UCP1

Data from a Phase I single ascending dose (SAD) study in Australia in subjects with elevated low-density lipoprotein cholesterol (LDL-C) showed that ASC47, via subcutaneous (SQ) injection, demonstrated a half-life of 21 days, supporting once-monthly administration in patients with obesity In multiple pre-clinical studies using the diet-induced obese (DIO) mouse model, ASC47 demonstrated healthy weight loss (muscle-preserving weight loss) Compared to semaglutide in a head-to-head pre-clinical study using a DIO mouse model, ASC47 reduced total fat mass (-63.5%), statistically and significantly more than semaglutide (-39.6%). In the same study, ASC47 statistically and significantly increased total muscle mass (+5.8%), while semaglutide decreased total muscle mass (-9.3%). Total body weight reduction was similar between ASC47 (-24.6%) and semaglutide (-23.1%), even though caloric intake reduction in ASC47-treated DIO mice was significantly less than semaglutide-treated DIO mice Compared to tirzepatide in a head-to-head pre-clinical study using a DIO mouse model, ASC47 reduced total fat mass (-68.0%), statistically and significantly more than tirzepatide (-50.4%). In the same study, ASC47 statistically and significantly increased total muscle mass (+8.1%), while tirzepatide decreased total muscle mass (-3.8%). Total body weight reduction was similar between ASC47 (-23.6%) and tirzepatide (-22.4%), even though caloric intake reduction in ASC47-treated DIO mice was significantly less than tirzepatide-treated DIO mice ASC47 was designed with unique and differentiated properties to enable targeted delivery to adipose tissue, resulting in high drug concentrations in the adipose tissue in a dose-dependent fashion. In DIO mice with SQ dosing of 15 mg/kg ASC47, once every two weeks, the drug concentration in the adipose tissue 14 days after the last dose was 7-fold of human efficacious drug concentration predicted by a preclinical model One of the key mechanisms of action of ASC47 to reduce fat and achieve muscle-preserving weight loss is through uncoupling protein 1 (UCP-1)-mediated thermogenesis in the adipose tissue HONG KONG, Nov. 7, 2024 /PRNewswire/ -- Ascletis Pharma Inc. (HKEX:1672, "Ascletis") announces topline results of its Phase I single ascending dose (SAD) study in Australia in subjects with elevated low-density lipoprotein cholesterol (LDL-C) (NCT06427590) for its first-in-class, muscle-preserving weight loss drug candidate, ASC47 for the treatment of obesity. Phase I Clinical Data ASC47 demonstrated a half-life of 21 days in subjects with elevated LDL-C > 110 mg/dL (2.8 mmol/L) who received ultra-long acting, subcutaneously injected ASC47, supporting once-monthly administration in patients with obesity. Furthermore, ASC47 demonstrated target engagement with significant reductions of lipid biomarkers at day 29 after single subcutaneous (SQ) injections. The SAD study of ASC47 monotherapy in subjects with elevated LDL-C has five cohorts with subjects receiving 10 mg, 30 mg, 90 mg, 180 mg, 360 mg ASC47 or placebo via SQ injections. The subjects have multiple outpatient visits over eight weeks after the single SQ injections of ASC47 or placebo. Dosing of the first three cohorts (10 mg, 30 mg and 90 mg) has been completed where a total of 20 subjects with elevated LDL-C have received ASC47 or placebo. ASC47 demonstrated a favorable tolerability profile with no serious adverse events (SAEs) and no discontinuations due to adverse events (AEs). The majority of AEs were mild (grade 1). Only two subjects (2/20) reported mild injection site reactions (grade 1 only). No gastrointestinal and cardiac AEs were reported. No abnormal liver enzymes were reported. No clinically meaningful findings in laboratory tests, electrocardiograms, vital signs, or physical examinations were observed. Based on safety, pharmacokinetic and target engagement data of the SAD study of ASC47 monotherapy in subjects with elevated LDL-C, the second Phase I study (SAD study of ASC47 monotherapy in patients with obesity) has been initiated in Australia. Topline data are expected in the first quarter of 2025. ASC47 has two additional Phase I studies in Australia: multiple ascending dose (MAD) study of ASC47 monotherapy in patients with obesity, and MAD study of ASC47 in combination with tirzepatide or semaglutide in patients with obesity. Detailed clinical data from these trials are expected to be presented at medical conferences in 2025. Preclinical Efficacy Data ASC47 monotherapy demonstrated dose-dependent healthy weight loss (muscle-preserving weight loss) in two head-to-head diet-induced obese (DIO) mouse studies compared to semaglutide and tirzepatide. In both studies, ASC47 demonstrated clinically meaningful weight loss at low doses of 15 mg/kg and 45 mg/kg (once every two weeks or once weekly) via