Close Concerns Weblog

ADA abstracts - excitement abounds about Amylin!

Life is just SWEET this time of year. Summer, warm breezes even in San Francisco, walking on Chrissy Field, children chasing birds, food like gazpacho, drinks like mojitos, lilles, - and ADA!!!!

Yes, the ADA is coming up in nine days and the abtracts came out on the ADA's website today. We'll have a full report in our June DCU, which will be published Wednesday, June 7. In the meantime, excitement is ABOUNDING for us. We love every spec of getting ready for ADA and we've been hard at work, pouring through the oral presentation descriptions, deciding on sessions (we'll have a top-flight team of seven there), developing all our questions, reading in and between the abstract lines. WOW!

We'll save most of our thoughts for DCU, but we do point out that Amylin posted its abstracts on its website, hurrah! Would that every company would make it so easy. Amylin has one of the most impressive ADA schedules we can remember seeing for a company, full stop - this is another Amylin year at ADA, zero doubt about it.
http://www.amylin.com/InvestorDocs/ADA_Schedule%20of%20Presentations_2006.pdf

In our view, the highlights, for Amylin:

First, Dr Alain Baron is doing a talk on obesity titled "Can We Cut our Losses?" This promises to be an extraordinarily interesting perspective on the biggest public health epidemic of our time. Of course, there is great interest in weight losing properties of Amylin's marketed drugs Byetta and Symlin as well as its drugs in development AC-137 (Symlin for obesity), PYY, and Leptin. We'll publish a Leptin 101 in the June DCU, by the way, and have an interview with a foremost expert on this subject. There was what we would term a profoundly interesting patent application involving Leptin over the past couple of weeks ~ we look forward to hearing much more about this at ADA. We've suspected for some time that Leptin is re-emerging -ever since it was announced, actually, that Amylin was purchasing the patent portfolio from Amgen. It makes sense that through combination therapy, Amylin would have something Amgen couldn't develop - read this application, and the way Leptin could interact with Symlin and another recently purchased technology and you'll be caught up too.

Back on the meeting! As we were noting, we heard Dr. Baron at a panel at Dr. David Klonoff's outstanding DT&T meeting last fall, where he discussed Byetta and the potential for the drug to treat at every stage of illness -- from pre-diabetes to advanced complications. Speaking of advanced complications, however, we suspect that Byetta can be used very effectively to help AVOID the complications, both micro- and macrovascular. Talk to any group of endos about Byetta as we have and you realize very quickly that the potential of the drug exceeds what what shown in the (admittedly very positive) AMIGO trials, because the power of weight loss and how that motivates patients to eat and exercise more effectively was not shown so much in the official clinical trials - patients had to follow very strict instruction. Left to their own devices, from anecdotal reports, many seem to lose weight more quickly and to key in on weight loss as a motivator to exercise more, eat better, etc.

Insulin companies, we imagine, particularly Sanofi, must be concerned, because Byetta is so good and the worst part may be no one knows HOW good. It may have been acceptable that Byetta would delay the move to insulin, but Byetta is also prompting patients to come off insulin - although not labeled for this, patients who want it can merely point out that were the drug approved earlier, they may well have gone on it and avoided insulin altogether! Speculation is rampant in this entire post, yes, but we doubt that it's a far cry that Sanofi is singing the Byetta blues as well as the rimonabant blues. Next worse off would be Novo, although they will be up next (albeit not for threeish years) with Liraglutide and have strong diversificaton in a growing market already. Lilly would appear the safest and best off as it co-promotes Byetta. What a pity that its co-promotion with Takeda's Actos just ended - promoting both drugs, particularly to patients taking TZDs who gain the most weight, would have been a nice idea, especially for PCPs, where Lilly's diabetes sales force has historically been strong.

Back to the schedule! For its Byetta symposium, Amylin will have dynamite Dr. D'Alessio, powerhouse Dr. Anne Peters, and influential Virginia Valentine speaking at a symposium - three outstanding thought leaders delivering a 2006 update on incretins in type 2 diabetes.

