Before the curtains even close on the 2015 American Society of Clinical Oncology annual meeting, attention is turning to the American Diabetes Association's (ADA) 75th Scientific Sessions, which begin Friday in Boston. Abstract titles suggest presentations will address not only the raft of current drug development efforts and large cardiovascular outcome trials (CVOT) that have weighed on biopharmas in the diabetes space but also some of the emerging technologies to treat the disease. Just as painfully clear is the prospect that, even as researchers close in on breakthrough treatments for type 1 diabetes, the raging obesity epidemic presents a daunting problem for companies seeking to tamp down type 2.

The ADA estimates that the total annual cost associated with diagnosed diabetes, which affects nearly 26 million individuals in the U.S. alone, now represents a staggering $174 billion. When costs related to gestational diabetes, pre-diabetes and undiagnosed diabetes are added, the price tag jumps to $218 billion. Each year, the disease contributes to the deaths of more than 230,000 individuals in the U.S.

Considering the human and economic impact, small wonder that more than 3,000 presentations at the ADA meeting, including 385 oral abstracts and 2,331 regular and late-breaking posters, will address topics ranging from improvements in the formulation and delivery of existing drugs to continuous glucose monitors to improve patient outcomes, potential targets for new therapeutic approaches and early stage research into technologies that could someday offer a cure for certain patients.

Iterative improvements in existing technology continue apace. Just last week, the FDA approved the Humalog 200 units/mL Kwikpen (insulin lispro 200 units/mL, U-200), a pre-filled pen containing a concentrated formulation of the rapid-acting insulin Humalog (insulin lispro 100 units/mL) developed by Eli Lilly and Co., of Indianapolis, to improve glycemic control in type 1 and 2 diabetes. The Humalog U-200 Kwikpen was the first FDA approval of a concentrated mealtime insulin analogue, according to David Moller, vice president of endocrine and cardiovascular research and clinical investigation at Lilly Diabetes.

That approval and similar progress – such as the FDA's nod earlier this year to Toujeo (insulin glargine [rDNA origin] injection, 300 U/mL) by Paris-based Sanofi SA as a once-daily, long-acting basal insulin to improve glycemic control in adults with type 1 and type 2 diabetes – represent incremental improvements in treatment rather than quantum leaps. For example, the Humalog U-200 Kwikpen holds twice as many units of insulin as the previous generation formulation in the same size cartridge, essentially offering patients a pen that simply lasts longer between changes and allows for fewer changes each month.

But interim steps like these while the science of diabetes care continues to advance "are helpful to patients," Moller told BioWorld Insight.

"The steep curve of advancement in insulin technology occurred many years ago," agreed Todd Hobbs, chief medical officer for North America at Novo Nordisk A/S, of Bagsvaerd, Denmark. "Improvements in analogue insulin were radical at the time. Now we are looking at more or less incremental innovation, but these advances are still very, very important to patients."

'WE THINK WE HAVE A SHOT AT CURING DIABETES'

Tomorrow's technology continues to advance on multiple fronts, though progress is bifurcated by the very different clinical manifestations of diabetes. In type 1, regenerative medicine organizations are moving rapidly to create an artificial pancreas or closed-loop system, with a fully functioning device "not a question of if but when," Moller predicted. The JDRF, which has funded some of these efforts, launched its Artificial Pancreas Project, or APP, in 2006 to accelerate the development of a commercially viable artificial pancreas for patients with type 1 diabetes. The effort has not been without challenges, including the delicate balancing act of mimicking the human organ's ability to deliver insulin and reduce blood sugar levels while also releasing glucagon, which is responsible for signaling to the liver to raise blood sugar levels.

In 2013, the JDRF provided funding to several biotechs to support the development of pumpable glucagon. One of those, Xeris Pharmaceuticals Inc., is developing a soluble, stable formulation of glucagon as an alternative to existing glucagon emergency kits to treat hypoglycemia. The company's principal technologies, Xeriject and Xerisol, are designed to improve the delivery and reduce the side effects associated with existing drugs by turning them into non-aqueous pastes and solutions. (See BioWorld Insight, July 1, 2013, and BioWorld Today, May 20, 2014.)

In April, the Austin, Texas-based company was awarded a Small Business Innovation Research phase I grant to advance its room-temperature stable, non-aqueous glucagon formulation to treat congenital hyperinsulinism as the initial installment of a fast track program to support the manufacturing of drug supplies as well as preclinical studies, regulatory development and an initial trial. The project aims to use a glucagon infusion pump that can be transitioned from the hospital to an outpatient setting, maintain blood glucose levels at near normal levels, and prevent hypoglycemia without the use of intravenous infusion – a step toward a closed-loop system.

