The Business of Diabetes: Big Changes May Be In Store For The U.S. Insulin Market

This posting originally started out with a press release I caught which I felt might be of interest to my readers, but as I began researching the subject further, it evolved into a broader discussion of the insulin market as we know it today.

Whether you realize it or not, the U.S. insulin market could soon see some of the most profound changes the industry has seen in decades. The reason: competition could soon change the dynamics of a once-comfortable oligopoly which we can only hope will result in a much more competitive and dynamic market. One look back to the 1970's U.S. automobile market to see what might happen to insulin in the coming years if new competition enters this staid market.

Until the 1970's, Detroit's "Big 3" dominated the U.S auto market and by many accounts, resulted in laziness and arrogance among them (there is also a "Big 3" in insulin providers, which makes this comparison especially relevant). Product quality wasn't really great, fuel-efficiency was practically non-existent, and prices hardly resembled what could be called a dynamic free-market. That very much resembles the U.S. (and worldwide) insulin market today; the barriers to entry were high. But in the 1970's, companies from Japan and to a lesser-extent, Germany sold high-quality cars that were an ideal fit for the OPEC oil embargo that occurred in 1973. Of course, many consumers were pleasantly surprised and Toyota and Honda would go on to become household names -- and would ultimately unseat GM for worldwide leadership in the auto industry. Germany focused on quality too, but realized it could not really compete in mass-market products, effectively creating a new paradigm for luxury cars and that the country retains leadership even today. The insulin market badly needs competition. The current market leaders have steadily increased prices their and abused the private healthcare providers because the barriers to market entry for competition is quite high in spite of the fact that the technology to make insulin is has existed for decades. The insulin cartel has also been slow to introduce much in the way of innovation, and has abused their market leadership in much the same way as GM abused its leadership in autos back in early 1970's by aggressively increasing prices above the rate of inflation without consummate merit in product design or quality because there really were no practical alternatives.

Insulin: Once The Deprived Stepchild of Research Investments Until the 1990's; Then Transformed Into A Cash Cow

It used to be that insulin, first discovered in 1921 by Canadian researchers, was viewed by the pharmaceutical industry as the neglected stepchild to more creative, interesting and profitable new type 2 diabetes medicines (most of which were oral meds), leaving insulin for all practical purposes, desperately starved for research dollars and talent who tended to migrate towards the much larger and more lucrative ailment of insulin resistance.

In terms of money spent, some analysts estimate that until the early-1990s, the total dollars spent on insulin resistance treatments dwarfed the dollars spent on insulin treatments by a ratio of as much as 90 to 1, meaning for every $1 spent on insulin research, $90 was spent investigating new type 2 treatments. But in the mid-1990's, with 1996's FDA approval of the first man-made insulin-like molecule (known as insulin analogues), that business dynamic was turned upside down (see here for more on that subject). Soon, researchers outside of an academic setting began to see potential in interest in insulin, a hormone which remains remarkably well-preserved across most different species of animals (humans could actually use fish insulin to manage their blood glucose if they had to).

The reason for this change was that researchers discovered they could patent-protect "proprietary" molecules that were similar to (but not exactly the same as) the hormone produced endogenously by virtually every primate under the sun -- except, perhaps those hapless individuals with type 1 diabetes and some patients with later-stage type 2 diabetes. Insulin became something of a cash-cow to the drug industry, and the margins have steadily increased, which stands in stark comparison to many oral diabetes drugs whose prices have plunged thanks to vibrant generic competition (today, there STILL is no generic insulin, see here, here and here for some more background on that anomaly).

Once insulin lispro was approved by the FDA in 1996, the floodgates were effectively opened. Although relatively few of these molecules have actually made it to market (as of today, just 5 have been approved: lispro, aspart, glulisine, glargine, and detemir), there has been no shortage of interest from big pharma and big biotech.

The Future of Insulin Therapy Includes Some Names You Might Not Recognize ... Yet!

Once the floodgates were opened, what was once a boring, not very dynamic industry saw millions in new investments from researchers and startups (as well as established players) eager to cash in on insulin's new-found status as a cash cow. Today, there are at least 3 late-stage insulin formulations (meaning they have all either completed Phase III clinical trials or are pretty close to and are planning to apply for FDA approvals in 2010), and several others aren't too far behind. Interestingly, none of the newest insulin innovations are from the dominant players in the business (Novo Nordisk, Sanofi Aventis or Eli Lilly & Company), but from startups.



