Hope on Horizon for Newer Obesity Drugs in Europe?

June 03, 2014

SOFIA, Bulgaria — The European Association for the Study of Obesity (EASO) is calling attention to the dire lack of obesity drugs in the European Union.

"We cannot solve the obesity problem by surgery, and we know the clinical reality is that lifestyle therapy is failing in 80% to 90% of our patients. We are living in a very difficult environment, so we need drugs," president-elect of the EASO, Hermann Toplak, MD, from the Medical University of Graz, Austria, told a session entitled, "Where are the Antiobesity Drugs in Europe?" here at the 2014 European Congress on Obesity last week.

Referring to the fact that, due to safety concerns, the European Medicines Agency (EMA) has rejected 2 obesity drugs that are currently on the market in the United States, lorcaserin (Belviq, Eisai) and phentermine/topiramate (Qsymia, Vivus), he said that the EASO will shortly issue a position statement on this. The only available option for pharmaceutical treatment of obesity in Europe is orlistat, which is available without a prescription in a low dose (Alli, GlaxoSmithKline) or by prescription at a higher dose (Xenical, Genentech).

Many doctors speaking in the same session agreed that Europe is crying out for obesity medications, while others had a more cautious attitude to pharmacotherapy for obesity. And while the experts in Sofia don't hold out much hope of either Qsymia or Belviq being approved in Europe anytime soon, there is hope in the form of 2 new agents awaiting approval there.

The combination of bupropion/naltrexone, from Orexigen Therapeutics, is awaiting clearance both in the European Union and the United States. Following an earlier rejection by the US Food and Drug Administration (FDA), the company gathered more data from its ongoing LIGHT study and is expecting a decision on approval from both agencies this summer.

And the established type 2 diabetes drug, the GLP-1 agonist liraglutide (Novo Nordisk), a once-daily injectable agent, has also been filed for approval for obesity in the European Union and the United States for use at a higher dose (3 mg per day) than that approved for diabetes.

In Sofia, John Wilding, MD, from the University of Liverpool, United Kingdom, presented the results of the largest phase 3 trial with liraglutide in obesity to date, the SCALE study, also recently presented at the American Association of Clinical Endocrinologists (AACE) meeting, as reported by Medscape Medical News, and there was much discussion there about the future potential of this agent.

"Pent-up Demand" for Obesity Agents in Europe

Arne Astrup, MD, of the University of Copenhagen, Denmark, told the meeting that obesity specialists are feeling increasingly frustrated at the lack of pharmaceutical options open to them: "We really are left with very little to treat obesity in Europe," he observed.

"We need to fill the gap between the 20% weight loss with surgery and the 10% weight loss we can achieve with nonpharmacological means. Although we have some good dietary tools, we know that some of the patients are gaining weight no matter what you are doing, and they have a lousy quality of life and probably [a 20-year] reduced life expectancy, so we need to have some drugs that we can combine with effective diet," he said.

 
We know that some of the patients are gaining weight no matter what you are doing, and they have a lousy quality of life.
 

Dr. Wilding agrees. "There is this pent-up demand among physicians in Europe for something that works, because even if you take those patients who might be eligible for bariatric surgery, only about 1% are getting surgery in the UK and the rest of Europe, so this treatment gap is absolutely massive, and there is a very great need for these medications," he told Medscape Medical News.

Another physician, Mike Lean, MD, from the University of Liverpool, has a similar view. "Obese people have a real problem, because their appetites are driving them very hard; this is physiology. We've done everything we can with diet, exercise, advice, etc, and we can't beat it," he observed.

But Nadka Boyadjieva, MD, from the Medical University Sofia, an endocrinologist and pharmacologist who was a cochair of the session, argued that she isn't so certain that drugs are of such great importance in the treatment of obesity.

"I trust prophylaxis with diet, lifestyle, and exercise, and for me the 'pill' of exercise is very important," she commented

And Margaret Ashwell, PhD, a nutritionist and former science director of the British Nutrition Foundation, agrees. "In my time, I've seen so many drugs come and go. I think prevention is so much more important," she told Medscape Medical News.

Liraglutide: Experience With Diabetes Helps Inform on Safety

Drs. Wilding and Astrup, who have both been involved in trials of liraglutide for obesity, are hopeful that the long experience with this agent in type 2 diabetes will lead to a smoother approval path for the obesity indication in Europe than is usually the case for agents of this kind.

"We have raised the bar for safety, and when we look at liraglutide, it's already on the market and used in millions of type 2 diabetes patients, and although that's at a lower dose, the safety data are accumulating," Dr. Astrup told Medscape.

And at least liraglutide appears to be "clean" in terms of neuropsychiatric side effects — something that has plagued many previous obesity agents, he noted. Similarly, "in terms of cardiovascular events, all risk factors are moving in the right direction, apart from a small increase in heart rate (2–3 bpm), which I don't think is a matter of concern," he added.

 
After very many big trials and thousands of patients being through it for many years, liraglutide still looks good.
 

But he acknowledged that there remains the niggling matter of pancreatitis, which was 3 times more common in patients treated with liraglutide in SCALE compared with placebo. "It's a fact, but quite rare and transient and no fatal cases as far as I know," he observed. Gallbladder disorders were also 3 times more likely to occur in liraglutide treated patients in SCALE, Dr. Wilding reported.

