Close Concerns Weblog

Strike one, strike two ...Sanofi's Acomplia receives approvable letter for weight management and non-approvable for smoking cessation

News came across this afternoon (Feb 17) that Sanofi received an approvable letter on rimonabant for weight management and an actual non-approvable letter for smoking cessation. There were no details given on what further data Sanofi needs to provide to the agency, on further trials that may need to be done, etc.

While we believe there is no question that rimonabant has provided metabolic benefit for some who took it, the questions about safety loom larger - the approvable letter for weight management certainly seems to relate to lack of confidence by the FDA on this front. A study came out earlier this week in JAMA, the psychiatric concerns about which we detailed on our Feb 15 blog entry (www.closeconcerns.com). The adverse event table for RIO-North America is on page 772 of the JAMA piece and shows the adverse events detail, the most concerning of which are the psychiatric adverse events as we noted a few days ago. We can't imagine, for example, that footnote about a gunshot doesn't refer to a suicide and a 2.7x higher drop out rate for psychiatric events should certainly raise eyebrows - plus a 50% dropout overall - where are all these people?! While no direct conclusions can be made, the data certainly suggested more study should be required, and we are very glad to see that the drug didn't receive outright approval.

We expect more data has been requested in the approvable letter; following this, the FDA could undoubtedly benefit from a panel, in which obesity experts, cardiologists, endocrinologists, and psychiatrists could weigh in. This is despite the extent to which some say the advisory panel process is broken - we don't entirely disagree, but just advocate fixing it! Ultimately, the actions today suggest that the ultimate drug approval may be years away. This is further suggested by the fact that on the smoking cessation front, the company received an actual non-approvable letter - seems likely that there were major addiction worries and concerns about off-label use, etc., though of course this is speculative.

Sanofi confidence HAS been projected within the financial community throughout the development of the drug, and especially within recent months, which had been surprising. For example, in late January, the company characterized the collaboration with the FDA as excellent, noted that they have developed the product with close coordination with the authorities, and said that they "remain confident that we will launch Acomplia in the second quarter of 2006" - this comment seemed especially surprising in front of an agency decision. Notably, Sanofi management had said in mid May 2005 that it would position this drug as prevention for metabolic disorders - seemed a little of the cart getting ahead of the horse, since they hadn't even been willing at that point to disclose what indications for which they were filing (turns out to be obesity management and smoking cessation). Primary endpoints for all RIO trials relate to weight management while secondary endpoints cover lipids, waist circumference, and blood pressure, elements of most metabolic syndrome definitions.

One more speculative suggestion - this action may also signal that a non-request for a panel by the FDA should perhaps be viewed more ominously when there are safety questions - although Amylin's Byetta also didn't receive a request for a panel, its clean safety profile certainly seems a major advantage of the drug.

From a patient perspective, it is a great signal to see that the FDA is taking safety very seriously across all fronts (cardiovascular, CNS, etc.), especially among areas that are more "gray" and less tangible. We believe today's news also implies that we are still very far away from a metabolic syndrome indication for any drug.

What next? Sanofi has analyst meetings Feb 24 in Paris and March 22 in New York, where more information on next steps with the FDA may be given - it would have seemed that the analyst meeting in Feb was scheduled to coincide with news about approval. It will be interesting to see what is happening on the European approval front - Sanofi acknowledged in an analyst Q&A that they had also filed rimonabant in Europe.

Abbott Diabetes Care exceeds $1B in revenue

Abbott reported yesterday its 4Q05 earnings, highlighting that Abbott Diabetes Care has exceeded the milestone $1.0 billion mark in revenue. Management remarks on the Navigator indicated a very positive outlook on this device, suggesting that they are pleased with the clinical trials results and expect it to be launched later this year. They indicated that the clinical trials are finished. “The clinical studies for the PMA approval are now complete and we are very pleased with the result. This completes the clinical session of the PMA and Abbott anticipates launching the Freestyle navigator later this year.”

