Amylin's Pullback Is Unjustified

In a 6-6 vote by the FDA Scientific Advisory Committe, it was determined that Liraglutide (a diabetes drug made by Novo Nordisk (NVO)) posed a significant risk in causing thyroid tumors in humans. While the panel was worried about animal studies showing that liraglutide caused medullary thryroid cancer in both mice and rats, Novo Nordisk denied any evidence of the drug causing such a cancer in humans.

Moroever, some members of the panel were worried that any thyroid risk might apply to the whole class of drugs: GLP -1 class. However, there is currently no clinical evidence that thyroid cancer is a GLP-1 class effect. Amylin Pharmaceuticals (AMLN), which is conducting clinical trials on the safety and efficacy of another diabetes agent, Byetta (GLP -1 drug), found no thyroid C-cell carcinoma association. Amylin executives stated that they haven't seen any risks of cancerous tumors with Byetta, and only minimal evidence with the long-acting version, exenatide LAR, which will be submitted for FDA approval in coming months.

No cases of thyroid cancer have been documented in patients enrolled in clinical trials of Byetta, according to Amylin Pharmaceuticals. Amylin conducted a two-year cancer study of long-acting Byetta in rats and mice and found a statistically significant increase in tumors only in female rates treated with doses of long-acting Byetta four-fold higher than what would be given to humans. By comparison, Novo Nordisk's liraglutide was found to cause tumors in male and female rats, sometimes at human-equivalent doses.

Last week, Amylin released positive results from DURATION-2 that demonstrated superiority of Byetta once weekly as compared to two commonly prescribed diabetes medications, Januvia(TM) (sitagliptin) and Actos® (pioglitazone). Also, a meta-analysis of primary cardiovascular events across controlled clinical studies of three months or greater, from the BYETTA® (exenatide) injection database, showed no increased risk of cardiovascular events associated with the use of exenatide.

Since Byetta and liraglutide are distinct molecules, how is it scientifically sound to assume that what is seen with one molecule will automatically be seen with the other? Clearly, the FDA's concern regarding the threat of thyroid cancer in Amylin's Byetta is ridiculous! As a matter of fact, FDA officials publicly pointed out, last week, that they did not see any risk of thyroid cancer with Byetta after re-examining data on the four-year-old drug. Additionally, animal testing of Byetta did not uncover the same level of a thyroid tumor risk as Novo Nordisk's Liraglutide.

Though both liraglutide and Byetta belong to the sames class of drugs called GLP-1s, the latter may deliver a cleaner preclinical safety profile than liraglutide. However, there is one shortcoming in Byetta's clinical trial. Scientists wonder if less than 500 patients from Byetta's LAR's DURATION-1-3 trials are sufficient to address the FDA's concern over a potential 'class effect' for thyroid cancer that could increase with longer-acting agents, and if additional trials would be required. I think not.

According to President and Chief Executive Officer Daniel M. Bradbury and his management team, exenatide once weekly is on track for a planned launch in 2010. The steps that the company has taken to enhance the commercial opportunities of the product are already beginning to yield results. With data supporting efficacy, safety and manufacturing now in hand, Amylin anticipates filing a new drug application (NDA) for exenatide once weekly by the end of this quarter.

Disclosure: Long AMLN.

Comments

[nova:]

Jack,

You are correct. Byetta and liraglutide are distinct molecules even they do belong to the same "class."

FDA Scientific Advisory Committee concluded that Liraglutide (a diabetes drug made by Novo Nordisk (NVO)) posed a significant risk in causing thyroid tumors in humans. The vote was 12:1 to support such conclusion.

Unfortunately many people on Wall-Street have no clue about a degree of devastation cancer can bring to people and their families. In a case if the FDA give a "green light" to Liraglutide, it will be an incredible travesty to our health care exposing a great number of patients to cancer devastation and consequences.

Assuming that, at best for Liraglutide, it approval will be delayed by at least a few years, Byetta with it superior to other diabetic drugs efficacy profile will be able to substantially penetrate the huge diabetic market.

The major problem with AMLN is its management: highly incompetent, highly greedy and corrupt. It is of interest that Amylin reminds me ImClone. As soon as ImClone got rid off its old Board and CEO, the company, in spite of Wall-Street insinuations and lies, was able to move forward successfully and be sold later to LLY at a very substantial premium.

In my opinion, as soon as Amylin will get a new management and LAR Byetta approved, it can be sold in two years at ~$6B+ or for $50+ per share. The present AMLN price below $10 is just ridiculous.

