Phase 1, Open Label, Single Dose Study to Investigate the Effect of Renal Impairment on the Pharmacokinetics of Enpatoran in Male and Female Participants

The purpose of this study is to assess the effect of renal impairment on the pharmacokinetics of enpatoran.

Start Date24 Sep 2024

Sponsor / Collaborator

Merck Healthcare KGaA

[+1]

NCT06589726 / RecruitingPhase 1

A Single-Dose, Randomized, Double-Blind, Placebo- and Positive-Controlled, 4-Way Crossover Study to Evaluate the Effect of Enpatoran on the QTc (Corrected QT) Interval in Healthy Adult Participants

The purpose of this study is to assess potential effects of enpatoran on cardiac repolarization (i.e. prolongation of QT interval).

Start Date10 Sep 2024

Sponsor / Collaborator

Merck Healthcare KGaA

[+1]

CTR20222533 / RecruitingPhase 2

一项II 期、双盲、剂量范围探索、平行分组、长期扩展研究，在已完成WILLOW（MS200569_0003）研究治疗的亚急性皮肤红斑狼疮、盘状红斑狼疮和/或系统性红斑狼疮受试者中，评价Enpatoran 的安全性和有效性

[Translation] A Phase II, double-blind, dose-ranging, parallel-group, long-term extension study to evaluate the safety and efficacy of Enpatoran in subjects with subacute cutaneous lupus erythematosus, discoid lupus erythematosus, and/or systemic lupus erythematosus who have completed study treatment in WILLOW (MS200569_0003)

主要目的：评价enpatoran在SCLE、DLE和/或SLE受试者中的长期安全性和耐受性。次要目的：评价enpatoran在SCLE、DLE和/或SLE受试者中的长期安全性和耐受性及疾病控制方面的长期有效性；第三/探索性目的：评价enpatoran在SCLE、DLE和/或SLE受试者中的疾病控制方面的长期有效性；评价enpatoran在SLE受试者中的疾病控制方面的长期有效性；评价enpatoran在SCLE、DLE和/或SLE受试者中对患者报告的症状和功能状态方面的长期有效性；评价enpatoran在活动性SLE受试者中对患者报告的症状和功能状态方面的长期有效性；研究活动性SLE受试者中，Enpatoran对生物标志物的影响；研究Enpatoran对免疫细胞亚群和免疫球蛋白的影响；研究Enpatoran对PD生物标志物的影响；通过稀疏PK采样采集enpatoran血浆浓度数据；评价enpatoran对疫苗免疫状态的长期影响。评价Enpatoran对比安慰剂对活动性狼疮皮疹受试者红斑的影响。

[Translation]

Primary objective: To evaluate the long-term safety and tolerability of enpatoran in subjects with SCLE, DLE and/or SLE. Secondary objectives: To evaluate the long-term safety and tolerability of enpatoran in subjects with SCLE, DLE and/or SLE and the long-term effectiveness of enpatoran in disease control; Tertiary/exploratory objectives: To evaluate the long-term effectiveness of enpatoran in disease control in subjects with SCLE, DLE and/or SLE; To evaluate the long-term effectiveness of enpatoran in disease control in subjects with SLE; To evaluate the long-term effectiveness of enpatoran in patient-reported symptoms and functional status in subjects with SCLE, DLE and/or SLE; To evaluate the long-term effectiveness of enpatoran in patient-reported symptoms and functional status in subjects with active SLE; To study the effects of enpatoran on biomarkers in subjects with active SLE; To study the effects of enpatoran on immune cell subsets and immunoglobulins; To study the effects of enpatoran on PD biomarkers; To collect enpatoran plasma concentration data by sparse PK sampling; To evaluate the long-term effects of enpatoran on vaccine immune status. To evaluate the effects of Enpatoran versus placebo on erythema in subjects with active lupus rash.

Start Date16 Mar 2023

Sponsor / Collaborator

R-Pharm Germany GmbHStartup

[+3]

100 Clinical Results associated with Enpatoran

100 Translational Medicine associated with Enpatoran

100 Patents (Medical) associated with Enpatoran

Literatures (Medical) associated with Enpatoran

01 Oct 2024·Clinical and Translational Science

Asia‐inclusive drug development leveraging principles of ICH E5 and E17 guidelines: Case studies illustrating quantitative clinical pharmacology as a foundational enabler

Review

Author: Kuroki, Yoshihiro ; Bolleddula, Jayaprakasam ; Venkatakrishnan, Karthik ; Gao, Wei ; Klopp‐Schulze, Lena ; Strotmann, Rainer ; Lu, Hong ; Dong, Jennifer ; Li, Dandan ; Mukker, Jatinder Kaur ; Goteti, Kosalaram ; Terranova, Nadia

