Tirzepatide

While U.S. shortages of Novo and Lilly's immensely popular GLP-1 drugs have been formally resolved by the FDA, access barriers to the lucrative weight loss and diabetes medications remain. Still, indulging the mass compounding of cheaper GLP-1 imitations is misguided and potentially unsafe, multiple experts have warned. Though much of the dust has settled around Novo Nordisk and Eli Lilly’s crusade against compounded GLP-1s, the recent implosion of Novo’s partnership with telehealth firm Hims & Hers suggests there is still very much a demand for imitation weight loss drugs.After Novo and Hims butted heads over a contentious Super Bowl ad earlier in the year, the companies became unlikely partners in the marketing of Novo’s obesity blockbuster Wegovy in late April. The collaboration didn’t last long, however, with Novo backing out this week over concerns that its telehealth partner was continuing to sell and promote compounded GLP-1 medicines in addition to Novo’s branded product.Crucially, Novo accused Hims of failing to honor mass compounding restrictions "under the false guise of 'personalization.'" The Danish drugmaker alleged that its former partner was guilty of "deceptive promotion" and that it was selling "illegitimate, knockoff versions of Wegovy" that could pose a risk to patients' health.The situation between Novo and Hims reflects the complex market for GLP-1 drugs for diabetes and obesity, which have enjoyed tremendous popularity despite the branded drugmakers behind them not always having the supply to match.Federal law allows the compounding of drugs that are in shortage to help meet patient needs. But in the case of the GLP-1 drugs, supply shortages spawned a lucrative and unwieldy cottage industry, plus a web of litigation that's still not resolved. Amid that backdrop, the blockbuster GLP-1 drugs are now off of the FDA's shortage list, meaning that the mass compounding should—in theory—be over.But as Novo's allegation shows, it's not quite that simple.Of compounding and shortagesTo untangle the predicament Novo and Lilly have found themselves in, it’s important to first understand the role compounding has traditionally played in healthcare and the legal frameworks that allowed compounding pharmacies to swoop in during protracted shortages of both companies' GLP-1 drugs.Compounding is nothing new in the world of medicine. In fact, pharmacies were compounding drugs in the U.S. well before the FDA ever existed, Scott Brunner, CEO of the Alliance for Pharmacy Compounding (APC), said in an interview earlier this year.Traditionally, compounders have made customized medicines tailored to individual patients, he explained.As an example, in wanting to adjust hormone levels for menopausal or perimenopausal women, a doctor might prescribe a bespoke combination of ingredients in precise dosages, Bill Coyle, region managing principal for Europe at the life sciences consulting firm ZS, said in a separate interview. A compounder would then formulate that unique mix in a process that's “highly personalized and often used when no commercially available product meets the patient’s specific requirements,” he explained. There are two primary types of compounding pharmacies in the U.S. First, there are 503A compounding pharmacies, which fill the traditional role of creating customized drug formulations for individual patients. The counterparts to 503A operations are 503B pharmacies with outsourcing facilities. The latter type of compounding pharmacy can make bulk drug batches that must adhere to current good manufacturing practices, but only when the reference drug is listed by the FDA as in short supply, Brunner explained.Brunner noted that FDA-approved drugs are always the “gold standard,” and if the drug in its approved form is appropriate and accessible for the patient, “the FDA-approved drug is always what should be prescribed.”But in the case of GLP-1s, the branded drugs were not readily available for quite some time. As mainstream hype built around a new generation of metabolic medicines from Novo and Lilly, the companies' major GLP-1s utilizing semaglutide and tirzepatide fell into shortage in the U.S. by the second half of 2022. Novo and Lilly began pouring billions of dollars into their respective manufacturing networks in a bid to boost supplies, but the shortages dragged on, providing an opening for compounders—especially of the larger 503B variety—to step in.Lilly’s tirzepatide shortage ended first, with the FDA officially declaring the situation resolved early last October. The regulator erased Novo’s semaglutide from its shortage list in February.Despite legal challenges against the FDA from compounding trade groups like the Outsourcing Facilities Association (OFA), all compounding of semaglutide and tirzepatide, except in rare circumstances, is now illegal under U.S. compounding laws, following off-ramp periods designed to smooth the transition. The last of those grace period deadlines, which pertained to 503B compounding of semaglutide, passed on May 22.The recent shortages and compounding influx surrounding semaglutide and tirzepatide were unprecedented in the obesity space, Martin Binks, Ph.D., chair and professor of the Department of Nutrition and Food Studies at the George Mason University College of Public Health, told Fierce Pharma.Previously, a lack of insurance coverage for obesity medicines and a failure to recognize the condition as a legitimate metabolic disease meant that those drugs were not in high demand, he explained in an interview. That changed, however, with the impressive effectiveness displayed by Novo and Lilly’s respective obesity blockbusters.Binks has been involved with GLP-1s since their inception and received consulting fees from Novo Nordisk tied to the launch of its first GLP-1 weight loss drug Saxenda.The safety questionOne major concern surrounding compounded weight loss drugs—which Novo and Lilly have highlighted frequently in ads and lawsuits—hinges on the uncertain safety, quality and effectiveness of GLP-1 copies.After Hims & Hers took aim at obesity drug pricing in a controversial ad during the Super Bowl earlier this year, Novo shot back with a scathing ad of its