The $100,000 Diabetes Cure

At a scheduled chat held on Twitter by the Diabetes Social Media Advocacy (DSMA) folks held on Weds., November 3, 2010 (see HERE), one of the topics was related to pharmaceutical companies and social media. There is a great deal of well-deserved skepticism about pharma's über-lusty interest in largely patient-controlled social media space, because right now, they do not engage in much two-way conversation which is at the very heart of what social media is all about (see HERE for more). Presently, pharma is trying to use social media as an advertising channel which does not accept comments, to talk AT patients, not WITH them. Needless to say, this type of communication really does not fly in social media, so most pharma social media efforts have bombed royally. Many claim they do not accept comments to protect adverse reporting which must be directed to the FDA, but many patients suspect that's a cop out because they want the FDA to issue formal guidance that will absolve the industry of any legal liability for what is really little more than common-sense behavior in the social media space. Anyway, in the chat, there were many comments on the theme of how pharma isn't interested in cures, just in selling more product. I commented that I felt the profits in a cure would blow away those earned on selling the next-best-treatment which has pretty much been the diabetes model since the discovery of insulin in 1921.

Conventional wisdom among people with diabetes (PWDs) is that because diabetes is such a huge cash cow for the drug, biotech and medical device companies that this industry (some call it "Dia-Business", the "Diabetes Industry" ... Diabetic Investor David Kliff once even referred to it as the "Diabetes Industrial Complex") that there's no chance of a cure coming from any of these companies who are the biggest financial beneficiaries of keeping patients chronically ill, but never cured. Many just lump all of it together under the collective umbrella of "Big Pharma"), but the idea is that because the industry makes so much money from keeping people with diabetes just well enough to survive, that they are knowingly not pursuing curative therapies. I don't believe this to be true. But before I delve into that, perhaps I should share some relevant historical (that's relative, I'll only go back earlier in the last decade) perspective.

Would You Cure A Profitable Disease?

Back in October 2003, a very popular article by author Dara Mayers entitled "Would You Cure A Profitable Disease?" was published in Diabetes Health magazine (the magazine was still known as "Diabetes Interview" back in those days) explored this topic. The author, Ms. Mayers, tried to be objective, but still suggested that profits were a big dis-incentive to the diabetes industry, thus discouraging at least this segment from actually seeking a cure. She wrote: "Nonetheless, cures for type 1 and type 2 do not seem to be coming from the pharmaceutical industry."

However, that logic is a tad hypocritical (a bit like the pot calling the kettle black), as neither federally-funded researchers, nor researchers funded by non-profits at universities and/or other research centers have managed to find a cure yet, so pharma is in exactly the same boat.

Prospects for drug and biotech companies look very rosy indeed because of demographic growth in the elderly population (which account for about 33% of all drug industry sales anyway, but is expected to grow rapidly as the Baby Boom heads into retirement and their senior years) as well as huge potential for new drugs stemming from discoveries in genomics and biotechnology. There is little doubt that manufacturers have aggressively raised prices to increase their margins, although there is little solid evidence of actual financial benefits to healthcare providers who are footing the bill for their "new and improved" products. That's exactly what has happened with former commody products like insulin. Whether its good or bad is irrelevant; businesses have logically chosen to increase their margins because they have a fiduciary responsibility to do so, and if they can get away with it, why not?

But increasing margins on old products can only work in a non-competitive environment. Pharmaceuticals is already one of the widest-margin U.S. industries, and as long as these companies enjoy monopolies, that can occur. Patent expiration has historically slashed the prices on widely-used medicines.

Now, thanks to The Patient Protection and Affordable Care Act (the so-called healthcare reform legislation sometimes derided by opposition as "Obamacare") which was signed into law by President Obama on March 23, 2010 contains a section called the "Biologics Price Competition and Innovation Act of 2009" (a.k.a. BPCI Act), that's pretty certain to change. That legislation amends the Public Health Service Act, and the Federal Food Drug and Cosmetics Act to create an abbreviated approval pathway for biologic products that are demonstrated to be "highly similar" (biosimilar) to, or "interchangeable" with an FDA-approved biological product. Whether any biologics can EVER be considered "interchangable" remains an unclear, although the FDA has in the past hinted that would not be the case (see HERE).

Regardless, since this is now law, it means the FDA is now obliged by U.S. law to provide guidance for follow-on biopharmaceuticals (generics) inclduing insulin, which has potential to reduce costs significantly, so the era of 10% annual price increases may soon come to an end, especially since the patents on most pricey insulin analogues are due to expire in the next few years (see HERE).

Is Diabetes Too Profitable to Cure?

Aside from fatter profit margins, in the grand scheme of things, when one compares the margins on chronic medicines to those of specialty medicines (think of things like cancer treatments, which are given quite rarely to a relatively small number of patients), the margins are comparatively low on chronic medicines, but much higher on specialty medications like cancer treatments. Thus, if one could transform a disease like diabetes from being a chronic disease to a curable disease, it's safe to presume that a curative medicine(s) would be among the world's biggest blockbusters, making today's blockbusters like Pfizer's Lipitor look pretty miniscule by comparison.

In fact, a diabetes cure (or cures) might possibly be some of the biggest blockbusters the drug and/or biotech industry has ever witnessed. And there is a rapidly growing number of companies whose very business models do not exactly focus on keeping patients chronically ill, but on eradicating their diseases. They haven't succeeded ... yet, but these companies see enormous profits in bringing cures to market.

Finally, the drug industry doesn't hold secret, backroom meetings about how to keep would-be competitors out of their business; they are fiercely competitive with each other, and there are genuine risks that Federal antitrust regulators would step in if they acted in a truly anticompetitive manner, which does serve as a natural control mechanism. It also seems unlikely that any drug company would want to tip off their competitors what they plan or are researching unless it's pretty far along in development and already in the public domain.

To cure type 1 diabetes, the consensus among researchers is that two things need to happen: 1) first, the autoimmune response that caused the disease to occur in the first place must be fixed, creating a state of "self-tolerance" to islets/pancreatic beta cells and 2) second, the functionality of the destroyed islets/pancreatic beta cells must either be replaced with new islets, or restored via regeneration.