AbstractWith the International Conference on Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) E17 guidelines in effect from 2018, the design of Asia‐inclusive multiregional clinical trials (MRCTs) has been streamlined, thereby enabling efficient simultaneous global development. Furthermore, with the recent regulatory reforms in China and its drug administration joining the ICH as a full regulatory member, early participation of China in the global clinical development of novel investigational drugs is now feasible. This would also allow for inclusion of the region in the geographic footprint of pivotal MRCTs leveraging principles of the ICH E5 and E17. Herein, we describe recent case examples of model‐informed Asia‐inclusive global clinical development in the EMD Serono portfolio, as applied to the ataxia telangiectasia and Rad3‐related inhibitors, tuvusertib and berzosertib (oncology), the toll‐like receptor 7/8 antagonist, enpatoran (autoimmune diseases), the mesenchymal–epithelial transition factor inhibitor tepotinib (oncology), and the antimetabolite cladribine (neuroimmunological disease). Through these case studies, we illustrate pragmatic approaches to ethnic sensitivity assessments and the application of a model‐informed drug development toolkit including population pharmacokinetic/pharmacodynamic modeling and pharmacometric disease progression modeling and simulation to enable early conduct of Asia‐inclusive MRCTs. These examples demonstrate the value of a Totality of Evidence approach where every patient's data matter for de‐risking ethnic sensitivity to inter‐population variations in drug‐ and disease‐related intrinsic and extrinsic factors, enabling inclusive global development strategies and timely evidence generation for characterizing benefit/risk of the proposed dosage in Asian populations.

01 Jun 2024·Clinical Pharmacology & Therapeutics

Asia‐Inclusive Global Development of Enpatoran: Results of an Ethno‐Bridging Study, Intrinsic/Extrinsic Factor Assessments and Disease Trajectory Modeling to Inform Design of a Phase II Multiregional Clinical Trial

Article

Author: Goteti, Kosalaram ; Gopalakrishnan, Sathej ; Dong, Jennifer ; Fluck, Markus ; Venkatakrishnan, Karthik ; Krebs-Brown, Axel ; Nogueira Filho, Marco ; Shaw, Jamie ; Gradhand, Ulrike ; Klopp-Schulze, Lena ; Kuroki, Yoshihiro ; Lu, Hong ; Yalkinoglu, Özkan

Enpatoran is a novel, highly selective, and potent dual toll‐like receptor (TLR)7 and TLR8 inhibitor currently under development for the treatment of autoimmune disorders including systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), and myositis. The ongoing phase II study (WILLOW; NCT05162586) is evaluating enpatoran for 24 weeks in patients with active SLE or CLE and is currently recruiting. To support development of WILLOW as an Asia‐inclusive multiregional clinical trial (MRCT) according to International Conference on Harmonisation E5 and E17 principles, we have evaluated ethnic sensitivity to enpatoran based on clinical pharmacokinetic (PK), pharmacodynamic (PD), and safety data from an ethno‐bridging study (NCT04880213), supplemented by relevant quantitative PK, PD, and disease trajectory modeling (DTM) results, and drug metabolism/disease knowledge. A single‐center, open‐label, sequential dose group study in White and Japanese subjects matched by body weight, height, and sex demonstrated comparable PK and PD properties for enpatoran in Asian vs. non‐Asian (White and other) subjects across single 100, 200, and 300 mg orally administered doses. DTM suggested no significant differences in SLE disease trajectory for Asian vs. non‐Asian individuals. Aldehyde oxidase (AOX) is considered to be a key contributor to enpatoran metabolism, and a literature review indicated no relevant ethnic differences in AOX function based on in vitro and clinical PK data from marketed drugs metabolized by AOX, supporting the conclusion of low ethnic sensitivity for enpatoran. Taken together, the inclusion of Asian patients in MRCTs including WILLOW was informed based on a Totality of Evidence approach.

01 Dec 2023·Clinical and Translational Science

Enpatoran in COVID‐19 pneumonia: Safety and efficacy results from a phase II randomized trial

Article

Author: Murta de Oliveira, Claudia ; Khursheed, Mukhy ; Roy, Sanjeev ; McKinnon, John E ; Santiaguel, Joel ; Moreau, Flavie ; Shaw, Jamie ; Kao, Amy H ; Yu, Dongzi ; Klopp-Schulze, Lena

AbstractEnpatoran is a selective inhibitor of toll‐like receptors 7 and 8 (TLR7/8) that potentially targets pro‐inflammatory pathways induced by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). A phase II study conducted in Brazil, the Philippines, and the USA during the early pandemic phase assessed the safety and efficacy of enpatoran in patients hospitalized with COVID‐19 pneumonia (NCT04448756). A total of 149 patients, who scored 4 on the World Health Organization's (WHO) 9‐point ordinal severity scale, were randomized 1:1:1 and received enpatoran 50 mg (n = 54) or 100 mg (n = 46), or placebo (n = 49) twice daily (b.i.d.) for 14 days plus standard of care. The primary objectives were safety and time to recovery (WHO 9‐point scale ≤3). Clinical deterioration (WHO 9‐point scale ≥ 5) was a key secondary objective. Treatment‐emergent adverse events (TEAEs) were comparable across groups (56.5%–63.0%). Treatment‐related TEAEs were numerically higher with enpatoran 50 mg (14.8%) than 100 mg (10.9%) or placebo (8.2%). Serious TEAEs were numerically lower with enpatoran (50 mg 9.3%, 100 mg 2.2%) than placebo (18.4%). The primary efficacy objective was not met; median time to recovery was 3.4–3.9 days across groups, with placebo‐treated patients recovering on average faster than anticipated. Clinical deterioration event‐free rates up to Day 7 were 90.6%, 95.6%, and 81.6% with enpatoran 50 mg, 100 mg, and placebo, respectively. Enpatoran was well tolerated by patients acutely ill and hospitalized with COVID‐19 pneumonia. Positive signals in some secondary end points suggested potential beneficial effects, supporting further evaluation of enpatoran in patients with hyperinflammation due to infection or autoimmunity.

