Close Concerns Weblog

Dex Com continues momentum

Dex Com CEO Andy Rasdal presented at Lazard's meeting today in NY. Key takeaways:

1) They will their STS pivotal trial study published in Diabetes Care in Jan 2006 - this will be the second Diabetes Care publication for this young company - very impressive - and will be the first prospective continuous trial published, full stop. 2) It is too soon to say conclusively (probably) but it's looking less and less like a panel meeting will be required for the STS - we think, more to the point, that even if a panel meeting is required, we really can't imagine that approval wouldn't be granted. Although a panel meeting would delay a launch, it would also probably generate some great media; 3) Dex Com has 18 patient-years of data, which we understand translates to use in 500-600 patients; 4) The company says they have HCP training to less than one hour and patient training to less than half an hour - "easy to teach and learn" is key, and this is quite something if it holds; and 5) Their next submission, the 7-day sensor, is done and ready to be submitted; to boot, the company was clear that replacement claim labeling is next - on this front, Dex Com looks to be in discussions with the FDA and clinicians on the most appropriate study design. Feasibility studies were initiated two weeks ago. Serious investment looks to be going into this, which seems very appropriate.

All in all, looks to be very strong momentum and we would expect an approval in the not too distant future. Reimbursement will be the next hurdle and we would imagine all the players would benefit from Medtronic's investments on this front. We'll be staying tuned ...

Consumer demand for obesity drugs real

We've heard a lot of predictions that rimonabant uptake will be accelerated by patient demand, and we're convinced that discussion of obesity drugs has hit the mainstream media: this month's issue of Shape magazine (yes, Shape!) informs readers that "researchers are working on new diet pills to help curb cravings. One is rimonabant (trade name Acomplia), and one is dubbed APD356." If Shape magazine is reporting on these drugs before they're even available, we expect an explosion of interest in obesity drugs - though we think it's fascinating that Acomplia is being touted as a "diet drug," which in our view, seems a bit different than a drug for the medical condition of obesity.

GLP-1 competition looks like it may finally emerge, through Novo's Liraglutide, in 2009

These results on liraglutide came out Friday, when we were eating leftover cranberry sauce:

Key takeaways are: 1) The results of the 165-patient Phase 2b trial look very good, although this is still Phase 2 data - we don't see the data as as good as LAR data, though they are being positioned similarly; 2) Nausea of 5-10% was a major positive; 3) Some may make a lot of the fact that the A1C drop compared to placebo was 1.5-2 points... this isn't so notable in our view since still only 45% got to an A1C of less than 7 from a starting average of around 8.4-8.5%. It sounds like the placebo arm actually increased somewhat significantly - otherwise, well more than 45% should be at less than 7%! It's also possible some patients experienced significant reduction in A1C (say over 2%) while others didn't. Bottom line, while we think the 1.5 - 2 point A1C drop is very impressive, it is irresponsible in our view not to quote BOTH from baseline as well as from placebo so that we have the right context. 4) Average weight loss was 3 kg for this trial - good. 5) There was no "major or minor" hypoglycemia - none would be expected since this is a monotherapy study.

If this data holds in Phase 3 trials, there would be some distinct advantages vs Byetta, namely once-daily dosing and far less nausea. The dosing for Liraglutide is confusing, however, so much so that we don't really want to discuss it. One disadvantage versus Byetta is that dosing isn't nearly as low as Byetta, thus a larger gauge needle is probably needed. This may sound like not a big deal, but it actually does make a big difference.

One might ask should we compare Liraglutide to Byetta or LAR. Versus LAR, which we might expect to be approved around the time liraglutide is approved, we see no advantage and some disadvantages (once daily vs once weekly, mainly, plus competetion against the established leader). Phase III trials with 3800 patients should start in February 2006 - we would assume approval would come around in 2008 at the very earliest, more likely 2009. One question has arisen, why the HUGE trial - Byetta phase III trials were less than half the size. We assume Novo is looking for a lot of subsets that they can call significant.

Novo didn't give more data than this (press release below, as no doubt you have seen) - more will be given at upcoming scientific meetings - likely AACE or ADA. In the meantime, we're very curious about baseline A1C info, when the baselines were taken, how the control group was washed out, etc.

