Close Concerns Weblog

New obesity partnership - Metabasis Therapeutics and Merck

Metabasis Therapeutics and Merck announced this morning that they are joining forces to develop a novel treatment for type 2 diabetes, hyperlipidemia and obesity. At the center of this venture is a tiny molecule that would activate a liver enzyme called AMP-activated Protein Kinase (AMPK). Over the past several years, researchers have seen AMPK as a potential therapy for metabolic diseases.

Using its NuMimetic™ technology, Metabasis research targets molecules that bind to regulatory enzymes in metabolic pathways. By fitting nucleotide binding sites, these potent molecules mimic the natural regulators of enzymes and hence are called nucleotide mimetics. The compound in focus today is an AMP mimetic, which activates a liver protein kinase. The liver protein kinase, in turn, regulates levels of fat and cholesterol. Metabasis has already developed a library of nucleotide mimetics, including ones that appear to lower glucose, cholesterol, and lipids in preclinical models.

As a reminder, Merck is currently working on with Bristol-Myers Squibb on the new drug Pargluva (previously called Muraglitizar), a dual PPAR agonist for the management of diabetes and associated heart disease. Pargluva has not yet been approved by the FDA.

As well, Metabasis currently has two other drug candidates for treatment of diabetes. CS-917, a treatment for type 2 diabetes that was also discovered using NuMimetic technology, is entering Phase IIb clinical trials. Metabasis believes that CS-917 is the first drug candidate to be studied in human clinical trials that is designed to directly block the gluconeogenesis pathway. CS-917 significantly reduced blood glucose levels in patients with type 2 diabetes during two Phase II clinical trials. The other drug candidate, MBO7803, is another type 2 diabetes treatment designed to inhibit gluconeogenesis. MBO7803 is still in pre-clinical development.

This is not the first time that Merck has collaborated with Metabasis—they began working together on a hepatitis C project in 2004. Metabasis and Merck have agreed to each contribute research efforts and drug candidates for the collaboration. Merck will pay $5 million upon signing the agreement and will fund Metabasis for its research input. While Metabasis would receive a royalty on sales if a product is commercialized, Merck will hold primary responsibility, including (importantly) financial responsibility, for the clinical production of any drug therapy resulting from the research. Merck will also hold the right to market any product internationally, while Metabasis may co-promote a product in the United States. It is estimated that Metabasis would receive $54 million, excluding royalties, if a product is marketed for single-indication usage in patients. This cash amount could jump to $74 million if a product is approved for additional indications.

We continue to see huge growth in interest in obesity among pharmaceutical companies. Sanofi-Aventis appears to be the leader, with Rimonabant having been filed with the FDA earlier this year (though it is unclear for what indication - smoking or obesity or otherwise - we ultimately expect at least one indication to be lipids-oriented). Merck currently has three obesity drugs in Phase 2 development, and Lilly announced at a 2004 analyst meeting that it was planning to increase R&D investment in early stage obesity compounds. In late May, Medtronic jumped on the bandwagon by announcing the creation of a new business unit: Medtronic Obesity Solutions.

Diabetes management: clarion call needed!

Diabetes is the perfect disease for disease management. Investment in the best drugs and devices and education (patient and providers) can have profound impact on long term microvascular and macrovascular complications. So American Healthways reported third quarter revenues yesterday - they are doing a 3-year pilot program for diabetes and CHF - this could double their addressable market. We'll be staying tuned. They say roughly 10% of population accounts for 70% of expenditures - for diabetes, those are the small percentage (but still large absolute number) of folks who have let disease progress far too far. What would happen if these folks were on more aggressive therapy earlier - and if they monitored their disease? We'd all be better off - patients, families, friends, healthcare providers, hospitals - and yes, taxpayers. Chronic care is biggest problem with diabetes - here's hoping for more pressure to manage it more intensively.

Rimonabant and Oprah and Arena's APD356

As just seen in Safeway: the front cover of the July Oprah magazine trumpets the line "New Diet Drugs" - Rimonabant is mentioned as such and is characterized as the most highly anticipated new generation diet drug. We would concur - very highly anticipated - the sanofi PR machine is impressive. We pause, however, over side effect profile, particularly related to CNS, and we'll be eager to see more data on this front. At one of the posters at ADA, we asked about side effects related to depression - it struck us that depression was high compared to placebo (especially since depression was an exclusion criteria in these trials). One of the authors said depression wasn't as high as 5% "or anything like that" - so if 1% of overweight or obese patients with diabetes took the drug - call it, 110,000 (assuming a denominator of 11 mm overweight or obese PWD, basically 90% of type 2s and 10% of type 1s) people - so if there were more than zero but fewer than 110,000 more clinically depressed people around, would that be okay? Rhetorical, yes, mmm.

