Lotte Bjerre Knudsen

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Lotte Bjerre Knudsen (born 10 March 1964) is a Danish scientist and university professor. She led the development of liraglutide and oversaw the development of semaglutide, [1] [2] two notable drugs approved for indications in the treatment of diabetes and obesity. [2] [3]

Contents

Early life and education

Knudsen originally studied chemical engineering at the Technical University of Denmark,[ citation needed ] and obtained a doctorate in scientific medicine (DMSc) from the University of Copenhagen in 2014. [2]

Career

Knudsen began work as a scientist at the pharmaceutical company Novo Nordisk in Denmark in 1989. [2] As of December 2015, she was being referred to as Scientific Vice President for Global Research at Novo-Nordisk. [4] She served as an adjunct faculty member at Aarhus University from 2015-2020, as a professor in translational medicine. [2]

Knudsen has been employed as a Chief Scientific Advisor in Research and Early Development at Novo Nordisk. [5] [6]

Contributions

While still a student, Knudsen worked at Novo Nordisk, initially working on laundry detergent enzymes. Alongside fellow student Shamkant Patkar, she discovered an enzyme capable of removing microscopic strands of cotton that pill up on clothing from repeated wear. [7]

After this project, Knudsen joined full-time as part of a research group at Novo Nordisk that aimed to identify new treatments for diabetes, by developing small molecule drugs targeting specific metabolic pathways. [7] One project revolved around glucagon-like peptide-1 (GLP-1), [7] a hormone that stimulates the production of insulin but has a short half-life of minutes in the body. [3] [ third-party source needed ]

GLP-1 had been previously identified by researchers such as Jens Juul Holst in Denmark, who joined Novo Nordisk as a consultant, [7] [ full citation needed ] and Joel Habener, Daniel J. Drucker, and Svetlana Mojsov at Massachusetts General Hospital. [8] [9] [ verification needed ] Knudsen's team screened numerous chemical compounds to identify whether they could bind to the GLP-1 receptor sufficiently to stimulate insulin secretion. [10]

Eventually, they developed a new compound called liraglutide, which is an agonist for the GLP-1 receptor. [11] It is a chemical analogue of GLP-1, with a fatty acid and spacer attached. These modifications increased its ability to dissolve in water and bind to albumin, which increase its bioavailability—its lifetime in the bloodstream, and so the duration of its action in the body. [3] [6] Liraglutide was approved as a treatment for diabetes under the brand name Victoza in the United States in 2010. [12]

Knudsen’s team, specifically Jesper Lau and Thomas Kruse, then worked on what became semaglutide, which had greater stability and affinity to albumin, lengthening its duration of action further to a once-weekly drug. [6] [13]

Semaglutide was approved in the United States under the brand name Ozempic as a treatment for type 2 diabetes in 2017, [14] [15] and under the brand name Wegovy, as a first injectable (at 2.4 mg once weekly), for chronic weight management in June 2021. [16] [17] [ needs update ]

Impact

Martin Müller and Alexander Preker, writing for Der Spiegel in January 2024, have referred to Knudsen discovery in inventing the semaglutide weight-loss injections as "revolutionary", with the "drug Wegovy... [having] changed the world," and having made Novo Nordisk "Europe's most valuable company, [more valuable] than Daimler, Bayer, Lufthansa and BMW combined". [2]

Honors and recognition

Knudsen received the 2023 Paul Langerhans Medal by the German Diabetes Society for her work developing liraglutide. [18] [19] In October 2023, she received the STAT Biomedical Innovation award, [20] and in 2024, she received the Mani L. Bhaumik Breakthrough of the Year Award. [6] In 2024 she received the Lasker Award in clinical research. [21]

Further reading

Related Research Articles

Drugs used in diabetes treat diabetes mellitus by decreasing glucose levels in the blood. With the exception of insulin, most GLP-1 receptor agonists, and pramlintide, all diabetes medications are administered orally and are thus called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of hypoglycemic drugs, and selection of the appropriate agent depends on the nature of diabetes, age, and situation of the person, as well as other patient factors.

