2007 Wrap-Up and Outlook for 2008

Hmmmm, another year begins! Although other bloggers beat me to it this year, this year, I will continue a tradition I first began in 2005: my annual wrap-up and outlook for the upcoming year as far as diabetes is concerned. (By the way, please feel free to look back at my 2005 summary or my 2006 summary, as you'll note most of my observations are accurate even today!)

Time to Think Beyond Glycemic Control

Since the DCCT was published, the burden for secondary complications has shifted from away the disease itself to the person who has diabetes, despite the fact that no study (not even the DCCT) has ever been able to show that diabetes management alone can completely prevent complications, rather it only reduces the likelihood. Compare that to virtually any other disease, where the disease is blamed for a patient's condition, not the patient themselves. The reality is that at best, glycemic control is an inadequate treatment until a cure is found.

Just as JDRF co-founder Lee Ducat learned when her son Larry was diagnosed with type 1 diabetes in the late 1960's, her son still lives with type 1 diabetes today. But she has dedicated herself to continue supporting organizations whose objectives she supports, and has also pushed into new directions, too. Unfortunately, changing public perception and medical dogma is no easy task, although 2007 brought signs of progress in this regard.

2007: A Paradigm Shift in How Diabetes is Viewed

Its hardly news that the incidence of diabetes is growing on a worldwide basis - even The National Enquirer got that headline. But 2007 brought what is surely a paradigm shift in terms of thinking about diabetes. Not only did the world mark the first annual World Diabetes Day, in which the United Nations and the World Health Organization now recognizes diabetes as a chronic, debilitating and costly disease -- the first ever acknowledgment of this type for a non-infectious disease. But beyond the news headlines, there has been a more subtle, yet in some ways, more noteworthy development.

For most the past 30 years (certainly since the conclusion of the DCCT and the U.K. Prospective Diabetes Study), the medical profession has been fixated almost exclusively on glycemic control. In fact, as I wrote in November 2007, most diabetes clinical trials ignore everything BUT glycemic control. While there have been some improvements made towards the objective of glycemic control, that has not been sufficient to halt the devastating damage inflicted by diabetes across the world. Why? Because diabetes is not simply a problem of elevated glucose levels (caused by autoimmunity or insulin resistance). There is now a growing body of scientific evidence that suggest glycemic control alone is insufficient to address a whole host of metabolic abnormalities associated with diabetes. Perhaps the best acknowledgment of this fact was exemplified in groundbreaking The New York Times article entitled "Looking Past Blood Sugar to Survive With Diabetes" which was published in August 2007.

More recently, authors in the world's oldest, peer-reviewed medical journal The Lancet called attention to this fact, and called for a medical consensus on the the issues besides hemoglobin A1C reduction that are important to patients with diabetes, something which has traditionally been irrelevant in an overwhelming majority of clinical trials. They noted that hemoglobin A1C loses its validity as a mark of improvement when patients with diabetes have "a constellation of metabolic abnormalities".

To be sure, no one is abandoning the idea of glycemic control, but there is a push to look beyond metabolic control as a means to address diabetes. Perhaps the best example of this was exemplified by the Juvenile Diabetes Research Foundation. I was initially less than enthusiastic with CEO Arnold W. Donald's direction (or what I perceived to be a lack of direction) for the diabetes research organization.

But 2007 brought some concrete examples of Mr. Donald's goal to have more JDRF-funded research translate into actually helping patients living with the disease (who constitute a majority of JDRF's fundraisers), not just to act as a funding mechanism for researchers searching for the ever-elusive cure. In the 2007 State of the Foundation address, he highlighted progress made in that direction. He noted an article from The Wall Street Journal published in January (see here for the article) which noted how innovative and potentially successful partnering with industry could be. The paper ran a positive and prominent story about JDRF's partnerships and their success in leading the way in what they called "Venture Philanthropy".

The basic idea behind it is that JDRF and its fundraisers, donors and supporters have grown tired of funding research that never seems to translate into improvements in the lives of people living with type 1 diabetes, so the organization is helping to fill in research gaps or working with startups to bring promising, innovative therapies to patients that might not have occurred without the organization's help.

