What's next in diabetes drugs? The pulse of R&D at ADA14

Diabetes drug developers have their work cut out for them.

More than 29 million Americans have the disease, according to the Centers for Disease Control and Prevention. More alarming, another 86 million are considered prediabetic, CDC says, meaning their blood sugars are unhealthily high but not quite in Type 2 territory. Without intervention, as much as 30% of that population will develop diabetes within 5 years.

"Those numbers are just unfathomable," Eli Lilly's ($LLY) diabetes president Enrique Conterno said. "It's a significant problem and a significant epidemic," he said, and one the global drug development is racing to help control. United Healthcare expects the cost of diabetes care to reach $500 billion by 2020 in the U.S. alone, providing plenty of motivation for the makers of tablets, shots, insulins and medical devices designed to control blood sugar and save lives.

Convening in San Francisco for the annual conference of the American Diabetes Association this weekend, Big Pharma angled for the spotlight in a field made up mostly of similar treatments with small differentiations that could spell the difference between blockbuster sales and also-ran status.

Much of the debate has focused on two newfangled treatment models: Injectable therapies that have shown big benefits but are yet to make a splash among doctors, and oral drugs that come with noteworthy efficacy but some alarming risks.

A promising new class

GLP-1 drugs at a glance

AstraZeneca's exenatide

Regulatory status: Approved in 2005 as daily Byetta and in 2012 as weekly Bydureon
2013 sales: $555 million combined
Peak estimate: Up to $1.3 billion combined

Novo Nordisk's liraglutide

Regulatory status: Approved in 2010 as daily Victoza
2013 sales: $2 billion
Peak estimate: Up to $3 billion

Sanofi's lixisenatide

Regulatory status: Approved in Europe in 2013 as daily Lyxumia; FDA application expected in 2015
2013 sales: $12 million
Peak estimate: Up to $900 million

GlaxoSmithKline's albiglutide

Regulatory status: Approved in 2014 as weekly Eperzan (in Europe) and weekly Tanzeum (in the U.S.)
2013 sales: N/A
Peak estimate: Up to $800 million

Eli Lilly's dulaglutide

Regulatory status: Under FDA review as a weekly agent
2013 sales: N/A
Peak estimate: Up to $2 billion

Intarcia's once-a-year ITCA 650 (exenatide)

Regulatory status: In Phase III development with filing expected in 2016
2013 sales: N/A
Peak estimate: N/A

The former group, called GLP-1 therapies, are injectable treatments that work by bolstering the hormone glucagon-like peptide-1, which is naturally released after eating and regulates the body's insulin secretion. The treatments bind to GLP-1 receptors and stimulate the release of glucose-dependent insulin while suppressing the release of glucagon, a hormone that raises blood sugar concentration.

While analysts expect the market for GLP-1 drugs to top out at around $5 billion a year, it's been something of a slow trip upward since the first one, AstraZeneca's ($AZN) Byetta, debuted in 2005.

"For whatever reason, primary care physicians have not exactly swarmed to the GLP-1 class," Novo Nordisk ($NVO) Chief Medical Officer Alan Moses said. "Part of that is just the inherent conservatism toward new therapies. And, in the U.S., it's related to the fact that, considering an injectable versus an oral therapy, there's still a perceived barrier there."

In order to get exclusive rights to Byetta and Bydureon, its weekly counterpart, AstraZeneca signed a deal worth up $4.3 billion this year to take full control of its former diabetes alliance with Bristol-Myers Squibb ($BMY). But despite strong clinical results and a global marketing push, the two treatments brought in just $555 million combined in 2013.

Novo's Victoza, a daily GLP-1 therapy approved in 2010, is the standard-bearer and sole commercial success among the class, bringing in $2 billion last year.

That figure makes it a big target for throne-watching rivals, including GlaxoSmithKline ($GSK), whose weekly albiglutide (recently approved as Tanzeum) tried and failed to demonstrate noninferiority to Victoza in its Phase III program.

Only one weekly agent has measured up: Lilly's dulaglutide, a Phase III GLP-1 agonist that many consider the only significant threat to Novo's leadership.

Lilly, starved for new products on a company-wide level, believes dulaglutide's expected FDA approval and U.S. launch will give it a significant revenue-generator to dull the effects of some major patent losses. In the microcosm of diabetes, however, the drug's impact will be even greater, Conterno said.

"We view dulaglutide as a catalyst for the whole GLP-1 class," he said. "Our thinking is we want for dulaglutide to become foundational to diabetes therapy."

And Novo, while quick to point out that no GLP-1 entrant has topped Victoza on efficacy, believes a rising tide may raise all ships in the fledgling space.

"Dulaglutide's comparability is good for the field," Moses said. "Lilly is a viable competitor, and I think together the two of us--with two good drugs--will have the potential of expanding the appreciation of the value of this class of drugs in Type 2 diabetes."

Analyst projections for dulaglutide's sales peak vary widely, with bulls expecting it to hit $2 billion with ease, while others worry that Victoza's better marks in weight loss will keep Lilly's drug from taking significant share.