We digress. We won't know more 'til we see more data and certainly it is wonderful to hear about effective new drugs - but this is the Vioxx era so of course, even more these days, we look at side effect profile first and last and all the way through the middle.

The Oprah piece also mentioned a "safer" fen/phen that Arena Pharmaceuticals is developing - we know this as APD356, which is said to stimulate the 5-HT2C serotonin receptor more selectively (less noise) than fenfluramine and dexfenfluramine. Speaking of side effects, Fen-phen, aka appetite suppresents previously marketed by Wyeth, were withdrawn from the market in 1997, due to cardiovascular side effect profile (heart valve disease and pulmonary hypertension). At their height, sales apparently reached ~$400 million, according to the WSJ, and the slope of the curve was still pretty steep at that stage. Back on Arena. They announced Phase 2 results around the time of the AACE meeting in May - basically the 15mg dose (the highest dose) prompted a 3 pound weight loss over 28 days, compared to a 0.7 - 0.9 pound weight loss in placebo and the lower two doses. In the highest dose, 20% had headaches and 7% had nausea, compared to 14% and 4%, respectively, in the placebo arm. Next, the company will do a three-month Phase 2b trial - we'll look for results late this year.

STOP THE PRESSES!!! APPROVED: NOVO NORDISK’S LEVEMIR (insulin detemir)

We’re all very excited to report that it was announced today that the US FDA granted its approval for Novo Nordisk’s intermediate-acting insulin analog Levemir (insulin detemir) to be marketed in the US. Levemir became available in Australia in April, 2004 and it was approved in Europe in June 2004. We have been waiting for the US decision for so long, ever since the FDA granted an approvable letter in October of 2003. Now, nearly two years later, detemir is finally approved. From what we understand, the hold-up at the FDA was down to a simple question: would Levemir have the same effects on patients of color as it did on more homogenous groups of presumably Caucasian types? The answer, presented in the form of poster 458-P (see abstract below) at the ADA this past weekend, appears to be a resounding “yes.”

We’re positive about another alternative: “You’re on pumps; why do you care about a new intermediate-acting insulin analog?” we hear you murmuring. Well, we may be on pumps now but if we ever wanted to try something like Dr. Steve Edelman’s “untethered regimen” of part-time pump use (fascinating – see http://www.tcoyd.org/05/Dr_Edelmans_Corner.shtml), or we needed a pump vacation, we knew someone who definitely was not a pump candidate but who needed a reliable, flexible basal insulin, we’d look toward Levemir. Every study has its liabilities, but we remain impressed by the intrapatient reproducibility that has been noted in all published clinical trials of detemir. The other day in an ADA symposium on basal insulin analogs, Dr. Malcolm Nattrass interpreted data from Dr. Tim Heise to indicate that if NPH has 60% intrapatient variability, insulin glargine (Lantus) has 40% variability and insulin detemir has 25% variability. We would love to have totally reliable, non-variable insulin but we certainly prefer the idea of 25% variability to the other numbers on the menu. 25% - that’s not so bad! Now NPH, we personally thought that was an evil insulin …

“Okay, so what will Levemir do to Lantus? To the pump market?” you ask. Well, patients who have needed two injections of Lantus per day to achieve good blood glucose control, or who have experimented with many doses of Lantus and still not achieved their targets may find Levemir attractive (or at least want to try it – switching costs are low) because, for those who take two injections per day anyway, one may appreciate less variability. We imagine even some who take just one injection a day will probably want to try Levemir (once daily dosing represents much of the key behind Lantus’ simplicity, which has had fabulous success by anyone’s reckoning. Sales hit ~ $1 billion worldwide for Lantus last year and we expect sales to continue to rise regardless of Levemir’s regulatory status – now, the impact on Lantus/Levemir by Byetta will prompt some delay in some moves to the long acting analogs, but that’s a whole different piece). The upside to taking two injections of a dependable analog for basal insulin coverage is flexibility in terms of timing and dose strength, such as taking less insulin in the evening if one has had an active afternoon and can anticipate a delayed nocturnal hypo, for example. Overall, we also know that once Novo is marketing a long-acting analog, the entire pie will likely increase – from the marketing and from more and more real pressure coming from the move toward earlier, more aggressive therapy. We see that last – earlier, more aggressive therapy – as the tailwind, and Byetta as the headwind – look out! This will be fascinating to watch.

