The field of weight-loss drug development in 2024 witnessed a spectacle reminiscent of "the noblemen of the Five Mausoleums, in their silken robes and fine steeds, disregarding their own opulence." Developers, both large and small, ventured into this domain brimming with boundless opportunities, each striving to outdo the other, creating ripples that set off waves of innovation. Following the dominance of semaglutide and tirzepatide, what challenges and opportunities will the development of weight-loss drugs face in 2025?  

1.  Potential Efficacy of Weight-loss Drugs in Organ Protection

GLP-1 receptor agonist drugs were originally developed to help diabetic patients control their blood glucose levels. However, more and more research has revealed their benefits to health in other areas, particularly in organ protection. Generally, GLP-1 drugs promote insulin secretion, assisting diabetic patients in maintaining normal blood glucose levels. Yet, even individuals without diabetes, such as those with heart disease who are overweight, can benefit from these drugs. For instance, the SELECT research found that individuals using semaglutide not only had a reduced risk of dying from cardiovascular disease but also experienced a decreased likelihood of heart attacks and strokes.

This has led scientists to ponder whether GLP-1 improves health not solely through weight loss but also through direct organ protection. To elucidate this matter, more research is needed, especially among individuals without diabetes and with normal weight, to understand how these drugs work.

Currently, we are not entirely certain whether the organ-protective effects of GLP-1 drugs are a result of the drugs themselves or a consequence of the health improvements brought about by weight loss. Clarifying this issue will help doctors better utilize these drugs, not only for diabetic patients but also potentially bringing health benefits to other populations.

Can GLP-1 Drugs Manage Neurodegenerative Diseases

GLP-1 drugs not only aid in weight loss but also alleviate inflammation, which partly explains their potential to slow down neurodegenerative diseases. Both Parkinson's disease and Alzheimer's disease are associated with inflammation in the brain.

In a small clinical trial, the GLP-1 drug exenatide improved symptoms in patients with moderate Parkinson's disease. In another small-scale experiment, liraglutide slowed the rate of cognitive decline in patients with mild Alzheimer's disease by 18% over a year.

Some researchers believe that GLP-1 drugs have the potential to cross the blood-brain barrier. If this is indeed the case, the effectiveness of these drugs in treating neurodegenerative diseases could be significantly enhanced. However, it is still unclear to what extent these drugs enter the brain, and animal research has shown differences among GLP-1 drugs in this regard. For example, exenatide appears to cross the blood-brain barrier, and Christian H?lscher, a neuroscientist at the Henan Academy of Innovations in Medical Science in Zhengzhou, China, attributes the initial success of exenatide in treating Parkinson's disease to its ability to cross the blood-brain barrier. H?lscher points out that a modified exenatide analogue with a larger molecular weight lost its ability to cross the blood-brain barrier and, consequently, its ability to manage Alzheimer's disease, indicating the importance of delivering GLP-1 drugs into the brain for treating neurodegenerative diseases. H?lscher also notes that semaglutide lacks the potency to cross the blood-brain barrier, so its ability to improve cognitive decline in Alzheimer's disease patients may not be as good.

There are differing opinions on this viewpoint. Some argue that current data are insufficient to establish a correlation between the drug's ability to cross the blood-brain barrier and its effectiveness in treating neurodegenerative diseases. Regardless, the potential of GLP-1 drugs in managing Alzheimer's disease and Parkinson's disease is one of the key fields of focus for the pharmaceutical industry in the future.

Can GLP-1 Drugs Manage Kidney Disease

GLP-1 drugs also offer hope for chronic kidney disease, which affects over 10% of the global population. In particular, chronic kidney disease is considered "one of the world's largest untreated public health disasters".

In the FLOW clinical research, which investigated the impact of semaglutide on the progression of renal impairment in patients with T2D and chronic kidney disease, researchers found that semaglutide reduced the risk of death by 20% in these patients. Semaglutide and other incretin-based therapies appear to be "effective in all aspects, from primary prevention of kidney disease to treatment of advanced kidney disease". The FLOW research was also terminated early due to its outstanding data performance. However, researchers now need to explore whether GLP-1 drugs directly affect the kidneys or the immune system. A major question is whether the organ-protective effects are independent of metabolic effects.

