Crofelemer

iStock/ panchanok premsrirut While drug developers work to mitigate the side effects associated with GLP-1–based obesity drugs, recent studies reveal that myriad variables are causing patients to stop treatment. When GLP-1 drugs recently became a trendy talking point for their impressive weight loss efficacy, their less-than-appealing aspects also came into focus, particularly gastrointestinal side effects. Nausea, vomiting, diarrhea, constipation and abdominal pain are all commonly reported by people dropping pounds with Novo Nordisk’s Wegovy (semaglutide) and Eli Lilly’s Zepbound (tirzepatide). In fact, real world studies indicate these GI adverse events develop in between 40-70% of GLP-1 treated patients. With discontinuation rates a concern for companies, drug developers and practitioners are working together to help patients manage the worst of these side effects so they can stay on drug and benefit from the significant weight loss generated by the popular injectables. In a recent survey of 50 physicians conducted by strategic advisory firm DNB Markets and Back Bay Life Science Advisors, 94% of doctors ranked the benefit-safety pro one of the most important factors in prescribing a weight loss medication. Physicians seem to be clamoring for drugs with fewer side effects, Peter Bak, partner and managing director of Back Bay Life Science Advisors, told BioSpace last month. Careful titration or dose adjustments, updated or combination formulations, and drugs targeting side effects are all strategies being deployed to improve the palatability of GLP-1s. For David Cummings, director of the weight management program for VA Puget Sound Health Care System, side effects are less of a deciding factor. “For my patients, [the gastrointestinal side effects] are not a huge deal, but it’s not a trivial deal either,” he told BioSpace. Titration, Combinations and Secondary Drugs Side effects like nausea and constipation are “easy to understand” as they relate to the drug’s mechanism of action, Cummings explained. One of the ways in which GLP-1s make patients feel full is by slowing GI motility. If the drug has too great an effect in the upper GI system, it can cause nausea, as happens when eating a huge meal too fast. If the drug has too strong an effect in the lower intestine, slow GI motility leads to constipation, he said. “In both cases, that’s just the drug doing what it’s supposed to do,” and the proper response is to decrease the dose to a level that is still efficacious but with fewer side effects, Cummings said. Interestingly, he said researchers are uncertain why diarrhea occurs with GLP-1 treatment. A key strategy being deployed by drug developers to improve side effect profiles is titration. The starting dose and length of time to maintenance dose are critical to optimizing patient tolerability, Blai Coll, chief medical officer of Structure Therapeutics, told BioSpace . Another popular approach is combination formulas. The addition of a gastric inhibitory polypeptide (GIP)—such as in Zepbound’s formulation—or an amylin receptor agonist can mitigate the gastrointestinal effects driven by the GLP-1, Coll said. Amylin has become a hot mechanism for weight loss drug developers as companies like Novo , Structure , AstraZeneca and Viking Therapeutics chase after approval of their candidates. Still other companies aim to target GLP-1-associated side effects with a separate, secondary drug. In January, Jaguar Health subsidiary Napo Pharmaceuticals filed a patent application for Mytesi to treat the GI side effects common with GLP-1 and GIP treatments used for obesity. Mytesi is a plant-based oral drug already approved for HIV-related diarrhea that has shown additional benefits for abdominal pain, discomfort, bloating and constipation when studied in HIV, irritable bowel syndrome (IBS) and cancer therapy-related diarrhea. While Cummings isn’t familiar with Mytesi in particular, he said that if the drug truly helped to treat GLP-1 side effects, “I’d certainly consider using it.” Ben Urick, senior director of health outcomes at Prime Therapeutics, isn’t convinced, however. He told BioSpace that the clinical goal is usually to instead find an alternative treatment with less burdensome side effects. “You’d have to really convince me that we would need another drug,” said Urick, a pharmacist. For a patient with dire disease circumstances and no other option, it may be useful, he added, “but not for your average user.” GLP-1 Discontinuation Is Multifactorial Despite these extensive efforts, the jury is still out on just how much of a problem GLP-1–associated side effects are. Cummings noted that only about 5% of his patients on GLP-1 medications have really had problems with side effects. A series of real-world studies mirror this assertion, with a 5% discontinuation rate found for patients taking semaglutide over roughly 30 weeks due to adverse events. Another real-world study , published in July 2024 by Prime Therapeutics, showed that 85% of patients were no longer taking GLP-1 drugs two years after starting treatment. But this isn’t only due to tolerability concerns. Urick said discontinuation can be attributed to five common causes, of which side effects are only one, along with affordability, availability, physician drug switches and the achievement of weight loss goals. However, “I don’t think shortages have quite as big of an impact as you would think,” Urick said, adding that patients on lower doses of the drugs are more likely to be affected. Despite literature touting GLP-1s as long-term treatments, prescribers have indicated to Urick that patients often only use the drugs to reach certain weight loss goals and then discontinue treatment once these are accomplished. Another indicator of this phenomenon is that in Prime’s study, patients without type 2 diabetes discontinued treatment at a higher rate than those with the disease. Urick also noted that Prime’s study data was initiated in 2021 and included older products that are no longer used as often, causing the treatment persistence rate to drop to 15%. With a “more modern product mix” led by heavy hitters like Zepbound and Wegovy, Urick said he expects to see two-year persistence rise to closer to 25%. That’s not to say that side effects are not an issue for patients. In fact, Urick believes the role of side effects and achieved weight loss goals have been underestimated in efforts to uncover the cause of GLP-1 discontinuation. While this study wasn’t designed to measure it, a further probe into Prime’s data revealed those who persisted on treatment had lower side effect rates than those who discontinued their GLP-1. For Urick, this is a signal that side effects could be associated with stopping a drug early. “There is a relationship between the two,” he said. Ultimately, Coll said, “I don’t think there’s a silver bullet by which we can continue benefiting from the GLP-1s while completely eliminating all the GI events.” He reiterated an emphasis on combination therapies with GIP and amylin to optimize tolerability. “That’s how we’re looking into the future.”

