Argenx: A Clinical-Stage Biotech with Near $1.2B in Net Product Sales Despite Recent Phase 3 Setbacks

In November 2023, biopharmaceutical company Argenx announced that its Phase 3 ADVANCE-SC study of subcutaneous efgartigimod for the treatment of primary immune thrombocytopenia (ITP) failed to meet its primary endpoint. One month later, Argenx revealed that its Phase 3 ADDRESS study evaluating the drug for the treatment of adult patients with pemphigus vulgaris (PV) and pemphigus foliaceus (PF) also failed to meet both its primary and secondary endpoints, causing its stock price to plummet by 25% on the same day.

Founded in the Netherlands in 2008, Argenx focuses on developing differentiated therapeutic antibodies for the treatment of cancer and autoimmune diseases. In July 2014, Argenx successfully completed its initial public offering (IPO) on Euronext Brussels, raising €40 million. Since its listing in 2017, the company’s market capitalization surpassed $10 billion within just two years. Even in 2023, a year marked by setbacks, the company’s net product sales reached $1.191 billion, with a compound annual growth rate (CAGR) of 21% in global product revenue. Although the growth rate of net product sales slowed compared to 2022, the overall trend remained steadily upward.

 Net Product SalesVariation Diagram（(Image source: Argenx official website)

Despite repeated failures in Phase III clinical trials and setbacks across multiple indications, Argenx’s net product sales still reached nearly $1.2 billion. ArgenxUltimatelyUpholdingWhat kind ofDevelopmentStrategy,CanMarket“Like a Fish in Water”？

Argenx was co-founded by Tim Van Hauwermeiren and Hans de Haard, with its headquarters in the Netherlands and offices in the United States, Japan, Switzerland, and Belgium.。

The Founder's Global“Footprints” have laid the foundation for Argenx’s global expansion. Tim has more than 20 years of experience in general management and business development. He holds a Master of Science in Bioengineering from Ghent University and an Executive MBA from Vlerick Business School.

Tim Van Hauwermeiren（Image source:Argenx Official Website)

Hans holds a Ph.D. in Molecular Immunology from Maastricht University in the Netherlands and serves as a Professor of Immunology at the University of Franche-Comté in France. Active in the field of antibody engineering since 1989, Hans is undoubtedly a pioneer in antibody platforms.He established a large non-immune human Fab library at Maastricht University., this library later became the core asset of the biopharmaceutical company Dyax, leading to the development of multiple therapeutic antibodies, including IMC-1F8, the high-affinity humanized anti-IGF-1R monoclonal antibody IMC-A12, and the human vascular endothelial growth factor receptor 2 (VEGFR2) antagonist ramucirumab (IMC-1121B).

From 1998 to 2002, Hans was responsible at Unilever for developing products based on VHHs (naturally occurring heavy-chain antibodies lacking light chains found in camels; cloning their variable regions yields single-domain antibodies composed solely of the heavy-chain variable region). Prior to joining Argenx, Hans worked at Ablynx, an innovative Nanobody pharmaceutical company (acquired by Sanofi for €3.9 billion in 2018), where he was responsible for establishing Nanobody^®Discovery Engine, and as a core member, participated in the development of Nanoclone based on B-cell selection^®Methods.

Hans de Haard（Image source:Argenx Official Website)

ArgenxAble toAcquisitionGoodMarketPresentation，TechnologyAdvantagesYesImportantFactors。Among themPackageParenthesesSIMPLE Antibody™ Platform,Three ItemsFc Engineering Technology (NHANCE^®、ABDEG^™andPOTELLIGENT^®) andENHANZESC^®Drug Administration Techniques. The following sections provide a detailed introduction to each.

·SIMPLE Antibody™ Platform

Hailed as“Ships of the Desert”: Camels can survive in harsh environments; even when high viral loads are detected in their bodies, they rarely exhibit clinical symptoms. This raises the question: Do camelids possess unique adaptive immunological features not widely observed in other species? In fact, the camel immune system contains two types of antibodies with distinct structures: heavy-chain-only antibodies (HCAbs) and conventional antibodies (IgG1), which differ from traditional antibody architectures.