News (Medical) associated with Enpatoran

04 Nov 2024

·www.prnewswire.com

Lupus Research Alliance Announces Lupus Research Highlights at ACR Convergence 2024

Sixteen presentations of preclinical studies funded by the Lupus Research Alliance (LRA) to advance understanding of lupus and potential treatment pathways, including four oral presentations Two reports by Lupus Therapeutics, the clinical affiliate of the LRA, and the Lupus Clinical Investigators Network (LuCIN) on promoting equity in lupus clinical trials, and identifying trial barriers and solutions Fifteen industry-sponsored clinical research studies supported by Lupus Therapeutics and LuCIN, including positive results from the late-breaking Phase 3 dapirolizumab pegol trial NEW YORK, Nov. 4, 2024 /PRNewswire/ -- The Lupus Research Alliance (LRA), the largest private funder of lupus research worldwide, today announced that a total of 33 studies, funded by the organization or supported by its clinical research affiliate Lupus Therapeutics, will be presented at ACR Convergence 2024. The annual meeting of the American College of Rheumatology takes place November 14-19, at the Walter E. Washington Convention Center in Washington, D.C. The LRA, which seeks to accelerate the discovery and development of patient-centered treatments and diagnostics, pursues strategies to spur advancements from "bench to bedside." LRA-supported studies presented at ACR Convergence 2024 represent the full continuum of lupus research, from foundational research exploring new avenues of knowledge, to clinical trials evaluating potential new treatments. "ACR Convergence 2024 is met with pride and excitement by the Lupus Research Alliance and Lupus Therapeutics – pride in seeing the fruits of our funding and other initiatives to accelerate drug discovery and development, and excitement as we stand on the precipice of some important advancements," said LRA President and CEO Albert T. Roy. "There are more trials in mid-to-late-stage development than ever before, including dapirolizumab pegol in Phase 3 from UCB/Biogen, a Lupus Therapeutics partner. And we are gratified to witness the volume of CAR T cell therapy approaches in clinical development, having invested in 2014 in early research suggesting this approach as a promising intervention to explore for treating lupus," Roy added. Foundational Research Funded by the LRA Sixteen studies of LRA-funded research (four oral presentations and 12 posters) will be presented. Several focus on Childhood-Onset Systemic Lupus Erythematosus (cSLE), including: a detailed characterization of the disease; the effects of fatigue on pediatric patients' mental and physical health; and the discovery of Anti-Mitochondrial Antibodies (AMA), which are linked to higher disease activity. Other studies include: the development of a precision immunotherapy to target harmful B cells in Antiphospholipid Syndrome (APS) patients; the discovery of innate signaling pathways crucial in causing inflammation in lupus patients; and the epidemiology of strokes in children and adults with lupus. ORAL PRESENTATIONS Saturday, Nov. 16 Abstract #0837: Bispecific Autoantigen-T Cell Engagers (BaiTE) to Selectively Target Autoreactive B Cells in Antiphospholipid Syndrome 3:00-3:15 PM, Room 103AB Sunday, Nov. 17 Abstract #1702: Placental Developmental Defects in a Humanized-TLR8 Mouse Model of Spontaneous Anti-Phospholipid Antibody Induced Pregnancy Loss 3:15-3:30 PM , Room 103AB Monday, Nov. 18 Xist and XChromosome Inactivation in Female Biased Autoimmunity 9:00-9:30 AM, Room 145AB Abstract #2625: Brain Injury Markers Correlate with Impaired Executive Function and Disease Activity in Children with Systemic Lupus Erythematosus 3:30-3:45 PM, Room 202AB POSTERS Saturday, Nov. 16 Poster Session A, 10:30 AM-12:30 PM, Poster Hall: Abstract #0091: Targeting Endothelial Dysfunction in Lupus Nephritis: Effect of Sepiapterin, a Drug That Restores Endothelial Nitric Oxide Synthase Function, in a Murine Model of Lupus Nephritis Abstract #0098: Anti-HSP90α as a Protective Natural Antibody Against Secondary Antiphospholipid Syndrome in Systemic Lupus Erythematosus Sunday, Nov. 17 Poster Session B, 10:30 AM-12:30 PM , Poster Hall: Abstract #1266: Anti-Mitochondrial Antibodies Associate with Disease Activity and IFNα Expression