Wal-Mart Takes on Big Pharma?

A potentially important development was announced today in The Wall Street Journal. Apparently, Wal-Mart Stores Inc. is stepping into the highly lucrative pharmacy-benefits arena.

In a speech yesterday before 7,000 Wal-Mart store managers at a meeting in Kansas City, MO, Wal-Mart CEO Lee Scott said the company is initiating a pilot program to help "select employers ... manage how they process and pay prescription claims."

Pharmacy benefits managers (PBMs) have a sometimes little-recognized, but hugely important role in the pharmacy benefits chain operating in the United States. PBMs are the third-party administrators of prescription drug programs. These companies, dominated by just a handful of companies (see here for market share information), including Medco Health Solutions, CVS Caremark Rx, and Express Scripts/CuraScript, are primarily responsible for processing and paying prescription drug claims for healthcare providers. These include insurance companies, health maintenance organizations and even some government plans. PBMs may own their own mail-order pharmacies, and increasingly make much of their profits from big markups on generic drugs. PBMs are also responsible for developing and maintaining the drug formularies, contracting with pharmacies, and negotiating discounts and rebates with drug manufacturers.

PBMs use their collective bargaining power for prescription drugs, therefore PBMs are able to negotiate huge rebates and discounts on behalf of their clients. It is estimated that PBMs manage about 70% of the more than 3 billion prescriptions dispensed in the U.S. each year, and cover roughly 95% of all patients in the U.S. today (although only about 46% of prescription drug expenditures are paid for via PBMs, partially a function of the huge discounts PBMs are able to command).

This is a big reason there is such a huge difference in the prices the uninsured pay for drugs relative to the prices paid by those who have insurance (co-pays aren't even factored into the equation). Based on IMS Health data, excluding the effect of rebates, the typical cash customer pays nearly 15% more for the same medicines than do customers with third-party coverage. For a quarter of the most common drugs, the price difference between cash and third-parties is even higher - over 20%.

According to the article, "Wal-Mart wouldn't name the companies, and details of how this would be achieved were sketchy. But Mr. Scott said that by taking out unnecessary costs he believes Wal-Mart can save employers more than $100 million this year alone."

Wal-Mart is known for its efficiency -- the company has used its massive buying power to push vendors for ever-lower prices and more efficient distribution systems, and the company also accelerated the drive to manufacture products in Asia, driving countless small shops out of business as part of that process. But a recent article questions whether this is the end of the Wal-Mart era. And there is no guarantee Wal-Mart will be as successful here, in part, because PBM's are already far more efficient than the traditional outlets Wal-Mart was largely responsible for putting out of business. And, again, as the WSJ article noted, Wal-Mart will still have convincing to do. Says David Veal, PBM analyst at Morgan Stanley: "Traditionally, employers are risk-averse; they're hesitant to move just on price."

Others joke that selling drugs is not the same thing as selling toilet paper. The company is already the third-largest pharmacy in the U.S. in terms of sales, after CVS and Walgreen Co., so its unclear whether there's as much room as there was when Wal-Mart wreaked havoc on Main Streets across America. But there is no denying when Wal-Mart speaks, much of the world still listens. Things could get interesting!

Author Postscript, January 25, 2008: The Wall Street Journal's Health Blog written by Jacob Goldstein commented on the announcement which was made yesterday in his posting entitled "Should PBM Investors Worry About Wal-Mart?". In essence, he agrees with my assessment, saying: "Don’t panic. (But don't rush to buy more shares in PBMs, either.)"

On January 30, 2008, the blog Drug Channels, written by Dr. Adam J. Fein, further investigated the potential economic impact that Wal-Mart's PBM announcement could have.

More Questions on the Value of Statins

Statins, (technically known as HMG-CoA reductase inhibitors) form a class of lipid-reducing drugs which are prescribed to reduce the so-called "bad" low-density lipoprotein (LDL) cholesterol levels in the blood of people with or who are believed to be at risk of cardiovascular disease. Cardiovascular disease is the single biggest killer of all people with diabetes (type 1 and type 2), so as a group, patients with diabetes have long been assumed to have the same risk as someone who has already had a heart attack.

For those of you who aren't familiar with them (or having been living in a cave for the past decade), statins are perhaps the drug industry's biggest category of blockbusters (meaning annual sales are well over $1 billion for each drug) and include such drugs as atorvastatin (Pfizer's Lipitor), fluvastatin (Novartis' Lescol), pravastatin (Bristol-Myers Squibb's Pravachol), rosuvastatin (AstraZeneca's Crestor), and simvastatin (Merck's Zocor, which is now widely available as a generic since its patent expired in June 2006). The drug industry has made a fortune off these drugs, and they are among the most widely prescribed medications on earth. In fact, BusinessWeek reported that statins are the best-selling medicines in history, used by more than 13 million Americans and an additional 12 million patients around the world, producing $27.8 billion in sales in 2006.

Of course, we have also seen a pattern emerge recently, whereby the drug industry tends to release only studies which show a benefit to their drugs, while studies which do not show a clear benefit are seldom (if ever) published. I wrote about this last week (see here for that article). No doubt, the statins fall into the same pattern (at least when they were launched a number of years ago), although truthfully, this drug category has seen far more objective research than most others, so it's now easier to sort fact from fiction when it comes to statins.

