Close Concerns Weblog

Kendall on TZDs

Kendall on TZDs

In the current Diabetes Care (Jan 1), there is a piece by Dr. David Kendall that reviews and supports early TZD use, based on: 1) improved insulin sensitivity and beta cell secretory function; 2) role of TZDs to improve CVD risk factors (hyperglycemia, hypertension, dyslipidemia, endothelial inflammation markers [c reactive protein, white blood cell count, fibrinogen, TNF alpha] and markers of elevated thrombotic risk) and to reduce CVD events.

Strangely, there's a line about how the ability of glitazones to improve insulin secretion is unique among current diabetes therapies - this strikes us as odd because Byetta does this also, in the presence of hyperglycemia. However, it may be that this paper is based on the ADA 2004 debate with Dr. Philip Home - in that case, at that time, Byetta wasn't approved. The article notes that there was supposed to be a "counterpoint" to this paper but that the author didn't submit it.

Back on TZDs! Kendall's piece notes that metformin probably just masks hyperglycemia but how TZDs appear to both prevent and delay diabetes onset. Kendall suggests that this is explained by an "off-loading" of the beta cell due to reduced insulin requirements resulting from increased insulin sensitivity in peripheral tissue. Theoretically, he says, off-loading preserves beta cell mass and improves secretory response, allowing secretion of insulin for a longer period, and effectively preventing diabetes development. There are a bunch of trials in process examining TZD use for pre-diabetes; DREAM is probably the highest profile. We are following the trials with bated breath!

The implications for Byetta on early TZD use and eventually early DPPIV use are of interest - right now, SFUs seem relatively tough early therapy due to tolerability although the A1C drop is decent at ~ 1.0.

Since TZD use is associated with weight gain, edema, and congestive heart failure (to what extent is controversial), it seem particularly important to get alternatives out, especially for early therapy. That said, it appears that edema/CHF is seen less when TZDs are taken early in disease progression, though the impact of taking over a longer period hasn't yet been reported.

We expect TZDs to get a major boost from pre-diabetes progression data; evidence from these trials won't be available for some time, however.

DexCom in diabetes care – 10-day shows impact of CGM

Dex Com Publishes in Diabetes Care

The current (Jan 1) issue of Diabetes Care shows new research by Dr. Satish Garg, et. al.  - the first randomized controlled trial on continuous monitoring to be published (n=91, 75 type 1 and 16 type 2, nine days).  Although most of the data were presented at ADA, we hadn’t seen the special breakout of glycemic data at night, where there was a 38% reduction of time below 55 mg/dL (now known to us as profound hypoglycemia), a 33% reduction of time at 55-80 mg/dL (mild to moderate hypoglycemia), a 14% increase at 81-140, basically euglycemic, an 8% increase at 141 -240 mg/dL, and a 9% reduction at 241-400 mg/dL. Brilliant strategy to show this, both from regulatory and reimbursement perspectives.

Although this literally translates into minute differences (literally minutes of difference), any parent or patient can tell you that the less, the better. The 8% increase at 141-240 mg/dL was a bit unexpected, but this was only a 9-day trial. The continued hyperglycemia probably reflects “off” basal rates (or Lantus doses) – continuous would help all patients who want to improve control. The most notable line in the article was the third-to-last sentence:  “….with evidence of reduced exposure to hyperglycemia along with reduced risk of hypoglycemia, HMOs are likely to reimburse use of continuous sensors.” Check that out ~ the success of continuous monitoring certainly hinges, in our view, on reimbursement and coverage, so we’re heartened by the authors’ confidence (yes, seeing it in Managed Care Weekly might’ve been even more exciting, but to have the views respected of the researchers is certainly encouraging).  We expect approval of DexCom’s STS in early to mid 2006. 