in Childhood-onset Systemic Lupus Erythematosus Abstract #1273: An Investigation of Traumatic Events and Mental Health in cSLE Abstract #1274: Comparing Performance-Based Measures and Self-Reported Questionnaires for Assessment of Executive Function for Youth with Childhood-Onset Systemic Lupus Erythematosus Abstract #1278: The Effects of Fatigue on Self-Reported Mental and Physical Health in Childhood-Onset Systemic Lupus Erythematosus: A Cross-Sectional Study Abstract #1279: Cerebrovascular Accidents in Pediatric and Adult Systemic Lupus Erythematosus: A Comparison of Epidemiology and Outcomes Abstract #1280: Abnormal Cortical Gyrification Patterns in Adolescents with Childhood-onset SLE: Early Associations with Perceived Fatigue Abstract #1504: Novel Analytes Associated with Cognitive Impairment in Patients with Systemic Lupus Erythematosus: Serum S100A8/A9, MMP-9 and IL-6 Abstract #1506: Cognitive Impairment Prevalence and Most Affected Domains in Patients with SLE by the ACR Comprehensive Neuropsychological Battery Monday, Nov. 18 Poster Session C, 10:30 AM-12:30 PM, Poster Hall: Abstract #1788: Memory B Cell Activation and Dysregulation in Systemic Lupus Erythematosus Abstract #2380: Characterizing SLE Patients into Type 1 and Type 2 Disease States: Insights from a Single Lupus Cohort Research Conducted by Lupus Therapeutics and the Lupus Clinical Investigators Network (LuCIN) Lupus Therapeutics, the clinical affiliate of the Lupus Research Alliance, oversees the Lupus Clinical Investigators Network (LuCIN), consisting of 50+ premier, leading medical research institutions in North America, comprised of 200+ providers with expertise in lupus care and clinical trials. The following studies are based on annual surveys of LuCIN investigators and research teams on promoting equity in lupus clinical trials and identifying trial barriers and solutions. POSTERS Saturday, Nov. 16 Abstract 0180: Collaborative Solutions to Lupus Trial Challenges for Underrepresented Participant Recruitment & Engagement: Perspectives from the Lupus Clinical Investigators Network (LuCIN) Poster Session A, 10:30 AM-12:30 PM, Poster Hall Sunday, Nov. 17 Abstract #1039: Through the LuCIN Lens: Defining Barriers and Forging Solutions for Lupus Clinical Trials in North America Poster Session B, 10:30 AM-12:30 PM, Poster Hall Clinical Research Supported by Lupus Therapeutics and LuCIN The primary goal of Lupus Therapeutics and LuCIN is to accelerate and enhance the quality of lupus clinical trials through clinical expertise, advisory services, patient engagement and partnership/collaboration with biopharmaceutical companies and research partners. Lupus Therapeutics and LuCIN are involved in nearly 25% of active lupus clinical trials. Fifteen Lupus Therapeutics/LuCIN-supported programs and collaborations are being presented at ACR Convergence 2024: ORAL PRESENTATIONS Sunday, Nov. 17 Abstract #1773: Safety and Efficacy of CABA-201, a Fully Human, Autologous 4-1BB Anti-CD19 CAR T Cell Therapy in Patients with Immune-Mediated Necrotizing Myopathy and Systemic Lupus Erythematosus from the RESET-MyositisTM and RESET-SLETM Clinical Trials 3:30-3:45 PM, Room 145AB Monday, Nov. 18 Abstract #2577: Efficacy and Safety of ABBV-599 (Elsubrutinib and Upadacitinib Combination) and Upadacitinib Monotherapy for the Treatment of Systemic Lupus Erythematosus: Results Through 104 Weeks in a Long-Term Extension Study 1:30-1:45 PM, Room 146AB Abstract #2580: Safety and Efficacy of Subcutaneous Ianalumab (VAY736) for up to 68 Weeks in Patients with Systemic Lupus Erythematosus: Results from Phase 2 Study 2:15-2:30 PM Room 146AB Tuesday, Nov. 19 ***LATE-BREAKING ABSTRACT*** Abstract #L16: Dapirolizumab Pegol Demonstrated Significant Improvement in Systemic Lupus Erythematosus Disease Activity: Efficacy and Safety Results of a Phase 3 Trial 8:00-9:30 AM, 146AB POSTERS Saturday, Nov. 16 Poster Session A, 10:30 AM-12:30 PM, Poster Hall: Abstract #0087: SYNCAR: An Engineered IL-2/IL-2R-system That Selectively Enhances CD19 CAR T Cells to Deplete B Cells and Provide Therapeutic Benefit in SLE and RA Mouse Models Without Lymphodepletion Abstract #0324: Correlative Studies of CABA-201, a Fully Human, Autologous 4-1BB Anti-CD19 CAR T Cell Therapy in Patients with Immune-Mediated Necrotizing Myopathy and Systemic