JDRF has a number of such partnerships, and some are very close to bringing ideas to fruition. Among the most prominent was the partnership with Maryland-based MacroGenics, Inc. In November, an announcement was made that insulin giant Eli Lilly and Company acquired the company and the rights to commercialize teplizumab, a humanized anti-CD3 monoclonal antibody, as well as other potential next generation anti-CD3 molecules for use in the treatment of autoimmune diseases, including type 1 diabetes. The payoff for JDRF could be over $1 billion, and could help the pioneering work done by Dr. Jeffrey Bluestone at UC San Francisco become a standard treatment protocol upon diagnosis. Beyond improved metabolic control, retention of functioning beta cells also provides noteworthy protection against severe hypoglycemia, reduces total insulin requirements, and may also help in the prevention of some forms of complications.

While the anti-CD3 monoclonal antibody therapy so far has only demonstrated efficacy in newly diagnosed patients, there has been little (if any) research done into long-standing patients. But as UCLA's Dr. Peter Butler and colleagues reported at the ADA Scientific Sessions in 2005, there is some evidence that in people with long-standing type 1 diabetes still have beta cells which continue to be destroyed in the setting of low-grade inflammation, therefore we should look for researchers to investigate the possibility of whether this type of therapy may also have applicability to others with type 1 diabetes beyond the newly diagnosed. Given the genuine commercial interest in bringing these products to market from companies like Lilly, there is little doubt these studies will be pursued, whereas in the past, they were simply ideas that some researchers suggested.

Not to be outdone, Israel's Pharmaceutical giant, Teva, signed a deal to commercialize DiaPep277 with Clal Biotechnology Industries Ltd. It is a peptide derived from the human protein, HSP60, which immunomodulates the immune system, prevents the destruction of pancreatic cells that secrete insulin and preserves their natural function. In essence, the drug performs a very similar function as MacroGenics' anti-CD3 monoclonal antibody treatment: stopping the immune system attack on the pancreatic beta cells. But DiaPep277 has changed hands repeatedly over the past 10 years, most recently being licensed to French drug giant Sanofi Aventis. At present, DiaPep277 is in phase III clinical studies, which could wrap up in late 2008 or early 2009.

Beyond retraining the immune system, others made solid progress in 2007 as well. Most notably, New Zealand-based Living Cell Technologies, Ltd. (LCT) began clinical trials in Russia. LCT's trials involve pig islet cells that are encased in capsules that allow insulin to be released but prevents the patient's immune system from attacking the cells. This would resolve two key issues which have prevented islet transplantation from becoming a cure for more patients: 1) a shortage of islets for transplant and 2) the body's immune response to the transplanted pig islets.

At the company's November 27, 2007 annual meeting, a progress report was given (which can be reviewed here). So far, the trial results seem to be going as expected, and could yield important progress in the coming year.

Science Proves Insulin Analogs Are NOT Superior

There is a growing list of meta-analyses which have proven without a shadow of a doubt that insulin analogs, sometimes called "modern" or "designer" insulins and are now promoted almost exclusively by the manufacturers because they still enjoy patent protection, have failed to demonstrate any superiority to regular insulin with regards to patient outcomes, but are in fact, significantly more expensive.

The most recent review, undertaken by the Canadian Agency for Drugs and Technology in Health (CADTH), found in its 2007 comparison of the effects of insulin analogs and plain synthetic human insulins and that insulin analogs failed to show any clinically relevant differences, both in terms of glycemic control and adverse reaction profile. This means that not only is glycemic control no better with analogs, but that there is no difference in side-effects like severe hypoglycemia, a decidedly different perspective than the manufacturers have led everyone to believe about insulin analogs.

This finding echoes the Germany's Institute for Quality and Cost Effectiveness in the Health Care Sector [IQWiG] which in a July 2007 report concluded that there is currently no evidence available of the superiority of rapid-acting insulin analogs over synthetic human insulins in the treatment of adult patients with type 1 diabetes, and that many of the studies they reviewed were either too small to be considered statistically reliable, and perhaps more significantly, none of the studies included in their widespread review was blinded. The lack of study blinding increases the risk of bias in these studies. The reason this is important is because patients, if they know their type of insulin, might behave differently (such as testing more frequently, for example), which would subsequently lead to bias in the study results, rendering the results inapplicable to the diabetes population at large.

These findings echo the results of the July 2002 Cochrane Review which analyzed the results from hundreds of clinical trials, only to find no evidence of superiority the newer insulin varieties over their predecessors. All of these findings are collectively summarized in the Insulin Dependent Diabetes Trust's report which reviews the evolution over past 30 years of diabetes treatment.

