Maximizing Molecules and Medicines
From the discovery of new molecules to lifecycle management of our approved medicines, Horizon scientists and technical experts are actively and compassionately exploring potential new treatments for patients with rare, autoimmune and severe inflammatory diseases.
Our philosophy is to follow what the data tell us. We evaluate avenues to maximize each molecule’s scientific potential and the profound impact it could have on a patient’s life. This has resulted in a curated pipeline of targeted experimental medicines and novel mechanisms of action.
Watch to learn more about the Horizon research and development (R&D) team’s practical and creative approach to thinking differently about science:
Creative Approaches to Experimental Medicines
In this section, we explore how our scientists and technical experts are investigating targeted therapies to treat a variety of diseases. First, we explain the origination and development of different diseases in the body. Then, we dive into the experimental medicines our team has developed as a potential solution. Take a look:
Lysophosphatidic acid (LPA) is a bioactive molecule that works through several receptors (LPAR) on a human cell. Dysregulated signaling via LPAR1 can cause leaky blood vessels, inflammation and fibrosis, leading to diseases such as idiopathic pulmonary fibrosis (IPF) and diffuse cutaneous systemic sclerosis (dcSSc).
As a potential solution, HZN-825 is a molecule that blocks one of the receptors, LPAR1, and has been shown to reduce collagen deposition, fibrosis and the molecules involved in signaling to immune cells, preventing and potentially reversing the disease processes.
Plasmacytoid dendritic cells (pDCs) are present in high numbers in tissue and constantly activated in certain autoimmune diseases, which causes them to secrete large amounts of inflammatory molecules, especially Type 1 Interferons. This can lead to a variety of autoimmune conditions.
As a potential solution, daxdilimab (HZN-7734) is an anti-ILT7 human monoclonal antibody that has been shown to deplete plasmacytoid dendritic cells (pDCs) and reduce levels of these cells and Type 1 Interferons. Depleting these cells may interrupt the cycle of inflammation that causes tissue damage in diseases such as lupus, alopecia areata, discoid lupus erythematosus, dermatomyositis and lupus nephritis.
CD40 is a well-established receptor pathway that contributes to autoimmune and inflammatory disease when it binds to the CD40 ligand (CD40L) causing B cell and T cell interaction that creates inflammation and disease.
As a potential solution, dazodalibep (HZN-4920) is a novel, non-antibody fusion protein that blocks CD40L activity, that has been shown to reduce B cell activation and autoantibody production, potentially halting inflammation and autoimmunity and diseases such as Sjögren’s syndrome, rheumatoid arthritis, kidney transplant rejection and focal segmental glomerulosclerosis.
Our scientific teams are exploring ways to bring novel small molecules, first-in-class biologics and new medicine administration options to patients.
Discovery Efforts to Target Uncontrolled Gout
Horizon is bringing its knowledge of uncontrolled gout into the lab to build a portfolio of new approaches to targeting this disease’s underlying causes and improve existing therapies.
People Behind the Science
Our work at Horizon is personal. Our R&D team is fueled by more than 200 scientific minds across the company.
Saba Sile, M.D., the clinical development lead for our medicine for Thyroid Eye Disease (TED), is dedicated to creating healthy communities through medicine development, patient engagement and empowerment. She has spent a decade in the biopharmaceutical industry leading clinical trial development across multiple indications with a special focus on rare disease. Sile’s drive to succeed comes from her desire to help people who lack adequate treatment options. “It has been well documented that certain medications—most likely due to genetic variations—metabolize differently in different populations. This is one of the reasons why diversity in clinical trials is extremely important,” Sile said.
Sile plays a pivotal role in the design and execution of important clinical trials at Horizon. “I’ve become intrigued by the racial differences in TED, and my team examined the discrepancy in the literature to understand whether there is some factor that protects Black patients with Graves’ disease from progressing to TED, or if the condition is simply underdiagnosed in this group because of disparities in care,” she said. Sile advocates for education of both patients and physicians in order to achieve more equitable clinical trial enrollment. “By pursuing this, our industry can start to address the inequity that has plagued clinical scientific research for decades.”Read more
Sadiye Rieder, Ph.D., associate director and research scientist, spends her days in the lab asking questions about how autoimmunity develops in humans. As the leader of Horizon’s early preclinical programs, she builds research strategies to uncover new information about autoimmune diseases that have limited treatment options. She is specifically looking at T cells and the role they play in preventing these diseases. “If you understand the biology of how different cells work in the body, you can break down these disease processes and create targeted medicines that can help patients,” Rieder said.