Lupus Erythematosus from the RESET-MyositisTM and RESET-SLETM Clinical Trials Abstract #0620: Clinical Efficacy and Patient-Reported Outcomes in Anti-Ro/Sjögren's Syndrome–Related Antigen a Antibody–Positive Patients with Active SLE Treated With Deucravacitinib in the Phase 2 PAISLEY Trial Abstract #0659: Obinutuzumab Benefits Patients with Active Lupus Nephritis Irrespective of Baseline Proteinuria Severity: A Post Hoc Analysis of a Phase II Trial Abstract #0662: Deucravacitinib, a First-in-Class, Oral, Selective, Allosteric Tyrosine Kinase 2 Inhibitor, in SLE: Efficacy by Baseline Demographics and Disease Characteristics in the Phase 2 PAISLEY Trial Abstract #0671: Effect of Litifilimab on Cutaneous Lupus Disease Area and Severity Index–Activity (CLASI-A) Subcomponents and Physician Global Assessment–Skin (PGA–Skin) in Patients with Cutaneous Lupus Erythematosus (CLE) in a Phase 2 Study Sunday, Nov. 17 Poster Session B, 10:30 AM-12:30 PM, Poster Hall: Abstract #1496: Dysregulated Serum Cytokines in Association with Clinical Manifestations in Patients with Systemic Lupus Erythematosus Abstract #1552: Kinetics of Mucocutaneous and Musculoskeletal Responses to Deucravacitinib in Patients with Active SLE in the Phase 2 PAISLEY Trial Abstract #1553: Safety, Pharmacokinetics, Clinical Efficacy and Exploratory Biomarker Results from a Randomized, Double-Blind, Placebo-Controlled Phase 1b Study of Enpatoran in Active Systemic and Cutaneous Lupus Erythematosus (SLE/CLE) Monday, Nov. 18 Poster Session C, 10:30 AM-12:30 PM, Poster Hall: Abstract #2425: Ianalumab Induced Durable Depletion of Circulating B Cell Subsets and Associated Changes in B Cell and Neutrophil Transcriptomic and Proteomic Profiles in Patients with Systemic Lupus Erythematosus: 52-Week Treatment Results from a Phase 2 Trial Abstract #2430: Dapirolizumab Pegol Impacts Important Immunologic Pathways in Systemic Lupus Erythematosus: Pharmacodynamic Analysis of T Cell and Antigen Presenting Cell Pathways from a Phase 2b Trial About Lupus Lupus is a chronic, complex autoimmune disease that affects millions of people worldwide. In lupus, the immune system, meant to defend against infections, produces autoantibodies that mistake the body's own cells as foreign, causing other immune cells to attack organs such as the kidneys, brain, heart, lungs and skin, as well as blood and joints. Ninety percent of people with lupus are women, most often diagnosed between the ages of 15-45. Black, Latinx, Indigenous, Asian and Pacific Islander people are disproportionately affected by lupus and more likely to experience severe lupus symptoms. About the Lupus Research Alliance The Lupus Research Alliance is the largest non-governmental, non-profit funder of lupus research worldwide. The organization aims to transform treatment by funding the most innovative lupus research, fostering diverse scientific talent, and driving discovery toward better diagnostics, improved treatments and ultimately a cure for lupus. Because the Lupus Research Alliance's Board of Directors funds all administrative and fundraising costs, 100% of all donations goes to support lupus research programs. For more information, please visit the LRA at LupusResearch.org and on social media at: X, Facebook, LinkedIn, and Instagram. About Lupus Therapeutics Lupus Therapeutics, the clinical research affiliate of the Lupus Research Alliance, aims to accelerate the development of curative treatments for all patients living with lupus. Lupus Therapeutics collaborates with premier research institutions, biopharmaceutical partners, and those living with lupus through the unprecedented Lupus Clinical Investigators Network (LuCIN) to drive rapid and meaningful progress in treatment development. The organization elevates the patient voice, engages community stakeholders, and strives for representation of the diverse lupus community in the clinical research process with the most innovative and renowned experts throughout North America. Visit LupusTherapeutics.org for more information. This information is brought to you by the Lupus Research Alliance and is not sponsored by, nor a part of, the American College of Rheumatology. SOURCE Lupus Research Alliance WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Phase 2Clinical ResultPhase 3Immunotherapy

