Arrowhead has established a robust and versatile drug discovery and development platform based on proprietary technologies, broad licenses to fundamental intellectual property and extensive scientific expertise after more than a decade working on RNAi-based therapies. This platform enables the company to develop effective new therapies rapidly, cost effectively and potentially with lower risk relative to traditional approaches.
One of the most important recent advances in biology, the discovery of RNA interference, or RNAi, led to a Nobel Prize in 2006. RNAi refers to a natural cellular mechanism whereby short oligonucleotide molecules called RNAi triggers silence gene expression and regulate the production of proteins. Arrowhead’s RNAi-based therapeutics leverage this natural pathway of gene silencing to target and shut down specific genes that cause disease. This mechanism offers many potential advantages in the development of disease therapies, including the ability to target a broad range of genes and proteins with high specificity, and also target disease pathways that have proven difficult to address with traditional small molecule and biologic therapeutics.
This figure depicts the mechanism by which gene silencing occurs. Double stranded RNAi triggers are introduced into a cell and get loaded into the RNA-induced silencing complex, or RISC. The strands are separated leaving an active RISC/RNAi trigger complex. This complex can then pair with and degrade the complementary messenger RNAs, or mRNA, and stop the production of the target proteins. RNAi is a catalytic process, so each RNAi trigger can degrade mRNA hundreds of times, which results in a relatively long duration of effect for RNAi therapeutics.
Targeted RNAi Molecule (TRiMTM) Platform
Arrowhead’s Targeted RNAi Molecule, or TRiMTM, platform utilizes ligand-mediated delivery and is designed to enable tissue-specific targeting while being structurally simple. Targeting has been core to Arrowhead’s development philosophy and the TRiMTM platform builds on more than a decade of work on actively targeted drug delivery vehicles. Arrowhead scientists have discovered ways to progressively “TRiM” away extraneous features and chemistries and retain optimal pharmacologic activity.
The TRiMTM platform comprises a highly potent RNA trigger with the following components optimized, as needed, for each drug candidate: a high affinity targeting ligand; various linker and chemistries; structures that enhance pharmacokinetics; and highly potent RNAi triggers with sequence specific stabilization chemistries.
Therapeutics developed with the TRiMTM platform offer several advantages: simplified manufacturing and reduced costs; multiple routes of administration; potential for improved safety because there are less metabolites from smaller molecules, thereby reducing the risk of intracellular buildup.
At Arrowhead, we also believe that for RNAi to reach its true potential, it must target organs outside the liver. Arrowhead is leading this expansion with the TRiMTM platform that holds the promise of reaching multiple tissues, including liver, lung, and tumor.
The structure and chemistries of the oligonucleotide molecules used to trigger the RNAi mechanism can be tailored for optimal activity. Arrowhead’s broad portfolio of RNA trigger structures and chemistries, including some proprietary structures, enable the company to optimize each drug candidate on a target-by-target basis and utilize the combination of structure and chemical modifications that yield the most potent RNAi trigger.
As a component of the TRiM platform, Arrowhead’s design philosophy on RNA chemical modifications is to start with a structurally simple molecule and only add selective modification and stabilization chemistries as necessary to achieve the desired level of target knockdown and duration of effect. The conceptual framework for the stabilization strategy starts with a more sophisticated RNAi trigger screening and selection process that identifies potent sequences rapidly in locations that others may miss. We pursue chemical stabilization strategies with a target duration of effect of 30-90 days, and typically limit the use of strategies that produce longer activity because we anticipate that such strategies will increase long-term safety risks.
Our intellectual property portfolio provides broad freedom to apply multiple RNAi delivery technologies, chemistries, structures and manufacturing techniques in the development of novel therapeutics. Access to a broad range of technologies allows us to choose the best approach for a wide range of gene targets and disease indications.
