Diabetes – the battle for control

pharmafile | February 15, 2012 | Feature | Business Services, Manufacturing and Production, Research and Development, Sales and Marketing |  Novo Nordisk, Sanofi, Victoza, degludec, diabetes 

This year marks the 90th anniversary of the first ever successful use of insulin to treat patients with type I diabetes.

A 14-year-old boy, Leonard Thompson from Toronto became the first patient to benefit from this breakthrough in medicine and since then, insulin treatment has been helping to avert major medical complications and save lives; type I diabetes is the classic example of a disease which has been turned from a death sentence into a chronic disease by advances in medicine. 

Type II diabetes is much more common than type I diabetes – although ninety years ago, it was not the widespread disease it is today.

The rise in obesity and more sedentary lifestyles around the world is behind the alarming growth in the number of people suffering from type II diabetes.

There are currently around 250 million diabetic patients worldwide, but this figure is set to rise to 380 million by 2025. The condition is seen as such a threat to public health, it is sometimes labelled a global ‘pandemic’.

Research into how to prevent, treat and even cure both type I and type II diabetes is one of the main areas of pharmaceutical R&D today, with scores of new treatments in the pipeline. 

In commercial terms, just a few companies lead the diabetes market, and the two main players are Novo Nordisk and Sanofi. 

Novo’s diabetes franchise earned $8.91 billion in 2011, with Sanofi not far behind on around $7.36 billion. Lantus (insulin glargine) is Sanofi’s long acting insulin analogue, and is the world’s biggest selling diabetes treatment, earning around €4 billion ($5.2 billion) in 2011, well ahead of Novo’s rival product Levemir ($1.35 billion).

Meanwhile Novo’s Victoza is the leading drug in the GLP-1 analogue class, a relatively new class of injectable drugs which adds to the existing choices of oral treatments and short and long-acting insulin products. 

Two challengers to these respective market leaders – Novo with insulin degludec and Sanofi’s new GLP-1 analogue Lyxumia (lixisenatide) – are expected to hit the market in 2012/13. The two companies are locked into fierce competition, and are looking to gain the upper hand in three growing areas – earlier use of long-acting insulin, greater use of GLP-1 analogues, and new combinations of insulins or insulins and GLP-1s. 

Early insulin treatment

There is growing evidence that earlier and more aggressive treatment of type II diabetes can help reduce the damage caused by the disease, and ultimately save lives. 

“I think there is a consensus that appropriate therapy needs to start earlier. That may include insulin, depending how far along a particular individual is in terms of their disease,” Dr Alan Moses, corporate vice president and chief medical officer, Novo Nordisk, told InPharm.

He says GLP-1s can also be used earlier.  “What we have seen with the GLP-1 drugs is that they have the potential to improve glucose control when used relatively early, but even when used just prior to what would traditionally be the insulin starting point. 

“What we don’t know is how long those agents will work for. I think it is recognised that patients need to be treated earlier in the course of their disease.”

Both Novo Nordisk and Sanofi are conducting major clinical trial programmes to back up greater use of insulin in these patients. There are two longstanding clinical concerns about insulin use in type II patients – the risk of hypoglycaemia and the risk of weight gain, but the firms are now producing data suggesting these problems are not so significant for either Lantus or Levemir. 

But they are also addressing positive advantages to earlier insulin use. Sanofi’s ORIGIN study is investigating whether Lantus in early/ pre-diabetes can reduce cardiovascular events more effectively than current standard care. 

The study has now been completed, and results are expected to be published in mid- 2012. If results show early use of Lantus can actually prevent heart attacks and strokes, the trial could bring about a major change in how type II diabetes is treated, and Lantus will be the chief beneficiary.

There is already plenty of evidence that type II diabetes patients around the world do not have their condition under control, despite already being on medication. Speaking at a briefing hosted by Sanofi, Professor David Owens, clinical Professor, Department of Medicine, Cardiff University School of Medicine, said specialists and primary care doctors were failing patients.

“The case is very clear for early insulinisation – do not delay therapy,” he said.

But there are a number of other practical barriers to earlier insulin use. Prof Owens says one of these barriers is that patients perceive insulin as ‘the end of the road’, a last resort which most want to put off for as long as possible. 

This is a formidable obstacle to overcome, but research suggests that by informing and empowering patients, they will be much more willing to begin insulin therapy. 

