Issued: London UK, Durham USA.
GSK and the Duke Clinical Research Institute (DCRI) today announced publication of positive results from the Harmony Outcomes study which assessed the cardiovascular (CV) safety and efficacy of albiglutide, a GLP-1 receptor agonist, in patients with type 2 diabetes and cardiovascular disease. Results were presented at the European Association for the Study of Diabetes congress 2018 with simultaneous publication in The Lancet.[i]
The study was initiated in July 2015 and GSK remained committed to completing it following an announcement in July 2017 of GSK’s intention to cease further R&D, manufacturing and sales activity for albiglutide (Tanzeum™/Eperzan®). Prior studies of GLP-1 receptor agonists when used in patients with diabetes and CV disease had provided inconsistent results regarding the potential benefit, and GSK believed that the data generated from this study could contribute important new evidence to the field.
The primary outcome showed that albiglutide, administered subcutaneously once-weekly in
9463 patients over a median period of 1.6 years, was superior to placebo in reducing the risk of major adverse cardiovascular events (MACE) by 22% (95% confidence interval [CI] 10% to 32%) when used in addition to standard of care in patients with type 2 diabetes and cardiovascular disease (p<0.0001 for non-inferiority; p=0.0006 for superiority). MACE occurred in 7.1% (N=338) and 9.0% (N=428) of patients receiving albiglutide and placebo in addition to standard of care, respectively. Overall, the number of patients who would need to be treated with albiglutide to prevent one event over a median of 1.6 years was 50.
The incidence of acute pancreatitis was <1% (10 patients for albiglutide; 7 patients for placebo) and the incidence of pancreatic cancer was <1% (6 patients for albiglutide; 5 patients for placebo). No events of medullary thyroid carcinoma were observed, and other serious adverse events did not differ significantly between the two groups.
Professor Adrian F. Hernandez, MD, MHS, Vice Dean for Clinical Research, Duke University School of Medicine and Professor of Medicine, Cardiology said: “This large cardiovascular outcome trial has shown impressive results for albiglutide in lowering the risk of major adverse cardiovascular events and adds important evidence that certain GLP-1 receptor agonists can improve cardiovascular outcomes. Despite the need for treatments to manage these events, there was uncertainty about the cardiovascular effects of GLP-1 receptor agonists as a class due to mixed results from previous studies. We are fortunate that all involved maintained their commitment to participants to complete the trial, which helps address this knowledge gap for patients and clinicians alike on the role of GLP-1 receptor agonists in diabetes.”
Dr John Lepore, Senior Vice President R&D Pipeline, GSK said: “We would like to thank all the investigators and patients who participated in this study. Harmony Outcomes was an important study for us to complete to generate new data and insights about the role of the GLP-1 receptor agonist class in the management of patients with diabetes and cardiovascular disease. GSK continued to invest in this study following a decision last year to cease all other activities on albiglutide, and we continue to explore opportunities to divest this medicine to a company with the right expertise and resources to realise its full potential for patients.”
About the HARMONY Outcomes study
The Harmony Outcomes study (NCT02465515) is a GSK sponsored study conducted in collaboration with the DCRI (Duke Clinical Research Institute).
It was a randomised, double-blind, placebo-controlled study to assess the effect of albiglutide on major adverse cardiovascular (CV) events in 9,463 patients with type 2 diabetes and cardiovascular disease which took place at 610 sites in 28 countries. Patients were randomised to the addition of once-weekly subcutaneous injection of albiglutide 30mg (potentially increasing to 50 mg) or matching placebo in addition to standard care.
It was hypothesised that albiglutide would be noninferior to placebo for the primary outcome of first occurrence of cardiovascular death, myocardial infarction, or stroke. The study continued until ≥611 confirmed primary outcome events (CV death, myocardial infarction, or stroke) occurred over a median follow-up of at least 1.5 years.
Diabetes is a common and increasing problem that affects 30.3 million Americans[ii] and 422 million people worldwide.[iii] In 2015, some 1.6 million deaths were directly caused by diabetes worldwide.[iv] There remains a pressing need to improve health outcomes in this population, especially for cardiovascular events, which pose the greatest burden in terms of morbidity and mortality.
Albiglutide (brand name Tanzeum™ in the US and brand name Eperzan® in Europe) is a glucagon-like peptide-1 receptor agonist (GLP-1), a biological product for the treatment of type 2 diabetes, administered once-weekly using an injector pen supplied with a 5mm 29-gauge thin-walled needle. Albiglutide is not currently marketed or distributed by GSK. Glucagon-like peptide-1 is an important incretin hormone that helps reduce blood glucose levels but, in people with type 2 diabetes, its production is reduced or absent.
Full US Prescribing Information, including BOXED WARNING and Medication Guide are available here.
The European Summary of Product Characteristics is available here.
Indications and Limitations of Use for TANZEUM
TANZEUM is a GLP-1 receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
- TANZEUM is not recommended as first-line therapy for patients inadequately controlled on diet and exercise because of the uncertain relevance of the rodent C-cell tumor findings to humans; prescribe only to patients for whom the potential benefits are considered to outweigh the potential risk.
