INDUSTRIALIZATION AND COMMERCIALIZATION OF SEMAGLUTIDE

From Lab to Market: The Industrial and Commercial Journey of Semaglutide

Aish Tuli | 501118912

CHY599 - The Business of Chemistry and Biology

Dr. Ted Petroff

November 27, 2023

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Introduction

In regards to diabetes, both the disease and the evolution of its treatment have been on the

rise. With a diverse array of drugs designed to manage blood glucose levels and mitigate the

condition’s impact on patient health, pharmaceutical interventions play a crucial role in

providing effective and personalized solutions for individuals living with diabetes - aiming not

only to control symptoms but also to improve the quality of life. Semaglutide, a groundbreaking

pharmaceutical innovation commonly known as the brands Ozempic and Wegovy, is the latest

trend. It has not only revolutionized type 2 diabetes treatment but has also exerted a profound

commercial impact, reshaping market dynamics, influencing sales strategies, and contributing to

a paradigm shift in the pharmaceutical industry's approach to chronic disease management.

History and Innovation

The history of weight loss drugs originates in World War I, when dinitrophenol, one of

the first, was originally used in munitions factories as an explosive but was then marketed as

“antiobesity therapy” in the 1930s after workers who came into contact with it reported weight

loss. Shortly after, dinitrophenol was removed from the market and declared “not fit for human

consumption” by the FDA after it was proven dangerous at high doses, causing blindness and

neuropathy (Bray & Purnell, 2000). Amphetamines followed through as the next diet pill of

choice - Benzedrine in the 1940s (Rasmussen, 2008), HCG in the 1950s (Holles, 1974), and

Obetrol in 1960 (Sharma, 2017). Until the FDA restricted its availability to prescription only,

amphetamines contributed to appetite suppression and increased basal metabolism and energy

expenditure through their stimulating effect. In 1985, obesity was declared to be a chronic

disease by the National Institutes for Health, inviting treatment solutions such as the Fen-Phen

that caused pulmonary hypotension and heart valve abnormalities, resulting in its exit from the
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market (Kolata, 1997). Subsequently, several other drugs were approved by the FDA only to be

withdrawn, such as orlistat (Xenical) in 1999, and lorcaserin in the 2000s (Huxford, 2023).

The connection between the pancreas, gut, and incretin (gut polypeptide) hormones was

discovered in the early twentieth century by William Bayliss and Ernest Starling, with the

identification of secretin as the first gastrointestinal peptide hormone (Bayliss & Starling, 1902).

In 1921, insulin was discovered (Banting et al., 1922), followed by the discovery of glucagon,

the “glucose antagonist” hyperglycemic hormone, two years later (Kimball & Murlin, 1923). The

first glucagon-detecting antibody was created by Roger Unger in 1959, leading to the

development of the first radioimmunoassays (RIA) to detect glucagon in blood and tissue

samples (Unger et al., 1959). Subsequently, in the early 1970s, the first incretin hormone gastric

inhibitory polypeptide (GIP) was recognized as a gastric motility suppressor and gastric acid

secretor (Brown et al., 1970). However, the breakthrough occurred in the 1980s when Jens Juul

Holst, a professor at the University of Copenhagen in Denmark, and his colleagues were also

studying the incretin effect through research involving the gastrointestinal tracts of pigs. After

finding two glucagon-like peptide hormones (Ørskov et al., 1986), they decided to isolate the

naturally occurring hormone from porcine and human and gut extracts, resulting in the

identification of the hormone glucagon-like peptide-1 (GLP-1) as a stimulator of insulin

secretion (Ørskov et al., 1989). A few years later, Holst went on to infuse GLP-1 into type 2

diabetic patients, demonstrating blood glucose lowering to normal levels in four hours, the

stimulation of insulin, and inhibition of glucagon (Nauck et al., 1993). The conclusion reached

was that exogenous GLP-1 (7-36 amide) is effective in normalizing the fasting plasma glucose

concentrations in individuals with poorly controlled type 2 diabetes.

