Rozanolixizumab for Myasthenia Gravis: a breakthrough treatment and future prospects

ABSTRACT

Myasthenia gravis is a rare chronic autoimmune disorder affecting the post-synaptic neuromuscular junction, primarily mediated by pathogenic immunoglobulin G (IgG) targeting specific proteins like acetylcholine receptor (AChR), muscle-specific tyrosine kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (LRP4). Modulating pathogenic IgG is a promising approach for disease management. Rozanolixizumab, a human IgG4 neonatal Fc receptor (FcRn) inhibitor, enhances the degradation of pathogenic IgG by 78%, marking a significant advancement in treating generalized myasthenia gravis. It offers effective management for patients with AChR or MuSK antibodies and is administered subcutaneously with mild to moderate adverse events. However, the safety and efficacy of rozanolixizumab require further validation through real-world post-marketing studies. If current trial results are confirmed, rozanolixizumab may become a preferred treatment option for myasthenia gravis in the near future. This review examines clinical trials evaluating the pharmacokinetics, efficacy, and safety of rozanolixizumab in patients with generalized myasthenia gravis and discusses ongoing trials and future research directions.

Plain Language Summary

Myasthenia gravis is a rare disease where the immune system attacks nerve-muscle connections, causing muscle weakness. This happens because the body produces harmful antibodies against certain proteins involved in muscle movement. Rozanolixizumab is a new treatment that targets these harmful antibodies. It works by helping to remove these antibodies from the body more effectively. This treatment has shown promise in helping people with myasthenia gravis, especially those with specific types of antibodies. It is given as an injection under the skin and usually has only mild to moderate side effects. However, more studies are needed to confirm how well it works and how safe it is in everyday use. If future research supports the current findings, rozanolixizumab might become a top choice for treating this condition. This review looks at the studies done so far on rozanolixizumab, including how the drug behaves in the body, how effective it is, and its safety. It also covers ongoing research and what the future might hold for this treatment.

1. Introduction

1.1. Background on generalized myasthenia gravis (gMG)

Myasthenia gravis (MG) is a chronic autoimmune disorder affecting the neuromuscular junction, characterized by fluctuating muscle weakness with an annual incidence of 10–29 cases per 1 million people and a prevalence of 100–350 cases per 1 million [1]. This condition arises from the production of immunoglobulin G (IgG) autoantibodies targeting post-synaptic membrane proteins, which include acetylcholine receptors (AChR) around 80% of the time, and the remaining 20% may either have muscle-specific tyrosine kinase (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4) or maybe seronegative [2]. Anti-AChR and anti-LRP4 antibodies are primarily of the IgG1 subtype, whereas anti-MuSK antibodies are of the IgG4 subtype [3]. Patients with MG can experience varying clinical symptoms and responses to treatment, which are linked to these specific antigenic targets [4]. During flare-ups, severe muscle weakness can lead to significant health issues, including morbidity and mortality. The severity of symptoms can vary greatly among patients, potentially leading to both physical and psychological challenges.

1.2. Overview of current treatment options

Over time, the prevalence of MG has increased due to advancements in therapeutic medications and an extended life expectancy among patients [5]. Immunosuppressive agents play a crucial role in the management by suppressing the production of autoantibodies and facilitating its clearance [6]. Corticosteroids are the primary and most used immunotherapeutic agent in MG due to the relatively fast onset of action (around 2–5 weeks). Corticosteroids work by suppressing T cells and reducing the activation of inflammatory monocytes and macrophages [7]. However, with chronic use of steroids, a range of systemic side effects may happen, which include metabolic and endocrinologic (hyperglycemia, Cushing syndrome, hirsutism), musculoskeletal complications (avascular necrosis, osteoporosis), neuropsychiatric symptoms (mood alterations, insomnia and psychosis), gastrointestinal issues (gastric ulcers), cardiovascular and ophthalmologic problems [8]. With these adverse effects, clinicians and patients opt to use non-steroidal immunosuppressive agents, which are effective steroid-sparing medications, including azathioprine and mycophenolate mofetil. However, with these medications, there is a long delay to onset of treatment effect [3]. These treatments broadly suppress the immune system rather than specifically targeting the IgG autoantibodies involved in the condition [9].