Asking questions about scientific processes is what initially sparked Rieder to follow her career path. At a young age, she wanted to understand why people developed certain diseases. She credits several influential female mentors for empowering her to translate her autoimmune disease research into something meaningful for others. At Horizon, she aims to do the same with her female colleagues and those she mentors. “Knowing I can inspire young women to pursue a career in science by showing them that their work can ultimately turn into something life-changing for patients is what fuels me every day.”Read more
Bill Rees, Ph.D., Horizon’s leader in translational medicine, is focused on science that puts an emphasis on people as individuals rather than on the patient population as a whole, a discipline he calls “Big Science.” Rees leads toxicology, bioanalytic, pharmacology and translational medicine teams to produce the data needed to understand diseases. “Our team recognizes that one medicine isn’t going to fit all patients with the same disease, which is unique in biotech,” Rees said.
Rees and his team work closely with Horizon’s clinical development and medical affairs teams to examine and tell the story of how Horizon’s molecules interact with the human body. He is a strong believer in the benefit of collaboration to help break down barriers and spur growth. “True strength is not in white papers or guideline documents; it’s in the people and collaboration across all functions,” Rees said. He also looks across therapeutic areas to explore treatments to help patients manage their diseases. “Our goal is to bring the right medicine, right dose and right timing to the right patient.”Read more
Articles and Publications
Our team’s discoveries and scientific findings extend beyond the lab. Review some of our scientific publications and articles below:
- Herbst R, et al. B-cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody. J Pharmacol Exp Ther. 2010 Oct;335(1):213-22.
- Ward E, et al. A glycoengineered anti-CD19 antibody with potent antibody-dependent cellular cytotoxicity activity in vitro and lymphoma growth inhibition in vivo. Br J Haematol. 2011 Nov; 155(4):426-37.
- Matlawska-Wasowska K, Ward E, Stevens S, et al. Macrophage and NK-mediated killing of precursor-B acute lymphoblastic leukemia cells targeted with a-fucosylated anti-CD19 humanized antibodies. Leukemia. 2013;27(6):1263-1274. doi:10.1038/leu.2013.5.
- Chen D, et al. Single dose of glycoengineered anti-CD19 antibody (MEDI551) disrupts experimental autoimmune encephalomyelitis by inhibiting pathogenic adaptive immune responses in the bone marrow and spinal cord while preserving peripheral regulatory mechanisms. J Immunol. 2014 Nov 15;193(10):4823-32.
- Yusuf I, et al. Germinal center B cell depletion diminishes CD4+ follicular T helper cells in autoimmune mice. PLoS One. 2014 Aug 7;9(8):e102791.
- Chen D, et al. Autoreactive CD19+CD20- Plasma Cells Contribute to Disease Severity of Experimental Autoimmune Encephalomyelitis. J Immunol. 2016 Feb 15;196(4):1541-9.
- Gallagher S, et al. MEDI-551 Treatment Effectively Depletes B Cells and Reduces Serum Titers of Autoantibodies in Mice Transgenic for Sle1 and Human CD19. Arthritis Rheumatol. 2016 Apr;68(4):965-76.
- Gallagher S, et al. Pharmacological profile of MEDI-551, a novel anti-CD19 antibody, in human CD19 transgenic mice. Int Immunopharmacol. 2016 Jul;36:205-212.
- Wang S, Wang J, Kumar V, et al. IL-21 drives expansion and plasma cell differentiation of autoreactive CD11chiT-bet+ B cells in SLE. Nat Commun. 2018;9(1):1758.
