Chapter 16: Beyond the Horizon – Exploring Alternative Weight Loss Medications.

In recent years there has been a significant uptick in the number and types of weight loss medications hitting the market. With each coming year, there are more and more options becoming available to those that are struggling with their weight. But can the pharmaceutical industry maintain this momentum?

The good news is that research continues to advance in the weight loss realm with each passing day. This progression is fueled by the seemingly uncapped potential of the obesity drug market, which is expected to grow by as much as $100 billion by 2030 (1). These numbers incentivize pharmaceutical companies and biotech to push the limits of science, looking for new opportunities to capitalize off of weight management.

This is good news for patients. The market potential for obesity drugs is what drives the development of new and innovative therapies for weight loss. Currently, there are several medications in the pipeline that are being investigated for chronic weight management, some showing fairly robust safety and efficacy profiles. These investigational mediations have the potential to bring new hope to patients, providing better results, increased convenience, or more tolerable side effect profiles. In this chapter, we will review some of the promising candidates and the preliminary data supporting their development.

Retatrutide

Eli Lilly is a pharmaceutical company that has made strides in the weight loss world. It is the manufacturer of tirzepatide, also known as Zepbound and Mounjaro, a drug that has seemingly unmatched potential when it comes to weight loss. In clinical trials, patients taking the highest dose of Zepbound lost an average of 48 pounds (2). The results are striking, but Lilly isn’t quite done yet. The company has a multitude of other drugs in the pipeline aimed at treating obesity.

Amongst Lilly’s comprehensive portfolio, one drug candidate stands out: retatrutide. Retatrutide works similarly to tirzepatide, acting as a glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) agonist. However, retatrutide takes it one step further, also acting as a glucagon receptor agonist. As a triple agonist, retatrutide has the potential to offer even more potent results than the current single and dual agonists on the market.

Retatrutide is administered as a once weekly injection under the skin. It is currently being investigated in phase 3 trials, and results from a phase 2 trial published in the New England Journal of Medicine are show great promise. In this study, adults that were either obese or overweight with one weight associated condition were randomized to get subcutaneous retatrutide at various doses or placebo for a period of 48 weeks.

By the end of the trial, retatruitde resulted in an average loss of around 24 percent of patients’ body weight, which amounted to around 58 total pounds. Additionally, 92, 75, and 60 percent of individuals lost at least 5, 10, and 15 percent of their body weight, respectively. The most common side effects were gastrointestinal (GI) related (3).

If these results are replicated in the larger phase 3 trial, retatrutide could potentially surpass the efficacy of other weight loss drugs on the market. So, when can we expect results? Currently, the phase 3 trial is expected to continue through the end of 2025 (4), and afterwards the drug application would be submitted to the Food and Drug Administration (FDA) for approval. Though it may be a few years before patients can access retatrutide, hope is on the horizon.

VK2735

Continuing on with the GLP-1 and GIP agonist theme, VK2735 from Viking Therapeutics is another potential candidate in the pipeline. Its dual mechanism works similarly to tirzepatide (Mounjaro/Wegovy). As a GLP-1 receptor agonist, VK2735 increases insulin and insulin sensitivity, decreases gastric emptying, and increases satiety. As a GIP agonist, VK2735 increases insulin and insulin sensitivity, increases glucagon, and decreases food intake.

The company started a phase 2 trial studying VK2735 in obese patients back in September 2023 with the purpose of assessing the safety and efficacy of the once weekly subcutaneous drug. Viking Therapeutics announced in February 2024 that the medication met all of its primary and secondary endpoints, significantly reducing body weight versus placebo with a tolerable side effect profile. Patients lost as much as 13.1 percent of their body weight, and as many as 88 percent had a weight loss of at least 10 percent. The most common side effects were nausea and vomiting. In terms of next steps, the company will meet with the FDA to discuss the future development of VK2735.

Viking Therapeutics isn’t stopping there. In addition to the subcutaneous formulation, they are also in the early phases of assessing VK2735 as an oral medication. This could potentially offer a different dosage form for patients with different preferences as a once daily dosing regimen (5).