<span class="mw-page-title-main">Anti-obesity medication</span> Class of pharmacological agents

Anti-obesity medication or weight loss medications are pharmacological agents that reduce or control excess body fat. These medications alter one of the fundamental processes of the human body, weight regulation, by: reducing appetite and consequently energy intake, increasing energy expenditure, redirecting nutrients from adipose to lean tissue, or interfering with the absorption of calories.

<span class="mw-page-title-main">Novo Nordisk</span> Danish pharmaceutical company

Novo Nordisk A/S is a Danish multinational pharmaceutical company headquartered in Bagsværd with production facilities in nine countries and affiliates or offices in five countries. Novo Nordisk is controlled by majority shareholder Novo Holdings A/S which holds approximately 28% of its shares and a majority (77%) of its voting shares.

<span class="mw-page-title-main">Incretin</span> Group of gastrointestinal hormones

Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels. Incretins are released after eating and augment the secretion of insulin released from pancreatic beta cells of the islets of Langerhans by a blood-glucose–dependent mechanism.

<span class="mw-page-title-main">Exenatide</span> Medication

Exenatide, sold under the brand name Byetta among others, is a medication used to treat type 2 diabetes. It is used together with diet, exercise, and potentially other antidiabetic medication. It is a treatment option after metformin and sulfonylureas. It is given by injection under the skin.

<span class="mw-page-title-main">Glucagon-like peptide-1</span> Gastrointestinal peptide hormone involved in glucose homeostasis

Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from the tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and certain neurons within the nucleus of the solitary tract in the brainstem upon food consumption. The initial product GLP-1 (1–37) is susceptible to amidation and proteolytic cleavage, which gives rise to the two truncated and equipotent biologically active forms, GLP-1 (7–36) amide and GLP-1 (7–37). Active GLP-1 protein secondary structure includes two α-helices from amino acid position 13–20 and 24–35 separated by a linker region.

<span class="mw-page-title-main">Glucagon-like peptide-1 receptor</span> Receptor activated by peptide hormone GLP-1

The glucagon-like peptide-1 receptor (GLP1R) is a G protein-coupled receptor (GPCR) found on beta cells of the pancreas and on neurons of the brain. It is involved in the control of blood sugar level by enhancing insulin secretion. In humans it is synthesised by the gene GLP1R, which is present on chromosome 6. It is a member of the glucagon receptor family of GPCRs. GLP1R is composed of two domains, one extracellular (ECD) that binds the C-terminal helix of GLP-1, and one transmembrane (TMD) domain that binds the N-terminal region of GLP-1. In the TMD domain there is a fulcrum of polar residues that regulates the biased signaling of the receptor while the transmembrane helical boundaries and extracellular surface are a trigger for biased agonism.

<span class="mw-page-title-main">Liraglutide</span> Anti-diabetic medication

Liraglutide, sold under the brand names Victoza and Saxenda among others, is an anti-diabetic medication used to treat type 2 diabetes, and chronic obesity. It is a second-line therapy for diabetes following first-line therapy with metformin. Its effects on long-term health outcomes like heart disease and life expectancy are unclear. It is given by injection under the skin.

Albiglutide is a glucagon-like peptide-1 agonist drug marketed by GlaxoSmithKline (GSK) for treatment of type 2 diabetes. As of 2017 it is unclear if it affects a person's risk of death. In 2017 GSK announced Albiglutide's withdrawal from the worldwide market for economic reasons, and remaining stocks in the supply chain were effectively depleted by 2018.

Glucagon-like peptide-1 (GLP-1) receptor agonists, also known as GLP-1 analogs, GLP-1DAs or incretin mimetics, are a class of anorectic drugs that reduce blood sugar and energy intake by activating the GLP-1 receptor. They mimic the actions of the endogenous incretin hormone GLP-1 that is released by the gut after eating.