There are a variety of companies, many of which are startups, pursuing various parts of this equation. For example, on islet replacement, there are companies who are pursuing xenotransplantation by encapsulating islets from another species (such as pigs, whose insulin is more similar to regular human insulin than some insulin analogues like Novolog, Apidra, Lantus or Levemir based on amino acids and molecular weight). Listed below are a number of companies operating in various spaces in the cure-related therapies (by category).

Islet Replacement Therapies:

Living Cell Technologies (LCT), a publicly-held firm based in New Zealand but listed on the Sydney, Australia stock-exchange.

In addition, others are trying a slightly different route, developing what they are calling Islet Sheet Technologies. Several companies which are not publicly-held firms are pursuing this technology. While it does not appear they are quite as far along as LCT, fellow d-blogger Elizabeth Snouffer did a great piece back in April 2010 about Islet Sheet Technology. Visit her post HERE for more details. Among the firms she writes about are Scott King's (NOT the former editor of Diabetes Health magazine, the OTHER Scott King heading up a firm known as Cerco Medical).

Both involve masking islets to protect the transplanted cells from immune response. The long-term viability is still being researched, but could potentially be replaced without major surgery.

Autoimmunity Treatments:

MacroGenics, Inc. is a publicly-held company based in Rockville, Maryland whose partnership with Eli Lilly & Company, Inc.'s failed to meet it's Phase III trial objectives in October 2010 (see HERE)

Tolerx, Inc. is another firm based in Cambridge, Massachusetts that has a similar, but not identical approach to addressing the autoimmune response that causes type 1 diabetes. Tolerx claims to have a slightly different approach, and was paired with GlaxoSmithKline plc thanks to the JDRF. The company's Phase III human clinical trials are reportedly complete, although the trial results have not yet been released to the public. (Note: in March 2011, Tolerx and GSK ANNOUNCED that otelixizumab had failed to meet its primary efficacy endpoint, although full details will be announced at the American Diabetes Association's Scientific Sessions taking place in June 2011).

Another privately-held firm, DiaKine Therapeutics, Inc. has several products for diabetes in it's development pipeline. On the autoimmunity front is a product known as lisofylline (LSF), which the company describes as a synthetic small molecule with "novel" anti-inflammatory properties that may work in stopping the autoimmune response that causes type 1 diabetes. This is presently in Phase II human clinical trials according to the U.S. Government's ClinicalTrials.gov site, so it has a longer development timeframe than Tolerx's product.

In March 2009, the JDRF announced a partnership on another autoimmunity treatment from Bayhill Therapeutics, Inc. and what was then known as Genentech (now part of Roche). Known by the unglamorous name "BHT-3021" which differs slightly in that it works as an antigen-specific treatment for the insulin molecule itself. However, details on progress have been few and far between on this treatment.

July 2011 Update: Following disappointing results for both the Macrogenics and Tolerx treatments (though the Macrogenics treatment will go back to trials with funding from the National Institutes of Health, suggesting that there may be some evidence that this treatment was not a total failure), in June and July 2011, there were two new autoimmunity partnership deals announced, the first via the JDRF, the second via the Iacocca Foundation. The first one was with a Watertown, Massachusetts-based biotech company named Selecta Biosciences, Inc. for the development of an type 1 diabetes autoimmunity vaccine technology. The other was ANNOUNCED on July 19, 2011 where The Iacocca Family Foundation boosted investment in a Seattle-based biotech firm known as Kineta, Inc. which also has an autoimmunity treatment known by the acronym "ShK-186" in development which is being developed not only for type 1 diabetes, but several other autoimmune diseases as well. For more detail, see the press release HERE.

Islet Regeneration Therapies:

Finally, the companies now pursuing islet regenerative therapies (once dismissed as wishful thinking, but since proven to be not only realistic, but possibly a better alternative to transplantation) are the following different firms:

Transition Therapeutics, Inc., a Toronto (Ontario), Canada-based biotech startup, is a privately-held firm funded by venture capitalists.

Exsulin Corporation based in Burnsville, Minnestota is another privately-held firm that is majority owned by a limited liability corporation (LLC) known as Kinexum, LLC which is based in Harpers Ferry, West Virgina (in the Washington, DC exurbs).

CureDM, Inc., based in Wilmington, Delaware developing a product they call Pancreate™ (proisletide acetate). In April 2010, the firm signed a commercialization agreement with Franco-German global pharmaceutical giant Sanofi Aventis S.A. best known as the maker of Lantus and Apidra insulin analogues.

So Where Are the Cures?

All of this begs the question: where are the cures, then?

This year, one of my favorite medical writers, Sharon Begley, who writes for Newsweek magazine, but previously wrote for such well-known newspapers as The Washington Post and The Wall Street Journal, looked directly at this question.

In the May 15, 2010 issue of Newsweek, the cover story was hers and entitled, appropriately enough "Desperately Seeking Cures", probing into why the road from promising scientific breakthroughs to real-world remedies has become all but a dead-end (those are her words, not mine!).

In fact, she even cited stats from the FDA, stating that from 1996 to 1999, the U.S. Food and Drug Administration approved 157 new drugs. In the comparable period a decade later—that is, from 2006 to 2009—the agency approved 74. Not among them were any cures, or even meaningfully effective treatments, for Alzheimer's disease, lung or pancreatic cancer, Parkinson's disease, Huntington's disease, diabetes or a host of other afflictions that destroy lives.

Her story found several culprits, most notable was the fact that the nation's biomedical funding and training system are set up to do one thing, and she notes that they do that superlatively: make discoveries. Back in 2008, Ms. Begley wrote another story with a similar title, although less in-depth "Where Are the Cures?".

In that article, she wrote "Discoveries is what scientists dream of, that is what gets them published in leading journals (the coin of the realm in academia) and that is what gets them grants from the National Institutes of Health. She added that the less glamorous work of testing potential treatments in actual patients -- the grunt work, as she referred to it, that turns a breakthrough into something that can actually be tried in patients is seldom on their academic agenda. That responsibility falls elsewhere, and helps explain why so much money is spent yet few cures ever seem to emerge from the billions we spend.

Patent Problems

Another factor: the nation's patent system, which tends to reject applications that are already published in scientific and medical journals that helps researchers advance their own careers, and without patent protection, hardly any drug or biotech company would be interested.

Then there is a not-so-little matter of licensing discoveries from NIH-funded research; sometimes startup firms see potential in these discoveries, but cannot afford big upfront payments that a big drug company like Pfizer or Lilly could afford, and the NIH has been asking as if all companies had Pfizer's pockets.

"NIH has no skin in the game, so they have no inducement to work with a company" to get a discovery from the lab to patients, says Eric Gulve, president of BioGenerator, a nonprofit in St. Louis that advises and provides seed money for biotech startups. "There isn't a sense of urgency." A top lab chief at the NIH laments that when scientists like himself push the licensing office to move a discovery toward commercialization, "it's just another piece of paper to them." Without the license, the startup struggles to stay alive.

The Role of Nonprofits

Of course, Ms. Begley did mention how an increasing numbers of nonprofit organizations are trying to fund the next steps in "translational research". Among them is a big one in type 1 diabetes research: the Juvenile Diabetes Research Foundation (JDRF). Increasingly, nonprofits like JDRF are stepping in to fund the research needed to take promising concepts from discovery to commercialization, filling a badly-needed void.

In fact, Ms. Begley wrote an entire article on that very subject back when she was still writing for The Wall Street Journal back in 2007 entitled "Why Nonprofits Fund For-Profit Companies Doing Drug Research" in which the JDRF along with others like the Michael J. Fox Foundation for Parkinson's Research, and the Myelin Repair Foundation (for multiple sclerosis) who have all veered away from the NIH model of "here's some money; go discover something."

Instead, these organizations are managing and directing scientists more closely, requiring them to share data before it is published, cooperate, and do the nonsexy development work required after a discovery is made. But it isn't always popular to do so. In the 2007 Wall Street Journal article very clearly acknowledged that:

"Charities realize that writing checks to for-profits might not be what their donors had in mind. 'We debated whether it was right for our money to go to a company that might make a profit,' says JDRF board member Michael White. 'We're not unconcerned about that. But we've invested so much in discovery, what we need now is to take these things to market. We're taking on the role of 'venture philanthropists.'"

And not all of these investments will even pay off; for a very relavant example, as already noted, on October 20, 2010, MacroGenics, Inc. and it's big pharma partner, Eli Lilly and Company announced that a potential autoimmunity treatment called teplizumab, whose Phase III human clinical trial called Protégé, did NOT meet the primary efficacy endpoint of the study, which was a composite of a patient's total daily insulin usage and HbA1c level at 12 months (see HERE for more detail). A similar treatment from a startup called Tolerx and it's big pharma partner (thanks to the JDRF's involvement) GlaxoSmithKline remains upbeat about their own treatment, called otelixizumab, is wrapping up analysis of it's own Phase III human clinical trial called DEFEND.

One key unresolved pitfall Sharon Begley wrote about: "blockbuster-itis" in the drug industry, but it appears that experience may have taught non-profits how to prevent pharma "blockbuster-itis" from killing the goose that lays the golden cure egg.

Egg on the JDRF's Face?

Occasionally, the big pharma company will do something that really p!$$es their nonprofit "partner" off in their relentless drive for fat profits. In one JDRF program for islet regeneration efforts, the Toronto-based biotech startup known as Transition Therapeutics, which JDRF partnered with Eli Lilly & Company, did see fairly solid evidence of efficacy of it's gastrin-based therapies in patients with both type 1 diabetes as well as type 2 diabetes.

But then big-pharma partner Eli Lilly & Company decided to push clinical trials towards type 2 diabetes and cancelling the type 1 trials, theorizing that it could potentially sell the product to far more type 2's than patients with type 1, thus increasing the company's bottom line faster. The company likely assumed if is eventually approved for that indication, then they could then move to "extend" the drug's label approval to type 1 patients, albeit that could take many years more, which was not quite what the JDRF had in mind when pairing these organizations together. In fact, JDRF had invested fundraiser dollars in the program only to see clinical trials in type 1 patients cancelled by a greedy pharma partner.

Social Media Pushes for Greater Transparency

Of course, things were easier before patient-bloggers hit the scene. For example, last autumn (2009), fellow diabetes blogger Joshua Levy and I speculated on what Lilly's move meant as trial results for Transition Therapeutics treatment known as TT-223 and the fact that they pulled the plug on the type 1 trial. I actually wrote about it in my mid-year progress report. Bill Ahearn is the Vice President, Strategic Communications for JDRF International went so far as to contact Joshua Levy in the comments on his blog about the Transition Therapeutics approach, while I received an e-mail from another JDRF staffer with very similar comments. Had this occurred a decade ago, the organization might have controlled the dialog either by ignoring it and allowing it to pass, or with carefully-scripted press releases. But it became a public relations disaster for the organization, and patient bloggers effectively forced the JDRF to confront it head-on, as these things had gone viral, hence the response.

To be sure, there is no prior, proven pathway for "venture philanthropists" as JDRF called themselves (in Ms. Begley's 2007 Wall Street Journal article), so one can call this a training exercise for JDRF's Industry Discovery and Development Partnerships (IDDP) program. No doubt, the JDRF was embarrassed by Lilly's move and had to do damage control as a result. But this move demonstrates the power that the social media space (including patient bloggers) has had on even nonprofit organizations. Although the investment was reportedly relatively small and Lilly's interest in the treatment (especially now that the company faces a "patent cliff") could bring it to market, where it could then be researched "off-label" in the type 1 universe, thereby saving Lilly millions. If it does not gain approval for type 2 diabetes, that does not necessarily mean the drug would be dead, either (although Lilly might loose interest by then) forcing the JDRF to find a new pharmaceutical partner.

One thing is certain: JDRF probably learned it's lesson from this experience. In recent IDDP announcements, virtually all require the partners to meet key milestones before the organization pays any more. This may prevent another of the TT-223 fiasco from occurring on the organization's dime in the future.

Be Prepared to Mortgage Your House for a Cure

In 2008, diabetes writer David Mendosa INTERVIEWED Zoe Heinenman Myers, the vice president of marketing for the company now known as Exsulin (it was known as Kinexum Metabolics at that time), and then at length with Lisa Jansa, the company's new CEO about where this interesting treatment stood. David asked numerous questions that would be of interest to patients with diabetes. But the element that really stood out in my mind was the following quote, which was taken from PAGE 3 of the story:

"Something as big as INGAP won't come cheap. 'We don't anticipate that it will exceed $20,000 for a single course of treatment,' Lisa [Jansa, CEO of Exsulin] told me. Later, however, she is confident that as they scale up production they will be able to bring the cost down."