- TANZEUM has not been studied in patients with a history of pancreatitis; consider other antidiabetic therapies in patients with a history of pancreatitis.
- TANZEUM is not indicated in the treatment of patients with type 1 diabetes mellitus or for the treatment of patients with diabetic ketoacidosis; is not a substitute for insulin in these patients.
- TANZEUM has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis; is not recommended in patients with pre-existing severe gastrointestinal disease.
- TANZEUM has not been studied in combination with prandial insulin.
Important Safety Information for TANZEUM
WARNING: RISK OF THYROID C-CELL TUMORS
Carcinogenicity of albiglutide could not be assessed in rodents, but other glucagon-like peptide-1 (GLP-1) receptor agonists have caused thyroid C-cell tumors in rodents at clinically relevant exposures. Human relevance of GLP-1 receptor agonist induced C-cell tumors in rodents has not been determined. It is unknown whether TANZEUM causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. TANZEUM is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with the use of TANZEUM and inform them of the symptoms of thyroid tumors (e.g., mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound monitoring is of uncertain value for early detection of MTC in patients treated with TANZEUM.
Hypersensitivity: TANZEUM is contraindicated in patients with a prior serious hypersensitivity reaction to albiglutide or to any of the product components. Serious hypersensitivity reactions including angioedema have been reported with TANZEUM.
WARNINGS AND PRECAUTIONS
Risk of Thyroid C-cell Tumors: Counsel patients regarding the potential risk for MTC with the use of TANZEUM and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, or persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TANZEUM. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.
Acute Pancreatitis: In clinical trials, acute pancreatitis has been reported in association with TANZEUM. After initiation of TANZEUM, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, promptly discontinue TANZEUM. If pancreatitis is confirmed, TANZEUM should not be restarted. TANZEUM has not been studied in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis.
Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin: The risk of hypoglycemia is increased when TANZEUM is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Therefore, patients may require a lower dose of sulfonylurea or insulin to reduce the risk of hypoglycemia in this setting.
Hypersensitivity Reactions: Serious hypersensitivity reactions (including angioedema and generalized pruritus and rash with dyspnea) have been reported with TANZEUM. If hypersensitivity reactions occur, discontinue use of TANZEUM; treat promptly per standard of care and monitor until signs and symptoms resolve. Do not use in patients with a previous hypersensitivity reaction to TANZEUM.
Acute Kidney Injury: There have been postmarketing cases of worsening renal function and acute kidney injury in patients treated with TANZEUM, some of which required hemodialysis. Some of the postmarketing events were reported in the absence of gastrointestinal adverse reactions and in patients without known underlying renal disease. In a trial of TANZEUM in patients with renal impairment, the frequency of such gastrointestinal reactions increased as renal function declined. Because these reactions may worsen renal function, use caution when initiating or escalating doses of TANZEUM in patients with renal impairment and/or in those reporting severe gastrointestinal symptoms. Advise patients of the potential risk of dehydration in relation to gastrointestinal side effects and to take precautions to avoid fluid depletion.
Macrovascular Outcomes: There have been no clinical trials establishing conclusive evidence of macrovascular risk reduction with TANZEUM or any other antidiabetic drug.
The most common adverse reactions, excluding hypoglycemia, reported in ≥5% of patients treated with TANZEUM and more commonly than in patients treated with placebo, are: upper respiratory tract infection (14.2 vs 13.0); diarrhea (13.1 vs 10.5); nausea (11.1 vs 9.6); injection site reaction (10.5 vs 2.1); cough (6.9 vs 6.2); back pain (6.7 vs 5.8); arthralgia (6.6 vs 6.4); sinusitis (6.2 vs 5.8); influenza (5.2 vs 3.2).
TANZEUM delays gastric emptying and may impact absorption of concomitantly administered oral medications. Caution should be exercised when oral medications are concomitantly administered with TANZEUM.
USE IN SPECIFIC PATIENT POPULATIONS
Pediatric Use: Safety and effectiveness of TANZEUM have not been established in pediatric patients (younger than 18 years).
Tanzeum™ and Eperzan® are trademarks of the GlaxoSmithKline group of companies.
GSK – a science-led global healthcare company with a special purpose: to help people do more, feel better, live longer. For further information please visit www.gsk.com/about-us
DCRI – The Duke Clinical Research Institute (DCRI), part of the Duke University School of Medicine, is the largest academic research organization in the world. Its mission is to develop and share knowledge that improves the care of patients through innovative clinical research. The DCRI conducts groundbreaking multinational clinical trials, manages major national patient registries, and performs landmark outcomes research. DCRI research spans multiple disciplines, from pediatrics to geriatrics, primary care to subspecialty medicine, and genomics to proteomics. The DCRI also is home to the Duke Databank for Cardiovascular Diseases, the largest and oldest institutional cardiovascular database in the world, which continues to inform clinical decision-making more than 45 years after its founding.
Cautionary statement regarding forward-looking statements
GSK cautions investors that any forward-looking statements or projections made by GSK, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Such factors include, but are not limited to, those described under Item 3.D ‘Principal risks and uncertainties’ in the company’s Annual Report on Form 20-F for 2017.