Insulin degludec

Novo Nordisk’s insulin degludec is a new ultra long-acting basal insulin analogue, which works for much longer than current long-acting insulins Lantus and Levemir. Its profile is so promising that analysts predict it will one day usurp Lantus as the standard insulin treatment.

Dr Alan Moses says that if degludec is approved and takes off commercially, it will bring about nothing less than a ‘paradigm shift’. 

Injected subcutaneously three-times a week, insulin degludec works for up to 40 hours, much longer than the 18-26 hours of Lantus. The company filed degludec with the EMA and FDA in September 2011, which if successful, could mean approval by the autumn, and its first launch before the end of 2012. 

The filings are based on the BEGIN and BOOST clinical trial programmes which involved nearly 10,000 type I and type II diabetes patients. Trial data have shown degludec to effectively lower blood glucose levels, while consistently showing a significantly lower rate of hypoglycaemia than Lantus, especially during the night. The trials also showed that degludec can be taken once-daily at any time of the day with the freedom to change injection time from day to day without compromising glycaemic control or safety. 

Novo Nordisk hopes that regulators will allow insulin degludec to be used by patients at any meal. This would allow diabetes patients more flexibility, as current long-acting insulins have to be taken with a main meal. 

GLP-1 and exenatide market

The first of the new injectables was Byetta (exenatide) and was launched by Lilly and Amylin in 2005, and represented a new class of injectables, the incretin mimetics, which mimic GLP-1 rather than being a direct analogue. Byetta is injected twice a day, but a new long acting formulation called Bydureon is available in the US and Europe, and needs to be taken just once a week. 

Novo Nordisk’s Victoza (Liraglutide) is a long-acting glucagon-like peptide-1 analogue and was approved in Europe and the US in 2010. GLP-1 analogues work by stimulating insulin secretion only when blood sugar levels are too high. This means they do not carry the risk of hypoglycaemia associated with insulin.     

Novo’s Victoza has produced convincing data, and has outperformed Byetta and Merck’s new oral treatment Januvia (sitagliptin) in head-to-head trials. In addition to controlling blood sugar, Victoza has shown other benefits including weight loss, blood pressure reduction and can even improve the function of beta-cells in the pancreas. This helped Victoza reach $1 billion in a relatively short time, and looks likely to overtake rival Byetta in 2012.

The promise of GLP-1s mean a number of other compounds in the class have been developed, but have not fared as well as Victoza so far. Taspoglutide was being co-developed by Ipsen and Roche, but significant levels of nausea and vomiting seen in trial patients resulted in the companies abandoning the drug in early 2011. Meanwhile GSK’s albiglutide looks to be on shaky ground as well. Data from a head-to-head trial showed GSKs’ drug failed to show non-inferiority to Victoza in type II patients in controlling HbA1c.

Sanofi filed its once-daily GLP-1 Lyxumia (lixisenatide) with the EMA in November as a standalone product, but also in combination with Lantus. Lixisenatide’s mode of action complements that of basal insulin, and can be added once- daily to optimally titrated Lantus. Studies show it safely improved HbA1c benefitting on both post-prandial glucose (often hard to influence) and body weight. 

Combination products

Sanofi is hoping combining Lyxumia with Lantus will help it consolidate its lead position in the insulin market. Pierre Chancel, senior vice-president of Sanofi Diabetes says the Lyxumia and Lantus combination offers something entirely new to the market. 

“Achieving glycaemic control and compliance with treatment is a complex challenge. These positive results show that once-daily lixisenatide in combination with Lantus could be an innovative therapeutic option for the treatment of uncontrolled type II diabetes by addressing its pathophysiology, especially regarding post-prandial glucose control with a convenient once-daily regimen, helping those patients who fail to meet HbA1c target despite controlled fasting plasma glucose.”

Sanofi has the advantage regarding a GLP-1 and insulin combination, as Novo’s application to combine Victoza and insulin (Levemir) was rejected by the EMA in September. The regulator rejected the application because of a flaw in the clinical trial, but the study also found that patients taking the combination also suffered more cases of hypoglycaemia. 

Sanofi is also taking a conservative approach to filing Lyxumia in the US, clearly mindful of the FDA’s own caution about side effects seen in Victoza and other GLP-1s. Sanofi says it expects to file with the US regulator in Q4 this year. Novo is taking a different approach, hoping a combination of degludec and a short-acting insulin could (to be called DegludecPlus) will eventually be the market leader. 

