LIPG

According to information from the U.S. clinical trial registry Clinicaltrials on December 10, Chinese company Heng Rui Pharma has launched its first Phase III clinical trial (SHR-1918-301) for the ANGPTL3 monoclonal antibody SHR-1918. This drug marks the first domestic ANGPTL3 monoclonal antibody to enter the Phase III clinical trial stage. SHR-1918 is an ANGPTL3 monoclonal antibody developed by Heng Rui Pharma, which works by inhibiting ANGPTL3 activity to lower triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) levels in serum. LDL-C and TG are significant risk factors for the development of atherosclerotic cardiovascular diseases. ANGPTL3 plays a key role in lipid metabolism regulation by inhibiting lipoprotein lipase and endothelial lipase, thereby reducing the clearance of TG and LDL-C. In September this year, Heng Rui Pharma announced the results of its first Phase I study (SHR-1918-101) at the European Society of Cardiology (ESC) annual meeting. The study showed that SHR-1918 (100-1200mg, subcutaneously) demonstrated good tolerance and pharmacokinetic characteristics in healthy subjects, with a peak time of 8.0-10.0 days and a half-life of 29.4-53.5 days. Additionally, SHR-1918 effectively and durably reduced LDL-C and TG levels: patients receiving doses of SHR-1918 of 300mg or higher had LDL-C levels reduced by over 30% (up to 49.1%), lasting more than 64 days; TG levels were reduced by over 50% (up to 82.8%), lasting more than 85 days. Given the potential of SHR-1918 for treating rare dyslipidemia disorders, the drug received breakthrough therapy designation for homozygous familial hypercholesterolemia (HoFH) from the Chinese National Medical Products Administration (NMPA) in September. The launched Phase III study is a multicenter, randomized, double-blind, placebo-controlled clinical trial (n=45), aimed at evaluating the efficacy and safety of SHR-1918 in treating homozygous familial hypercholesterolemia (HoFH). The primary endpoint is the percentage change in LDL-C levels from baseline at week 12. Homozygous familial hypercholesterolemia (HoFH) is a rare and severe genetic disorder where patients accumulate LDL-C in the blood due to defects or deficiencies in low-density lipoprotein receptors (LDLR), increasing the risk of heart disease and stroke. Currently, available treatment options for these patients include statins (simvastatin, atorvastatin, and rosuvastatin), ezetimibe, lomitapide, mipomersen, PCSK9 monoclonal antibodies (evolocumab and alirocumab), and evinacumab. Among these, evinacumab (Regeneron/Ultragenyx) is the only marketed ANGPTL3 monoclonal antibody, with global sales of $80.9 million in 2023.

Zodasiran significantly reduced triglycerides and atherogenic triglyceride rich lipoproteins across all dose levels at Week 24 Data presented at European Atherosclerosis Society 92nd Congress and simultaneously published in the New England Journal of Medicine PASADENA, Calif.--(BUSINESS WIRE)-- Arrowhead Pharmaceuticals, Inc. (NASDAQ: ARWR) today announced results from the Phase 2b double blind, randomized ARCHES-2 study of investigational zodasiran (formerly ARO-ANG3) in patients with mixed hyperlipidemia. Zodasiran was associated with robust and durable reductions in triglycerides, triglyceride rich lipoprotein remnants, and total atherogenic lipoproteins, including LDL-C. These data were presented in a late-breaking oral presentation today at the European Atherosclerosis Society (EAS) 92nd Congress and simultaneously published in the New England Journal of Medicine. “Results from clinical studies of zodasiran, including those for the ARCHES-2 study in patients with mixed hyperlipidemia presented today at EAS and published in the New England Journal of Medicine, continue to support ANGPTL3 as an exciting target for an RNAi-based gene silencing strategy,” said Bruce Given, M.D., interim chief medical scientist at Arrowhead. “Genetic studies show that ANGPTL3 loss-of-function variants lead to enhanced lipoprotein lipase and endothelial lipase activity, resulting in lower concentrations of most plasma lipoproteins, including triglyceride rich lipoproteins, LDL-C, VLDL/remnant cholesterol, and HDL-C. Individuals with these variants also have demonstrated a markedly reduced risk of ASCVD and have no known adverse clinical phenotypes1-3.” Robert Rosenson, M.D., Icahn School of Medicine at Mount Sinai, and Principal Investigator for the ARCHES-2 study added, “The potent reductions in serum lipids and lipoproteins and favorable safety pro in the