Lixisenatide is a once-daily injectable GLP-1 receptor agonist for the treatment of type 2 diabetes.

<span class="mw-page-title-main">Dulaglutide</span> Diabetes medication

Dulaglutide, sold under the brand name Trulicity among others, is a medication used for the treatment of type 2 diabetes in combination with diet and exercise. It is also approved in the United States for the reduction of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors. It is a once-weekly injection.

<span class="mw-page-title-main">Semaglutide</span> Anti-diabetic and anti-obesity medication

Semaglutide is an antidiabetic medication used for the treatment of type 2 diabetes and an anti-obesity medication used for long-term weight management. It is a peptide similar to the hormone glucagon-like peptide-1 (GLP-1), modified with a side chain. It can be administered by subcutaneous injection or taken orally. It is sold under the brand names Ozempic and Rybelsus for diabetes, and under the brand name Wegovy for weight loss.

Joel Habener is a Professor of Medicine at Harvard Medical School.

<span class="mw-page-title-main">Tirzepatide</span> Anti-diabetic and weight loss medication

Tirzepatide is an antidiabetic medication used for the treatment of type 2 diabetes and for weight loss. Tirzepatide is administered via subcutaneous injections. It is sold under the brand names Mounjaro for diabetes treatment, and Zepbound for weight loss.

Svetlana Mojsov is a Macedonian American, ex- Yugoslavian-born chemist who is a research associate professor at Rockefeller University. Her research considers peptide synthesis. She discovered the glucagon-like peptide-1 and uncovered its role in glucose metabolism and the secretion of insulin. Her breakthroughs were transformed by Novo Nordisk into therapeutic agents against diabetes and obesity.

NNC9204-1706 or NN9423 is a GLP-1/GIP/glucagon receptor triple agonist developed by Novo Nordisk. It was evaluated in a clinical trial; adverse effects such as "dose-dependent increases in heart rate and reductions in reticulocyte count, increases in markers of inflammation and hepatic disturbances, and impaired glucose tolerance at the highest dosages" meant that the drug was declared to have an inadequate safety profile and discontinued.

GLP1 poly-agonist peptides are a class of drugs that activate multiple peptide hormone receptors including the glucagon-like peptide-1 (GLP-1) receptor. These drugs are developed for the same indications as GLP-1 receptor agonists—especially obesity, type 2 diabetes, and non-alcoholic fatty liver disease. They are expected to provide superior efficacy with fewer adverse effects compared to GLP-1 mono-agonists, which are dose-limited by gastrointestinal disturbances. The effectiveness of multi-receptor agonists could possibly equal or exceed that of bariatric surgery. The first such drug to receive approval is tirzepatide, a dual agonist of GLP-1 and GIP receptors.

Amycretin is a single molecule that operates as a GLP-1 receptor agonist and amylin receptor agonist. It is under development by Novo Nordisk as a weight loss drug; unlike some competitors, it can be delivered orally.

Jens Juul Holst is a Danish physician and physiologist. He is known for discovering and describing the hormone glucagon-like peptide-1 (GLP-1), a hormone in the gut that plays an important role in the onset and development of Type 2 diabetes. In collaboration with researcher and author Arne Astrup, he discovered that GLP-1 acts as a satiety hormone in humans.

