efgartigimod Indications

Clinical trial overview

gMG

Overview

gMG is a rare and chronic autoimmune disease where IgG autoantibodies disrupt communication between nerves and muscles, causing debilitating and potentially life-threatening muscle weakness.

In myasthenia gravis (MG), IgG autoantibodies either bind and occupy or cross-link and internalize the receptor on the muscle cells, thereby preventing the binding of acetylcholine, the signal sent by the nerve cell. In addition, these autoantibodies can cause destruction of the neuromuscular junction by recruiting complement, a potent cell-destroying mechanism of the human immune system. The muscle weakness associated with MG usually presents initially in ocular muscles and can then spread into a generalized form affecting multiple muscles, known as gMG. Approximately 85% of people with MG progress to gMG within 24 months (source: Behin et al. New Pathways and Therapeutics Targets in Autoimmune Myasthenia Gravis. J Neuromusc Dis 5. 2018. 265 – 277). MG in the ocular form initially causes droopy eyelids and blurred or double vision due to partial paralysis of eye movements. As MG becomes generalized it affects muscles in the neck and jaw, causing problems in speaking, chewing and swallowing. MG can also cause weakness in skeletal muscles leading to problems in limb function. In the most severe cases, respiratory function can be weakened to the point where it becomes life-threatening. These respiratory crises occur at least once in the lives of approximately 15% to 20% of MG patients. The U.S. prevalence of MG is estimated at approximately 20 cases per 100,000 (source: Philips et al, Ann NY Acad Sci. 2003).

Patients with confirmed AChR antibodies account for approximately 85% of the total gMG population (Behin et al. New Pathways and Therapeutics Targets in Autoimmune Myasthenia Gravis. J Neuromusc Dis 5. 2018. 265 – 277).

In May 2020, we announced positive topline results from the pivotal ADAPT clinical trial of efgartigimod for the treatment of gMG. The topline results from the ADAPT clinical trial showed that efgartigimod was well-tolerated, demonstrated clinically meaningful improvements in strength and quality of life measures, and provided the option of an individualized dosing schedule for gMG patients. The full Phase 3 ADAPT results were published in The Lancet Neurology in July 2021. The data from the ADAPT clinical trial and the subsequent OLE (ADAPT+) formed the basis for the regulatory approvals of VYVGART in the U.S., Japan, the EU, Mainland China, Israel, the UK and Canada.

On March 22, 2022, we announced positive topline results from the Phase 3 ADAPT-SC clinical trial, a registrational non-inferiority bridging clinical trial of efgartigimod SC for the treatment of gMG. efgartigimod SC achieved the primary endpoint of total IgG reduction from baseline at day 29, demonstrating statistical noninferiority to VYVGART IV formulation in gMG patients. Based on these results, we received regulatory approval in the U.S., the EU, China, Japan, Switzerland, the UK, Israel and Australia.

Other clinical trials

In 2024, we initiated registrational clinical trials to expand the VYVGART label into broader MG populations, including in seronegative gMG patients (ADAPT-SERON) and ocular MG patients (ADAPT-OCULUS). We also have clinical trials ongoing in pediatric gMG patients (ADAPT-JUNIOR) with efgartigimod IV and efgartigimod SC..

CIDP

Overview

CIDP is a chronic autoimmune disorder of peripheral nerves and nerve roots caused by an autoimmune-mediated destruction of the myelin sheath, or myelin producing cells, insulating the axon of the nerves and enabling speed of signal transduction. The cause of CIDP is unknown, but abnormalities in both cellular and humoral immunity have been shown. CIDP is a chronic and progressive disease: onset and progression occur over at least eight weeks in contrast with the more acute Guillain-Barré-syndrome. Demyelination and axonal damage in CIDP lead to loss of sensory and/or motor neuron function, which can lead to weakness, sensory loss, imbalance and/or pain. U.S. prevalence for CIDP patients is 42,000 of whom 24,000 are treated patients.

Most CIDP patients require treatment, the majority currently with IVIg. Glucocorticoids and plasma exchange are used to a lesser extent as they are either limited by side effects upon chronic use, in the case of glucocorticoids, or invasiveness of the procedure and access, which is restricted to specialized centers in case of plasma exchange. Alternative immunosuppressant agents are typically reserved for patients ineligible for or refractory to IVIg, glucocorticoids or plasma exchange.

In July 2023, we announced positive topline results from the ADHERE clinical trial evaluating VYVGART SC (efgartigimod alfa and hyaluronidase-qvfc) in adults with CIDP. The clinical trial met its primary endpoint (p=0.000039), demonstrating a significantly lower risk of relapse with VYVGART SC compared to placebo (HR: 0.39 95% CI: 0.25; 0.61). 67% of patients in open-label Stage A demonstrated evidence of clinical improvement, indicating that IgG autoantibodies play a significant role in the underlying biology of CIDP.

VYVGART SC was well-tolerated with a safety profile that is consistent with prior clinical trials and the known profile of VYVGART. The most frequent treatment-related adverse event was ISRs, which occurred in a lower percentage of patients than previous VYVGART SC clinical trials (20% in Stage A; 10% in Stage B). All ISRs were mild to moderate and resolved over time. 99% (226/249) of eligible patients continued to the ADHERE-Plus OLE clinical trial.

Based on these results, we received regulatory approval in the U.S. in June 2024, in China in November 2024 and in Japan in December 2024. Regulatory review is currently ongoing in other jurisdictions including in the EU.

Primary ITP

Overview

Primary ITP is an acquired autoimmune bleeding disorder, characterized by a low platelet count (<100×109/L) in the absence of other causes associated with thrombocytopenia. In most patients, IgG autoantibodies directed against platelet receptors can be detected. They accelerate platelet clearance and destruction, inhibit platelet production, and impair platelet function, resulting in increased risk of bleeding and impaired quality of life. Primary ITP is differentiated from secondary ITP, which is associated with other illnesses, such as infections or autoimmune diseases, or which occurs after transfusion or taking other drugs, such as cancer drugs. Platelet deficiency, or thrombocytopenia, can cause bleeding in tissues, bruising and slow blood clotting after injury. Patients may suffer from depression and fatigue as well as side effects of existing therapies, impairing their quality of life. Current therapeutic approaches include non-specific immunosuppression (e.g., steroids and rituximab), inhibition of platelet clearance (e.g., splenectomy, IVIg, anti-D globulin, and spleen tyrosine kinase inhibitor fostamatinib13) or stimulation of platelet production (e.g., thrombopoietin receptor agonist TPO-RA). Splenectomy remains the only treatment that provides sustained remission off therapy for one year or longer for a high proportion of patients. ITP affects approximately 72,000 patients in the U.S. (sources: Current Medical Research and Opinion, 25:12, 2961-2969; Am J Hematol. 2012 Sep; 87(9): 848 – 852; Pediatr Blood Cancer. 2012 Feb; 58(2): 216 – 220).

Phase 3 ADVANCE Clinical Trials

In 2019, the first of two registrational clinical trials, the ADVANCE clinical trial, was initiated to evaluate efgartigimod IV (VYVGART) for the treatment of primary ITP. The second registrational ADVANCE-SC clinical trial of efgartigimod SC for the treatment of primary ITP was initiated in 2020.

In May 2022, we announced positive Phase 3 data from the ADVANCE clinical trial. Primary endpoint was met, demonstrating that a significantly higher proportion of patients with chronic ITP receiving VYVGART (17/78; 21.8%) compared to placebo (2/40; 5%) achieved a sustained platelet response (p=0.0316), defined as having platelet counts greater than or equal to 50x109/L on at least four of the last six scheduled visits between weeks 19 and 24 of treatment. There was also a statistically significant separation from placebo in key platelet-derived secondary endpoints. Additional secondary endpoint data from the ADVANCE clinical trial are consistent with primary and secondary platelet-derived endpoints and provide additional context on metrics that often drive treatment decisions, including on International Working Group responder status.

VYVGART was well-tolerated in this 24-week clinical trial and the observed safety and tolerability profile was consistent with previous clinical trials. Results from ADVANCE-IV clinical trial were published in The Lancet in September 2023.

In November 2023, results of the second registrational clinical trial as part of the ongoing ITP development program for VYVGART in adult patients with chronic and persistent ITP were announced. Patients were heavily pre-treated and 75% of patients had received three or more prior ITP therapies. The clinical trial did not meet the primary endpoint of a sustained platelet count response in chronic ITP patients. Secondary endpoints were also not met, including additional endpoints on International Working Group responder status and mean platelet count change from baseline.

VYVGART SC was well-tolerated in ADVANCE-SC; the observed safety and tolerability profile was consistent with ADVANCE-IV and the confirmed safety profile of VYVGART and VYVGART SC.

Based on the results of the ADVANCE-IV clinical trial we received regulatory approval for VYVGART for the treatment of adults with ITP in Japan in March 2024. We have initiated ADVANCE-NEXT in the U.S. with efgartigimod IV in ITP in 2024.

Myositis

Overview

Myositis are a rare group of autoimmune diseases that can be muscle specific or affect multiple organs including the skin, joints, lung, gastrointestinal tract and heart. Myositis can be very severe and disabling and have a material impact on quality of life. Initially these Myositis were classified as either DM or polymyositis, but as the underlying pathophysiology of Myositis has become better understood, including through the identification of characteristic autoantibodies, new polymyositis subgroups have emerged. Two of these subtypes are IMNM and ASyS. Proximal muscle weakness is a unifying feature of each Myositis subset.

IMNM is characterized by skeletal muscle weakness due to muscle cell necrosis. The muscle weakness is typically symmetrical – on both sides of the body – and affects proximal muscles including hips, thighs, upper arms, shoulder and neck. The muscle weakness can be severe and lead to difficulty in completing daily tasks. Characteristic autoantibodies of IMNM, include anti-signal recognition particle and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase autoantibodies.

ASyS is characterized by muscle inflammation, inflammatory arthritis, interstitial lung disease, thickening and cracking of the hands (mechanic’s hands) and Raynaud phenomenon. Autoantibodies associated with ASyS attack tRNA synthetase enzymes and include anti-Jo-1 and anti-PL1 and PL-12 most commonly.

DM is characterized by muscle inflammation and degeneration and skin abnormalities, including heliotrope rash, Gottron papules, erythematous, calcinosis and edema. DM is associated with Myositis-specific autoantibodies, including anti-Mi-2, anti-MDA-5, anti-TIF-1γ and others.

There are no current FDA-approved therapies for IMNM or ASyS. IVIg (Octagam 10%) was approved by the FDA for the treatment of DM in July 2021. Myositis patients are most often treated with high-dose steroids.

ALKIVIA Clinical Trial

We initiated the registrational ALKIVIA clinical trial of efgartigimod SC for the treatment of Myositis in 2022. The clinical trial will enroll approximately 240 patients in three Myositis subtypes, IMNM, ASyS and DM. The clinical trial is being conducted in two Phases, with an analysis of the Phase 2 portion of the clinical trial, including 30 patients of each subtype, followed by conduct of the Phase 3 portion of the clinical trial only if a signal is observed in the Phase 2 portion of the clinical trial.

The primary endpoint is the total improvement score (TIS) at the end of the treatment period. Key secondary endpoints include response rates at the end of treatment, time to response, and duration of response in TIS, as well as change from baseline in individual TIS components. Other secondary endpoints include quality of life and other functional scores.

In November 2024, argenx announced our ‘GO’ decision to continue clinical development of efgartigimod SC in the seamless phase2/3 ALKIVIA clinical trial (ongoing) in all three Myositis subtypes following analysis of topline data from the Phase 2 portion of the clinical trial. The decision is supported by the efficacy and safety results from the Phase 2 portion of the seamless Phase 2/3 ALKIVIA clinical trial. Overall, the clinical trial met its primary endpoint, demonstrating a statistically significant treatment effect in mean TIS at Week 24, and showed improvement across all six core set measures of the TIS in favor of efgartigimod SC compared to placebo. The observed safety and tolerability profile was consistent to that demonstrated with other clinical trials.

TED

Overview

TED is an autoimmune orbital disease associated with Graves’ disease and other autoimmune thyroid pathologies such as Hashimoto’s thyroiditis. TED is characterized by extraocular muscle enlargement, orbital adipose tissue expansion, and orbital inflammation, which can lead to proptosis, diplopia, or vision loss in severe cases. Persistent orbital symptoms often impair patient QoL long-term.