Proven benefits, established risks

SGLT-2 drugs at a glance

Johnson & Johnson's canagliflozin

Regulatory status: Approved in 2013 as Invokana
2013 sales: Undisclosed
Peak estimate: Up to $1 billion

AstraZeneca's dapagliflozin

Regulatory status: Approved in Europe in 2012 as Forxiga; FDA approved in 2014 as Farxiga
2013 sales: $33 million
Peak estimate: Up to $850 million

Eli Lilly and Boehringer Ingelheim's empagliflozin

Regulatory status: Rejected by FDA in 2014 with resubmission expected this year; approved in Europe as Jardiance
2013 sales: N/A
Peak estimate: Up to $800 million

Pfizer and Merck's ertugliflozin

Regulatory status: In Phase III development with no announced filing date
2013 sales: N/A
Peak estimate: N/A

The same uncertainty applies to another new class of diabetes treatments, a cadre of pills that promise to reduce blood sugar without the need for needles.

These oral treatments work by targeting the protein sodium/glucose transporter 2, or SGLT-2, which is responsible for steering blood sugars toward the kidney for reabsorption. By blocking the protein's function, SGLT-2 inhibitors funnel that excess blood glucose away from the kidneys and spur the body to dispose of it through the urine. Such treatments have demonstrated significant reductions in hemoglobin A1c--a common biomarker for diabetes--as well as body weight and blood pressure.

But then there are the risks. SGLT-2 blockers have been linked to increased rates of genital and urinary tract infections, plus kidney damage and cardiovascular issues. A potential link to bladder and breast cancers tanked AstraZeneca's attempt at FDA approval for dapagliflozin in 2012, and only after gathering new safety data could the company sway regulators this year.

In the meantime, Johnson & Johnson ($JNJ) became the first on the SGLT-2 market with its Invokana, approved in 2013, but that drug's cardiovascular risks led the FDA to require a large post-market outcomes trial to ensure its safety.

Analysts expect the market for SGLT-2 blockers to reach about $2 billion globally, but it's tough to say with any certainty whether they'll get there. J&J didn't break out 2013 sales for Invokana in its last annual report, and AstraZeneca's entrant grossed just $33 million overseas last year. Eli Lilly and Boehringer Ingelheim endured an FDA rejection for their SGLT-2-blocking empagliflozin this year, and while the agency has since signed off the manufacturing problems that prevented an approval, the pair will likely struggle to meet their goal of launching the treatment this year.

Merck ($MRK), a relatively late entrant to the SGLT-2 space, believes the drugs' brightest future may come as part of a fixed-dose combination. The New Jersey pharma giant turned heads last year it struck a deal with rival Pfizer ($PFE), paying $60 million to get its hands on the Phase III SGLT-2 blocker ertugliflozin. The drug has great promise as a monotherapy, Merck vice president of diabetes research Peter Stein said, but the company is particularly enamored with its potential as a complement to the blockbuster Januvia, which lowers blood glucose by blocking a protein called DPP-4.

"I still practice," Stein said, "and my practice perspective is that physicians have come to rely on the DPP-4 inhibitor class as a go-to option. But we know many patients need more than one agent, so the ability to combine a DPP-4 with an SGLT-2, that may be the most exciting opportunity."

The future of diabetes R&D

And Novo's Moses agrees: No one drug will be a panacea for the growing scourge of diabetes. GLP-1 treatments have their limitations, and SGLT-2 therapies pose "a rather inelegant way" of lowering blood glucose, he said; they're clinically effective, but they don't get at pathophysiological problems at the heart of diabetes.

Instead, the future of diabetes treatment will rely on a more holistic approach to the disease, marrying weight management and glycemic control to both prevent the onset of diabetes and treat patients who already have the disease, Moses said.

"Overall we as an industry and as a society have done a terrible job to slow the rate of progression of this endemic," he said. "... My personal bias is that either sequential therapies or combo therapies are going to be the rule rather than the exception and become the standard of therapy to prevent the development of diabetes."

To that end, Novo is leading the way among drugmakers looking to match the glycemic benefits of GLP-1 treatments with long-acting insulin analogs, and the company's cocktail of Victoza and Tresiba charted impressive results in late-stage study. Sanofi ($SNY) is working up a similar treatment that combines its daily GLP-1 agonist Lyxumia with the market-leading Lantus, and while Lilly hasn't announced plans to follow suit, it has two pipeline insulin analogs that could pair well with dulaglutide.

But beyond new combinations of existing treatments and longer-lasting formulations of proven therapies, diabetes researchers have often struggled to come up with the breakthroughs seen among their counterparts in oncology and immunology.

"Identifying new mechanisms critical to the pathways of disease has proven to be far more challenging than we might have hoped," Moses said. "I think we still have a long way to go there."

However, looking at diabetes drug development through a "What have you done for me lately?" lens risks short-changing the enormous patient benefit derived from each incremental step forward, Lilly's Conterno said.

"I take issue with that," he said. "We've seen significant improvements in care. Better glycemic control leads to better microvascular health, rate of heart attack, decreases in amputations... Those reductions are very important toward managing the overall cost of disease, as well."

The next major advances in diabetes may be years away, Merck's Stein said, but there's loads of potential in the early-phase pipeline.

Looking across the industry's preclinical assets, there are treatments that target betatrophin, a hormone that can boost pancreatic cell counts and thus spur insulin production; glucose-responsive insulins, which promise to regulate themselves and slash rates of hypoglycemia; and a host of other innovative programs.

"Every time I go to ADA, we know more and more, and more and more targets emerge that let us know where to look next," Stein said. "... An incredible amount has been done, and an incredible amount has yet to be done."

-- Damian Garde email | Twitter