own, asking users of compounded GLP-1s whether they “really know" what they're injecting.The ad went on to warn that some vials of compounded semaglutide had been found to contain dangerous impurities, banned substances or dose miscalculations.Angela Fitch, M.D., co-founder and chief medical officer at weight health specialist knownwell and former president of the Obesity Medicine Association, told Fierce Pharma that her company—which provides virtual obesity care and care through a number of brick-and-mortar clinics—has been “passionate about not compounding.” She credited that decision to the uncertainty around the active pharmaceutical ingredients used in compounded products and the fact that drugs like semaglutide are quite tricky to produce properly.Novo made that case itself when it petitioned the FDA last fall to place semaglutide on the agency’s Demonstrable Difficulties for Compounding lists. For his part, APC’s Brunner took issue with the popular refrain that compounded drugs are unregulated or subpar compared to their branded counterparts, though he did acknowledge that compounded medicines technically aren’t approved by the FDA.“Federal law and FDA guidance allow for the preparation of these drugs within a tight regulatory framework, but it’s a framework that is not as rigorous, shall we say, as that for FDA-approved drugs, because we’re not talking mass manufacturing here,” Brunner clarified.George Mason University’s Binks stressed in his interview that there are many legitimate and reliable compounding pharmacies out there. But the influx of demand for GLP-1 weight loss drugs “gave rise to a ridiculous number of bad actors, and the public doesn’t have a whole lot of tools to understand the differences,” he said.He specifically highlighted the frequency with which people were previously accessing compounded GLP-1s for cosmetic weight loss, which he noted could put those users at risk since Novo and Lilly’s drugs were approved on a risk-benefit profile that only accounted for people diagnosed with diabetes or obesity.Access hurdles remainWith mass access to compounded GLP-1s now seemingly in the rearview, access hurdles remain for patients. Nevertheless, ZS’ Coyle suggested that the temptation to use compounding as a more affordable alternative to genuine semaglutide and tirzepatide is misguided.“Taken to its extreme, would we want to allow any compounder or generic manufacturer to step in and supply a patent-protected product within its exclusivity period when the market—or a subset of the market—is dissatisfied with the price of branded products,” he asked. “Where does one draw the line? It’s a very slippery slope.”The prices for Novo and Lilly’s GLP-1s are certainly much higher than those for compounded alternatives, which have generally been priced at around $200 for a month’s supply, according to Hims & Hers and its telehealth compatriot Ro. By comparison, Lilly and Novo's drugs cost more than $1,000 per month for insurers before rebates and discounts. But the companies have offered the opportunity for cash-paying customers to access the drugs for under $500 per month.And, just this week, Novo noted that a new $299 introductory offer for cash-paying Wegovy patients is designed, in part, to help those who were previously prescribed "unapproved" semaglutide transition to the FDA-approved product. Both companies have also made a direct-to-consumer push for their obesity meds this year by teaming up with prominent telehealth outfits like Teladoc Health, LifeMD, WeightWatchers and Knownwell. ZS' Coyle noted that these telehealth team-ups are likely enticing for Novo and Lilly because they provide patients with a “low-friction ‘digital front door’ to get a prescription and have it fulfilled.” Though the experts suggested there may still be room for improvement on the steep costs of Lilly and Novo’s GLP-1s, they largely agreed that a lack of insurance coverage for obesity meds—rather than prices alone—is the main barrier to access.On the coverage front, GLP-1s for obesity have so far “not been treated the same as the diabetes or other life-saving medicines,” Binks said, highlighting historic issues with the recognition of obesity as a legitimate metabolic disease.Where GLP-1 compounding stands todayWhile mass compounding of GLP-1s is now illegal, Brunner said there's still a case to be made for compounders continuing to produce customized GLP-1 doses for a much smaller subset of patients, which is allowed under current FDA guidance.But he didn’t mince words about the actions of certain companies that have attempted to jump on the GLP-1 compounding bandwagon.“I do believe there is what I might call some opportunism in the compounding space,” he said earlier this year. “Right now, I’m concerned when I see certain players in the space—and some of these didn’t exist a year ago, two years ago."Brunner noted that some telehealth companies’ practices appeared to involve creating a “cottage industry” around a particular dosage form, strength or combination and prescribing that same formulation to large numbers of patients.“That doesn’t look to me like customization, it looks to me like competition,” he said.“Future compounding of GLP-1s is going to be on the 503A side by traditional compounding pharmacies, unless the drug goes back into shortage,” he said.But if Novo's recent allegation is to be trusted, some companies may try to have it both ways by playing the "personalization" card while also shipping large quantities of compounded medicines. Against this backdrop, Novo and Lilly have pledged to continue rooting out GLP-1 imitators that defy FDA guidelines.“As the FDA has warned, compounders cannot rely on mere pretextual differences between unapproved compounded drugs and FDA-approved medicines—under the guise of making ‘personalized’ drugs—in order to evade federal law,” Dave Moore, EVP of U.S. operations at Novo Nordisk, said in a statement earlier this year.Lilly likewise “intends to continue monitoring entities and will take action against entities who threaten the health and well-being of Americans by unlawfully continuing to make or sell risky compounded tirzepatide knockoffs,” a company spokesperson warned. 

