Argenx's VYVGART Hytrulo Approved for CIDP, First Novel Therapy in Over 30 Years

On June 21 local time, immunology company Argenx announced that the U.S. FDA has approved an expanded indication for VYVGART Hytrulo (efgartigimod subcutaneous injection) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).

VYVGART is currently the first and onlyThe FcRn antagonist approved for the treatment of CIDP is also the first new therapy with a clearly defined mechanism of action to be approved for CIDP in more than 30 years. According to the press release, VYVGART is administered once weekly for the treatment of CIDP, with each injection taking approximately 30 to 90 seconds.

According to forecasts by ODDO BHF analysts, VYVGART’s sales across multiple indications are projected to peak at $11 billion (approximately RMB 79.879 billion) in 2035, positioning it as a potential blockbuster drug on par with Humira.

Among the approximately 100 known autoimmune diseases worldwide, a significant proportion are associated with autoantibodies (AAb), including common and severe conditions such as type 1 diabetes, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis, and inflammatory bowel disease. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is also a rare autoimmune disease linked to AAb.

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is an immune-mediated polyneuropathy (clinically also referred to as symmetric weakness), characterized by demyelination resulting from autoimmune antibody (AAb) attacks on the myelin sheath, accompanied by endoneurial interstitial and perivascular infiltration of inflammatory T cells and macrophages. Its prevalence ranges from 1/10,000 to 9/10,000, with a clinical course marked by chronic progression or slow relapse. Typical clinical manifestations include bilateral symmetric proximal or distal limb weakness accompanied by sensory disturbances. Cerebrospinal fluid examination reveals albuminocytologic dissociation, while neuroelectrophysiological studies demonstrate slowed peripheral nerve conduction velocity, conduction block, and abnormal temporal dispersion of waveforms.

Following disease onset, patients experience a range of motor and sensory issues, including difficulty rising from a seated position, pain, fatigue, and frequent tripping or falling. As the disease progresses, many patients become dependent on wheelchairs and are unable to work. Without timely treatment, severe cases can lead to quadriplegia, respiratory failure, and death.

Currently, the diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) relies primarily on clinical assessment and electrophysiological studies. In recent years, with the continuous advancement of magnetic resonance imaging (MRI) technology, an increasing number of researchers have applied MRI to evaluate CIDP.However, from a diagnostic perspective, CIDP lacks highly characteristic symptoms and a single, definitive diagnostic test; therefore, establishing a confirmed diagnosis may require a prolonged period.

From a therapeutic perspective, intravenous immunoglobulin (IVIG), glucocorticoids, and plasma exchange are commonly used treatments for chronic inflammatory demyelinating polyneuropathy (CIDP); however, their efficacy is quite limited. Currently, approximately 85% of patients require ongoing treatment, and nearly 88% of treated patients still experience functional impairment and disability.

Taking intravenous immunoglobulin (IVIG) as a first-line therapy, the dosage for each patient is calculated by physicians based on disease severity and body weight. If IVIG proves effective, it can be administered repeatedly at intervals of 4–8 weeks. Currently, there are approximately 16,000 patients with chronic inflammatory demyelinating polyneuropathy (CIDP) in the United States, corresponding to an IVIG market size of nearly $1.5 billion (approximately RMB 10.89 billion). However, as IVIG is a blood-derived product with limited supply, the approval and launch of VYVGART offers a complementary or alternative treatment option.

VYVGART is a subcutaneous combination therapy comprising efgartigimod alfa (an FcRn antagonist, which is a human IgG1 antibody fragment administered via intravenous infusion) and recombinant human hyaluronidase PH20.This therapy binds to the neonatal Fc receptor (FcRn), thereby reducing the interaction between FcRn and IgG, accelerating IgG degradation, and lowering circulating levels of various antibodies—including those implicated in myasthenia gravis—thus exerting an effect similar to that of plasma exchange.

Its intravenous (IV) formulation was approved in December 2021, becoming the first FDA-approved FcRn blocker. Recombinant human hyaluronidase PH20, developed by Halozyme Therapeutics, degrades hyaluronic acid in the body to facilitate the penetration and absorption of subcutaneously injected drugs, providing patients with additional treatment options.

This FDA approval of VYVGART for CIDP is based on the data results from the ADHERE clinical study (the ADHERE study is the largest clinical study to date for the treatment of CIDP).In clinical studies, 69% (221/322) of patients receiving subcutaneous efgartigimod treatment, regardless of prior treatment history, confirmed clinical improvement, including improvements in mobility, function, and strength.

The ADHERE study met its primary endpoint (p<0.0001). The study demonstrated that subcutaneous efgartigimod reduced the risk of relapse by 61% compared with placebo (HR: 0.39; 95% CI: 0.25, 0.61). Upon completion of the ADHERE study, 99% of eligible patients continued to participate in the ADHERE+ open-label extension study. The safety profile of subcutaneous efgartigimod was generally consistent with the known safety profile observed in previous clinical studies and real-world use of intravenous efgartigimod.

In actual clinical practice, efgartigimod can be used as a rescue therapy or for rapid symptom improvement, similar to intravenous immunoglobulin (IVIG) or plasma exchange. It can also be administered periodically as maintenance therapy for myasthenia gravis, particularly in patients who have an inadequate response to conventional immunotherapies or who are intolerant to other immunotherapies.

Overall, this therapy is characterized by rapid onset of action and low immunogenicity. It improves muscle strength and function across multiple muscle groups and has demonstrated a favorable safety profile in both clinical trials and expanded access studies.