Overall, this is the best competitive data we've seen - and we do look forward to seeing all the details, since some of the takeaways, namely the 1.5-2.0 drop, still confuse us, and it will be terrific to get more details on dosing.

********

Press release

Promising clinical results from liraglutide phase 2b study (25 Nov 2005)

Read in PDF format
Providing glucose control and weight loss without hypoglycaemia
Novo Nordisk today announced clinical results from its phase 2b study of the safety and efficacy of liraglutide, the once-daily, fully-human GLP-1 analogue. The study, which was a double-blind, placebo-controlled, randomised, monotherapy study over 14 weeks, included 165 patients with type 2 diabetes that were previously treated with diet or oral antidiabetic agents.

An improvement of haemoglobinA1c (HbA1c) of between 1.5 and 2 percentage points was achieved by treatment with liraglutide compared to placebo. At the highest dose more than 45% of patients achieved a target of HbA1c equal to or below 7% compared to less than 8% treated with placebo. An HbA1c level below 7% is recommended by the American Diabetes Association. The average HbA1c level at the beginning of the study was just below 8.5%.

At the highest liraglutide dose the improvement in fasting plasma glucose achieved was above 3 mM (> 54 mg/dl). In addition, these patients reduced their bodyweight by approximately 3 kg from a baseline of around 90 kg.

Liraglutide was well tolerated and nausea was reported at a level of 5-10%. Gastrointestinal side effects occurred most frequently in the beginning of the study, whereafter the frequency decreased substantially. There were no cases of major or minor hypoglycaemia in spite of the significant improvement in glycaemic control.

Mads Krogsgaard Thomsen, chief science officer and executive vice president of Novo Nordisk, said: "The impressive clinical data for liraglutide holds great promise for improving the treatment of type 2 diabetes; simultaneous glucose control and weight loss in the absence of hypoglycaemic events."

Novo Nordisk expects to communicate full results from the phase 2b study at a scientific meeting in 2006. As previously communicated, phase 3 studies with liraglutide including approximately 3,800 patients are expected to start in February 2006.

Novo Nordisk is a healthcare company and a world leader in diabetes care. The company has the broadest diabetes product portfolio in the industry, including the most advanced products within the area of insulin delivery systems. In addition, Novo Nordisk has a leading position within areas such as haemostasis management, growth hormone therapy and hormone replacement therapy. Novo Nordisk manufactures and markets pharmaceutical products and services that make a significant difference to patients, the medical profession and society. With headquarters in Denmark, Novo Nordisk employs approximately 21,600 full-time employees in 78 countries, and markets its products in 179 countries. Novo Nordisk's B shares are listed on the stock exchanges in Copenhagen and London. Its ADRs are listed on the New York Stock Exchange under the symbol 'NVO'. For more information, visit novonordisk.com.

Banning surgery below BMIs of (gasp ...) 30 in where else, England

This just in from BBC - some surgeries are apparently being denied because of high BMI. Seems like some Suffolk, England healthcare organizations have put a blanket ban on hip and knee replacements unless a person's BMI is under 30, the idea being that anyone with a BMI over 30 should lose weight before just being approved for surgery.

Some Brits close to me argue that healthcare in the UK is fantastic - and certainly here, we have our problems, MANY of them ... but I always say that in the UK, healthcare is fantastic til you need anything. Case in point today -

On that note, Happy Thanksgiving to the Americans and friends of America!

***
Obese patients denied operations
Obese people are to be denied some surgical procedures in a bid to cut costs in the NHS.
Three Suffolk primary care trusts have ruled patients with a body mass index (BMI) over 30 will not get operations like hip and knee replacements.

A person of average weight would have an BMI of between 18.5 and 24.9.

Dr Brian Keeble, a director of Ipswich PCT said: "We cannot pretend that this work wasn't stimulated by pressing financial problems."

Under new guidelines surgery will not be performed unless "the patient has a body mass index below 30 and conservative means have failed to alleviate the patient's pain and disability".

This level condemns a quarter of the population to misery - there's a huge number of people with a BMI of over 30
Dr David Haslam, National Obesity Forum
"Pain and disability should be sufficiently significant to interfere with the patient's daily life and/or ability to sleep."

Hospital consultants and GPs in East Suffolk came up with a list of 10 conditions for which there must be a threshold in order for surgery to be performed.