Next, they have two orals - v. prestigeous (very few are granted) - one, by noted insulin expert Dr. Bernard Zinman, is on TZDs, and we're so looking forward to that as we're very interested to hear more about the AMIGO-TZD trial. We believe this indication will be approved shortly, which could add hundreds of millions of dollars to Byetta's current revenue over the next several years - this is going to be very interesting to watch unfold. The other oral focuses on Byetta's impact on gastric emptying; we question ADA's choice here since we think it would have been one zillion times more relevant and interesting for ADA to choose something on LAR for an oral, although anything on Byetta will likely be extremely interesting as well. While it's true that the LAR data has been released for some time now, no doubt there will be details of big interest in the poster, #487P.

Overall, on posters, Amylin has fourteen, which is an outstanding showing. One is a late breaker on Leptin (52-LB), which is excellent! We will have a Leptin 101 article in our next DCU - written is outstanding. There is also great pramlintide poster for obesity (#1722-P) - about satiety - those are the only two on programs in development. There are four symlin posters - one by Dr. Ceriello (#447-P), who is Mr Glycemic Variabilty (Dr.!). This is about oxidative stress, which by the end of the meeting will be one of the top ADA buzzwords. Then, there is one about symlin and glargine (#472P) by Dr. Frias (amylin), one that looks the same but with non-Lantus long acting insulin (#521P), and then one about symlin in the elderly (publication only, #2102-PO). On byetta, there is far far too much to even talk about it. One (#2009-PO) by Dr. Buse looks quite something -- on ALTS (Hepatic Alanine Transaminase), which we although it is publish only. Powerhouse Dr. Dennis Kim will do the LAR poster (#487P), and highly respected Dr. Bob Henry will do the open label update. The latter two are definitely ones we do NOT want to miss ... cannot wait to be standing there with bated breath. Both will be so interesting. While many show little regard for open label data, we're the opposite - sure, it's a specific population for whom Byetta obviously worked - so it's not the randomized group - but Byetta is working so incredibly well for so many people that there's clearly a pretty big sub-group of patients for whom the results may have real implications. What will three-year data show? We look so forward to sharing our thoughts as the meeting unfolds. Excitement abounds ....!

DPP-4 smackdown!

DPP-4 Smackdown!

Only two weeks to go (less!) before the American Diabetes Association conference in Washington, D.C and things are heating up. Diabetes continues to hit the mass market - on CNN just the other day (as well as the cnnmoney.com website), there was news of drug giants Merck and Novartis preparing to unveil clinical trial data for their DPP-4 inhibitor compounds, both of which are at the FDA as longtime industry watchers know. CNN, yes.

So the drugs were described broadly - designed for patients with type 2 diabetes - as were the companies, who were characterized as fighting viciously for their (rightful, it seemed to suggest) place in the $12 billion and growing market for diabetes drugs. Although Merck’s drug, Januvia, was submitted a bit earlier than Novartis’ Galvus, we would think both may go to panel at the same time.

Our takeaway from the clip was that Novartis' PR did a better job -- their main talking point should be, and was, that Galvus is a better drug.  Still, score one for Merck as well, who managed to get across in this super-short clip that it plans to file a Januvia-metformin cocktail in 2007. Although this wasn't news to industry or to investors, we see it as a win since 20% of people of 20 have diabetes and many more than that have friends with diabetes - so word should travel fast. Witness what the New York Times piece in March did for Byetta - 30 days later, the article was still one of the very most emailed articles around (they don't show data over 30 days but on day 30 it was about #15 of all NYT articles in the last month). 

Meanwhile, Eli Lilly will deliver results on Arxxant, an experimental treatment for diabetes-related vision loss. We wonder how this will do at FDA since only one (albeit large) trial was submitted (versus the more typical two) and since it did somewhat miserable in neuropathy trials. Although analysts are projecting modest sales because the drug has had mixed results so far in trials, we see the drug treating a (some?) major unmet need(s?) in retinopathy. 

