Semaglutide(Vivani Medical)

Eli Lilly stressed that tirzepatide has never been studied in combination with vitamin B12 and warned that the compounders making these products aren’t required to monitor and report potential negative reactions to their medicines. Though it’s hard to say exactly what the future holds for mass GLP-1 compounding, the pressure is mounting from multiple angles in the U.S. as drugmakers and the FDA alike seek to crack down on the practice. Now, Eli Lilly—which has already staged multiple efforts in court to protect sales of its diabetes and obesity meds Mounjaro and Zepbound from compounders, medical spas and telehealth firms—is launching a new salvo focused on the potential safety risks behind a common compounding tactic. Lilly cautioned Thursday that through its own testing, it has “uncovered significant levels of an impurity” in certain compounded products marketed in the U.S., which seem to stem from a chemical reaction between vitamin B12 and tirzepatide, the active ingredient in Mounjaro and Zepbound. Lilly called the impurity “concerning” given what little is known about its short- or long-term effects in humans, as well as its potential to interact with the GLP-1 itself or how it is absorbed, distributed, metabolized and eliminated from the body. The Indianapolis pharma stressed that tirzepatide has never been studied in combination with B12 and warned that the compounders making these products, who are beholden to different regulations than branded drugmakers are, aren’t required to monitor and report potential negative reactions to their medicines.  Lilly’s targeting of the apparent tirzepatide reaction with B12 is notable as it addresses one of the key justifications for the current GLP-1 compounding industry in the U.S. After the ability to mass compound Lilly’s tirzepatide and Novo’s rival GLP-1 semaglutide ended in the U.S. with the resolution of those companies’ documented shortages, many compounders that capitalized on the supply gap have now pivoted to a personalization argument to keep their GLP-1s on the market. This often takes the form of minor adjustments to dosing or formulation via the inclusion of additives like vitamin B12. In light of the impurity concerns, Lilly is urging people who take compounded tirzepatide-B12 products get in touch with their doctors for an alternative. The company says it has also alerted the FDA to its findings. Lilly noted that the FDA itself has cautioned the public about the potential risks of compounded GLP-1s in recent years, flagging the potential for dosing errors, mislabeling of products and other potential concerns. “Our discovery of this new impurity created when tirzepatide is compounded with B12 highlights the risks to patients of haphazardly mixing untested additives with complex molecules like tirzepatide without rigorous testing, clinical trials and FDA approval,” Lilly explained in its warning. “B12 is just one of the many untested additives used in the mass production of compounded GLP-1s under the guise of ‘personalization,’” the company added, flagging the inclusion of other chemicals like glycine, pyridoxine, niacinamide and carnitine with compounded tirzepatide to create a “range of new and untested combination drugs.” Lilly concluded by branding the mass compounding practice an “unacceptable risk for patients,” calling on the FDA to recall all compounded tirzepatide combined with untested additives, such as vitamin B12. In a rebuttal to Lilly’s impurity warning, Scott Brunner, CEO of trade group the Alliance for Pharmacy Compounding (APC), caveated that “we don’t know much based on what the drugmaker has said so far,” adding that B12 is a “well-studied and remarkably benign drug.”In his statement, Brunner noted that compounding of tirzepatide with B12 has been taking place for roughly four years now without a major trend of adverse events, further questioning whether the results were sourced from state-licensed compounding pharmacies rather than “unlicensed or illicit actors” like medspas.Brunner also raised questions about how Lilly obtained its prescription-based samples and handled them prior to testing, arguing that the responses to several unanswered questions in Lilly’s communique “matter when we’re talking about the presence of impurities or other contamination.”While he acknowledged that the company may have identified legitimate safety concerns, he maintained that Lilly has failed to provide enough information “for anyone outside the company to evaluate the claim.” Shortages early into the launch of the GLP-1 drugs opened the doors to mass compounding in the U.S., which is permitted in times of supply shortfalls. Still, the loopholes the industry has used to stay afloat now that those shortages are over have proved difficult to close, despite multiple lawsuits and safety warnings from Lilly and Novo. Novo, for its part, has also sought to warn the public about the potential risks of compounded incretin drugs for weight loss. On its website, the Danish drugmaker warns that its testing has found compounding semaglutide “often involves synthetic processes that can compromise safety.” Compounded samples Novo has tested may contain lower product strengths than indicated or “no semaglutide at all,” and they “often introduce new impurities or higher levels of impurities compared to Novo Nordisk’s products,” according to the company. Meanwhile, Lilly’s latest move against mass compounding comes as the practice has faced increasing scrutiny in recent weeks. Notably, the FDA pledged to “take swift action against companies mass-marketing illegal copycat drugs” in early February, responding to an announcement at the time that online health and wellness firm Hims & Hers planned to launch a compounded version of Novo’s newly approved Wegovy pill just weeks into the drug’s launch. Novo and Hims had been butting heads over the latter company’s promotion of compounded GLP-1s for months, but, in a surprise pivot, the sides reached a resolution this week, with Novo agreeing to sell its branded weight loss and diabetes GLP-1s on Hims' telehealth platform. As part of the deal, Hims will stop promoting its compounded GLP-1s, though it will still permit access to those products for a much more “limited set” of patients whose needs can’t be met by Novo’s brand-name incretin medicines.  The FDA has also followed through on its pledge to crack down, last month unleashing a wave of 30 warning letters to telehealth companies it alleged make “false or misleading” claims about their compounded obesity drugs. That action followed a similar round of reprimands the regulator dished out in September to firms accused of deploying misleading direct-to-consumer drug advertising.  Editor's note: This story has been updated with a statement from the CEO of the trade group the Alliance for Pharmacy Compounding.