SQ injections. These doses in mice are predicted to translate into clinically applicable doses in humans. Compared to semaglutide (30 nmol/kg, once daily, SQ), a clinically relevant dose of ASC47 (45 mg/kg, once every two weeks, SQ) reduced total fat mass (-63.5%, p=0.007 vs semaglutide), statistically and significantly more than semaglutide (-39.6%) in a DIO mouse study (Table 1). ASC47 increased total muscle mass (+5.8%, p<0.0001 vs semaglutide) compared to a decline in total muscle mass of semaglutide (-9.3%) (Table 1). Total body weight reduction was similar between ASC47 (-24.6%) and semaglutide (-23.1%) (Table 1), even though caloric intake reduction in ASC47-treated DIO mice was significantly less than semaglutide-treated DIO mice. Table 1. ASC47 reduced more fat and increased muscle in a dose-dependent manner compared to semaglutide in a head-to-head DIO mouse study Note: Q2W: once every two weeks; SQ: subcutaneous; QD: once daily Compared to tirzepatide (3 nmol/kg, once daily, SQ), a clinically relevant dose of ASC47 (45 mg/kg, once weekly, SQ) reduced total fat mass (-68.0%, p=0.01 vs tirzepatide), statistically and significantly more than tirzepatide (-50.4%) in a DIO mouse study (Table 2). ASC47 increased total muscle mass (+8.1%, p=0.004 vs tirzepatide) compared to a decline in total muscle mass of tirzepatide (-3.8%) (Table 2). Total body weight reduction was similar between ASC47 (-23.6%) and tirzepatide (-22.4%) (Table 2), even though caloric intake reduction in ASC47-treated DIO mice was significantly less than tirzepatide-treated DIO mice. Table 2. ASC47 reduced more fat and increased muscle in a dose-dependent manner compared to tirzepatide in a head-to-head DIO mouse study Note: QW: once weekly; SQ: subcutaneous; QD: once daily ASC47 - Adipose-targeted THRβ Selective Agonist As a potential first-in-class muscle-preserving weight loss drug candidate, ASC47 is an adipose-targeted thyroid hormone receptor beta (THRβ) selective small molecule agonist. ASC47 is a new molecular entity (NME) discovered and developed in-house at Ascletis. ASC47 possesses unique and differentiated properties to enable adipose targeting, resulting in dose-dependent high drug concentrations in the adipose tissue. In DIO mice with SQ dosing of 15 mg/kg ASC47, once every two weeks, the drug concentration in the adipose tissue 14 days after the last dose was 7-fold of human efficacious drug concentration predicted by a preclinical model. Adipose tissue plays an important role in metabolic diseases including obesity[1]. Adipose-targeted delivery of ASC47 differentiates ASC47 from other THRβ selective agonists[2], which are primarily liver-targeted. Expression of THRβ is high in adipose tissue as well as in liver tissue[3]. As such, clinically meaningful weight loss requires high concentrations of THRβ selective agonists in adipose tissue. In recent years, a number of THRβ selective agonists showed success for treatment of metabolic dysfunction-associated steatohepatitis (MASH, a liver disease) through liver-targeted delivery. However, these THRβ agonists lack adipose-targeting properties. For example, there is significant high concentration of resmitirom in liver tissue but little or no resmitirom in adipose tissue[2]. ASC47 possesses both THRβ selectivity and adipose-targeted delivery. Targeted delivery of ASC47 to the adipose tissue enables the use of low and clinically applicable doses of ASC47 for the treatment of obesity. Mechanism s of Action of ASC47 One of the key mechanisms of action of ASC47 to reduce fat and achieve muscle-preserving weight loss is through uncoupling protein 1 (UCP-1)-mediated thermogenesis in the adipose tissue. In a head-to-head study in DIO mice, at clinically relevant doses of 15 mg/kg and 45 mg/kg ASC47 (SQ, once every two weeks), expression of UCP-1 in adipose tissue of ASC47-treated DIO mice was up to 4-fold of that of semaglutide-treated DIO mice. The levels of expression of UCP-1 in adipose tissues between semaglutide-treated and vehicle control treated DIO mice were essentially the same. This mechanism differentiates ASC47 from incretin-based drug candidates as well as other muscle-preserving drug candidates in preclinical and clinical development. The detailed mechanisms of action, preclinical efficacy and muscle preservation, and other preclinical data are expected to be presented at medical conferences in 2025. ASC47 Phase I Studies in Australia for the Treatment of Obesity SAD study of ASC47 monotherapy in subjects with elevated LDL-C: Study objectives include safety, tolerability, target engagement and pharmacokinetics in subjects with elevated LDL-C receiving SAD of ultra-long-acting ASC47 monotherapy via SQ injections. SAD study of ASC47 monotherapy in patients with obesity: Study objectives include safety, tolerability, pharmacokinetics and