FDA approves first ‘artificial pancreas’ for diabetes treatment

The first "artificial pancreas" was developed by Medtronic.

By REBECCA ROBBINS @rebeccadrobbins

The Food and Drug Administration on Wednesday approved the first so-called artificial pancreas, an out-of-body device expected to lift the burden for some diabetics on the daily grind they must go through to keep their blood sugar levels stable. It will be available next spring for patients with type 1 diabetes who are over age 14.

The device, which looks like a smartphone, is designed to automatically monitor and administer the delivery of insulin for type 1 diabetes patients, whose ability to provide insulin naturally is impaired. It wirelessly links up an insulin pump and glucose monitor, allowing patients to partly turn over the process of testing and adjusting their blood sugar levels. It’s not unlike cruise control: Patients still have to manually control their glucose levels before they eat.

In the diabetes community, optimism about the new device is tempered by fears that it will command a high price tag that could put it out of reach for patients already grappling with the soaring cost of insulin. Medtronic, which developed the “MiniMed 670G,” has yet to announce how much it plans to charge. But spokeswoman Leslie Bryant said the company expects to offer it “at currently offered Medtronic pump system pricing” and is talking with health plans to “enable patient access.”

Medtronic’s application was approved on the back of a study that tested how 123 type 1 diabetes patients fared on the device. No patients reported developing complications like excess blood acids or low glucose levels that can result from poor monitoring of the disease.

Medtronic is also testing the device on pediatric patients. One such patient, 13-year-old Jonathan Platt of the Los Angeles area, is still using his device after the completion of the trial. “For our family, it’s been life-changing,” his mother, Angie Platt, said. She said that after an initial adjustment period, blood sugar imbalances that prompt middle-of-the-night trips to Jonathan’s room have been reduced from several times a night to half a dozen times a month.

The device’s approval brought cheers from JDRF, the world’s largest charitable funder of type 1 diabetes research. Over the past decade, the group, formerly known as the Juvenile Diabetes Research Foundation, has aggressively pushed to get such a device to market by funding research and pressing the federal government.

“I’m very excited about the fact that there is a system that will help people lead fuller, safer, higher quality lives,” said Derek Rapp, JDRF’s president and CEO.
Rapp said it’s important that people are able to afford and purchase not only the basic device but also disposable products like a catheter, tubing, and tape that go along with it.

“Medtronic is already aware of our belief that that is an important item to address,” he said.

Diabetes therapeutics: A hotbed of innovation and reservoir of pharma progress

Flickr, le vent le cri

By Nicole Gray

 If the last 10 years is any indication, we have entered an era in which morbid obesity and related metabolic disorders are so prevalent that they are becoming the norm. Between 1993 and 2013, the prevalence of diabetes in the U.S. increased 135%, from 3.06% of the population to 7.18%, according to the Centers for Disease Control and Prevention (CDC).

But even though the prevalence of diabetes has increased substantially in the last 20 years—29 million Americans now have diabetes—the CDC recently reported that the rate of death from diabetes-related complications has declined significantly in the last 20 years. This decline is largely a function of patients having access to better treatment options, resulting in improved long-term glycemic control and stability.

Across every category in the oral and injectable diabetes treatment markets—thiazolidenediones, sulfonylureas, DPP-4 inhibitors, SGLT2 inhibitors, meglinitides, biguinides, alpha-glucosidase inhibitors, and insulins—there has been some degree of innovation, and in some cases, major treatment advances.

Whether it’s implementing better glycemic control, more weight loss, a lower incidence of hypoglycemia, more convenient drug delivery, or a unique mode-of-action, drug companies are advancing the standard of care for type 2 diabetes (T2DM), and there’s even more to come—the latest Pharmaceutical Researchers and Manufacturers of American report cites 86 diabetes-related therapies in the pipeline.

Game-changing clinical trial results

A little more than a year after Eli Lilly and Boehringer Ingelheim’s Jardiance (empagliflozin), an SGLT2 inhibitor, was approved by the FDA for treatment of T2DM, the companies jointly announced the results of an FDA-mandated, randomized, controlled, phase 3, cardiovascular (CV) safety trial. The trial showed that Jardiance was not only safe in terms of CV risk, but provided patients with a CV treatment-related benefit.

In the 7,000-subject EMPA-REG OUTCOME trial, patients who received Jardiance (in addition to background treatments, such as metformin, insulin or other drugs) had a 38% reduction in the risk of CV-related death, a 35% reduction in the risk of hospitalization, and a 32% reduction in the risk of all-cause mortality.