At ADA, there will be plenty of other junior contenders around to check out, but our money is on the Merck-Novartis fight as one event you do not want to miss. See next post for ADA poster fodder ...

Reference:
Smith, A. "Drug giants fight for diabetes market". CNNMoney.com, May 24, 2006.

Killer Girl Scouts - on thin mints and trans fats

We liked yesterday's column in the NYT featuring killer Girl Scouts…or at least, their killer cookies. Finally, someone coming down on Mom and apple pie! While initially, terrorism and Girl Scouts seemed an unlikely comparison, quickly it became clear that it actually is pretty apt and the comparison ultimately emerged as a highly effective one. The main takeaway? The delicious cookies sold to us by the cute girls in cute uniforms contain partially hydrogenated vegetable oils, trans fatty acids that clog our arteries, lower our good cholesterol, and make bad cholesterol levels rise faster than gas prices. Sick!

Columnist Nicholas Kristof admits that we can’t just pick on the Girl Scouts as "trans fats are all around us, from French fries to some brands of ice cream" but we should be as wary of them as we can. He gives us some statistics regarding trans fatty acids that stop us in our boots... Consider. Trans fats cause 228,000 heart attacks and 30,000 deaths in the US annually thus "killing far more Americans than Al Qaeda manages to." An excellent comparison in our opinion, as many fear another 9/11 but very few of us stop and think what these mysterious ingredient labels on our favorite snacks contain. Hard to accept that every time we have between meal cravings we are killing ourselves much quicker than the terrorists are, right?

Mmmmm. At least the Scouts have begun to make their cookies healthier, Lemon Coolers and Tagalongs are safe and trans fat free. (We wonder, does anyone order these? How many are willing them not to change the thin mints?) Although the authorities won’t be declaring a ‘war on trans fat’ anytime soon we should all think before digging into that enticing box of Samoas sitting in the cupboard. Reference: Killer Girl Scouts; Nicholas D. Kristof; New York Times, May 21 2006