But in people with diabetes (both type 1 and type 2), there has always been some question whether there was any real benefit, or whether doctors were simply prescribing these pills without having sufficient evidence of incremental benefit in people with diabetes who are already at at increased risk for cardiovascular disease because of diabetes (although the risks are different in both type 1 and type 2, it is nevertheless a risk in both groups) -- often at considerable expense. I have already called attention to the fact that there needs to be a separate cardiovascular risk model in people with type 1 diabetes because there is not currently a cardiovascular risk model exclusively for this group in spite of the fact that heart disease remains the single biggest killer for them as a group. But he real question was whether statins provided any incremental benefit over the population at large?

Recently, a large meta-analysis was conducted looking at the results for nearly 20,000 patients with type 1 or 2 diabetes, and the conclusion was that all-cause mortality decreased by 9% with every 1 mmol/L decline in LDLs, the international Cholesterol Treatment Trialists' Collaborators reported in the Jan. 12 issue of The Lancet. This means statins for all adults with diabetes, right? That is certainly what the media is telling everyone. Not so fast.

While the supposed benefits of statins have been well-established, another fairly recent study also shows that taking statins destroys your muscle to at least some degree, which also includes the heart as one of the most important muscles in the body. Some bloggers find the way statin drugs have been marketed to be a scam. While I am not big on conspiracy theories, I do think the supposed benefits have been pushed without the same consideration given to the risk or expense.

Something else to consider: last week, in a cover story, BusinessWeek cast further doubt on the benefits of statins for the general population. That article singled out Pfizer's Lipitor, noting that in a 3 1/3 year study, the drug reduced the rate of heart attacks from 3% to 2%. In other words, to prevent a single heart attack, 100 people needed to take the drug for more than 3 years, prompting some scientists to suggest that patients who don't have heart disease don't really need statins.

BusinessWeek reported that drug companies made "everyone with high cholesterol think they really need to reduce it," according to Dr. Bryan A. Liang, who directs the Institute of Health law Studies at the California Western School of Law.

The reality is that the LDL cholesterol itself is not "bad", but how and where the cholesterol is being transported, and in what amounts over time, is what causes adverse effects. And not all people with diabetes have the same risk. Certainly many do, particularly those who are overweight and have type 2 diabetes may have significantly increased risk because their lipid profiles are impacted.

Diabetes in Control notes that "In type 2 diabetes, triglyceride levels are frequently elevated, and HDL cholesterol levels are suppressed. However, in type 1 diabetes, HDL cholesterol levels are generally normal or even elevated. Meanwhile, LDL cholesterol levels among patients with both type 1 and type 2 diabetes are frequently reflective of those of the general population and are not necessarily elevated."

But those people with diabetes who do not already have heart disease may not benefit any more than people without diabetes. And we cannot not conclude that a statin should automatically be prescribed for all patients with diabetes.

"It was once believed that the mere fact of having diabetes gives a person the same risk of heart attack as a person who had a heart attack before," lead-researcher Cheung said. "We are now treating people's diabetes much better than before, and their baseline risk of heart disease is lower than before."

Cheung also said that everyone with diabetes should discuss cholesterol-lowering therapy with their doctors, but he does not think doctors should always recommend drug therapy.

The most recent meta-analysis concluded that in people with diabetes, whether they are male or female, get just as much benefit from statins as anyone else -- not more. If 1,000 people with diabetes took statins for 5 years, 42 of them would avoid heart death, heart attack, or coronary revascularization (bypass or stenting). That is an improvement, but not a major one, and it comes at considerable expense to patients and/or their healthcare providers.

The reality is that statins may provide benefit for some, but the drug has almost certainly been over-prescribed, and the benefits may not be worth the huge expense for everyone. Generics are helping with the cost, and should continue next year. Once again, I will point to a particular posting from fellow d-blogger Ryan Bruner, who so eloquently wrote "I don't need no stinkin' statins!" Nor we should not conclude that everyone with type 2 diabetes needs a statin. Some may, but that needs to be evaluated relative to their risk of heart attack, not automatically prescribed. We need to be a bit more cautious in prescribing drugs among those who don't need them. This wasteful habit has cost our healthcare system (or rather the lack thereof) billions unnecessarily, for a benefit has not been proven conclusively.

Selective Disclosure of the Truth: When Is the Line Crossed?

In this month's edition of The New England Journal of Medicine, a review of data submitted to the U.S. Food and Drug Administration (FDA) for a dozen popular antidepressants suggests that their effectiveness was exaggerated by the selective publication of favorable results. In fact, nearly a third of those antidepressant drug studies were never published in the medical literature and nearly all happen to show that the drug being tested did not work, researchers reported. This is a very common tactic used in many different places, including in industry, advertising among salesmen (and women) and even job candidates.