Apr 09 10:54 PM

[Furd Turgeson:]

"According to President and Chief Executive Officer Daniel M. Bradbury and his management team, exenatide once weekly is on track for a planned launch in 2010"

The absolute last person anyone should be quoting is Dan Bradbury. I agree with the above poster. Amylin is the worst run company probably on the Nasdaq. The board and management both need to go, particularly the greedy, incompetent, arrogant, and pathetic Chairman of the Board. Regardless of the potential of the product, if you don't have a capable captain and crew steering the ship you will go no place fast. That has been clear the past two years.

Apr 10 09:22 AM

[Doc Jones:]

I am truly upset about this article, there is a lot of speculation here not based on facts. I am a Endo that participated in the the original byetta studies and just recently the liraglutide Lead-3 and Lead-6. It should be noted that Liraglutide and Byetta have the exact same mechanism of action. Liraglutide is 97% homologous to endogenous GLP-1 and Byetta is 57% homologous. Both molecules are albumin bound and resist the action of DPP-4. The question about the c-cell tumors came about when a few instances were seen and mice and rats. It is important to note that rats develop c-cell tumors on their own and the mice and rats that developed c-cell tumors on Liraglutide had 36 times the normal human dose. When doses 60 times the normal human dose were used in primates there was no traceable action on calcitonin levels. All 5000+ patients that took also had no change in calcitonin levels. Novo Nordisk knew there could be a link and decided to monitor calcitonin levels unlike Byetta trials.
As for the FDA advisory committee, the major concern was cardiovascular risk and Liraglutide passed with an 8 to 5 vote based on the favorable lipid profile and blood pressure data up to 1 year (Lead-3). The question asked about the c-cell tumors was can the occurrence in animals be linked to humans and the first vote was 12 to 1 and after the thyroid expert explained c-cell tumor occurrence and overall physiology the panel voted 6 to 6 with 1 vote abstained. The fact of the matter is there could be a link but in order to study this link studies would have to be done in excess of 10 years due to nature of these type of tumors. If the FDA does accept the NDA for Liraglutide it will likely require more safety data. I have clinical experience with Liraglutide and have seen the benefits and feel that it is a needed drug in diabetology. I suggest you write an article based on facts rather than opinions and fore-drawn conclusions.
Doc Jones MD

Apr 10 10:24 PM

[Jack Haddad:]

Nova, having Carl Ichan as "activist investor is a blessing. We need him to keep riding the executive board until good change is done. I'm very optimistic.

I will re-enter AMLN this coming Monday; the May strike 10 calls at 1.10 and more are a great premium and a hedge against a downside.


On Apr 09 10:54 PM nova wrote:

> Jack,
>
> You are correct. Byetta and liraglutide are distinct molecules even
> they do belong to the same "class."
>
> FDA Scientific Advisory Committee concluded that Liraglutide (a diabetes
> drug made by Novo Nordisk (seekingalpha.com/symbo...)) posed
> a significant risk in causing thyroid tumors in humans. The vote
> was 12:1 to support such conclusion.
>
> Unfortunately many people on Wall-Street have no clue about a degree
> of devastation cancer can bring to people and their families. In
> a case if the FDA give a "green light" to Liraglutide, it will be
> an incredible travesty to our health care exposing a great number
> of patients to cancer devastation and consequences.
>
> Assuming that, at best for Liraglutide, it approval will be delayed
> by at least a few years, Byetta with it superior to other diabetic
> drugs efficacy profile will be able to substantially penetrate the
> huge diabetic market.
>
> The major problem with AMLN is its management: highly incompetent,
> highly greedy and corrupt. It is of interest that Amylin reminds
> me ImClone. As soon as ImClone got rid off its old Board and CEO,
> the company, in spite of Wall-Street insinuations and lies, was able
> to move forward successfully and be sold later to LLY at a very substantial
> premium.
>
> In my opinion, as soon as Amylin will get a new management and LAR
> Byetta approved, it can be sold in two years at ~$6B+ or for $50+
> per share. The present AMLN price below $10 is just ridiculous.

Apr 11 12:42 AM

[Jack Haddad:]

DocJones, I still do not understand your anger? What's so upsetting about the contents of this article. Why don't you provide me a link to show evidence of how these two molecules have the same mechanism of action.

Furthermore, you have to understand that Liraglutide got denied based on a weak "methodology and design" clinical trial. The safety and efficacy of the the agent could have been demonstrated and presented in a much improved manner to the FDA.