Included in the procedures for which there are conditions are such things as varicose veins and grommets for glue ear in children.

Dr Keeble said: "Our work on clinical thresholds has been a key part of this process.

"We started from the idea that operating on some conditions, either at an early stage or before other treatments have been tried, could actually be detrimental to the patient because of the risk of side effects from the procedure."

To deny someone surgery because they are obese, unless there is a clinical reason, is unfair
Patients Association
But he admitted financial pressures were a factor in the decision.

"I believe that these thresholds will produce some clear benefits in that both patients and their GPs will know when these procedures will be performed," he added.

The clinical director of the National Obesity Forum, GP Dr David Haslam, said that he was alarmed by the level being set at a body mass index (BMI) of 30.

"This level condemns a quarter of the population to misery - there's a huge number of people with a BMI of over 30.

"The argument that the life of joints is reduced because people are overweight is more relevant to those with a BMI of above 40.

Ruling 'unfair'

"But I think that the trusts would be better off treating obesity or getting people to lose weight rather than introducing a blanket ban," Dr Haslam said.

A spokeswoman for the Patients Association said: "People are obese for all sorts of reasons.

"Unless there is a clinical reason for not carrying out surgery they should be entitled to have an operation as anyone else would be.

"People who are obese need education and help about healthy living. To deny someone surgery because they are obese, unless there is a clinical reason, is unfair."

A spokeswoman for the Norfolk, Suffolk and Cambridgeshire Strategic Health Authority said: "Patients will be assessed according to their clinical needs, as is the norm, and if necessary advised to lose weight before treatment, which will reduce the risks and improve outcomes for surgery.

"The message is that patients who need clinical treatment will get it."

Addition of Amylin's Byetta lowers A1c in poorly-controlled TZD patients

Addition of Amylin's Byetta lowers A1c in poorly-controlled TZD patients

New results on Byetta are out today from Amylin and Lilly, this time from a study of Byetta as an addition to TZD therapy. In a 16-week study of 233 poorly-controlled type 2 patients on TZD therapy, 62% of patients who added Byetta to their regimen achieved an A1c below 7%. In the control group, only 16% of patients achieved an A1c of less than 7%. The average A1c of participants at the start of the study was 7.9%, a relatively low baseline, indicating that Byetta could be useful to patients with poor control seeking to advance to tight control.

While weight loss is typically unheard of for TZDs, the patients who added Byetta lost an average of three pounds during the study, while control patients saw no change in weight. Weight gain is one of the more disturbing side effects of TZDs. Nausea was the dominant side effect, occuring at a rate of 40% in comparison with 15% in the control group. This rate of nausea is actually a bit lower than what was seen in the AMIGO trials (around 50%).

We look for Byetta to continue to be used more broadly as more data is announced and published - the Byetta label would likely be expanded in early 2007 as a result of an FDA submission for the TZD data in mid-2006 (data crunching takes awhile!). There is a lot of other information about this trial we'd like to see and we'll look for abstracts at the 2006 ADA meeting in DC (June 9-13) and publications late next year. (Deadline for abstract submission to the ADA is Jan. 9, with the late-breaking abstract submission deadline in early April, which is probably how the LAR data will be submitted.) Specifically, we're curious to see if there is A1C improvement and more weight loss at 30 weeks (timing for AMIGO studies, compared to this 16 week study) and we would expect reduced nausea for some patients at that time.

Separately, we would love to see a study of Byetta naïve and TZD naïve patients to see what the synergistic effects would be, i.e., what the A1C drop would be when patients go on both compounds together for the first time. TZDs provide help to patients on the insulin resistance front, which Byetta doesn't do so we're fascinated by that combination. We also wonder the extent to which a relatively lower dose of TZDs would prompt less edema/CHF.

The big label expansion we'd like to see explored with Byetta is for patients with pre-diabetes - that would likely be an extremely long study but potentially quite a powerful one. No word on whether this is in the works so pure speculation on our end ~

AHA musings - drugs and more drugs and more on FIELD

AHA musings - drugs and more drugs and more on FIELD

So we keep talking about how cardiology is becoming so much more focused on endocrinology and diabetes ... welllll, that's sort of true, but we believe it's a bit less apt than we had thought, based on a wild search about drugs on the exhibit floor, where we lived the following:

BMS/MERCK:

Kelly: "Hi, are you giving any information about Pargluva here?"
Medical Rep (irritated): "Absolutely not!"

LILLY:

Kelly: "Hi, are you giving any information about Byetta?"
Rep (confused): "By-what?"
Kelly: "Byetta."
Rep (mystified): "By-ate-a?"
Kelly (incredulous): "Yes, Byetta! You know your amazing new drug, the GLP-1?"
Rep (sad): "I don't know about it." (Turning to another rep ... "Do you know about - what is it called? - Byetta?"
Second rep (enthusiastic): "Oh yes! That's doing great! But we don't have it here. That's not our division."
Kelly (questioning): "But aren't cardiologists moving into diabetes? Don't you have a big diabetes division? How can you not have Byetta here?"
First Rep: "Yeah! How can we not have Byetta here? Here, can you fill out this comment card and we'll get you some info .... let me swipe your badge!"
Overweight doctor from Cornell, joining the conversation: "How about Symlin!"
First Rep: "Sim-lin? What's Sim-lin?"
Second Rep: "Sim-lin? What's Sim-lin?"

GLAXO-SMITH-KLEIN: 
Kelly: "Hi, are you giving any information about Avandia here?"
Rep (on it): "YES! Please go see this film and then I'll answer all your questions! This is a very important area for us."
There is a film, starting Della Reese and some of her friends with names like Fred and Millie. This is sort of well done, not on the Sanofi scale (see below), but they have a new little song "Get Rosi on board..." It has a nice ring to it and I might find myself singing it to Coco if I'm not careful. The whole film is brilliant at giving data that isn't WRONG exactly, but also isn't footnoted, and if it were, wouldn't be sourced from, say, a NEJM published study. There are statements from the narrator like "In another study, there was an A1C drop of 1.5%, in patients with A1Cs of 9% or higher. Then in another study, there was an A1C drop of 3%, where the baseline was 11.5% - dropouts were high, but it's much better to go on Avandia than up-titrate Metformin! 50% of patients got to goal! Yes, adding Avandia works on core defects - lowering insulin resistance and improving beta cell function ... " 

After the film (which was packed for all three times I watched it), the reps came back, offered coffee commuter cups (with red "get Rosie on board" labels), and $30 coupons for a program called "I Can.." (see www.avandia.com - they are taking the DTC pretty seriously.) To top it off, they gave away Hershey's kisses. I took 10 and ate them on the spot, shooting up Symlin as I went .. "What's that?" the rep asked ...

Maybe it's just me, but it really seems like in a little bit here, we're going to start hearing a LOT about TZDs and prevention of diabetes. They are just gearing up...

ABBOTT: I went here before FIELD was announced (see previous post).  They were happy and nice and told me FIELD slides would be up November 17 at www.lipidforum.com.  They then offered some excellent espresso and biscotti.  I asked them about mixing fenofibrate with a glycemic lowering compound and doing a combo drug ... "are you nuts?!" the rep asked.  Score one for Abbott on that basis alone ... we talked about how combo drugs are overrated, how dosing is complex, how if the drug works it is fantastic, but if it doesn't, the doc gets a million calls ... I went by after and dejection abounded. I know it's not as positive as it would've been had it been a positive study, but I think either way, it's got to be good add-on therapy, no?

PFIZER:

Kelly: "Hi, are you giving any information about inhaled insulin?"
Rep: "Go talk to the medical director - we're just reps."
Kelly: "Hi, are you giving any information about inhaled insulin?"
Medical director: "No, we're not really saying much about that."
Kelly: "Do you think it'll be approved soon?"
Medical rep: "Let me show you some data on Lipitor ..."

