HighTide Therapeutics (Hong Kong) Ltd.

ROCKVILLE, MD and SHENZHEN, CHINA, HighTide Therapeutics, Inc. (Stock Code: 2511.HK), a clinical stage biopharmaceutical company specializing in the development of multi-targeted therapies for chronic liver and metabolic diseases, announced that it will make multiple presentations at the European Association for the Study of the Liver (EASL) Congress, taking place from June 5-8, 2024 in Milan, Italy. The presentations include post-hoc analyses of the Phase 2a clinical study of berberine ursodeoxcyholate (HTD1801), a gut-liver anti-inflammatory metabolic modulator, in patients with metabolic dysfunction-associated steatohepatitis (MASH) and comorbid type 2 diabetes mellitus (T2DM) (NCT03656744). “These data provide additional insight on the potential benefits of HTD1801, a novel, multifunctional therapy being developed for the treatment of patients with MASH and T2DM. The ongoing multi-regional Phase 2b study (CENTRICITY, NCT05623189), now fully enrolled, evaluates the histologic benefit of HTD1801 in this same patient population. We look forward to the results of CENTRICITY which is on track to read out in the first half of 2025,” said Dr. Leigh MacConell, Chief Development Officer of HighTide. “Efficacy of Berberine Ursodeoxycholate (HTD1801) Compared to Ongoing Use of GLP-1 Receptor Agonists in Patients with MASH and T2DM” (Abstract SAT-227, Poster Presented June 8) About the Abstract: As GLP-1 Receptor Agonists (GLP-1RAs) are prominently used in patients with T2DM and gaining attention as a potential treatment for MASH, this post-hoc comparative efficacy analysis evaluated ongoing GLP-1RA use compared to newly initiated HTD1801 treatment. This analysis suggests that HTD1801 provides greater benefit across multiple cardiometabolic endpoints compared to ongoing GLP-1RA use. These findings are important as they suggest that patients with MASH and T2DM, on concomitant GLP-1RA treatment, could achieve additional benefit with HTD1801 in terms of further glucose and lipid lowering as well as weight loss. “Berberine Ursodeoxycholate (HTD1801) Provides a Unique Therapeutic Approach for Patients with Metabolic Liver Disease and Severe Insulin Resistance” (Abstract SAT-225, Poster Presented June 8) About the Abstract: Insulin resistance is a significant risk factor for T2DM, obesity and MASH. HTD1801 enhances the utilization of glucose and fats through activation of AMP-activated protein kinase (AMPK), thereby improving insulin sensitivity. As HTD1801 is under development as a treatment for patients with MASH and T2DM, the objective of this post-hoc analysis was to evaluate the effects of HTD1801 based on degree of insulin resistance. These data demonstrate that HTD1801 can alleviate the metabolic inhibitory effects caused by hyperinsulinemia, leading to even greater metabolic benefits in patients with MASH and more severe insulin resistance and therefore may offer a unique therapeutic approach for individuals with MASH and T2DM. “Time Course of Onset, Incidence, and Prevalence of Gastrointestinal Adverse Events with HTD1801 (Berberine Ursodeoxycholate) in Patients with MASH and T2DM” (Abstract SAT-243, Poster Presented June 8) About the Abstract: The most commonly occurring adverse events (AEs) in studies of HTD1801 across several indications have been mild to moderate gastrointestinal (GI) AEs, primarily diarrhea and nausea. The purpose of this post-hoc analysis was to characterize the time course and severity of GI AEs in patients with MASH and T2DM treated with HTD1801 for 18 weeks. Diarrhea and nausea, the most commonly occurring of GI AEs, followed a trend that was consistent with all reported GI AEs; they showed early onset (within the first 4 weeks), were mild or moderate in severity, and importantly, showed a decreasing incidence and prevalence over the course of treatment. These data demonstrate that with continued treatment with HTD1801, GI tolerability improves supporting its potential for long-term use for the treatment of chronic disease, such as MASH. About HighTide Therapeutics HighTide