It is what like to call "selective disclosure of the truth". It's not exactly lying (admittedly, it's a very fine line) rather its just omitting those things that happen work against whatever is trying to be accomplished. There are many examples of using "selective disclosure of the truth" -- even in healthcare. For example, New York City Health Officials did this when they pushed (some would say steamrolled) to implement mandatory surveillance of glycosated hemoglobin (better know as A1c) test results, which was the first for a non-infectious disease. Diabetes was addressed mainly because it was an easy target, a simple blood test to measure A1c is done and that is indicative of glycemic control. The same cannot be done for other health problems such as asthma or hypertension.

In an interview with CNN and the media, New York City Health Commissioner, Dr. Thomas R. Frieden stated, "There will be some people who will say, 'What business of the government is it to know that my diabetes is not in control?'" The answer, he said, is that diabetes costs an estimated $5 billion a year to treat in New York and was the fourth leading cause of death in the city in 2003, killing 1,891. Sounds like a pretty convincing argument, only it wasn't exactly truthful.

Frieden's statement was very carefully worded to suggest that diabetes costs New York City far more than the city actually spends on the disease. Of the estimated $5 billion spent to treat diabetes in New York, private health insurance and the Federal government via Medicare and Medicaid pay the overwhelming majority of this figure, not the City of New York.

In fact, as of February 2006, the NYC Health Department had an annual budget of just $950,000 allocated to diabetes and a staff of just 3 people, again according to The NEJM. I wrote more about that in my posting about that topic, but I don't want to stray too far away from the central point: how prevalent is "selective disclosure of the truth" in drug marketing?

I suspect the latest example is only the tip of the iceberg, and we are starting to see a growing body of evidence suggesting that in drug marketing in particular, its far more common for the negative studies never to see the light of day than for the positive studies. This has ramifications beyond getting FDA approvals. Doctors never see the negative studies in their medical journals, and therefore are persuaded (or some would say misled) to believe they are safe and to continue prescribing them.

Clearly, not all cases of "selective disclosure of the truth" are the same. Let's be honest, in your last job interview, you probably didn't mention those things which made you look bad, and why would you? Why raise such an issue unless someone asks? Consider when someone has had a long absence from the workplace. Although someone who was in jail for a few years might have different reasons for not highlighting this than someone who took a leave from the workplace to raise their children, but the company interviewing a candidate is free to question it. Few (if any) people are hurt by leaving it out. And while no one would question that your local, polyester leisure suit wearing used car salesman probably pushes those limits of selective truth disclosure too far, even so, it usually only impacts the individual buying the car. But when drug companies do this, millions of people risk dying as a result.

If this posting seems a bit like deja vu, its because it is. Last year, I wrote about the type 2 diabetes drug Avandia being as being another, all-too-painful example of what is wrong with the process. Unfortunately, now we have yet another example of this in action, this time with antidepressants. It is the job of our regulators to mandate where that line happens to be, but having the pharmaceutical industry pay for a majority of the FDA's budget with user fees (see here and here for more background) clearly blurs where that line should be. In 2008, let's get Congress to kick the FDA user-fee habit and start funding it from taxpayer dollars again!

Rethinking the "Dark Ages" of Treatment for Type 1 Diabetes

When I was diagnosed with type 1 diabetes as a 7 year-old kid on July 24, 1976, not much had really changed since the discovery of insulin. I began this trip using Clinitest urine testing and that lasted for over a decade. I made slight adjustments to my short-acting insulin if my test results were on the high-end of the scale. Blood glucose monitors were introduced in the mid-1980's, and I recall my family was one of the first to get a meter (since there were two of us who had it, I guess the price was justified); but the other kids I knew used color-coded strips and they told stories of how they could slice the strips in half and double the number of tests they got from a single vial. I remember thinking that was pretty cool.

When I was quite young, I did experience some problems with nocturnal hypoglycemia, and I would wake up in the middle of the night screaming with the most horrible nightmares. I was taken to the hospital as they tried different insulin regimens and finally settled on a combination that worked quite well until the manufacturer stopped making one of the insulin varieties I relied upon for glycemic control. This was my first, rude introduction to the business of diabetes. I struggled to find a comparable insulin with the same kinetics, but I was told, that's the way things were.

Aside from insulin, treatment consisted of adherence to a diet of largely whole foods with strict limits on refined carbohydrates (bread, crackers, rice, potatoes, etc.), and a mandate to ride my bicycle, play ball outside with other kids or do whatever else we could to amuse ourselves (my mother didn't want the kids inside, glued to the TV and pestering her while she prepared dinner anyway). In the summer, we got to spend time swimming in the pool to keep cool. For snacks, we were given things like carrot and celery sticks or peanuts that we shelled ourselves, and we drank water from the hose in the backyard when we were thirsty. Occasionally, we would get unsweetened Kool-Aid that my mother sweetened with Sweet & Low.

For much of my early life, I was treated with that supposedly allergenic animal insulin that I have been told repeatedly by promoters was "unpure" and was supposed to cause all kinds of allergic reactions (although I didn't have any) and I did not have the wild gyrations in my blood glucose levels that kids with diabetes seem to have today. My older sister, who was diagnosed with type 1 in 1969, did have some visible examples of lipodystrophy, but over time, that all but disappeared, probably due to greater purity of the insulin starting in the early 1970's. In fact, I could make a fairly convincing argument that our lifestyle was actually far superior to the way many kids live today.