TAKEDA:
Kelly: "Hi, are you giving any information about Actos?"
Rep: "Why, yes! What can we tell you?"
Kelly: "Is it being used as first-line therapy?"
Rep: "Yes! And for pre-diabetes!"
Kelly: "Really? I hadn't realized that trial had come out yet. What did those results show!?!"
Rep: "Well, the trials aren't completed yet. We do not encourage use for pre-diabetes. But it is being used for that."
Kelly: "The ADA '03 DPP data was really powerful with Troglitazone, showing a 70% reduced progression to diabetes ... compared to much lower for Metformin and lifestyle ..."
Rep: "Yes, and you should see the follow up gestational data ..."
Kelly: "How's the edema and CHF?"
Rep: "Well, patients need to be chosen and followed appropriately ...they are seeing a lot fewer problems like that in pre-diabetes .. they are the younger, relatively healthier patients, of course ... now this drug is great in combo with Metformin ...."
Ironically, the Lilly reps _were_ at the Actos booth, since they co-market it for a bit longer ...

ASTRAZENECA:

Kelly: "Hi, are you giving any information about Galida here?"
Rep: "No."
Kelly: "Nothing you can say about this dual PPAR?"
Rep: "We haven't been talking about dual PPARs much lately ..."
Kelly: "Because of the FD ..."
Rep (interrupting): "Yes.  But check out our LDL/HDL ratio with Crestor .... "
The conversation then turned to another discussion of how combination therapy isn't as easy as it looks (dosing, mixes, etc.), which I buy, and then to personalized medicine, and the rep explained there was some kind of research ongoing to figure out which type of patient would actually benefit particularly from diet and exercise, etc - they felt more personalized medicine would revolutionalize lipids.  I explained that I thought lipids had been revolutionalized ...."$26 billion category and all..." This rep felt some PCPs were seeing as many as 50-60 patients a day "a factory .. and would you want to be dealing with nausea phone calls....?"

SANOFI:
Kelly: "Hi, are you giving any information about Acomplia here?"
Rep (super nice): "Absolutely! See the booth over there? There's an excellent movie there about endocannabanoid systems. I can't even say it yet! But we're learning! Go ahead and watch it ... then let me know any questions you have! We'd love to help in any way possible."
Kelly: "ohhhh - I'll go watch it! When will Acomplia be approved?"
Rep (super nice): "April 2006 is what they're telling us! Go watch the movie, it's in 3-D, and fantastic! It doesn't have the word Acomplia in it, but it'll teach you a lot..."
Kelly: "OK thanks! oh and one other thing, how's Lantus doing?"
Rep: "Fantastic. We love selling this drug - it really changes people's lives."
Kelly: "Mm.. how do you think Levemir will do?"
Rep: "Oh please! Levemir is a glorified NPH!!!"

So I made my way over to the movie, "Exploring the ECS," which WAS in fast, fantastic. These guys don't skip a beat.  Sanofi really knows how to market - even at 9 am, there were scads of people lined up grabbing at the 3-D glasses. The film (I can't believe I'm calling it that) was quite educational, and used lots of phrases like "appears to play a role" "seems to be linked" "apparently meaningful" etc. It reminds me of Wall Street days. Hedging is an excellent sport. 

But, again, this was very well done ... it reviewed how a "newly discovered" physiologic system, the ECS (endocannabinoid system) plays a key role (see?) in glucose metabolism, lipid metabolism, and insulin resistance.  CB1 receptors are found through the body - say, GI tract, brain, adipose tissue and skeletal muscle, for example, and they affect many processes.   In the liver, CB1 activity is apparently associated with development of adiposity, dyslipidemia, and insulin resistance - all bad. In the brain, central CB1 activation influences feeding behavior and energy balance. This means satiety ... I really respect now anything that plays on satiety. I used to think it was sort of made up, but boy does Symlin work on satiety - almost sneakily, like I don't really notice it, but then I do ("wow I've eaten half my bacon cheeseburger and I'm not that hungry suddenly...").  I respect satiety, so it'll be interesting to see if that works with this drug.

Then, in adipose tissue, it is said, CB1 activation "appears to stimulate" lipogenesis and to inhibit adiponectin expression. What does adiponectin expression mean? Wellll, so as I understand it, adipose tissue used to be viewed as inert, but now it's seen as an active organ.  Low adiponectin levels are commonly found in diabetics and those that are obese. Got it ... that's all we need to know, right ... CB1 activation is bad and adiponectin is good and there isn't enough adiponectin going on ... so we should be wary at the very least of adiponectin inhibition.  Low levels of adiponectin, I then learned, are associated with high free fatty acids (FFA), low HDL, high triglycerides, and AND insulin resistance.  In skeletal muscle, CB1 activity is associated GI motility and safety signalling. I have to check this out with all my smart connections in pharma, but this gives you an idea how the story is forming ...