The world's only one based on llamaSIMPLE Antibody™, Argenx’s proprietary platform for the development of therapeutic antibody drugs targeting the IgG1 variable (V) region.Camelids'IgG1 antibodies offer the following advantages: ① High diversity and high affinity: Camelids have low rates of inbreeding, significant genetic background diversity, and strong immune responses to exogenous antigens. ② High degree of humanization: The variable (V) regions of camelid IgG1 antibodies share high structural homology with human antibody V regions, facilitating simpler subsequent humanization engineering and demonstrating substantial therapeutic potential.When the llama immune system mounts an immune response against human disease targets, it generates a highly diverse antibody repertoire, thereby enabling the development of novel therapeutics targeting complex disease biology.

· Three Fc engineering technologies (NHANCE^®、ABDEG™ and POTELLIGENT^®）

IgG1 antibodies comprise two light chains (composed of VL and CL domains) and two heavy chains (composed of VH, CH1, hinge, CH2, and CH3 domains), NHANCE^®、ABDEG™ and POTELLIGENT®^®Technologies can engineer antibodiesFc region (CH2 and CH3 domains), thereby enhancing its intrinsic therapeutic properties. In addition, Argenx obtained a non-exclusive research license and option from Chugai Pharmaceutical Co., Ltd. of Japan for the SMART-Ig and ACT-Ig technologies.These technologies enableArgenx can expand the therapeutic index of its drug candidates by modulating their half-life, tissue penetration, clearance, and potency.

Schematic Diagram of IgG1 Antibody (Image Source: Argenx Official Website)

·ENHANZESC^®Drug Administration Techniques

Argenx and drug delivery technology company Halozyme Therapeutics announced a global collaboration and license agreement in February 2019, and expanded the agreement in October 2020, granting Argenx rights to ENHANZE® for FcRn, C2 targets, and four other targets.^®Exclusive right to use the technology.ENHANZE^®The technology can shorten administration time, offering flexibility and convenience in drug delivery.

Currently,Argenx has more than 20 drug pipelines, including two products, VYVGART^®andVYVGART^®HYTRULOCompletedMarket Launch, VYVGART^®Global net product sales reached US$400.7 million in the first year after launch (2022).

 2022 Global Net Product Sales (Source: Argenx Official Website)

In December 2021, the FDA approvedEfgartigimod（VYVGART^®，efgartigimod alfa-fcab）"Launched for the treatment of"Generalized myasthenia gravis (gMG) in adult patients who are positive for AChR antibodies. Approved by Japan’s PMDA in January 2022（VYVGART^®，efgartigimod alfa-fcab）For the treatment of adult patients with generalized myasthenia gravis (gMG) who have had an inadequate response to steroid or non-steroid immunosuppressive therapies (ISTs).Thus,VYVGART^®The first and only approved in the United States and JapanFcRn Inhibitors.

VYVGART^®(Image source: AArgenx Official Website)

VYVGART^®HYTRULO is a combination formulation targeting FcRn, containing two components: efgartigimod alfa and hyaluronidase (recombinant human hyaluronidase PH20). InVYVGART^®on the basis of improvement and addition of agents that can enhance the permeability of subcutaneous tissuehyaluronidase, thereby transitioning from intravenous infusion to a subcutaneous injection formulation. It was approved by the FDA in June 2023 for the treatment of adult patients with anti-acetylcholine receptor (AChR) antibody-positive generalized myasthenia gravis (gMG).In January 2024, Argenx announced that Japan’s Ministry of Health, Labour and Welfare had approved VYVDURA^®For subcutaneous injection in the treatment of conditions responsive to steroid or non-steroid immunosuppressants (ISTs) adult patients with generalized myasthenia gravis (gMG) who have had an inadequate response.Based on this,Efgartigimod has been approved in Japan for both intravenous infusion and subcutaneous injection formulations.

VYVGART^®HYTRULO (Image source: Argenx official website)

Efgartigimod, the “flagship” investigational product in Argenx’s drug pipeline, is a class of antibody fragments designed to target the neonatal Fc receptor (FcRn).TargetedFcRn antibodies can be used to treat patients with severe autoimmune diseases characterized by pathogenic immunoglobulin G (IgG) autoantibodies.。FcRn can extend the half-life of IgG. Argenx’s ABDEG™ technology enhances the affinity of efgartigimod for FcRn, thereby blocking the binding of IgG to FcRn, accelerating IgG degradation, and reducing its recycling. As shown in the figure below:

 Mechanism of Action of Efgartigimod (Image source: Argenx official website)

andSimilar to antibody drugs with multiple indications, such as those targeting PD-1 and TNF-α, efgartigimod holds the potential of being “a pipeline in a drug.” This answers the question raised at the beginning of the article: it is precisely its broad range of clinical indications that has enabled Argenx to achieve success in generalized myasthenia gravis (gMG) and chronic inflammatory demyelinating polyneuropathy (CIDP), while continuing to actively expand into several other indications despite successive setbacks in immune thrombocytopenia (ITP), pemphigus vulgaris (PV), and primary focal segmental glomerulosclerosis (PF).