It’s more difficult to assess the impact that Levemir might have on the US insulin pump market. Early on, Lantus had some impact as patients stopped to try basal therapy – we ultimately view long-acting analogs as mostly neutral to pumps at this stage because some found Lantus a great drug and never moved to pump therapy while for others, the whole notion of basal/bolus would never have arisen without Lantus – and some of those have moved to pump therapy who wouldn’t otherwise have done so! When Medtronic purchased MiniMed, it looked forward to 30% growth – although we aren’t there, MiniMed, still the biggest player, has certainly had a couple of positive quarters and Animas is also posting strong revenue growth. Smith’s Deltec is harder to tell and Roche isn’t back on the market yet, but we’ll keep watching. We believe the availability of continuous monitoring will really drive pump sales because patients will start to realize just how much more correction therapy is needed – pumps are the easiest way to do this. Dr. Irl Hirsch also said the other day that he expects the approval of Symlin to prompt more pump therapy (or a return to pump therapy for some) as patients willing to do just a few shots a day go for Symlin shots and a pump. And there will be many takes on this - we do have a few European friends who ditched their pumps and switched to Levemir when it became available in their countries. We also know some Novo employees who are still pumping even though they could have all the Levemir they wanted. As in so many disease states, patient selection and preference is a key issue in the diabetes market. As always, we celebrate patient choice: Levemir represents another option in insulin therapy, so we’re enthusiastic.

Postscript: With Levemir being approved now, Levemir will beat Apidra to market. This means that Novo's portfolio of insulin products is complete and Sanofi-Aventis's is not. Of course Lilly's portfolio is incomplete but they do not appear close to an intermediate/long-acting analog - we saw something early stage at EASD last year in Munich but at the booth we learned that it wasn't going to be pursued in later stage trials. On the insulin front, we sense more competition between Novo and Sanofi-Aventis than we sense between Lily and Novo at this stage.

Similar Pharmacodynamic and Pharmacokinetic Dose-Response Relationship of Insulin Detemir and NPH Insulin in African Americans, Hispanics or Latinos and Caucasians

458-P

BARBARA TROUPIN, BODIL ELBROEND, ROBERT BERNHARD, TIM HEISE, HANNE HAAHR, OLGA SANTIAGO, LARS ENDAHL, MARCUS HOMPESCH Institutions: San Diego, CA; Neuss, NRW, Germany; Bagsvaerd, Denmark

Results: In order to evaluate a potential impact of ethnicity on pharmacodynamics and pharmacokinetics of the long-acting insulin analogue insulin detemir (IDet), we investigated the pharmacodynamic and pharmacokinetic dose-response relationships in 48 subjects with Type 2 diabetes of different race/ethnicity (16 African Americans (AA), 52±10 years (mean±SD), BMI 30±4 kg/m²; 16 Hispanics or Latinos (HL), 51±8 years, BMI 29±4 kg/m² and 16 Caucasians (C), 54±13 years, BMI 29±4 kg/m²). Each subject participated in six 16-hour iso-glycemic clamps (clamp target 7.2 mmol/L) and was randomly allocated to three doses (0.3, 0.6, 1.2 (I)U/kg) of IDet and NPH, respectively, in this double-blind, cross-over trial. The area under the glucose infusion rate curve (AUC(GIR)) was used as the primary outcome measure. Both IDet and NPH showed a linear dose-response relationship on logarithmic scales in all three groups (p=0.31), without any significant differences in slope (p=0.71) or intercept (p=0.51) as shown on the figure. Similar results were obtained for pharmacokinetics. In conclusion, similar dosing recommendations can be used for IDet in subjects of different race and ethnicity.

Category: Clinical Therapeutics/New Technology - Pharmacologic Treatment of Diabetes or its Complications

ADA - Day Five -

ADA 2005 - day four

The development of pulmonary antibodies is a possible concern for inhaled insulin devices. In many devices two thirds of insulin is retained in the upper respiratory tract. The proliferation of antibodies has initially been deemed to be not harmful, but the long term effects are unknown. On a positive note the antibodies do not appear to persist after the insulin dose is terminated. (Joseph D. Brain ScD)

Dyslipidemia in metabolic syndrome plays a strong role in endothelial dysfunction through oxidative stress. Oxidative stress leads to the development of endothelial dysfunction, due to the decrease of NO (a strong vasodilator) and the increase in several inflammatory factors. Glitazones improve endothelium dependent vasodilation via the inhibition of TNFα, an inflammatory factor, as well as, through the inhibition of  various immunological factors (chemokines). (Bart Staels Ph.d)