Exsulin also told David Mendosa that the company was not certain if periodic re-treatments might be required, something that current clinical trials may answer. Perhaps with an effective autoimmunity treatment, that need would be eliminated. Right now, we simply do not know the answers to these questions. This is why the term "remission" has become favored by the medical profession over using the term "cure". As former New York Yankees player and manager Yogi Berra once famously said "It ain't over till it's over." But regenerating islets solves only half the type 1 diabetes puzzle; the autoimmunity issue must also be solved, so its possible that the cost of a cure could easily be in the $100,000 range, including any periodically necessary re-treatments for either (or both) components.

All of this makes me wonder: will we see an asset-backed securities market emerge for diabetes cures (maybe as "Cure-Backed Securities?"), and how much will for-profit insurance companies be willing to pay for? What if that market works anything like Fannie Mae and Freddie Mac?

It seems clear that the margins on any curative therapies are destined to become blockbusters, which means the drug industry's own desire for billion-dollar products may push even more of them into the high-margin cure therapies, rather simply more than new-and-improved versions of lower-margin century-old products, and follow-on biologics will undoubtedly help. We have already seen Lilly, Sanofi Aventis and others partner with startups in curative therapies. It appears that non-profits like the JDRF's experience with Lilly and Transition Therapeutics means the days of writing checks without milestones being met required of pharma partners are permanently over, and not a moment too soon!

Key Challenges Ahead For JDRF's New CEO

On May 13, 2010, the Juvenile Diabetes Research Foundation (JDRF) issued a press release that it's CEO, the guy who formerly ran Novocell (a company that hopes to cash in on widespread islet transplantation for type 1 diabetes -- note that the company recently changed it's name to ViaCyte) had resigned, after just a little over 1 year on the job -- in fact, he didn't even stick around long enough to give the organization's annual "State of the Foundation" address! He claimed he was leaving for personal reasons, and would be returning to be with his family in Southern California (the JDRF is based in New York, although the CEO before him lived in St. Louis and split his time between his home and JDRF headquarters New York).

I could understand it better if this wasn't becoming a recurrent pattern for JDRF's CEOs in recent years. But for some reason, the JDRF has not been able to hold onto a CEO lately. What makes this even more puzzling is the fact that the job market has been tight for many top executives in many fields, including the nonprofit sector. According to The Wall Street Journal "No one knows how many out-of-work CEOs are looking for corner office suites, but recruiters say their numbers are growing. Fewer big businesses are switching bosses these days and mergers and bankruptcies have further reduced their job prospects. Only 48 companies in the S&P 500 index changed leaders last year, the lowest level since recruiters Spencer Stuart began tracking it in 2004."

Over the last few years, there has been a parade of new CEO's in the top slot at JDRF, each leaving sooner than the predecessor. In each case, the CEO stepped down rather unexpectedly after a short time on the job. JDRF Board Members should probably be asking WHY is this happening, and then what is the organization's leadership doing to prevent it from happening again so quickly?

I believe the JDRF needs solid leadership, but frankly, I think it's been a huge mistake to try recruiting leaders from the "diabetes industry" because of the very reasons we saw with Alan Lewis. Private industry can offer executives more money, and it's very tempting for them to take their leadership skills elsewhere and/or to cash out altogether. By looking to diabusiness for candidates, the organization likely hopes to have someone who has some understanding of the disease so their learning curve won't be so steep. That's fair enough, but isn't the lure of big bucks from a for-profit company a bit too tough for a nonprofit to compete with?

In fact, during 2009, we know that CEO Alan Lewis took no salary from the organization, although it's worth mentioning that he volunteered to do so. But going back to previous CEOs, the salary in 2008 for Arnold Donald was $531,040 plus another $82,138 for contributions to employee benefits plans and/or deferred compensation plans. Grand total: $613,178. When it comes to CEO and other top executives' pay, that's quite low on the scale. Most CEOs have unexercised options in the stock of the companies they lead that's worth more than 10 times that amount (or more). So we know that the pay as CEO of JDRF isn't extraordinary. As a matter of fact, the organization's Senior Vice President of Scientific Affairs, Robert Goldstein, and Richard Insel, JDRF's Chief Scientific Officer -- according to the organization's annual IRS filings -- are the highest paid employees, not the CEO. But the demands and hours required for the CEO of the JDRF are typically far less than they are for CEO of almost any for-profit company, so it's a pretty cushy job with a big-shot title. The top job is usually awarded to someone who has already lead a company or organization, but has no other responsibilities and is now quite financially comfortable and doesn't really need a salary. But that also means that they could easily be distracted or lured away, as was the case with Mr. Lewis.

JDRF's Latest CEO Search Ended More Quickly Than The Last

In June, the JDRF announced that it had hired yet another new CEO (this one to replace Alan Lewis). The organization filled this position much, much more quickly than it did when Peter van Etten stepped down (it took the organization well over a year to fill the vacancy at that time), but given the recent history of CEOs stepping down, I think the JDRF absolutely must have succession plans outlined and in place so the organization isn't left without clear leadership in the event that the top exec leaves again. I should remind my readers that the newest CEO is the third CEO the organization has had since Peter van Etten retired from the position at the end of 2005 after serving 6 years in the position. In other words, the last CEO was the organization's third new leader in less than four years. Mr. Lewis also had the decidedly unflattering description of having had the shortest tenure as JDRF's CEO since the CEO position was first created in the oranization.

JDRF's Board of Directors named fellow-JDRF Board Member Jeffrey Brewer as CEO, who is perhaps best known for a string of internet startups which he then sold and made a personal fortune from. Mr. Brewer also has a personal connection with type 1 diabetes, as his young son Sean was diagnosed the disease since 2002, but he's also a relative newcomer (although not as new as several of the recent lineup of JDRF CEO's have been), having quickly risen through the ranks of various leadership posts in the largely-volunteer run organization.