To understand how GLP-1 drugs directly affect kidneys, researchers are conducting a one-year study on people with chronic kidney disease who will receive GLP-1 drug treatment. A thorough analysis of a series of molecular markers will be conducted using single-cell transcriptomics, spatial localization of metabolites, and other techniques. Through this work, it may be possible to reliably trace the pathology and truly understand how GLP-1 drugs work against kidney disease. At that time, people will have a deeper understanding of the pharmacology of GLP-1 drugs in managing kidney disease, thereby driving the success of the next-generation GLP-1 drugs for kidney disease.

When Was GLP-1 Drug Approved by MASH

The development of GLP-1 drugs for MASH has been a highly valued field for pharmaceutical companies, driven by the enormous potential market and unmet needs in this field. On March 14, 2024, Madrigal Pharmaceuticals' thyroid hormone receptor β selective agonist, Rezdiffra (resmetirom), was approved as the first drug to treat patients with moderate to advanced fibrosis due to MASH, although there remains a significant unmet need in this field. Weight-loss drugs primarily based on GLP-1 have made key breakthroughs in the MASH field, promising to bring groundbreaking new drugs for MASH.

Novo Nordisk's semaglutide has reported positive results from the first part of the Phase III test ESSENCE research targeting MASH, showing progress in treating MASH and moderate to advanced liver fibrosis with 2.4 mg of semaglutide. The test met its primary endpoint, with a significant improvement in liver fibrosis compared with placebo. 37% of participants showed an improvement in liver fibrosis at 72 weeks without worsening of steatohepatitis, compared with 22.5% in the placebo group. Additionally, 62.9% of participants achieved resolution of steatohepatitis without worsening of liver fibrosis, compared with 34.1% in the placebo group. Novo Nordisk plans to seek approval for semaglutide for MASH in the United States and the EU in the first half of 2025. The second part of the ESSENCE test will continue, with results expected in 2029.

Zealand Pharma, in collaboration with Boehringer Ingelheim, has also developed survodutide, a GLP-1/glucagon dual receptor co-agonist weight-loss drug, which has undergone research targeting MASH and has been granted breakthrough therapy designation by FDA for the treatment of adult patients with non-cirrhotic MASH and moderate or advanced fibrosis. Boehringer Ingelheim has initiated two pieces of Phase III research for survodutide: the LIVERAGE research for adult patients with MASH and moderate or advanced fibrosis, and the LIVERAGE-Cirrhosis research for patients with MASH and cirrhosis.

Eli Lilly's tirzepatide is also undergoing the Phase II research called SYNERGY-NASH, evaluating its use in adult patients with biopsy-confirmed MASH and stage 2 or 3 fibrosis Efficacy assessments showed that after 52 weeks of treatment, 51.8%, 62.8%, and 73.3% of participants taking 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, achieved MASH resolution without worsening of liver histological fibrosis, compared with 13.2% of participants taking placebo, meeting the primary endpoint of the research. Although the Phase II research was not designed to prove that tirzepatide can improve fibrosis, the results suggest that all doses have the potential to produce clinically meaningful therapeutic effects.

2.  Development of New Mechanisms for Weight-Loss Drugs

Semaglutide has ushered in a new era in obesity treatment, with tirzepatide following closely behind and sharing the spotlight. These two drugs have demonstrated the enormous potential of targeting the GLP-1 receptor, with tirzepatide also activating the glucose-dependent insulinotropic polypeptide receptor (GIPR). Both the GLP-1 receptor and the GIP receptor belong to the family of G protein-coupled receptors (GPCRs).

Another GPCR, the neurokinin 2 receptor (NK2R), holds promise as a new target for the development of weight-loss drugs and could be the next major breakthrough in the treatment of metabolic diseases. Research has shown that drugs targeting NK2R can achieve healthier weight loss that is not possible with current obesity medications. For individuals who have not responded well to existing drugs for weight loss, drugs targeting NK2R may also bring significant weight reduction. Researchers have found that activating the NK2 receptor not only increases energy consumption but also reduces appetite, without triggering side effects such as nausea and vomiting, which are associated with current drugs like semaglutide and tirzepatide. In experiments, obese and diabetic mice not only lost weight but also showed significant metabolic improvements, such as enhanced insulin response, reduced blood glucose levels, and lower triglyceride and cholesterol levels. More notably, NK2R agonists also preserve muscle mass, whereas existing GLP-1 receptor agonists may lead to a reduction in both muscle and adipose. Preserving muscle mass is crucial for long-term weight loss, as weight regained after muscle loss often returns as adipose, potentially increasing body adipose percentage. NK2R agonists would represent a new drug class, and if successfully marketed, they could help obese and diabetic patients achieve sustained weight loss and prevent cardiometabolic diseases.