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The 30 amino acid peptide hormone, however, has the limitation of a very short half-life

of 1.5-5 min in plasma, which raised concern about therapeutic use in the clinical setting (Hui et

al., 2002) since “a constantly high and stable plasma level is required” (Larsen et al., 2001).

After GLP-1 was understood to be a potential therapeutic target, various approaches have been

used to extend its half-life - such as the binding of albumin, the most stable plasma protein.

Credit for the commercialization of semaglutide (Ozempic and its sister brands Wegovy

and Rybelsus) is due to Novo Nordisk, the Danish healthcare company specializing in diabetes

treatment. Originally, liraglutide was “selected as the first GLP-1-based analog suitable for OD

dosing”, and after successful trials with it, “further interest developed in GLP-1-based therapies”

(Knudsen & Lau, 2019). The focus was to “achieve plasma levels sufficient to control blood

glucose” and “avoid unnecessary risks in terms of immunogenicity” (Knudsen & Lau, 2019),

resulting in the birth of semaglutide. The company conducted several phases of clinical trials to

assess semaglutide’s safety and efficacy and to establish its potential to lower blood sugar levels.

From 2008 to 2009, a phase II clinical trial was conducted in Europe, Asia, and Africa with

randomized treatment of semaglutide, placebo, or liraglutide (Novo Nordisk A/S,

NCT00696657). In 2015, Novo Nordisk announced the advancement to phase III trials (diaTribe,

2015), which took place in Asia, Europe, and the USA from 2016 to 2017 (Novo Nordisk A/S,

NCT02648204) before the drug was branded under the name Ozempic. Subsequently, Ozempic

received its first approval from the Food and Drug Administration (FDA) in 2017 to assist in

diabetic blood sugar management. However, when the side effect of weight loss was noticed

during pre-approval studies (Shmerling, 2023), the higher-dosed version of semaglutide called

Wegovy was approved as a weight-loss drug in addition to a reduced-calorie diet and increased

physical activity (FDA, 2021).

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Chemical and Biological Functionality

An imbalance of the insulin and glucagon hormones is present in those with type 2

diabetes - having too much glucagon secreted and too little insulin secreted from the pancreas,

promoting elevated blood sugar levels (Hædersdal et al., 2018) resulting from β-cell failure

(Meloni et al., 2012). Semaglutide (C₁₈₇H₂₉₁N₄₅O₅₉) classified under the umbrella of

Glucagon-Like-Peptide-1 antagonists (GLP-1 RAs), mimics the function of the GLP-1 hormone

and activates the GLP-1 receptors in the pancreas. The drug has a double mechanism on blood

glucose by stimulating insulin and inhibiting glucagon, consequently lowering blood sugar and

hemoglobin A1C, delaying gastric emptying and gut motility (Shah & Vella, 2015), and

restraining food intake (Drucker et al., 2017).

Insulin is stimulated from pancreatic β-cells via a glucose-dependent process. Elevated

glucose levels in the hyperglycemic state are sensed by the β-cells which allow cellular entry

through glucose transporters (Meloni et al., 2012). This initiates the glycolysis stage in cellular

respiration, in which glucose is converted into pyruvate, followed by the transportation of

pyruvate to the mitochondria before the citric acid cycle. Once the glucose is converted into

Adenosine Triphosphate (ATP), the ratio of ATP to ADP levels increases to initially trigger the

closure of K⁺ATP channels that are located on the plasma membrane of the pancreatic β-cells

(Gromada et al., 2004). GLP-1 plays an important role in inhibiting these K⁺ATP channels, as the

binding of it to the GLP-1 receptor on the membrane triggers the production of cyclic adenosine

monophosphate (cAMP) that further activates the protein kinase A that depolarizes the β-cell and

its plasma membrane. This opens the voltage-dependent K⁺ channels (Kᵥ) to repolarize the cell

and activates the voltage-dependent L-type Ca²⁺ (VDCC) channels, leading to an influx of
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calcium (Gromada et al., 2004). Insulin, synthesized in the endoplasmic reticulum part of the

cell, is then transported out of the pancreatic β-cells and released into the blood once the

membrane is repolarized (Meloni et al., 2012). The blood sugar levels decrease once the insulin

shuttles the glucose from the blood into the cells to be stored as energy in the form of glycogen.