Dr. Lois Jovanovic started off the day with a presentation on the importance of achieving euglycemia—according to her, HbA1c should be below 6%.  This is obviously below the ADA recommendation of 7 and the ACE recommendation of 6.5% - but it makes a lot of sense to us as we know there isn’t really a lower threshold for reduction in complications stemming from better control.  Among ways to achieve such strict glycemic control, Dr. Jovanovic mentioned frequent self-monitoring of blood glucose and the need to adjust insulin dosages depending on stress level.  The “balancing act” of normalizing blood glucose must include exercise, insulin, diet, and stress; the ADA generally neglects to include this fourth factor, she noted.  According to Dr. Jovanovic, people must test their blood glucose levels eight to ten times a day in order to achieve HbA1c levels between 5% and 6%.  This will be very aggressive for some patients, given the average for all patients with diabetes is just a couple of times a day and even for many intensively controlled patients, only four times per day. We have learned so much more about the importance of stemming glycemic variability and expect to hear only more about this not less in future – it was certainly a key theme of this ADA, and reinforces all the important research on this front by Dr. Irl Hirsch.

Dr. Bo Ahrén from Sweden talked briefly about the ten (10!) GLP-1 analogues and DPP-IV inhibitors that are now in clinical trials – some of these are old and some are newer – we’ll be having a story coming up in DCU on the specific updates on these.  He went into more detail on the safety and efficacy of four of these new drugs: Liraglutide (Novo Nordisk), CJC-1131 (ConjuChem), Vildagliptin (Novartis), and Sitagliptin (Merck).  Clinical trials show that these GLP-1 analogues and DPP-IV inhibitors reduce HbA1c by about 1%.  The drugs are generally well-tolerated and safe, although some of the GLP-1 analogues may cause nausea.  What’s interesting about that is that we also heard a number of clinicians that had exp Accoreding to Dr. Ahrén, GLP-1 based therapy is a potential breakthrough for the treatment of Type 2 diabetes – this certainly reinforced all we had heard. Although

When asked if he would consider using gastric bypass surgery on non-obese people with Type 2 diabetes, Dr. Schauer from The Cleveland Clinic said that indeed he would!  In fact, there is a currently a prospective study in Australia to evaluate the effects of gastric banding on patients who have BMI’s in the low 30s.  We can’t wait to see this, especially given some of the data we’ve seen in terms of type 2 patients and gastric surgery – some of these outcomes are nothing short of amazing, especially in terms of implications from a cost-benefit perspective.  Currently, of course, U.S. insurance carriers will not cover this operation unless the patient’s BMI is over 35 and in some cases 40, depending on co-morbidities present.

Dr. George Bakris, while speaking on how to protect cardiovascular and renal function in patients with Type 2 diabetes and metabolic syndrome, emphasized the need to include microalbuminuria as a cardiovascular risk factor.  According to him, “the more protein you’re spilling, the more likely you are to die.”  Just as we aggressively treat diabetes and continue to lower the recommended HbA1c level, we need to aggressively treat cardiovascular disease.  The new blood pressure goal for people with diabetes is 130/80 mmHg or lower.

ADA 2005- day three - it's all about ...

Someone asked me today what I thought were the biggest takeaways from the meeting. I said, I thought, Edic, Edic, Edic, Symlin, Byetta, glycemic variability, and retinopathy. More to follow on all these.

A word from the President of the ADA, Dr. Alan Cherrington: While there has been tremendous progress in the field of diabetes in terms of new drugs and technologies, there has not been much improvement in the quality of care.  Dr. Cherrington reported that only 45%--less than half!—of patients with diabetes receive “recommended care” from their doctors. We doubt it is even this high.  Because there are so few endocrinologists in the United States, most people with diabetes are treated by primary care physicians, who have innumerable other illnesses to treat and who all can't stay up to date on new drugs.  Therefore, our focus should not just be on developing new drugs and technologies, but also on the ability of health care providers to use these drugs.  Dr. Cherrington also recommended giving physicians financial incentives for achieving good outcomes in patients. Here, here...

Dr. Marion Nestle from NYU shared that food suppliers in the U.S. have a total of 3,900 kcal/day available for every person.  This is up 600 kcal/day since 1980.  What’s the result of having so much extra food?  Pressure for companies to sell more food, which translates into pressure for people to eat more.

In this year’s ADA Banting lecture, Dr. Jeffrey Flier from Harvard Medical School discussed some of the excellent progress researchers have made in elucidating the pathogenesis of obesity, both in terms of genetics and environmental causes.  Several genetic disorders relating to obesity are now known, including the MC4R mutation.  We expect to be hearing a lot more about this, we imagine...