New York Times series highlights funding challenges for diabetes

This week the New York Times ran a two part series on research funding aspects of diabetes.  The first part, Rising Diabetes Threat Meets a Falling Budget , focused on federal research funding.  The second part, Cost and Effect: Beyond 'I'm a Diabetic,' Little Common Ground, described the differences in type 1 and type 2 diabetes as a disease and how these differences have impacted private fundraising for research.  These articles held the 7 th and 8th respectively most emailed article position. We applaud the continued effort by the New York Times to report on the problems diabetes – both type 1 and type 2 – pose for us as a country.  While each article approaches the issue differently, the overarching theme of scarce funding dollars and choices made is an important one to continue revisiting.  The first article describes the current federal funding situation as fairly bleak, especially juxtaposed against the wildly increasing population of type 2 diabetics.  Heading into 2007, the NIH budget allocates $1.2 million less for diabetes; the CDC allocates $700,000 less.  It's true that NIH and CDC funding is declining across the board.  No chronic desease is left unscathed; in absolute and relative terms, research dollars allocated for cancer and heart disease are declining even more than diabetes.  But given the outpaced growth of type 2 diabetes, it's hard not to be alarmed by anything other than increased effort and focus by everyone. The New York Times offers a few examples of just the kinds of consequences that frighten us most, at least for the population of type 2s.  (A group which is likely to add 500,000 or more people to its roster each year for the forseeable future.)  Programs heavy on prevention are at risk in light of the funding constraints:  reduction or elimination of classes for type 2 diabetics on how to avoid foot amputations; slower than needed implementation of church-based programs in poorer communities to teach the benefits of diet and exercise; elimination of other grass roots efforts to prevent type 2 diabetes and its complications. Our healthcare system is tragically geared towards expensive treatments and interventions rather than inexpensive investments in prevention.  We see ample evidence – and have written on the topic before – of our system's perverse logic in caring for complications associated with type 2 diabetics in particular.  Payors (and we most certainly include Medicare in that lot) regularly swallow camels and choke on gnats.  Willing to spend $30,000 on amputating a diseased foot, payors do so not long after balking at spending $150 on podiatry care that would have negated the need for such extreme surgery.  The kinds of programs mentioned above aren't nice extras; we see them as essential components in managing the ticking time bomb of expensive and deadly complications associated with type 2 diabetics. The second part of the series considers the stark differences between type 1 and type 2 diabetics – both from the fundamental nature of the disease as well as the attendant demographics of each group.  In some ways, the only common ground between the two types is the fact that both involve elevated blood sugar levels.  The roughly 1 million type 1 diabetics first experience the disease as children; type 1 crosses all socioeconomic boundaries and strikes without warning.  The 20 million type 2 diabetecs tend to be older adults, frequently in poorer demographic groups and sometimes obese.  What also differs dramatically, is the success respective advocacy groups have had galvanizing financial support.  The Juvenile Diabetes Research Foundation (JDRF), which focuses its efforts on funding research to cure type 1 diabetes, has experienced phenomenal success in terms of organization and execution.  The Times reports that last year JDRF raised $183 million – over half of which goes towards research for a cure.  This rivals the $209 million raised by the much larger American Diabetes Association (ADA) – an organization usually associated with focusing on type 2 diabetes.   And, of all public and private funds raised, approximately 30% is earmarked for type 1, 40% for type 2, and 30% for both.  The Times almost successfully resists the temptation to pit the two disease types against each other in terms of equitable funding patterns and levels.  Clearly that line of thinking isn't productive.  For type 2 in particular, we would argue that the measure of appropriateness isn't relative to type 1 support levels, but to the enormity of the problems ahead given the growth prospects we are facing.   Without delving into the complexities of the relationship between the two groups and their respective missions, it does seem that type 2s have lessons to learn from the success of the JDRF in constructing an effective message capable of attracting resources and garnering influence.  To be sure, the diseases are so very different, but it is reasonable to hope that successes for one will benefit the other. The one important commonality for both types is that addressing the pressing issues posed by diabetes will require continued significant financial investments -- by government, by industry, and by individuals.  To that end, we want to see more scary articles, keeping diabetes in the forefront of public imagination as well as in its pocketbook. Reference: Rising Diabetes Threat Meets a Falling Budget; Ian Urbina; New York Times, May 16, 2006 Cost and Effect:  Beyond 'I'm a Diabetic,' Little Common Ground; Richard Perez-Pena; May 17, 2006

UCSF's Dr. German cites one year time frame for islet from embryonic stem cell

Dr. Michael German of UCSF presented Wednesday night as part of UCSF's "Mini Medical School" series, updating us on the progress his lab has made in differentiating an embryonic stem cell into an insulin-secreting islet cell. Dr. German explained that with current islet cell transplantation, most grafts fail after one year; while there is a 90% success rate, defined as immediate success in getting the patient off of insulin, there is only a 10% 5-year success rate.

Of course, because the islet cell transplantation procedure is so minimally invasive--the islets are injected with a long needle into the hepatic portal vein--this procedure could be repeated annually. The major barrier is that the supply of islet cells is limited, as no islet cells can be taken from a live donor. Estimates suggest that if every possible pancreas were recovered from cadavers, there would be a maximum of 5,000 per year available, which pales in comparison to the 50,000 new cases of diabetes diagnosed each year. Relatedly, part of the reason for the high failure rate is that only a few cells are transplanted; more successful procedures have used islets from 2-3 pancreases per patient, and Dr. German said that transplating even more, on the order of the equivalent of 4-6 pancreases, may lead to lower failure rates. The promise of embryonic stem cell research is that it could provide an unlimited source of islet cells.