preliminary efficacy in patients with obesity (body mass index (BMI) 30-40) receiving SAD of ultra-long-acting ASC47 monotherapy via SQ injections. MAD study of ASC47 monotherapy in patients with obesity: Patients with obesity (BMI 30-40) receive MAD of ASC47 (a total of 3 doses), once every four weeks via SQ injections. Study objectives include safety, tolerability, pharmacokinetics and preliminary efficacy of ultra-long-acting ASC47 monotherapy. MAD study of ASC47 in combination with tirzepatide or semaglutide in patients with obesity: Patients with obesity (BMI 30-40) receive combination therapy of ASC47 with tirzepatide (or semaglutide) or tirzepatide (or semaglutide) monotherapy. SQ dosing frequency of ASC47 is once every four weeks with a total of 3 doses. SQ dosing frequency of tirzepatide (or semaglutide) is once a week with a total of 12 doses. Study objectives include safety, tolerability, pharmacokinetics and preliminary efficacy of combination therapy of ASC47 with tirzepatide (or semaglutide) versus tirzepatide (or semaglutide) monotherapy. References Gilani A, et al. Diabetes. 2024; 73(2), 169-177. Harrison SA, et al. Lancet 2019; 394: 2012–24. . About Ascletis Pharma Inc. Ascletis is an innovative R&D driven biotech listed on the Hong Kong Stock Exchange (1672.HK), covering the entire value chain from discovery and development to GMP manufacturing. Led by a management team with deep expertise and a proven track record, Ascletis has rapidly advanced its pipeline, focusing on two therapeutic areas with unmet medical needs from a global perspective: metabolic diseases and viral diseases. Ascletis has multiple clinical stage drug candidates in its R&D pipeline. For more information, please visit . Contact: Peter Vozzo ICR Healthcare 443-231-0505 (U.S.) [email protected] Ascletis Pharma Inc. PR and IR teams +86-181-0650-9129 (China) [email protected] [email protected] SOURCE Ascletis Pharma Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

TERN-501 significantly improved the efficacy of a GLP-1 receptor agonist by normalizing energy expenditure, resulting in greater weight loss, increased fat mass loss and relative preservation of lean massFOSTER CITY, Calif., June 21, 2024 (GLOBE NEWSWIRE) -- Terns Pharmaceuticals, Inc. (“Terns” or the “Company”) (Nasdaq: TERN), a clinical-stage biopharmaceutical company developing a portfolio of small-molecule product candidates to address serious diseases, including oncology and obesity, today announced that preclinical data supporting TERN-501, a highly selective thyroid hormone receptor beta (THR-β) receptor agonist, in combination with a GLP-1 receptor agonist for obesity will be highlighted in a poster presentation at the American Diabetes Association (ADA) 84th Scientific Sessions, taking place June 21 – 24, 2024 in Orlando, FL. “While GLP-1 receptor agonists facilitate weight loss by suppressing food intake, efficacy may be limited by metabolic adaptation, a counter regulatory process that lowers energy expenditure in response to weight loss. THR-β agonism, an orthogonal mechanism to GLP-1, appears to unlock additional efficacy of GLP-1 therapies by normalizing energy expenditure during weight loss, while preserving relative lean mass,” said Emil Kuriakose, M.D., chief medical officer at Terns. “These exciting results suggest that TERN-501 may be an ideal combination partner for injectable and oral GLP-1 agonists for use in obesity and other metabolic disorders by potentially offering broader metabolic benefits beyond additional weight loss.” The poster and viewing detail are listed below: Presentation Title: TERN-501 Enhances Weight Loss Efficacy of a GLP-1R Agonist in Obese Mice via Increased Fat Mass Loss without Additional Loss of Lean MassAbstract Number: 760Presentation Date and Time: Sunday, June 23, 2024 from 12:30 p.m. – 1:30 p.m. ETSession: Clinical Therapeutics—Incretin-Based TherapiesPresenter: Christopher Jones The presentation reports results from a preclinical study in mice fed a high fat diet for 24 weeks prior to study start. Obese mice were treated once daily with vehicle, TERN-501, semaglutide, TERN-501+semaglutide, or tirzepatide for six weeks. The combination of TERN-501+ semaglutide significantly enhanced weight loss compared to semaglutide alone. Additionally, the TERN-501+semaglutide combination showed proportionally greater loss of fat mass relative to lean mass compared to semaglutide alone, indicating improved quality of weight loss. The study also explored metabolic adaptation, a counter regulatory process that decreases energy expenditure and limits the magnitude and sustainability of weight loss. Mice treated with semaglutide and tirzepatide showed significant weight loss that was associated with decreases in energy expenditure. When TERN-501 was combined with semaglutide, weight loss-induced