Biodel's VIAject

On December 30, 2009, the first newcomer announced a significant milestone: Danbury, Connecticut-based Biodel, Inc.'s VIAject was submitted for FDA approval, and is widely expected by analysts to be approved without significant delay. Interestingly enough, VIAject isn't an insulin analogue at all, but humble, regular old insulin containing some already FDA-approved additives which prevent the molecule from forming hexamers which normally delay the insulin molecule's absorption into the bloodstream. Because of this, the company was able to apply using section 505(b)(2) of the Federal Food, Drug and Cosmetic Act which governs the review of a New Drug Application (NDA) for a modified form of a previously-approved product. Because of this, the company's VIAject is likely to encounter less scrutiny than a brand new drug filed under section 505(b)(1), which requires original clinical trial results to be submitted with the application. In addition, this saves the company significant money.

Biodel was not assured to be the first out of the gate (it still may not be, as the FDA is set to make a ruling on MannKind's Afrezza (which was formerly called Afresa, but the company reports that the FDA requested a name change to avoid confusion with another drug) by January 16, although the FDA can always delay, and some reports hint at a later date, the company suggested otherwise). Biodel encountered some thorny issues related to its Phase III trial results in India with the FDA, and the reason was because the blood test results were tainted by the hot India temperatures, and when those samples are excluded from the results, the FDA found the Indian trial results were comparable to those in the U.S. and Germany. I'll reference back to this in a minute.

Generex's Oral-Lyn and MannKind's Afrezza

In addition to Biodel, there is also Generex's Oral-Lyn, which I wrote about previously, and MannKind's Afrezza which I noted in the preceding paragraph. As I also noted, the FDA is set to make a ruling on Afrezza's approval by January 16, 2010 although the FDA can always delay, and although some reports are hinting at a later date, the company is suggesting otherwise. MannKind has even bought its own factory to make insulin, rather than using third-party contract manufacturers (as Eli Lilly is now doing for most vials of insulin, including Humalog sold in the U.S., and most of the others including the other startups, are using contract manufacturers rather than making insulin themselves). In March 2009, the company submitted a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) for it under section 505(b)(1) of the Federal Food Drug and Cosmetics Act, although the FDA is taking a much harder look at the impact on the lungs, so this product still hasn't yet received approval. But in January 2010, Bloomberg reported that company executives expect U.S. FDA to approve its version of inhaled insulin, which suggests the company has received indications from the FDA that it will ultimately be approved.

There are also at least 5 other earlier-stage "advanced" insulin and/or insulin analogues that are known about from established players in this industry including Novo Nordisk, Lilly, Sanofi Aventis just to name a few. Even Merck, now in a place to make the insulin itself after acquiring Schering-Plough (now one of the largest contract manufacturers of insulin on earth with its Organon N.V. unit based in the Netherlands), is reportedly shopping around for new insulins.

Halozyme Therapeutics

Another player is San Diego-based Halozyme Therapeutics, which I mentioned a while back. Like Biodel, Halozyme's work would use additives it says target the "extracellular matrix" (subcutaneous) to insulin and/or insulin analogues to speed them up. The company is also doing a number of research trials comparing their additives to regular insulin, as well as insulin lispro, aspart and glulisine. Although the company has done Phase 2 clinical trials it still needs to do much larger Phase 3 trials which require many more participants and therefore cost a LOT of money. In the company's 2009 Investor Day presentation, the company elaborated somewhat indicating that the company is targeting 2014 to be ready for prime-time, and it's likely that the company will partner with an existing insulin manufacturer (or possibly more than one) to commercialize its product.

Thermalin Diabetes

The original news story behind this posting was from December 14, 2009, when news broke of another potential player hoping to cash in on the proprietary insulin-like formulations, this one based in Cleveland, Ohio whose name you may see more of in the coming years: Thermalin Diabetes, Inc. A detailed press release indicated that Case Western Reserve University in Cleveland had granted an 18-month, exclusive option to the Cleveland, Ohio-based startup regarding an entire portfolio of insulin analogues.

Richard Berenson, executive chairman of Thermalin Diabetes Inc. says he has no fantasies about making a couple billion dollars from Thermalin over time. Presently, insulin is a $12 billion market which is growing quite quickly. That growth in spending on insulin is not due as much to growth in new patients taking insulin, but developments which have enabled manufacturers to develop more costly insulin-like molecules called insulin analogues and cover these inventions by patents, meaning patients today pay significantly more for insulin than they did 30 years ago on an inflation-adjusted basis. The Express Scripts annual Drug Trend Reports for the past several years (in particular, the 2007 report looked very closely at insulin spending) made it quite clear that spending increases in spending on insulin are not due to increased utilization, but higher prices in recent years.

While proponents of new insulins are very quick to make bold claims about how much these proprietary new insulin formulations have done to improve glycemic control, this claim is not backed by very solid statistics in clinical practice. Virtually every major meta-analysis (done in countries ranging from Australia, Germany and the UK to Canada) to compare insulin analogues to first-generation insulin varieties has raised questions about to whether these more costly so-called "innovations" have really been the big advancement in glycemic control their proponents seem to suggest, because the average glycosated hemoglobin (HbA1c) results have barely budged (they have come down slightly in recent years, but very slightly, and far less than the increase in spending would appear to justify) over the same period of time. That's not to dismiss them altogether: insulin analogues may very well make patients' lives easier, but healthcare providers cannot point to substantive quantitative reductions in average glucose levels alone as justification for the increased spending on these products.