References

  1. ↑ Molteni, Megan; Chen, Elaine (30 September 2023). "GLP-1 drugs are transforming diabetes, obesity and more. Could a Nobel be next?" STAT News. . "Some of the most compelling evidence for this came when Novo Nordisk began testing a once-weekly version developed by Knudsen’s team, called semaglutide. Whereas liraglutide has been shown to cut a person’s food intake by 15%, semaglutide reduced it by up to 35%."
  2. 1 2 3 4 5 6 Müller, Martin U.; Preker, Alexander & Knudsen, Lotte Bjerre (4 January 2024). "Interview with Weight Loss Drugs Inventor Lotte Bjerre Knudsen". Der Spiegel . Retrieved 6 January 2024. Lotte Bjerre Knudsen, born in 1964, studied biotechnology and has worked for the Danish pharmaceutical company Novo Nordisk since 1989, including many years in drug discovery and development. She is interested especially in the use of the peptide hormone GLP-1 to combat obesity. She has held a doctor of medical science (DMSc) in scientific medicine from the University of Copenhagen since 2014 and served as an adjunct professor in translational medicine at Aarhus University from 2015 to 2020. Before joining Novo Nordisk, she traveled on the Trans-Siberian Railway.{{cite news}}: CS1 maint: multiple names: authors list (link).
  3. 1 2 3 Knudsen, L. B. & Lau, J. (11 April 2019). "The Discovery and Development of Liraglutide and Semaglutide". Front. Endocrinol. 10: 155ff. doi: 10.3389/fendo.2019.00155 . ISSN   1664-2392. PMC   6474072 . PMID   31031702.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ↑ Nielsen, Malene Løvig (18 December 2015). "Pharmaceutical Researcher is New Honorary Professor at Health". AU.dk . Retrieved 13 May 2024. Lotte Bjerre Knudsen from Novo Nordisk is a new honorary professor at Health, Aarhus University. She is the person behind the discovery of liraglutide, a new class of drugs for Novo Nordisk that are used in the treatment of type 2 diabetes and obesity.
  5. ↑ Knudsen, Lotte Bjerre (21 April 2024). "Lotte Bjerre Knudsen: Experience" (autobiographical post). LinkedIn.com . Retrieved 21 April 2024.[ third-party source needed ]
  6. 1 2 3 4 Phelan, Meagan (4 April 2024). "Innovators Who Fought to Unlock GLP-1 Drugs for Obesity Awarded Mani L. Bhaumik Breakthrough of the Year Award." AAAS.
  7. 1 2 3 4 Molteni, Megan (17 October 2023). "How One Scientist's Determination Made Novo Nordisk an Obesity-Drug Powerhouse" . STAT . Retrieved 21 April 2024.
  8. ↑ Drucker, Daniel J.; Habener, Joel F. & Holst, Jens Juul (1 December 2017). "Discovery, Characterization, and Clinical Development of the Glucagon-like Peptides". J. Clin. Invest. 127 (12): 4217–4227. doi:10.1172/JCI97233. PMC   5707151 . PMID   29202475 . Retrieved 21 April 2024.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ↑ Dolgin, Elie (2023). "Weight-Loss-Drug Pioneer: This Biochemist [Svetlana Mojsov] Finally Gained Recognition for her Work" . Nature . 624 (13 December): 506. doi:10.1038/d41586-023-03927-1. PMID   38093064 . Retrieved 21 April 2024. Svetlana Mojsov led early studies of GLP-1, the hormone behind Wegovy, Ozempic and other blockbusters.
  10. ↑ Molteni, Megan; Chen, Elaine (30 September 2023). "GLP-1 drugs are transforming diabetes, obesity and more. Could a Nobel be next?" STAT News. . "Knudsen spent her first year as a diabetes researcher working in a cold room with three technicians to screen hundreds of thousands of compounds to see if they could wedge into the GLP-1 receptor and other targets of interest just snugly enough to stimulate insulin secretion. To make it go faster, she updated the assays so they could test 96 candidates at a time instead of just one. But it didn’t change the fact that nothing worked."