lowering of energy expenditure was prevented and increases in the thermogenesis marker, UCP-1, were observed in subcutaneous adipose tissue. TERN-501 has potential to attenuate metabolic adaptation and normalize energy expenditure, which may enhance the weight loss efficacy of GLP-1 therapies. The full poster is available on Terns’ scientific publications website. In addition, Terns announced that management will participate in a fireside chat at the Piper Sandler Virtual Obesity Day on June 26, 2024 at 12:30pm ET. The Piper Sandler event webcast link is available from Piper Sandler and will require registration. About TERN-501 TERN-501 is a THR-β agonist with high metabolic stability, enhanced liver distribution and greater selectivity for THR-β compared to other THR-β agonists in development. The Phase 2a DUET trial (NCT05415722) produced positive top-line data in August 2023; showing compelling MRI-PDFF reductions and best-in-class safety and tolerability profile with TERN-501 in MASH. Terns has deprioritized development for MASH given the current regulatory and clinical development requirements for the indication. Terns continues to evaluate opportunities for TERN-501, including in other metabolic diseases, with a focus towards combination regimens for obesity. About Terns Pharmaceuticals Terns Pharmaceuticals, Inc. is a clinical stage biopharmaceutical company developing a portfolio of small molecule product candidates to address serious diseases, including oncology and obesity. Terns’ pipeline contains three clinical stage development programs including an allosteric BCR-ABL inhibitor, a small molecule GLP-1 receptor agonist, a THR-β agonist, and a preclinical GIPR modulator discovery effort, prioritizing a GIPR antagonist nomination candidate. For more information, please visit: www.ternspharma.com. Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements about the Company within the meaning of the federal securities laws, including those related to expectations, timing and potential results of the clinical trials and other development activities of the Company and its partners; the potential indications to be targeted by the Company with its small molecule product candidates; the therapeutic potential of the Company’s small molecule product candidates, including when used in combination with another product or product candidate; the potential for the mechanisms of action of the Company’s product candidates to be therapeutic targets for their targeted indications; the potential utility and progress of the Company’s product candidates in their targeted indications, including the clinical utility of the data from and the endpoints used in the Company’s clinical trials; the Company’s clinical development plans and activities, the Company’s expectations regarding the profile of its product candidates, including efficacy, tolerability, safety, metabolic stability and pharmacokinetic profile and potential differentiation as compared to other products or product candidates; and the Company’s plans for and ability to continue to execute on its current development strategy, including potential combinations involving multiple product candidates. All statements other than statements of historical facts contained in this press release, including statements regarding the Company’s strategy, future financial condition, future operations, future trial results, projected costs, prospects, plans, objectives of management and expected market growth, are forward-looking statements. In some cases, you can identify forward-looking statements by terminology such as “aim,” “anticipate,” “assume,” “believe,” “contemplate,” “continue,” “could,” “design,” “due,” “estimate,” “expect,” “goal,” “intend,” “may,” “objective,” “plan,” “positioned,” “potential,” “predict,” “seek,” “should,” “target,” “will,” “would” and other similar expressions that are predictions of or indicate future events and future trends, or the negative of these terms or other comparable terminology. The Company has based these forward-looking statements largely on its current expectations, estimates, forecasts and projections about future events and financial trends that it believes may affect its financial condition, results of operations, business strategy and financial needs. In light of the significant uncertainties in these forward-looking statements, you should not rely upon forward-looking statements as predictions of future events. These statements are subject to risks and uncertainties that could cause the actual results and the implementation of the Company’s plans to vary materially, including the risks associated with the initiation, cost, timing, progress, results and utility of the Company’s current and future research and development activities and preclinical studies and clinical trials. These risks are not exhaustive. For a detailed discussion of the risk factors that could affect the Company’s actual results, please refer to the risk factors identified in the Company’s SEC reports, including but not limited to its Annual Report on Form 10-K for the year ended December 31, 2023. Except as required by law, the Company undertakes no obligation to update publicly any forward-looking statements for any reason. Contacts for Terns InvestorsJustin Nginvestors@ternspharma.com MediaJenna UrbanBerry & Company Public Relationsmedia@ternspharma.com