Dr. German's lab is working on understanding the factors that influence differentation. Embryonic stem cells can be induced to differentiate first to endoderm, then to pancreatic progenitors, then to endocrine/islet progenitors,and finally to beta cell progenitors and beta cells. A number of critical transcription factors have been identified, including PDX-1 and neurogenin 3. It is especially difficult to differentiate cells into endoderm, and investigators were first successful in this one year ago. Dr. German believes that in the next year, investigators will have success in deriving an insulin-producing beta cell from an embryonic stem cell. He noted that embryonic stem cell therapy has an advantage in diabetes, because transplantation of this type of cells has already been done; once cells are produced, they can be immediately used in patients. Of course, patients will most likely need to be on immunosuppressive drugs. Alternatively, stem cells could be created that match the patient's DNA--so-termed therapeutic cloning--but experiments have shown that autoimmunity recurs, within days, when islet cells are transplanted between identical twins.

Critically ill patients live longer if obese?

On Tuesday, the New York Times published an article about recent findings regarding obesity and critical illness.  The conclusion? Heavy people survived more than thin people.

The study, led by James O'Brien of Ohio State University Medical Center and published recently in Critical Care Medicine, explored the relationship between BMI (Body Mass Index) and hospital mortality for critically ill adults.  The research team gathered data over a 6-year period from 84 hospitals on 1,488 patients being treated for acute lung injury, all on mechanical ventilators.  Over half the patient group had higher than normal BMIs.  The data showed a clear relationship between BMI and survival to hospital discharge.  Those patients with the higher BMIs enjoyed a lower risk of death than those patients with low BMIs.

Huh?

Before obesity starts getting a good name…The conclusion only tells part of the story.  The research team notes that the use of heparin differed in the patient groups.  High BMI patients were more likely to get prophylactic treatment for blood clots – a possible factor in better outcomes.  Also, the research team noted that those folks with low BMIs were potentially much sicker at the start – their low BMIs resulting from illness rather than health.

With obesity associated with so many deleterious health problems, this article was confounding and almost disturbing at first blush. However, the notion that very heavy people might be treated differently in a critical care setting because of their size helps make sense of the outcomes data.  Similarly, outside a hospital thinness is easy to associate with robust good health.  But inside an ICU, thin can look much more like frail and vulnerable to death.

Interesting findings to be sure – and a good reminder to peel the onion another layer or two in pursuit of the answer to "Why?"

Reference:
Body mass index is independently associated with hospital mortality in mechanically ventilated adults with acute lung injury *.
Critical Care Medicine. 34(3):738-744, March 2006.
O'Brien, James M. Jr. MD, MSc; Phillips, Gary S. MAS; Ali, Naeem A. MD; Lucarelli, Maria MD; Marsh, Clay B. MD; Lemeshow, Stanley PhD

New York Times
Outcomes: Heavy People May Beat Critical Illness More Often
By ERIC NAGOURNEY
Published: May 9, 2006

Beverage industry leaders agree to eliminate sweetened drinks from schools

The three largest soft-drink companies in the U.S. announced Wednesday a plan to remove soft-drinks and sweetened juices from the nation’s schools.  Under the agreement, which was brokered by the William J. Clinton Foundation and American Heart Association, Coca-Cola, PepsiCo Inc., and Cadbury Schweppes are aiming to eliminate these drinks from school cafeterias and vending machines.  The beverage makers will replace the drinks with water, unsweetened juices, and milk products; high schools will additionally be able to purchase diet sodas and sports drinks.  Although schools may choose whether to accept the changes, a NYT article says that Susan Kneeley, president of the American Beverage Association, expects most schools will want to follow the agreement. A WSJ article predicts that this will affect less than 1% of the companies’ sales while the NYT estimates it will affect 35 million children in public schools.  Fifteen million children will not be affected because their schools already do not allow sweetened juices and sodas.  Referring to the benefits of the agreement, Mr. Clinton said, “if an 8-year-old child took in 45 less calories per day, by the time he reached high school, he would weight 20 pounds less than he would have weighed otherwise.”