  11. ↑ Molteni, Megan; Chen, Elaine (30 September 2023). "GLP-1 drugs are transforming diabetes, obesity and more. Could a Nobel be next?" STAT News. . "Following that approach would soon kick off a revolution in how doctors think of and treat obesity. Knudsen created a longer-lasting analog of GLP-1 that became liraglutide, a medication approved in 2010 and sold as Victoza that helped diabetes patients control their blood sugar and lose weight. An even more effective version would soon follow in semaglutide, the active ingredient in Ozempic and Wegovy."
  12. ↑ Iepsen, E. W.; Torekov, S. S.; Holst, J. J. (2015). "Liraglutide for Type 2 diabetes and obesity: a 2015 update". Expert Review of Cardiovascular Therapy. 13 (7): 753–767. doi:10.1586/14779072.2015.1054810. PMID   26106933.
  13. ↑ Lau, Jesper; Bloch, Paw; Schäffer, Lauge; Pettersson, Ingrid; Spetzler, Jane; Kofoed, Jacob; Madsen, Kjeld; Knudsen, Lotte Bjerre; McGuire, James; Steensgaard, Dorte Bjerre; Strauss, Holger Martin; Gram, Dorte X.; Knudsen, Sanne Møller; Nielsen, Flemming Seier; Thygesen, Peter; Reedtz-Runge, Steffen; Kruse, Thomas (2015). "Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide". Journal of Medicinal Chemistry. 58 (18): 7370–7380. doi:10.1021/acs.jmedchem.5b00726. PMID   26308095.
  14. ↑ FDA Staff (5 December 2017). "Ozempic (semaglutide) Injection". FDA.gov. Retrieved 13 May 2024. Company: Novo Nordisk Inc. / Application No.: 209637 / Approval Date: 12/05/2017
  15. ↑ Clarke, Toni (5 December 2017). "FDA approves Novo Nordisk diabetes drug Ozempic." Reuters.
  16. ↑ Kahn, Jeremy (4 June 2021). "FDA Approves New Drug Treatment for Chronic Weight Management, First Since 2014" (press release). FDA.gov. Retrieved 13 May 2024. Today, the U.S. Food and Drug Administration approved Wegovy (semaglutide) injection (2.4 mg once weekly) for chronic weight management in adults with obesity or overweight with at least one weight-related condition (such as high blood pressure, type 2 diabetes, or high cholesterol), for use in addition to a reduced calorie diet and increased physical activity.[ better source needed ]
  17. ↑ Skydsgaard, Nikolaj (4 June 2021). "U.S. FDA approves Novo Nordisk's semaglutide as obesity treatment." Reuters.
  18. ↑ Monecke, Angela (13 September 2023). "Paul-Langerhans-Medaille geht an die "Mutter der Moleküle"". Medical-Tribune.de (in German). Retrieved 8 January 2024. Für ihre Forschung zu Liraglutid und Semaglutid erhält Dr. Lotte Bjerre Knudsen beim Diabetes Kongress die höchste Auszeichnung der DDG. / Wohlverdient: Dr. Lotte Bjerre Knudsen nahm beim Diabetes Kongress 2023 in Berlin die Paul-Langerhans-Medaille entgegen. Die Laudatio hielten Prof. Dr. Matthias Blüher und Prof. Dr. Michael Nauck gemeinsam.
  19. ↑ JournalMed.de Staff (26 May 2023). "News-Medizin: Paul-Langerhans-Medaille für die Entwicklung von Liraglutid bei Adipositas und Typ-2-Diabetes". JournalMed.de (in German). Retrieved 29 May 2023. Für ihre Arbeit zur Entwicklung des GLP-1 Rezeptoragonisten (GLP-1 RA) Liraglutid, einem Grundpfeiler der modernen Adipositas- und Typ-2-Diabetes-Therapie, erhielt die Diabetes Forscherin Lotte Bjerre Knudsen beim Kongress der Deutschen Diabetes Gesellschaft (DDG) 2023 die höchste Auszeichnung der Fachgesellschaft – die Paul-Langerhans-Medaille.
  20. ↑ Chen, Elaine (18 October 2023). "Lotte Knudsen, who pushed Novo Nordisk into the Ozempic era, wins STAT Innovation award". STAT. Retrieved 21 April 2024.
  21. ↑ Lasker Award 2024
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