Developing targets for obesity beyond GLP-1, GIP, and glucagon is undoubtedly a challenging task, partly because the understanding of the pathogenic mechanisms and heterogeneity of obesity is still not thorough enough. For example, setbacks have been encountered in the development of weight-loss drugs that block the cannabinoid receptor CB1. Inhibition of the CB1 receptor reduces appetite and also affects other biological functions such as inflammation. However, the data for Novo Nordisk's Phase II CB1 blocker weight-loss drug asset, monlunabant, did not meet expectations, and Novo Nordisk is currently investigating the determination of the optimal dose.

The next candidate for CB1 may be nimacimab from Skye Bioscience, which is expected to produce Phase II results by mid-2025. The test, named CBEYOND, tests nimacimab versus placebo and the combination of Wegovy and nimacimab versus Wegovy alone. The research will measure weight loss over 26 weeks. According to the test plan, 120 volunteers have been recruited for the research.

3.  Emerging Weight-Loss Drug Pipeline Products

Currently, the weight-loss drug market is dominated by semaglutide and tirzepatide, creating a "dual reign" scenario. However, the weight-loss drug assets in the pipeline are eager to make their mark, aiming to quickly secure a share in the opportunity-rich obesity market. The most promising candidates poised to expand the weight-loss drug market include the following:

Oral Semaglutide

Oral semaglutide has already been launched under the brand name Rybelsus for the treatment of T2D, but obesity is set to become its next target. Novo Nordisk has tested the impact of oral semaglutide on obesity in a Phase III trial called OASIS 1. Participants taking 50 mg of semaglutide once daily achieved up to a 15% weight loss after approximately 15 months (68 weeks), comparable to the weight loss effects of Wegovy.

Orforglipron

Orforglipron is an oral small-molecule GLP-1 agonist weight-loss drug developed by Eli Lilly, taken once daily. Phase III research of Orforglipron for adult chronic weight management is currently underway. It commenced in June 2023 and is expected to continue until mid-2027. Phase II tests revealed that Orforglipron may help people lose up to 15% of their body weight after approximately 8 months (36 weeks), and it may also offer some cardiac-related benefits.

Danuglipron

Danuglipron is an oral small-molecule GLP-1 weight-loss drug developed by Pfizer, with a mechanism of action similar to orforglipron. Initially researched as a twice-daily drug, a once-daily version is now in development. Pfizer has announced that they are advancing a specific version of once-daily sustained release danuglipron and are currently conducting further drug evaluation research.

APHD-012

APHD-012 is an oral drug developed by Aphaia Pharma that mimics the metabolic effects of gastric bypass surgery (bariatric surgery). It is a glucose pill that stimulates certain parts of the small intestine. APHD-012 is taken once daily and is described by Aphaia Pharma as a distal jejunal release glucose bead. Phase II tests for APHD-012 completed enrollment of its first participants in April 2024. If the data are positive, Phase III research may follow.

Oral Amycretin

Amycretin is a GLP-1/amylin dual receptor co-agonist in Novo Nordisk's pipeline for chronic weight management, administered orally once daily, with a subcutaneous injection version also under development. Amycretin completed Phase I tests in December 2023 and is currently in Phase II research. Novo Nordisk predicts that amycretin may be launched before 2030. Phase I data for Amycretin showed an average weight loss rate of 13% in subjects after 12 weeks of use, which is almost comparable to semaglutide.

Retatrutide

Eli Lilly's pipeline weight-loss drug asset retatrutide is perhaps the most anticipated next-generation weight-loss product at present, not only because of its 24% weight loss rate over 11 months but also due to its unique mechanism that simultaneously targets GLP-1, GIP, and glucagon receptors, earning it the nickname "3G weight loss drug". Retatrutide is administered via weekly subcutaneous injection.