Therapeutics, Inc. (HKEX: 2511) is a globally integrated biopharmaceutical company focusing on the discovery and development of first-in-class multifunctional multi-targeted therapies with chronic liver and metabolic diseases with significant unmet medical needs. The company is developing multiple clinical assets, including therapy for metabolic dysfunction-associated steatohepatitis (MASH), type 2 diabetes (T2DM), severe hypertriglyceridemia (SHTG), primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC). Berberine ursodeoxycholate (HTD1801), the company’s lead drug candidate, received Fast Track designation from the U.S. FDA for both NASH and PSC, as well as Orphan Drug designation for PSC. In China, HTD1801 has been included in the National Major New Drug Innovation Program under the 13th Five-Year Plan for Major Technology Project. Disclaimer The information contained herein is based solely on events or data available as of the date of this document. Unless required by law, we are under no obligation to update or publicly revise any forward-looking statements or events beyond those anticipated, even if new information, future events, or other circumstances arise after the date of the forward-looking statement. Please review this document carefully and be aware that our actual future performance or results may significantly deviate from expectations. All statements in this document are made as of the publication date and may change considering future developments. For more information, please visit Contact: pr@hightidetx.com

Pliant Therapeutics is part of a small band of biotechs working to address the unmet need in primary sclerosing cholangitis. Investors are swayed by Pliant Therapeutics’ data. The biotech posted early clinical evidence that its lead drug candidate reduces scarring and itching in a chronic liver disease, sending its share price up around 15%. The phase 2a trial is comparing bexotegrast, an oral, dual-selective inhibitor of two integrins, to placebo in patients with primary sclerosing cholangitis (PSC) and suspected liver fibrosis. PSC, a condition with no FDA-approved therapies, causes scarring of bile ducts and cirrhosis. Through tissue specific inhibition of TGF-β, bexotegrast may block fibrosis, leading Pliant to identify it as a potential treatment for PSC. In the phase 2a trial, participants received one of three doses of bexotegrast or placebo. While the study is primarily designed to assess safety, tolerability and pharmacokinetics, Pliant also looked at exploratory efficacy endpoints such as changes in the fibrosis, biochemistry and imaging of the liver. The exploratory endpoints revealed early signs that bexotegrast may improve outcomes.  After 12 weeks of dosing, the ELF score, a blood test of fibrosis markers, was significantly lower in the high, 160-mg dose cohort than in the placebo group and numerically lower in all the bexotegrast arms. Pliant linked the high dose to an 84% reduction relative to placebo. The reduction was underpinned by significant declines in all three markers that make up the ELF score.  Pliant also reported a significant drop in collagen synthesis and, at the high dose, in the score on an itch scale. Other liver biochemistry and imaging parameters favored bexotegrast, too, giving Pliant data with enough promise to send its share price up around 15% to $16.60 in premarket trading. The data set is small—each arm featured around 20 patients—but the signs of efficacy and lack of safety red flags have encouraged Pliant and its investors. Attention now turns to the anticipated publication of 12-week data on a higher, 320-mg dose, which is scheduled for the first quarter of next year.   Pliant is part of a small band of biotechs working to address the unmet need in PSC, a disease that companies including Gilead Sciences have targeted in the past without delivering a FDA-approved treatment. The current crop of companies going after the liver condition includes Chemomab Therapeutics, Dr. Falk Pharma, Escient Pharmaceuticals, HighTide Therapeutics and Mirum Pharmaceuticals.

89bio said its drug was better than placebo at lessening fibrosis without worsening nonalcoholic steatohepatitis, or NASH, in two of three dose groups. The San Francisco biotech said it thinks the Phase IIb data pave the way for a potential Phase III, following in the footsteps of another biotech in its drug class, Akero Therapeutics. To fund a late-stage study, CEO Rohan Palekar told Endpoints News 89bio “would need to raise additional capital,” with the company having about $188 million at the end of last year. Both 89bio and Akero are making analogs of FGF21 — a hormone normally produced in the liver at low levels to manage energy and lipid metabolism and insulin sensitivity — in the hopes of treating the fatty liver disease. They’re attempting to wade into a disease that has tripped up biopharmas for years but might soon see the first two treatment approvals, with Intercept awaiting an FDA decision in June and Madrigal Pharmaceuticals headed to the regulator next year . Akero previously said it would meet with the FDA this month to discuss a late-stage trial after reading out a positive Phase IIb last September. For 89bio’s Enliven study , 27% of patients receiving the investigational drug pegozafermin at 44mg every two weeks experienced a decrease of at least one stage of fibrosis with no worsening of NASH, the biotech said Wednesday, compared to 7% of those on placebo. For those who got 30mg every week, 26% of patients saw that improvement. Those pegozafermin groups came in at a p-value of 0.008, which the company said was “high statistical significance.” About 22% of the 15mg group saw that improvement, for a p-value of 0.1. On the other primary endpoint, looking at NASH resolution without a worsening of liver fibrosis, 89bio said 26% of those on the 44mg dose every two weeks met that bar compared to 2% on placebo. The weekly 30mg group saw 23% meet that endpoint, and 37% did so in the weekly 15mg set of patients. P-values were 0.0005 for 44mg, 0.0009 for 30mg and less than 0.0001 for 15mg. The potential Phase III dosing regimen hasn’t been determined yet, but Palekar said an every-two-week injection is more ideal for patients than a weekly one, especially given the chronic nature of NASH. The data, with more to be submitted to a medical conference and journal, are likely to draw fine-combing from other NASH drug developers, physicians and investors as the analysis of two primary endpoints came from 192 of 219 patients dosed. The 27-patient difference came after the biotech changed from consulting one pathologist to having three independent pathologists score each liver biopsy slide, which CMO Hank Mansbach called a “much more precise approach” that resulted in those patients no longer meeting the histological inclusion criteria. “Insight from the landscape about how” NASH trials were being conducted led to the adjustment, he said in an interview. “There is a large variability when a pathologist reads that slide, and in some ways, this has plagued some of the prior studies in NASH,” Palekar said in a separate interview. The biotech homed in on the prospectively identified population of those with F2 and F3 stages of fibrosis, or liver scarring, which are the “population of interest for regulatory submission,” Mansbach said. Other NASH drug trials have looked at patients with additional stages of fibrosis, but they typically isolate data from the F2 and F3 group, he noted. On the safety front, 89bio said five patients on pegozafermin versus none on placebo discontinued because of treatment-related adverse events. The biotech said the most frequently reported side effects were grade 1 or 2 diarrhea, nausea or increased appetite at mild to moderate levels. One drug-related serious adverse event occurred in which a patient experienced “uncomplicated pancreatitis associated with gallbladder sludge” after receiving one dose in the 44mg every-two-week group. Liver fat levels dropped more for patients on 44mg every two weeks and 30mg weekly. 89bio reported 54% and 52% declines for those groups, respectively, versus 14% for the patients on placebo. Liver damage was also lower on the study drug than placebo. Up next, 89bio plans to meet with regulators in the US and Europe to discuss a Phase III clinical trial, Palekar said. To fund that, the biotech will need more capital, he noted, as current funds are also being directed toward an upcoming Phase III that will test pegozafermin in patients with severe hypertriglyceridemia. The FDA approved the late-stage study after 89bio presented data last year on the condition, which can lead to cardiovascular disease. As 89bio gears up for the next stage, patients and the field await an FDA decision on Intercept’s obeticholic acid. The agency will convene its outside advisors on May 19. Mansbach, the 89bio CMO, said a thumbs up from the experts and a subsequent approval for Intercept’s treatment candidate would be “very welcomed certainly by patients as well as by physicians” because it would be the first treatment approved for the indication. Meanwhile, multiple other biotechs are in the mid-and-late stages of NASH drug development, with Inventiva working on Phase III studies of its drug lanifibranor and HighTide Therapeutics reeling in $107 million to help support a Phase IIb trial. Chemomab Therapeutics, when presenting Phase IIa results in January, said it’d focus on other diseases because of the cash required for running later-stage studies in NASH.