Stuart R. Gallant, MD, PhD

Insulin is a subject on a lot of people’s minds—C&E News just came out with a cover story on insulin [1].  This post focuses on the manufacturing and marketing of insulin.  It’s part of an occasional PharmaTopo^TM series called “Pharmaceutical Design Focus.”

Manufacturing Insulin

43 years ago, a team assembled by Herb Boyer and Bob Swanson of Genentech announced the first synthetic production of insulin.  Their Proceedings of the National Academy of Sciences paper, announcing this massive step forward in genetic engineering, described how genes for the two insulin chains (A and B) had been spliced into two separate plasmids and expressed in two separate strains of E. coli [2].  Following the description of insulin production and purification, almost as an afterthought, the paper recounted the triumphant moment when the insulin molecule was reconstituted from its two component chains, “Easily detectable radioimmune insulin activity is produced when purified E. coli A chain is mixed and reconstituted with partially purified (≈10% pure) E. coli B chain.”

In healthy people, insulin is produced in the pancreas as a single protein (preproinsulin), and then processed in the rough endoplasmic and the Golgi apparatus to produce the active, two-chain molecule responsible for control of blood sugar.  Insulin hexamers, the stable storage form of insulin, await release from the beta cells of the pancreas, after which insulin is distributed in the blood throughout the body.  Insulin rapidly binds to cellular insulin receptors (plasma half-life:  4-6 min) [3], and the cells of health individuals import glucose from the blood, normalizing blood sugar.

In patients with diabetes, recombinant insulin (known commonly as “human insulin” to distinguish it from insulin extracted from animal pancreases) is used to prevent excessive elevation of blood glucose.  Three related illnesses account for most usage of human insulin:  a) Type 1 diabetes results from autoimmune destruction of the pancreatic beta cells leading to a low insulin level in the patient, b) Type 2 diabetes results from insulin insensitivity—these patients produce large amounts of insulin, but their cells do not respond appropriately, and c) gestational diabetes is an elevated blood sugar level in the context of pregnancy.  Human insulin is always required in the treatment of Type 1 diabetes; in Type 2 diabetes, human insulin may be required if oral medications are insufficient; and in gestational diabetes, human insulin is sometimes used to protect the baby and its mother during the pregnancy.

An Outpouring of Insulins

Human ingenuity accelerated in the years following the 1979 PNAS insulin paper from the Genentech team.  On one single day in October 1982, the FDA licensed both Lilly’s “regular” form of insulin Humulin R and Lilly’s “isophane” form Humulin N.  (In healthy humans, insulin secretion occurs at a low “basal” level punctuated with spikes in response to meals.  Regular insulin is a quicker acting form (onset:  30 to 60 min; peak:  3 hours after administration).  Isophane insulin, a formulation of insulin with protamine, zinc, and phenol, has slower onset and a longer duration of action (from 14 to 24 hours).  By combining these two forms of insulin, natural insulin secretion can be mimicked.)

Following Lilly’s dual licensures, a four-decade long string of innovative insulin products followed.  In 1991, the FDA licensed Novo Nordisk to market two products (Novolin R and Novolin N) competing with Lilly’s 1982 licensed products.  Other significant US approvals in the following years included [4]:

Brand	Type	Manufacturer	Approv.	Action	Onset	Peak	Duration
Humalog	lispro	Lilly	1996	Quick	15-30 min	30 min-2 1/2 hr	5 hr
Lantus	glargine	Sanofi	2000	Long			11-24 hr
Novolog	aspart	Novo Nord.	2000	Quick	15 min	1-3 hr	3-5 hr
Apidra	glulisine	Sanofi	2004	Quick	20 min	30 min-1 1/2 hr	5 hr
Levemir	detemir	Novo Nord.	2005	Long			6-23 hr
Afrezza	human	Mannkind	2014	Inhaled Powder	5-10 min	30-60 min	3 hr
Tresiba	degludec	Novo Nord.	2015	Long			24 hr

When thinking about regulatory approvals, it is helpful to divide insulin products into three categories.  First, there are innovative products; examples would be Humulin N and Humulin R, both approved by the FDA in 1982.  Second, there are products which constitute a different dosage strength or presentation from an already licensed manufacturer, an example would be Lilly’s licensure of Humulin N in a 300 IU/3 ml vial and a separate 1000 IU/10 ml vial in 1982—one product counts as an innovative product, the second counts at a separate dosage strength.  Finally, there are competitors, an example would be licensure of Novolin N by Novo Nordisk in 1991.  In the figure below, the three categories of insulin are plotted versus year of licensure:

Together, by 2021, these approvals represent 16 innovative products, 41 dosage or presentation changes to innovative products, and 27 competing products.  The increase of total insulin products is depicted with the solid blue line (measured against the right vertical axis).