This precedent-setting data was, and still is, astonishing for the medical community, as well as Americans with T2DM—not to mention the 387 million people worldwide with this disease. Even the research team at Eli Lilly, normally a pragmatic and reserved group, stood up and applauded when Jan Lundberg, Executive VP of Science and Technology and President of Lilly Research Laboratories, revealed the EMPA-REG OUTCOME results to his team.

Suddenly, an overlooked flozin is on the radar

Many of the internists, diabetologists, and primary care physicians on the front lines of treating patients with diabetes are still digesting the news, but the implications are clear. Considering the fact that about two-thirds of patients with T2DM die of CV disease, Jardiance (in combination with other therapies and lifestyle modifications) could improve long-term outcomes for many, if not most, of their patients with T2DM.

In addition, it might be time for them to take a look at two recently introduced combo drugs—Synjardy (empagliflozin/metformin) and Glyxambi (empagliflozin/linagliptin), both of which were approved within the last 12 months.

The physician perspective

Dr. Barry Mennen is a Washington, D.C.-based physician has been treating obese patients and patients with T2DM for years. Although the SGLT inhibitors (also known as flozins) have been around since Johnson & Johnson’s Invokana (canagliflozin) was approved in 2013, Dr. Mennen has not used them—mainly because of his concerns about the risk of ketoacidosis associated with this class.

After reviewing the results of the Jardiance CV safety trial, including the 0.1% rate of ketoacidosis in Jardiance patients, Dr. Mennen told BioPharma Dive, "I am heartened to see the very low levels of ketoacidosis in the Jardiance trials. As far as whether or not I would prescribe Jardiance, the answer is yes—but not yet."

Before predicting immediate blockbuster status for Jardiance, it’s important to remember that diabetes is treated within the framework of an algorithm that generally relies on major lifestyle changes and combinations of oral antidiabetics, while saving insulin as a last-resort treatment option. (Note that almost 50% of sales of diabetes drugs are for insulin).

"First, I want to be clear that I spend a fair amount of time with patients explaining how their overweight/obesity/visceral fat is related to their disease," Dr. Mennen said. "I then explain the dual issues of increased insulin resistance and decreased beta-cell insulin response. I give them a program of weight reduction and maintenance that emphasizes decreased carbohydrate intake above all else.

"As for treating garden variety type 2 diabetes, metformin forms the foundation, and I add a gliptin to that if needed. If patients need more, then a flozin would make sense, especially if they have trouble maintaining their weight. Type 2 diabetes is not a one-size-fits-all disease, and different patients require different approaches. The more I see with the flozins—and the Jardiance data is impressive—the more I am being pulled to prescribe them."

Market considerations

Currently, the market for diabetes is dominated by ten blockbuster drugs, which together generated $28.6 billion in revenues last year. At the top of the list are Sanofi’s long-acting basal insulin, Lantus, and Merck’s oral DPP-4 inhibitor, Januvia (sitagliptin). Merck has the largest oral diabetes franchise, with a total of $6 billion in sales when you add Janumet (sitagliptin/metformin). Much has been made of whether or not Jardiance could muscle in on Merck’s oral antidiabetic market share, but the conversation is premature.

Combined, the three drugs that comprise the SGLT2 inhibitor class—Invokana, AstraZeneca’s Farxiga (dapagliflozin), and Jardiance—only represent 4% of all prescriptions for oral antidiabetics. However, growth is expected for the entire class, with Invokana favored as a frontrunner (at least until now). Clearly, the new CV data for Jardiance will accelerate its uptake, and most likely have a positive class effect. J&J has even said that it expects this class effect to occur.

It should also be noted that the label has not been updated to reflect the new CV data. "We are providing the CV data to global regulators and can’t speculate on decisions the regulators may make on inclusion of these data in the Jardiance label," Dr. Thomas Seck, Vice President of Clinical Development and Medical Affairs-Metabolism at Boehringer Ingelheim, told BioPharma Dive in an interview.

Recalibrating the competitive landscape

Regardless of what’s happening with the Jardiance label, this drug is still the first and the only diabetes medication (at least for now) to show a significant reduction in both CV risk and CV-related death in a dedicated outcome trial. In addition, it can easily be used as part of combination therapy.

"Jardiance is not contraindicated to be used with any anti-diabetic medications, though it would not make sense to combine it with another SGLT2 inhibitor," said Seck. That being said, treating physicians, who are well aware that their patients with T2DM face a two- to four-fold increased risk of CV, are going to consider adding it to the prescribing mix.

Even before the news came out, many analysts were becoming bullish about Jardiance after previewing data that Lilly put out in August. Several days ahead of the announcement about the Jardiance CV data, Jeffrey Holford from Jefferies & Co. increased his peak sales estimate for Jardiance from $1.2 billion per year to $6 billion per year. 