 Drug Pipeline Chart (Source:Argenx Official Website)

According toArgenxOfficial website,itsThe main body of R&D work is not limited to company employees,AlsoThrough the Immunology Innovation Program(IIP) collaborates with leading academic researchers, including Columbia University, NYU School of Medicine, and the University of Turin. IIP translates academic breakthroughs in disease biology and disease pathways within the field of immunology into clinical development candidates, thereby enabling the development of novel antibody drugs. As shown below:

 IncompleteIIP Table (Compiled by VCBeat based on public data)

In addition to R&D collaborations with academia, in the current financing environment, such asLicense-outetc.BD partnership models are highly valued by biotech companies. Argenx is no exception, having explored various collaboration approaches, including early-stage R&D partnerships, cost-sharing agreements, and exclusive licensing deals.

 NearThree YearsBD Cooperation Table (Compiled by VCBeat Based on Public Data)

In January 2021, Argenx entered into an exclusive licensing agreement with Zai Lab, a rising star in China’s biotechnology sector (listed on the NASDAQ in September 2017), for efgartigimod. Since then, Zai Lab has been accelerating the commercialization of efgartigimod in China.

Last yearIn June, efgartigimod intravenous injection (brand name: Vyvgart®) Approved by China’s National Medical Products Administration, in combination with conventional therapeutic agents, for the treatment ofAdult patients with AChR antibody-positive gMG. Last July, the National Medical Products Administration (NMPA) accepted the new drug application for the subcutaneous formulation of efgartigimod for the treatment of generalized myasthenia gravis. Last September, the Center for Drug Evaluation of the NMPA granted breakthrough therapy designation to the subcutaneous formulation of efgartigimod for the treatment of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).Wei Weijia®It is the first and currently only approved product in China.FcRn antagonist, which was included in China's National Reimbursement Drug List last December.

According to The Lancet (Research data published in The Lancet) indicate that the incidence and prevalence of 19 common autoimmune diseases have generally increased over time, with the overall prevalence reaching 11. during 2017–2019.0%。^[1]SinceAutoimmune diseases have numerous triggers, are associated with factors such as age, sex, season, and comorbidities, and are difficult to prevent. Therefore, targetingThere is a medical need for novel FcRn-targeting antibody drugs. By blocking the binding of FcRn to pathogenic IgG antibodies, these agents can reduce IgG antibody levels, thereby achieving the treatment of autoimmune diseases.

《The “14th Five-Year Plan” for the Development of the Pharmaceutical Industry also mentions promoting the industrialization of innovative pharmaceutical products, with a focus on developing new chemical drugs with novel targets and mechanisms to address major clinical needs such as autoimmune diseases, as well as the treatment needs for rare diseases. In the field of antibody drugs, priority is given to the development of novel antibody drugs targeting immune-related diseases.

Last YearIn June, Harbour BioMed announced that the National Medical Products Administration (NMPA) had accepted its Biologics License Application (BLA) for batoclimab (HBM9161), an investigational drug for the treatment of generalized myasthenia gravis (gMG). Earlier this February, Johnson & Johnson announced that nipocalimab, an investigational antibody, had met its primary endpoint and achieved positive top-line results in the pivotal Phase 3 VIVACITY trial evaluating the treatment of adult patients with generalized myasthenia gravis (gMG). Currently, few companies in China are intensifying their strategic investments in the field of novel FcRn-targeting therapeutics, indicating promising development prospects.

References:

[1]Conrad N, Misra S, Verbakel JY, Verbeke G, Molenberghs G, Taylor PN, Mason J, Sattar N, McMurray JJV, McInnes IB, Khunti K, Cambridge G. Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: a population-based cohort study of 22 million individuals in the UK. Lancet. 2023 Jun 3;401(10391):1878-1890.