During myasthenic crises, treatments that primarily act on removing autoantibodies are preferred due to the rapid onset and relief of symptoms, including plasma exchange and immunoadsorption, which have demonstrated a reduction in the IgG of up to 73% [10]. However, aside from IgG plasma, it also lowers the exchange of the circulating plasma concentration of other immunoglobulins (IgM and IgA) [10]. Intravenous immunoglobulin (IVIG) also plays an important role during myasthenic crises as it works by different mechanisms, which include modulation of autoantibodies and downregulation of antibody production. These treatments provide rapid and effective relief of symptoms during periods of significant exacerbation or myasthenic crises. However, accessibility and cost are drawbacks of these therapies [6].

MG is one of the auto-immune diseases that has been well studied and investigated. In line with this, novel target-specific immunotherapies have been developed, which include B-cells, complement binding, and neonatal Fc Receptors (FcRn). Medication such as rituximab targets CD20 on B-cells, leading to their depletion and subsequent reduction in antibody production [11]. Moreover, chimeric antigen receptor (CAR) T cells have been promising in directly targeting and eliminating B cells [12]. In addition, complement inhibitors such as eculizumab and zilucoplan act further downstream in the autoimmune process by blocking the complement pathway, which prevents the formation of membrane attack complexes and post-synaptic membrane damage [13]. However, these complement inhibitors have only been proven to be effective and approved in AChR antibody-positive patients since they do not act on IgG 4 antibody, which is involved in MuSK-positive MG [3].

Neonatal Fc receptor (FcRn), which consists of an MHC Class I-like alpha chain and a beta-2 microglobulin chain, plays a significant role in managing the transport and degradation of IgG and albumin [14]. Figure 1(a) depicts that in an acidic endosome, FcRn primarily binds with IgG, and this binding prevents the lysosomal degradation of the IgG antibodies, facilitating further recycling and reentry to the bloodstream [15]. This prolongs the half-life of the IgG to three to four weeks [3,16]. The IgG recycling rate is 42% faster than IgG production, which implies that IgG recycling is the most important factor in maintaining IgG plasma concentration [6]. This knowledge has facilitated the development of novel medications that directly target the FcRn. In less than five years, there have been two FcRn blocking agents approved by the US FDA in the treatment of AChR Ab positive gMG, efgartigimod and rozanolixizumab [17,18]. Rozanolixizumab has been approved also for MuSK-positive MG [19].

Figure 1.

(a) Role of neonatal fc receptors. FcRn plays a significant role in the homeostasis of IgG. FcRn and IgG bind optimally in an acidic endosome. This binding prevents IgG degradation via lysosomes. This favors the release of the IgG back into circulation. (b) Role of rozanolixizumab-noli. Rozanolixizumab-noli is a fully humanized anti-human FcRn receptor blocker. The binding of rozanolixizumab with FcRn prevents the attachment of IgG to FcRn, promoting IgG degradation and preventing IgG recycling. Created with Biorender.com.Adapted with permission from “an evaluation of rozanolixizumab-noli for the treatment of anti-AChR and anti-MuSK antibody-positive generalized myasthenia gravis.,” by A. Matic, N. Alfaidi and V. Bril. 2023, July-Dec;23(12):1163–1171. This is permitted by the authors and Taylor & Francis ltd.

The central focus of this drug review is the efficacy and safety of rozanolixizumab for the treatment of gMG, AChR and MuSK antibody-positive patients.

2. Rozanolixizumab

Rozanolixizumab is a fully humanized IgG4 monoclonal antibody targeting the IgG binding region of FcRn, which primarily works via competitive inhibition [14]. As depicted in Figure 1(b), this mechanism facilitates the degradation of IgG via the lysosomal pathway while simultaneously inhibiting the recycling of IgG back into circulation, thereby reducing overall IgG concentrations [15].

The pharmacokinetics of rozanolixizumab exhibit non-linear behavior with respect to the dose. The drug achieves its maximum concentration within 48 hours following the initial administration [6]. Pharmacokinetic analysis indicates that the concentration of rozanolixizumab is not influenced by age, sex or race [20]. Although theoretically, hepatic or renal impairment is not expected to impact the pharmacokinetics of rozanolixizumab, dedicated pharmacokinetics studies in patients with such impairments have not yet been conducted [20].