JDRF names Arnold W. Donald new President and CEO

After six years of leadership, Peter Van Etten, the President and CEO of the JDRF, is retiring, and the JDRF announced Wednesday that Arnold W. Donald will be instated as the new President and CEO. Mr. Donald has spent much of his career at companies that focus on pharmaceutical, agricultural, and other food products, most recently as Chairman and CEO of Merisant Company. For more details on Mr. Arnold’s background, see the press release below. Under Mr. Van Etten’s leadership, the JDRF has really worked as a catalyst in accelerating progress toward a cure – a role that is very much needed in the often slow-moving world of research. As of late, we’ve written much about Goal Six, the JDRF’s goal of achieving an artificial pancreas, and the JDRF’s involvement was critical in bringing together the NIH, FDA, and industry, as well as members of the JDRF, at this week’s meeting in Bethesda to discuss the artificial pancreas (see DCU #54). Mr. Donald’s background is impressive and we look forward to seeing him guide the JDRF’s drive for a cure and improved therapeutics for patients with type 1.

BusinessWeek names Byetta a best product of 2005 ~

Check it out. Byetta is one of BW's top products for 2005. So the interesting thing is that there are fewer than 40 products on this list! Diabetes of course has gone mainstream this century ~

A picture of the Byetta pen is shown, along with the phone number, the website, and assurances that most of the "$2700/year" price will be covered by insurance. http://images.businessweek.com/ss/05/12/bestproducts/index_01.htm?campaign_id=yahoo

And! The Byetta pen is in good company, right alongside the 2006 Michelin Red Guide for New York City and the Porsche Cayman S.

OSI pharmaceuticals grants license for DPPIV

OSI Pharma says it has granted a ww nonexclusive license for its DPPIV patent portfolio to a "major British pharma company" (press release below). These are "non-exclusive" licenses - OSI already granted Merck and an undisclosed Japanese company non-exclusive licenses to this portfolio in June and July, 2005. PSN 9301 apparently emerged from a proprietary DPP IV technology platform developed by the German company Probiodrug - the drug was licensed for $35 million plus future milestones in June '04, not that high for a drug in phase 2. They announced preliminary positive results earlier this month in a phase 2a 51-patient study: data showed that AUC was reduced by 24-42% compared to placebo (?) in the three highest doses - mean 24 hour blood glucose didn't reach significance (reduced by 13%). No hypo; no info on weight gain. Sounds like this is still pretty early though its worth noting that in preclinical studies, the compound is said to have delayed progression of glucose resistance in Zucker rates. The companies with DPP-IVs in development still seem to all have the same habit of trying to make safety synonymous with side effects. While the side effect profiles seem clean, the mechanism of action still isn't well understood for the class (what else is being inhibited, etc. - remains a question) so safety hasn't been established, though many of the companies would have you believe otherwise. It would be interesting to see what the potency of this particular lead compound is. The one upside for DPPIVs is that it may be these drugs will do well in combination with patients whose diabetes isn't so progressed - they aren't that potent, but they are better than SFUs and maybe that's all some of the very early patients need -- seems like the companies are preparing to market these as SFU replacements.

Muraglitazar - R.I.P.?

The BMS/Merck partnership over muraglitizar is finally over, as of a press release just out - all rights officially returned to BMS yesterday. This is as expected - Merck appears to be pouring more funds into its DPP-IV, though hallway conversations at its analyst meeting seemed to imply extra funds wouldn't necessarily go toward diabetes. BMS says it is still talking to the FDA about what it will do. It appeared from the analyst meeting that it already feels a little guilty about stopping development so ... we would guess that'll be the next announcement on this drug but it's still unclear. At the very least, we expect it to be several years before muraglitazar reemerges. BMS said at the analyst meeting off-podium it would announce a decision in the first half of 2006.

EDIC => Landmark data on the importance of glycemic control and macrovascular risk

Close Concerns on the DCCT/EDIC Study Research Group on “Intensive Diabetes Treatment and Cardiovascular Disease in Patients with Type 1 Diabetes”

In the New England Journal of Medicine dated today, Dr. David Nathan of Mass General penned, with the DCCT/EDIC study group, a landmark piece on the importance of tight glycemic control on macrovascular risk. This data was presented at ADA this year as a late-breaker and we called it in our ADA wrap-up the most important data coming out of the meeting (see DCU, June-July 2005), because it really reinforces what DCCT showed - but for macrovascular risk rather than just microvascular risk. As cardiovascular disease dangers have become more clear this year, the ability to prevent them is all the more important.

We found these data striking as they indicate that in EDIC intensive treatment in the form of a 1% A1C drop lowered the risk of any CVD event for type 1 patients by 42% and lowered the risk of nonfatal myocardial infarction, stroke, or death from CVD by 57%. As you may recall, a 1% drop had reduced microvascular risk by closer to ~ 25% with DCCT. These EDIC results are impressive results and reinforce not only the utter importance of getting patients in tight glycemic control, but in getting patients under control early in the course of their disease state, because when the two groups were compared, both had A1Cs around 8, but the intensively treated group that had far less CVD, had had scores of under 7 during much of the DCCT itself.

The paper touches on the concept of metabolic memory - basically that the intensively treated group had significantly less macrovascular disease than the control group did, 11 years out, even though their A1C scores essentially converged at around 8%. This underscores, as noted, the importance of tight control early on in the course of disease. Dr. Cefalu, who wrote an accompanying editorial, says that it is difficult to convince people to adhere to intensive therapy, basically defined at four shots a day. We're less sure about how difficult it is, but we think it will become easier - just as we think continuous monitoring will make improved glycemic control much easier. Too, we strongly believe Symlin will make this it easier in the future to reach glycemic targets.

By and large, we believe EDIC results should have the impact of underscoring the importance of tight control, which should be positive for all companies working on blood glucose and insulin pumps and A1C visibility as well as drugs designed to improve glycemic control.

Interestingly, no one can really explain this “metabolic memory” although I’m sure that more ideas will be forthcoming– but the conclusion to the study in the editorial by Dr. Cefalu certainly indicates that tight glycemic control is imperative. It questions, moreover, whether current glycemic targets are too high, and essentially arrives at an impasse, noting that to date, glycemic targets have not been met by most patients and questions what lowering the goals further would do. We would think that goals should be lowered if there isn’t a lower threshold (which their doesn’t appear to be) for the benefits of tight glycemic control. We believe hypoglcyemia is the largest barrier to tight glycemic control, and that as such, more funding and focus should be put on reducing the risks of glycemic variability – it should be pointed out here (but isn’t) that hyperglycemia often prompts hypoglycemia (overcorrections), etc.

Nice visibility all around for such an important topic though we really feel like one next big step is to get more focus on glycemic variability (GV) - no one really seems to focus on it now beyond a few critical thought leaders. The final big question stemming from this piece is whether this analysis can be extended to type 2 patients – we will be watching ACCORD and Bari-2 trials closely for more visibility on this front.

Aymlin adds fabulous BOD member, Dr. James Gavin

Hurrah for Amylin, the company has added yet more strength to its board of directors by bringing on Dr. James R. Gavin (see press release below). Dr. Gavin is a powerhouse - he is known for a passionate desire to facilitate the translation of meaningful clinical/academic findings and best practices to the understanding and implementation of the primary care givers and then on to the "masses". He has a unique ability to teach appropriate diabetess care and to share pearls of information that are meaningful in a simplistic manner such that those not as deep into the science of diabetes can understand the value and implement it. He is also known for taking proven outcome information and tries to translate it for use by all ethnicities and persons of all backgrounds. He is incredibly respected and extremely proficient - as a past ADA President, he has enormous contacts that we believe will be of big help to Amylin as sales continue to expand for Byetta and Symlin.

We last heard Dr. Gavin speak at AACE and ADA, last May and June, respectively. At AACE, he gave a talk on paradigm shifts in how diabetes is approached - there, one of his areas of focus was ways in which macrovascular risks also apply to prediabetes. Another wake up call! At ADA, he focused in part on ways in which glycemic control is worsening in the US, and how a new approach is needed - clearly, Amylin has some different approaches, and it will be fascinating to watch how Dr. Gavin's views will be integrated into the company.

Amylin Pharmaceuticals Elects Dr. James Gavin to Board of Directors

SAN DIEGO, Dec. 21 /PRNewswire-FirstCall/ -- Amylin Pharmaceuticals, Inc. (Nasdaq: AMLN) today announced that Dr. James R. Gavin III was elected to the company's Board of Directors on December 16. Dr. Gavin will serve on Amylin's Nominating and Governance Committee.
"We're thrilled to welcome Dr. Gavin to the Amylin Board," said Ginger L. Graham, President and CEO of Amylin Pharmaceuticals. "His extensive diabetes knowledge, distinguished academic career, and substantial board and governance experiences will be a tremendous asset to Amylin's Board of Directors."
Dr. Gavin currently serves as Clinical Professor of Medicine at Emory University School of Medicine and is Executive Vice President for Clinical Affairs for Healing Our Village, Inc. He also serves as National Director of the Harold Amos Medical Faculty Development Program. He previously held numerous research and academic positions including Senior Scientific Officer at the Howard Hughes Medical Institute (HHMI) and Director of the
HHMI-National Institutes of Health Research Scholars Program. Dr. Gavin was also the William K. Warren Professor for Diabetes Studies and Acting Chief, Section of Endocrinology, Metabolism, and Hypertension at the University of Oklahoma Health Sciences Center.
He has served as president of the American Diabetes Association and on the editorial board of The American Journal of Physiology. Dr. Gavin is immediate Past Chair of the National Diabetes Education Program. He is also a member of the Institute of Medicine of the National Academies of Sciences and the recipient of numerous awards, including the Banting Medal for Distinguished Service from the American Diabetes Association. He serves as director for several organizations including Baxter International, Inc. and MicroIslets, Inc. and is a member of the Board of Trustees for Duke University, Livingstone College, and Emory University. Dr. Gavin received a B.S. in Chemistry from Livingstone College, a Ph.D. in biochemistry from Emory University, and an M.D. from Duke University.

Amylin Pharmaceuticals is a biopharmaceutical company committed to improving lives through the discovery, development, and commercialization of innovative medicines.

SOURCE Amylin Pharmaceuticals, Inc.
-0- 12/21/2005
/CONTACT: Mark Foletta, VP, Finance and CFO of Amylin Pharmaceuticals, Inc., +1-858-552-2200/

JDRF prompts excitement surrounding closed loop

There were a range of highlights coming out of the NIH/FDA/JDRF meeting “Obstacles and Opportunities on the Road to an Artificial Pancreas: Closing the Loop” that met in Washington DC today.

1. Overall, the FDA appears extremely refreshed and engaged in the project regarding the closed loop.

2. Glycemic variability is very negative and should be reduced – this theme was stressed by a number of doctors, including Dr. Tamborlane, Dr. Clarke, and Dr. Bergman. Dr. Bergman put it in the context of macrovascular disease and noted that although many type 1 patients had no sign of microvascular complications, macrovascular complications were extremely common and were exacerbated by glycemic excursions.
o The dangers of hypoglycemic related to the central nervous system (CNS) were stressed, as were the dangers of hyperglycemia.
o In particular, the dangers of high post-prandial glucose were emphasized – it seems to be thought by many speakers that previous thresholds for hyperglycemia should be reduced.
o In addition, it appears to be that not just insulin, but other hormones in the body are missing in those with diabetes, including GLP-1 and amylin. Additionally, dangers surrounding lipids were discussed – these are thought to be very central to heart disease.
o Overall, we felt that the needs of patients were spelled out extremely starkly - this was a positive, as it underscored the absolute need for the next generation real-time monitoring to be approved and reimbursed and covered!

3. Unpublished data by Dr. Michael Brownlee showed that after as little as 90 minutes of exposure to 180 mg/dL blood glucose, prostacyclin synthetase activity shuts down for 24 hours in non-diabetic subjects. Prostacyclin synthetase is a major anti-atherosclerotic enzyme.

4. The degree of the closed loop was discussed – it was felt that modified open loop is a good place to start, by and large, although several of the participants had the view that a more ambitious goal should be undertaken. The whole theme of “incremental or more?” resonated throughout the entire meeting.

5. The FDA did not make it clear what it is “looking for” in terms of continuous data; rather, they stressed that companies should decide what indication they are pursuing and then they should give the FDA the data to back it up. In short, it shifted responsibilities back to clients. The agency urged companies to be in touch with the agency early on in trial design planning and suggested it would take 120-180 days to get an application reviewed and approved. “If it’s a horrible filing, it might take up to three years!”

6. Ultimately, the FDA appeared to suggest that companies begin with a narrow label and generate market experience, returning when they are ready to seek a broader label. For the first time in memory, the FDA noted that it would certainly consider quality of life data.

7. Physiology in people without diabetes is very precisely controlled. No wonder it is so difficult to copy!

8. Aaron Kowalski urged attendees to look at the standard of care today and to note that there is a lot of room for improvement across a variety of fronts.

9. Dr. Chirstopher Saudek suggested that patients will have too much data to look at – Abbott reimbursement director Jay Dunigan had a wonderful response as he reminded doctors that 30 years ago, the same issues existed in terms of home blood glucose monitoring. Too, he urged clinicians to choose the right patients for data management and to consider the best data management for them.

10. Dr. Bill Tamborlane stressed that the loss of physiological defenses against hypoglycemia in patients with diabetes is an acquired loss, caused by diabetes treatment itself.

11. Dr. Michael Brownlee said that we have the tools reduce the risk of microvascular complications by 2/3 using current diabetes treatment tools, without even developing a closed-loop system. He showed data from Dr. Hirsch showing that even at the same A1C, patients from the DCCT who were intensively controlled had 2/3 the risk as patients who were in the conventional control group. The key is to reduce glycemic variability while maintaining a low A1C.

12. In relation to the glycemic variability idea, Dr. Irl Hirsch posed the critical question: "When will we recognize, as a group, the glycemic variability is an independent risk factor for glycemic complications?"

13. Controversies included the following:
o Reportable vs adjunctive
o Timing – how long will it take?
o Projects that are incremental versus big movements

The day's agenda:

OPTIMAL TARGETS: WHAT LEVELS OF BLOOD GLUCOSE SHOULD WE BE SHOOTING FOR?

Chair and Discussion Leader: Francine Kaufman, Children’s Hospital Los Angeles

1. Hypoglycemia: The Barrier to Effective Insulin Therapy
Bill Tamborlane, M.D. (Yale University)

2. Hyperglycemia and Diabetic Complications
Michael Brownlee, M.D. (Albert Einstein College of Medicine)

3. Clinical Trial Design
Christopher Saudek, M.D. (The Johns Hopkins University)

WHERE DO WE STAND? THE CLOSED LOOP SYSTEM
Chair and Discussion Leader: Irl Hirsch, University of Washington

1. What Is the Perfect Artificial Pancreas? Nature’s Specifications
Richard Bergman, M.D. (Keck School of Medicine, University of Southern California)

2. The Fast Track To Make the Artificial Pancreas a Reality for Children with T1DM
William Tamborlane, M.D. (Yale University)

3. Mechanical Artificial Pancreas: Current Issues and Future Directions
Jeffrey Joseph, D.O. (Thomas Jefferson University)

4. Semi-Closed Loop Algorithms: Practical Experience
Guido Freckmann, M.D. (Institute for Diabetes Technology, University of Ulm, Germany)

TECHNICAL CHALLENGES
Chair and Discussion Leader: Bruce Buckingham, Stanford University

1. Amperometric Glucose Sensors: Design Factors and Biological Issues
W. Kenneth Ward, M.D. (Legacy Health System)

2. Glucose Sensor Biofouling
Francis Moussy, Ph.D. (University of South Florida)

3. Algorithms for Continuous Glucose Monitoring and Control
B. Wayne Bequette, Ph.D. (Rensselaer Polytechnic Institute)

4. Statistical Considerations
William Clarke, M.D. (University of Virginia Health System)

INDUSTRY PERSPECTIVE: ROUNDTABLE DISCUSSION

Kerstin Rebrin, Abbott Diabetes Care
Garry Steil, Medtronic Diabetes
Jim Brauker, DexCom
Matthias Essenprais, Roche

REGULATORY CHALLENGES: COMMENTS AND ROUNDTABLE FROM FDA

Steve Gutman, M.D., Office of In Vitro Diagnostics
Patricia Bernhardt, Office of In Vitro Diagnostics
Marina Kondratovich, Ph.D., Office of Surveillance and Biometrics
Shewit Bezabeh, M.D., M.P.H., Medical Officer
Ron Kaye, Human Factors Group
Anthony Watson, M.S., M.B.A., Chief of General Hospital Device Branch

J&J buys Animas - win/win

J&J’s LifeScan announced this morning that it intends to buy Animas Corporation for $518 million in cash, or $24.50/share, a 35% premium over Animas’ closing price yesterday. We think this acquisition makes very good strategic sense – essentially it’s the #1 glucose monitoring company buying the #2 pump player – how can that not be an excellent combination for both? All day, we heard the same question, were we surprised? Not so much, just glad. In some respects, this was a classic J&J deal – Animas is newly profitable this year, the deal is immediately accretive, and offers J&J an excellent leg up. Now, while Animas is #2, it is still far behind leader Medtronic, whom we’ve been very impressed by under new leadership over the last year by cardiac surgery veteran Bob Guezuraga, who appears very serious about taking the business to the next level. Lots of ambition all around – what could be better?

What J&J gets:
• A valuable new technology platform in the form of Animas’ insulin pump franchise.
• Next-generation pump technology with Animas’ Debiotech micropump. Starting with Insulet, we believe next-generation insulin pump technology will be game changing, particularly as we near the advent of real-time continuous, which reinforces the value of physiologic delivery.
• Top notch infrastructure. Animas has built fantastic infrastructure all around, from an incredible sales force - 55 top notch reps supported by 70 so-together CDEs - to stellar reimbursement (major, especially if J&J acquires a continuous player) and smooth fulfillment.
• Tight patient and professional relationships. Animas has built extremely strong relationships with a coveted group of patients, the intensively and hyper-intensively managed.
• Potentially key intellectual property in the general area of continuous glucose monitoring, specifically fully implantable infrared sensor and fourth-generation Cygnus technology.
• Oh, and growth and immediate accretion… While this purchase is clearly a strategic play, Animas’ expected revenue of ~$105+ million in 2006 adds about 5 percentage points of growth to LifeScan’s expected 2006 base of $2.2+ billion. How excellent will it be to have 300+ LifeScan reps humming about the benefits of pump therapy? The deal should be immediately accretive, which matters to large-cap investors.

What Animas gets:
• Significantly deeper R&D pockets.
• Sales and marketing prowess.
• Strong international presence.
• Outstanding clinical research team.
• Exciting product integration.
• Less scrutiny.

Why is this good for patients? From a patient perspective, we think this combination bodes well as we expect it to prompt faster innovation industry wide as competition heightens. J&J will come up to speed quickly on pumps and will offer very welcome resources.

Why is this good for investors? From an investor perspective, Animas shareholders did quite well from a premium perspective and both sides got a good deal in our view. From a multiple perspective, J&J paid on a trailing revenues basis about 7.6x trailing sales – more than Abbott paid for TheraSense (5.7x) in 2004 or Roche paid for Disetronic (5.1x) in 2003 but a lower multiple than Medtronic paid for Minimed (11.2x) or J&J paid for Inverness (11.2x), both in 2001. We frankly wouldn’t want to be across the table from either team in a tough negotiation – CEO Kathy Crothall once again did an incredibly admirable job for her shareholders, in selling a third company to J&J.

What’s next? We think continuous will be the next step for J&J and suspect plenty of work has been ongoing behind the scenes already. Clearly, J&J with valuable pump and continuous platforms will make it a formidable competitor to both Medtronic and Abbott. They’ll have infrastructure, they’ll have the pump platform, they’ll have the management … stay tuned!