Potential New Sources of Insulin

From a business perspective, there has been considerable consolidation of insulin manufacturers in recent years. While countries including Canada, Brazil, Russia and the Ukraine previously had their own domestic sources of insulin, those companies have since been acquired by multinational drug companies. While consolidation does reduce inefficiencies, it also raises concerns about access (particularly in poorer nations) as well as competition in terms of price, quality and choices available to patients with insulin-dependent diabetes which are not resolved by having a few giant players in the market.

But May 2007 also brought a potential new company to the worldwide insulin market. Although they are currently undertaking Phase III Clinical Trials for their rapid-acting insulin formulation, Connecticut-based Biodel, Inc. went public and listed the company's shares on the Nasdaq stock exchange. The company, which develops drug delivery technologies which increase drug efficacy, enhance drug performance, and make drugs easier for patients to take, develops its product candidates by applying proprietary formulation technologies to existing drugs in order to improve their therapeutic results. Biodel's VIAject insulin was highlighted at 2007 American Diabetes Association's Scientific Sessions.

VIAject would be a proprietary injectable formulation of recombinant human insulin designed to be absorbed into the blood faster than currently marketed rapid-acting insulin analogs. A key difference, however, is that unlike insulin analogs, which are not technically insulin and may actually be carcinogenic over the long-term, Biodel's product would be plain old regular insulin with some proprietary (but already FDA-approved) additives to enable the insulin to reach the bloodstream much more rapidly.

Although considerable work on VIAject remains to be done, so far, it appears to have met all of its trial benchmarks and could emerge as the company's first FDA-approved product in the not-too-distant future. Although the company has not stated whether it will seek a marketing partner, the consensus seems to be that shareholders get more benefits when the company retains control over its patented technology, so the company is likely to be better off to contract manufacturing to a third-party rather than ceding it to a partnership similar to the Amylin-Lilly partnership, where control (and profits) are shared. Biodel's founders have a record of success in startups in the medical field, so upon conclusion of VIAject's Phase III clinical trials in the U.S. and Europe, the company will soon need to address this critical question.

Beyond Biodel, in March 2007, another company with a very similar name -- Poland's biotechnology crown jewel, Bioton, S.A. officially announced plans to enter the U.S. insulin market, and the company would have its shares listed on the U.S. Nasdaq stock exchange. The company has disclosed plans to raise its annual revenues almost fivefold within 3 years.

Although Bioton is financing its growth largely with debt, and tightening of the worldwide credit markets could slow their plans slightly, the fact is that the U.S. insulin market is simply too large for the company to ignore if they hope to become a major worldwide player. Bioton is already Poland's largest insulin supplier (although another Polish supplier, called Polfa Tarchomin, who once sold a clone of Humalog in Russia and the Ukraine, aggressively competes with them). Bioton also has a large share of the market elsewhere in Eastern Europe (particularly Russia, the Ukraine and elsewhere in the former Soviet Union, but also in neighboring Lithuania, as well as Vietnam). But the real benefit that Bioton can bring to the market, aside from offering a more complete product line of both natural and synthetic insulins, is the cost differential they can support relative to Novo Nordisk, Lilly and Sanofi-Aventis matched with top-notch manufacturing skills. It seems very likely that they will offer generics (e.g. Humulin/Novolin, notably Regular, NPH, but they could also re-introduce some discontinued products like Lente, Semilente, and Ultralente), as insulin analogs will not lose patent protection until 2014 at the earliest. If the company's plans stay on schedule, they would be the first new insulin supplier to enter the U.S. market in over 30 years.

"The insulin market in the United States is worth $1.5 billion," CEO Adam Wilczega reportedly told Gazeta Prawna daily in an interview.

"If we manage to gain just 5% of that market, it would boost our revenues by over 200 million zlotys ($68.63 million)," he added.

Wilczega reiterated that the company is interested in listing its shares on the New York Nasdaq stock exchange as part of its U.S. expansion.

"Our presence on the U.S. market would justify the Nasdaq listing," Wilczega was quoted as saying. "The 2010 is a realistic date, when we could start selling insulin there."

As I noted in my groundbreaking article in January 2007, for a variety of reasons, the U.S. Food and Drug Administration (FDA) has been a major obstacle for generic biopharmaceutical manufacturers, but it seems almost certain that U.S. Congress will pass some form of legislation in 2008 not only authorizing but requiring the FDA to outline procedures for approvals of products like insulin (even though generic insulin could legally be offered today if it weren't for the FDA's failure to outline procedures). The main question will be what the final legislation will look like? Big pharma has its own ideas (see here for details), but don't forget, that's up to you to tell your Congressmen and women!