The reverse occurs with glucagon - when blood glucose levels are low, the hormone signals the

body to release the stored glycogen to be used as energy (EKU Online, 2019).

Through the process of insulin stimulation by GLP-1, glucagon is indirectly suppressed.

The exact process by which GLP-1 suppresses glucagon is currently indeterminate (Ramracheya

et al., 2018), although it is known that the secretion of glucagon is similar to insulin, except

occurring from the α-cells of the pancreas, with glucagon being “the principle measure” of their

function (Sandoval & D’Alessio, 2015). Thus, GLP-1 inhibits glucagon secretion from the

pancreatic cells specifically with direct action on the α-cells (Ramracheya et al., 2018), which

also express glucagon receptors (Sandoval & D’Alessio, 2015). Much like insulin, glucagon

exocytosis is also dependent on the influx of Ca²⁺ (Ramracheya et al., 2010). Scientific

consensus suggests that Ca2+ channels and its interaction with cAMP (Acreman & Zhang,

2022), inhibits the exocytosis of glucagon.

Reduced gastrointestinal (GI) motility and the delay of gastric emptying are other notable

outcomes of semaglutide, which also reduces the extent of the post-meal glycemic response

(Linnebjerg et al., 2008). Most GLP-1 is produced in the GI tract and neurons in the gut that

allow it to regulate GI motility (Knudsen & Lau, 2019), hindering gastric contractions and

slowing down the rate of the stomach emptying its contents into the small intestine (Camilleri,

2019). A byproduct of gastric emptying, appetite suppression, has been demonstrated to be

induced by the appetite-and reward-related brain areas. Many regions of the brain that regulate
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food consumption, such as the acruate nucleus and other hypothalmic regions, contain GLP-1

receptors (Göke et al., 1995) and serve as secretion sites for the hunger hormone ghrelin

(Ronveaux et al., 2015). The activation of GLP-1 receptors reduces the brain’s responses to food

cues in the insula, amygdala, OFC, and putamen parts of the brain and hinders ghrelin - thus

reducing food consumption (Bloemendaal et al., 2014).

Commercial Impact and Market Dynamics

The discovery and commercialization of semaglutide has significantly impacted the

pharmaceutical industry as an innovative approach to metabolic health. After its late 2017

approval, semaglutide was strategically introduced into the market through differentiation, as it

holds a distinctive market positioning due to its target of multiple aspects of diabetes

management and its once-weekly dosing schedule that provides a convenient alternative to daily

oral medications and insulin administration. More than 1.3 billion may be living with diabetes by

2050 (The Lancet, 2023) and as the incidence rate climbs, so do the opportunities for increased

profit margins. Not only has semaglutide’s popularity increased as a next-generation diabetes

medication, but has gained momentous demand in its off-label use as a weight loss “quick-fix”,

which will only grow as Morgan Stanley projects the global obesity market to reach $77 billion

by 2030 (Adegbesan & Bloomberg, 2023).

Being the fourth-highest-spending drug nationally in 2021, (Tichy et al., 2022) the

number of prescriptions quadrupled from the previous year with over nine million prescriptions

written for weight loss drugs at the end of 2022 (Gilbert, 2023). Since 2017, Ozempic has grown

to acquire 65.4% of all GLP-1 prescriptions (Trilliant Health, 2023), attracting many after the

2022 Wegovy shortage (Shmerling, 2023), leading to Ozempic’s own shortage expected to last
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until 2024 (Stassen, 2023). Consequently, consumers took extreme measures such as traveling to

other countries to obtain the drug (Vanek Smith, 2023).