Thomas N. Kakuda, PharmD1 , Atef Halabi, MD, PhD2, Gernot Klein, MD3, Madhu Sanga, PhD1, Carine Guinard-Azadian, MD4, Monika Kowalik, MD5, Katja Nedoschinsky4, Julius Nangosyah, MS4, Emmanuel Njumbe Ediage, PharmD4, Vera Hillewaert, MS4, Peter Verboven, BS4, Ivo Goris4, Jan Snoeys, PhD4, Martyn Palmer, MBA5, and Michael Biermer, MD4, Pharmacokinetics of JNJ-73763989 and JNJ-56136379 (Bersacapavir) in Participants With Moderate Hepatic Impairment, Clin Pharmacol. 2023 Feb 14
Haiyan Li, Xiaoye Niu, Yu Zhang, Danning Zhang, Yanqing Zhang, Liqun Wang, Yongqing Miao, Yanxin Jiang,Jia Ji, Qiaoqiao Chen, Xiaoyun Wu, Emmanuel Njumbe Ediage, Thomas N. Kakuda, and Michael Biermer, Pharmacokinetics, Safety, and Tolerability of the siRNA JNJ-73763989 in Healthy Chinese Adult Participants, Clinical Pharmacology in Drug Development 2023, 12(2) 175–180
Mak, Lung-Yi, Gane, E., Schwabe, C., Yoon, K., Heo, J., Scott, R., Lee, J., Kweon, Y., Weltman, M., Harrison, S., Neuschwander-Tetri, B., Cusi, K., Loomba, R., Given, B., Christianson, D., Garcia-Medel, E., Yi, M., Hamilton, J., Yuen, M., A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis, Journal of Hepatology (2023), VOLUME 78, ISSUE 4, P684-692.
Full Text: https://www.journal-of-hepatology.eu/article/S0168-8278(22)03320-7/fulltext
Ed Gane, Man-Fung Yuen, Thomas N Kakuda, Tetsuro Ogawa, Yasushi Takahashi, Nele Goeyvaerts, Isabelle Lonjon-Domanec, Tamisha Vaughan, Thomas Schluep, James Hamilton, Emmanuel Njumbe Ediage, Vera Hillewaert, Jan Snoeys, Oliver Lenz, Willem Talloen, Michael Biermer, JNJ-73763989 pharmacokinetics and safety: Liver-targeted siRNAs against hepatitis B virus, in Japanese and non-Japanese healthy adults, and combined with JNJ-56136379 and a nucleos(t)ide analogue in patients with chronic hepatitis B Antivir Ther. 2022 Jun;27(3)
Yuanqing Ma, Allison Joyce, Olivia Brandenburg, Faeze Saatchi, Christina Stevens, Vanina Toffessi Tcheuyap, Alana Christie, Quyen N. Do, Oluwatomilade Fatunde, Alyssa Macchiaroli, So C. Wong, Layton Woolford, Qurratulain Yousuf, Jeffrey Miyata, Deyssy Carrillo, Oreoluwa Onabolu, Tiffani McKenzie, Akhilesh Mishra, Tanner Hardy, Wei He, Daniel Li, Alexander Ivanishev, Qing Zhang, Ivan Pedrosa, Payal Kapur, Thomas Schluep, Steven B. Kanner, James Hamilton, and James Brugarolas, HIF2 Inactivation and Tumor Suppression with a Tumor-Directed RNA-Silencing Drug in Mice and Humans
Michael J. Koren, Patrick Maurice Moriarty, Seth J. Baum, Joel Neutel, Martha Hernandez-Illas, Howard S. Weintraub, Monica Florio, Helina Kassahun, Stacey Melquist, Tracy Varrieur, Saptarsi M. Haldar, Winnie Sohn, Huei Wang, Mary Elliott-Davey, Brooke M. Rock, Tao Pei, Oliver Homann, Jennifer Hellawell & Gerald F. Watts, Preclinical development and phase 1 trial of a novel siRNA targeting lipoprotein(a), Nature Medicine volume 28, 96-103 (2022)
Lung-Yi Mak, Ed Gane, Christian Schwabe, Ki Tae Yoon, Jeong Heo, Russell Scott, Jeong-Hoon Lee, Jung Il Lee, Young Oh Kweon, Martin Weltman, Stephen A. Harrison, Brent A. Neuschwander-Tetri, Kenneth Cusi, Rohit Loomba, Bruce D. Given, Dawn R. Christianson, Eric Garcia-Medel, Min Yi, James Hamilton, Man-Fung Yuen, A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis, J Hepatol. 2023 Apr;78(4):684-692
Michelle L. O’Donoghue, MD, MPH, J. Antonio G. López, MD , Beat Knusel, PhD, Baris Gencer, MD, Huei Wang, PhD, You Wu, PhD b , Helina Kassahun, MD, and Marc S. Sabatine, MD, MPH, Study design and rationale for the Olpasiran trials of Cardiovascular Events And lipoproteiN(a) reduction-DOSE ﬁnding study (OCEAN(a)-DOSE), American Heart Journal, Volume 251, September 2022, Pages 61-69.