Substantial nonclinical and clinical evidence supports thyrotropin receptor autoantibodies as causative in the pathology of TED. Clinical evidence supports the removal of autoantibodies as a mechanism for the treatment of TED. By reducing IgGs, including TED-associated pathogenic IgG autoantibodies, efgartigimod is expected to ease disease manifestations. Additionally, IgG reduction could address the underlying hyperthyroidism. Side effects and tolerability issues with current therapies, including steroids and teprotumumab (only FDA-approved biologic), are treatment limiting for many patients based on comorbidities and a significant unmet need remains for safe and convenient therapies.

UplighTED Clinical Trials

The UplighTED program aims to evaluate the efficacy and safety of weekly efgartigimod for SC administration in pre-filled syringe, coformulated with rHuPH20 (efgartigimod PH20 SC) in two randomized, placebo-controlled, double-blinded studies. Adult participants with moderate-to-severe active TED, with controlled baseline autoimmune thyroid pathology are dosed with 1000mg efgartigimod PH20 SC or placebo PH20 SC for 24 weeks and evaluated for proptosis response. At the end of the treatment period, participants will enter a follow-up observational period to assess safety, tolerability, and durability of efgartigimod PH20 SC treatment while off therapy or an open-label treatment period depending on their response to study treatment.

SjD

Overview

SjD is a chronic, progressive autoimmune disease, characterized by lymphocytic infiltration and progressive destruction of exocrine glands. B-cells play a pivotal role in the development of the disease and this results amongst others in production of IgG autoantibodies, especially those which target SSA/Ro, SSB/La ribonuclear complexes. In addition to symptoms of dry eyes, dry mouth, chronic pain and fatigue, a substantial subset of patients suffer from extraglandular systemic disease. There are no FDA-approved treatments currently registered for the treatment of SjD.

Phase 2 RHO Clinical Trial (in partnership with IQVIA)

In March 2024, argenx announced its plan to continue the development of efgartigimod to Phase 3 in adults with primary SjD, following the analysis of topline data from the Phase 2 RHO clinical trial.

• The decision to advance the clinical development of efgartigimod in SjD was supported by the safety, efficacy and biomarker results from the clinical trial. The observed safety and tolerability profile was consistent with other clinical trials. Efficacy assessments showed a treatment effect across multiple clinical endpoints, which were also consistent with biomarker data.
  • In the RHO clinical trial, efgartigimod demonstrated increased response on composite endpoints (CRESS, STAR, ESSDAI (22 – 34%)). A response was observed in four out of five items of CRESS.
  • The IgG reduction and biomarker data correlated to clinical benefit and efgartigimod was well tolerated and safe similar to other clinical trials.

Phase 3 UNITY Clinical Trial (in partnership with IQVIA)

In 2024, we initiated a Phase 3 clinical trial evaluating efgartigimod PH20 SC for the treatment of SjD. The Unity clinical trial is a randomized, placebo-controlled, double-blind clinical trial evaluating safety and efficacy of efgartigimod PH20 SC. The clinical trial plans to enroll 480 patients with at least moderate systemic disease (ClinESSDAI ≥6). Patients have to be on stable background treatment and positive for anti-SSA/Ro. At the end of the 48-week treatment period, participants who complete the clinical trial may roll over into an OLE. The primary endpoint is change from baseline in the clinESSDAI (Clinical ESSDAI). Key secondary endpoints will focus on patient-reported outcomes, ESSDAI (EULAR Sjögrens Syndrome Disease Activity Index), and STAR (Sjögren’s Tool for Assessing Response, composite endpoint).

LN

Overview

LN is an inflammatory autoimmune disease of the kidney and one of the most severe and common organ manifestations of the autoimmune disease systemic lupus erythematosus (SLE). In patients with SLE, approximately 25% to 50% have signs or symptoms of kidney disease at SLE onset. Approximately 40% to 60% of patients with SLE will develop renal involvement during the course of disease, with substantial morbidity or mortality. Pathogenic autoantibodies and complement deposits are critically involved in SLE pathogenesis and particularly LN, where renal deposition of immune complexes is a hallmark of the disease. Autoantibodies associated with LN include anti-dsDNA, anti-C1q, anti-cardiolipin, anti-Smith and anti-nuclear antibodies. 10 – 30% of LN patients progress to end-stage renal disease. Oral corticosteroids and broad immunosuppressants are current standards of care but are not uniformly effective. Belimumab (Benlysta) and voclosporin (Lupkynis) are approved by the FDA for the treatment of LN.

