Toujeo and Afrezza: New and Improved Insulins, Limited by FDA Labeling Constraints

Existing treatments are effective enough to control diabetes in most patients, but drug makers spend huge sums to keep developing new products and improving old ones.

Indeed, Sanofi just rolled out 2 novel versions of the very oldest diabetes treatment, an insulin glargine formulation called Toujeo and an inhalable form of human insulin called Afrezza.

Sanofi officials say both products will benefit large numbers of insulin users with both type 1 and type 2 diabetes mel-litus (T1DM, T2DM). Outsiders express a wide range of opinions.

Trial data indicate that Toujeo controls glycated hemoglobin (A1C) levels about as well as Lantus, an insulin glargine formulation approved in the year 2000 that has just lost patent protection after years of blockbuster sales. Toujeo lasts longer than Lantus, however.¹ It also provides the body a steadier stream of insulin1 and is associated with a significantly lower risk of nocturnal hypoglycemia.¹

Afrezza performed similarly in a phase 3 trial. It roughly matched an existing competitor, insulin aspart (Novolog), in A1C reduction, and slightly outperformed it in several secondary ways. Afrezza use was associated with less hypoglycemia, lower fasting blood glucose, and slight weight loss rather than slight weight gain. It also reached peak levels very quickly, in just 12 to 14 minutes on average.²

That said, Afrezza’s medical importance will likely hinge on something that no trial can measure: how the change from injection to inhalation affects patient behavior. If the delivery method inspires patients to medicate themselves more consistently, Afrezza could produce huge health benefits. If patients use Afrezza like they use insulin aspart (a fast-acting insulin analogue), the new product could prove to be an expensive convenience.

Financial analysts mostly predict solid but unspectacular sales for both drugs, in part because federal regulations for-bid Sanofi from touting the comparative advantages of either drug. (The FDA did not allow language about less hypoglycemia in the label it approved, and therefore Sanofi cannot mention it in language it uses to promote the drug.)

Consensus estimates reported by Bloomberg predict annual Toujeo sales will reach about $1.3 billion by 2020³ far below the $7.1 billion that Lantus generated in 2014. As for Afrezza, annual projections range from a paltry $182 million up to $2 billion, with the median in the $600 million range. The treatment’s unexpectedly poor performance during its first month on the market led Goldman Sachs to cut its annual sales projections by $1 billion^.4

In other respects, however, both medications have gotten a good reception.

“The response to Afrezza on social media has been tremendous,” Rachele Berria, MD, PhD, who heads the Diabetes Medical Unit for Sanofi US, told Evidence-Based Diabetes Management in an interview. “Healthcare providers don’t seem to anticipate that patients will see much of a need to move away from injections, but actual patients see this as a valuable feature.”

Berria says the company will study real-life Afrezza use to see if patient enthusiasm translates into patient compliance, and that it will follow real-world Toujeo users to measure the practical effect of its longer, steadier flow of medication. “The goal in treating diabetes is to avoid peaks and valleys in both insulin and sugar, and Toujeo does that to a degree that once seemed impossible,” she said. “There’s no insulin spike when each new injection gets absorbed, and there’s no loss of efficacy in the final few hours. It’s a big stride forward from Lantus.”

Physicians have been using insulin to treat diabetes since 1922, when Frederick Banting and Charles Best injected the hormone into a diabetic teenager at a hospital in Toronto. Eli Lilly began producing it commercially within the year, and diabetes was transformed, virtually overnight, from a speedy death sentence to a chronic condition.⁵

Intermediate acting Neutral Prot-amine Hagedorn (NPH) insulin arrived about a quarter century later, in 1950. Long-acting insulin, on the other hand, didn’t reach patients until 2000, when Lantus went on sale in the United States and Europe.

The new drug reduced A1C levels about as much as NPH insulin, but trials demonstrated that it produced a greater reduction in fasting plasma glucose and fasting blood glucose as well as a far lower risk of nocturnal hypoglycemia.⁶

The other big advantage of Lantus was the convenience of longer action. Patients who had spent years toting around basal insulin and setting alarms for midday injections suddenly had nothing to carry and nothing to remember except a single injection before bed. By then, of course, insulin was not the only effective treatment for T2DM. The FDA had approved metformin in 1994, and its huge success spurred drug companies to develop the other oral treatments that now crowd the market.

Many of these treatments are quite effective, especially when used in combination. Indeed, if used properly, their excellent disease control could greatly reduce diabetic complications and the need for new drugs.