Nearly four dozen presentations at ADA are slated to address various aspects of artificial pancreas development.

Islet cell transplantation – the replacement of insulin-producing cells lost in type 1 diabetes – continues to draw attention and is the subject of more than 100 presentations at the ADA meeting. Pioneered in Canada in the 1990s, the so-called "Edmonton protocol" for transplanting pancreatic islet cells was published in the New England Journal of Medicine in 2000. In 2013, scientists at the University Hospital of the German University of Dresden reported a method to shield transplanted cells from the transplant recipient's immune system, enabling them to transplant a diabetic patient with insulin-producing islet cells that remained invisible to his immune system, though the researchers acknowledged technical challenges to adopt the process for widespread use. (See BioWorld Today, Nov. 1, 2013.)

But such challenges haven't prevented companies from pursuing the approach. For example, Islet Sciences Inc., of Raleigh, N.C., has encapsulated FDA-approved porcine islet cells with the highly biocompatible biopolymer alginate to reduce the body's immune response to the implanted material. The company's pipeline also includes immune-modulating small-molecule IL-12 antagonists targeting beta-cell preservation and inflammation. (See BioWorld Today, Dec. 27, 2012.)

Earlier this year, Islet Sciences entered an exclusive license agreement with Brighthaven Ventures LLC for rights to develop and commercialize an SGLT2 inhibitor, remogliflozin etabonate, contingent on raising specific funds to advance the therapy into a phase IIb study, expected to begin this quarter.

Another regenerative medicine company, Viacyte Inc., of San Diego, is pursuing a curative approach to type 1 and insulin-dependent type 2 diabetes with stem cell-derived therapy known as VC-01. The combination product consists of pancreatic precursor cells, designated PEC-01, manufactured through directed differentiation of stem cells sourced from a proprietary human embryonic stem cell line and encapsulated in an immune-protecting and retrievable device, called Encaptra. When implanted under the skin, the PEC-01 cells are designed to mature into functional insulin-producing islet cells, regulating blood glucose in a manner similar or identical to a normal pancreas. (See BioWorld Today, July 11, 2013.)

Pharmacyte Biotech Inc. (formerly Nuvilex Inc.), of Silver Spring, Md., is taking a different cell therapy approach with its Cell-in-a-Box technology, originally developed by its partner, Austrianova Singapore Pte Ltd., of Singapore. Using a multi-step process, the live cells are suspended in a medium that contains a polymer and sodium cellulose sulfate. The suspension is passed through a droplet-forming machine and the resulting droplets fall into a solution containing another polymer. The interaction between the two polymers causes a membrane, or "shell," to form around each droplet.

The live cell encapsulation technology serves as a platform to treat multiple diseases. In type 1 and insulin-dependent type 2 diabetes, the Cell-in-a-Box technology is used to encapsulate a human cell line that's been genetically modified to produce insulin on demand and secrete it in proportion to glucose levels in the body. The company has global rights to the insulin-producing, or Melligen, cells developed at the University of Technology Sydney (Australia). Although the program is still in preclinical development, "we think we have a shot at curing diabetes," said Kenneth Waggoner, the company's CEO, president and general counsel. "We certainly know we can reverse the diabetic condition for those with type 1."

Orgenesis Inc., of White Plains, N.Y., is advancing another potential curative approach, initially in type 1 diabetes, with its functional autologous insulin-producing cell regeneration technology, gained in a 2012 licensing deal with Tel Hashomer - Medical Research, Infrastructure and Services Ltd.

Since the technology is based on adult stem cells, "we don't have any of the risks associated with stem cells, which is an important factor," explained Vered Caplan, the company's interim CEO. The beta cell replacement technology has shown a clean safety profile in proof-of-concept studies that also demonstrated the ability to induce a shift in the developmental fate of cells in the liver and convert them into pancreatic beta-cell-like cells.

In April, Orgenesis inked a three-year agreement with the Global Stem Cell & Regenerative Medicine Acceleration Center commissioned by Ministry of Health and Welfare of Korea to advance collaborative research in stem cell and regenerative medicine. The company also has a memorandum of understanding with Seoul, South Korea-based Curecell Co. Ltd. to finalize a joint venture to develop and commercialize its autologous insulin producing cell therapy product in Korea.

ORAL INSULIN 'A POTENTIAL GAME-CHANGER' IN TYPE 2

In type 2 diabetes, oral insulin is a huge area of interest, as indicated by more than 150 ADA presentations. Novo Nordisk has OG217SC (NN9924), an oral formulation of the long-acting glucagon-like peptide-1 (GLP-1) analogue semaglutide, in phase II development. Data so far support continued development of the candidate, which Hobbs called a "potential game-changer" in diabetes. He predicted the first oral insulin candidate could reach the market in the next five to seven years.