ARCHES-2 clinical study of zodasiran suggest its potential to treat residual ASCVD risk in patients with elevated triglyceride rich lipoproteins. The genetic data around ANGPTL3 as a target are very compelling and support further Phase 3 studies to determine whether the large reductions in triglyceride rich lipoproteins observed after zodasiran treatment can replicate the genetic data and reduce ASCVD risk.” Select ARCHES-2 Results Zodasiran treatment was associated with dose-dependent placebo adjusted reductions in triglycerides, remnant cholesterol, LDL-C, ApoB, and Non-HDL-C across all dose levels in patients with mixed hyperlipidemia. At week 24, representing trough effect, zodasiran treatment at 50, 100, and 200 mg on day 1 and week 12 was associated with placebo adjusted reductions in triglycerides of -51%, -57%, and -63% (all p<0.001) respectively. ANPTL3, the genetic target of zodasiran, was reduced compared with placebo by -54%, -70%, and -74%, and remnant cholesterol levels were reduced by -73%, -76%, and -82%, which strongly correlated with changes in triglyceride levels. Changes in other atherogenic lipoprotein parameters were also observed across all three dose levels. At week 24, the following placebo adjusted changes were observed for the 200 mg dose: LDL-C -20%, ApoB -22%; Non-HDL-C -36%. In a subset of patients with baseline liver fat fraction greater than 8%, dose-dependent liver fat reductions, measured by MRI-PDFF, were observed reaching -28% with the 200 mg dose compared with -2% with placebo. Safety and Tolerability Zodasiran demonstrated a favorable safety pro patients with mixed hyperlipidemia in the ARCHES-2 study. Treatment-emergent adverse events (TEAEs) were generally balanced between treatment and placebo groups and generally reflected the comorbidities and underlying conditions of the study population. There were no clinically meaningful changes in laboratory safety evaluations, no changes in mean platelet counts, and modest changes in HbA1c. Details about the EAS presentation is listed below. European Atherosclerosis Society (EAS) 92nd Congress – May 26-29, 2024 Title: ZODASIRAN SILENCES HEPATIC ANGPTL3 LEADING TO DEEP AND DURABLE REDUCTIONS IN ATHEROGENIC LIPIDS AND LIPOPROTEINS IN MIXED DYSLIPIDEMIA PATIENTS: FINAL RESULTS FROM ARCHES-2, DOUBLE-BLIND PERIOD Date/Time: May 29, 2024, 11:30 a.m. CEST Presenter: Robert Rosenson, M.D. Session: Late Breaker Session 2: New Therapeutic Agents Presentation materials may be accessed on the Events and Presentations page under the Investors section of the Arrowhead website after the presentation concludes. About ARCHES-2 ARCHES-2 (NCT04832971) is a double-blind, placebo-controlled dose-ranging Phase 2b clinical study of zodasiran in 204 participants with mixed hyperlipidemia. Participants with fasting triglycerides between 150-499 mg/dL and either LDL-cholesterol greater than 70 mg/dL or non-HDL-cholesterol greater 100 mg/dL were randomly assigned in a 3:1 ratio to receive subcutaneous injections of 50, 100, or 200 mg zodasiran or placebo on day 1 and week 12 and followed through week 36. The primary objective of the study was to evaluate the safety and efficacy of plozasiran in adults with mixed hyperlipidemia. About Mixed Hyperlipidemia Mixed hyperlipidemia, also called mixed dyslipidemia, is a highly prevalent disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) and triglyceride levels. Despite the efficacy of LDL-C-lowering therapies in reducing atherosclerotic cardiovascular disease (ASCVD) risk in mixed hyperlipidemia, there remains substantial residual risk attributed to elevated non-HDL driven by remnant cholesterol in triglyceride-rich lipoproteins4-7h. Genome-wide association and Mendelian randomization studies also support a causal role for triglyceride rich lipoproteins in ASCVD8-11. About Zodasiran Zodasiran, previously called ARO-ANG33, is a first-in-class investigational RNA interference (RNAi) therapeutic designed to reduce production of angiopoietin-like protein (ANGPTL3), which is a hepatocyte expressed regulator of lipid and lipoprotein metabolism with multiple potential modes of action, including inhibition of lipoprotein lipase (LPL) and endothelial lipase (EL)12,13. Genetic studies suggest that individuals with ANGPTL3 loss-of-function variants have enhanced lipoprotein lipase and endothelial lipase activity, resulting in lower levels atherogenic lipoproteins and a reduced risk of ASCVD1-3. In clinical studies, investigational zodasiran demonstrated a favorable safety pro was associated