Yet pharmaceutical companies continue developing treatments like Toujeo and Afrezza because a huge percentage of diabetics fail to control their condition with current options. A recent study that examined records from more than 43,000 patients found that less than 55% of all Americans who have been diagnosed with diabetes, and prescribed medication to control blood sugar, actually man-age to keep their A1C level under 7%^.7

The main cause of this problem seems to be patient behavior. Studies have found that patient adherence to oral treatment protocols can range from more than 90% down to just over 50%. Strict adherence to guidelines concerning injectable medications and proper diet tends to be lower, while strict adherence to guidelines concerning mod-erate, regular exercise and blood sugar checks is downright rare.⁸ The chance that any patient will adhere perfectly to a complex regimen is low, and studies of people with all types of chronic disease have typically found that only about half of them will make a serious effort to manage their condition^.8

The consequences of this behavior are dire.

Diabetes is the nation’s seventh-lead-ing cause of death. It increases the risk of stroke (by 50%), heart attack (by 80%), and death from cardiovascular disease (by 70%). It is also the leading cause of kidney failure and non-traumatic lower limb amputation. The American Diabetes Association estimates that the di-rect medical cost of treating diabetes reached $176 billion in 2012, and indi-rect costs such as lost productivity add-ed another $69 billion to the tally.

⁹

Studies have demonstrated that in-creased adherence to a treatment regi-men can reduce A1C levels,¹⁰ and many other studies have shown that A1C reductions prevent complications. A 1% reduction in A1C is associated with a 14% reduction in the risk of heart attack and a 40% reduction in the risk of eye, kidney, and nerve disease.¹¹ (Logic says that better adherence would also slash healthcare costs, but the findings from research on that topic are mixed.¹⁰)

A number of experiments have tested different strategies for improving ad-herence to existing treatment regimens. Many have failed, but many others have produced significant gains, at least over the study period, with simple ap-proaches such as asking pharmacists to provide patients a little extra information.¹² While some researchers continue to study ideas for motivating patients, others work to improve treatments.

Some people, for example, respond poorly to existing medications, so even if patients used existing options perfectly, there would still be a need for more effec-tive options. The biggest need, however, appears to be medications that promote compliance by making treatment regimens less arduous and more tolerable. Only real-world use will show if Toujeo and Afrezza meet that second need, but there are several reasons for hope.

For one, the reduction in nocturnal hypoglycemia associated with using Toujeo rather than Lantus is reasonably large. A meta-analysis of 3 of the drug’s phase 3 trials found a 31% reduction in such reactions among 2476 patients (risk ratio, 0.69; 95% CI, 0.57-0.84; P = .0002).¹³

While the biggest original selling point for Lantus may have been the relatively low rate of nocturnal hypoglycemia, low blood sugar remains a serious problem. Hypoglycemia is the primary cause of roughly 282,000 emergency department visits each year,9 and many patients fear it enough to risk high blood sugar by taking less insulin than their doctors prescribe^.14

Thus, the lower nocturnal hypoglycemia incidence associated with Toujeo could produce 2 distinct benefits for patients who switch from Lantus:

• a reduction in hypoglycemia among those who always used a full dose, and
• a reduction in hyperglycemia among those who only begin taking a full dose after the switch. (Sanofi’s inability to advertise the lower hy-poglycemia risk in the United States may curtail its potential for improving compliance here, but Toujeo’s relative safety may improve patient behavior in Europe, where the ap-proved label mentions the reduc-tion in nocturnal hypoglycemia.)

Another potential advantage for realworld patients who switch from Lantus is Toujeo’s greater length of action. The older medication barely lasts 24 hours, so patients must inject themselves promptly or risk high blood sugar. Toujeo’s (as yet untested) longer action will theoreti-cally improve outcomes by protecting occasionally tardy users from themselves.¹⁵

Afrezza’s trial performance suggests that it, too, may benefit real-world pa-tients in subtle ways that Sanofi cannot advertise, but its main selling point is obvious to anyone who has ever endured an injection. While research indicates that needles rank among the biggest barriers to treatment compliance in diabetic patients,¹⁶ opinions vary wildly about the market for alternatives that are inhaled rather than swallowed.

Some wonder who wouldn’t want to inhale medication rather than inject it. Others say that the failure of Pfizer’s Exubera proves the answer is “nearly everybody.” (Pfizer lost $2.8 billion on the product before pulling it from the market in 2007, just a year after launch. Its reception was so brutal that large drug companies abandoned all work on inhal-able insulin. Afrezza was developed by a much smaller firm called MannKind.¹⁷)

“Exubera failed because it came via a large and odd-looking device that was hard to carry and embarrassing to display. If you took the thing out at a res-taurant to get some insulin before you ate, people might turn and stare be-cause it looked like you were smoking pot from some sort of unique bong,” said Mark Peyrot, PhD, a sociology professor at Loyola University of Maryland, in an interview with EBDM. Peyrot studies the psychological aspects of diabetes.