I started remembering right about then how excited I got about this drug at ADA - doesn't it seem like, IF safety is established (the CNS questions are big) and for those that can get over side effects, that this should be mixed with Byetta? Byetta has all the glucose pieces that this doesn't have plus Byetta doesn't have insulin resistance and this doesn't have beta cell regeneration ... could be a mix, no? (We know Byetta doesn't necessarily have beta cell preservation or regeneration either - that is yet to be proven. We also are excited about Byetta with TZDs, which seems also complimentary - insulin resistance, potential beta cell regeneration from both, weight loss from Byetta offsetting weight gain from TZDs, potentially lower edema/CHF from combo due to lower dose TZD, etc.)

BMS/MERCK (second lap):

Kelly: "Hi, are you giving any information about Pargluva here?"
Rep: "Pargluva? We don't have a drug called Pargluva."

NOVARTIS:
Kelly: "Hi, are you giving any information about LAF-237 here?"
Rep (cold): "No."
Kelly: "Hmm. How about Vildagliptin?"
Rep: "No, we're not talking about that one either."
Kelly: "Anything in diabetes?"
Rep: "No. This is a cardiology meeting!"

And on that note ....

*                          *                          *

So with FIELD, we're a little confused. We made a big deal about the tertiary benefits of reduced microvascular complications, but we realize we do not really understand what prompted the improvement - why would PPAR alpha cause better complications data? And it really was QUITE good complications data!  These outcomes seem like they must've been very unexpected. Had they been delivered at a diabetes meeting, perhaps more would've been made of them - as I'm thinking about it now, for any type 2 patient (which these all were, recall, all 10,000 of them!), why wouldn't you give them Tricor as an add-on? I completely see how you wouldn't give Tricor instead of a statin (not sure if you would've seen that even with a positive trial) - but why wouldn't you give it to patients - it's safe, can probably lower microvascular complications, and if it's early in the disease state (earlier, more aggressive therapy - here's that them again) there's a decent chance that it might help reduce events.

Another complications drug – SPP301 for diabetic nephropathy reports positive Phase 2b data and enters phase 3

"SPP301 Phase IIb Results in Diabetic Nephropathy Presented at ASN"

IN BRIEF

Speedel announced positive Phase IIb results for SPP301, an endothelin-A receptor antagonist (ERA), in diabetic nephropathy (DN) on November 11 at the American Society of Nephrology (ASN) Meeting in Philadelphia.  These results indicate that SPP301 significantly decreases urinary albumin excretion rate (UAER) and total cholesterol in patients with diabetic kidney disease when administered on top of standard treatment with ACE-inhibitors or ARBs.  Based on these positive results, Speedel began a Phase III trial of SPP301 in July 2005.   

SPP301 IS CURRENTLY IN PHASE 3

§    SPP301 is a once daily oral ERA that Speedel licensed from Roche in October 2000.  It was specifically optimized for improved liver safety. 

§    SPP301 is the only ERA currently in development for diabetic nephropathy. 

§    Phase 3 testing began in July 2005 and is expected to be completed in approximately 3.5 years. 

§    The FDA has granted Fast Track status for SPP301 in DN and has agreed to a Special Protocol Assessment defining Phase III design and endpoints. 

Diabetic nephropathy

Diabetic nephropathy is one of those complications we always vaguely hear about but don’t write much about.  DN affects 20-40% of patients with Type 1 or Type 2 diabetes, which translates in to 8 million people in the U.S., Europe, and Japan according to Speedel's estimates.  DN is the leading cause of end-stage renal disease in the U.S.  Current treatment options are limited to anti-hypertensives and renin angiotensin inhibitors, which slow the progression of the disease.  However, the mortality rate remains high.   

Phase IIb results indicate strong efficacy and good safety

SPP301 results in substantial additional benefit when administered on top of standard treatment (ACEI or ARB).

§    All four doses of SPP301 (5, 10, 25, and 50 mg) significantly decreased UAER compared to placebo, with the highest 2 doses demonstrating the greatest reduction in UAER. 

§    All doses also significantly reduced total cholesterol compared to placebo.

