oxide in Prolonged Cardiopulmonary Bypass A Double Blind Randomized Controlled Trial Chong Lei & Lorenzo Berra Emanuele.

Hypothalamic & Pituitary Hormones

Growth Hormone (somatotrophin)

ACROMEGALY Prof. Gaetano Lombardi Prof. Gaetano Lombardi Dept. of Clinical and Molecular Endocrinology and Oncology University “Federico II”, Naples,

For each hormone you should know the following: Chemical Structure Source and mode of action Metabolic effects Clinical disorders Laboratory use.

Carla Chieffo, David Cook, Qinfang Xiang, and Lawrence A. Frohman Efficacy and Safety of an Octreotide Implant in the Treatment of Patients With Acromegaly.

The hypothalamus and the pituitary gland

TURNING PEPTIDES INTO DRUGS Background Materials & Methods 1) Bataille et al., FEBS Letters, 146, 79-86, ) Gros et al., Endocrinology, 133, ,

April 23, 2015 Mini-Lecture Nathan King M.D. Anticoagulation Reversal Part 1: Warfarin.

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Chapter 59 Drugs Related to Hypothalamic and Pituitary Function.

Antibiotics in Addition to Systemic Corticosteroids for Acute Exacerbations of Chronic Obstructive Pulmonary Disease Johannes M.A. Daniels; Dominic snijders;

POPLAR: Atezolizumab Improved Survival vs Docetaxel in Patients With Advanced NSCLC and Increasing Levels of PD-L1 Expression CCO Independent Conference.

Cardiovascular Disease and Antihypertensives The RENAAL Trial Reference Brunner BM, and the RENAAL study group. Effects of losartan on renal and cardiovascular.

Telbivudine Versus Lamivudine in Chinese Patients with Chronic Hepatitis B: Results at 1 Year of a Randomized, Double-Blind Trial HEPATOLOGY 2008;47:

Annual meeting NZ Acromegaly Society, 2016

Abnormalities of Growth (GH) Lecture NO: 2nd MBBS

B C SIMULTANEOUS COEXISTENCE OF GH-SECRETING

Pegvisomant(DB00082) Approved Drug

Michael H. Shanik, MD, FACP, FACE AACE 2016

A GH antagonist fusion with GH binding protein is biologically active, shows delayed clearance and inhibits growth in rabbits Ian Wilkinson, Sarbhendra.

Acromegaly is characterized by excessive growth hormone (GH) secretion and is primarily caused by a GH-secreting pituitary adenoma, which stimulates.

Soverini S et al. Proc ASH 2015;Abstract 346.

Number of NAT/QAT motifs in linker region Molecular weight (kDa)

The HEMO Study Hemodialysis (HEMO) Study Reference

علم راهی بسوی آفریدگار جهان

Introduction Conclusions

You will be given the answer. You must give the correct question.

Possible new treatments for Congenital Hyperinsulinism

Pharmacology of Endocrine System

Antidiarrheal agents Domina Petric, MD.

Figure 5 Schematic illustration of different clinical trial designs

Figure 3 Monitoring clonal evolution using liquid biopsies

Figure 1 Current treatments for PNETs

Faster-Acting Insulins

Nat. Rev. Endocrinol. doi: /nrendo

A model for the biological rationale for rechallenge therapy: clonal selection in heterogeneous baseline RAS a wt tumours during anti-EGFR therapy. aAdditional.

Acromegaly By Kelsie Bonow.

Schematic overview of the suggested pharmacological management of chronic obstructive pulmonary disease (COPD). Schematic overview of the suggested pharmacological.

Least squares mean (LSM) changes from baseline in (A) Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Total score and (B) Ankylosing.

(A) Mean (SD) serum continuous erythropoietin receptor activator (C. E

Concentration-time profiles of repeated weekly infusions of (A) 720 mg and (B) 990 mg tomuzotuximab measured in individual patients before and at the end.

Recent developments in the management of secondary hyperparathyroidism

Percentages of patients reporting improvements from baseline ≥minimum clinically important difference (MCID) and number needed to treat (NNT) in (A) patient-reported.

Appearance of insulin in plasma and CSF at different times after the administration of subcutaneous DET and GLAR in mice and the effect of chronic DET.

The 22 study patients: overall survival (first patient enrolled 9 May 2014, last patient enrolled 26 August 2015, censoring date 9 May 2016); primary tumour.

Kaplan-Meier plot presenting PFS for patients with BRAFV600-mutated ctDNA at first visit (

Mean serum concentration time profiles of anifrolumab following subcutaneous and intravenous administration of anifrolumab.a aData below the limits of.

Giulia Tarantola, Humanitas University

Presentation transcript:

Development of a Long-Acting Growth Hormone Antagonist for the Treatment of Acromegaly ECE 2016

Acromegaly & Treatment Acromegaly: Chronic debilitating condition Excess Growth hormone from pituitary tumour Results in high IGF-I Increased morbidity and mortality Primary treatment: Pituitary surgery cures ~50% Secondary medical treatment: Somatostatin analogues effective in ~60% Postcard courtesy of Wouter W. de Herder in Acromegaly and Gigantism in the 20th century ECE 2016

Tertiary Medical therapy: Pegvisomant GH Antagonist (GHA) Effective in >90% of patients Daily injections 10-30mg daily Expensive ECE 2016

Aim: Create a Second Generation GH antagonist Target product profile of weekly subcutaneous injection at <30mg per injection Design based on long-acting GH agonist: IV SC ECE 2016

GHA Candidate Molecules ECE 2016

Hypothesis The W104A mutation reduces both intra and inter-molecular interactions producing a more active molecule ECE 2016

In Vitro Bioactivity Assay SAMPLE IC50 (nM ) SEM GHA1 44 4.7 GHA2 198 25 GHA3 17 1.3 ECE 2016

Terminal half-life (hrs) PK in Rats after IV injection SAMPLE Terminal half-life (hrs) GHA1 20 GHA2 GHA3 ECE 2016

PK in Rabbits After SC Injection SAMPLE Terminal half-life (hrs) GHA1 23.6 GHA2 17.4 GHA3 40.5 ECE 2016

Rabbit Model for Analysis of IGF-1 Bielohuby, M., et al., Validation of serum IGF-I as a biomarker to monitor the bioactivity of exogenous growth hormone agonists and antagonists in rabbits. Dis Model Mech, 2014. 7(11): p. 1263-73. ECE 2016

Conclusions Site 1 mutations decrease bioactivity of fusion GHA presumed to result from intra- and inter-molecular interactions W104A mutation in GHA3 increases bioactivity presumed by reducing intra- and inter-molecular interactions GHA3 shows half-life of 20 hrs in a rat after IV and 40 hours in rabbit after SC injection Single injection GHA3 reduces IGF-1 levels in a rabbit model GHA3 candidate molecule for second generation long-acting GH antagonist ECE 2016

Acknowledgements MRC DPFS Grant, Euro 3M (3 years) Grant# X/004883-11-4 ECE 2016