Vor Bio and RemeGen's market-dividing licensing deal, Otsuka and Harbour BioMed's BCMA T-cell engager pact, and Datroway's second FDA nod made our news this week. A potential $4 billion licensing deal with Vor Bio triggered a slide in RemeGen's stock price. Otsuka obtained a BCMAXCD3 bispecific from Harbour BioMed to develop against autoimmune diseases. AstraZeneca and Daiichi Sankyo's Datroway secured a lung cancer approval from the FDA. And more.1. Vor Bio's surprise $4B revival deal for RemeGen's autoimmune drug triggers divergent stock reactionsOn the brink of shutting down, Vor Bio has been revived by a licensing deal with China’s RemeGen. For $45 million upfront and up to $4.1 billion in milestones, the Massachusetts biotech is gaining ex-China rights to RemeGen’s BLyS/APRIL dual-target fusion protein telitacicept, which is approved in China to treat several autoimmune diseases. However, RemeGen’s stock price dropped sharply after the news.2. Otsuka pens $670M pact to point Harbour's preclinical T-cell engager toward autoimmune diseaseIn another autoimmune-focused deal involving a Chinese biotech, Otsuka agreed to pay Harbour BioMed $47 million upfront for ex-China rights to a preclinical BCMAxCD3 bispecific candidate. While Harbour got the Chinese green light to test the asset in cancer patients, Otsuka plans to test the drug, HBM7020, against autoimmune conditions.3. AZ, Daiichi's Datroway scores its 2nd FDA approval—this time in lung cancer subsetAstraZeneca and Daiichi Sankyo’s TROP2-targeted antibody-drug conjugate Datroway has picked up its second FDA nod after a refile. Datroway secured the EGFR-mutated non-small cell lung cancer indication after the companies had withdrawn an earlier application in nonsquamous NSCLC following a phase 3 overall survival miss.4. Corxel, Sciwind post GLP-1 data as China's obesity push gathers paceGLP-1 assets from China are showing their power at the American Diabetes Association Scientific Sessions. Sciwind’s phase 3 data linked its injectable GLP-1 receptor agonist ecnoglutide to a mean weight loss of 15.4% after 48 weeks. Phase 2 data on Corxel and Vincentage’s small-molecule GLP-1 candidate showed a 9.7% weight reduction in 16 weeks when given at a fast titration to the highest dose.5. BrightGene tops Novo drug in diabetes ahead of Zepbound showdownAlso at ADA, China’s BrightGene reported that its GLP-1/GIP receptor agonist BGM0504 topped Novo Nordisk’s Ozempic in Chinese patients with Type 2 diabetes in a midstage trial. The drug saw dose-dependent reductions in HbA1c of up to 2.48% after 12 weeks, versus 1.43% for Ozempic and 0.28% for placebo. The biotech also shared phase 2 obesity data comparing BGM0504 against placebo, and the company is pitting the drug against Eli Lilly’s Zepbound in another phase 2 study.6. FDA moves to block Olympus endoscope imports over manufacturing issuesThe FDA warned healthcare providers that it’s shutting down imports of 58 models of aparoscopes, bronchoscopes, nasopharyngoscopes and ureteroscopes, as well as automated cleaners and reprocessing accessories, made by Olympus. The agency cited concerns around quality requirements at a production site in Japan.Other News of Note:7. GSK, Bharat Biotech to slash the price of first malaria vaccine to less than $5 per dose by 20288. Hummingbird uses VISTA buzz to secure $290M pact for phase 2-ready tumor drug9. Arbutus regains China rights to potential functional hep B cure as part of strategic rethink10. Korea’s Abion Bio inks $1.3B deal over CLDN3, other cancer targets (Korea Biomedical Review)