The agreement is also an encouraging sign that the beverage industry is acknowledging the growing need to address our nation’s obesity problem… or at least, that it can no longer ignore mounting pressure from health advocacy groups, which have long pushed for such an agreement. Both WSJ and NYT articles note that prior to the agreement, the Center for Science in the Public Interest, a Washington, D.C., consumer-advocate group, and the Public Health Advocacy Institute, a public-health law group in Boston, were in the process of bringing a lawsuit against the industry in Massachusetts that would have forced a similar agreement (the suit has been dropped in response to the agreement). The NYT article quotes Richard Daynard, a tobacco lawsuit veteran, saying that the agreement represents “the first major victory for the obesity-litigation strategy." Mr. Clinton took a different perspective, emphasizing the fact that the agreement is also a positive sign that successful negotiation can be achieved without litigation, saying, “We've been talking to them for months and months, and they may have liked the way we were working with them, not just singling them out," he said in a telephone interview. “I'm glad we did it without litigation and could accelerate the process.”

Morgan Stanley Unplugged - Pfizer's Exubera, delayed

Morgan Stanley Unplugged is happening now in Miami. This is an excellent conference. There are no standard presentations at all, only analysts and CEOs in conversation - sometimes combative, usually genial.

From the Pfizer conversation, we learned that inhaled insulin is definitely delayed, as we had heard - likely 'til at least mid-July. This reflects the rather muted AACE presence they had. It sounds like pricing is very tricky, and they admitted as much, saying they wanted to find the "sweet spot"  ... they expect normal reimbursement over time. So they have to price it high enough that they can earn enough to make the return on investment (ROI) worthy but low enough that managed care will take it seriously.

That may be easier said than done.

We certainly know that many MANY people should be on more aggressive therapy and if there were an easy way to put such people on insulin and lower the A1C by 2,3, even 4 points, that would be fantastic. It isn't quite that easy.

We're now thinking pricing perhaps upwards of $6/day.

Hospitals offer obesity programs for children

Jennifer Yates of AP describes the recent increase in hospital weight management programs for children. This is our second blog in the past month about hospitals improving their treatment of obese patients (see 4/10 blog, “AP article draws attention to hospital care for obesity”)– hopefully this is the beginning of a trend; at the very least it is encouraging that the media recognizes the significance of these changes as the obese population continues to grow.

The article balances facts about the growth in obesity in the U.S. and the associated health risks with personal accounts of the positive developments in hospitals working to address these issues. Yates quotes numerous medical directors, speaking about the important of treating obesity through positive lifestyle changes. "It's scary and we're going to end up with young adults who should be healthy who are bearing the burden of a chronic illness,” said Dr. Sandra Hassink, director of the weight management program at the Alfred I. duPont Hospital for Children in Wilmington, Del. Accordingly, the hospital programs are primarily designed to promote physical activity and healthful nutrition, although some also offer more drastic measures such as bariatric surgery in severe cases.  Both patients and doctors alike seem overwhelmingly in favor of the programs. Yates notes that the clinics are opening at the same time obesity rates are “skyrocketing,” citing government figures that show nearly one out of five children is obese.  Not surprisingly, a major barrier to such programs is the fact that insurance programs usually do not provide reimbursement, despite clear long-term potential of the benefits of preventive care.  However, clinics have had success from alternative funding sources, in some cases.  For example, a Pittsburgh clinic received a $3 million dollar federal grant that allows it to serve patients for free.

While the scope and prevalence of these programs will always be limited in the absence of solid reimbursement, we believe such programs have the potential to produce very real change in the lives of these children— as a source of knowledge for families who lack the resources to alter their lifestyle, a “refuge” for children who may feel embarrassed to discuss their obesity with family and friends, and a source of hope for children facing what can often seem like an inexorable pattern of weight gain.  Most importantly, as the prevalence of obesity and associated diseases continues to grow—a recent report by the American Diabetes Association estimates that one in three children born in 2000 will develop diabetes—these programs have the potential to prevent costly and unnecessary complications.

Original AP article is included below.