The World Health Organization (WHO) declared obesity a disease in 1948, although it took decades before it was considered truly relevant in terms of public health by international health organizations and professionals. In 1995, the WHO began to observe greater problems of overweight than underweight in many developing countries, and it took two more decades until the American Medical Association (AMA) joined that declaration of obesity as a disease in 2013 following a review of the medical literature that revealed its harmful effects on health. Today the WHO warns that it is "an important public health problem due to its relationship with chronic diseases such as diabetes, hypertension and cardiovascular diseases."

What is clear is that its prevalence is growing at a worrying rate. Thus, the latest WHO figures, corresponding to 2016, reveal that more than 1.900 billion adults worldwide were overweight, of which 650 million were obese, more than triple the number in 1975. In Spain, the most recent data collected in the National Health Survey are from 2017, when 17.1% of the population over 18 years of age was obese and 38.5% overweight.

It is not surprising, therefore, that efforts to develop drugs specifically aimed at combating obesity are also increasing. Thus, a report by the specialized consultancy Evaluate indicates that a battle is brewing for participation in the growing obesity market, as a new generation of more effective drugs arrives. Novo Nordisk's Wegovy, a higher dose of its antidiabetic GLP-1 agonist semaglutide, is at the forefront of the new anti-obesity according to the aforementioned consultancy, with expected sales of more than 8,000 million dollars for the period 2021-28. Lilly would also be in this race with its phase 3 compound tirzepatide, a GLP-1/GIP agonist approved by the FDA in May 2022 for diabetes under the name Mounjaro, and by the EMA in September 2022 as a treatment for adult patients with insufficiently controlled type 2 diabetes, associated with diet and exercise. In Spain, tirzepatida is awaiting financing and reimbursement conditions for its introduction on the market.

The most promising

Ana de Hollanda, coordinator of the Obesity Area of the Spanish Society of Endocrinology and Nutrition (SEEN) considers that the most promising areas in the development of new drugs are "the combination of drugs that affect gastrointestinal hormones stimulated by intake -which potentiate the action of these drugs separately-, such as dual GLP1/GIP agonists and GLP1/GIP/glucagon triagonists, and precision medicine in the case of setmelanotide, a melanocortin receptor agonist that is highly effective in obese patients with certain genetic mutations."

"Another mechanism is also being studied that is aimed at activating a muscle receptor that leads to weight loss and increased muscle mass, extremely necessary in some people who, in addition to obesity, suffer from low muscle mass and function," adds the endocrinologist.

At the moment, De Hollanda believes that "we are still far from the optimal management of obesity, given that it is a very complex pathology with multiple determinants. Only with medicines, which at the moment are not financed by the National Health System, we will not achieve it. We need to act at different points and at all levels, that is, from prevention by governments and health institutions to the creation of obesity units in hospitals, the training of general practitioners, nurses and dieticians, health education in schools, universities, etc. There is much more to do and perhaps it is a more difficult task than drug development because it requires, above all, political will."

For the multinational Novo Nordisk, this pathology has become increasingly relevant in the last decade, as a result of the strategic decisions that made obesity one of the important areas of development in the company, beyond diabetes, according to Francisco Pajuelo, its medical director in Spain.

Along with therapies based on GLP-1 receptor analogues, Novo Nordisk has molecules under development "that act on other neuronal pathways that are also responsible for regulating appetite, and that will facilitate this treatment at different levels that this pathology needs," says Pajuelo. "Specifically," he adds, "our company is investigating the role of amylin analogues or PYY analogues (another peptide involved in appetite regulation)." Especially relevant, in Pajuelo's opinion, is the multi-level approach – GLP-1, amylin and PYY pathways – and the development of GLP-1 analogues that can be administered orally.

The combination of semaglutide with the amylin analogue cagrilintide -CagriSema-, is one of the compounds that Evaluate highlights as especially promising, and predicts that it could surpass Wegovy, both in weight loss and in reducing blood sugar levels, judging by the premiline data of phase 2.

As for the great promise of Lilly, tirzepatide, the medical director of the Diabetes area of the company in Spain, Miriam Rubio de Santos, explains that "it is a single agonist molecule that binds to two receptors (the glucose-dependent insulinotropic polypeptide receptor -GIP- and the glucagon-like peptide 1 receptor -GLP-1). It is the only drug that acts on these two incretin hormones."