Retatrutide is currently in Phase III research for weight loss and is expected to be completed by early 2026. The latest research findings indicate that retatrutide can help reduce liver adipose levels. A new analysis of a Phase II test found that metabolic dysfunction-associated fatty liver disappeared in over 85% of people treated with retatrutide for 48 weeks.

CagriSema

CagriSema is a next-generation weight-loss drug asset in Novo Nordisk's pipeline, combining the GLP-1 drug semaglutide with the amylin analogue cagrilintide. Novo Nordisk announced the latest Phase III research results for CagriSema in late December 2024. Although the weight loss rate of 23% did not meet the 25% threshold set by investors and analysts, causing Novo Nordisk's stock price to plummet, from a scientific perspective, the introduction of the amylin analogue provides CagriSema with a new mechanism of action for managing obesity, potentially leading to better outcomes in terms of side effects. Therefore, the future of CagriSema remains promising.

Mazdutide

Eli Lilly's GLP-1/glucagon dual receptor agonist, Mazdutide, is also a peptide-based weight-loss drug asset currently in Phase III tests, administered once weekly via subcutaneous injection, and targeted at T2D. Mazdutide has undergone several Phase III research studies in China. Phase II research results indicated a 15% weight loss rate over 24 weeks. A recent Phase III research found that Mazdutide was superior to Trulicity in reducing body weight and A1C (glycated hemoglobin). This 6-month research enrolled adults with T2D.

Survodutide

Survodutide, a weight-loss drug jointly developed by Zealand Pharma and Boehringer Ingelheim, is a GLP-1/glucagon dual receptor co-agonist, similar to mazdutide. It is administered once weekly via subcutaneous injection and is currently in Phase III clinical stage. Phase II data for survodutide showed that participants achieved a weight loss rate of 19% after 46 weeks. In addition to obesity, survodutide is also being developed for the treatment of MASH. In the recent 48-week Phase II research, over 80% of individuals treated with survodutide showed significant improvements in their liver biopsy reports.

Petrelintide

Zealand Pharma's pipeline also includes an exciting weight-loss drug asset, petrelintide, which, as its name suggests, is an amylin analogue, similar to cagrilintide. Amylin analogues are expected to achieve weight loss effects comparable with those of semaglutide and tirzepatide, but with potentially fewer tolerability issues, including advantages in terms of nausea, high discontinuation rates, and lean body mass loss. In June of this year, Zealand Pharma announced top-line results from a Phase Ib study of petrelintide, showing an average weight loss of up to 8.6% (6.9% after placebo adjustment) after 16 weeks of dosing. This result outperformed that of Novo Nordisk's amylin analogue candidate drug, cagrilintide, which achieved a 5.0% weight loss in its Phase II research. An additional advantage of petrelintide is its tolerability even at the highest tested dose, with a safety profile significantly better than that observed in the cagrilintide research.

MariTide

Amgen's weight-loss drug asset, MariTide, stands out in the weight-loss drug landscape due to its unique antibody-peptide conjugate (also known as peptibody) modality. Even within the broader scope of all drugs, peptibodies represent a highly distinctive drug modality. The MariTide molecule consists of two GLP-1 receptor agonist peptides conjugated to an anti-GIP antibody, forming a three-part antibody-peptide conjugate. The GLP-1 receptor agonists activate the GLP-1 receptor to stimulate insulin secretion, while the anti-GIP antibody downregulates GIP secretion. These two forces work together to achieve controlled weight loss. The antibody-peptide conjugate modality of MariTide determines its longer half-life compared with peptides and small molecule drugs. The ongoing clinical trials are being conducted with a dosing frequency of once monthly, and researchers are also considering extending the dosing interval to once every quarter. Phase II data for MariTide showed that obese and overweight subjects who used MariTide achieved a weight loss rate of 20% after 52 weeks, with an average reduction in glycated hemoglobin of 2.2%, and significant improvements in cardiac metabolic parameters. Although, like CagriSema, the weight loss rate of MariTide did not meet investors' expectations, its unique mechanism of action has the potential to carve out a niche for it in the vast weight-loss drug market.

References

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