Orforglipron

Taking another look at Eli Lilly, their portfolio consists of several other potential drug candidates in the weight loss space. Orforglipron is another drug in the pipeline, demonstrating activity only as a GLP-1 agonist. Though it has only a single mechanism, the medication is provided as an oral formulation that has the potential to increase adherence and patient access to the medication.

Results from the drug’s phase 2 trial were published mid-2023, showing promising results. Patients received either placebo or one of orforglipron’s four investigational doses for a period of 36 weeks. The average weight loss at week 36 ranged between 9.4 to 14.7 percent, with weight loss in the placebo group amounting to only two percent. As many as 75 percent of patients lost at least 10 percent of their body weight at week 36. Nausea, vomiting, diarrhea, and constipation were common side effects (6).

So, what’s next? Lilly has begun its phase 3 development program to further characterize the safety and efficacy of orforglipron. The phase 3 trials, the ATTAIN trials, will hopefully confirm these initial results in obese and overweight patients. The medication is also being studied for the treatment of type 2 diabetes (7).

Cagrisema

We’ve all heard the buzz around Ozempic and Wegovy, two medications containing semaglutide. This blockbuster drug is one that has gained immense popularity and publicity for its potent weight loss effects. But what if we could combine it with another medication to enhance its results even further?

Novo Nordisk is doing just that, developing CagriSema, a medication that combines semaglutide with a novel drug known as cargrillintide. While semaglutide is a GLP-1 agonist, cagrillintide is known as an amylin analogue. As such, it mimics the hormone known as amylin in the body, which makes people feel fuller for longer after having a meal. Together, these two compounds can work synergistically to produce more robust weight loss.

A phase 2 trial evaluating the safety and efficacy of CagriSema demonstrated that the drug candidate induced an average weight loss of 15.6 percent. Compared to only 5.1 and 8.1 percent reductions in the semaglutide and cagrillintide groups, respectively, CagriSema has the potential to out-perform either drug alone (8).

AMG 133

Amgen has become another key player in weight loss space, particularly with regards to its experimental drug AMG 133 (maridebart cafraglutide). AMG 133 is another GLP-1 and GIP agonist. This medication is a bit earlier on in development, having completed both animal studies and a phase 1 trial in humans.

In the phase 1 trial, results indicated that body weight changes ranged from 7.2 percent at the lowest dose to 14.5 percent at the highest dose. The clinical development continues with its phase 2 study having already completed enrollment. Results are expected to be released in late 2024 (9).

Danuglipron

Danuglipron is yet another GLP-1 receptor agonist under investigation for chronic weight management. As an oral tablet, this candidate can offer patients increased convenience and adherence versus some of the injectable weight loss medications. In a clinical study, this twice daily medication demonstrated significant reductions in body weight from baseline, with average decreases totaling 6.9 to 11.7 percent.

However, despite its efficacy, high dropout rates from the study were seen due to side effects. As many as 73 percent of subjects experienced nausea, 47 percent vomiting, and 25 percent diarrhea. Because of this, the manufacturer Pfizer will not continue studying the twice daily regimen. An ongoing study, however, will assess the potential of the once daily formulation.

Though investigations will continue exploring the potential of danuglipron, this molecule shows that not every drug candidate will be successful. Though we can only hope for more efficacious options in the future, only time will tell.

Conclusion

In summary, drug development in the weight loss space is far from over. In fact, it seems like we may just be getting started. An array of promising small molecules are under investigation, and the preliminary results are promising. So, for those still struggling with weight despite the influx of new treatment options, have no fear! There may be some new therapies available in the future (10).

Author

David J. Bauder, PA-C David Bauder, PA-C, is a certified physician assistant and the assistant medical director at Weight Loss and Vitality in Manassas and Alexandria, Virginia, Washington, DC; and Gaithersburg, MD. He enjoys helping patients optimize their physical and mental health to improve their overall well-being. He earned his physician assistant degree from the University of Texas Health Science Center at San Antonio. Afterward, he gained admission into the reputable graduate program for physician assistant studies at the University of Nebraska Health Science Center in Omaha. David has over 26 years of experience working as a physician assistant. He’s practiced in podiatry, family medicine, emergency medicine, general surgery, urgent care, and functional medicine.