with dose-dependent reductions in triglycerides, triglyceride rich lipoprotein remnants, and total atherogenic lipoproteins, including LDL-C, in patients with homozygous and heterozygous familial cholesterolemia (HoFH) and mixed hyperlipidemia. About Arrowhead Pharmaceuticals Arrowhead Pharmaceuticals develops medicines that treat intractable diseases by silencing the genes that cause them. Using a broad portfolio of RNA chemistries and efficient modes of delivery, Arrowhead therapies trigger the RNA interference mechanism to induce rapid, deep, and durable knockdown of target genes. RNA interference, or RNAi, is a mechanism present in living cells that inhibits the expression of a specific gene, thereby affecting the production of a specific protein. Arrowhead’s RNAi-based therapeutics leverage this natural pathway of gene silencing. For more information, please visit , or follow us on X (formerly Twitter) at @ArrowheadPharma or on LinkedIn. To be added to the Company's email list and receive news directly, please visit . Safe Harbor Statement under the Private Securities Litigation Reform Act: This news release contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. Any statements contained in this release except for historical information may be deemed to be forward-looking statements. Without limiting the generality of the foregoing, words such as “may,” “will,” “expect,” “believe,” “anticipate,” “hope,” “intend,” “plan,” “project,” “could,” “estimate,” “continue,” “target,” “forecast” or “continue” or the negative of these words or other variations thereof or comparable terminology are intended to identify such forward-looking statements. In addition, any statements that refer to projections of our future financial performance, trends in our business, expectations for our product pipeline or product candidates, including anticipated regulatory submissions and clinical program results, prospects or benefits of our collaborations with other companies, or other characterizations of future events or circumstances are forward-looking statements. These forward-looking statements include, but are not limited to, statements about the initiation, timing, progress and results of our preclinical studies and clinical trials, and our research and development programs; our expectations regarding the potential benefits of the partnership, licensing and/or collaboration arrangements and other strategic arrangements and transactions we have entered into or may enter into in the future; our beliefs and expectations regarding milestone, royalty or other payments that could be due to or from third parties under existing agreements; and our estimates regarding future revenues, research and development expenses, capital requirements and payments to third parties. These statements are based upon our current expectations and speak only as of the date hereof. Our actual results may differ materially and adversely from those expressed in any forward-looking statements as a result of numerous factors and uncertainties, including the impact of the ongoing COVID-19 pandemic on our business, the safety and efficacy of our product candidates, decisions of regulatory authorities and the timing thereof, the duration and impact of regulatory delays in our clinical programs, our ability to finance our operations, the likelihood and timing of the receipt of future milestone and licensing fees, the future success of our scientific studies, our ability to successfully develop and commercialize drug candidates, the timing for starting and completing clinical trials, rapid technological change in our markets, the enforcement of our intellectual property rights, and the other risks and uncertainties described in our most recent Annual Report on Form 10-K, subsequent Quarterly Reports on Form 10-Q and other documents filed with the Securities and Exchange Commission from time to time. We assume no obligation to update or revise forward-looking statements to reflect new events or circumstances. Source: Arrowhead Pharmaceuticals, Inc. ________________ 1. Dewey, et al. N Engl J Med. 2017;377 (3):211-21. 2. Minicocci, et al. J Lipid Res. 2013;54(12): 3481-90 3. Musunuru, et al. N Engl J Med. 2010; 363(23):2220-7 4. Gugliucci A. J Clin Med. 2023;12:4399. 5. Silverman MG, et al. JAMA. 2016;316(12):1289-1297 6. Langsted A, et al. J Int Med. 2020;288:116–127. 7. Fu L, et al. Diabetes Care. 2022;45(9):2136-2143. 8. Bjornson E, et al. Eur Heart J. 2023;44:4186-4195 9. Nordestgaard BG. Circ Res. 2016;118:547-563. 10. Virani SS, et al. J Am Coll Cardiol. 2021;78(9):960-993 11. Hussain A, et al. Curr Atheroscler Rep. 2020;22:25. 12. Adam, et al. J Lipid Res. 2020;61(9): 1271-86. 13. Rosenson. J Lipid Res. 2021:62:100060. View source version on businesswire.com: Contacts Arrowhead Pharmaceuticals, Inc. Vince Anzalone, CFA 626-304-3400 ir@arrowheadpharma.com Investors: LifeSci Advisors, LLC Brian Ritchie 212-915-2578 britchie@lifesciadvisors.com Media: LifeSci Communications, LLC Kendy Guarinoni, Ph.D. 724-910-9389 kguarinoni@lifescicomms.com Source: Arrowhead Pharmaceuticals, Inc. View this news release online at:

- 44-48% Mean Reductions in LDL-C Achieved on Top of Continued Standard of Care - Phase 3 Planning is Ongoing PASADENA, Calif.--(BUSINESS WIRE)-- Arrowhead Pharmaceuticals, Inc. (NASDAQ: ARWR) today presented interim data from the ongoing Phase 2 GATEWAY clinical study of ARO-ANG3, the company’s investigational RNAi therapeutic designed to reduce expression of angiopoietin-like protein 3 (ANGPTL3), in patients with homozygous familial hypercholesterolemia (HoFH). The company is currently planning a Phase 3 study to further investigate ARO-ANG3 and intends to conduct a meeting with regulatory authorities in the second half of 2023 to discuss the proposed study design. The data were presented at the 91st European Atherosclerosis Society Congress in a poster titled, “ARO-ANG3, an Investigational RNAi Therapeutic, Decreases Serum LDL-Cholesterol, Apolipoprotein B, and Angiopoietin-like Protein 3 in Patients with Homozygous Familial Hypercholesterolaemia,” which may be accessed on the Events and Presentations page under the Investors section of the Arrowhead website. Javier San Martin, M.D., chief medical officer at Arrowhead, said: “Despite advances in the treatment of cardiovascular disease associated with high LDL-cholesterol, patients with HoFH have a particularly high need for additional therapy with a mechanism working outside of the LDL receptor, such as ANGPTL3 inhibition, and with a dose regimen which can help improve adherence and compliance. The data generated in the GATEWAY study of ARO-ANG3 in patients with HoFH and our prior clinical studies in patient populations with different levels and cause of hypercholesterolemia, demonstrate that ANGPTL3 inhibition led to substantial reductions in LDL-cholesterol, Non-HDL-C, triglycerides, ApoB, and other key lipids and atherogenic lipoproteins. These results are very encouraging and support our plan to rapidly advance ARO-ANG3 into a Phase 3 clinical study in patients with HoFH.” Key findings from the GATEWAY study include the following: At study week 20, administration of 200 mg or 300 mg ARO-ANG3 on day 1 and day 84 led to the following changes: Mean reductions in LDL-C (Martin-Hopkins) of 48.1% and 44.0%, respectively These reductions were achieved on top of continued standard of care, including statins, ezetimibe, PCSK9 inhibitors, and apheresis Mean reductions in ApoB of 39.2% and 34.5%, respectively Mean reductions in ANGPTL3 of 82.7% and 80.1%, respectively ANPTL3 inhibition with ARO-ANG3 also reduced HDL-C, non-HDL-C, and triglycerides, consistent with published human genetic data Safety and tolerability Overall, no newly identified patterns of adverse events in HoFH patients No treatment emergent adverse events leading to drug discontinuation, dose interruptions, or study withdrawal One serious adverse event of second degree atrioventricular block reported in a patient with extensive atherosclerotic cardiovascular disease history, considered not related to ARO-ANG3 About Homozygous Familial Hypercholesterolemia Homozygous familial hypercholesterolemia (HoFH) is the most serious and rare form of familial hypercholesterolemia, which if left untreated leads to early clinical manifestations of coronary artery disease. Most cases of HoFH are due to mutations in the low-density lipoprotein receptor (LDLR) gene coding for the LDL receptor. Thus, patients with HoFH due to dysfunctional or absent LDLR can be resistant to standards of care such as statins and even resistant to alternatives such as PCSK9 inhibitors. Patients with HoFH are therefore a population with a particularly high need for additional therapy with a mechanism working outside of the LDL receptor, such as therapeutic ANGPTL3 inhibition. About the GATEWAY Phase 2 Study The AROANG3-2003 GATEWAY study (NCT05217667) is a Phase 2 open-label study to evaluate the efficacy, safety, and tolerability of 200 mg and 300 mg of ARO-ANG3 administered once every 12 weeks in 18 