The Business of Diabetes: FDA Delays Afrezza, Byetta LAR (now Bydureon)

The U.S. Food and Drug Administration, now under new leadership, appears to be taking the agency's role as protector of the U.S. public health more seriously instead of being viewed as a "partner" to the pharmaceutical industry. On Monday, March 15, 2010, the FDA delayed decisions on two diabetes medicines now pending approval. In a dramatic break from practices that had been underway for the past decade or longer, the FDA did not simply rubber-stamp approve two new diabetes treatments, instead, it asked the applicants for additional information before reaching a final decision.

The two medicines impacted are MannKind Corp's Afrezza inhalable insulin for type 1 and type 2 diabetes, which would compete with injectable, rapid-acting insulin formulations such as Lilly's Humalog (insulin lispro), Novo Nordisk's Novolog (insulin aspart) and Sanofi Aventis' Apidra (insulin glulisine). The other is Amylin Pharmaceuticals' Byetta LAR (which means "Long-Acting Release") which has now branded as Bydureon -- using Alkermes technology to extend the release of the drug, and is seeking approval only as a type 2 diabetes treatment. Bydureon is an extended-action version of Byetta, an already FDA-approved drug available today. Because both of these drugs are for modified forms of already FDA-approved medicines, both were submitted via the the 505(b)(2) process, which is usually regarded by the investment community as very likely to be approved, often with few (if any) expected delays.

Under the new Obama-appointed FDA leadership of Dr. Margaret Hamburg and her chief deputy, Dr. Joshua Scharfstein, the FDA has worked very hard to restore public trust and confidence in the FDA, which had been beset by one safety scandal after another in food, drugs and medical devices during the preceding 8 years. While numerous reforms have yet to be implemented, these delays are viewed by many healthcare professionals that the FDA is not simply there to serve the needs of the industries (namely, pharmaceuticals, biotechnology, medical devices and certain areas of food production) it is there to regulate, but to ensure public safety as the primary goal of the agency.

Consider this scathing commentary on the FDA under previous leadership as a sad example of exactly what the new leadership walked into.

This is really a dramatic change from the recent culture at the FDA under the previous leadership of Dr. Andrew von Eschenbach, who implemented a culture of fear among FDA staffers were made to feel accountable to the very industries the FDA regulates because of user fees mandated by Congress in a budget deal under the leadership of Newt Gingrich but signed into law by President Clinton back in 1992. These were often implemented with threats of job termination to whistle-blowers.

It should be noted that although the user-fees have saved taxpayers a tremendous amount of money, there were no user fees required of generic drugmakers, and the impact had the unintended impact of shifting staff towards new drug applications, while staff for generics, enforcement and post-market analysis were overburdened more work than they could effectively handle. Although the the FDA can theoretically demand post-market analysis from the very same user fees that fund the new drug applicants, practically speaking, the FDA should have been mandating those fees at the time approvals were granted, so the Agency has struggled to restore the agency's credibility among lawmakers.

Indeed, this year, Dr. Hamburg stated "We very much want to work with you to see generic drug user fees enacted this year" and has indeed asked Congress to pass legislation to enable the agency to hire staff to address the massive backlog these functions (generics and enforcement) now face.

Rather than provide written details, you may watch the following two short news summaries (albiet with commercials) on these decisions below.

FDA Delay #1: MannKind's Afrezza

First, the move on MannKind's Afrezza inhalable insulin, which can be viewed here:



The U.S. Food and Drug Administration sent MannKind a so-called "complete response letter" Friday requesting additional information. The fact remains that the FDA could have simply declined the insulin, but the agency instead asked about the medication and the inhaler patients will use, MannKind said on Monday in a statement. The regulators didn't cite any safety concerns as many analysts had expected, but they did request updated safety data. MannKind said it had not planned to launch a commercial version of the device in its current form, and had hoped to follow-up with a supplemental new drug application (NDA) to market a next-generation version of the inhaler device known as Dreamboat instead.

MannKind was planning to submit a new drug application for the Dreamboat inhaler in Q2 2010. But at the urging of the FDA, the company will now request an "end-of-review" meeting with the agency in an effort to hopefully resolve the regulator's concerns.

In particular, the FDA questioned whether the inhaler used by MannKind in clinical trials was comparable to a newer one the company has developed and wants to market with the drug, MannKind's chief financial officer, Matthew Pfeffer said. The FDA letter also requested changes to the proposed labeling of the cartridges, foil pouches and cartons. MannKind also said that the FDA was concerned about Afrezza's clinical utility, which a number of analysts reacted very negatively to.