§    SPP301 also had an additive effect on reduction in proteinuria.  In 55% of patients across all dose groups, SPP301 reduced proteinuria by at least 30% on top of standard treatment.  Data from the US National Kidney Foundation suggests that such a sizable reduction in proteinuria could reduce morbidity and mortality in patients with DN.

§    Although other ERAs have previously been associated with liver toxicity, SPP301 did not result in significant increases in liver enzymes compared to placebo. 

§    This looks like a nice drug – lipid lowering, complication reducing, oral, once-daily pill…Now we just need to make sure that it is safe and then reimbursed!  Can’t imagine there would be any problems with the latter…On the safety front, liver problems remind us of Rezulin and make us catch our breath a bit…

                                                                

IMPLICATIONS

§    These results are important because diabetic nephropathy is a large and growing unmet medical need with a high mortality rate and limited treatment options. SPP301 and ERA may offer clinicians a novel approach to treating DN. 

§    We believe that we are going to start seeing an increase in the number of drugs for complications of diabetes, such as SPP301.  Although we need to both treat and prevent complications, the key question is whether it is better to treat or prevent complications. 

FIELD results negative ... no home run for Fournier

FIELD results negative on death prevention
...not a home run by any stretchbut positive on microvascular complication reduction ...

FIELD trial results were just announced in Dallas. The main points from our perspective:

1. It was a negative study - results indicate that fenofibrate didn't save lives so it wasn't significant on the primary outcome. Thus, no home run for Fornier.
2. Interestingly, on the secondary outcome, it did reduce total CVD events in the group of patients who had NOT had a previous event - so fenofibrate worked better in "healthy" patients, a good talking point for sales reps.
3. This study was all about reducing death, and it didn't do that. There were some nice positive results in terms of complications, however, namely that fenofibrate does confer beneficial microvascular associated effects on renal and eye disease and amputations. So, FIELD was an important study from our perspective in that it showed that fenofibrate did significantly reduce microvascular complications
--In the treated group, there was a 30% reduction in need for first retinal laser therapy (p = 0.003)
--In the treated group, 9.5% progressed to microalbuminuria vs. 11% in placebo group (p = 0.002)
--In the treated group, there were 50% fewer amputations (1%, or 51) in the treated group vs the placebo group (1.5% or 74) (p =0.004)
4. Safety of fenofibrate seems pretty established, on the level of well-established statin - so from that perspective, it might be recommended to "compliant" patients as sort of a "why not ...?" drug - why not take it, it shouldn't hurt, and might help on some fronts - not the most important fronts (death), but certainly some fronts (complications).
5. It would have been spectacular to hear positive macrovascular results with such an apparently safe drug - this study is obviously disappointing on that front. We'll take the microvascular complications positive points since we care a lot about that personally, but we don't think these results are significant enough to prompt major uptake. It'll probably serve as a modest positive - certainly Tricor has momentum and sales will continue to grow regardless of the impact of this study. In terms of the complications results, there are other landmark studies (DCCT and UKPDS) that have shown clear ways to reduce microvascular disease and with 66% of patients with diabetes in the US not at glycemic goal, it's prety clear we haven't listened particularly closely - but from a compliance perspective, it's easier to improve microvascular disease risk by popping a Tricor vs thinking closely about eating, insulin, exercise ... from that perspective, docs in the know may well recommend the addition of Tricor. While it's not a strong enough message to prompt major changes, on the periphery, it very well could do some good... if we hear anything interesting on this front, we'll report back.

FIELD trial results out tomorrow ~

Here in Dallas at the AHA ~ FIELD trials are out tomorrow at 11:20 local time.

We’ve been writing a lot lately about the crossover between cardiology and diabetes, and the soon-to-be-released FIELD trial results highlight this intersection. Tomorrow, Monday, Nov. 14 at the annual meeting of the American Heart Association, investigators will release the results of the FIELD trial, a study of the effect of fenofibrates on coronary heart disease (CHD) in type 2 diabetes patients. FIELD—the full name of which is Fenofibrate Intervention and Event Lowering in Diabetes— enrolled nearly 10,000 type 2 diabetes patients at 63 centers in Australia, New Zealand, and Finland. It is the first study to assess the affect of fibrates on cardiovascular health in diabetes, and it reflects the growing interest in preventive treatment for diabetes patients at high cardiovascular risk.