Interestingly enough, I have actually had parents of newly-diagnosed children make the bold claim that I grew up in the so-called "dark ages" of diabetes care, but I beg to differ with that assessment. Although I can't know for certain because we didn't have an accurate method for monitoring, I believe my blood sugar levels were within a reasonable range. In fact, when I had my first hemoglobin A1C test done (remember, I lived for quite a while before that test was created), my doctor told my parents to keep doing whatever they were doing. Because I have yet to have any real complications so far, I would dare say that I was pretty well cared for in spite of suggestions to the contrary.

In 1982, Eli Lilly and Company received FDA approval for Humulin, which was supposedly human insulin -- just like the body makes (in reality, it is synthetic, a good comparison is the difference between artificial vanilla and natural vanilla -- it tastes similar, but not exactly). I recall that company advertised the heck out of that insulin in magazines like the ADA's Diabetes Forecast and elsewhere, but almost no one I knew with diabetes switched because doctors were reluctant to switch patients who were already doing well with a prescribed treatment plan. Also, the new synthetic human insulin was more expensive and offered no apparent benefit. It wasn't until the company announced plans to discontinue those insulins when patients switched to Humulin en masse.

On the surface, the argument seems logical enough -- that humans should use human insulin, but the reality now looks rather different. First, there is a growing body of evidence that now suggests that human insulin is what the body's immune system is attacking, thus it is one of the causes of type 1 diabetes. In May 2005, for example, the journal Nature published an article which suggested that insulin may itself may be a primary autoantigen for autoimmune diabetes. But the 2005 article was done in mice, and there are sufficient differences between humans and mice to remain skeptical of this finding, even if it was an interesting possibility. But this month, in the January 4, 2008 edition of the journal Current Opinion in Immunology, appears to confirm that finding, and I suspect additional studies will further validate this.

I would add that the SEARCH for Diabetes in Youth, a five-year, $22 million research project that ended in October 2005 jointly funded by the CDC, the NIH/NIDDK and JDRF, found that a growing number of children with a clinical diagnosis of type 2 diabetes also now had signs of autoimmunity. We also know that patients with type 2 who initiate insulin therapy also start to show signs of autoantibodies normally associated with type 1.

Elizabeth Mayer-Davis, Ph.D., the principal investigator for the SEARCH study told JDRF's Countdown in March 2006 "We didn't expect that some 30% of children with a clinical diagnosis of type 2 would have positive diabetes autoantibodies."

With that being the case, we should give serious consideration to the impact that using so-called human insulin (and perhaps moreso with non-insulin products like insulin analogs) have on the population this medicine is supposed to be helping.

In retrospect, I'm not convinced that I lived in the "dark ages" of diabetes treatment and witnessed a great awakening while I was growing up. In fact, I would argue quite the opposite. Sound dietary and exercise habits, combined with highly purified animal insulin was far better than today's kids have it.

Novo's AERx® Inhaled Insulin Also Bites the Bong

Wow! Just a few years ago, many on Wall Street were convinced that Pfizer's Exubera was going to be a surefire blockbuster. We all know how that turned out (see here for my chronicling of that business debacle).

More recently, the worldwide insulin market leader, Novo Nordisk A/S has tried to temper expectations for their own inhaled insulin product, which the company anticipated bringing to market by 2009 or 2010. In a November 6, 2007 interview with Dow Jones, a Novo executive said the company thought that the AERx iDMS inhaled insulin product it has been developing would be a niche product, not a blockbuster.

"We don't think for us it's a blockbuster," Martin Soeters, president of Novo Nordisk's U.S. unit, said on November 6, 2007 at a pharmaceutical industry conference in Philadelphia.

Soeters told Dow Jones Newswires that Novo Nordisk has long had lower expectations for AERx than Pfizer had for Exubera. He said inhaled insulin might not be appropriate for use over multiple decades, but rather for shorter-term users such as the elderly or women who have pregnancy-related diabetes.

"We think it will be for a certain part of the population," Soeters said.

Today, Novo Nordisk announced that based on a detailed analysis of the future prospects for inhaled insulin and a review of the medical and commercial potential of the AERx iDMS inhaled insulin system (AERx) which was licensed from Aradigm Corp., the company has decided to refocus its inhaled insulin activities and discontinue all further development of AERx. The press release noted, however, that the decision to discontinue the development of AERx was NOT due to safety concerns.

"We have concluded that fast-acting inhaled insulin in the form it is known today is unlikely to offer significant clinical or convenience benefits over injections of modern insulin with pen devices such as Novo Nordisk's FlexPen®," said Lars Rebien Sørensen, president & CEO of Novo Nordisk. He continued: "In general, people with type 2 diabetes start insulin therapy with long-acting or premixed insulin, and experience shows that they want very simple, very convenient devices for administering their insulin. This requires a completely new approach to inhalation of insulin."