Abbott executives cited the strength and success of ADC on multiple occasions during the call. The company announced that 05 sales grew 34.8% while 4Q05 sales rose 18.1% from 4Q04. Management indicated that they currently have 20% market share in this industry. Abbott expects its new Freestyle Connect blood glucose monitor, which received FDA approval in 2005, to help continue its success in the hospital. In support of this assertion, an executive said that it will be the fastest monitor available, generating results in 15 seconds, and requires the smallest blood sample of any current monitor.

In other related diabetes/CVD/obesity results, Abbott commented that it has ongoing trials looking at combination therapy possibilities for Tricor with statins. Initially, executives said to expect data sometime in 2006 – when someone asked if the data could be expected by March, they said this was probably too early but that it would be available later in the year.

In response to a question concerning what products/divisions of Abbott the street may be underestimating, the company said they felt that public expectations should be higher for Humira (emphasized throughout the call), Tricor, and Abbott Diabetes Care.

BMS 4Q05 results – Saxagliptin benefits from R&D increase

We learned no real news on BMS and diabetes/obesity in the BMS 4Q05 comments yesterday. Nothing was said about muraglitizar or Saxagliptin in the press release, although on the call, there was sort of a generic statement about how Saxagliptin is one of the late stage products that BMY continues to invest in and is one contributor to the double digit growth in the R&D budget - R&D spending rose 14% in 4Q05, by the way! On muraglitazar, management says they "continue to evaluate their options", but certainly at this point, it seems likely to be shelved: 1) first, of course, it sounds like FDA would require more studies that would take time to generate - a couple of years, minimum - and since the data we've seen on this one hasn't been stunning, it's hard to argue conclusively that the commercial opportunity justifies a major (further) investment. Just, it's far from a home run, especially with Byetta new to the market, and there must be countless competing priorities in terms of R&D resources); 2) the other question is who would help market this to PCPs with MRK having dropped out. We're staying tuned - we look for Merck to make more early stage investments.

JNJ reports $1.9 billion in sales for 2005

JNJ LifeScan reported 4Q05 earnings yesterday morning. Results were definitely on the weaker than expected side with worldwide sales up just 5% for the quarter – results haven’t been this weak for LifeScan since mid-2003, when sales fell 7% -- since then, global sales have always increased at least 10%. While this quarter was a “tough comparison” in that fourth quarter 2004 sales had risen a whopping 19% (up 12% domestically and 28% internationally), there is no doubt that it's getting very tough to keep up such high historic growth rates. Some of this is that the base is getting bigger and some is probably that this is just becoming a business where it is difficult to squeeze out such high profits as has been seen in the last decades! What’s notable here is that neither LifeScan's US or international sales were supremely strong – although historically, there have been times when LifeScan sales were weak from either a US or international perspective, almost always either the US or international sales were very strong and could bolster the other. This is actually the first quarter in nearly five years (since the second quarter of 2001) where both domestic and international sales growth was under 10%. Still, reaching $1.9 billion in sales for the year is an incredible achievement. LifeScan will benefit from pump sales starting in 2006 and the extra revenue will certainly benefit LifeScan – the $100 million in sales that Animas would add for 2006 would add about 5 percentage points of growth.

Conference call comments:

Medical Devices and Diagnostics (MD&D) sales were $19.1 billion in 2005, with 12.5% operational growth in 2005. Profit contribution from (MD&D) has increased more than threefold. Highlights related to diabetes and obesity from the call:

• Lifescan achieved operational growth of 5% in 4Q05 as compared to the same period in 2004. This growth was led by U.S. growth of 8%.

• One Touch Ultra was the major growth driver of both U.S. and WW sales

• One Touch Ultra achieved 34.9% scrip share as of 3Q05 - we look for this to strengthen further when the new Ultra is introduced this year.