Still, the question is how long Jardiance will hold onto to its CV outcomes-related advantage. "Other companies are also testing their antidiabetic drugs in CV outcomes trials," said Oscar Virgilio, Senior Strategic Consultant for Swat Team Inc. in New York City, in an interview. 

"However, CV outcomes data is not expected for Farxiga until 2019. This provides the Lilly/BI Jardiance marketing team with a considerable time period in which to promote Jardiance’s combined advantages on blood glucose levels and CV outcomes without direct competition."

The spillover effect

At the same time that Jardiance sales are expected to increase, most analysts predict that there will also be a spillover effect to the other SGLT2 inhibitors. But Dr. Seck is cautious about the tendency to extrapolate benefits just because drugs are in the same class.

"It is important to highlight that every molecule is unique and different," he said. "SGLT2 inhibitors have differences in several pharmacological features, such as potency, target selectivity and drug metabolism and excretion."

Competition is part of the innovation game, but in a therapeutic area like diabetes, having numerous treatment options allows for more flexibility with combination therapy. For companies involved in diabetes therapeutics, including Sanofi, Merck, Novo Nordisk, Eli Lilly, Boehringer Ingelheim, Johnson & Johnson, Novartis, AstraZeneca, OraMed, Mannkind, as well as the companies that manufacture diagnostics and devices, there is recognition that there is a great need for different types of diabetes therapies—and lots of room for innovation.

You say you want a revolution? Lilly, BI and Jardiance may trigger one in diabetes

Top-line data on Eli Lilly ($LLY) and Boehringer Ingelheim's SGLT2 med, Jardiance, is out, showing the drug cut the combined risk of heart attack, stroke and death from cardiovascular causes by 14% in high-risk Type 2 diabetes patients. But what does it mean for the ultracompetitive diabetes landscape?

Potentially a lot of things, according to analysts. First, the implications for the rest of the SGLT2 class, which comprises Johnson & Johnson's ($JNJ) Invokana and AstraZeneca's ($AZN) Farxiga in addition to Jardiance. Given the shared mechanism of action across the trio, doctors "will likely assume that the effect of Jardiance is a class effect," giving Jardiance's rivals a boost in the process, Evercore ISI analyst Mark Schoenebaum wrote in a Friday note to investors.

Leerink Partners analyst Seamus Fernandez thinks the magnitude of the survival benefit--Jardiance reduced CV death by 38% and all-cause mortality by 32%--will also lead to guideline changes that bring the med and its peers much earlier in lines of diabetes therapy.

But for now, Jardiance is the only one that could add the CV benefit to its label--provided the FDA approves the update, of course. And that means sales reps from Lilly and BI will "be able to more easily speak to it and to the fact that if the doctors want to be intellectually honest and practice evidence-based medicine they should really be prescribing Jardiance," Schoenebaum pointed out. Fernandez agreed, predicting Jardiance would "take the lion's share of the upside."

Another key will be how the warring pharmas navigate the payer landscape, Bernstein analyst Tim Anderson wrote to clients Thursday. J&J, which currently boasts "formulary dominance," may be able to preserve its position by offering rebates and riding on the coattails of its fellow SGLT2 med's success. AstraZeneca, on the other hand, "to some degree … gets left out in the cold," he wrote.

The data also stands to affect other classes of diabetes drugs--most notably DPP-4 inhibitors, led by Merck & Co. ($MRK) behemoth Januvia--that haven't turned up a cardiac benefit in post-marketing examinations. While analysts have different opinions on just how much DPP-4s might suffer now that SGLT2s can tout a CV edge, they agree on one thing: It's bad news.

Schoenebaum, for his part, expects to see the SGLT2 class overtake the DPP-4s in the next three to six years. Peak sales estimates for Jardiance currently sit below $2 billion, while Januvia is a $6 billion seller, but "these could invert," he forecast.

Anderson, though, was more cautious. "Paradigm shifts in primary care simply take time, and patients who currently use medicines like DPP4-s are unlikely to switch in droves," he warned. Instead, the "low-hanging fruit" will be new patients starting on therapy, who make up "a smaller slice of the pie in most chronic diseases." Still, he took his 2020 Januvia sales predictions down a notch, adjusting them from $7.8 billion to $6 billion.

And what about GLP-1 drugs, like Novo Nordisk's ($NVO) Victoza? They may be preparing for their own moment in the sun, Fernandez wrote. The next diabetes CV outcomes trial to report will be Novo's LEADER study for Victoza, with top-line results expected late this year or early next. If that trial shows a statistically significant reduction in CV outcomes, physicians foresee a serious uptick GLP-1 use, as well as SGLT2 use. And if they don't?

"We expect moderately negative impact to overall GLP-1 sales," he said.

By Carly Helfand