Dr. Brian M. Frier, from Scotland, gave a talk on hypoglycemia during driving.  He reported that the frequency of mild hypoglycemia in diabetic patients does not change over twenty years, but rather stays constant at about two episodes per week.  In contrast, the frequency severe hypoglycemia increases steadily over time, such that the longer a person has diabetes, the higher his or her risk of having an episode of severe hypoglycemia.  At the same time, awareness of hypoglycemia (symptoms such as shaking and trembling) declines with time.  Impaired awareness of hypoglycemia affects 25% of adults with Type 1 diabetes.

Cognitive function deteriorates at a blood glucose level less than 54mg/dl and does not recover fully until 40-90 minutes after the blood glucose level returns to normal.  Applying this to daily life, Dr. Frier recommended that a person with diabetes wait at least 45 minutes to begin driving after having a hypoglycemic event.

Dr. Frier gave us some numbers to use as guidelines regarding driving and hypoglycemia.  He told us that driving becomes impaired at 68 mg/dl.  Also, driving has a significant metabolic demand--we burn many calories while driving!  Therefore, people with diabetes should measure their blood glucose level before driving and take a snack if it is lower than 90mg/dl.

Dr. James Gavin III, while advising how to improve glycemic control in Type 2 diabetes, pointed out that each 1% increase in HbA1c level causes a 28% increase in risk of death, according to the EPIC-Norfolk study.

In highlighting the effectiveness of frequent self-monitoring of blood glucose (SMBG), Dr. Lawrence Blonde cited a study which found that people with Type 1 diabetes who performed SMBG at least three times per day had an HbA1c value 1.0% lower than people who performed SMBG less fewer times per day.  In people with Type 2 diabetes, performing SMBG at least once per day was associated with an HbA1c value 0.6% lower than not performing SMBG.  More people should be getting blood glucose meters, even if they are not taking insulin.

When asked if he would consider using gastric bypass surgery on non-obese people with Type 2 diabetes, Dr. Schauer from The Cleveland Clinic said that indeed he would!  In fact, there is a currently a prospective study in Australia to evaluate the effects of gastric banding on patients who have BMI’s in the low 30s.  Just one minor glitch: U.S. insurance carriers will not cover this operation unless the patient’s BMI is over 35.

ADA 2005 - day two ~ June 11, 2005 ~ top ten musings

And on it goes! Day two of ADA has been terrific. Here are ten items of interest ...

1.  In a session that was packed to overflowing – seven rows of chairs were set up in the hall outside the room to accommodate the overflow -  Dr. Tim Heise offered a thorough comparison of NovoLog, Humalog, and Apridra (glulisine), Sanofi-Aventis’s rapid-acting insulin analog that was approved by the FDA last year but has not yet been launched in the US (why? apparently they want to get the pen first - it's all so complicated) though some physicians now have it (we have not been blessed with samples ourselves). Contradicting chatter that we heard at the ADA last year and which has resurfaced in other contexts, Heise found no statistically significant differences between the onset of action of Apidra versus either Humalog or NovoLog. That was sort of what had been exciting - insulin is too slow! - but it will also be fascinating to see how Apidra is marketed with Lantus, i.e., whether we will see more promotion of prandial insulin, which it seems we really need. BUT (!) of course prandial insulin is far more complex to dose than basal insulin, and Lantus success has been founded on simplicity - we look so forward to watching this.

2.  It was very interesting to see more Byetta data - the A1C effect at 82 weeks was sustained, unlike most oral drugs to treat type 2 and, AND, the weight curve continues to slope down – weight loss actually continues to get better at 82 weeks versus 52 weeks.  We were wondering about two-year data and we heard at the end of the session that at two years, A1C impact continues to persist and that weight loss also (!) continues – about 11 pounds two years out, so it sounds.  Excellent.

On the Byetta-versus-Lantus front, study (26-week, multi-center, open- label, randomized, two-arm, parallel trial) showed that A1C effect was the same (the same as the insulin that has been a smash commercial success – basically down a point with half reaching 7% or lower A1C) with the difference that those taking Byetta experienced weight reductions and those taking Lantus gained weight – a difference of about nine pounds (those taking Byetta were down five pounds on average after six months, while Lantus users gained four pounds).  We’re not sure what average weight gain is for Lantus – an average of four pounds up sounds a bit high – but clearly relatively speaking, Byetta wins.  Now, which is easier becomes a key question – it’s no doubt that much of Lantus’ success has been due to the simplicity of the treatment.  Byetta looks pretty simple too.  There are side effects associated with both (nausea with Byetta, probably greater fear of hypoglycemia with Lantus, although actually, actual hypoglycemia was similar between the groups) and although it doesn't sound like nausea is such a big deal - it isn't nothing but the fact that people see how Byetta works immediately is a real positive (people often need to wait weeks and weeks to see a TZD impact for example - not a deal breaker for TZDs, just not a positive).

3. Symlin sounds like an official sleeper drug.  People (yes, n is low for my discussions) like this drug - it's wonderfully hilarious, actually, they really can't tell you why, but people who are willing to take the shots seem pretty happy.  Must say, from perspective of type 1 patient - so SO great to hear about a positive new therapy. "It's, um, it's really great, I just feel a lot better. Why?  Um, I don't know. I can't really explain it. I just, um, really like it ...."  We think it's all about post-prandial control, which has never been a big focus.  This drug is also highlighting what's wrong and difficult about insulin.  We heard tonight about a 300-pound patient of a noted endo whose weight -- and yes this is hugely anecdotal! -- dropped to 180 and whose insulin was cut by a third. "Oh, so she took Byetta," said a fellow conference goer. No, this was Symlin! Yes, n=1, etc - but what a story.

4.  Merck and Bristol-Myers Squibb have unveiled a brand name for muraglitazar: Pargluva, which hints at the drug’s class identification as a dual-PPAR agonist and the word glucose.  They had a long line of people at their booth, where they were engraving fountain pens with healthcare provider names.

During the Merck/Bristol-Myers Squibb corporate sponsored symposium, Dr. John Buse elucidated the adverse event data arising from a study presented at the American Association of Clinical Endocrinologists meeting a few weeks ago that compared 2.5 mg and 5 mg muraglitazar in terms of blood glucose and lipid control. 10% of patients in the study had edema at baseline, and in the course of the study edema rates ranged from 8–11%, which was not substantial compared to the placebo group’s edema rate of 16%. As one might have expected, slightly more edema was detected in the 5 mg dosage group than was seen in the 2.5 mg group. One case of congestive heart failure was seen in the 2.5 mg group. Two percent of placebo takers discontinued treatment because of edema but no patients taking muraglitazar discontinued because edema. We look forward to hearing “more on mura” at the late-breaking sessions.

5.  In Paradigm Shifts in Insulin Treatment, sponsored by Pfizer and Sanofi-Aventis (the biggest Big Pharma force, of course, behind inhaled insulin), it was stressed that insulin as well as insulin sensitizers earlier in a treatment course may have greater protective effects for beta islet cells.  As we have known, use of GLP-1 in rodent studies has shown to increase beta cell mass. Use of TZDs may also be effective, due to decreased glucotoxicity, apparently. Protective effects apparently occur even when therapies are of limited duration, it was said. A Turkish/Israeli study, where intense insulin treatment lasted only a week, still produced post-trial sustenance of glycemic levels. It will be interesting to see how beta cell function results emerge - we're aware this is very hard to measure, but from our discussions with HCP, we believe sustained A1C reductions may be accepted as a surrogate.

Inhaled insulin was positioned in this session as providing a patient-friendly insulin delivery method, in contrast to multiple daily subcutaneous injections. Compared to other alternative delivery methods, we were told that inhaled insulin allows for greater diffusion due to its greater vascular surface area (1000x greater nasal SA).  The creation of pulmonary antibodies was not explored in depth but was acknowledged as requiring more investigation.

On a different insulin front - have you heard of insulin-eluting stents? We had not, until we heard about a company called Conor. We'll have to check that out.  Another interesting company is Neurometrix. We typed it into yahoo finance and see that it's got a market cap under $200 million and the stock price has doubled since last year's ADA - we never recommend or even advise on stock investments, but we do watch the financial side and movement like this always makes us make a double take (in our head if nothing else.) This company is all about proprietary products used to diagnose neuropathies from what we just learned - we don't know much more at this stage, but the most serious neuropathy is a major unmet need, major expense ... major opportunity to help patients ... we'll do our research. We'll also look more into insulin-eluting stents, which sounds quite interesting in light of potential non-glcyemic benefits.

6.  This is a meeting where the benefits and drawbacks of TZDs have been widely discussed.  Lots of talk about weight gain and edema and CHF and then lots of discussion about how the use of TZDs can curb inflammatory effects on vasculature following internal trauma, can reduce inter-medial coronary artery thickness, can produce a decrease in C-reactive protein halting inflammation. We need to follow this further. We also hear a lot about how the kind of weight gain is the "good" weight gain and we're very excited to hear that from a technical perspective though we don't think most patients really care. After conversations with PCPs, we're not sure they care either - if the patient leaves the practice, they leave the practice, and there's no opportunity to help them ....