“The unique way in which insulin degludec/insulin aspart works, with the basal insulin component providing an ultra-long and steady action profile, plus a bolus boost of insulin aspart, provides a simple way to introduce mealtime dosing at any meal,” said Dr Moses. “These benefits, along with the lower risk of hypoglycaemia and improved FPG shown in these studies, are very promising for people living with type II diabetes.” 

A separate Phase III study showed that rates of hypoglycaemia at night were lowered by 37% in people with type I diabetes using once-daily insulin degludec/insulin as part at any meal (with additional insulin aspart doses for the remaining meals), compared to those using insulin detemir once-daily plus insulin as part at all main meals. 

Clinical studies have shown the combination provides an optimal glycaemic control with significantly less nocturnal hypoglycaemia compared to premix insulin.

Insulin degludec has a unique, slow rate of absorption which provides a flat and stable action profile. In several clinical trials, insulin degludec has demonstrated effective glycaemic control and improvements in both HbA1c and FPG. It has also demonstrated a significantly lower rate of nocturnal hypoglycaemia when compared to insulin glargine. 

Asked if the flexibility of degludec could be seen negatively – perhaps encouraging patients to abandon a disciplined regime, Dr Moses says: “That could be a criticism of degludec and the combination product, But we have to realise, that while we clinicians would certainly recommend a patient takes his insulin at the same time every day, in reality people with diabetes live as chaotic lives as the rest of us do.  

“These patients don’t have complete control over their lives, so degludec allows for that.” DegludecPlus will be the first ever mix of basal insulin (degludec) with short acting insulin (Novolog), which could work longer and lead to a reduction in hypoglycaemia. Older pre-mix products are currently popular in Asian markets, so an updated pre-mixed product could dominate in the fast-growing region. Sanofi are well aware of the threat that degludec poses.

In November, Sanofi’s chief executive Chris Viehbacher announced that his firm was accelerating the development process for a new formulation of Lantus, moving it straight from Phase I to Phase III. There are few details about the new formulation, but it will have to compete with degludec’s longer duration if it is to make an impact.

Emerging markets

As in other therapy areas, the emerging markets are now one of the hot topics in diabetes. Contrary to perceptions of diabetes as a ‘western’ disease, the International Diabetes Federation estimates that 80% of people with diabetes live in low or middle-income countries. Rapidly industrialising nations such as India and China have a massive, burgeoning problem with type II diabetes.

A recent study published in the New England Journal of Medicine estimates there are now around 92 million people with type II diabetes in China, with 60% of cases undiagnosed. Therefore, China is likely to be a major driver for the diabetes sector over the next decade, and sales growth in the country are expected to grow 15-17% from 2010-2030.

Companies are investing heavily in engaging directly with healthcare payors and patients in the emerging markets. Sanofi is conducting an arm of its Lyxumia trials specifically looking at Asian patients, called GetGoal L-Asia. One of the reasons for this is that Asian patients with type II diabetes tend to be leaner than western patients, which means their condition often progresses differently.

Cancer and safety concerns

As the use of diabetes medicines continues to grow, scrutiny of their safety is also increasing. New concerns about safety in diabetes medicines have arisen in the last few years, with none of the treatment types escaping suspicion.

Large meta-analyses have linked the long-acting insulin analogues with increased risk of cancer, GLP-1s and the oral DPP-IV drugs (including Merck’s Januvia and BMS and AstraZeneca’s Onglyza), carry warnings about acute pancreatitis. 

Bydureon’s US approval followed a protracted review by the FDA, the main reason was pre-clinical data showing the drug caused medullary thyroid carcinoma in rats. The drug carries a prominent warning about the data, whilst pointing out that there is no evidence to suggest it raises the cancer risk in humans. Nevertheless, the label also says Bydureon shouldn’t be used in patients with a personal or family history of medullary thyroid carcinoma. 

Meanwhile a new drug from AstraZeneca and Bristol-Myers Squibb which would be a first in a new class of diabetes treatments has just been rejected by the FDA.

Dapagliflozin is a sodium-glucose cotransporter-2 (SGLT2) inhibitor, which acts independently of insulin mechanisms and facilitates the excretion of glucose and associated calories in the urine, thereby lowering blood glucose levels.

The FDA says more data is needed from ongoing clinical trials, and may also want information from new ones. Its main concern is in relation to instances of breast and bladder cancer in patients seen in clinical trials. 