Grow Your Own Insulin? Maybe. Stay Tuned!

This year, researchers at the University of Central Florida made headlines because they successfully grew synthetic human insulin in lettuce plants, which was published in the Plant Biotechnology Journal. The fact was that Canadian researchers had grown synthetic insulin in safflower plants a over a year earlier. (See here for details. The company expects that their safflower-produced insulin could reach the market as early as 2010), but UCF's spin on it was that their version actually cured diabetes in non-obese diabetic mice (the most frequently used animal model for type 1 diabetes), and the researchers proclaimed that the study holds promise for humans.

Naturally, most patients with type 1 diabetes (including me) reacted to the news skeptically, and with good reason. Diabetic mice now have a choice of over 25 different treatments that will cure their diabetes, but not a single one of these has ever successfully translated into human cures.

Should it be pursued? Certainly. Should we get excited about it? Yes, but not as a cure, but as a potential new way to bring insulin to people with diabetes in remote parts of the world. (Notably, parts of Africa, where patients diagnosed with type 1 diabetes often die because of logistical problems which prevent insulin from getting to patients who need it.) This is consistent with the theme of the International Diabetes Federation's campaign to call attention to the fact that no child should die of diabetes. Imagine if some lettuce seeds could in effect, turn fields in these places into insulin factories? Those plants would in turn produce seeds that already contained the insulin gene, creating a sustainable local source for the critical, life-sustaining hormone that is now made exclusively in multi-million dollar factories. Now, that would be something to celebrate, and it's entirely possible, too!

Looking Ahead to 2008

In recent years, CGMS (continuous glucose monitoring systems) came to market. Yet today, CGMS are still out of reach for many, although the groundwork has been laid to get them into the hands of more. Clinical evidence of their benefits is being assembled now (surprisingly, funded not by the CGMS manufacturers, but by nonprofit foundations like JDRF), and even Medicare has assigned coding to for the devices. But I would be foolish to predict that 2008 will see widespread adoption because frankly, there is not a clear sign that these devices will be covered almost universally. The main obstacle: the dysfunctional U.S. healthcare system, and the fiendishly high cost of the devices/sensors.

The ability to see trends and directions in blood glucose levels is as revolutionary to diabetes management as home blood glucose testing was in its day. But the reality is that aside from insurance coverage issues, there are also issues with teaching patients how to use this information. A shortage of diabetes educators, combined with a surge in patients who need diabetes education spells more trouble on the horizon. I wish I could say that the future looks good for these devices, but the data suggests that for the immediate future, patients will struggle to get coverage. There are, however, some resources for people trying to get coverage. Most notably, cgmscentral.com is a website dedicated to helping people secure reimbursement for their continuous glucose monitoring systems.

But until we see substantiative reform in the current healthcare system, one which has left 47 million Americans (most of whom are employed full-time) uninsured, the outlook remains unclear at best. But with an election around the corner, perhaps we will finally see some progress made. Although the experiments in Massachusetts have not been without problems, it does appear to be the first progress made since 1993, when then President Bill Clinton and first-lady Hillary Rodham Clinton proposed a healthcare reform plan that was embarrassingly defeated. However, among domestic issues, healthcare reform is one of the top concerns among American voters, suggesting that the government can no longer afford to ignore the issue, hoping it will go away. While some speculate that the differences between major candidates (and parties) are only marginal, nevertheless, there are some differences which are worth considering.

In summary, look for more doctors to finally start considering the "big picture" more than A1C alone - there's more to quality diabetes care than a low A1C. Cure research will continue, but with major trials pending (I'm thinking of Dr. Faustman's work, for example), most will remain in early stages, so don't expect any cures to emerge in 2008. Remember, science is incremental, and there are some important studies investigating the field of immunology, long overlooked yet a critical element in the quest towards a cure for type 1 diabetes. Also, look for more insulin suppliers in coming years (perhaps not in 2008), and also look for progress towards coverage on CGMS, but by no means should we expect universal coverage. But for those looking for these devices, harness the power of social networking sites and other resources to build your case, and remember, that no doesn't mean the decision is final, only that the right person has not yet reviewed your case!

As always, I'll continue with ongoing coverage throughout the year. Best wishes for a happy, healthy 2008 to everyone!