• The only comment about the very weak international growth was that growth outside the U.S. was negatively impacted by sharp reductions in retail trade inventory.

• CEO Bill Weldon highlighted the “alarming” increase in the prevalence of diabetes worldwide.

• Currently J&J is focused on episodic glucose monitoring with its One Touch line.

• However, J&J is moving from measurement towards “broad management of the entire diabetes spectrum.” (they began this at the summer 2005 meetings, when they started positioning as “not just a monitoring company.”)

• It is introducing “transformational technology” to develop diabetes management solutions that will transform patient care, and “bringing affordable BG monitoring to new geographies.” Its strategy is focused on continuous monitoring.

• Weldon highlighted the pending acquisition of Animas, which will “broaden [J&J’s] reach in diabetes management,” as one of J&J’s key acquisitions.

He also briefly mentioned obesity as one of the “best opportunities for significant and sustainable growth” that J&J is pursuing, along with nutrition and colon cancer. Splenda was also touted as am important alternative for patients struggling with diabetes and obesity. We didn't hear anything about Obtech, its obesity device company.

J&J will hold a full-day review of its MD&D segment in September 2006.

Pharmacogenetics promises to predict individual drug reactions

"A Special Drug Just For You, at the End of a Long Pipeline"
Andrew Pollack, NYT, Nov. 8, 2005

Another piece in the New York Times today discussed the emerging interest in pharmacogenetics, or genetic testing designed to assess the appropriateness of a drug therapy for an individual patient. It is most often used to detect variations in an enzyme that breaks down a drug, thereby avoiding a dangerous build-up that could result. Though the drugs mentioned in the article were largely those used to treat depression, cancer, and acne, we wonder whether there may be implications of this for drugs used to treat type 2 diabetes and obesity. Certainly anything that could be used to limit side effects of medications--say finding a genetic test to identify those particularly susceptible to CHF or fluid retention before prescribing a TZD--would be a step toward eliminating barriers to aggressive therapy.

FDA says hold on to Pargluva!

Pargluva got an approvable letter, it was announced earlier today ~ more safety data is needed. The company seems to imply it's more data, as in, more data, but not new trials. The FDA went against the advice of its panel, and we think it bodes well for patients since there were so many uncertainties. This of course is a net positive for Amylin since Byetta won't have competition from Pargluva (muraglitizar) for some time, call it at least a year for now, but likely considerably longer, if it comes out at all. Safety, safety, safety is the focus right now, which from a patient, HCP, and payor perspective, is exactly appropriate. We expect to hear more on this on earnings calls for BMS and Merck later this month.

Friday stream of consciousness on ranbaxy-lantus-apidra-symlin-pumps

The FDA approved yesterday a generic glimepiride tablet, manufactured by Ranbaxy, that will compete with Sanofi-Aventis’s Amaryl. The generic will be offered in three additional dosages—4 mg, 6 mg, and 8 mg—in addition to those already available in Amaryl (1 mg, 2 mg, and 3 mg). Sanofi-Aventis also mentioned at its August 31 investor meeting (see our comments on that meeting from our blog on date X) that it will look into marketing their own generic glimepiride, though we haven’t heard much more on this front as of yet. The expiration of the patent will be a net negative for Sanofi, since Amaryl sales broke $1 billion in 2004. We expect their marketing strategy with type 2 patients to change to reflect both the loss of Amaryl sales and the introduction of their new rapid-acting insulin glulisine, Apidra. Apidra - finally! - is starting to be more widely available in pharmacies and promises a quick onset and shorter duration of action. It is pen only, which is why the delay in launch, given the April 2004 approval. Sanofi used to target (at least unofficially) type 2s with a “one shot a day, one pill a day (Lantus and Amaryl)” campaign—we are fascinated to see how the message will change, given that Apidra before meals is way more complicated than one Amaryl pill a day. We've heard that some type 2s have actually been overdosing Lantus in order to make up for absence of prandial insulin (previously only Humalog and Novalog were available) - will be interesting to see how much more prandial insulin grows as a class with this new entry. Some may recall that for awhile, it was thought that Apidra had some sort of beta cell regeneration qualities - that hasn't been raised in awhile, and we're not sure about the quick onset, but we'll both (Kelly and Erin here) look forward to testing it! What we're really interested to see if one of the insulin manufacturers (Lilly would be the logical one obviously due to its partnership with Amylin, but since no one is linked with Amylin on Symlin, who knows?) could possibly do a rapid acting analog/Symlin mix. We aren't sure if this is possible due to pH etc but wow how fantastic!