Indeed, MannKind's eagerness to introduce a slightly modified version of the inhaler device can be viewed as an "amateurish" mistake due to it's lack of experience in working with the FDA. The company probably should have waited for an approval on the drug before even trying to modify the device it planned to bring to market, which would almost certainly would have been the approach taken by any experienced pharmaceutical company such as Novo Nordisk or Eli Lilly & Co., whose experience in working with the FDA and many other regulators around the world is far lengthier than is MannKind's.

But in spite of yesterday's delay, MannKind's senior management team remain upbeat about Technosphere insulin's prospects.

"We think the issues raised by the letter are completely addressable," company CFO Pfeffer said in a telephone interview.

"If we are allowed to incorporate this information on the inhaler in our response, we can stay on schedule for the commercial launch," Pfeffer said. He said the FDA would take 6 months to respond to new information from the company once it is submitted, so this particular inhalable insulin has suffered a lengthy delay, realistically, it may be postponed until 2011.

As a result of this delay, the reaction among the investment community on Wall Street was mostly pessimistic. The news sent MannKind shares tumbling nearly 25% Monday, on fears that the FDA might not actually approve the product.

"The fact that the FDA wants more data supporting clinical utility is not good for Afrezza," said Jon LeCroy, an analyst at the New York office of the Israel-based bank Hapoalim Securities. "We have always questioned the need for a new inhaled insulin and it looks as if the FDA may have similar questions."

A few other analysts echoed LeCroy's opinion.

JPMorgan Chase analyst Cory Kasimov said "The complete response letter in our view is an onerous one."

But whether Wall Street responds positively is really only a minor consequence.

To date, MannKind has been kept afloat with the help of its founder and CEO, Alfred Mann, who has poured millions of dollars of his own money into the company.

Mann, who owns roughly 46% of MannKind's shares, is one of the world's richest men, ranking No. 721 on Forbes' list of the world's billionaires. He built his fortune as an entrepreneur who helped develop solar cells, cardiac pacemakers, insulin pumps and implantable technology designed to restore hearing and sight.

Mann remains convinced that Afrezza can have the same revolutionary impact on the treatment of diabetes as cardiac pacemakers had on the treatment of heart disease.

To address the investment community, MannKind scheduled a conference call on Tuesday (March 16, 2010) morning to discuss the FDA's requests.

"We will discuss with the FDA whether it is appropriate to use what would otherwise have been a supplemental NDA submission, which we had planned to make during the second quarter of this year, to address the agency's requests," Mann said in a statement. "If this approach is acceptable, we believe that this regulatory action will not have a significant impact on the timing of the commercial launch of Afrezza."

"At this point, we have no reason to believe that our plans to launch in 2011 are adversely impacted by issues raised in the ... letter," CEO Alfred Mann said.

But whether doctors and patients are anxiously awaiting Afrezza's approval remains to be seen, especially given the competition expected to emerge in the coming years (see my previous post here for more details).

FDA Delay #2: Amylin's Bydureon (formerly known as Byetta LAR)

Second, the FDA's delayed its decision on Amylin Pharmaceuticals' (along with partner Eli Lilly & Co. and using Alkermes technology) for a drug formerly dubbed Byetta LAR (which means "Long-Acting Release") -- now branded as Bydureon -- which is seeking approval only as a type 2 diabetes treatment. Bydureon is an extended-action version of Byetta, an already FDA-approved drug available today. Again, rather than providing complete details in writing, you may watch the following short news summary for the basic information. The FDA's decision on Amylin's Bydureon can be viewed here:



Byetta already has annual sales of $700 million, and the long-acting release version would only have to be injected once weekly instead of daily for Byetta. But a similar drug just approved by the FDA, Novo Nordisk's Victoza (liraglutide) was approved, albiet with noteworthy delays and an FDA-mandated black-box warning over pancreatitis, suggesting far more caution from the FDA than Wall Street analysts gave the Amylin/Lilly drug on March 15, 2010. Bydureon is also delayed, though the reaction on Wall Street was mostly more positive than the news on MannKind, perhaps given the relative experience in resolving issues with the FDA on issues raised.

Conclusion

My take on both news releases is pretty much the same: the newly, more-cautious FDA is asking for more information, rather than simply awarding approvals and asking questions later. These are delays for both, although due to the nature of MannKind's letter, if I had to guess, that drug will be delayed longer than Amylin's Bydureon.