16 Oct 2024

·www.merckgroup.com

Capital Markets Day 2024: Merck KGaA, Darmstadt, Germany, Reiterates Confidence in Returning to Sustainable Growth

Tailwind thanks to robust global growth trends in all three business sectors Life Science to be back on course as company’s growth engine Healthcare with ambition for mid-single-digit long-term growth Age of artificial intelligence (AI) drives medium-term growth upgrade for Electronics Acquisitions remain an integral component of company strategy Merck KGaA, Darmstadt, Germany, a leading science and technology company, is looking confidently toward the future. At today’s Capital Markets Day, the company shared its expectation of profitable and financially strong growth in the coming years. After the transitional year of 2023, Merck KGaA, Darmstadt, Germany, considers the medium-term growth opportunities in its markets to be intact. With its three business sectors, the company is in a strong strategic position to partake in these opportunities. In Electronics, which develops solutions for the semiconductor and display industries, the Group even expects business performance to accelerate in the next few years. This is thanks in particular to the trend toward artificial intelligence. “We committed to return to growth in 2024 and this is materializing already,” said Belén Garijo, Chair of the Executive Board and CEO of Merck KGaA, Darmstadt, Germany. “Furthermore, we are well positioned to deliver sustainable growth through innovation and our high-performing global talent.” Innovations as growth drivers Merck KGaA, Darmstadt, Germany, relies on its diversified business model to spark discovery and elevate humanity in accordance with its new company vision. In its Life Science business sector, the company sees the globally growing later-stage pipeline of complex molecules and novel modalities, among other things, as key growth drivers. Novel modalities include new therapies such as viral vector-based cell and gene therapies, antibody-drug conjugates (ADCs), and mRNA applications. The company has in-depth knowledge and offers a broad portfolio of products and services in these areas. ADCs are experiencing remarkable growth, for example. The Group has significantly increased its ADC and highly potent active pharmaceutical ingredient (HPAPI) capacities in recent years. In Healthcare, Merck KGaA, Darmstadt, Germany, takes up leading positions in therapeutic areas within its Fertility and Cardiovascular, Metabolic & Endocrinology franchises, leveraging the company’s broad geographical footprint. Innovations in Oncology and Neurology & Immunology will continue to drive long-term growth. In June 2024, the company started a Phase III trial with cladribine capsules to treat the neurological disease myasthenia gravis. With enpatoran, developed for lupus erythematosus, it expects the full Phase II readout in early 2025. For pimicotinib [1] for the treatment of benign tumors of the joints, the Phase III readout is expected later this year. In addition, the company is executing its early-stage oncology development strategy, which it outlined in its R&D update call earlier this year . In the Electronics business sector, Merck KGaA, Darmstadt, Germany, has deliberately focused on solutions for the semiconductor and display industries. The company supports its customers in developing ever smaller, more powerful, and more efficient chips, among other things. In doing so, it helps to meet global demand for AI applications and modern semiconductors. For example, with the intended acquisition of Unity-SC , the Group will expand its portfolio with high-precision metrology instruments to optimize the quality and production yield and thus also the manufacturing costs of chips for its customers. Merck KGaA, Darmstadt, Germany, is also recording growing sales from sustainable solutions. For example, the company has increased its portfolio of more sustainable products in Life Science by an average of 30% annually since 2020. For example, Milli-Q ® systems for the purification of lab water that contain the ERA ™ technology can save up to 50% in water usage compared with other systems. The company’s innovative power drives organic growth. At the same time, the strong market position and stringent cost management of Merck KGaA, Darmstadt, Germany, ensure good profitability. It intends to normalize its current capital expenditure (capex) of approximately € 1.6 billion to € 1.8 billion per year at a slightly lower level once again from 2026 onwards. In previous years, the company had significantly increased its capex to prepare for medium- and long-term growth trends by expanding capacities in research and development as well as production, for example. Having reached these goals, Merck KGaA, Darmstadt, Germany, now expects less capital-intensive growth, which will facilitate stronger cash flow development. Strategic acquisitions Acquisitions also remain an integral component of the strategy of Merck KGaA, Darmstadt, Germany. On July 31, 2024, it acquired Mirus Bio . The U.S. life science company specializes in transfection reagents, which help introduce genetic material into cells and play a key role in the production of viral vectors for cell and gene therapies. Also in July 2024, Merck KGaA, Darmstadt, Germany, announced the acquisition of Unity-SC . For larger future transactions, the company is focusing on the Life Science business sector. The company will additionally intensify the in-licensing of drug candidates in Healthcare. Belén Garijo said: “M&A remains a key priority for us. And we remain disciplined and patient in our approach in order to maximize the strategic impact of any acquisitions. Our guiding principle is and always has been: The right target, at the right time, for the right price.” Medium-term ambitions: Growth trends in the markets remain intact At Capital Markets Day 2024, Merck KGaA, Darmstadt, Germany, slightly adjusted the mid-term growth ambitions for its three business sectors. The company is confident that the growth opportunities in its markets remain intact after the transitional year of 2023. It expects the following average annual organic sales growth rates: Life Science: 7% to 9% (previously: 7% to 10%) and therefore still above the market average. The main reason for the refined ambition is the updated view on China’s mid-term growth prospects. Healthcare: slight growth (previously: growth in the mid-single-digit percentage range). This is due to the recently announced pipeline setbacks. In the long term, the company intends to return to growth in the mid-single-digit percentage range, also supported by external innovation. Electronics: 5% to 9%, a significant uplift from the previous 3% to 6%. This is largely driven by Electronics becoming a pure play in the areas of Semiconductor and Display Solutions and enabling the trend toward artificial intelligence. The company benefits here from its unique position as a supplier of semiconductor solutions that meet the high demands of chips for AI applications. Company confirms guidance for fiscal 2024 For fiscal 2024, Merck KGaA, Darmstadt, Germany, confirms its guidance and the return to profitable growth : Sales: between € 20.7 billion and € 22.1 billion (organic growth: +2% to +5%). EBITDA pre: between € 5.8 billion and € 6.4 billion (organic growth: +4% to +10%). EPS pre: € 8.20 to € 9.30. [1] Sponsor: Abbisko Therapeutics Co. Ltd.; Merck KGaA, Darmstadt, Germany, holds an exclusive license to commercialize pimicotinib in China, Hong Kong, Macau, and Taiwan, with an option for the rest of the world. About Merck KGaA, Darmstadt, Germany Merck KGaA, Darmstadt, Germany, a leading science and technology company, operates across life science, healthcare and electronics. Around 63,000 employees work to make a positive difference to millions of people’s lives every day by creating more joyful and sustainable ways to live. From providing products and services that accelerate drug development and manufacturing as well as discovering unique ways to treat the most challenging diseases to enabling the intelligence of devices – the company is everywhere. In 2023, Merck KGaA, Darmstadt, Germany, generated sales of € 21 billion in 65 countries. The company holds the global rights to the name and trademark “Merck” internationally. The only exceptions are the United States and Canada, where the business sectors of Merck KGaA, Darmstadt, Germany, operate as MilliporeSigma in life science, EMD Serono in healthcare and EMD Electronics in electronics. Since its founding in 1668, scientific exploration and responsible entrepreneurship have been key to the company’s technological and scientific advances. To this day, the founding family remains the majority owner of the publicly listed company. All Merck KGaA, Darmstadt, Germany, press releases are distributed by e-mail at the same time they become available on the EMD Group website. In case you are a resident of the USA or Canada, please go to www.emdgroup.com/subscribe to register for your online, change your selection or discontinue this service.