So the FIELD results come on the heels of the presentation of the PROactive trial, which quantified the cardiovascular risk reduction in type 2 patients treated with pioglitazone. Like PROactive, the FIELD trial identified real cardiac events as endpoints, rather than more easily obtained surrogate endpoints, such as cholesterol levels. As its primary endpoint, the study measured CHD deaths as well as nonfatal heart attack. The study investigators anticipated 500 coronary heart disease events between the study initiation in 1997 and its conclusion in 2005. FIELD was powered to detect a 22% reduction in CHD events. Among the study population, 72% of patients were classified as having metabolic syndrome.
Fenofibrate, which is marked by Fournier Pharma under the name Tricor in the U.S., is a peroxisome proliferators-activated receptor (PPAR) alpha agonist. Fibrates operate via the PPAR transcription factor that influences the expression of proteins responsible for regulating lipid metabolism. As such, fibrates improve lipid profiles by raising HDL cholesterol and lowering triglycerides. Tricor, by the way, has been doing pretty well and will only do better – much better! – with a positive trial. As you may know, lipid management is particularly important in patients with diabetes – they likely have a genetic predisposition to cardiac risk, plus they live in the same toxic environment the rest of us live in. Recent studies (Carr, Diabetes 2004 53:2087-2094) suggest that of the NCEP criteria for metabolic syndrome, waist circumference and triglycerides may best identify insulin resistance and visceral obesity – which themselves, of course, appear to be positive markers for metabolic syndrome, although it’s unclear which one has a larger influence.

Prior studies on fibrates have found positive results but have not focused on patients with diabetes. Two large-scale studies of gemfibrozil included small numbers of diabetic patients. The Helsinki Heart Study included only 135 diabetic patients but found a 68% reduction in CHD events, a number that was not statistically significant because of low power. The Veterans Low-HDL Cholesterol Intervention Trial (VA-HIT) included 627 diabetic subjects and found a significant 24% CHD event reduction in this subgroup, similar to the overall risk reduction.

The Diabetes Atherosclerosis Intervention Study (DAIS) included patients with diabetes exclusively but was not powered to assess CHD events. Rather, this study of fenofibrate focused on lipid profiles, where significant improvements were seen in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides. In the study, CHD events were reduced by 23%, but this result was not significant, as the sample size was small at n=737.

The PPAR agonists have the focus of diabetes therapies more broadly as of late, as PPAR gamma agonists influence glucose metabolism and have glycemia-lowering benefits for patients with diabetes. Thiazolidinediones (TZDs) like rosiglitazone (Avandia) and pioglitazone (Actos) operate as PPAR gamma agonists. While patients can take a TZD and a fibrate to benefit from both a PPAR gamma and a PPAR alpha agonist, pharmaceutical companies are scrambling to offer “dual PPARs”—drugs that lower glycemia and improve lipids in a single pill. This is especially interesting right now, of course, due to the major setback received by Bristol-Myers Squibb’s muraglitazar, Pargluva, last month.

FIELD study investigators hope to generate clinical evidence in support of fibrates that is similar to what exists for statins. Statins have been conclusively established as standard practice in the treatment of high cholesterol, with studies demonstrating risk reductions in coronary events as high as 55%. Statins target high LDL levels, whereas fibrates raise HDL and lower triglycerides; in patients with lipid problems in each category, physicians may opt for combination therapy, although there is currently limited evidence (at best) as to the safety of combining the two drugs.

Stay tuned for tomorrow – as for us, we know we’ll hardly be able to sleep tonight!

Novo moves ahead of Lilly ~ what, six months only!?

We reported a few weeks back that Novo was hiring 400 new diabetes reps - well even before they are hired and trained, they've moved ahead of Lilly in total insulin volume. Pretty amazing! And this without the launch of Levemir ...

One interesting tidbit from the meeting - there was a very good talk by Novo about why Novo is better in pumps, etc.  We have heard this is true for a number of patients, but interestingly, we have also heard that this is for others true only for a time - Barbara Davis is apparently doing a trial where people will use Novo for six months, then Lilly, then Novo .. to ward off antibodies. This is the first we have heard of this and will be checking around ....