On Tuesday, January 15, 2008, Novo Nordisk will hold a conference call for investors to discuss the withdrawal. Investors will be able to listen in via a link on novonordisk.com found under 'Investors - Download centre'. Because the conference call will be held at 10:00 AM Central European Time, which corresponds to 4:00 AM EDT, I will be tuning into the replay.

"Pfizer's decision on Exubera prompted this," said Mads Krogsgaard Thomsen, Novo's chief scientific officer. "We have realized that the trend is for physicians to start treatment with something simple rather than a device that has to be loaded with insulin for each mealtime use."

Eli Lilly and Company as well as MannKind Corp. (whose owner, Alfred Mann, remained unusually bullish on the concept in spite of Pfizer's costly failure, see the article here for details) are still proceeding with their own inhaled insulin plans, but when the leader in the insulin market pulls the plug, it raises questions about the commercial viability.

While this does not mean the end of inhalable insulin, as fewer players increases the chance of success for those who ARE offering it, it's starting to look like this idea was one of the biggest busts in drug marketing history.

Travel Plans to Include Food Can Be a Wise Investment

Who among us hasn't flown? I'd be willing to bet the percentage is strikingly small. Yet how many of us devote as much attention to our dietary needs in transit as we do to schedules and/or prices? An investment of as much time as it takes to find a flight that leaves or arrives when we need it, or to secure the lowest price, is well worth it. Its no secret that the food in airports, when available, is typically dominated by fast-food giants such as McDonalds and Dunkin' Donuts, but even there, the selection may be limited, so even a salad may not be an option. Certain airports have marginally better fare, but even that varies considerably from one terminal to the next. There is some effort to improve the offerings, but its not always a simple task and finding high-volume tenants who can make the economics work is tough. Even the salads, a seemingly healthful option, typically come with salad dressings that make a regular hamburger or chicken nuggets seem low-calorie by comparison.

Nice. So what can you do? For short flights, it may not be a big deal to just wait and eat when you arrive. But travel inherently can bring delays, missed connections, etc., which may force you to alter your plans, so planning for the unplanned can help. Bringing your own food in a carry on is always the better option. Making your own food is best, but if you're returning from a trip, consider picking up a sandwich at a deli or even a Subway outlet which may be a healthier alternative what the airport and the airlines have to offer. A trip to your local supermarket may also be a decent option if one is nearby. There, in addition to pre-made salad offerings and also vegetable packages meant for kids to pack in their school lunches, but virtually anyone will find these travel-sized packages perfect. My only gripe is that most of these salads and snack packages seem to love ranch dressing, which is not only high-calorie, but also not my idea of great taste. The ban on liquids can present a challenge (for example, don't plan on bringing a small bottle of salad dressing for your fast-food salad to save yourself hundreds of calories, because you can't bring it through. But you may order packets to take with you (just be sure to place them in another plastic bag with a zipper to avoid leaking that can occur). Individual packets can be ordered in advance online from minimus.biz, who also offers a variety of other travel-sized products. A visit to a local Costco, BJ's or Sam's Club may also have these items, although selection may be more limited. Other options in the canned foods aisle include Bumble Bee Sensations (a bit high in salt, but not bad if you want to take something with you and don't want to prepare it), or in the deli or packaged meat aisle, Oscar Meyer has options, too -- just watch the calorie counts on those and select accordingly.

Then there is the in-flight food offerings, which are often limited to greasy potato chips or sugar-coated nuts (euphemistically called "honey roasted, even though they don't contain a trace of genuine honey). Fortunately, a growing prevalence of nut allergies has made these far less common today. To make matters worse, the latest DietDetective.com survey of airline food indicates that it may be a lot worse than you think. "The individually packaged snacks are oversized and have mega calories," the survey's author, Charles Stuart Platkin, writes of American Airlines' in-flight cuisine. "These snacks should be for a family of four, not one person. They really are a disaster." Northwest Airlines admitted that it doesn't even track the nutritional information in its on-board food.

For longer-trips (such as trans-continental, trans-Atlantic or trans-Pacific flights), people using insulin may not be able to afford the luxury of waiting. Of course, if your flight does offer a meal, ordering the special entrees for passengers with dietary restrictions, such as vegetarian and/or vegan, Kosher or Muslim meals, or even meals that are supposedly for people with diabetes. Based on experience, I will say that diabetes meals are seldom a wise choice (always consisting of bread and some other high-carb but low-fat items). I have consistently found the vegetarian meals tend to be healthier and far better tasting. On trans-Atlantic flights, ordering a Muslim meal can mean the difference between a microwaved sandwich and freshly-prepared food that is far lower in calories. To order a special meal, contact your airline at least a day in advance to order the meal. It's well worth the call.

Travel need not result in a caloric and carb-laden nightmare, but you probably need to dedicate as much time to your dietary needs as you do to finding the right flight to avoid the inherent travel pitfalls.

The Good News, and The Bad News

Well, you've probably already seen the news on the ADA's website, and while this is the first indication that all of the efforts of patients, their doctors and CDE's have yielded actual proof that their efforts have paid off. But naturally, a slight majority (60%) isn't good enough.

Dr. Earl S. Ford, of the Centers for Disease Control and Prevention, Atlanta said "As welcome as the recent favorable trends in glycemic control are, additional efforts are needed to help the approximately 40% of patients with diabetes who do not have adequate glycemic control."

But I think its very unrealistic to assume it will get much better than this -- honestly. First of all, the struggle to achieve this was monumental, with tools that could best be described as prehistoric at best. Think about how crude they are: most patients puncture themselves regularly to test, and the insulin injections, the Symlin injections, the Byetta injections or pumps also involve another puncture. For those who take meds, a majority experience some kind of nasty gastrointestinal side-effects, or perhaps yet-undiscovered side-effects, all of which aren't very pretty.

Then there is the bigger issue which AmyT has brilliantly written about, which indicates the outlook isn't all that pretty. And if that wasn't bad enough, but its really the tip of the iceberg! There's also the other issue which leaves some 3 million Americans with diabetes without healthcare insurance.

I thought I'd share that report the ADA has cited with you. "Is Glycemic Control Improving in U.S. Adults?"; Thomas J. Hoerger, Joel E. Segel, Edward W. Gregg, and Jinan B. Saaddine; Diabetes Care 2008 31: 81-86.

From my perspective, I think it is an admirable goal to improve glycemic control in patients with diabetes, but I also think in today's environment, it is unrealistic to expect much in the way of future improvement until we can resolve the issue of universal healthcare coverage and the shortage of diabetes educators.

Protein Treatments to Cure Type 1 Diabetes?

Proteins are being investigated for use in treating a variety of diseases because they can influence cell behavior by fueling or dampening certain molecular signals, therefore their use may be used to influence the regeneration of certain cells, in the case of diabetes, the pancreatic beta cells. This falls under the broader diabetes research objective to investigate inducing beta cell regeneration. Several methods are now being investigated or reviewed, including (among others), INGAP as well as several other techniques that were seen as useful in beta cell regeneration. If you aren't familiar with INGAP, that story was chronicled a few years ago. To read the background on that, please see the following archived story links below:

Spring 2002
Winter 2002
Summer 2003
Spring 2004
Fall 2006
Current

Beta cell regeneration has emerged in recent years as at least a possible element required to successfully reverse type 1 diabetes. Previous medical dogma had dismissed the idea, with the idea (supported by a handful of incomplete studies) that once the damage was done, the beta cells are history and cannot be replaced except by using transplantation. But in recent years, a number of new studies have since proven that long-held belief was incorrect.

At the 2005 ADA Scientific Sessions in San Diego, UCLA's Dr. Peter Butler and colleagues published results from an extract under the title "Evidence for Sustained Islet Turnover in Humans with Long-Standing Type 1 Diabetes" which showed that even patients with long-standing type 1 diabetes (50 years was the longest duration in the test group if I recall correctly) had evidence of beta cell generation, but that the immune system continues to destroy the new cells. Although these results were never published in a medical journal, a small page was published a while back on the now-defunct "Join Lee Now" website. The extract can be found on the Internet Archive Wayback Machine, provided you know the address for what you're looking for in the archive). For simplicity sake, just use this link.) That study, followed by research announced by Joslin and others, have shown there is indeed evidence that even people with long-standing type 1 diabetes still have beta cells which continue to be destroyed in the setting of low-grade inflammation.

Yesterday, a press release from the University of Florida announced findings from a study involving the use of proteins a potential therapy for type 1 diabetes. University of Florida (UF) researchers were able to coax liver and pancreatic cells in diabetic mice into producing insulin by injecting the animals with a protein known as Pancreatic Transcription Factor (known more commonly as Pdx1 or simply PDX). The protein itself is not a new discovery, having been investigated and reported in several scientific and medical journals for a number of years now. Pdx1 in turn activates the genes controlling the development of the pancreatic beta cells. The UF research team's novel approach is described online in the journal Diabetes.

Earlier research showed that inserting the Pdx1 gene into liver or pancreas cells can induce insulin production, but most gene therapy methods use viruses to introduce a piece of genetically engineered DNA into cells. The disadvantage of such approaches is that researchers can never be certain the viruses are entirely harmless, Chief Researcher Li-Jun Yang, an associate professor of pathology, immunology and laboratory medicine at UF's College of Medicine said.

The basic idea with protein therapy is that a person's own cells could possibly be reprogrammed to naturally produce the hormone, restoring the body's ability to properly regulate blood sugar levels without having to use a potentially hazardous virus to slip corrective genes into the body or having to transplant pancreatic cells from someone else. That might also eliminate the adverse effects sometimes associated with gene therapy and eliminate the need for lifelong suppression of the immune system so transplanted cells are not rejected, Yang said.

"What's so innovative about UF's approach is the ability to normalize blood glucose levels in diabetic mice simply by delivering Pdx1 protein in the target cells, thus effectively eliminating the side effects associated with gene therapy," Yang said.

"Right now, promoting beta cell regeneration has become such a hot topic," she added. "The trick is to figure out how to trigger glucose-regulated insulin-producing cells to regenerate."

Still, the UF researchers admit that this approach will have to be tested in studies that assess its safety before scientists could conduct patient trials to determine whether it works in people, and those studies that are still years away.

Bear in mind, this was yet another mouse study, so don't get too excited just yet. Still, it IS progress towards treatments which can induce beta cell regeneration. Perhaps, when combined with another therapy to address the problem of ongoing autoimmunity towards the pancreatic beta cells, that will do it. I'm thinking, for example, of the recent deal with MacroGenics, Inc. by Eli Lilly and Company in November 2007 to commercialize teplizumab, a humanized anti-CD3 monoclonal antibody treatment. Another one is Clal Biotechnology Industries Ltd./Teva's DiaPep277 which was announced earlier last year. The latter is slightly different, being a peptide - rather than an antibody - derived from the human protein, HSP60, which could immunomodulate the body's errant immune system. Both were highlighted in my 2007 Wrap-Up and Outlook for 2008 published recently. Oh, and I never mentioned Dr. Faustman's and her colleague, Dr. David Nathan's human clinical trials, also meant to stop the ongoing issue of autoimmunity. I hardly need to elaborate on that one!

One thing I think has become abundantly clear, however, is that any "cure" for type 1 diabetes is likely to consist of several distinct components. It may not be a single surgery, transplantation or treatment, but multiple surgeries, transplantations of treatments needed to address several different problems. I am not the only one to reach this conclusion. Dr. Camillo Ricordi at the University of Miami's Diabetes Research Institute and his colleagues also have gone on the record as stating this, too. Regardless, another piece to the diabetes puzzle is slowly, but surely, being chipped away!

Another Progress Report on Islet Transplantation

In my 2007 Wrap-Up and Outlook for 2008, I had noted some progress made towards curing type 1 diabetes. Specifically, I noted the work being undertaken by New Zealand-based Living Cell Technologies, Ltd. (LCT), as that company is now undertaking human clinical trials in Russia. I hadn't mentioned another company, this one based in San Diego, California named MicroIslet, Inc., a biotechnology company engaged in the development and commercialization of transplantation therapies for diabetes. I chose not to report on MicroIslet's innovations not because of lack of progress, but because MicroIslet is not as far along in trials of their product as LCT is with theirs. Perhaps did a disservice in not reporting it, therefore, I am reporting on their 2007 progress today.

MicroIslet's innovation involves the use of islet cells extracted from the pancreases of a very unique, and highly quarantined, herd of pigs. Normally such cells would be immunogenic since they are derived from another species. MicroIslet's technologies mitigate the problem of tissue rejection by encapsulating the islet cells in a biocompatible material known as alginate, a viscous gum derived from seaweed and used worldwide in many food, dental, and medical products. A protective covering of alginate allows the islet cells to receive nutrients and excrete insulin and waste products through the bloodstream, while also serving as a barrier that blocks the host's immune system from entering the capsule and thereby destroying the transplanted islets.

At the recently completed Global Diabetes Summit in Columbus, OH (Nov. 29-Dec. 1, 2007), MicroIslet's President and Chief Scientific Officer, Dr. Jonathan Lakey, explained the potential for treating diabetics with pig islet cells. "Xenotransplantation [from one species to another] has the potential to solve many of the problems associated with the transplantation of islet cells from one human to another," he said. Dr. Lakey presented compelling animal data from his company's preclinical studies and outlined the likely scenarios under which pig islets could one day emerge as a significant treatment modality for type 1 diabetes.

Then, in December 2007, MicroIslet also announced that it had met with the U.S. Food and Drug Administration (FDA) to discuss requirements for the filing of an Investigational New Drug (IND) application for MicroIslet-P™, a microencapsulated suspension of pancreatic islet cells.

As a result of the FDA meeting, MicroIslet has clarified details of the development path for its xenotransplantation approach, which involves microencapsulation of insulin producing porcine islet cells. The Company's last meeting with the FDA in December 2006 related to a proposed IND for allotransplantation of microencapsulated human islet cells. [this means the islets are encapsulated in the company's proprietary casing which enables insulin to be released without The Company's current strategy is to proceed directly to human clinical trials of its xenotransplantation approach, which overcomes the inherently limited supply of human islets. The proprietary encapsulation methods used in MicroIslet-P™ are designed to shield the islet cells from immune system rejection, while the planned implantation procedures will be minimally invasive. The Company's pre-clinical testing to date has demonstrated a strong safety profile for xenotransplantation of porcine islets in rodents and non-human primates.

The company notes that islet cell transplantation has met with limited success for several reasons. Because the body recognizes transplanted cells as "foreign" it tries to eliminate or "reject" them, which is also seen in the transplantations of kidneys, livers, and other organs. Patients receiving islet cell transplants must therefore take anti-rejection drugs for the rest of their lives – or the life of the transplant. The tradeoff in reducing or eliminating insulin is the need to take immunosuppressive drugs. For this reason, islet cell transplants are currently only given to patients who really cannot control diabetes or its complications through insulin injections, or who are already undergoing organ transplantation due to diabetic complications.