Smaller companies also are pursuing the oral approach. Founded in 2011 by former Pfizer Inc. R&D executives, Thetis Pharmaceuticals LLC, of Southport, Conn., is developing TP-113 – an ionic compound that delivers docosahexaenoic acid, or DHA, and metformin from a single chemical entity – to provide glucose and triglyceride control superior to metformin alone. In April, the company presented preclinical data at the GTC Diabetes Summit and Diabetes Drug Discovery & Development Conference in Boston showing that oral candidate has the potential to reduce insulin resistance, decrease hepatic glucose output and reduce plasma triglycerides.

In addition to glucose control, the need to address the "significant deficits" of insulin resistance and lipid levels in patients with diabetes is urgent, as these are "important contributors to the pathology," said Frank Sciavolino, co-founder and chief scientific officer of Thetis. "That's the driver behind our strategy."

The company expects to file an investigational new drug application early next year and could potentially advance the candidate through the 505(b)(2) pathway.

Other companies are seeking to enhance or modulate the effect of metformin. Microbiome Therapeutics LLC, of Broomfield, Colo., is advancing a microbiome modulator, NM504, to improve blood glucose control and other metabolic parameters in type 2 and pre-diabetes. But the company also is advancing a second candidate, NM505, that combines the active ingredients of NM504 with metformin to improve glycemic control while reducing side effects associated with metformin. Last month, the company reported the FDA approved its pre-investigational new drug request to use the 505(b)(2) abbreviated regulatory pathway to develop NM505 in type 2 diabetes.

The technology platform at Nusirt Biopharma Inc., of Nashville, combines the amino acid leucine with existing medicines targeting metabolic diseases that may be addressed by activating sirtuin pathways.

"Leucine activates one of the pathways that is common to metformin, which has found a niche off-patent, is being prescribed extensively and does a very good job," observed Joseph Cook Jr., Nusirt's president and executive chairman. "The idea was to develop a product where we could add leucine and lower the quantity of metformin to achieve the same or better dose control results."

The company's diabetes candidate is in a phase II study, with top-line data expected to report at the end of the month. If positive, the company hopes to move into a pivotal program that would result in a new drug application filing using the 505(b)(2) pathway.

Researchers also are making progress in delaying and potentially reversing the loss of human beta cells that trigger the onset of diabetes. Lilly's Moller cited findings reported by Andrew Stewart, director of the Diabetes, Obesity and Metabolism Institute at the Icahn School of Medicine, and colleagues at Mount Sinai Medical Center that suggested a screen of 100,000 potential drugs yielded one, harmine, that drove human insulin-producing beta cells to multiply. The study offered the first evidence of such a feat in human cells, representing an early but potentially key step toward more effective treatments for type 2.

TYPE 2 DIABETES 'A NET SUM GAME'

Long term, however, tackling the treatment of type 2 diabetes isn't likely to succeed without also confronting the multi-faceted issue of obesity.

"You'd like to be able to intervene at an early point to prevent the syndrome, but you've got to have something that's going to work quite effectively and you've got to be able to identify the patients who will progress the most quickly," Moller observed. "People who may have a high risk of diabetes or pre-diabetes don't always progress to diabetes."

Lilly made a strategic decision to target diabetes treatment rather than "trying to prevent the public health problem," Moller said.

Novo Nordisk, where diabetes treatment has been a mainstay, went the other direction. The company's once-daily human glucagon-like peptide-1 (GLP-1) analogue, liraglutide, originally approved as Victoza to treat type 2 diabetes, late last year gained FDA approval in a different dose to treat adult obesity. Marketed as Saxenda, the drug is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults who are obese or who are overweight (BMI ≥27 kg/m2) in the presence of at least one weight-related comorbid condition. (See BioWorld Today, Jan. 27, 2010, and Sept. 12, 2014.)

Novo Nordisk is "fully engaged and committed" in the obesity space, Hobbs told BioWorld Insight.

"Type 2 diabetes is a continuum of life, starting with overweight, going to obesity, then pre-diabetes, then diabetes, then insulin-dependent diabetes," observed Nusirt's Cook. "This is really a net sum game. If you consume energy, you've got to use it or it's going to get stored or excreted. Until we figure out a way to reduce weight in the population, we have a real battle on our hands in fixing this disease."

Reimbursement is part of the problem for companies seeking to develop drugs that distinctly target pre-diabetes or prevention of the disease.

"Payers are very reluctant to open the coffers to pay for pre-diabetes," Cook acknowledged, noting that one of the biggest questions is how to define an acceptable clinical endpoint. Nevertheless, "the reality is that this is the direction where we're going to have to go."