Leveraging this advantage, Argenx has maximized the therapeutic potential of VYVGART.

In addition to CIDP, VYVGART is being evaluated for its efficacy in treating a variety of severe autoimmune diseases, including myasthenia gravis, thyroid eye disease (TED), bullous pemphigoid (BP), primary Sjögren’s syndrome (pSS), post-COVID-19 postural orthostatic tachycardia syndrome (PC-POTS), membranous nephropathy (MN), lupus nephritis (LN), primary immune thrombocytopenia (ITP), pemphigus vulgaris and pemphigus foliaceus (PV and PF), idiopathic inflammatory myopathies, ANCA-associated vasculitis (AAV), and antibody-mediated rejection (AMR), with up to 13 indications under investigation.

According to forecasts by ODDO BHF analysts, VYVGART’s sales across multiple indications are projected to peak at $11 billion in 2035, positioning it as a potential blockbuster “drug king” akin to Humira.

Previously, in June 2023, the FDA approved VYVGART Hytrulo (efgartigimod alfa and hyaluronidase-qvfc) for subcutaneous injection to treat adult patients with generalized myasthenia gravis (gMG) who are positive for anti-acetylcholine receptor (AChR) antibodies. In the same month and year, efgartigimod for subcutaneous injection (brand name: Weijiajia) was approved for marketing by the National Medical Products Administration (NMPA), becoming the first and currently only approved FcRn antagonist in China. It is used in combination with conventional therapeutic agents for the treatment of adult gMG patients who are AChR antibody-positive.

Since January 1, 2024, efgartigimod has been included in the updated National Reimbursement Drug List (NRDL) and implemented uniformly across China. It is currently the only FcRn antagonist eligible for medical insurance reimbursement in the country. Prior to its inclusion in the NRDL, the annual treatment cost for patients with generalized myasthenia gravis using efgartigimod was approximately RMB 400,000, based on five treatment cycles per year. After its inclusion, the reimbursement rate for local patients in Jinan ranges from 40% to 81%. For eligible patients undergoing five treatment cycles annually, the out-of-pocket annual treatment cost after insurance reimbursement is reduced to a minimum of RMB 40,000–50,000.

Behind the future “blockbuster drug” stands Argenx, a global immunology company. Founded in 2008, Argenx has seen its stock price soar since its NASDAQ listing in 2017, achieving a peak return of nearly 2,000% (as of July 2023). Its market capitalization stood at approximately $23.44 billion as of June 24, 2024.

In the autoimmune disease sector, teeming with large multinational corporations (MNCs), Argenx’s achievement of its current success is underpinned by a logic worthy of emulation.

First, technically,Argenx’s SIMPLE Antibody platform is the world’s only technology platform for developing therapeutic antibody drugs based on the variable regions of llama IgG1 antibodies. Due to the low rate of inbreeding in llamas, this platform can generate antibodies with high affinity and high diversity. Furthermore, the variable region of llama IgG1 antibodies shares over 80% homology with that of human antibodies, facilitating humanization.

Secondly, at the level of indication layout strategy,Argenx has opted to temporarily avoid direct confrontation with multinational corporations (MNCs), instead focusing on differentiated indications, including relatively “rare and niche” yet underserved autoimmune diseases such as myasthenia gravis, chronic inflammatory demyelinating polyradiculoneuropathy, primary immune thrombocytopenia, prurigo nodularis, lichen planus, bullous pemphigoid, idiopathic inflammatory myopathies, and thyroid eye disease.

On the other hand, rare autoimmune diseases may not be so rare. According to data from Debang Pharmaceutical, the total number of patients in the United States across the 13 indications targeted by VYVGART exceeds 1.4 million.

Furthermore, Argenx has a long-term strategy—the Immunology Innovation Program (IIP)., committed to combining the deep understanding of disease and biological mechanisms from the company’s external scientific and academic collaborators with its antibody engineering expertise to build a highly differentiated pipeline. VYVGART, approved in this article, was born out of this initiative. Argenx obtained the exclusive patent for VYVGART through collaboration with Professor Sally Ward’s team at the University of Texas Southwestern Medical Center.

Finally, regarding the overarching direction of drug structure,VYVGART differs from its competitors. VYVGART is an in vitro recombinant protein fragment of the Fc region derived from human IgG1. Using Argenx’s proprietary mutation platform, the Fc fragment sequence was mutated at five sites, significantly enhancing the binding affinity between the Fc protein and FcRn under both neutral and acidic conditions. In contrast, competitors such as UCB and Johnson & Johnson offer humanized antibodies in various forms.

In China, Zai Lab secured the rights to efgartigimod (VYVGART) for mainland China, Hong Kong, Macao, and Taiwan in January 2021, with an upfront payment of $75 million (totaling $175 million). On June 30, 2023, efgartigimod was approved in China for use in combination with standard therapies for adult patients with generalized myasthenia gravis who are positive for acetylcholine receptor (AChR) antibodies. In May 2024, the National Medical Products Administration (NMPA) accepted and granted priority review to the supplemental Biologics License Application (BLA) for the subcutaneous formulation of efgartigimod for the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP). The anticipated approval of subcutaneous efgartigimod is expected to bring significant benefits to Zai Lab.

References:

1. “The Power of a Blockbuster: A Hundred-Billion-Dollar Acquisition in the Making, Two Domestic Lucky Winners Set to Skyrocket”

2. “FDA Grants Priority Review to Supplemental New Drug Application for New Indication of Subcutaneous Efgartigimod”

3. “Biotech: A Hundred-Billion-Dollar Market Cap, Powered by Just One Product”