But then there's MKC253...

The second drug that Mannkind is developing with the Technosphere platform is code-named MKC253, an inhaled version of GLP-1. Let me back up a bit. In a healthy person, as soon as he starts eating, the pancreas releases a spike of insulin, known as the Phase 1 spike, followed by a lower sustained level throughout the digestion period (Phase 2) until it drops back down to its pre-meal levels. (Insulin acts to lower the increased blood sugar from the meal. The Phase 1 spike also signals the liver to stop releasing sugar into the blood, and instead to absorb sugar from the blood and store it for later.) In a diabetic, the insulin levels do not rise robustly in response to a meal, especially missing the Phase 1 spike. What signals the pancreas to release more insulin for the meal? Well, the sugar from the meal itself does trigger the pancreas to produce more insulin. But that’s not the whole story. If a person would be given sugar intravenously, bypassing the digestive system, the insulin levels would not go up nearly as much. The reason for this is because when a person starts to eat, the intestine releases various hormones (known as incretins) which signal the pancreas to produce more insulin. One of these hormones is GLP-1 (glucagon-like peptide-1). One of the major advantages of GLP-1 is that it only prods the pancreas to make more insulin if there is also an elevated level of sugar in the blood. Since when the blood sugar is normal GLP-1 does not cause the pancreas to release more insulin, there is much less risk of hypoglycemia (dangerously low blood sugar) when using GLP-1, in contrast to the risk of hypoglycemia when injecting insulin or using sulfonylureas (drugs that prod the pancreas to produce more insulin indiscriminately).

So, naturally, we would think that helping the GLP-1 signal in a diabetic would improve the post-meal insulin response. Let’s just administer GLP-1 by every meal. But it’s not that simple. GLP-1 has a very short half-life in the body, about 2 minutes (i.e. ½ of the GLP-1 produced by the intestine is deactivated in about 2 minutes). The deactivation of the GLP-1 is mostly carried out by an enzyme called DPP-IV (dipeptidyl pepitidase-4). In other words, in a healthy body, when a person starts eating there is an extremely short burst of GLP-1 which quickly dies out. This triggers a short burst in insulin – the Phase 1 spike that diabetics are missing. But if you would try to inject GLP-1, the GLP-1 by injection will only trickle slowly into the bloodstream. Combined with this that GLP-1 is so rapidly destroyed by the body, you will not get the desired effect on insulin production that we are looking for.

So far, there have been two methods to try to solve this problem. First, companies have developed drugs that are similar to GLP-1 (with similar effects on the pancreas), but are resistant to DPP-IV. So although these drugs are given by injection and do not simulate the short burst of GLP-1 in a healthy body, they nevertheless cause extended long periods of GLP-1-like substances in the blood, causing greater insulin production post-meals and lower blood sugar levels. They do not, however, bring back the Phase 1 insulin spike missing in diabetics. The first drug in this class to be approved was the well-acclaimed exenatide, under the trade-name Byetta, co-developed by Amylin Pharmaceuticals (AMLN) and Eli Lilly (LLY). It is used as a twice-daily injection. The second drug in this class is liraglutide, developed by Novo Nordisk (NVO), and is expected to file for FDA approval this year. It is meant to be used as a once-daily injection. Amylin and Eli Lilly are currently developing a longer-lasting version of Byetta, Byetta LAR (long-acting release), which is meant to be injected once weekly. It has had very favorable trials so far and they expect to file for approval during the first half of 2009.

The second attempted solution is a class of drugs that inhibit DPP-IV from working, keeping the GLP-1 at elevated levels for longer. The first drug in this class to be approved was sitagliptin, under the trade-name Januvia, developed by Merck (MRK). It is taken as a pill once a day. There are also other drugs in this class currently being developed. Again, these drugs do not bring back the Phase 1 insulin spike missing in diabetics.

Mannkind’s proposed solution to the problem is to administer regular human GLP-1 by inhalation, instead of by injection. Because inhalation gives direct access to the bloodstream, the GLP-1 will immediately enter the body, quickly signal the pancreas to release more insulin, and quickly be deactivated by DPP-IV. This should closely mimic the short burst of GLP-1 released by the healthy body and bring back the Phase 1 insulin spike of a healthy body. Indeed, in their first human trial, Mannkind found that their inhaled GLP-1, code-named MKC253, had the desired effect. MKC253 produced a sharp pulse of GLP-1 in the bloodstream that peaked in less than 3 minutes. This, in turn, induced a spike of insulin from the pancreas that peaked in less than 6 minutes.

MKC253 is still in Phase 1 trials, so it still needs much further testing and is not close to market. However, being that this is simply administering a natural hormone found in the body but missing in diabetics, GLP-1, it is extremely likely to be found to be both effective and safe. In fact, since it is mimicking the natural function of a healthy body, it is likely to be safer than the first two methods outlined above, with fewer side effects. Byetta, although very effective, was found to have major side effects of nausea, vomiting, and diarrhea. As much as maybe 25% of patients can’t take Byetta for these reasons. Recently, the FDA added a warning to Byetta’s label that Byetta may cause acute pancreatitis (due to reports of acute pancreatitis in people taking Byetta). Presumably, these side effects come from the elevated levels of GLP-1 for an unnaturally long time and/or the differences between Byetta and GLP-1 (that make it resistant to DPP-IV breakdown). Mannkind’s inhaled GLP-1 would likely not have these problems because it is mimicking the natural body.

Indeed, in their first human trial, Mannkind found that MKC253 was well tolerated by the trial participants. Even with the highest dosage of MKC253, they did not find any of the nausea and vomiting characteristically associated with such dosage levels. In fact, they reached levels of GLP-1 in the blood of more than 3 times the level which has been found to cause unacceptable side effects when injecting, and still found no side effects by inhalation! (By the way, it should be pointed out that all this talk about GLP-1 and DPP-IV is only pertinent to Type 2 Diabetics, whose bodies are still capable of making insulin. Type 2 Diabetics comprise 90% – 95% of all diabetics.)

http://seekingalpha.com/article/81899-mannkind-overlooked-biotech-with-excellent-prospects-part-v