"In diabetes," adds Rubio de Santos, "it has achieved unprecedented results to date, superior to those of all the drugs with which it has been compared, and in patients with obesity, a weight reduction similar to bariatric surgery."

In addition, Lilly has another molecule in phase 2 development, retatrutide, being studied as a potential treatment for obesity. In this case, "it is a molecule that acts as a triple agonist for the glucose-dependent insulinotropic polypeptide (GIP) receptor, for the glucagon-like peptide 1 receptor (GLP-1) and for the glucagon receptor."

In addition, Lilly has three other biologic compounds in phase 1 clinical development: a long-acting amylin agonist, DACRA QW II, and the YY peptide analog agonist.

Top Anti-Obesity Drugs on the Market

  • Xenical-orlistat, from Roche: Approved for weight loss in obese or overweight adults. It works by inhibiting the absorption of fat in the digestive system.
  • Saxenda, liraglutide, Novo Nordisk: An injectable drug approved for weight loss in obese or overweight adults. It works by mimicking the effect of the hormone GLP-1, which helps regulate metabolism and appetite.
  • Qsymia, phentermine/topiramate, from Vivus: An injectable combination of an appetite suppressant and an anticonvulsant for weight loss in obese or overweight adults.
  • Contrave, naltrexone/bupropion, from Valeant: A combination of an opioid antagonist and an antidepressant that reduces appetite and increases energy expenditure.
  • Belviq -lorcaserin-, from Arena Pharmaceuticals: serotonin receptor agonist that reduces appetite.

The director of diabetes of Lilly Spain recalls that the company "is a pioneer in research in the area of diabetes, in which we have been working for more than a hundred years. We are now in a challenging era in our company's history, and the progress of our pipeline underscores the breadth and depth of this exciting long-term advancement, which will reinforce and consolidate our historical trajectory. This is a priority area for Lilly, and one in which the largest investments are being made in the pipeline. We optimistically believe that we will be able to make new medicines available over the next two years, which could drive world-class growth for the company for decades to come."

Sales potential for 2028

Evaluate's forecasts put combined sales of obesity drugs above $11 billion in 000, more than four times the roughly $2028.2 billion at the end of 500, though if Lilly's tirzepatide versus obesity is approved, the difference may be even greater.

The combined portfolio of the global pharmaceutical sector in R+D against obesity is composed of more than 20 candidate products in phases 2 or 3 in 2022, more than double those developed in 2017. The potential market is large, but so are the requirements and costs of developing new compounds, as patients often must also follow a diet and change their lifestyle. Even the growing pipeline in development accounts for less than one-tenth the number of compounds in development for non-Hodgkin's lymphoma, for example. Along with the aforementioned Novo Nordisk CagriSema, the anti-obesity pipeline also includes cotadutide, AstraZeneca's GLP-1/glucagon receptor agonist in phase 2 for non-alcoholic steatohepatitis with obesity; Altimmune's phase 2 pemvidutide for obesity, and Pfizer's phase 1 oral GLP-2 agonist, called danuglipron.

However, "we are still far from considering obesity as a disease at all levels of the health system, but there is no doubt that there is increasing awareness of its importance and the impact it can have on the development of other metabolic, cardiovascular, oncological or osteoarticular pathologies, to cite just a few examples. The combination of increasingly effective therapies, together with this greater awareness of the disease around obesity, triggers more visible efforts by the different actors involved in the management of this disease," says Pajuelo.

For Miriam Rubio de Santos, in recent years there has been "a greater awareness of obesity as a chronic disease, which cannot always be managed with diet and exercise, and which can condition the appearance of other diseases, which has led to an increase in basic research in this regard. In addition, the benefit in weight loss that some drugs for type 2 diabetes have shown has led to the development of clinical research programs to seek effective treatments in chronic weight management. In this regard, Lilly works tirelessly to modernize obesity treatment care by discovering and developing potential drugs that allow people with obesity to receive the care and outcomes they deserve."

The medical director of Novo Nordisk points out, for his part, that the treatment of obesity is "increasingly effective, in all its aspects; pharmacological, surgical and in other related areas, such as prevention, psychological and nutritional support". But the biggest challenge, he concludes, "is that the number of patients who receive them is still very small compared to the number of people living with the disease. Increasing training at all levels of the health system, in order to offer the best treatment to people who need it, should be one of our main objectives in the short and medium term."

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