On that note! We've heard pump sales have seen an uptick in the (admittedly still small but growing) set of patients going on Symlin.

We've also heard that some patients are actually returning to regular insulin because it has a longer duration of action, which is sometimes helpful for some taking Symlin. Personally we'd never do it, easier just to pump or take a quick pen bolus in our view ~

Novo (Novo!) downgraded due to LAR strength

JP Morgan's pharma analysts downgraded Novo Nordisk (Novo!) due to perceived strength of LAR. This downgrade is huge - pharma (not biotech) analysts are beginning to figure out the score. For them to acknowledge biotech - enormous!

They noted that competition from non-insulin competitors (read: Byetta) will slow the growth of the US insulin market volume from 5% to flat by end of the decade. But not only THAT - they say that of greatest concern is LAR, Amylin's once weekly injectable GLP-1 analog, which will have the potential to transform the management of diabetes (note - they don't mention for any particular segment) .. this leaves Novo vulnerable.

Byetta update - wow!

This was in this morning from Dr. Joe, who writes frequently on diabetes. He comments here on use of Byetta in his 130 patients on the drug - 150 mg/dL as a ceiling for blood glucose is quite incredible, no?! Eight pounds down on average for ten weeks for n=130 is also quite something. Here is Dr. Joe's post in its entirety - if you want to subscribe to his musings, see http://www.endocrinemetabolic.com/programs/.

"As we enter the fourth month of Byetta, what do we see? The glucose excursions appear normal. Where has the diabetes gone?

Phone calls “I can't get my glucose up!” really represent the fact that it won't go over 150 no matter what you eat. That was from a person with zero C- peptide who was on 120 U of insulin daily when he started.

“ How much insulin are you on now?” I yelled into the phone. “4 Units” he replied. “Four? You’re just jerking my chain” I replied. “Cut in to one unit until we check your C - peptide” I said but I stopped worrying about him from that night on.

We will be measuring the C- peptide over the next 30 days. I can't “weight.” Of the 130 people on Byetta now, we have lost over 1.000 lbs in the last two and a half months. It is hard to believe."

Dr. Joe, The Diabetes Doctor

Novartis pipeline update - LAF237 fails to show non-inferiority to Metformin ~

Novartis said today it will file LAF-237 in the first half of 2006 - this is its DPPIV inhibitor. Talk at EASD focused on safety of the class, particularly in the wake of the FDA panel on inhaled ~ lots to watch out for. (By the way! Did anyone really focus on the fact that two out of the nine votes that were _no_ were both from pulmonary specialists and that there were only three pulmonary specialists total?)

I liked how Novartis discussed LAF-237 in depth on its pipeline update call BUT the most critical element of the drug, the long-term safety, wasn't really addressed in depth in my view. They discussed how there are fewer GI side effects with this drug vs Metformin, etc. but they didn't address the worries that many have, what else (<--italics) is being inhibited with this compound.

