November 29, 2012 3:25 pm
This article is provided to FT.com readers by BioPharm Insight—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.biopharminsight.com
Sanofi (EPA:SAN) and Zealand Pharma’s (ZEAL:CPH) diabetes drug lixisenatide has been met with skepticism on its ability to demonstrate a cardiovascular (CV) benefit in its CV outcomes study, experts told BioPharm Insight.
Still, glucagon-like peptide-1 (GLP-1) drugs like lixisenatide show the most potential for showing a CV benefit and should at least demonstrate CV neutrality, they added.
Sanofi did not return requests to comment.
The US Food and Drug Administration (FDA) mandates drugs for type 2 diabetes be evaluated in CV outcomes studies, as per its Guidance for Industry, issued in December 2008. The guidance was issued in the wake of findings that showed GlaxoSmithKline’s (LON:GSK) antidiabetic Avandia (rosiglitazone) increased the risk of heart attack.
ELIXA, the lixisenatide CV outcomes study, is a 6,000-patient trial. The main endpoint is to demonstrate that lixisenatide can reduce CV morbidity and mortality, and the estimated primary completion date is May 2014.
CV outcomes studies of fellow GLP-1s – Bristol-Myers Squibb (NYSE:BMY) and AstraZeneca’s (LON:AZN) Bydureon (exenatide once-weekly) and Novo Nordisk’s (NOVOB:CPH) Victoza (liraglutide once-daily) – are being evaluated in the 9,500-patient EXSCEL and 9,341-patient LEADER studies, respectively.
GLP-1 effects generally seen as beneficial
GLP-1s will probably have the highest chance of showing CV benefit among all the other diabetes drugs being developed at the moment, said Dr Abd Tahrani, clinical research fellow, Diabetes, Endocrinology & Metabolism, University of Birmingham, UK. GLP-1s not only reduce weight but also have a positive impact on free-fatty acid metabolism and other areas of the CV system, including autonomic heart functions, he noted.
The drug class also reduces blood pressure, though it does not have any clear effects on lipid profile, said Susan Cornell, assistant professor, Department of Pharmacy Practice, Midwestern University Chicago College of Pharmacy. Lipids include fats and along with proteins and carbohydrates constitute the main structural components of living cells. It is possible GLP-1s have a favorable effect on lipids, though they do not target fat or peripheral tissue, she added.
There is a sense that because these drugs not only improve glucose but also have somewhat of an effect on blood pressure and lipids, that they may reduce CV risk, said Dr Naveed Sattar, professor of metabolic medicine, University of Glasgow.
Yet the Avandia experience is still fresh in people’s minds, making many cautious, noted Sattar. Experts had gone through the same intellectual process for Avandia, because the drug had effects on vascular function and other features where it was thought it must also reduce CV risk, he said. But it turned out not to be the case, he added.
Avandia increased low-density lipoprotein (LDL) cholesterol - the bad cholesterol - which likely negated other positive factors, Sattar explained. This taught people not to rely on surrogate CV risk markers, necessitating large CV outcomes trials.
Benefits of acute window may be missed
The ELIXA study will evaluate CV outcomes during treatment with lixisenatide within 90 days after an acute coronary syndrome (ACS) event. ACS refers to a spectrum of clinical presentations including heart attack, or myocardial infarction (MI). The BMS/AstraZeneca and Novo CV outcomes trials, however, do not require the enrolled type 2 diabetes patients to be post-ACS.
There are a number of reasons to believe GLP-1s will have a benefit in the acute phase, or immediately after an ACS event, Gerstein noted. There is less known, however, about the postacute, yet still relatively short-term, three-month period, he said. The different periods post-ACS would have different types of vulnerability to additional events, said Sattar.
There have been studies of patients who immediately after MI are treated with a relatively high dose of human GLP-1 and showed marked reduction in infarction size, said Dr Edoardo Mannucci, director, Diabetes Agency, Careggi Teach Hospital, Florence, Italy. These studies came after similar promising results in several animal models, Mannucci noted.
The lixisenatide study may, however, be getting patients a little too late, thus missing the acute phase where a GLP-1 can have a positive effect, said Mannucci.
Indeed, the ELIXA study has been difficult to recruit, said trial investigator Dr Helena Rodard, Endocrine and Metabolic Consultants, Rockville, Maryland. As the protocol calls for patients to have had an MI within 90 days before enrollment in the trial, these patients are often missed by endocrinologists, she added. Her practice is working with cardiologists to enroll patients and maintain recruitment, she noted.
Even if Sanofi and Zealand get a positive result in post-ACS patients, it is not clear a benefit claim can be made for patients without ACS, said Sattar. If it works in one group, by and large, it should work in another group, but whether the drug gets a license for CV risk reduction in all diabetics is questionable, he noted. The first trial to show a favorable CV profile, however, should cause an uptick in the drug’s use, irrespective of whether it gets a full indication for CV risk reduction, Sattar added.
Lixisenatide has an annual global sales estimate of USD 547m in 2019, according to BioPharm Insight data.
The US Centers for Disease Control and Prevention estimates 25.8 million people in the US have diabetes, more than 8% of the total population, according to its 2011 National Diabetes Fact Sheet.
Sanofi has a current market cap of EUR 91bn. Zealand has a current market cap of DKK 12.6bn.
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