Are We Compounding Semaglutide, Tirzepatide, and Thymalin Risks?

Me-too drugs typically follow a strong novel medicine into a developing market segment. The therapeutic advantages of me-too drugs may include “improved target specificity, reduced risks of off-target adverse reactions and drug-drug interactions, increased chance of benefit in some patients, and improved drug delivery and pharmacokinetics. Me-too drugs can also demonstrate incremental innovation. Their availability may help in coping with drug shortages” (1). So far so good. This clinical pharmacology review article goes on to point out, however, that “they may occasionally cause unexpected adverse reactions that are not class effects” (1).

When it comes to semaglutide, tirzepatide, and thymalin, the picture is a lot more complex than for a standard me-too entrant. For example, “the GLP-1 weight loss drugs are projected to hit $100 billion in prescription sales by early 2030s, making it the largest therapeutic market we’ve ever seen, … and to alleviated bottlenecks, production capacity is expected to double in 2024, and rise again by 50% in 2025” (2). This is in part driven by Hollywood’s least-best kept secret being shouted from the rooftops. However, apropos to drug shortages and the ongoing manufacturing glitches that helped create GLP-1 scarcity, pharmaceuticals arrived at astonishing juncture in 2023; Novo Nordisk stated “to avoid stimulating further demand for this medicine, we’re pausing some key Wegovy promotional efforts. We are pausing all local television advertising and postponing planned national television advertising for Wegovy. We are also assessing our promotional efforts to healthcare professionals and adjusting accordingly” (3).

Alongside weight loss drugs, US Chem labs has started compounding thymalin. Thymalin helps regulate the thymus, especially in creating T-lymphocytes or T-cells, but also modifies cardiovascular endocrine feedback loops. It is used for “immunodeficiency in adults and children (from six months to 14 years) with infectious purulent and septic processes; acute and chronic viral and bacterial infections; regenerative processes disorders; and Immunosuppression and hematopoiesis after chemotherapy or radiation therapy in cancer patients” (4). While thymalin has no clearly reported adverse effects, the same has yet to be verified for the new weight loss drugs. FDA had this to say on that subject, “preliminary FDA evaluation does not suggest a causal link between GLP-1 RA’s (glucagon-like peptide-1 receptor agonists which mimic natural hunger-suppressing hormones that are triggered when the stomach is) and suicidal thoughts” (4).

The reason driving that announcement was the large number of reports received in FDA Adverse Event Reporting System. The announcement went to say, “our reviews of the clinical trials, including large outcome studies and observational studies, did not find an association between use of GLP-1 RAs and the occurrence of suicidal thoughts or actions. However, because of the small number of suicidal thoughts or actions observed in both people using GLP-1 RAs and in the comparative control groups, we cannot definitively rule out that a small risk may exist; therefore, FDA is continuing to look into this issue” (4).

In a warning letter to US Chem Labs, FDA called out grave concerns over their compoundingof me-too versions of semaglutide, tirzepatide, and thymalin, saying, “despite statements on your product labeling marketing your products as ‘research chemicals only’ and ‘not for human consumption,’ evidence obtained from your website establishes that your products are intended to be drugs for human use. Your products are drugs as defined by section 201(g)(1) of the FD&C Act [Food, Drug, and Cosmetic Act] 21, U.S.C. 321(g)(1) because they are intended to prevent, treat, or cure disease conditions and/or affect the structure or function of the body” (5).

Despite there being no evidence of adverse effects associated with thymalin, the warning letter went on to say, “in addition, FDA is particularly concerned that you market your ‘Thymalin’ product for use in children. Your product has not been evaluated by FDA for safety, effectiveness, and quality. The use of untested drugs can have unpredictable and unintended consequences, especially in vulnerable populations such as children and infants who may be at greater risk for adverse reactions associated with certain drug products due to differences in the ability of children to absorb, metabolize, distribute, or excrete such drug products or their metabolites” (5).

A similar warning letter was also sent to Synthetix at the same time, for similar reasons. Compounding companies US Chem Labs and Synthetix are in trouble for introducing unapproved and misbranded semaglutide, tirzepatide ,and thymalin products into interstate commerce. Even in the case of thymalin, this caused fears of adverse reactions, particularly in children. The overarching point being, in times of both surplus and also shortage, compounding companies can amplify both good and bad situations, and in their haste to make me-too products, there needs to be a close check on their activities and ambitions.

References

1. Aronson, J. and Green, R. Me-too Pharmaceutical Products: History, Definitions, Examples, and Relevance to Drug Shortages and Essential Medicines Lists. Clin Pharmacol. 2020 86 (11).
2. Hennessy, M.J.P. Morgan Losing Weight, Pharm. Technol. 2024 48 (2).
3. Chen, E. Novo Nordisk Pauses Ads for Weight Loss Drug Wegovy as It Struggles to Meet Demand. Stat News. May 19, 2023.
4. FDA. Update on FDA’s Ongoing Evaluation of Reports of Suicidal Thoughts or Actions in Patients Taking a Certain Type of Medicines Approved for Type 2 Diabetes And Obesity, FDA Drug Safety Communication, FDA.gov. Feb. 11, 2024.
5. FDA. Warning Letter to US Chem Labs dated Feb. 07, 2024. FDA.gov. https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/us-chem-labs-669074-02072024