- Schiopu E, Chatterjee S, Hsu V, et al. Safety and tolerability of an anti-CD19 monoclonal antibody, MEDI-551, in subjects with systemic sclerosis: a phase I, randomized, placebo-controlled, escalating single-dose study. Arthritis Res Ther. 2016;18(1):131.
- Guo X, Higgs BW, Bay-Jensen AC, et al. Suppression of T Cell Activation and Collagen Accumulation by an Anti-IFNAR1 mAb, Anifrolumab, in Adult Patients with Systemic Sclerosis. J Invest Dermatol. 2015;135(10):2402-2409.
- Agius MA, Klodowska-Duda G, Maciejowski M, et al. Safety and tolerability of inebilizumab (MEDI-551), an anti-CD19 monoclonal antibody, in patients with relapsing forms of multiple sclerosis: Results from a phase 1 randomised, placebo-controlled, escalating intravenous and subcutaneous dose study. Mult Scler. 2019;25(2):235-245.
- Streicher K, Sridhar S, Kuziora M, et al. Baseline Plasma Cell Gene Signature Predicts Improvement in Systemic Sclerosis Skin Scores Following Treatment With Inebilizumab (MEDI-551) and Correlates With Disease Activity in Systemic Lupus Erythematosus and Chronic Obstructive Pulmonary Disease. Arthritis Rheumatol. 2018;70(12):2087-2095.
- Cree BAC, Bennett JL, Kim HJ, et al. Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial. Lancet. 2019;394(10206):1352-1363.
- Blüml S, McKeever K, Ettinger R, Smolen J, Herbst R. B-cell targeted therapeutics in clinical development. Arthritis Res Ther. 2013;15 Suppl 1(Suppl 1):S4.
- Chen D, Gallagher S, Monson NL, Herbst R, Wang Y. Inebilizumab, a B Cell-Depleting Anti-CD19 Antibody for the Treatment of Autoimmune Neurological Diseases: Insights from Preclinical Studies. J Clin Med. 2016;5(12):107.
- Forsthuber TG, Cimbora DM, Ratchford JN, Katz E, Stüve O. B cell-based therapies in CNS autoimmunity: differentiating CD19 and CD20 as therapeutic targets. Ther Adv Neurol Disord. 2018;11:1756286418761697. Published 2018 Mar 21.
- Patra K, Cree BAC, Katz E, Pulkstenis E, Dmitrienko A, Cutter G. Statistical Considerations for an Adaptive Design for a Serious Rare Disease. Ther Innov Regul Sci. 2016;50(3):375-384.
- Cree BA, Bennett JL, Sheehan M, et al. Placebo-controlled study in neuromyelitis optica-Ethical and design considerations. Mult Scler. 2016;22(7):862-872.
- Karnell JL, Kumar V, Wang J, Wang S, Voynova E, Ettinger R. Role of CD11c+ T-bet+ B cells in human health and disease. Cell Immunol. 2017;321:40-45.
- Oganesyan V, Ferguson A, Grinberg L, et al. Fibronectin type III domains engineered to bind CD40L: cloning, expression, purification, crystallization and preliminary X-ray diffraction analysis of two complexes. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2013;69(Pt 9):1045-1048.
- Mahmoud TI, Wang J, Karnell JL, et al. Autoimmune manifestations in aged mice arise from early-life immune dysregulation. Sci Transl Med. 2016;8(361):361ra137.
- Voynova E, Mahmoud T, Woods LT, Weisman GA, Ettinger R, Braley-Mullen H. Requirement for CD40/CD40L Interactions for Development of Autoimmunity Differs Depending on Specific Checkpoint and Costimulatory Pathways. Immunohorizons. 2018;2(1):54-66.
- Karnell JL, Albulescu M, Drabic S, et al. A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity. Sci Transl Med. 2019;11(489):eaar6584.
- Karnell JL, et al. Depleting plasmacytoid dendritic cells reduces local type I interferon responses and disease activity in patients with cutaneous lupus. Science Translational Medicine. 2021;13(595).
- Panda SK, et al. Plasmacytoid dendritic cells in autoimmunity. Curr Opin Immunol. 2017 Feb;44:20-25.