It’s hard to say exactly what the future holds for mass compounding of GLP-1, but pressure is mounting from a variety of angles in the U.S., with drug companies and the FDA alike trying to crack down on the practice.
Eli Lilly, currently engaged in multiple efforts in court to protect its diabetes and obesity treatments Maunjaro and Zepbound from pharmacists, medical spas and telemedicine companies, is launching a new salvo focused on the potential safety risks behind common compounding tactics.
Lilly warned on Thursday that its own testing had “discovered significant levels of impurities” in certain compounded products sold in the United States. This is believed to be due to a chemical reaction between vitamin B12 and tirzepatide, the active ingredient in Mounjaro and Zepbound.
Lilly called the impurity a “concern” given that little is known about its short- or long-term effects on the human body, how it might interact with GLP-1 itself, and how it is absorbed, distributed, metabolized, and excreted from the body.
The Indianapolis drugmaker stressed that tirzepatide has never been studied in combination with B12 and cautioned that compounders that make these products are regulated differently than branded drug companies and are not required to monitor and report potential negative reactions to their drugs.
Lilly’s targeting of the apparent tirzepatide reaction with B12 is noteworthy as it addresses one of the key justifications for the current GLP-1 compounding industry in the United States.
After bulk compounding capacity for Lilly’s tirzepatide and Novo’s rival GLP-1 semaglutide ended in the U.S. due to these companies’ documented shortage closures, many compounders who took advantage of the supply gap are now pivoting to individualization arguments to keep their GLP-1s on the market.
This often takes the form of tweaking the dosage or formulation by including additives such as vitamin B12.
Given the impurity concerns, Lilly recommends that people taking tirzepatide-B12 combination products talk to their doctors about alternatives. The company said it also alerted the FDA to its findings.
Lilly noted that the FDA itself has warned the public in recent years about the potential risks of compounded GLP-1, warning of the possibility of dosing errors, product mislabeling, and other potential concerns.
“The discovery of this new impurity produced when combining tirzepatide and B12 highlights the risks to patients of randomly mixing complex molecules like tirzepatide with untested excipients without rigorous testing, clinical trials, or FDA approval,” Lilly explained in the warning.
“B12 is just one of many untested excipients used in the mass production of formulated GLP-1 under the guise of ‘personalization,'” the company added, warning against including other chemicals such as glycine, pyridoxine, niacinamide, and carnitine in formulated tirzepatide to create “a series of new, untested combination products.”
Lilly concluded that mass compounding poses an “unacceptable risk to patients” and called on the FDA to recall all tirzepatide compounded with untested additives such as vitamin B12.
Shortages in the early days of GLP-1 drugs opened the door to large-scale compounding, which is allowed in the United States during times of supply shortages. Still, now that the shortage has ended, the loopholes the industry has exploited to survive are proving difficult to close, despite multiple lawsuits and safety warnings from Lilly and Novo.
Novo has also sought to warn the public about the potential risks of combination incretin drugs for weight loss. The Danish drugmaker warns on its website that tests have found that semaglutide formulations “often contain synthetic processes that may compromise safety.”
The company said the formulation samples tested by Novo Nordisk may have a lower product strength than advertised or may “contain no semaglutide at all” and “often contain new impurities or higher levels of impurities compared to Novo Nordisk’s products.”
Meanwhile, Lilly’s latest move against mass compounding comes amid scrutiny of the practice in recent weeks.
Notably, the FDA pledged in early February to take “swift action against companies that sell large volumes of illegal copycat drugs,” in response to the then-announcement that online health and wellness company Hims & Hers was planning to launch a combination version of Novo’s newly approved WeGoBe pill just weeks after launch.
Novo and Hims have been at odds for months over the latter company’s promotion of compounded GLP-1, but in a surprising development, the companies reached a settlement this week, with Novo agreeing to sell its own brand of weight loss and diabetes GLP-1 through Hims’ telemedicine platform.
As part of the deal, Hims will stop advertising its formulated GLP-1 products, but will continue to allow access to those products for more “selected” patients whose needs cannot be met by Novo’s brand-name incretin drugs.
The FDA also made good on its promise to crack down, sending out 30 warning letters last month to telemedicine companies that it said were making “false or misleading” claims about compounded obesity drugs.
The action followed a similar disciplinary action taken by regulators in September against a company accused of running misleading direct-to-consumer drug advertising.