However, "after very many big trials and thousands of patients being through it for many years, liraglutide still looks good. With the previous medications, we didn't have those kind of large trials, so I think it's justified that we are optimistic," noted Dr. Astrup

Remarkable Effects of Liraglutide in Some Obese Patients

Dr. Lean, who has also participated in the liraglutide trials, stressed that while the agent is not a panacea, for some patients — around 30% of those he has used it in — he sees "really remarkable results, and we've learned a lot of things." For example, "taking it by injection is entirely acceptable, the patients like it; in fact, they prefer the injection to taking pills."

He notes also that even the more common nuisance side effects, such as those that are gastrointestinal in nature, have not proven to be a huge barrier. "The nausea and vomiting is very common, but it isn't severe; the patients tolerate it, and they get over it quickly and they are quite happy to carry on," he explained.

And these patients in whom liraglutide is effective "are people who have failed on everything we have ever tried," he adds. "Some of them in my hands have been able to lose 20 and 30 kg, and it has changed their lives completely. Patients with muscular dystrophy who can get up and walk, and leg ulcers, which were intractable, go away once they've lost a chunk of weight."

 
Some of them in my hands have been able to lose 20 and 30 kg, and it has changed their lives completely.
 

He is, however, somewhat critical of Novo Nordisk's decision to opt for a higher dose of liraglutide to treat obesity than the one used for type 2 diabetes.

"I think the company has been a bit disingenuous pushing all clinical trials up to 3 mg per day, because some patients can't tolerate it, and that's a shame, because they do very well with a lower dose.

"For some patients, once they are taking 1.2 mg or 1.8 mg, they are losing weight and on top of the problem, so you don't need to go to the higher dose," he observed.

What Are the Odds of 2 New Obesity Drugs in Europe by Year-end?

Asking the doctors whether they expect both bupropion/naltrexone and liraglutide to be approved for obesity by the EMA this year, Medscape Medical News received a mixed response.

"Obviously, we hope that the licensing authorities will allow [liraglutide] to be used for obesity, but the fear is that because it's expensive [and because they are concerned about side effects] they will either delay it or put very complicated restrictions on it," Dr. Lean said.

He said it is a shame that no one asks the patients what they think, particularly with regard to the potentially more severe, but much rarer, adverse events.

 
I have stopped making predictions.
 

"Any drug in obesity is going to be under huge scrutiny for historical reasons; people believe it might have all sorts of hazards, but the pity is no one has asked the patients what level of side effects they would be happy to tolerate. If you could ask them, 'What level of risk are you prepared to accept to take a drug that will help your weight to come down by 10 or 15 kg?' they would all say, 'The benefit for me has been colossal.' "

But that question is never asked, he says. "The regulatory authorities are so proud of the fact they've found an infinitesimal effect of heart disease or something that they then withdraw the drug."

Regarding bupropion/naltrexone, Dr. Lean said he did not have firsthand experience of this combination so did not want to hazard a guess as to what the EMA would decide.

Dr. Wilding said he wasn't sure about the new combination agent, either. "From the data we have seen, bupropion/naltrexone meets the efficacy criteria, and it probably has fewer concerns than, for example, the phentermine/topiramate combination. But it's hard to predict."

Dr. Ashwell told Medscape Medical News that the newer drugs awaiting approval in Europe "do seem to have some major side effects…so I have a horrible feeling they will go the same way that so many other [obesity agents] have gone."

Dr. Astrup was perhaps the most circumspect of all. "I have stopped making predictions," he said. "You have 2 agencies [US FDA and EMA] that have essentially the same guidelines, and then you produce a dossier and submit it to both of them. In some cases the US will say yes and the Europeans will reject, and then for other compounds it's the opposite."

Dr. Toplak reports being an advisor to Vivus and on the board of a trial with topiramate/phentermine and an advisor to Novo Austria; he has started a clinical study with Almased (VLCD, Gemany) and gave a lecture on Insumed (VLCD, Gemany) in 2013. Dr. Lean reports advisory-board fees from Novo Nordisk and Vivus; his university received a research contract from Novo Nordisk. Dr. Astrup has received research grants from Novo Nordisk and has served on the advisory boards of BioCare Copenhagen, Dutch Beer Knowledge Institute, Global Dairy Platform, McDonald's, and Pathway Genomics. He has also acted as a consultant to Arena Pharmaceuticals, Basic Research, Gelesis, Novo Nordisk, Orexigen Therapeutics, S-Biotek, Twinlab, and Vivus. He has also received honoraria as a speaker for a wide range of Danish and international concerns and owns shares in Mobile Fitness and is a board member of Dentacom and part owner of patents registered in collaboration with the University of Cophenhagen. Dr. Wilding has acted as a consultant to Novo Nordisk and has previously given paid lectures on diabetes and obesity at clinical meetings. He has also worked with a number of other companies developing treatments for diabetes and obesity. Dr. Ashwell is an independent scientific consultant, and her clients include a number of food manufacturers listed on her website. She is also a member of the advisory board of the Global Stevia Institute.

2014 European Congress on Obesity. Abstracts T4:RS2.2 and T4:RS2.3.

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