AcquisitionPhase 3License out/in

23 May 2024

·www.sciencedaily.com

Tracking down the genetic causes of lupus to personalize treatment

Treatment of autoimmune diseases like lupus has long relied on steroids to knock down the immune system, but more targeted therapies are currently undergoing clinical trials. To make sure these therapies get to the patients who will benefit, work is needed to identify the specific mutations behind each patient's disease. Researchers now report several dozen mutations associated with oversensitive toll-like receptors -- a major cause of autoimmune disease -- and linked two mutations to patients. Lupus is a lifelong, often painful and occasionally lethal autoimmune disease. Few treatments exist today beyond powerful steroids to knock down a patient's immune system -- a therapy that has its own serious risks. The good news is that new and promising treatments are in clinical trials. But the term lupus belies the fact that the disease has a variety of causes, which means that treatments will have to be highly personalized to guarantee that each patient is given the drug that targets the specific genetic mutation responsible for their variety of lupus. Researchers are just now beginning to link specific genetic mutations to subsets of lupus patients, allowing physicians to target therapies to those who will benefit most. In the latest advance, researchers at the University of California, Berkeley, report in a new paper the discovery of two sets of patients with genetic mutations that are nearly identical to mutations that the researchers had earlier pinpointed in mouse and cell lines as linked to autoimmune disease. These two genetic links are among several dozen mutations that the UC Berkeley team recently discovered and linked to lupus, all in one gene that regulates a prime suspect in a subset of lupus patients -- proteins called toll-like receptors (TLR), which enable immune cells to recognize foreign DNA and RNA. According to study leader Gregory Barton, UC Berkeley professor of molecular and cell biology, identifying these mutations could help doctors deliver a personalized treatment to patients with oversensitive TLRs and, in particular, oversensitive TLR7 receptors. "We basically have a map now," said Barton, who is also an investigator in the Howard Hughes Medical Institute. "It's not like everybody that has lupus has a mutation in the gene that causes overactivation of TLRs and TLR7. But there are drugs coming online that very specifically inhibit TLR7. As we sequence more and more people, it will become easier to identify those patients and put them on those drugs. That's a lot better than the current course of therapy for lupus, which is brutal." "This is exciting because the drug will be orally available and is in clinical trials now," said Victoria Rael, a UC Berkeley graduate student who, with fellow graduate student Julian Yano, is a co-first author of the paper. The results of the genetic screens and details of the patients' mutations were published today (May 23) in the Journal of Experimental Medicine. A problem recognizing 'self' Autoimmune diseases, which range from rheumatoid arthritis and Crohn's disease to scleroderma and numerous thyroid conditions, stem from attacks by the immune system on the body's own cells that destroy normal, healthy tissue. Many studies have linked at least two types of autoimmune disease, lupus and psoriasis, to TLRs, which are part of the innate immune system that initially detects foreign invaders, such as viruses and bacteria, and stimulates a first line of attack. Normally, TLRs are delicately tuned to react only to foreign DNA and RNA, but if that tuning is off, they can react to a body's own nucleic acids and proteins associated with nucleic acids, which look much like those of pathogens. What makes this autoimmune reaction so deadly is that the TLRs also activate the body's second-line defense, the more powerful adaptive immune response, mobilizing T and B cells, macrophages, and other cells. These cells then mount a sustained attack that destroys the body's healthy tissue and causes chronic inflammation. The most common form, systemic lupus erythematosus (SLE), for example, is characterized initially by skin rashes -- in particular, a butterfly-shaped rash on the face -- but later by damage to joints, muscles, organs and skin, causing pain and fatigue. It's most commonly seen in females, often starting during the teen years. Lupus, in general, is two to three times more prevalent among women from many ethnic and racial minority groups than among white women. "We think the way the system works is that if nucleic acids find these receptors, most likely they're going to be from a virus," Barton said. "But in some people, the receptor is more responsive, so now levels of self-nucleic acids that otherwise wouldn't stimulate the receptor in a normal person activate the receptor. We think that one of the ways that these mutations are working is that they're making levels of self-nucleic acids that normally wouldn't be stimulatory, stimulatory." Barton and his lab colleagues have been investigating the role of TLRs that are misregulated in lupus, and in particular, one of the main proteins that regulates them: UNC93B1, or UNC for short. Several years ago, a team of postdoctoral fellows and graduate students in his lab screened in cell culture more than 100 genetic mutations in the UNC gene to see which ones overstimulated TLRs and would be good targets for further study. While they published some details in earlier papers, they didn't publish the complete list because there seemed to be little point -- almost no data was available on the genome sequences of lupus patients to compare with the mutations that overstimulated TLRs. But that has changed in recent years, thanks to a plunge in the cost of genome sequencing. That's how the mother of a young girl with severe autoimmune disease found Barton. Her daughter's DNA had been sequenced and showed a mutation in a region of UNC that Barton's team had noted in an earlier paper. Lupus in the family Rael and undergraduate Madeleine Weiss used the same cell culture screening technique to test the novel mutation from the young girl and found that it had an overstimulating effect, similar to the effect of other mutations in that area of the UNC gene. Surprisingly, the patient had the genetic mutation on only one of the two UNC alleles, meaning that she had one normal UNC gene, yet she still suffered severe autoimmune symptoms. Barton and his team also connected with a family of five afflicted with lupus. All had mutations on one UNC allele in another area of the UNC protein that Barton's team had previously identified. That mutation, when screened in cell lines, also produced overactive TLRs. "We were skeptical that just one copy of a gene would be sufficient to cause a disease," Rael said. "It wasn't until we put the patients' mutations into cell lines and saw that they led to very convincing TLR hyper-responsiveness that we realized they had the possibility of being sufficient to be disease-causing." Rael and Yano then repeated the screening work previously performed in the lab and confirmed that 32 distinct mutations in the UNC gene -- about one-third of the mutations tested -- increased the sensitivity of TLR7 to nucleic acids at least twofold. About another five mutants increased TLR7 sensitivity but to a lesser degree. Before these screens, only two mutations in the UNC protein had been linked to increased sensitivity of TLR7 in mice, though three additional human mutations were reported within the last two months. Barton is hopeful that by publishing the complete list of TLR hypersensitivity mutations, doctors can identify other lupus patients who could benefit from the anti-TLR drugs now in clinical trials. One drug, M5049, or Enpatoran, appears to work by latching onto two human receptors, TLR7 and TLR8, and preventing them from binding nucleic acids. Rael, Yano and other members of Barton's lab are investigating further how these unique UNC mutations affect the way a patient manifests the disease. They have recreated these patients' mutations in mice so that they can model human lupus. "With mouse models, you can start thinking about how, even though the mutations are in the same protein, the different mechanisms of TLR regulation break down, which immune cells get activated as a result, and how this can lead to differences in the symptoms patients suffer from," Rael said. The lab also is trying to understand how UNC tunes TLRs, which may be by regulating the number and arrangement of TLRs on immune cells. More TLRs may make a person more sensitive to the small number of self-nucleic acids circulating in the body. "UNC93B1 is important for getting the receptors to the place where they can function, but it also is important for regulating them when they get there," Barton said. "The protein is a very baroque way of trying to make decisions about whether the nucleic acid that you just bound to a TLR is from a virus or from one of your own cells." He hopes that physicians add this gene to the list of lupus-associated genes, "so if they see a mutation like these, even a heterozygous mutation, they will investigate further." Other senior authors of the paper are Bo Liu of the Chinese Academy of Sciences in Shanghai and Olivia Majer of the Max Planck Institute for Infection Biology in Berlin, Germany. The co-authors also include physicians from UC San Francisco, Stanford University, and hospitals in Missouri, North Carolina and Washington. The work was funded in part by the Lupus Research Institute, the Lupus Research Alliance and the National Institutes of Health (R01AI072429).

