NovoRapid and NovoMix
NovoRapid was developed by pharma giant and diabetes dominator Novo Nordisk A/S (ADR) (NYSE:NVO), and picked up approval in the US in 2000. It is the third biggest selling diabetes treatment by revenues, and generated a little over $3.2 billion during 2015.
NovoRapid is the brand name for insulin aspart, and NovoMix is a combination of both fast acting and intermediate acting insulin aspart. NovoRapid is marketed as a fast-acting insulin analog meaning it has been altered by way of a change in its DNA sequence with the goal of changing the way it interacts with the body. Specifically, in the instance of NovoRapid, an amino acid called proline is removed and replaced with aspartic acid. When insulin stores inactively, six separate insulin molecules join together to form a hexamer as stated earlier. Hexamers are stable, and are the standard, natural way our bodies store insulin for future use.
In NovoRapid, proline plays a key role in the formation of hexamers, and so by removing it and replacing it with aspartic acid, the insulin molecules in insulin aspart are unable to form hexamers. This stops them from becoming dormant, and in turn, doesn’t allow for storage. Because the body cannot store the NovoRapid associated insulin molecules, they become active immediately, and herein lay the fast-acting nature of the treatment.
NovoMix is also a formulation of insulin aspart, however it differs in that it is a combination formulation. One part is the same insulin aspart found in NovoRapid. The other part is an intermediate-acting insulin because it is crystallized and takes time to dissolve in the blood. It takes a little longer for the insulin molecules to become active, and so the second part serves as a sort of longer tail supporting insulin dose. Together, the combination of fast and intermediate-acting insulin aspart serves to provide an immediate release, and a longer lasting release insulin treatment.
Just as with NovoRapid, NovoMix is a subcutaneous injection administration, designed for daily use flexible throughout the day, according to dietary habits.
Sales of NovoMix increased 13% from 2014 to 2015. NovoRapid sales are still growing rapidly, 19% from 2014 to 2015. Novo’s patent expires in one year, but like Eli Lilly, it is unlikely to be heavily affected.
NovoRapid was approved on the basis of a six-month open label study of 884 patients that showed HbA1c levels significantly lower in the aspart group than in the human insulin group. The side effect and safety profiles were similar between the two. The importance of this data is that it is not absolutely necessary to conduct placebo-controlled 3-year trials of thousands of patients. Smaller, quicker trials can still get through in some cases.
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Oramed and ORMD-0801
From the above four top best sellers in the type II diabetes market, two things have become clear. First, it is extremely difficult to dislodge a market leader either through a new product or by patent expirations. Biosimilars may have some effect, but probably not much because they are not exactly the same and changing insulin is a much bigger deal than simply going generic. Second, many of the best sellers are leveling off, most notably Lantus, and as growth slows or reverses, big diabetes players are going to be looking for replacements. But what could that replacement be besides yet another insulin analog with slightly different properties? Is there a way to completely change the diabetes market? It may be a long shot, but it is possible.
One company recently completed Phase IIb trials for an oral insulin pill, something that has been attempted since the 1920’s but no one has ever succeeded in creating. Insulin normally cannot get past the digestive system, and even if it did, it is difficult for the small intestine to absorb it due to the shape of the molecule and the way nutrients are absorbed in the intestinal tract.
Oramed Pharmaceuticals Inc. (NASDAQ:ORMP) may have just made the first step towards realizing this goal with ORMD-0801, which shows preliminary evidence of being able to get past the digestive system and be absorbed through the intestine via the portal vein directly to the liver.
Oramed’s insulin pill combines active insulin with enteric coating that prevents digestion from stomach acid. It also contains protease inhibitors that prevent digestion of the insulin in the intestinal tract, and absorption enhancers that guide the insulin molecules through the small intestine to the portal vein and then to the liver.
There is nothing unique about enteric coating, as it is a common technology to prevent drugs from being digested too quickly. There is also nothing unique about protease inhibitors. The company is mum on the nature of its absorption enhancers though for proprietary reasons, and it is the combination of these three factors that makes the approach unique.
Oramed just recently released Phase IIb data on 180 type II diabetics. The trial did not contain the traditional HbA1C endpoint that measures average glucose levels over a period of 8 to 12 weeks, but did show that, in principle, insulin can be taken orally and absorbed through the intestine. This is the very first time any company has proven that it can in theory be done. The endpoint of this trial was mean percentage change in pooled nighttime glucose, and there was a statistically significant decrease between the active arm and placebo of 6.47%.
What this means therapeutically is the question, as not even the company itself is sure how these results will translate to therapeutic outcomes. The only thing it does show is that some of the insulin did get through, though we don’t know how much because it never reached the blood so it cannot be tested that way. Any pivotal trial though will probably require an HbA1C endpoint like other insulin therapies.
The other question is why does oral insulin pose a bigger threat to established markets than another form of injectable insulin? For two reasons. First, an oral capsule is just easier to take and increases compliance. Injecting yourself with insulin is painful both physically and it is something that is hard mentally for many patients to accept. For this reason it is often postponed until symptoms of the disease worsen. Second, the reason that the insulin market is so bifurcated into long-acting, short-acting, intermediate-acting and mixes between them is that there are different matches for different patients depending on what their bodies work best with and what makes them feel normal.