Turning down the thermostat seems to make it harder for cancer cells to grow, according to a new study in mice. The study found that chilly temperatures activate heat-producing brown fat that consumes the sugars the tumors need to thrive. Similar metabolic mechanisms were found in a cancer patient exposed to a lowered room temperature. Turning down the thermostat seems to make it harder for cancer cells to grow, according to a study in mice by researchers at Karolinska Institutet in Sweden. The study, published in the journal Nature, found that chilly temperatures activate heat-producing brown fat that consumes the sugars the tumors need to thrive. Similar metabolic mechanisms were found in a cancer patient exposed to a lowered room temperature. "We found that cold-activated brown adipose tissue competes against tumors for glucose and can help inhibit tumor growth in mice," says Professor Yihai Cao at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, and corresponding author. "Our findings suggest that cold exposure could be a promising novel approach to cancer therapy, although this needs to be validated in larger clinical studies." The study compared tumor growth and survival rates in mice with various types of cancer, including colorectal, breast and pancreatic cancers, when exposed to cold versus warm living conditions. Mice acclimatized to temperatures of 4 degrees Celsius had significantly slower tumor growth and lived nearly twice as long compared with mice in rooms of 30 degrees Celsius. To find out why that is, the researchers analyzed markers in the tissue to study cellular reactions and used imaging tests to examine glucose metabolism. Cancer cells typically need large amounts of glucose, or sugar, to grow. They found that cold temperatures triggered significant glucose uptake in brown adipose tissue, also known as brown fat, a type of fat that is responsible for keep the body warm during cold conditions. At the same time, the glucose signals were barely detectable in the tumor cells. When the researchers removed either the brown fat or a protein crucial for its metabolism called UCP1, the beneficial effect of the cold exposure was essentially wiped out and the tumors grew at a pace on par with those that were exposed to higher temperatures. Similarly, feeding tumor-bearing mice with a high sugar drink also obliterated the effect of cold temperatures and restored tumor growth. "Interestingly, high sugar drinks seem to cancel out the effect of cold temperatures on cancer cells, suggesting that limiting glucose supply is probably one of the most important methods for tumor suppression," Yihai Cao says. To study the human relevance of the findings, the researchers recruited six healthy volunteers and one patient with cancer undergoing chemotherapy. Using positron emission tomography (PET) scanning, the researchers identified a significant amount of brown fat activated in the neck, spine and chest area of healthy adults wearing shorts and T-shirts while being exposed to a slightly chilly room temperature of 16 degrees Celsius for up to six hours per day for two weeks. The patient with cancer wore light clothing while spending time in rooms of 22 degrees Celsius for a week and then in rooms of 28 degrees Celsius for four days. Prior research has shown that even though there are significant individual differences, 28 degrees Celsius is generally considered a comfortable environmental temperature (the thermoneutral temperature) for most inactive humans. The imaging scans picked up increased brown fat and lowered tumor glucose uptake during the lower versus the higher temperature. "These temperatures are considered tolerable by most people," Yihai Cao says. "We are therefore optimistic that cold therapy and activation of brown adipose tissue with other approaches such as drugs could represent another tool in the toolbox for treating cancer." The study was funded by the European Research Council, the Swedish Research Council, the Swedish Cancer Society, the Swedish Childhood Cancer Fund, the Strategic research area in stem cells and regenerative medicine at Karolinska Institutet, the Torsten Söderberg Foundation, the Maud and Birger Gustavsson Foundation, the Novo Nordisk Foundation and the Knut and Alice Wallenberg Foundation.