Berenson however, puts things into perspective, suggesting that even if Thermalin captures a small slice of the market, it could be a very big deal for investors.

"... an exit in the regular drug-acquisition range of a couple hundred-million [dollars] is not crazy," he said. "And this is with a capital efficiency of investment of less than $10 million. So that's why I think there's interest in the angel community."

To date, Thermalin Diabetes has closed more than $275,000 in seed financing from individual investors. The company has also received a $254,000 Phase 1 Small Business Technology Transfer Grant from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (NIDDK). The latest Case Western grant is intended to support the development of one of Thermalin's portfolio of insulin analogues through large animal testing. When the company achieves the grant's specific aims, it will be eligible for significant additional grant funding to advance the compound to human clinical trials. This latest investment from Case Western is a sign that the underlying technology appears promising in terms of its likelihood to advance further. Of course, Case Western has hedged its bets a bit in that the company must reach certain milestones in order for it to exercise its option to obtain an exclusive license on therapies designed to help patients with diabetes.

Thermalin's name is derived (at least in part) from one of the primary product's key advantages: namely the molecule's ability to maintain its stability even without refrigeration at temperatures up to 40 degrees celsius (approximately 104 degrees fahrenheit). How is this accomplished?

A researcher at Case Western named Dr. Michael Weiss (David Edelman of Diabetes Daily did a podcast interview with Dr. Weiss in June 2008, see here for that very interesting interview) solved that problem by stretching the double-chained insulin molecule into to a single chain, Berenson said.

"Thermalin is a new kind of insulin," Weiss said. "Like insulin, it's injected or used in a pump. And like insulin, it causes the blood sugar to go down, and so it can be used to treat diabetes. But it's improved from insulin, in that, at high temperatures, it lasts for weeks and even months. It's almost indestructible at high temperatures, and so it affords enormous … lifestyle convenience to patients."

Is Heat-Resistant Insulin A Surefire Blockbuster?

I don't know. In 33 years of using insulin -- including when I wore an insulin pump, I NEVER had problems with heat breaking down my insulin and rendering it ineffective. But I also live in a place with a pretty moderate climate -- not the desert of Arizona or the subtropical climate of say, South Florida. Indeed, there is an entire group on the professional social network LinkedIn called "Change CVS/Caremark's Insulin Shipping Policy" pushing to change that pharmacy benefits manager's (PBM) current insulin shipping policy which violates the manufacturers' temperature guidelines. For most people, its a non-issue, but for residents of some states including Florida and Arizona, this is a big issue for patients ordering a 90-day supply of insulin by mail.

Biodel's Phase III Clinical Trial Problem in India Due to Heat

We need look no further than Biodel's Phase III human clinical trials earlier last year on its new rapid-acting insulin VIAject as a vivid example of how high temperatures nearly killed that company's Phase III clinical trial outcomes from one of 3 legs of its Phase III trial; fortunately those issues were resolved.

But VIAject's Phase III trials were undertaken in the United States, Germany and India. The results from the U.S. and Germany clearly demonstrated superiority (based on the narrow FDA evaluation criteria, which looks primarily at HbA1c reductions) while data from the pivotal Phase III clinical trial for patients with type 1 diabetes undertaken in India were found to be anomalous when compared to data from the U.S. and Germany for the same trial. When HbA1c data from patients in India were included in the analysis, change in HbA1c favored the Humulin R treatment group. Data from India was shown to be statistically different, which in the company's view made these data not comparable to the data collected in the U.S. and Germany. The analyses by independent clinical and regulatory experts at the FDA suggested there were specific factors that explain the results in India, specifically heat.

Among the causes noted in the briefing package, an identifiable subset of blood samples from patients in India was found to be compromised due to excessive heat exposure in transit to a central laboratory. When the compromised samples are removed from the efficacy analysis, non-inferiority in both the Type 1 and Type 2 trials is achieved, and the company is able to file a NDA (new drug application) for VIAject pretty much on schedule. Although the heat was not identified to have impacted the stability of the insulin molecules in either the control or test group, it was noteworthy enough to have compromised a sample of the blood samples while in transit to the labs, and that same heat could lead to a breakdown of the insulin molecule itself in a place where electric outages occur regularly and a significant portion of the population do not even have access to electricity.