Michelle L O’Donoghue, Robert S Rosenson, Baris Gencer, J Antonio G López, Norman E Lepor, Seth J Baum, Elmer Stout, Daniel Gaudet, Beat Knusel, Julia F Kuder, Xinhui Ran, Sabina A Murphy, Huei Wang, You Wu, Helina Kassahun, Marc S Sabatine; OCEAN(a)-DOSE Trial Investigators, Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease, N Engl J Med. 2022 Nov 17;387(20):1855-1864
Louis Sandra, Huybrecht T’jollyn, Nele Goeyvaerts, An Vermeulen, Anne-Ga€elle Dosne,
and Juan-Jose Perez-Ruixo, Plasma and Liver Pharmacokinetics of the N-Acetylgalactosamine Short Interfering RNA JNJ-73763989 in Recombinant Adeno-Associated–Hepatitis B Virus–Infected Mice, J Pharmacol Exp Ther. 2022 Oct;383(1):70-79
Winnie Sohn, PhD; Peter Winkle, MD; Joel Neutel, MD ; You Wu, PhD; Freeman Jabari; Caitlin Terrio, MSHS ; Tracy Varrieur, BSN ; Jingying Wang, PhD; and Jennifer Hellawell, MD, Pharmacokinetics, Pharmacodynamics, and Tolerability of Olpasiran in Healthy Japanese and Non-Japanese Participants: Results from a Phase I, Single-dose, Open-label Study, Clin Ther. 2022 Sep;44(9):1237-1247
Man-Fung Yuen, Danny Ka-Ho Wong, Thomas Schluep, Ching-Lung Lai, Carlo Ferrari, Stephen Locarnini, Regina Cheuk-Lam Lo, Robert G Gish, James Hamilton, Christine I Wooddell, Lung Yi Mak, Bruce D Given, Long-term serological, virological and histological responses to RNA inhibition by ARC-520 in Chinese chronic hepatitis B patients on entecavir treatment, Gut. 2022 Apr;71(4):789-797.
Man-Fung Yuen, Stephen Locarnini, Tien Huey Lim, Simone I Strasser, William Sievert, Wendy Cheng, Alex J Thompson, Bruce D Given, Thomas Schluep, James Hamilton, Michael Biermer, Ronald Kalmeijer, Maria Beumont, Oliver Lenz, Filip De Ridder, Gavin Cloherty, Danny Ka-Ho Wong, Christian Schwabe, Kathy Jackson, Ching Lung Lai, Robert G Gish, Edward Gane, Combination treatments including the small-interfering RNA JNJ-3989 induce rapid and sometimes prolonged viral responses in patients with CHB, J Hepatol. 2022 Nov;77(5):1287-1298
Pavel Strnad, M.D., Mattias Mandorfer, M.D., Ph.D., Gourab Choudhury, M.D., William Griffiths, M.D., Christian Trautwein, M.D., Rohit Loomba, M.D., Thomas Schluep, Sc.D., Ting Chang, Ph.D., Min Yi, Ph.D., Bruce D. Given, M.D., James C. Hamilton, M.D., Javier San Martin, M.D., et al., Fazirsiran for Liver Disease Associated with Alpha1-Antitrypsin Deficiency, N Engl J Med 2022; 387:514-524
Christine I. Wooddell, , Adam J. Gehring, Man-Fung Yuen and Bruce D. Given, RNA Interference Therapy for Chronic Hepatitis B Predicts the Importance of Addressing Viral Integration When Developing Novel Cure Strategies, Viruses. 2021 Mar 30;13(4):581
Andrew A Butler, James L Graham, Kimber L Stanhope, So Wong, Sarah King, Andrew A Bremer, Ronald M Krauss, James Hamilton, Peter J Havel, Role of angiopoietin-like protein 3 in sugar-induced dyslipidemia in rhesus macaques: suppression by fish oil or RNAi, J Lipid Res. 2020 Mar;61(3):376-386.