patients with HoFH. The initial treatment period is up to 36 weeks with an optional 24-month extension treatment period. The primary endpoint of the study is the percent change from baseline in LDL-cholesterol. About ARO-ANG3 ARO-ANG3 is an investigational RNAi therapeutic designed to reduce expression of angiopoietin-like protein 3 (ANGPTL3), a hepatocyte expressed regulator of lipid and lipoprotein metabolism with multiple potential modes of action, including inhibition of lipoprotein lipase and endothelial lipase. Given the inhibitory role of ANGPTL3 in the metabolism of various lipoproteins and triglycerides, reduced expression and reduced circulating levels of ANGPTL3 may increase clearance of LDL-cholesterol, HDL-cholesterol, and triglycerides. About Arrowhead Pharmaceuticals Arrowhead Pharmaceuticals develops medicines that treat intractable diseases by silencing the genes that cause them. Using a broad portfolio of RNA chemistries and efficient modes of delivery, Arrowhead therapies trigger the RNA interference mechanism to induce rapid, deep, and durable knockdown of target genes. RNA interference, or RNAi, is a mechanism present in living cells that inhibits the expression of a specific gene, thereby affecting the production of a specific protein. Arrowhead’s RNAi-based therapeutics leverage this natural pathway of gene silencing. For more information, please visit , or follow us on Twitter @ArrowheadPharma. To be added to the Company's email list and receive news directly, please visit . Safe Harbor Statement under the Private Securities Litigation Reform Act: This news release contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. Any statements contained in this release except for historical information may be deemed to be forward-looking statements. Without limiting the generality of the foregoing, words such as “may,” “will,” “expect,” “believe,” “anticipate,” “hope,” “intend,” “plan,” “project,” “could,” “estimate,” “continue,” “target,” “forecast” or “continue” or the negative of these words or other variations thereof or comparable terminology are intended to identify such forward-looking statements. In addition, any statements that refer to projections of our future financial performance, trends in our business, expectations for our product pipeline or product candidates, including anticipated regulatory submissions and clinical program results, prospects, or benefits of our collaborations with other companies, or other characterizations of future events or circumstances are forward-looking statements. These forward-looking statements include, but are not limited to, statements about the initiation, timing, progress and results of our preclinical studies and clinical trials, and our research and development programs; our expectations regarding the potential benefits of the partnership, licensing and/or collaboration arrangements and other strategic arrangements and transactions we have entered into or may enter into in the future; our beliefs and expectations regarding milestone, royalty or other payments that could be due to or from third parties under existing agreements; and our estimates regarding future revenues, research and development expenses, capital requirements and payments to third parties. These statements are based upon our current expectations and speak only as of the date hereof. Our actual results may differ materially and adversely from those expressed in any forward-looking statements as a result of numerous factors and uncertainties, including the impact of the ongoing COVID-19 pandemic on our business, the safety and efficacy of our product candidates, decisions of regulatory authorities and the timing thereof, the duration and impact of regulatory delays in our clinical programs, our ability to finance our operations, the likelihood and timing of the receipt of future milestone and licensing fees, the future success of our scientific studies, our ability to successfully develop and commercialize drug candidates, the timing for starting and completing clinical trials, rapid technological change in our markets, the enforcement of our intellectual property rights, and the other risks and uncertainties described in our most recent Annual Report on Form 10-K, subsequent Quarterly Reports on Form 10-Q and other documents filed with the Securities and Exchange Commission from time to time. We assume no obligation to update or revise forward-looking statements to reflect new events or circumstances. Source: Arrowhead Pharmaceuticals, Inc.