HIV Enteropathy

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.”

Gastrointestinal disorders are the most frequently reported adverse effects during clinical trials of GLP-1 agonists; GI adverse events usually develop in 40-70% of treated patients, and have been reported in up to 85% Crofelemer, approved by the FDA under the brand name Mytesi® for HIV-related diarrhea, has demonstrated a significant benefit in improving gastrointestinal symptoms, including diarrhea, abdominal pain and discomfort, incontinence, bloating and constipation, when studied in populations with HIV-related diarrhea, cancer therapy-related diarrhea, and IBS Crofelemer could have a significant supportive impact on GLP-1 therapies, one of the fastest growing classes of drugs, estimated to be a $56 billion global market in 2025 and projected to grow at a CAGR of 21% to $322 billion 20341 SAN FRANCISCO, CA / ACCESS Newswire / January 29, 2025 / Jaguar Health, Inc . (NASDAQ:JAGX) (Jaguar) family company Napo Pharmaceuticals (Napo) today announced Napo's filing of a broad defining provisional patent application with the U.S. Patent and Trademark Office (USPTO) for crofelemer, Jaguar's novel plant-based FDA-approved gastrointestinal normalizing prescription drug, to mitigate the gastrointestinal side effects associated with glucagon-like peptide-1 (GLP-1) receptor agonists and antagonists, together with other incretin-based therapies including glucose-dependent insulinotropic polypeptide (GIP) agonists and antagonists, and glucagon-agonist drugs. GLP-1 and GIP drugs are analogs for incretin hormones that are released by the gut and bind to receptors in the brain and gastrointestinal tract, suppressing appetite, which consequently leads to body weight loss. "Gastrointestinal disorders were the most frequently reported adverse effects during clinical trials and real-world experience of GLP-1 receptor agonists, 2 such as semaglutide, tirzepatide, and liraglutide. GI adverse events usually develop in 40-70% of patients treated with GLP-1 receptor agonists, although they have sometimes been reported in up to 85%, 3 which can lead to dose limitations or dose discontinuations. There are also numerous investigative agents, including incretins and combinations with GLP-1 drugs, both as receptor agonists and antagonists, all of which are associated with significant GI side effects, often in a dose-dependent manner. Our IP strategy includes claims for both commercialized obesity drugs and incretin-based therapies in development. Crofelemer, approved by the U.S. Food and Drug Administration under the brand name Mytesi for HIV-related diarrhea, has demonstrated a significant benefit in improving gastrointestinal symptoms, including diarrhea, abdominal pain and discomfort, incontinence, bloating and constipation, when studied in populations with HIV-related diarrhea, cancer therapy-related diarrhea, and IBS," said Lisa Conte , Jaguar's founder, president, and CEO. "Crofelemer has a safety profile supporting its chronic utilization, and we are excited about crofelemer's possible potential to normalize specific GI side effects associated with obesity therapies, address patient comfort, and help patient's stay on their therapy." About CrofelemerCrofelemer is a novel, oral plant-based prescription medicine purified from the red bark sap, also referred to as "dragon's blood," of the Croton lechleri tree in the Amazon Rainforest. Napo has established a sustainable harvesting program, under fair trade practices, for crofelemer to ensure a high degree of quality, ecological integrity, and support for indigenous communities. 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 StatementsCertain statements in this press release constitute "forward-looking statements." These include statements regarding Jaguar's expectation that crofelemer could have a significant supportive impact on GLP-1 therapies, and Jaguar's expectation that crofelemer may have the potential to normalize specific GI side effects associated with obesity therapies, address patient comfort, and help patient's stay on their therapy. 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. 1 GLP-1 Analogues Market Outlook: Rapid Growth at 21.3% CAGR to Surpass USD 322.85 Billion by 2034 | PMR 2 Sun F, Chai S, Yu K, Quan X, Yang Z, Wu S, Zhang Y, Ji L, Wang J, Shi L. Gastrointestinal adverse events of glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a systematic review and network meta-analysis. Diabetes Technol Ther. 2015;17(1):35-42. doi: 10.1089/dia.2014.0188 3 J Clin Med. 2022 Dec 24;12(1):145. Clinical Recommendations to Manage Gastrointestinal Adverse Events in Patients Treated with GLP-1 Receptor Agonists: A Multidisciplinary Expert Consensus CONTACT:hello@jaguar.healthJaguar-JAGX SOURCE: Jaguar Health, Inc.