The naming of Mr. Brewer as CEO, as might be predicted, did set off an immediate question given his role in pushing so the organization so hard to fund the so-called "artificial pancreas" project, which many long-time fundraisers (including a few of the organization's founders) and supporters view as a significant deviation from the organization's core mission to find a CURE for type 1 diabetes and put itself out of business. Some have called it a costly boondoggle that will mainly enrich the drug and medical device companies, who will charge healthcare providers handsomely for the technology that the JDRF has largely shepherded through the costly development cycle. This is no small issue, some 47 million Americans lack any sort of healthcare coverage at all (including an estimated 3 million Americans with diabetes) and they will most likely not have any sort of coverage until major portions of the U.S. Healthcare legislation become effective in 2014. Even if it gains FDA approval, the costly devices will very likely to remain inaccessible to many patients (even in spite of JDRF's support) largely because of the cost, thanks to durable medical equipment caps that exist on many plans. I recently communicated with a parent who had 2 children with type 1 diabetes, and she had to stagger the timing when each child could get a new insulin pump over a period of 2 years thanks to this very issue. She also felt that JDRF should not really have to fund studies to justify insurance coverage for the devices when for-profit companies stood to make millions on the devices. Her feeling was that the organization's resources would be better spent on autoimmunity treatments that would help with a so-called "biological" cure given the issues we collectively face with uncontrollably rising healthcare costs.

Donor-Centric Organizations Require Complete Financial Transparency; The JDRF Isn't There -- Yet!

The JDRF has provided few concrete details on the actual budget for it's Industry Discovery & Development Partnership (IDDP) program, which unless I'm mistaken, is how the "Artificial Pancreas" project is being funded. While JDRF funds certain elements of these programs, private industry should ideally be picking up part of the cost, but without financial disclosure, many fundraisers/donors feel as if they're deliberately being left in the dark about an important program being sponsored by the organization.

Section 6104 of the U.S. Internal Revenue Service code requires that a nonprofit organization to make its Form 1023 (or 1024 if applicable), 990, and 990T [501(c)(3)s only] available for public inspection, and JDRF claims this information is posted on it's website, but I have always found it far easier to locate these tax documents via The Foundation Center. The Foundation Center is a national nonprofit service organization recognized as the nation's leading authority on organized philanthropy, which maintains one of the most comprehensive databases of U.S. tax returns for U.S. nonprofit organizations anywhere. Using this, one need not search countless pages looking for a needle in a haystack; just enter the name or tax ID code (which can be found on the tax filing itself) and voila, a listing comes up without any other stuff. You can access this extensive database here or by using this widget (Note: the widget requires JavaScript to be installed on your computer in order to function):



(Incidentally, you can look up any other nonprofit here, too, including the ADA, the DRI, the Diabetes Hands Foundation and many others on this site.) But donors are left with few details on just how much the organization has allocated to the IDDP project, and some long-time fundraisers feel entitled to know. Former JDRF CEO Arnold Donald pushed to make the organization much more "donor-centric" (see here for details) but that requires an ongoing organizational commitment to succeed.

Not too long ago, a nonprofit survey asked "What does 'nonprofit transparency' mean to you?" and the responses generally fell into two categories: (1) financial accountability and (2) openness about missions and programs. Given how broadly-defined the JDRF's IDDP program really is, many donors/fundraisers want to know more about exactly how much is actually being spent on the various programs here to determine if it's a real deviation from the organization's stated mission or not. Unfortunately, the public filings have answered few (if any) of their questions.

Mr. Brewer has had the great fortune to be able to dedicate personal time that many parents of children with diabetes simply do not have the luxury of doing, which means he's out-of-touch with many donors'/fundraisers' needs. In fact, he's had no relevant personal experience in the kinds of day-to-day challenges many parents of kids with diabetes face. Today, many parents of kids with diabetes struggle with complicated insurance issues that grow ever more costly by the year, routine changing of drug formularies that virtually force the switching of preferred insulin brands, and routine denial-of-coverage for such things as insulin pumps not to mention long, drawn-out appeals processes. Many cannot even get such basics as test strips covered, and will likely never be able to get coverage for a costly, closed-loop "artificial pancreas" that Mr. Brewer has been such a big proponent of. We can only hope these not-so-small details are not lost on him. That's why I believe former CEO Arnold Donald's goal of making the JDRF more donor-centric was such a critical strategy, and why it will likely be even more critical moving forward.

Safety In The Organization's Highly Decentralized Structure

First and foremost, the JDRF is now, and always has been a highly decentralized organization. That's always been one of the organization's key strengths. While highly autocratic CEOs have found that challenging to adapt to, it also ensures the organization's creativity and resilience to setbacks like the loss of a leader. Have a look at this video presentation from the 2010 State of the Foundation address to JDRF board members:



Now the key speaker, Leo Mullin, sounds remarkably confident in JDRF's ability to recover from a fundraising perspective, as if the broader economy was a minor inconvenience. So far, JDRF's volunteers and fundraisers have done remarkable work to ensure the foundation has been able to keep funding its research commitments. In that regard, the organization has done better than many peers, but no one should delude themselves into thinking the organization is somehow immune to challenges in the nonprofit fundraising environment. Given that the prevailing economic consensus is generally that this will be a largely jobless economic recovery and even then, we shouldn't expect much of a turnaround until 2012. Clearly, the new CEO has his work cut out for him.

Can Changes At The Top Impact Continuity In JDRF's Strategy?

It's safe to say that during former CEO Alan Lewis' highly abridged tenure (you may catch an interview with Mr. Lewis here), he most likely was NOT able to make any meaningful changes in direction or influence the organization in any material way, shape or form. To his predecessor's credit, Arnold Donald, who stayed in the job only slightly longer, about 2-3 years if memory serves me correctly, did slightly better in his efforts to help reshape the culture of the organization to be more of a donor-centric organization. But that type of effort requires consistency and routine, not the annual CEO parade that has become such a regular occurence at the organization following Mr. van Etten's departure. Change in the corner office may actually have had the opposite effect -- alienating faithful fundraisers such as myself. Last year, although I attended the Manhattan walk with a group, I raised just $50 (a record low for me), which was at least $4,500 less than I had raised in each of the 6 previous walks. Although I have a very personal relationship with type 1 diabetes, having lived with this disease for 34 years (effective July 24, 2010), in recent years, the JDRF and in particular the New York City chapter, has done much to alienate me as an adult with type 1 diabetes.

That's a separate conversation about the clique-y and snobbish nature of the New York City chapter (which includes the money raised by outer-borough parents, even though those individuals are scarcely even represented in any boards or review panels) of wealthy parents of kids with type 1 (most send their kids to private schools, unlike the experience of many suburban parents), and the presumption that any adult affiliated with the chapter simply MUST be a parent of a child with type 1 diabetes was downright insulting. In the New York City chapter, my experience has been mostly negative, more closely resembling Bravo TV's "The Real Housewives of New York City" than it does an organization with a truly charitable mission. But I am optimistic that startup organizations like Act1Diabetes can wrestle some more meaningful representation within the JDRF New York City chapter than the current leadership does because I believe it's badly needed, at least in NYC. But my point is that donors must be central to the organization's ongoing success, and frankly, that varies considerably from one chapter to to the next. More uniformity in how donors are recognized and addressed would benefit the organization as a whole. Let's hope he keeps the "donor-centric" theme alive and well, because failure to do so could adversely impact fundraising for the organization!

The issue of who diabetes organizations represent is a hot topic nationwide these days, and it even came up in the recent Roche Social Media Summit I attended in Orlando a few weeks ago. The fact is that kids with diabetes eventually do grow up, and how well those connections established as children with diabetes survive is playing an increasingly important role in the ongoing sustainability of many charitable organizations. Other JDRF chapters are leading JDRF into this territory far better than the NYC chapter has, fortunately, and I think that's been a benefit to the organization. Let's hope he keeps the "donor-centric" theme started by former CEO Arnold Donald alive! Just how prepared Mr. Brewer is to address all of these issues is unclear, but I think it's apparent that he has his work cut out for him.

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!

2009 Mid-Year Progress Report: Part 1

At the end of 2008, I didn't do my annual review of the diabetes cure-advancement and treatment landscape (you can catch my 2007 summary, my 2006 summary and my 2005 summary), a tradition I began in early 2006 and continued for several years afterwords where I highlight some of the diabetes-related developments (from my perspective, naturally) during the preceding year and share my thoughts and insight into the coming year. Most of my readers know that my observations are far from casual, they are based on a thorough review of these trends for the past year (often more) and have a solid basis to substantiate them. Since we're now more than 3/4 into 2009, there's little point in trying to recap last year, as we'll be ready for a recap of 2009 in just a few months! But I can provide some perspective on where things stand right now, and perhaps frame where they're likely to be going in the foreseeable future.

Let me begin by saying that I had a very good reason for not writing a summary of 2008. I was in the process of moving into a new place. But United Moving didn't do the work for me, I did the move mostly by myself, and mostly when I had free time (meaning on the weekends and evenings). Of course, I still had a job to occupy my time during normal business hours. That resulted in blogging taking a back seat. Although I've since resumed, I haven't posted quite as often as I did, say, in 2005 or 2006 because the Diabetes OC community has grown so much since then that having thoughtful and unique content becomes more important today. Not all of my posts are the cheery, uplifting ones that some readers are necessarily seeking (that's never really been my focus or specialty ... there are plenty of others to fill that need, however), but from my perspective, I DO believe there is good news on cure-related progress to share. The challenge: where do I begin?

Some Good Sources for Research Progress Updates

First, let me share some places you might wish to be aware of related to progress reports. Ironically, I discovered these not from the JDRF website, but largely by accident. But this stuff is worthy enough of sharing with others -- the JDRF "shareholders"!!!

A while back, I have mentioned the Juvenile Diabetes Research Foundation (JDRF) New England project/blog, which had some very interesting presentations from their annual update near Boston this year. In fact, I lifted some of the New England chapter content and inserted it into my aforementioned blog posting. However, a few days ago, I received my college alma matter's alumni bulletin (the Bentley University Observer, page 12, although I found it took a long time to download). Anyway, that contained an interesting article I wanted to share with everyone (I scanned it, and you can download only that page/article here). Apparently, some faculty and students from Bentley were asked by the Bay State branch of the JDRF New England chapter to help create some online audio and video content for that particular blog. As might be expected, the article notes that the JDRF New England chapter's blog has since been recognized by other chapters throughout the U.S. and as an example of JDRF "best practices". We can certainly hope to see more of this type of stuff from JDRF's national organization in the future, and possibly other chapters following this lead, so that's good news indeed!

While some of my blogging peers (Kerri Morrone-Sparling of SixUntilMe.com, Manny Hernandez of TuDiabetes.com and a few others) have already joined, in 2006, JDRF's National organization evidently established a YouTube channel which anyone can join and follow at http://www.youtube.com/user/jdrfonline. That was done without much fanfare, but they've been better about putting some video content which is available to everyone (I don't find the TV commercials all that interesting, but some of the other stuff is).

Now, I could be mistaken, but the photo of the person on this YouTube channel appears to be Aaron Kowalski, who is perhaps best known for his work behind the "artificial pancreas" project, but has also been involved in the SmartCells/SmartInsulin deal signed last year. Anyway, the YouTube channel has some videos from JDRF's 2009 Annual Research Roundtable which took place in June 2009, including a short speech by international chairwoman Mary Tyler Moore, the new CEO Alan Lewis' 2009 State of the Foundation Address, and one from Dr. Richard Insel who is the Executive Vice President of Research for the organization. To the best of my knowledge, this is the first year that JDRF has featured videos of these speeches and presentations. I hope to see much more of this stuff in the future, but this is indicative of progress being made, although much of the work began under previous CEO Arnold W. Donald.

Finally, I would share a blogger who is relatively new to the diabetes blogging scene, Joshua Levy. He started a blog last June which can be found at http://cureresearch4type1diabetes.blogspot.com/. I knew of Josh, who has type 1 diabetes himself, from the Islet Foundation's Public Message Forum, and he is also a member of the Nathan-Faustman Yahoo! Group. Anyway, in the past, I followed his updates via an RSS feed of his Wiki updates/changes which alerted me of changes to his website related to diabetes. But his blog has some groundbreaking content, with the next item listed being a case-in-point.

JDRF-Backed Transition Therapeutics' Islet Regeneration Treatment Looks Dead for Type 1, Perhaps Not for Type 2

I generally share Josh's outlook and his definition of a cure, and although I don't always agree with everything he concludes, I'd say that 95% of the time, I do. Often, Josh has some observations which are well ahead of the public statements made by the JDRF or the researchers (not ALL research is funded by JDRF, even though much is). For example, he concluded (and I agree with him) that the JDRF's Transition Therapeutics islet regeneration treatment (based on gastrin, as Alan Lewis talks about) looks dead, at least for people with type 1 diabetes. See his posting here for more on that. Note that JDRF's 2009 Annual Update (which took place this summer) was still talking about this treatment, but as Josh writes:

"Transition Therapeutics is researching using a combination of two drugs to cause beta cell regrowth in an attempt to cure type-1 and type-2 diabetes. As of May 2009, they had officially marked their phase-I human trial for type-1 diabetes as closed. I haven't seen any published results for it, but I'm still looking. However, actions speak louder than words, and Eli Lilly (working with Transition Therapeutics) started a clinical trial in February 2009 using Transition Therapeutics's TT-223 product, but only for people with type-2 diabetes.