7.  Dr. Spiegel, Director of the NIDDK, said that islet/beta cell biology is at the heart of not only type 1 diabetes, but also type 2 diabetes.  The Beta Cell Biology Consortium shows great promise, with a mission to advance understanding of pancreatic islet development and function and to develop a cell-based therapy for insulin delivery.  Have a look at the website: www.betacell.org.  For obesity, Dr. Spiegel called www.obesityresearch.nih.gov the “one-stop shopping” site for finding out what’s going on in the science world of obesity. Wonderful resources.

8.  Dr. Dorothy Becker challenged the current classifications of diabetes.  Instead of using type 1, type 2, atypical diabetes (ADM), maturity-onset diabetes of youth (MODY), and secondary diabetes, Dr. Becker recommends that we move to the following three classifications: IDD (insulin deficient diabetes), IRD (Insulin resistant diabetes), and IDRD (insulin deficient resistant diabetes).  Her discussion of “double diabetes” – patients who have both type 1 diabetes (autoimmune) as well as type 2 diabetes (insulin resistance) was fascinating.

9.  We’re hearing a lot about obesity at this meeting and will be writing about this in more depth in our newsletter, particularly about Acomplia.  As in past years, we’ve heard it stressed in many sessions already that people do not need to drop down to the recommended BMI levels in order to achieve significant health benefits.  A modest weight loss, of 5-10% from baseline, can help a great  deal (from a low base).  Would that patients had been therapies and technologies to help them reach even this more modest goal.

10.  Dr. Richard Nesto from Harvard Medical School and the Lahey Clinic Medical Center said that there may be an application of TZDs to non-diabetic patients – pre-diabetes, in other words. We’re staying tuned on this front. We would imagine given the adverse event rate (edema, congestive heart failure, oh, and weight gain), prescribing TZDs off label at this point would be quite brave.  However, we’re extremely interested to see what the pre-diabetes trials show – staying tuned for now.

ADA 2005 - day one! June 10, 2005 - excitement abounds ...

ADA 2005
Close Concerns Blog

We’ve just arrived in San Diego today for the ADA. Fabuloso, that it is not in New Orleans or Orlando! San Diego – quick flight from San Francisco, the sun is shining, life is good ..

There are going to be over 12,000 people here and one can already tell. We attended a bunch of sessions today and everything was paaaaacked. Generally there hasn't been blowyouaway data but the tone is upbeat - new therapies out, new therapies on their way, excitement abounds. Here were some details from today ...:

• Comparison of Incidence of Topics for ADA Abstracts: Wow, so check these out. We compared keyword placement for last year versus this year. Of course keywords are just key-words, nothing more nothing less, but … metabolic syndrome has 208 placements this year in abstracts compared to 134 last year. Obesity now has 372, up from 299.  And inhaled insulin rose 80% from 10 to 18!

Comparison of Incidence of Topics for ADA Abstracts

Keyword               2003 2004 2005
Continuous        89        139        109
GLP-1               59        59        68
DPP-IV & DPP-4 7        11     15
Analog & Analogue 40     56        46
Obesity               283        299        372
Metabolic Syndrome 98        134        208
Inhaled Insulin 11    10        18
Pramlintide         8        8        4
Rimonabant         0     0        3
Dual PPAR         3        5        21

• Excellent sessions to start the day – one on insulin pumps and diabetes, with Drs. Wolpert, Bode, Schade, and Buckingham.  All the positives of pumps were discussed, with really the main negative being price.  Dr. Bode said that as of 2004, 250,000 people in the US have pumps. One question examined focused on type 2 patients – some said as many as 50,000 (“ok, 35,000”) type 2 patients wore pumps – Dr. Bode felt this was very high estimate. I agree. Really, probably no one knows! We need IMS for pumps : >.  This session was com-peting with multiple agent therapy for type 2 patients – Byetta looks good at 82 weeks, that’s for sure, in term of sustained (increased) A1C drop and reduced (further) weight.

• Metabolex’s metaglidasen is a novel TZD based on a single isomer of the compound halofenate, originally developed in the 1970s as a lipid-lowering agent. In original Phase III halofenate tri-als, Merck discovered that 50 type 2 diabetes patients who had accidentally been enrolled in the study saw lower blood glucose levels in addition to a reduction in lipid levels. Halofenate was never commercialized.  BUT! In a recent randomized controlled trial in 217 type 2 diabe-tes patients whose blood glucose levels were not adequately controlled by insulin therapy, the addition of metaglidisen (MBX-102) 400 mg lowered A1C by 1.0%±0.15% (± SE) from base-line (p<0.05), which was 0.7% better than placebo (p<0.05).  Lipid levels were unchanged ex-cept for a significant decrease in trigylceride levels with metaglidasen 400 mg (15% vs base-line, 38% vs placebo).  Metaglidisen looks unique among TZDs because it does not cause weight gain or edema. Metaglidisen was well tolerated and had less weight gain (0.3 and 0.7 kg) than insulin alone (0.8 kg). Edema was detected in 11.0 and 5.8% on metaglidasen 200 and 400 mg, respectively, and in 16.2% on placebo. We learned some of this from Dr. Julio Rosenstock and some from the company – we’ll be staying tuned.