“Afrezza is totally different. The device it comes in looks like an inhaler that is used to deliver asthma medication,” Peyrot told EBDM. “I’m not predicting this single improvement guarantees it will become a blockbuster, but there’s no reason to think Exubera’s performance dooms it.”

To the contrary, Peyrot thinks that many patients yearn for an injection re-placement (that doesn’t look like a bong) and that the new delivery system may significantly increase the wilingness of its users to take rapid-acting insulin with meals. “Only a small percentage of people are truly terrified of injections, but many feel some visceral aversion to them, and that’s only the beginning of the problem,” Peyrot said. “People find

needles embarrassing and don’t want to inject themselves with a needle in front of others, so they often find themselves doing it in toilet stalls, which are the last place on earth they want to use something that’s supposed to be sterile. Besides, injections can hurt.”

Despite the previous failure of inhalable insulin, there is some evidence in the track record of insulin pens that alternative delivery systems can attract large numbers of uses and improve in-sulin adherence. Insulin pens improve upon vial-syringe-needle systems in a wide variety of ways. They provide users with a quicker and more discreet way to inject themselves. They’re easier to carry around. They improve dosing accuracy. They eliminate the need for injection technique. They even tend to hurt less. These advantages have attracted significant user numbers in almost every wealthy country around the world except for the United States, where their adoption among insulin users may still be under 10%.¹⁸

People who do try pens tend to prefer them. More importantly, pens seem to promote treatment adherence. A study of more than 1800 patients concluded that use of one company’s pen (rather than a syringe) was associated with a 39% greater odds ratio (OR) of maintain-ing a medication possession ratio of 0.80 or higher over a 12-month follow-up period (OR, 1.385; 95% CI, 1.037-1.849).¹⁹ A recent review of compliance research found 4 pen-user studies, all of which re-ported significant compliance benefits.²⁰

And pen design keeps improving. Sanofi said the pen that comes with Toujeo requires less application force and less hold time than the model that comes with Lantus.

Such incremental improvements seem unlikely to change patient behavior as much as the transition from injec-tor to inhaler, but it’s still unclear what impact, if any, that transition will have. Afrezza hasn’t been on the market long enough for anyone to study its effects in real-world usage.

Sanofi and MannKind are planning post launch research, however, because any evidence that Afrezza significantly increases adherence and outcomes will surely boost sales and justify the product’s considerable price premium: $7.54 per day compared with $3.14 for Apidra.²¹ (The effective price premium for Toujeo remains unclear, as the drug retails for the same price as Lantus, but Lantus biosimilars have yet to hit the US market and begin price competition.³)

Even after real-world performance data do become available, the costeffectiveness of the new drugs may redmain unclear. Experts still argue about whether actual health benefits justify the price we pay for Lantus and other analogue insulin formulations that have been around for many years. Some say there’s little evidence that the (relatively) new products control blood sugar any better than far older products and argue that their few indisputable advantages, like the reduced chance of hypoglycemia, could be duplicated via strategies that cost billions less, like having a snack before bed.²²

Others argue that the benefits of analogue insulin treatments tend to be hard for trials to measure. For example, analogue formulas can save patients several shots per day, which boosts compliance in real life but not in trials. Analogues also hold blood sugar levels much steadier than human insulin, which has no effect on A1C reduction but may prove a major long-term benefit.²³

Experts may still be having the same argument a decade from now, but as-suming that no one discovers an actual cure for both types of diabetes, the slow but steady parade of new treatment options will continue, offering hope to both physicians and analysts.

References

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2. MannKind reports positive data from a phase 3 clinical study of Afrezza in patients with type 1 diabetes [press release]. Valencia, CA: Business Wire; August 14, 2013. http://www.news.mannkind-corp.com/phoenix.zhtml?c=147953&p=irol-newsArticle&ID=1847570.

3. Bennett S. Sanofi won’t discount Toujeo more than Lantus blockbuster. Bloomberg website. http://www.bloomberg.com/news/ articles/2015-04-13/sanofi-won-t-discount-toujeo-more-than-lantus-blockbuster. Published and accessed April 13, 2015.

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13. Sanofi reports positive phase 3 results for Toujeo (insulin glargine [rDNA origin] injection 300 U/mL) [press release]. Paris, France: Sanofi;June 14, 2014. http://www.news.sanofi.us/2014-06-14-Sanofi-Reports-Positive-Phase-3-Results-for-Toujeo-insulin-glargine-rDNA-origin-injection-300-U-mL.

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17. Stanton D. Inhaled insulin: Sanofi alone as big pharma declines to revisit past. InPharma website. http://www.in-pharmatechnologist. com/Drug-Delivery/Inhaled-insulin-Sanofi-alone-as-Big-Pharma-declines-to-revisit-past. Published February 4, 2015. Accessed April 27, 2015.

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