On Apr 10 10:24 PM Doc Jones wrote:

> I am truly upset about this article, there is a lot of speculation
> here not based on facts. I am a Endo that participated in the the
> original byetta studies and just recently the liraglutide Lead-3
> and Lead-6. It should be noted that Liraglutide and Byetta have the
> exact same mechanism of action. Liraglutide is 97% homologous to
> endogenous GLP-1 and Byetta is 57% homologous. Both molecules are
> albumin bound and resist the action of DPP-4. The question about
> the c-cell tumors came about when a few instances were seen and mice
> and rats. It is important to note that rats develop c-cell tumors
> on their own and the mice and rats that developed c-cell tumors on
> Liraglutide had 36 times the normal human dose. When doses 60 times
> the normal human dose were used in primates there was no traceable
> action on calcitonin levels. All 5000+ patients that took also had
> no change in calcitonin levels. Novo Nordisk knew there could be
> a link and decided to monitor calcitonin levels unlike Byetta trials.
>
> As for the FDA advisory committee, the major concern was cardiovascular
> risk and Liraglutide passed with an 8 to 5 vote based on the favorable
> lipid profile and blood pressure data up to 1 year (Lead-3). The
> question asked about the c-cell tumors was can the occurrence in
> animals be linked to humans and the first vote was 12 to 1 and after
> the thyroid expert explained c-cell tumor occurrence and overall
> physiology the panel voted 6 to 6 with 1 vote abstained. The fact
> of the matter is there could be a link but in order to study this
> link studies would have to be done in excess of 10 years due to nature
> of these type of tumors. If the FDA does accept the NDA for Liraglutide
> it will likely require more safety data. I have clinical experience
> with Liraglutide and have seen the benefits and feel that it is a
> needed drug in diabetology. I suggest you write an article based
> on facts rather than opinions and fore-drawn conclusions.
> Doc Jones MD

Apr 11 12:51 AM

[nova:]

Doc Jones MD,

I am NOT a MD or know much about endocrinology. But, I am a scientist and know something about oncology.

Ten years ago, I review C-225 (now known as Erbitux) small Ph II clinical data in H&N cancer and put my money on it.

The last year, ImClone, Erbitux's developer, was sold to LLY for $6.5B It was a very good investment for me. It is of interest mention that in mid 1990s, LLY owned Erbitux, found it totally useless, and gave it back to the inventor for free.

Now, few history points related to oncology. It still a mystery for the scientific community:
- After studying Erbitux for the last 15 years and over 150+ clinical trials all over the world, scientists still do not know why it works and when (OK, K-ras testing helps a lot)...
- Erbitux from ImClone and Pani from Amgen are both EGFr-drugs. They are "almost" absolutely identical having the exact same mechanism of action. Even more, due to superior Pani affinity, overwhelming majority of scientists and clinicians (many of whom were investigators in various Erby and Pani clinical trials) expected that Pani will be much superior to Erbitux. Erbitux was on a "death row" expecting to be killed by Pani.
Well, PACCE PhIII trials in mCRC has been terminated following early safety review: the death rate in Pani-arm was much higher than in a placebo-arm. Now, Pani is going to nowhere.
- Presently, Avastin is the "wonder" oncology drug. The FDA likes it. Medical community worships it. DNA, Avastin's developer, was just sold to Roche for a fortune. There is only one small problem: independently conducted clinical trials in mCRC, breast, lung cancer did NOT show any overall survival benefits. I hope you got my message.
- I can go on and on.

The bottom line
- Only clinical trials provide real and accurate answers to effectiveness and safety of drugs. Everything else are just hunches, guesses and speculations.
- Cancers are very poorly understood and very unpredictable
- Malignant tumors kill in very unpredictable and brutal ways. Consequently, any potentially cancer-promoting drug must be prevented from reaching the general patient population
- "Similar" drugs are not identical or even "close"

Apr 11 12:27 PM

[nova:]

Speaking about Carl Icahn at ImClone:
- Carl was very lucky
-- ImClone's Erbitux the only competition from another EGFr-drug Pani was out of the game for at least 3-4 years or even for ever due to disastrous PACCE trial
-- German Merck KGaA was successfully running all Erbitux registration trials in mCRC and Lung cancers

- Carl positive actions
-- Removed the old Board and some of bad management
-- Cut waste and expenses
-- Cut Board and management bonuses and compensations
-- Accelerated pipeline activities
-- Renegotiated the Erbitux partnership agreement with Bristol
-- Settled all outstanding lawsuits against ImClone
-- Negotiated the merger with LLY

- Carl has failed to
-- Bring a new capable management team keeping a lot of losers. His new CEO was just a "yes-man".
-- Settle a feud with Merck KGaA resulting in many headaches for ImClone and now for LLY

Summary
Carl did help ImClone and its shareholders a lot.

Apr 12 07:45 PM