Also, in May 2009 they announced that JDRF and Transition Therapeutics had agreed that JDRF would stop funding clinical development of TT-223. Transition Therapeutics and JDRF terminated their agreement. Eli Lilly is taking over support for TT-223, but is applying the technology only to type-2 diabetes.

So the news from Transition Therapeutics for type-1 diabetics is not good. I will move Transition Therapeutics to my 'boneyard' of research that has not panned out if there is no good news in the next 6 months."

So far, JDRF has been pretty quiet about their decision to stop funding Transition Therapeutics, but unless something changes, we can probably conclude it is dead (at least for type 1 diabetes). For those interested in more background on this, and perhaps its applicability towards type 2, catch a video here for more details.

Exsulin Is Still Progressing

Not to worry on the regeneration front (at least not yet!), however, Exsulin Corp. (the name given to the treatment formerly known as INGAP) announced it's regeneration treatment is entering a second Phase 2 human clinical trial in people with type 1 diabetes (see here and here), so even if JDRF isn't behind this particular treatment, the progress will continue. The good news is that Dr. G. Alexander Fleming, Kinexum's CEO (and former Chair of professional education and training for FDA's Center for Drug Evaluation & Research [CDER] among other things), which is the company behind Exsulin Corp., is among the brightest people in diabetes research and knows this subject far better than most, as he also has intimate knowledge of the Food and Drug Administration, and can therefore help maneuver through this dysfunctional regulatory agency better than perhaps almost anyone else, so we can expect to hear more news from Exsulin in the coming year.

Before I get too far, though, let me take a step back and note that before we can get to regeneration (that's a separate topic I'll address in another blog posting I'll put in Part 2 or 3 of this subject), we need to acknowledge the not-so-little problem of autoimmunity, for which there are several possible treatments in various stages of clinical trials.

Consensus on What Will Be Required to Cure Type 1 Diabetes

Let me begin by acknowledging something that the consensus among most diabetes "experts" seems to be that a definitive therapeutic approach to a "cure" for diabetes will have to include a treatment(s) to control the autoimmune response that causes type 1 diabetes (T1DM) combined with another treatment(s) to replace and/or restore lost pancreatic beta cells, and in the case of type 2 diabetes, another treatment to also address the underlying metabolic defects as well. As a well-known diabetes (she's actually an immunologist) researcher, Dr. Denise Faustman, suggested in an interview with dLife (towards the end of the interview), that she expects it to be entirely possible for several autoimmunity "cures" to emerge although she declined to speculate on when such treatments might emerge. But we're closer today than we have been in decades!

First, I should begin by noting that the JDRF has a graphically-rich page on it's website dedicated to biotechnology and pharmaceutical "Industry Development and Industry Partnerships" that has updates on cure therapeutics which I highly recommend visiting: (click on the JDRF website and from there, select the "research" tab, and select "Industry Partnerships" or simply see click here. Because JDRF has an unfortunate habit of reorganizing it's website leaving some of its links dead, I felt it was useful to provide more detail than I have in the past).

First and foremost, on the autoimmunity front, inflammation is hot!

It's no secret that the drug industry is in the doldrums these days, with many blockbusters whose patents are due to expire soon and nothing much in the pipelines to replace these cash cow blockbusters. But one therapeutic area which seems to very hot these days is in drugs and biotech medicines to treat "inflammation".

Merriam-Webster defines the medical term "inflammation" as "a local response to cellular injury that is marked by capillary dilatation, leukocytic infiltration, redness, heat, pain, swelling, and often loss of function and that serves as a mechanism initiating the elimination of noxious agents and of damaged tissue."

In short, it's an immune response by the body used to heal infections or other ailments. Under normal circumstances, inflammation serves a protective purpose, so it should not necessarily be viewed as a bad thing. Inflammation helps to rid the body of infections and to heal itself, but too much of anything can have the opposite effect, having a destructive rather than protective effect. Both type 1 and type 2 diabetes have inflammation issues which lead to beta cell destruction, although the origins for inflammation in each disease is apparently quite different, as more recent research seems to suggest. At present, approved treatments for inflammation in each disease are mostly non-existent except for a few ailments such as cancer, although others for different autoimmune diseases have also started to emerge. Several aimed at addressing type 1 diabetes are in various stages in development.

Historically, the medical profession has treated most forms of inflammation the same way. The term "anti-inflammatory" usually refers to the property of a substance or treatment that reduces inflammation. In fact, anti-inflammatory drugs make up about half of all analgesics sold (including many over-the-counter products), remedying pain by reducing inflammation as opposed to opioids which affect the brain. Among the more common, over-the-counter ones are ibuprofin (brand names include Advil and Motrin) and naproxen sodium (brand name Aleve).

But this approach, to use a metaphor, is akin to sending out an entire army (using immunosuppresant drugs that largely shut the entire immune system down) to do the job that a single soldier with highly specialized skills could have done alone, and it also leaves patients prone to infections and other illnesses because the effectiveness of their own immune system has been reduced.

During the late 1980's and 1990's, newer research revealed that we could selectively target certain leukocytes (white blood cells) that caused specific types of cancer. The result was a gold mine for the drug and biotech industries, with extremely costly (and lucrative) medicines which seemed to work wonders for a handful of patients as well the bottom line of drug/biotech companies alike! But that business model has run into limits of governments and healthcare providers worldwide and their willingness to pay outrageous sums of money to save a mere handful of ill patients with specialized cancers. Like it or not, one might call this a form of performance-based medicine.

Certainly, an immunologic intervention resulting in an effective modification of the underlying immune process could potentially interfere with the etiology of an autoimmune disease and thereby preserve beta cell function, and/or set the stage for successful beta cell regeneration and/or replacement, or both. Ideally, immunotherapy offered to type 1 diabetes patients could be aimed selectively at salvaging the remaining beta cell mass (if any exists), while also creating a state of "immune tolerance" for the insulin-producing beta cells as immunologists refer to it. (The term "immune tolerance" collectively refers to the safeguards that the immune system naturally possesses to protect from harming self.)