Surprisingly, and unfortunately for Novartis, metformin worked very well in the studies presented, so much so that the primary endpoint, non-inferioritity vs metformin, wasn't met (as it were). In 52-week study of about 750 people, the high dose of LAF237 resulted in an A1C drop from 8.7 to 7.5, while metformin had a drop from 8.8 to 7.1. This was statistically significant. The headline on this slide said "52 week data with monotherapy confirm early and sustained A1C reductions..." It is true the reduction is a good reduction, but not versus metformin's reduction (which was better than some would have expected, at over 1.6 points). They noted then that LAF237 is better tolerated. True, in the sense of traditional annoying side effects, but we think there are still some uncertainties on the long term impact of this new class, and without it beating traditional therapy, this isn't a place a company wants to be, in our view.

Novartis also did an Actos comparison and on this one, Actos had a 1.9% A1C drop, while LAF237 (100 mg) had a 1.6% drop. And this was using 30 mg of Actos not 45 mg! We're not major TZD fans overall (but we are for the right patients) but doing a study not using a fully powered dose seems wrong. Lest you note how impressive nearly 2 points drop is, we point out this is from a 10 A1C - impressive, yes, but it's not like the baseline was 7.0.

There was one 12 week study that was pretty impressive - the only point was to show dose-proportional drops in A1C, and that they did, but on the 50 mg and 100mg arms, they got drops of 1.0 and 1.2, respectively, from baseline A1Cs of 7.4.

Then! They had an add-on insulin trial that showed a non-wow 0.5 drop for LAF237 vs 0.25 drop for placebo plus insulin, over 24 weeks. What was impressive here was that there were six (count 'em six!) hypo events for the insulin group (defined at 3 mmol or less - that is 3x18=54 mg/dL for those that also always forget how to translate mmol).

Novartis also said it's working on a range of products with the FDA, one on manufacturing methods, a secnd on biomarkers to develop new therapies, and a third, interestingly, to look for "the simultaneous development of a particular therapy and a diagnostic test kit that would enable the identification of patients who are most likely to benefit from the particular therapy."

LAF237 appears to be weight neutral, which is better than insulin, but not as positive as Byetta.

Our main issues with the data summary is that they make a very big deal about LAS237 being well tolerated, but they don't say anything about unknown side effects that could be issues longer term AND they try to position as "ideal profile as first drug of choice" - this would never be first drug of choice given what isn'tknown and it seems irresponsible to position it as such.

At the start, Novartis positioned current oral therapies as not addressing multiple defects in type 2 - right! - but GLP-1 (Byetta) has been shown to address two labeled as "unmet need," namely inadequate glucagon suppression (beta cell dysfunction) and beta cell decline.

They also show key requirements for new therapies: 1) clinically meaningful a1c drop; 2) sustained a1c reduction; 3) weight neutrality; 4) well tolerated; 5) low hypos. We agree these are great requirements but they need to show what recently approved drugs can do, in our view.

Other problems: 1) they showed Novartis as the most productive big pharma company - in terms of approvals, they didn't give Lilly any credit for Byetta, which we thought was wrong; 2) They say there are 150 mm type 2 patients worldwide, but 194 million is a widely quoted number; 3) we don't necessarily know if this drug should be approved or not, but the panel meeting will hopefully focus on some of the uncertain safety issues and we would hope the panel would be very well informed. On that note - the FDA should in our view use more experts on panels that are close to industry but just get them to promise they are unbiased. Among the smartest endos in our view are the ones driving the studies, and it seems patently absurd to exclude them due to a suspicion they cannot put forward unbiased views.

Third to last comment - the name that seems to be catching on for this class is incretin enhancer - that's a great name.

Second to last comment - very interesting studies upcoming, including diabetes prevention (this will be very tough indication to get) in about 2009 and reduction of CVM complications in about 2011. Excellent!

Last - Novartis does a great job at melding CVD and diabetes. Just overall, the call really reinforced how hot diabetes is becoming/has become in Big Pharma. There is some chatter that the cardiologists are taking over, and we have certainly started to see it. This is happening at the same time that medical students aren't entering endocrinology as it is such a poorly-reimbursed speciality. Overall, we look for more and more critical data to be presented at CVD meetings rather than diabetes meetings ... onward!