Phase 2 POC Clinical Trial (in partnership with Zai Lab)

In 2023, we initiated a POC clinical trial to evaluate the efficacy and safety of efgartigimod IV in Chinese patients with active LN. The clinical trial plans to enroll approximately 60 patients with LN class III or IV (with or without class V).

The primary endpoint is the change in urine protein creatinine ratio from baseline to end of the treatment period. Key secondary endpoints include proportion of patients achieving complete and partial renal response at the end of treatment period and time to complete renal response and partial renal response. Other secondary endpoints include additional efficacy measurements, PK, PD, immunogenicity, biomarkers, safety, and quality of life assessments.

Other efgartigimod Indications

AMR

AMR is an autoimmune disease that affects transplanted organs and can contribute to allograft loss. AMR in kidney allografts is driven by donor specific antibodies, which often target HLA antigens expressed by endothelial allograft cells. Through different mechanism, donor specific antibodies can induce microvascular inflammation, a histopathological hallmark of AMR. Microvascular inflammation leads to loss in organ function which, if continued, can result in allograft loss. The unmet need for an efficacious treatment is very high, as evidenced by AMR being the leading cause of kidney transplant failure. There are currently no approved therapies for treating AMR.

Phase 2 shAMRock Clinical Trial Design

In the end of 2024, we initiated a Phase 2 POC study to evaluate efgartigimod PFS in kidney transplant recipients with AMR. The clinical trial will enroll ~30 participants, randomized 1x1x1 across 2 treatment arms and placebo. Primary endpoint is safety and tolerability and secondary endpoints include efficacy endpoints around estimated glomerular filtration rate, kidney biopsy, urine protein creatinine ratio and survival.

Partnerships for efgartigimod indications

Zai Lab Limited

Pursuant to the Zai Lab Agreement, Zai Lab obtained the exclusive right to develop and commercialize efgartigimod in Greater China. Zai Lab will also contribute patients to our global Phase 3 clinical trials of efgartigimod. Our Zai Lab strategic collaboration allows us to accelerate development of efgartigimod into new autoimmune indications with Zai Lab taking operational leadership of selected Phase 2 POC clinical trials.

In 2022 Zai Lab initiated the Phase 2 POC clinical trials in MN and LN, which both fall within the emerging nephrology indications. Zai Lab also completed a Phase 1 PK/PD clinical trial to support the approval of efgartigimod for gMG in Mainland China and to obtain regulatory approvals to enroll Chinese patient into our global Phase 3 clinical trials.

IQVIA

On December 2, 2021 we entered into a strategic asset development agreement (Asset Development Agreement) with IQVIA. Pursuant to the Asset Development Agreement, IQVIA shall perform asset and indication development services for efgartigimod through an advanced outsourcing model. Such services include, but are not limited to, overall product indication development strategy, design of clinical trial protocol, set-up, execution and management of clinical development plans for an indication for efgartigimod selected by us.

To enable and encourage fast and innovative delivery of the services by IQVIA, the Asset Development Agreement contains an innovative earn-back and bonus plan based upon the performance of IQVIA.

Clinical trials that have been discontinued:

• In May 2024, the decision was made to discontinue planned development of efgartigimod in AAV following the risk assessment of all ongoing clinical trials based on learnings from ADDRESS (PV) and ADVANCE SC (ITP) clinical trials. We determined the risk did not outweigh the benefit in AAV given the potentially unmanageable interference of background medications.
• In June 2024, we announced results from the Phase 2 ALPHA clinical trial of efgartigimod in PC-POTS. Based on the results, we decided not to move forward development of efgartigimod in PC-POTS.
• In October 2024, we announced the discontinuation of development of efgartigimod in MN. This decision was based on the observation that no clear signal was seen in the blinded data, which was part of an interim review by the executive data review team and the data and safety monitoring board.
• Early January 2025, we announced our decision to discontinue development in BP based on results from 98 patients in the Phase 2 BALLAD clinical trial.