The Future of the Insulin Market

Having looked at insulin products and seen the rapidly increasing number of products on the market in the US, what trends are important in the international insulin market?

• Shifts in the Supply and Demand Curves:  The number of patients requiring insulin is increasing due to the increased prevalence of Type 2 diabetes.  By itself, a shift in the demand curve results in an increase in price (movement from equilibrium price 1 to equilibrium price 2 in the graph below).  However, increasing demand is not the only change in the insulin market.  As seen earlier in this post, the number of licensed insulin products has increased dramatically in the past 4 decades (doubling in the last 10 years). Not only the number of products is increasing—also manufacturing capacity is increasing.  As an example, Novo Nordisk just announced a $2.6B investment in manufacturing capacity in Denmark [5].  The increase in supply has shifted the supply curve to the right, leading to a lower equilibrium at price 3 in the graph below:

• Below Cost Generics:  Americans are all familiar with Target and Walmart’s generic pricing strategy.  It’s been a boon to consumers and a headache to local pharmacies.  Target and Walmart price a range of generic drugs below the cost of purchasing and dispensing them [6].  This creates loyal customers who purchase other items (groceries, toys, clothing) at the regular retail price while they are in the store to fill their prescriptions. The reason this is germane to our discussion is that the consumer market of the 2020s is relentlessly competitive.  There is no reason to think that that the same downward pressure manifested through the Target $4 and $10 Generic Medication List won’t also act on insulin prices.  Already, Walmart markets ReLion insulin (which is Novolog aspart insulin rebranded as a Walmart product) at “58% to 75% off the cash price of branded insulin products [7].”

• Changing Location of Manufacture:  The pharmaceutical manufacturing countries with the highest rates of export growth (Italy at 11.2% per annum, Ireland at 28.8%, India at 13.5%, Spain at 10.1%, Slovenia at 42.2%, Singapore at 20.7%, and China at 13.5%) all have favorable costs of manufacturing (i.e., labor rates and cost of land) in comparison to the longtime power houses like Germany and Switzerland.  As more manufacturing of insulin occurs in lower cost countries, like India, it would be expected that further downward pressure on insulin prices will be generated.

In spite of a changing insulin marketplace over the last 4 decades, three companies have continued to dominate the world insulin market (Lilly, Novo Nordisk, and Sanofi).  This dominance shows itself not only in high-income countries, but also in low- and middle-income countries [9].  The next 4 decades will be a time of change.  One possible outcome is a gradual migration of insulin manufacturing to lower cost manufacturing countries—in the same way that small molecules such as antibiotics and analgesics have migrated.  Another possibility is that Lilly, Novo Nordisk, and Sanofi will continue to innovate, bringing out new and desirable products that make glucose management easier and safer and improving their manufacturing technology to remain cost competitive, even in a cut-throat marketplace.  Realistically, the big three will have to yield some market share (if only because they hold so much of the market at the current time).  Time will tell how much share they will be forced to relinquish.

[1]  Arnaud, C.H.  “Insulin’s Second Century,” C&EN, 2022, 100 (4), pp 26–31 January 31, 2022.

[2]  Goeddel, D.V., et al.  “Expression in Escherichia coli of chemically synthesized genes for human insulin,” PNAS January 1, 1979 76 (1) 106-110; doi.org/10.1073/pnas.76.1.106.

[3]  Duckworth, W.C., et al.  “Insulin Degradation: Progress and Potential,” Endocrine Reviews 19(5): 608–624.

[4]  FDA Purple Book.  www.fda.gov/drugs/therapeutic-biologics-applications-bla/purple-book-lists-licensed-biological-products-reference-product-exclusivity-and-biosimilarity-or

[5]  www.reuters.com/markets/europe/novo-nordisk-invests-26-bln-new-production-danish-plant-2021-12-13/

[6]  Target $4 and $10 Generic Medication List.  tgtfiles.target.com/pharmacy/WCMP02-032536_RxGenericsList_NM7.pdf

[7]  Walmart Press Release.  corporate.walmart.com/newsroom/2021/06/29/walmart-revolutionizes-insulin-access-affordability-for-patients-with-diabetes-with-the-launch-of-the-first-and-only-private-brand-analog-insulin

[8]  www.worldstopexports.com/drugs-medicine-exports-country/

[9] IQVIA Institute, “Understanding Insulin Market Dynamics in Low- and Middle-Income Countries,” August 2021.

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