By Wayne Koberstein, contributing editor
For decades, patients with diet-related (i.e. Type 2) diabetes have relied on drugs that improve insulin sensitivity and actions, such as metformin and the thiazolidinediones (pioglitazone and rosiglitazone). Drugs that stimulate insulin secretion (sulfonylureas) have been in use since the 1950s. But the treatments are far from perfect in safety or efficacy. Type 2 is about nine times more prevalent than Type 1, the autoimmune form of diabetes, for which insulin replacement is still the main therapy.
There are many contenders for the next blockbuster in diabetes, and it is easy to see why — a truly gigantic global market awaits. After efficacy and safety, which will determine the market leader, other products will have to compete on price, and who wants to do that? So, in discovery and development, the race is primarily scientific. Alliances at all scales, between companies far apart or equal in size, as well as academic innovators, will continue to form around diabetes R&D at an accelerating rate.
Here we focus on GSK as a company that can share insights from its long experience, challenges, and new approaches to diabetes prevention and therapy — speaking with Murray Stewart, head of GSK’s metabolic pathways therapy area unit.GSK and other drug discovery and development companies are taking new aim on the global diabetes explosion – sometimes alone, sometimes in league together.
GSK has changed its mode of operations to speed products from discovery through development and on to commercialization, organizing R&D by therapeutic areas, rather than by functions as it was in the past. Heading the metabolic pathways area, Stewart says he oversees the “end-to-end development” of diabetes drugs — from the earliest targeting of disease and drug mechanisms to the marketed product ready for all the regulatory, reimbursement, and other reality-based challenges of the competitive landscape.
“Historically in R&D, there were all these handovers between what the GSK scientists were discovering and what the GSK salespeople were selling. From one end of that continuum to the other, the story — everything the product was intended to address — might have changed completely,” says Stewart.
Scientists in diabetes drug discovery are now encouraged to keep a clear picture in mind of the patients who will be at the receiving end of new medicines, including the effects of their condition and how they manage them, specific treatment needs, and the particular elements of drug administration that affect their compliance
and response. Such patient visualization is also practiced by all the teams responsible for early development, later clinical trials, and market access. Stewart’s unit conducts focus groups out in the field to capture patient experiences with the disease, standard treatments, and new products in development. GSK’s therapeutic area (TA)-based organization is only a few years old, and it precedes further integration of product development
on a world scale. In the company’s “next evolutionary step,” Stewart says a new network of global franchise leaders, each one overseeing commercial strategy of a therapeutic area worldwide, will “partner” with the respective R&D unit leaders. Each TA will then have a global R&D strategy combined with a global commercial
“This will be particularly important in diabetes, which is growing rapidly around the world, including the Middle East, the Western Pacific region, and Asia. Although our research is driven by the research groups in North Carolina, Philadelphia, and the United Kingdom, our clinical trials are actually global; we conduct them wherever there are significant pockets of diabetes. And with the global franchise leaders, we will be thinking in terms of true global development.”
A global strategy in diabetes, however, is not a homogeneous one, says Stewart. Distinct differences exist in how the disease manifests itself in different regions. Type 1 diabetes is genetically more prevalent in Scandinavia. Type 2 diabetes, mostly related to a combination of genetics, family history, and obesity, is on the rise in the Middle East and Indo Asia, where contemporary changes in diet have caused weight gain in traditionally thin people. “When you think globally, you have to take the cultural differences into account — diet, exercise, genetics, and so on — and that may affect the approaches you take in discovery and development of
STRATEGIC COURSE OF DIABETES R&D
“In diabetes, we have two main scientific challenges — one, halting the progression of the disease, and two, tackling its complications,” Stewart says. The first challenge, halting or even curing diabetes, begins with the earliest signs of metabolic disease. Again, the pathways to the two main types of diabetes are different but related. In both, the problem is that the pancreas stops producing insulin, but in Type 1, the insulin-producing beta cells are destroyed by autoimmunity; in Type 2, the sensitivity of beta cells to insulin is reduced and thus their ability to increase insulin production to needed levels. Consequently, the therapeutic strategies for the two types have been and will continue to be quite different. For Type 1, Stewart says, “You may ask, why aren’t we looking at autoimmune therapies to prevent the destruction of beta cells in the pancreas? But the data published on preventing the destruction has been disappointing, probably for two reasons. One, there are multiple causes for autoimmune destruction, and the industry has tried to focus on single components. Some say successful drugs must tackle the B cells; others, the T cells. But we probably need a combination of therapies. Another reason we struck out trying to preserve beta cells is we were trying too late.
For Type 1, by the time you’re diagnosed, 90% of the beta cells have been destroyed, and we should probably look at relatives of Type 1 diabetics, the people at risk, and treat them before they get diabetes.”
Type 2 diabetes presents a more varied and practical therapeutic picture. Like Type 1, the disease rates are higher in some families, suggesting a genetic component; anyone who has a relative with Type 2 stands an 80% chance of getting it eventually, according to Stewart. Being overweight and having high blood pressure also increases risk, but clinical obesity is the largest risk factor of all.