Christine I. Wooddell, Keith Blomenkamp, Ryan M. Peterson, Vladimir M. Subbotin, Christian Schwabe, James Hamilton, Qili Chu, Dawn R. Christianson, Julia O. Hegge, John Kolbe, Holly L. Hamilton, Maria F. Branca-Afrazi, Bruce D. Given, David L. Lewis, Edward Gane, Steven B. Kanner, and Jeffrey H. Teckman, Development of an RNAi therapeutic for alpha-1-antitrypsin liver disease, JCI Insight. 2020 Jun 18;5(12):e135348
Man-Fung Yuen, Ingolf Schiefke, Jung-Hwan Yoon, Sang Hoon Ahn, Jeong Heo, Ju Hyun Kim, Henry Lik Yuen Chan, Ki Tae Yoon, Hartwig Klinker, Michael Manns, Joerg Petersen, Thomas Schluep, James Hamilton, Bruce D Given, Carlo Ferrari, Ching-Lung Lai, Stephen A Locarnini, Robert G Gish, RNA Interference Therapy With ARC-520 Results in Prolonged Hepatitis B Surface Antigen Response in Patients With Chronic Hepatitis B Infection, Hepatology. 2020 Jul;72(1):19-31
Andrew A Butler, Candice A Price, James L Graham, Kimber L Stanhope, Sarah King, Yu-Han Hung, Praveen Sethupathy, So Wong, James Hamilton, Ronald M Krauss, Andrew A Bremer, Peter J Havel, Fructose-induced hypertriglyceridemia in rhesus macaques is attenuated with fish oil or ApoC3 RNA interference, J Lipid Res. 2019 Apr;60(4):805-818
Alice M Turner, Jan Stolk, Robert Bals, Jason D Lickliter, James Hamilton, Dawn R Christianson, Bruce D Given, Jonathan G Burdon, Rohit Loomba, James K Stoller, Jeffery H Teckman, Hepatic-targeted RNA interference provides robust and persistent knockdown of alpha-1 antitrypsin levels in ZZ patients, J Hepatol. 2018 Aug;69(2):378-384
So C. Wong; Weijun Cheng; Holly Hamilton; Anthony L. Nicholas; Darren H. Wakefield; Aaron Almeida; Andrei V. Blokhin; Jeffrey Carlson; Zane C. Neal; Vladimir Subbotin; Guofeng Zhang; Julia Hegge; Stephanie Bertin; Vladimir S. Trubetskoy; David B. Rozema; David L. Lewis; Steven B. Kanner, HIF2α-Targeted RNAi Therapeutic Inhibits Clear Cell Renal Cell Carcinoma, Mol Cancer Ther (2018) 17 (1): 140–149
Wooddell CI, Yuen MF, Chan HL, Gish RG, Locarnini SA, Chavez D, Ferrari C, Given BD, Hamilton J, Kanner SB, Lai CL, Lau JYN, Schluep T, Xu Z, Lanford RE, and Lewis DL, RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg. Science Translational Medicine (2017 Sep 27), 9(409), eaan0241.
Full Text: http://stm.sciencemag.org/cgi/content/full/9/409/eaan0241?ijkey=ezDm7U1JaZbC6&keytype=ref&siteid=scitransmed
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