100 Deals associated with Enpatoran

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Lupus Erythematosus, Discoid	Phase 2	UA	R-Pharm Germany GmbHStartup	14 Feb 2022
Lupus Erythematosus, Discoid	Phase 2	RU	Merck Healthcare KGaA	14 Feb 2022
Lupus Erythematosus, Discoid	Phase 2	UA	Merck Serono (Beijing) Pharmaceutical R&D Co., Ltd.	14 Feb 2022
Lupus Erythematosus, Discoid	Phase 2	RS	R-Pharm Germany GmbHStartup	14 Feb 2022
Lupus Erythematosus, Discoid	Phase 2	ZA	R-Pharm Germany GmbHStartup	14 Feb 2022
Lupus Erythematosus, Discoid	Phase 2	JP	R-Pharm Germany GmbHStartup	14 Feb 2022
Lupus Erythematosus, Discoid	Phase 2	RU	R-Pharm Germany GmbHStartup	14 Feb 2022
COVID-19	Discovery	BR	Merck KGaA	29 Jul 2020
COVID-19	Discovery	PH	Merck KGaA	29 Jul 2020
COVID-19	Discovery	US	Merck KGaA	29 Jul 2020

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04448756 (ANEMONE, CTgov)	Phase 2	COVID-19	149	Placebo (Placebo)	vuknmsylbi(cfynsazfpk) = htilvwffvd wharjkrwpb (nzdrnptbqy, xcnurwgves - howeggwiqs) View more	-	06 Jun 2022
				M5049 (M5049 100 mg)	vuknmsylbi(cfynsazfpk) = ybxrfyzyea wharjkrwpb (nzdrnptbqy, qbzuvtmkge - gjcacbcwzq) View more
NCT04448756 (ANEMONE, EULAR2022)	Phase 2	COVID-19 cytokines \| C-reactive protein \| D-dimer ... View more	149	Enpatoran 50 mg BID	(pmalffwwwh) = qdnyuwoqsb lypsduelba (uknethtksj ) View more	Positive	01 Jun 2022
				Enpatoran 100 mg BID	(pmalffwwwh) = kakpsjzioq lypsduelba (uknethtksj ) View more
NCT03676322 (Pubmed) Manual	Phase 1	Autoimmune Diseases	96	M5049 (single-dose)	(ctxdehofyv) = gjntvmuwus bqilelkyml (ohunuoxeob ) View more	Positive	01 Oct 2021
				M5049 (multiple-dose)	(ctxdehofyv) = lgvhmtrsps bqilelkyml (ohunuoxeob )

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