• At the International Pancreas and Islet Transplant Association session, we heard about biolu-minescence as a possible method of detecting transplanted islet cell viability in vivo. To date, luciferin (the enzyme that makes fireflies glow) has been used to detect islet cell health in vivo in mice. Today, Alvin Powers (Vanderbilt University) explained the many potential benefits and few risks of luciferin in greater detail. Unfortunately, Powers concluded, luciferin will never find application in humans because the sheer quantity of body tissues between the loca-tion of implanted islets, whether placed in the portal vein of the liver or elsewhere, will absorb too much of the light given off by luciferin before it can be measured externally. Mice are small enough that luciferin can easily be detected externally using certain imaging techniques (but not by the naked eye, which would actually be pretty funny – would they be firemice?).

• In the Medtronic MiniMed corporate sponsored symposium, Dorothea Deiss discussed the German outcomes from the GuardControl trial, intended to showcase the utility of real-time continuous glucose monitoring for improving glycemic control in young type 1 patients. In 90 days, the A1C of the control group stayed at 10% while the A1C of the Guardian RT users reduced from 10% to 8.9%. This session was very well done – very popular – the excitement about continuous is nonstop.

• Chronic inflammation associated with obesity-- IL-6 in specific--was a hot topic today.  Dr. Robert Mooney from the University of Rochester pointed out that IL-6 levels are three to five times higher patients with insulin resistance and type 2 diabetes.  He said that IL-6 is a “bad guy” in the context of obesity and insulin resistance.  On the other hand, Dr. Bente Klarlund Pedersen accused TNF as being the driver behind metabolic syndrome and said that IL-6 is not to blame.  The proof from her view: she infused TNF in a study subject (never in the U.S.?!?) and found that TNF induced insulin resistance, resulting in an inhibition of glu-cose uptake.

• IL-6 is the center of more confusion: Dr. Bente Klarlund Pedersen found that high levels of IL-6 are associated with physical inactivity, but acute exercise causes an increase in levels of IL-6.  A paradox! Exercise enhances the transcription rate of the IL-6 gene in skeletal muscle.

• Said Dr. John N. Fain, in a sentence that captured our attention: “Human adipose tissue is like an endocrine tumor that is responsible for the hypertension and diabetes that accompanies obesity …” 45 minutes later, Dr. Bente Klarlund Pedersen added that skeletal muscle is also an endocrine organ, as it releases IL-6, which goes on to affect other parts of body. Who knew!

• Dr. Samuel Klein from Washington University in St. Louis spoke on the crisis of nonalcoholic fatty liver disease (NAFLD).  Steatosis is prevalent in 85% of people with extreme obesity, and cirrhosis is also frighteningly prevalent in cases of extreme obesity.  Dr. Klein said that NAFLD should be considered a part of metabolic syndrome.  As far as treatment goes for obesity, liposuction is not an effective way to treat fatty liver disease and insulin resistance.  He found that weight loss by dieting resulted in a decreased size of fat cells a decreased amount of fat in the liver and muscles.  Weight loss by liposuction, however, resulted in a de-crease in the number of fat cells but not a decrease in the size of the fat cells or a decrease in the amount of fat in the lever or skeletal muscle.  The therapeutic effects of gastric bypass surgery with respect to fatty liver disease are controversial, according to Dr. Klein.

• Dr. Meng Tan said that pioglitazone (Actos) lowers triglyceride levels more effectively than rosiglitazone (Avandia).

• Microcvascular complications and resulting nephropathy are generally indicative of larger car-diovascular dysfunction. Highly vascularized kidney is the canary in the coal mine said George L. Bakris, MD Considerations in the Management of Hypertension in  Patients with Diabe-tes.

• Impaired Glucose Tolerance can create dramatic effects in endovascular function (Richard Ne-sto, MD Managing the Metabolic Syndrome: The Evidence and the Options).

More soon – over and out …

Your ADA team: Kelly L. Close, Melissa P. Ford, Kaitlin L. Gamson, Clair A. Glogowsky, and Olayinka A. Olowoyeye