Life of a Child Example Suggests Third-World May Be Opportunity for Thermalin -- If they Can Pay For It

One of the things that has angel investors more excited about this company is not necessarily the prospects for the product in the developed world, however, but in the developing world, where many patients do not even have electricity to keep their insulin refrigerated. It's a huge market and the incidence of diabetes is growing rapidly in many of these countries.

Thermalin might prove attractive (such as for patients with insulin pumps who occasionally find that they need to refill their reservoirs because higher temperatures can cause their insulin [or analogue] insulin to break down). But the bigger advantage for the developed world is that this insulin analogue, because it is a single-chained molecule, it is also extremely rapidly-acting -- supposedly much faster than today's first-generation insulin analogues such as insulin lispro or glulisine.

Preliminary evidence also suggests that Thermalin might also pose less risk of a cancer or weight-gain than first- or second-generation insulin analogues. Dr. Weiss also has developed long-acting insulins, which Thermalin could commercialize in the future.

The prospects in developing world are very attractive due to the sheer size of the market. Two years ago, I attended the New York premier of a documentary, which aired on cable television for the first time this year on World Diabetes Day on the Sundance channel. The reality for people living with type 1 diabetes in the developing world is quite unlike what anyone from the developed world has to deal with. In that film, one of the children with diabetes is a little girl from Nepal named Anupa, who has to walk six to eight hours to get down the mountain only to then catch a bus (which her family may not be able to afford), and then travel by bus for another few hours to get to the capital, Katamandu, where she can get insulin. Her house has no electricity, no telephone, and no refrigerator. She carefully puts her insulin into a container inside the house, and then buries the container in the dirt floor to try and keep it closer to the ideal temperature, hopefully preserving her insulin long enough until she can trek into Katamandu again for some more. You can catch the clip to that film here:



The one disconnect in my mind, is that patients in the developing world cannot typically afford to pay premium prices for drugs, and it's less clear that heat-resistant insulin is a big enough advantage to justify higher prices to the developed world, but its speed should help. Whether that is sufficient to make it a blockbuster that enables the Western world to subsidize prices for the developing world remains a big question. The rapid-acting insulin market is becoming a crowded space, as this posting suggests given the sheer number of potential competitors. But that isn't the only thing Thermalin has in its business plan.

Arsenal of More Than 100 Analogues

Thermalin is working on more than just faster,heat-resistant insulin molecules. The company is also reportedly testing a portfolio of more than 100 different insulin analogues discovered by Dr. Michael Weiss at Case Western Reserve University School of Medicine, and Thermalin Diabetes believes the company is poised to address a number of significant unmet needs in many segments of the $12 billion, suddenly rapidly-growing insulin market. Among the other concepts being pursued are a longer-lasting analogue than current products. Of course, the company isn't alone. The already well-established competition is also pursuing similar products, but Thermalin believes they have a broader portfolio. One concept the company is also pursuing is another long-acting analogue, but unlike Sanofi Aventis' Lantus product, Thermalin believes their does not have mitogenic tendencies, for which there are some concerns may increase cancerous growths with long-term usage. Clearly, angel investors think this company has a lot of potential.

SmartCells' Smart Insulin

Of course, I haven't even mentioned SmartCells, Inc., a Beverly, Massachusetts-based startup that is developing a method to encapsulate human insulin nanoparticles in a polymer that would actually "detect" a diabetic's glucose levels automatically, and therefore release only the appropriate amounts of insulin at precisely the right time to keep blood sugar levels steady. (Catch my interview with the company CEO Todd Zion here) Of course, there was also the $1 million grant from JDRF announced last year which will support testing the safety and efficacy of Smart Insulin in preclinical type 1 diabetes trials. This partnership is intended to accelerate the product's development and reduce the time needed to progress to human testing. The grant is part of JDRF's innovative Industry Discovery and Development Partnership Program (IDDP), which supports companies developing drugs, treatments, and technologies to address type 1 diabetes and its complications. SmartCells still has to accomplish a number of milestones, since it hasn't yet even gone to Phase I human clinical trials, but this product could potentially render many of the other insulin analogues and insulins with special additives to make them even faster completely irrelvant, so it deserves mention here. The company has had no trouble in attracting venture capital, and in addition to the JDRF grant, the company has also secured financing from the U.S. National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), so the prospects look quite promising, although SmartCells still has a few years before even approaching commercialization, but the prospects look positive.

What's Next?!

This year, we are set to see a number of new insulins from a number of different companies. The success of these companies will depend not only on the quality of the products, but also the companies' ability to penetrate the pharmacy benefits managers (PBMs) such as Medco Health Solutions, CVS/Caremark and Express Scripts, who not only are among the biggest buyers if insulin in the U.S., but they also pay for over 80% of all prescriptions filled in the U.S. today, and could be even larger if Congress passes some type of healthcare reform and adds another 47 million to the system. But having more competition in the insulin market can be nothing but a benefit for people with diabetes!