Overall, this new regulatory scrutiny means that while diabetes can be a lucrative market, pharma companies must consider safety questions more than ever before, and invest in large-scale monitoring before and after launch. 

Future directions

For pharma company strategy, the question of how far to develop the ‘franchise’ model within diabetes is also a key one. Novo Nordisk remains a tightly-focused pharma and biotech company, while Sanofi is bigger and more diverse. Sanofi has diversified into the competitive field of glucose meters by teaming up with devices company AgaMatrix.

But Sanofi says its iBGStar is the best glucose meter on the market, both in terms of reliability and for user-friendliness. In December it gained FDA approval for use in conjunction with iPhones and iPads.

Pierre Chancel, head of Sanofi’s diabetes division says the iBGStar is part of the company’s aim to ‘deliver integrated solutions to patients’ which it hopes will give it the edge. But Sanofi and Novo Nordisk will both have to keep an eye out for other emerging fields, which may produce ‘disruptive innovation’.

There are many emerging trends and technologies within the field that could eventually prove to be hugely influential. Two examples of this are stem cell therapy and oral formulations of insulin, which are now being developed.

Although these have presented huge technical challenges, and could take a decade to resolve, companies in the diabetes field have to look to the long-term in order maintain a competitive advantage.

Interview: Riccardo Perfetti, VP Medical Affairs, Global Diabetes Division at Sanofi

Sanofi has just launched the iBGStar glucose meter, which your research claims is the best in class. Do you think you now have the best in class device, GLP-1 analogue and insulin?

Our ambition is to present solutions that are best in class, and certainly insulin glargine is number one, not just in insulins, but all diabetes products. But I’m not certain that aiming for number one has to be the target – it is more the ability of the compound or the device to be integrated.

Management of diabetes – like hypertension or oncology – is a polypharmacy situation condition. So to have different elements of treatment which can nicely integrate makes a big difference. So our ambition with our GLP-1 Lyxumia is that while basal insulin controls fasting glycaemia, overall control might still not be good. That can be because poor post- prandial controls. 

The device also fits nicely into this scenario, because it actually tells you whether the dosing of your insulin is working or if you need to change. And in this case, this device works better than the others. 

Can Lyxumia simplify treatment, for instance, standing in for short-acting insulin?

For a GLP-1 to have the greatest impact possible, it has to be used at a certain stage of the disease, where a biological response is still possible. The GLP-1 can be added when basal insulin is no longer sufficient, and an additional choice is needed. Today, that is often a bolus insulin, however there will always be a place for short-acting insulin because diabetes is progressive, and therefore you will eventually need the bolus. 

One day there may be agents which can lower blood glucose but also alter the progression of the disease. One of the objectives of our ORIGIN study is to see whether if you start really early, you promote a beta cell ‘rest’ in the pancreas, where the pancreas starts working again for a period. That could mean progress towards a really severe and complicated diabetes takes a little bit longer, which would make a big difference to the patient and their health.

Several studies of patients with ‘pre-diabetes’ treated for a short time with insulin, suggest you can actually halt the disease, so for one year or even longer they could be without the disease. So maybe we need to re-position how we see the different steps of the progression of diabetes.

Is there suspicion about the pharma industry trying to get their products being used earlier? 

Still today many patients think that once you start using insulin you have reached the point of no return. But it should not be a question of if you will continue to take insulin, it should be a question of if you will do better taking insulin. There is a severe risk of cardiovascular death, risk of cerebrovascular death, renal failure and dialysis and blindness. All of those could be significantly reduced if we get blood sugar under control.

So in a way, this hesitation and delay doesn’t make much sense because the science actually supports and aggressive, early treatment. Research into why there is typically a delay has found that patients are actually willing to do what it takes, but it needs to be explained to them, and what the benefits are. And surprisingly it is the physician that is a little bit more hesitant. So there is obviously some need for education there.

Are we likely to see inhaled or oral insulin?

These have been tried or are still under development, but none have been successful to date. Some day an easier route of administration might make it easier, or maybe an insulin that you inject that only works when you need it could be developed. We would call this ‘gluco-sensitive’ insulin, so there will certainly be additional discoveries. 

But in the meantime, patients need to understand that to minimise their chances of developing cardiovascular disease, or have to face renal failure, dialysis or blindness, insulin does work very well. It comes with a result, which is a reduction in all of those complications.

That is a very important trade off. There are many chronic conditions for which this remedy just doesn’t exist.