The surge in demand sparked new businesses, including several telehealth companies that

began advertising monthly subscriptions to weight loss services that include access to

semaglutide (Vanek Smith, 2023). Semaglutide has also established its prominence among

celebrities and influencers (Johnson, 2022), such as Elon Musk. The marketing strategy also

consists of social media with more than 4,000 campaigns running for semaglutide drugs (Ingram,

2023) and the hashtag #Ozempic itself surpassing 1.3 billion views on TikTok. Vivvix reported

Novo Nordisk’s $180.2 million spending on Ozempic promotions in 2022 - allocating $157

million of the budget to national TV (Adams & Taylor, 2023) and 41% to online video ads

(Adams, 2023).

Novo Nordisk has secured its position as the dominant market leader as Ozempic and

Wegovy makeup two of the three products capturing the current market. Considerable revenue

has been derived from Ozempic, as “net sales were 111.8 billion Danish krone, or $17.7 billion

USD in 2018”, and “it was only up from there: in the first six months of 2023, sales of Ozempic

and Wegovy rose by 58% and 363%, respectively” (Rice, 2023). In fact, Novo Nordisk’s

projected sales for 2023 were $12.5 billion, 54% greater than the closest competing drug

Trulicity by Eli Lilly, which had anticipated sales of $8 billion. The company exceeded this as

the total revenue for the first nine months of 2023 was almost doubled at $23.6 billion, with $4.8

billion from Ozempic and Wegovy in Q3 alone (Saul, 2023). Over the next five years, Ozempic

is expected to sustain its sales growth with forecasted annual sales of $17 billion in 2029,

representing an 83% increase from 2022 to 2029 and a compound annual growth rate of 9%

(GlobalData Healthcare, 2023). In fact, the market for semaglutide could reach $100 billion US
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by 2030 with Novo Nordisk sharing a duopoly with competitor Eli Lilly to capture 80% of the

obesity market (Pham & Barnert, 2023). As of November 2023, Novo Nordisk is ranked as the

15th largest company in the world by market capitalization possessing $470.41 billion USD,

(CompaniesMarketCap, 2023) which is higher than Denmark’s projected entire gross domestic

product of 409.38 billion USD (Trading Economics, 2023).

Despite the success, semaglutide faces potential challenges in its commercialization. The

uniqueness of semaglutide is still against strong competition in the diabetes market, such as the

introduction of other weekly injections Mounjaro (tirzepatide) and Trulicity (dulaglutide) by Eli

Lilly. Access also may be limited by high out-of-pocket costs and inadequate insurance (Chao et

al., 2022), with some providers ceasing coverage. Off-label use also presents challenges such as

legal and regulatory issues in varying countries, such as the United Kingdom’s ban on

non-prescription acquisition (Hignett, 2023). On the other hand, the rise of semaglutide has also

benefitted in challenging other industries, such as Walmart observing decreased purchases of

food and calories despite selling GLP-1 drugs (Case & Banjo, 2023) and Krispy Kreme

expressing concern over a potential decline in doughnut sales (Leon, 2023).

Conclusion

In essence, semaglutide, developed by Novo Nordisk and represented by its popular

brands Ozempic and Wegovy, stands at the forefront of diabetes treatment. Its unique

biochemical function and dual mechanism paired with convenient administration are pivotal in

its industrial and commercial success. The innovative incretin mimetic provides a nuanced

approach to glycemic control and metabolic health as a whole, carving a distinct niche in both

the diabetic management and weight loss markets. Semaglutide's influence extends beyond

healthcare, impacting consumer behavior and challenging traditional norms, though it is not
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without its challenges. Market competition and regulatory complexities underscore the dynamic

landscape, which may serve as obstacles in Novo Nordisk’s global approach of reshaping chronic

disease treatment.
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