Jaguar expects first results in Q2 2025 of proof-of-concept investigator-initiated trials of crofelemer for the rare diseases short bowel syndrome with intestinal failure and microvillus inclusion disease FDA meeting expected in Q2 2025 on the statistically significant results of the Phase 3 OnTarget trial of crofelemer in the prespecified subgroup of patients with breast cancer Jaguar has received an indication of interest to acquire the Company SAN FRANCISCO, CA / ACCESS Newswire / February 27, 2025 / Jaguar Health, Inc. (NASDAQ:JAGX) ("Jaguar" or the "Company") today announced that its Board of Directors (the "Board") has adopted a limited duration stockholder rights plan (the "Rights Plan"). "Jaguar, which, like many other biotechnology companies, continues to experience a significant and ongoing dislocation in the trading price of its common stock, has received an indication of interest to acquire the Company. Our Board intends the Rights Plan to give Jaguar stockholders more time to realize the long-term value of their investment by discouraging significant open-market accumulation of the Company's shares without appropriately compensating all the Company's stockholders for control," said Lisa Conte, Jaguar's president and CEO. The Rights Plan is not intended to prevent or interfere with any action with respect to the Company that the Board determines to be in the best interests of the Company and its stockholders. Instead, it will position the Board to fulfill its fiduciary duties on behalf of all stockholders by ensuring that the Board has sufficient time to make informed judgments about any attempts to acquire the Company. The Rights Plan will encourage anyone seeking to acquire the Company or gain a significant interest in the Company to negotiate directly with the Board. "Jaguar has multiple expected near-term catalysts. The Company is supporting three proof-of-concept (POC) investigator-initiated trials (IIT), and conducting two Phase 2 studies, of crofelemer, our novel plant-based anti-secretory prescription drug, for the rare diseases short bowel syndrome with intestinal failure (SBS-IF) and/or microvillus inclusion disease (MVID) in the US, European Union, and/or Middle East/North Africa regions. The first POC IIT results are expected to be available in the second quarter of 2025, with additional POC IIT results expected throughout 2025. In accordance with the guidelines of specific EU countries, published data from clinical investigations in MVID and SBS-IF could support reimbursed early patient access to crofelemer for these debilitating conditions," Conte said. "Additionally, the Company expects that, if even just a very small number of MVID patients show benefit with the extremely safe profile of crofelemer, this may potentially allow approval in the US for crofelemer for MVID and qualify crofelemer for participation in PRIME for this indication. PRIME is a European Medicines Agency (EMA) program providing enhanced interaction and early dialogue with developers of promising medicines that target an unmet medical need, with the goal of optimizing development plans and speeding up evaluation so the medicine can reach patients earlier." Jaguar also remains focused on development of crofelemer for cancer therapy-related diarrhea (CTD). As announced, the analysis of the prespecified subgroup of adult patients with breast cancer from the Company's recently conducted Phase 3 prophylactic OnTarget clinical trial for diarrhea in adult patients with solid tumors receiving targeted therapy with or without standard chemotherapy indicate that crofelemer achieved statistically significant results in this subgroup. These results were the subject of a December 11, 2024 poster presentation at the San Antonio Breast Cancer Symposium. The Company will request a meeting with the FDA to discuss the results of OnTarget in breast cancer patients and potential pathways to bring crofelemer to this patient population as efficiently as possible, and expects the meeting to take place in the second quarter of 2025. Further, the terms of the Rights Plan provide many recognized stockholder protections, including the following: The rights will be exercisable only if an entity, person or group acquires beneficial ownership of 20% or more of the total voting power of the aggregate of all shares of the Company's Voting Stock (as defined below) then outstanding in a transaction not approved by the Board; The Rights Plan does not contain any dead-hand, slow-hand, no-hand or similar features that would limit the ability of a future board of directors to redeem the rights; and The Rights Plan does not preclude the Board from considering an offer that recognizes the full value of the Company. Pursuant to the Rights Plan, the Company will issue a dividend of (i) one preferred share purchase right (a "Class A Right") for each share of common stock and (ii) one preferred stock purchase right (a "Class B Right" and together with the Class A Rights, the "Rights") for each share of non-voting common stock outstanding as of the close of business on March 10, 2025. While the Rights Plan is effective immediately, the Rights generally would become exercisable only if an entity, person or group acquires beneficial ownership of 20% or more of the total voting power of the