Quadri Pharma will cover 50% of the costs of development activity up to a capped dollar contribution Jaguar to host virtual educational webinar on intestinal failure with leading gastroenterologists and nutrition experts November 8th from 1:00 PM to 2:30 PM EST; Click here to register for the webinar SAN FRANCISCO, CA / ACCESSWIRE / November 2, 2023 / Napo Pharmaceuticals, Inc. (Napo), a Jaguar Health, Inc. (NASDAQ:JAGX) family company, today announced that it has entered a revenue sharing license and commercialization agreement (the "Agreement") with Quadri Pharmaceuticals Store LLC (Quadri Pharma) that grants Quadri Pharma exclusive promotional, commercialization, and distribution rights for the rare disease indications of microvillus inclusion disease (MVID), other congenital diarrheal disorders, and short bowel syndrome (SBS) with intestinal failure for a powder formulation of crofelemer for oral solution in multiple Middle East countries, following regulatory approval to market crofelemer for these indications. In addition, the Agreement grants Quadri Pharma exclusive rights to distribute the powder formulation of crofelemer for the specified indications through Named Patient Programs in the specified Middle East countries following regulatory guidelines. SBS can result from surgical resection of a portion of the small intestine, or from disease or injury, or be congenital. MVID is an ultra-rare congenital diarrheal disorder. An estimate of congenital birth defect rates shows a higher incidence of anomalies among live births in Arab countries compared to those in Europe, North America and Australia.1 Many Arab countries display some of the highest rates of consanguineous marriages in the world ranging around 20-50% of all marriages, contributing to a higher-than-normal rate of congenital abnormalities. "We are very happy to have entered this new collaboration with Quadri Pharma, which is distinct from the revenue sharing distribution and license agreement Napo and Quadri Pharma entered in early 2022 that granted Quadri Pharma exclusive promotional, commercialization, and distribution rights to the tablet formulation of crofelemer in certain Middle East countries for specified human indications including HIV-related diarrhea and cancer therapy-related diarrhea (CTD), following regulatory approval," said Karen Brunke, PhD, Jaguar Health's Executive Vice President of Corporate and Business Development. "Under the terms of this new Agreement, Quadri Pharma will cover 50% of the costs of development activity in the specified territory for the powder formulation of crofelemer for the specified rare disease indications for three years, up to a certain total dollar amount. We look forward to continuing our close relationship with Quadri Pharma and their team of experienced professionals as we work together to expand access to crofelemer to intestinal failure patients in need in this region." "We are very happy to enter into this new strategic relationship with Napo," said Dr. Hesham Elbakr, Chief Executive Officer of Quadri Pharma. "We expect crofelemer to be an important treatment option for patients suffering from the devastating rare diseases of SBS with intestinal failure and MVID in the Middle East countries specified in the Agreement. We have expertise in the distribution and marketing of prescription drugs throughout the Middle East, including the introduction and management of early access programs where that medicine does not have marketing approval and critically ill patients have very limited therapy options - such as requests related to Named Patient Programs, which provide access to individual patients ("named" patients) through physician requests." Napo to Host Virtual Educational Webinar on Intestinal Failure with Leading Gastroenterologists and Nutrition Experts November 8, 2023 from 1:00 PM to 2:30 PM Eastern Standard Time Participants in this virtual event, which will be moderated by Pravin Chaturvedi, PhD, Jaguar Health's Chief Scientific Officer and Chair of the Jaguar/Napo Scientific Advisory Board, will define intestinal failure, which is classified as a malabsorptive syndrome, discuss the current standards of care for SBS and MVID patients, including parenteral support, and address the major unmet need for treatment options for the debilitating, chronic, severe watery diarrhea that is associated with intestinal failure. Participants include these distinguished gastroenterologists and nutrition experts from the US, the Middle East and Europe: Professor Mohamad Miqdady, MD, Division Chief, Pediatric Gastroenterology, Hepatology & Nutrition Division, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates Professor Antonella Diamanti, MD, Head of Artificial Nutrition Unit, Bambino Gesù Pediatric Hospital, Rome, Italy Christos Tzivinikos, MD, DCH, FRCPCH, MSc, CEBP, Consultant Pediatric Gastroenterologist, Head of Pediatric Gastroenterology, Hepatology and Nutrition Department, Al Jalila Children's Specialty Hospital, Dubai, United Arab Emirates Lindsey Russell, MD, MSc, FRCPC, Department of Gastroenterology, Hepatology and Nutrition and the Digestive Diseases & Surgery Institute, Cleveland Clinic, Ohio Fabrizio Pasanisi, MD, PhD, Director of the Interuniversity Center for Studies and Research on Obesity (CISROD) and Professor of Internal Medicine, University of Naples Federico II, Naples, Italy Carol Wolin, MA, RDN, LD, Public Health Dietitian, Legacy Community Health, Houston, Texas Webinar registration required via Zoom. To register, please click here or email Jaguar@TogoRun.com for more information. MVID is a severe infantile disease characterized by diarrhea, malabsorption, and acid/base instability, requiring intensive parenteral support for nutritional and fluid management, and there are currently no approved drug treatments. MVID patients commonly face intestinal failure - a catastrophic health situation that also often afflicts patients with SBS, a rare and complex condition characterized by diarrhea and/or severe malabsorption of fluids and nutrients. Crofelemer has been granted Orphan Drug Designation (ODD) by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for both MVID and SBS. Jaguar is supporting investigator-initiated and investigator IND proof-of-concept studies of crofelemer for MVID and SBS with intestinal failure in the US, EU, and Middle East/North Africa (MENA) regions, with results expected before the end of 2023 and in 2024. In accordance with the guidelines of specific European Union countries, published data from such clinical investigations could support reimbursed early patient access to crofelemer for SBS or MVID for these debilitating conditions. Napo's Investigational New Drug application for crofelemer for the treatment of MVID was activated by the FDA August 7, 2023. Based in Abu Dhabi and Dubai in the UAE, Quadri Pharma provides services related to the registration, marketing, and distribution of pharmaceutical products in the MENA region in compliance with local and international regulatory standards. About Crofelemer Crofelemer is the only oral FDA-approved prescription drug under botanical guidance. It is plant-based, extracted and purified from the red bark sap of the Croton lechleri tree in the Amazon Rainforest. Napo Pharmaceuticals, a Jaguar family company, has established a sustainable harvesting program, under fair trade practices, for crofelemer to ensure a high degree of quality, ecological integrity, and support for Indigenous communities. 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 focuses on developing and commercializing human prescription pharmaceuticals for essential supportive care and management of neglected gastrointestinal symptoms across multiple complicated disease states. Napo Pharmaceuticals' crofelemer drug product candidate is the subject of the OnTarget study, an ongoing pivotal Phase 3 clinical trial for preventive treatment of chemotherapy-induced overactive bowel (CIOB) in adults with cancer on targeted 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 Napo Pharmaceuticals, visit Napo Therapeutics, visit napotherapeutics.com Magdalena Biosciences, visit magdalenabiosciences.com Visit Jaguar on LinkedIn: Visit Jaguar on X: Visit Jaguar on Instagram: Forward-Looking Statements Certain statements in this press release constitute "forward-looking statements." These include statements regarding the expectation that Jaguar Health will host a virtual educational webinar on intestinal failure on November 8, 2023, the expectation that crofelemer may be an important treatment option for patients suffering from SBS with intestinal failure and MVID in the Middle East countries specified in the Agreement, the expectation that results from proof-of-concept studies of crofelemer for MVID and SBS with intestinal failure may be available before the end of 2023 and in 2024, and the expectation that, in accordance with the guidelines of specific European Union countries, published data from such clinical investigations could support reimbursed early patient access to crofelemer for SBS or MVID. 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. 1 Call for improved genetic services in Arab countries, Nature Middle East, Published online May 21, 2014 CONTACT: hello@jaguar.health Jaguar-JAGX SOURCE: Jaguar Health, Inc. View source version on accesswire.com: