THE medications Ozempic and its competitors, such as Wegovy and Mounjaro, have affected the capital and market-driven US economy in interesting ways. These Glucagon Like Peptide-1 (GLP-1) agonists (meaning they combine with  GLP-1 receptors to initiate responses),  were initially developed to combat diabetes and obesity, They are supposedly reshaping US industries, altering consumption patterns, and signalling a change in the lifestyle of some well-to-do-sections of US population; so much so that there exist articles talking of the Ozempic economy. The entire consumption-driven economy of the US, wherein crores of Americans are using GLP-1 drugs, is supposedly undergoing a tremendous shift. The economic ripple effect is expected to be large: the market for GLP-1 drugs could be worth Rs 4 lakh crores in 2024 and is projected to ramp up ten times by 2032 – casting influence upon not just individual lives, but also entire industries across the US.

SCIENCE AND

SUCCESS OF GLP-1

GLP-1 (glucagon-like peptide-1) discovered in the 1980s functions as a hormone derived from the proglucagon sequence and was found to have a transformative impact on the treatment of diabetes and obesity. There are two critical hormones involved in glucose regulation. Insulin is produced by the pancreas and helps cells to absorb glucose from the bloodstream resulting in lowering of blood sugar levels. On the other hand, to ensure a steady energy supply, glucagon raises blood sugar by inducing the liver to release stored glucose. GLP-1 increases insulin secretion after meals and also suppresses glucagon release, which ensures a balanced level of glucose. Moreover, GLP-1 slows gastric emptying and also reduces appetite. So, it becomes an effective target for the management of obesity.

Four significant contributors who helped determine the physiological roles of the peptide GLP-1 were Svetlana Mojsov, Daniel Drucker, Joel Habener, and Jens Juul Holst. In Mojsov's early studies, the active form of GLP-1 (7-37) – with numbers referring to a segment of 31 amino acids between the 7th and the 37th positions of the GLP-1 peptide – was isolated and peptides essential for further experimentation were synthesized. However, the hormone GLP-1 was rapidly inactivated in the organism by the enzyme DPP-4 in the body – this limited therapeutic possibilities. Researchers therefore modified GLP-1 to create stable long-acting agonists.

The transformative success of GLP-1 agonists represents the vision and tenacity of scientists. Lotte Bjerre Knudsen rose to prominence at Novo Nordisk and played a pivotal role in stabilizing GLP-1 molecules and giving them the scope for use as a long-term medication.  She spearheaded the work on liraglutide (sold as Victoza) and semaglutide (sold as Ozempic and Wegovy). Richard DiMarchi, a professor at Indiana University, conceived of multi-action therapies, such as tripeptide (Mounjaro), which act through multiple hormonal pathways for enhanced efficiency. In clinical trials, patients lost about 15 per cent of their weight using semaglutide, the first drug with such amounts of weight loss during a time frame of 16 months. Tirzepatide emerged in the clinical trials as particularly compelling, with some trials noting as much as 21 per cent weight loss. Clinical trials validated their safety and efficacy, paving the way for regulatory approvals. Novo Nordisk’s semaglutide debuted in 2017 as Ozempic for type 2 diabetes management and in 2021 as Wegovy for obesity. Eli Lilly's tripeptide was approved for type 2 diabetes treatment in 2022 and was marketed as Mounjaro. It received approval in 2023 for obesity treatment and was sold as Zepbound.

The prototypes for GLP-1-based medications such as exenatide were based on a protein in the venom of Gila monster lizards. It has peptides that mimic the functions of GLP-1. Pharmaceutical houses like Novo Nordisk and Eli Lilly advanced these developments, from publicly funded research, into more effective GLP-1 receptor agonists. These therapies not only demonstrate metabolic benefits but also hint at neuroprotection, which may be of use in the treatment of Parkinson's disease Alzheimer's disease, and nonalcoholic fatty liver disease (NAFLD). This procedure of discovering and manipulating GLP-1 shows the power of biochemistry and physiology in parallel to one another which has helped to make the transition from fundamental science to applications in still-shaping therapies of chronic disease management.

The Harrington Award Prize in 2017 for Innovation in Medicine was given to Habener, Drucker, and Holst for their GLP-1 work. In 2021 the same three got the Canada Gairdner International Prize for biomedical/global health research. In 2023, Knudsen and DiMarchi were jointly awarded the Mani L. Bhaumik Breakthrough of the Year Award for their work on GLP-1. The award comes with a cash prize of USD 250,000 (equivalent to Rs 2.16 crores).

THE WOMAN

BEHIND IT

Svetlana Mojsov, a quiet collegial personality who thought about her work and family rather than awards, came from Yugoslavia. She completed her Masters in physical chemistry at the University of Belgrade and came to the US in 1972 to do her PhD in biochemistry at Rockefeller University. She worked on peptide synthesis at the Massachusetts General Hospital (MGH) in the 1980s when she identified and determined the biologically active form of GLP-1 (7-37). The first drug that came on the market, Victoza, was based on the GLP-1 sequence she discovered.

Despite the landmark role she played, Mojsov's contribution has been eclipsed in the awards and articles related to GLP-1. When it comes to visibilty and credit in science, it is a regular occurrence that recognition is more often given to established (predominantly male) scientists who are in positions of power, at the cost of less prominent (usually female) scientists.

Described by friends as “not a self-promoter” but urged by some supporters Mojsov took on the fight to get her dues. When a long article in The New York Times on GLP-1 research did not mention Mojsov, a chemist friend sent a letter for correction. The journal Nature carried an article omitting Mosjov and she reached out in protest to the journal. The journal agreed to publish a correction. The journal Cell brought out a correction after she objected to a 2021 essay on GLP-1 that did not acknowledge her contributions.

In June 1990, MGH filed two patents to protect GLP-1 intellectual property, not informing and including Mojsov, but putting only Joel Habener as the inventor. The patents were granted two years later. After she started to assert her rights, as a rightful and equal co-inventor, it took many years of constant legal effort for her name to be registered in the certificates of correction issued by the United States Patent and Trade Office (USPTO). Again in 1993 MGH on Habener’s behalf filed a patent, based on Mojsov’s GLP-1 (7–36) amide findings, which was granted in 1997. It was corrected in 2004 by the USPTO. The story repeated, the third time as a farce, on a patent filed in 2000 which was granted five years later, and corrected the next year in 2006.

Finally, in 2024 the Lasker-DeBakey Clinical Medical Research Award was given to Svetlana Mojsov along with Knudsen and Habener “for the discovery and development of GLP-1 drugs that have revolutionised the treatment of obesity.”

WHAT NEXT?

The benefits of GLP-1 drugs extend beyond weight loss. Clinical trials have shown that they reduce the risk of heart attacks, strokes, and progression to kidney disease as GLP-1 receptors, belonging to the class of G-protein coupled receptors, are present in a variety of cell types. Recent evidence suggests that GLP-1 agonists could help de-addiction and also offer relief from symptoms of Alzheimer’s and Parkinson’s diseases.

As demand increases, access is still a sore point. At an annual cost of more than Rs 8.6 lakh per patient, these drugs remain out of the reach of many. In the USA, where only 1.7 per cent have been prescribed Wegovy or Ozempic, there is usually a lack of insurance coverage for these drugs, as they are classified as weight-loss treatments rather than needed medication. These raise the question of sustainable and affordable treatment. There are efforts and hopes of introducing generic versions but challenges persist due to IPR issues, as always.