Januvia
The second best selling type 2 diabetes product last year was Januvia (sitagliptin) from Merck and Co., Inc. (NYSE:MRK) Januvia is a DPP-4 inhibitor. DPP-4 breaks down GLP-1, and GLP-1 ultimately instructs the pancreas to produce insulin. Since GLP-1 acts only in the presence of high blood glucose levels, Januvia operates in a self-regulating negative feedback loop as lower glucose levels tend to deactivate the mechanism, preventing overshoot or hypoglycemia. The other advantage is that it is an oral tablet rather than an injection, making it much more comfortable to take than insulin.
Januvia is Merck’s #1 bestseller with a patent until 2022, so no immediate danger for Merck here.
Sitagliptin was approved after showing that it could lower HbA1c level by 0.7% versus placebo. It is a second-line drug usually resorted to before insulin itself, but after metformin, and sometimes taken together with metformin in a combination branded Janumet.
The data behind its approval were as follows. Two monotherapy trials were conducted, one for 18 weeks and another for 24. The first had 521 patients in placebo and Januvia arms. The second tested 741 with the same arms. There were significant improvements in HbA1C in both trials for the Januvia arms vs. placebo, but no difference between a higher and lower dose.
Two combination therapy trials followed, one with 701 patients, and one with 353, so altogether we’re talking about 2,316 patients. In both trials, HbA1C improved for the combination metformin plus Januvia therapy over metformin alone. The second trial tested combination therapy with a different oral antidiabetics with similar results.
Merck has been sued by patients in the past for issues of pancreatitis and pancreatic cancer, which is not surprising given that the DPP-4 class manipulates pancreatic function. These issues have been minor enough for them not to derail the drug though.
In a sign of competition and pricing pressures in the diabetes market, Januvia sales have been plateauing since 2012. Januvia proper has been shrinking, but sales of the combination Janumet have more than compensated for that fall. The numbers show that despite a commanding lead in the DPP-4 market at 65% global market share, Januvia sales are near their peak and probably won’t climb too much higher until patent expiry.
Merck is another company whose #1 best seller will be under significant pressure in the medium term, and will be looking for a replacement for that bestseller in the next few years.
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Humalog and Humulin
Humalog, or insulin lispro, is yet another top bestselling product, this one from Eli Lilly and Co. (NYSE:LLY). In a sign of how much staying power diabetes biologic drugs have, Humalog was the first ever human insulin analog approved by the FDA in 1996. Humulin goes back even further as it was the first genetically engineered product ever approved by the FDA back in 1982. Eli Lilly’s patent on Humulin expired in 2000, but that has not stopped it from selling over $1.3 billion globally last year. Humalog’s patent expired in 2013 but that has not affected sales yet either.
Both Humalog and Humulin together sold over $4.15 billion in 2015. As far back as the SEC has online data, in 1991, Eli Lilly’s diabetic care segment logged $583.5 million in sales. That’s growth of over 7x in 25 years, despite patent expiries in the way.
What these numbers show is that the big bestselling diabetes drugs are not likely to quickly fade, though they are leveling off. More likely they will reach a peak (or have already done so) and then will slowly fade from there. Biosimilars will eat into some of the revenues, but not too heavily.
Both Humalog and Humulin are fast-acting insulins. Humulin is human insulin derived from recombinant DNA methods, basically the expression of human genes through a bacterial vector. Humalog is slightly tweaked human insulin, slightly changing the order of key amino acid sequences to prevent the molecule from clumping into hexamers. This keeps the insulin biologically active and is more suitable for people who do not want to wait long between injection and eating. Humalog closely mimics the body’s fast insulin response, so it may feel more normal to some patients than longer acting formulations like insulin glargine.
The approval for Humalog back in 1996 was also based on several Phase III trials totalling over 3,000 patients over 3 years. The reason that insulin trials are so protracted is that insulin is structurally similar to hormonal growth factors, and when tweaked it could affect cells in ways that are not good, such as causing too much growth as in cancer. Every time insulin is slightly changed to make a different formulation of it, large trials over long periods of time are generally required to make sure it does not cause cancer.
What both Humulin and Humalog show about the insulin market is that while there is competition between different kinds of insulin, it is only to a point. Once one form of insulin stakes out its market, it generally keeps it as patients get used to their brand and maintain it for maintenance of a consistent lifestyle. The new question is what effect will biosimilars have? Since biosimilars are not exactly the same as the drugs they copy, and since the characteristics of any particular insulin can change due to any small change, the biosimilar revolution will probably only succeed in introducing new kinds of insulin to the market that will stake out their own markets. Again, it may eat into some of the revenues of the drugs being copied, but patients are unlikely to adopt a biosimilar over their previous drugs in large numbers because changing the type of insulin you use is a big deal for diabetics. It is not a decision taken lightly like switching to identical generics over branded versions.