Another problem with islet transplants is the lack of availability of quality human pancreases. The donor organ shortage is compounded by the relatively low abundance of islets among pancreatic cells. Often two organs are needed to obtain sufficient cells to make the transplant work.

Even when transplanted islet cells take hold and produce insulin in the new host, the effect may not last very long. Possibly as a result of rejection, islet cells gradually lose their ability to produce insulin. In a study published in 2005, only 40% of recipients were off insulin a year after transplantation. After three years, the number fell to 17%. On the bright side, however, most patients were able to use less insulin, and appeared to manage their disease better. Furthermore, there is also evidence that the incidence of severe hypoglycemia, a side-effect of treatment with insulin, is significantly reduced as a result.


Will MicroIslet's or LCT's innovations enable more patients to receive islet transplants with a higher degree of success than those who received the original "Edmonton Protocol" did? Perhaps, but clearly, it's a race between them and rival LCT to see who gets there first ... successfully. Only time will tell, but clearly, any improvement upon the the success of islet transplants is an advance. However, I would caution that there is also growing evidence that the chosen location of the transplant, so far being done in the liver, may also contribute to the less-than-successful long-term results. After all, if nature had intended islets to be in the liver, wouldn't they be there in the first place? We can expect more progress made by both companies in the coming year. No doubt, 2008 will bring more advances in this field of islet transplantation which cannot be overlooked!

Biodel Announces Manufacturing Plans for VIAject™

Wow, that was quick! In my my 2007 Wrap-Up and Outlook for 2008, I mentioned a few outstanding items that hadn't been answered. Specifically, I mentioned Biodel, Inc. and noted that the company hadn't stated how it planned to manufacture its rapid-acting insulin formulation -- whether they would form a marketing partnership with another manufacturer, use contract manufacturing from a third-party, or go it alone.

Today, Biodel issued a press release which was primarily focused on the fact that the company had completed enrollment of its two pivotal Phase III clinical trials of VIAject (one for patients with type 1 diabetes, and another for patients with type 2 diabetes). That is certainly news that the company is adhering to its development timeline as disclosed in their most recent quarterly earnings release. But also included in that release was the answer to that question I raised. Specifically, I noted "Although the company has not stated whether it will seek a marketing partner ... 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". As of this afternoon, we now have an answer to that question.

The answer is that Biodel will likely acquire synthetic human insulin in bulk from another party, then the company will then take that bulk insulin, add their patented ingredients (which enables VIAject to be absorbed as rapidly as insulin analogs do), bottle it or put it into pens and/or pen cartridges in their own "fill and finish" factory, add the required FDA inserts, and package it for distribution.

Here's an excerpt from their press release:

"The Company also announced its intention to build and operate a fill and finish manufacturing facility for VIAject™ on the campus of its current headquarters in Danbury, Connecticut which will be dedicated to manufacturing a full line of VIAject liquid formulations and presentations. The dedicated manufacturing facility will improve margins, provide superior quality control, and better inventory control. Biodel anticipates that the facility will cost under $15 million and will be available for commercial production in 2009."

Just who will Biodel buy bulk insulin from? There are actually a number of possibilities and that question will likely be put out for competitive bidding once VIAject has received FDA approval. Among the potential suppliers: the Sandoz generics unit of Novartis, Teva Pharmaceutical Industries which has manufacturing facilities around the world, generic-giant Barr Pharmaceuticals, Diosynth (a Dutch contract biopharmaceutical unit of Schering-Plough), and Bangalore, India-based Biocon Pharmaceuticals, Ltd. immediately come to mind (largely because the company sells its ability to do contract manufacturing of this type). Since Poland's Bioton, S.A. has already announced its plans to enter the U.S. insulin market by 2010, they may not be a likely potential parter.

Another possibility I noted (kind of in passing) was a Calgary biotech company called SemBioSys Genetics Inc., which has developed a method of producing synthetic insulin in safflower plants, which may also be a possibility. SemBioSys is now currently working with the FDA for approval on its plant-based method of manufacturing insulin. They have announced plans to apply for FDA approval using the 505(b)(2) New Drug Application method. However, to date, Sandoz is one of the few companies to use this route for its Omnitrope Human Growth Hormone, and the company had to sue the FDA to get a decision from the agency (see here for background on that).

The current method of insulin manufacture is extremely capital-intensive, as recombinant insulin is cultured in stainless steel bioreactors, which must be approved by the FDA. The big advantage SemBioSys could bring is that the company claims factories used to make safflower insulin are significantly cheaper to build than the current method, therefore its production methods would be up to 40% less expensive.

To be sure, bio-engineering of plants has something of a public relations problem in many parts of the world (many people Europe, for example, call genetically modified vegetables "frankenfoods"), so the company may need to weigh that issue relative to quality control concerns at factories outside of the U.S., Canada or Western Europe (such as in India). That favors Sandoz, Teva or Diosynth, but right now, its anyone's guess.

But Biodel's latest news release does indeed suggest the company has a very high degree of confidence that Phase III clinical trials will not reveal any surprises (in part, because the company's patented additives basically use already FDA-approved ingredients added to recombinant human insulin). I will be eager to see the company's business presentations made to investors in the coming year.

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!