aggregate of all shares of the Company's Voting Stock then outstanding in a transaction not approved by the Board. If the Rights become exercisable, each holder of a Class A Right or Class B Right (other than the acquiring entity, person or group) will have the right to purchase from the Company for $4.50, subject to certain potential adjustments, shares of the Company's common stock or non-voting common stock, respectively, having a market value of twice that amount. In addition, at any time after an entity, person or group acquires 20% or more of the total voting power of the aggregate of all shares of the Company's Voting Stock then outstanding, but less than 50% of the total voting power of the aggregate of all shares of the Company's Voting Stock then outstanding, the Board may exchange (i) one share of the Company's common stock per Class A Right and (ii) one share of the Company's non-voting common stock per Class B Right (other than Rights owned by the acquiring entity, person or group, which would have become void). The Rights Plan has a term of one year and may expire earlier upon the occurrence of certain specified events. Further details about the Rights Plan will be contained in a Current Report on Form 8-K and in a Registration Statement on Form 8-A that the Company will file with the U.S. Securities and Exchange Commission. About the Jaguar Health Family of Companies Jaguar Health, Inc. (Jaguar) is a commercial stage pharmaceuticals company focused on developing novel proprietary prescription medicines sustainably derived from plants from rainforest areas for people and animals with gastrointestinal distress, specifically associated with overactive bowel, which includes symptoms such as chronic debilitating diarrhea, urgency, bowel incontinence, and cramping pain. Jaguar family company Napo Pharmaceuticals (Napo) focuses on developing and commercializing human prescription pharmaceuticals for essential supportive care and management of neglected gastrointestinal symptoms across multiple complicated disease states. Napo's crofelemer is FDA-approved under the brand name Mytesi® for the symptomatic relief of noninfectious diarrhea in adults with HIV/AIDS on antiretroviral therapy. Jaguar family company Napo Therapeutics is an Italian corporation Jaguar established in Milan, Italy in 2021 focused on expanding crofelemer access in Europe and specifically for orphan and/or rare diseases. Jaguar Animal Health is a Jaguar tradename. Magdalena Biosciences, a joint venture formed by Jaguar and Filament Health Corp. that emerged from Jaguar's Entheogen Therapeutics Initiative (ETI), is focused on developing novel prescription medicines derived from plants for mental health indications. For more information about: Jaguar Health, visit https://jaguar.health Napo Pharmaceuticals, visit www.napopharma.com Napo Therapeutics, visit napotherapeutics.com Magdalena Biosciences, visit magdalenabiosciences.com Visit the Make Cancer Less Shitty patient advocacy program on Bluesky, X, Facebook & Instagram Forward-Looking Statements Certain statements in this press release constitute "forward-looking statements." These include statements regarding Jaguar's expectation that the first POC IIT results may be available in Q2 2025 for crofelemer for SBS-IF and MVID, Jaguar's expectation that, in accordance with the guidelines of specific EU countries, published data from clinical investigations in MVID and SBS-IF could support reimbursed early patient access to crofelemer for these debilitating conditions, Jaguar's expectation that, if even just a very small number of MVID patients show benefit with crofelemer, this may potentially allow approval in the United States for crofelemer for MVID and qualify crofelemer for participation in PRIME for this indication, Jaguar's expectation that the Company will request a meeting with the FDA to discuss the results of the OnTarget study in breast cancer patients and potential pathways to bring crofelemer to this patient population as efficiently as possible, Jaguar's expectation that a meeting with the FDA will take place in Q2 2025, and Jaguar's expectation that the Rights Plan will give Jaguar stockholders more time to realize the long-term value of their investment by discouraging significant open-market accumulation of the Company's shares without appropriately compensating all the Company's stockholders for control. In some cases, you can identify forward-looking statements by terms such as "may," "will," "should," "expect," "plan," "aim," "anticipate," "could," "intend," "target," "project," "contemplate," "believe," "estimate," "predict," "potential" or "continue" or the negative of these terms or other similar expressions. The forward-looking statements in this release are only predictions. Jaguar has based these forward-looking statements largely on its current expectations and projections about future events. These forward-looking statements speak only as of the date of this release and are subject to several risks, uncertainties, and assumptions, some of which cannot be predicted or quantified and some of which are beyond Jaguar's control. Except as required by applicable law, Jaguar does not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. CONTACT:hello@jaguar.healthJaguar-JAGX SOURCE: Jaguar Health, Inc.