Although physicians are prescribing some drugs – notably metformin – off-label to treat pre-diabetic patients, the problem of which patients to treat, and how, is complex. Progress in understanding the genetic drivers of diabetes and marshalling that information to guide therapeutic development has not mirrored similar success in other large indications, such as targeted oncology drugs and, more recently, the cholesterol-fighting proprotein convertase subtilisin/kexin type 9, or PCKS9, antibodies.

Despite obvious lifestyle factors, "there's very clear evidence that diabetes is strongly genetically driven," Lilly's Moller said. "And yet, we now know that there are over 50 genes that contribute to that risk." When addressing a disease whose genetic basis might be related to a dozen genetic mutations rather than one or two, "it's a little bit challenging to take that information and try to translate it into a therapeutic approach," he admitted.

"In type 2, we know there's a genetic predisposition but yet we know that there are also many, many lifestyle factors that affect the success of treatment," Hobbs agreed. "I don't think in the near future we're going to see anything that will change that paradigm, but the exciting thing is that we're developing more effective but also safer options for patients with diabetes."

Companies in the space also are reluctant to look upstream when they already face murky guidance from the FDA on enormous and expensive CVOTs in diabetes. In April, panelists on an Endocrinologic and Metabolic Drugs Advisory Committee meeting raised a concern shared by many biopharmas by asking whether CVOTs in high-risk patients represent the best mechanism to assess the cardiovascular risks of diabetes drugs. (See BioWorld Today, April 15, 2015.)

"Thought leaders in the industry want to have another dialogue with FDA to clarify the guidance," issued in 2008, Hobbs said. "Many things have changed since then, and there is some question whether we need to do these outcomes trials. I'm still not comfortable there's a high degree of clarity from the FDA."

'MORE FOCUS EACH YEAR ON PATIENT OUTCOMES'

Not surprisingly, gene therapy approaches have lagged in diabetes, through scientific promise is on the horizon. Last year, researchers at Decode Genetics, of Reykjavik, Iceland, reported findings in Nature Genetics showing that individuals who carry one copy of the rare mutant gene SLC30A8 have a 65 percent lower risk of developing type 2 diabetes, raising the prospect that therapies could target the protein encoded by the gene, known to play a role in insulin secretion. (See BioWorld Today, March 5, 2014.)

And in a report published last week in Science Translational Medicine, Stanford University researchers said they applied the immune manipulation application of gene therapy to autoimmune diseases to induce tolerance to diabetes. (See BioWorld Today, and May 29, 2015.)

Companies active in diabetes R&D are confident that ongoing genetics research will lead to better identification of likely responders to certain types of treatments and, as an offshoot, better understanding of related indications, such as nonalcoholic steatohepatitis, or NASH.

But the breadth of the diabetes market demands that new therapies and technologies will ultimately emerge from a range of integrated partnerships among pharmas, biotechs, academic institutions and nonprofits. For example, Lilly is engaged with several consortia, including Europe's public-private Innovative Medicines Initiative 2, or IMI 2, whose diabetes component is seeking to answer fundamental questions about what drives beta cell dysfunction, diabetic nephropathy, obesity and other aspects of the disease. (See BioWorld Today, July 10, 2014.)

The pharma also is one of five pharmas working with the National Institutes of Health-sponsored Accelerating Medicines Partnership, or AMP, launched last year with a focus on improving the understanding of human genetics in three areas – type 2 diabetes, Alzheimer's disease and autoimmune disease – to characterize effective biomarkers and identify biological targets most likely to respond to new therapies. (See BioWorld Today, Feb. 5, 2014.)

Lilly also has a diabetes alliance with Germany's Boehringer Ingelheim GmbH that will offer up data from 35 studies at the ADA meeting. And the company has shown eagerness to partner, and re-partner, with academics and biotechs to accelerate diabetes technology. In December 2014, Lilly paid $50 million up front and committed to another $520 million in potential milestones to get its hands on Adocia SA's ultra-fast-acting insulin formulation, Biochaperone Lispro, just 18 months after terminating an original deal for the technology. (See BioWorld Today, July 31, 2013, and Dec. 22, 2014.)

Lilly plans to update that program in a late-breaking poster at the ADA meeting.

Ultimately, diabetes won't be solved by a one-size-fits-all solution, allowing room for multiple therapies.

"Diabetes is a global disease," Caplan said, "and the cure also has to be a global effort."

The ADA meeting will give companies in the space the latest look at the emerging science.

"It's always exciting," Hobbs said, noting that Novo Nordisk will present 36 abstracts. "What's interesting is that there's more and more focus each year on patient outcomes. Eight to 10 years ago, most of the attendees at ADA wanted to see randomized controlled trial data. That has changed dramatically, especially in the last two years. People now want to see what real-world data look like."

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