A Newer Approach to Immune Tolerance

In contrast to immunosuppressant therapies which essentially shut the immune system down, immune tolerance therapies are designed to work in a different way. Rather than suppressing the immune system as a whole, these newer treatments aim to suppress only those parts of the immune system responsible for the autoimmune attack (or perhaps prevent it in the first place). The goal is to stop the autoimmune disease while leaving the body's infection and disease-fighting abilities intact.

Although a variety of approaches to immune tolerance have been successful in rodent (or even in some larger animal) models of autoimmune diseases, or in pilot clinical studies, to date, the achievements in larger human clinical trials have been rather modest. Researchers have learned that the similarities between mouse and human immune systems are pretty limited.

But according to the NIH Autoimmune Diseases Coordinating Committee, the range of potential therapeutic approaches available to treat autoimmune disease is expected to expand rapidly during the next decade as a consequence of progress in genetic and immunologic research conducted in the public and private sectors. These therapies are likely to include drugs, biologic agents, gene-based delivery systems, immunomodulation, cell-based treatments, tissue and organ engineering procedures, as well as therapies based on complementary and alternative medicine.

I've shown the following chart many times, but I use it for a reason: 2010 is the estimated time that some of the newer autoimmune treatments are expected to emerge, with more likely in the following years.



The question is if this is more of a retrospective look with a short window into the coming years, where is the future headed?

Here's where my references to some past efforts comes in. For example, in June 2009, I reported on some progress the JDRF had made with it's Industry Discovery and Development Partnership (IDDP) program (see here), whereby JDRF provides early-stage research funding to drug and/or biotech companies working on technologies and therapeutic candidates in an effort to provide incentives to more risk-averse drug and biotech companies to help commercialize products that would help facilitate JDRF's cure-related goals.

As a result of the trends noted above, a more mass-market approach to treatment seems to be taking place now. The basic idea is that these treatments will be delivered to a larger audience, but in order to do this, the costs must come down significantly. As a result, some are testing meds that were tried and approved for one condition to test their applicability in others. More recently, drug companies have engaged in trials to try and expand the market on certain existing drugs (for example, Gleevec, a drug that treats leukemia and other cancers) is reportedly being tested to treat the autoimmune response that causes type 1 diabetes in recently-diagnosed patients, and more recently, trials were announced to examine the use of several Rheumatoid Arthritis drugs such as Embrel, Remicaid, and Humira to see if they might also work in type 1 diabetes, not to mention other autoimmune diseases. It is very tempting to believe that one drug might treat another autoimmune disease, but as researchers have learned the hard way in the case of Lupus, that some drugs actually made the disease worse, not better. But the basic idea is that by ramping up production by leaving production up to drug and biotechnology companies, the cost can be brought down enough to make these drugs cheaper while also enriching biotech and drug companies by making their drugs applicable towards other types of autoimmune diseases. I could talk about each of these, but the reality is that right now, they're all in various stages of clinical trials. None is ready to address type 1 diabetes autoimmunity, but these could emerge in the coming years.

Autoimmunity "Cures" are Closer, But Not Likely Around the Corner

One of Josh Levy's postings summarizes some possible autoimmunity treatments in late-stage clinical trials. However, he includes some which aren't being tested with JDRF's help. To give you some idea of just how far along these are, consider that the following 4 programs are all now in Phase III Human Clinical Trials (note that there are a number of others in Phase I or Phase II Human Clinical Trials which I haven't even addressed here):

* Diamyd's GAD65 (several different studies; note: Josh considers this which is being trialed as a vaccine to be an autoimmunity treatment, I am not convinced yet, but let's see where it goes!)
* TolerRx/GlaxoSmithKline's CD3 (several different studies)
* MacroGenics/Eli Lilly's CD3 (several different studies)
* Teva/Andromeda Biotech's DiaPep227

He states "Now, make no mistake, these trials do not (emphasis mine) mean a cure is right around the corner." I'll borrow Josh's comment because he said it as well as I could:

"It is important to remember, however, that although there are four treatments in Phase-III trials, we are not close to a cure or established type 1 diabetes. All of the clinical trials in Phase-III and Phase-II are targeted at honeymoon type 1 diabetes; none at established cases. Even with that restriction. None of the treatments in Phase-III trials resulted in cures during their Phase-II trials. They all extended or increased the honeymoon phase in some way."

However, while his caveats are important to keep in mind, they DO demonstrate the type of quantifiable progress that has been lacking for a very long time on the autoimmunity front, and do suggest that quantifiable progress is being made (the same could NOT be said as recently as a decade ago).

A case-in-point: MacroGenics/Eli Lilly's teplizumab treatment is not without adverse events, no matter how glowing some reports may be. For example, a friend of mine who attended the Children With Diabetes Friends For Life Conference in Orlando this year said "Dr. Harlan from NIH wisely pointed out at CWD FFL that the anti-cd3 drugs can cause recurrent mononucleosis which can increase one's propensity to develop lymphoma. Why would someone put their child at risk for that simply for a year and a half of extended honeymoon?"

As I responded, "The issue is that they first seek approval on newly-diagnosed patients for anti CD-3 treatments, and then, will ultimately extend it to others, possibly long-standing T1DM patients if past drug approval history is any guide. This remains an area of discovery, and I suspect, we'll find that some treatments work for certain patients, while others will not. Of course, no one seems to question using Lantus (insulin glargine rDNA origin), a completely man-made creation for an entire lifetime which also has proven mitogenic effects, which I also find questionable for a relatively small improvement in HbA1c ... that logic also escapes me, but I am one of the few who seems to question this." At least there has finally been some attention paid to this, although most Lantus supporters cannot seem to be convinced otherwise, and most seem to make excuses for the technology rather than acknowledging the legitimacy of the question. That's a separate conversation, however.

Ultimately, what is likely to come out of the different autoimmunity-related trials is more refinement and perhaps better definitions on just which patients each treatment is likely to work, and perhaps improvements to these, with more similar types of treatments to follow. Also, hopefully, the adverse events from the early autoimmunity treatments can hopefully be reduced and/or eliminated.

I will follow-up on this Progress Report with a Part 2 in the coming months which will address another part of the cure equation (perhaps regeneration or replacement of insulin-producing beta cells), so be sure to check back!