“In discovery in Type 2 diabetes at GSK, we believe that, if we tackle obesity, we will actually be tackling diabetes at the same time,” says Stewart. To that end, the company is following a big clue from an entirely different form of medical intervention for obesity, bariatric surgery. “Research shows that bariatric surgery has been very successful in getting people to lose weight — but it’s also been very successful in some cases of curing diabetes.” Some obese patients with diabetes not only have lost weight following the surgery but their diabetes has disappeared, with glucose levels returning to normal, all within a few days after the procedure. Scientists theorize a switch or trigger mechanism exists in the surgery that halted the diabetes even before significant weight loss occurred. The trigger may reside in the actual fat cells removed. In the so-called “centralized adiposity,” fat cells produce hormones that, along with stimulating appetite, suppress beta-cell insulin sensitivity and trigger the disease. GSK and other companies have thus opted for a strategy with the catchy but somewhat awkward name, “mimicking bariatric surgery with a pill.”
Another key to strategy is likely the body’s release of other biochemical factors in the absence of the excised fat cells and their insulin-desensitizing hormones. “One of our discovery units is looking at the polymers and peptides that influence appetite and might help weight loss and improve diabetes. You can’t give bariatric
surgery to everyone. But if we could prompt the release of the same hormones, chemicals, and peptides the surgery does, we can then start to tackle not only obesity but diabetes.”
Currently, the GSK unit has produced some animal data on a number of peptides in various combinations. But out in front of other candidates is “one of the biggest advances in the past five years,” glucagon-like peptide 1, or GLP-1. Once food enters the gut, GLP-1 is released into the circulation, and it then goes to the Islets of Langerhans in the pancreas and stimulates the beta cells, one of multiple islet cell types, to produce insulin. In patients with Type 2, GLP-1 levels are low, directly accounting for low insulin production insufficient to maintain normal glucose levels.
With the discovery of GLP-1, companies rushed in with GLP-1 analog drugs to mimic its function, including exenatide (Byetta, Lilly/Amylin) and liraglutide (Victoza, Novo Nordisk) now on the market. GSK’s once-weekly albiglutide is in Phase 3 trials, and Sanofi and Lilly have similar products in development. New approaches are already close behind.
“The biggest advances in diabetes therapies have been the introduction of incretin therapies which include the DPPIV (dipeptidyl peptidase 4 inhibitors) combined with GLP-1,” Stewart explains. “The DPPIV cause only modest efficacy by stopping degradation of GLP-1, whereas the GLP-1 part gives a supraphysiological increase in insulin, which results in greater reductions in glucose than the DPPIV alone — and also weight loss. Besides GLP-1, there are other peptides such as peptide YY (PYY) that have been associated with weight loss, and therefore one of the future developments in drug discovery is to combine peptides such as GLP-1 with PYY and other peptides to cause even greater weight loss and a reduction of glucose.”
DIABETES INNOVATION — BEYOND THE BEACHHEAD
Following the best science is a logical strategy, but never enough to bring a drug to market. Companies must still face the external challenges of regulation, reimbursement, and recognition by patients and physicians that a new drug is worth adopting. Too much is at stake for drugs with only modest benefits to succeed.
“You need plenty of evidence to show your drug works,” says Stewart. “It has to do more than glucose control. One of the main complications of diabetes is heart disease; 50% of patients will have heart disease related to diabetes and die from a cardiovascular event, a heart attack or stroke, so the drug has to be beneficial for cardiovascular morbidity and mortality. Now, how can we do that without doing a 20,000-patient study?”
The answer, Stewart says, is hopefully to start in discovery looking at risk factors for heart attacks and stroke. “When I evaluate a drug in development, the first thing I say is that it must be ‘glucose plus,’ that it doesn’t cause weight gain, and that it does not raise cholesterol. And if anything, we want to see an improvement in those parameters, and if we do, we will invest heavily in development, as we did with albiglutide, our long-acting GLP-1 inhibitor.”
For Type 1 diabetes, the main advances will continue to be new forms of insulin replacement. But for both Type 1 and Type 2, more sophisticated approaches are on the horizon that may come close to the holy grail — curing the disease completely. The top contenders, Stewart agrees, are beta-cell transplant and/or rejuvenation. Some recently published studies suggest that beta cells lost to diabetics are not actually dead but only “dedifferentiated” into more stem cell-like states. If that is true, it might be possible to “redifferentiate” such cells back into working beta cells. But Stewart advises caution.
“We might be able to shake up the beta cells and stop the destruction or, if they’re quiescent, revive them. That is worth looking at, but I’m not hopeful. I am more hopeful of finding a way to grow the cells or give patients a fresh supply. So I do like the stem cell approach.” Obtaining human beta cells, or islets, is quite difficult, and performing the transplantation surgery requires immunosuppression, he says. “The exciting thing is that if you take islets and you give them to someone who doesn’t have any functioning islets, providing you have the right environment, you can make some Type 1 diabetics insulin-independent.”
Stem cell therapy may be an even better option than transplant in 5 to 10 years, Stewart believes. In theory, the stem cells would differentiate into islet cells, so that Type 1 patients could grow their own islet cells in the pancreas and be free from insulin injections.
If the field were to go in the direction of stem cells, GSK would still be involved. “We’ve got a discovery group, we’ve got a clinical group, and I spend quite a bit of my time looking at business development opportunities because I think the future is partnership. So GSK is willing to partner with smaller companies, and perhaps with larger companies, to find the answers to diabetes, wherever the search leads us.”