In the Phase I study, the plasma concentration-time profile was compared between intravenous (IV) and subcutaneous (SC) administration routes [6]. The results demonstrated that SC infusion resulted in significantly lower rozanolixizumab concentration compared to intravenous infusion. However, the variability in the duration and extent of absorption was greater in the subcutaneous route. Moreover, the Phase 1 study proved that the SC route of administration at 7 mg/kg demonstrated a more favorable safety and tolerability profile compared to the IV route [6].

Rozanolixizumab follows a target-mediated disposition pattern and is rapidly eliminated, with plasma levels becoming undetectable within seven days post-administration [6]. The mean maximum reduction in total serum IgG from baseline was 74.7% with the 7 mg/kg dose and 78.4% with the 10 mg/kg dose. No reductions in albumin levels were observed [21]. Studies have shown that rozanolixizumab can reduce plasma IgG concentrations by 75–90% from baseline at doses of 50 and 150 mg/kg, with maximal effects typically achieved by day 10 [16]. In the open-label extension studies of 52 weeks’ duration, reductions in total serum IgG were consistent, at 74.7% for the 7 mg/kg and 78.4% for the 10 mg/kg dose [22].

2.1. Efficacy

The efficacy, safety, and tolerability of subcutaneous rozanolixizumab at a dose of 7 mg/kg, compared to placebo, were evaluated in a Phase II, multicenter, randomized, double-blind, controlled trial with a two-period treatment sequence. In the first period (days 1 to 29), participants received rozanolixizumab 7 mg/kg subcutaneously once weekly for three weeks (on days 1, 8, and 15). The study included 43 patients with MG (42 with AChR antibodies and 1 with MuSK antibodies) who had comparable baseline characteristics to placebo. The primary endpoint, which was the improvement in the Quantitative Myasthenia Gravis (QMG) score from baseline to day 29, did not demonstrate statistical significance (least squares mean [LSM] difference: −0.7; 95% upper confidence limit [UCL]: 0.8; p = 0.221). However, secondary endpoints, including MG Activities of Daily Living (MG-ADL) and MG Composite (MGC) scores, showed notable improvement. Specifically, MG-ADL scores improved with an LSM difference of − 1.4 (95% UCL: −0.4), and MGC scores demonstrated a reduction with an LSM difference of − 1.8 (95% UCL: 0.4). Additionally, serum IgG levels decreased by a maximum of 61% by day 22 [21].

In the second period (days 29–43), patients who continued receiving rozanolixizumab at 7 mg/kg exhibited further improvements in QMG, MG-ADL, and MGC scores. The maximal reductions in QMG and MG-ADL scores were observed 21 days after treatment was resumed, whereas the MGC score reached its peak improvement after 14 days. These improvements were sustained until the conclusion of the observation period (day 99). Furthermore, the reduction in IgG concentration was observed to be 68% in patients who received rozanolixizumab 7 mg/kg across both periods [21]. This Phase II study concluded that rozanolixizumab suggested substantial clinical benefit for patients with generalized MG, thereby justifying progression to Phase III trials.

The Phase III study, MycarinG, was a randomized, double-blind, placebo-controlled, parallel group with a two-stage adaptive design. It included a 6-week treatment period followed by an 8-week observation phase and involved 200 patients with similar baseline characteristics (90% AChR autoantibody-positive and 11% MuSK autoantibody-positive). The primary endpoint, MG-ADL, showed significant reductions from baseline at day 43 for both rozanolixizumab 7 mg/kg (LSM: −3.37) and 10 mg/kg (LSM: −3.40), with least squares mean differences from placebo of − 2.59 (95% CI: −4.09 to − 1.25, p < 0.0001) for the 7 mg/kg dose and − 2.62 (95% CI: −3.99 to − 1.16, p < 0.0001) for the 10 mg/kg dose. Secondary endpoints, including MGC scores, QMG scores, and Myasthenia Gravis symptoms PRO (muscle weakness, fatigability, physical fatigue, bulbar muscle weakness) showed significant improvements were seen as early as day eight and throughout the treatment period [23]. Subgroup analysis for MuSK antibody patient was performed and showed significant reductions from baseline MG-ADL to day 43 for both rozanolixizumab 7 mg/kg (LSM: −7.28, SE 1.94), 10 mg/kg (LSM: −4.16, SE 1.78) and placebo (LSM: 2.28, SE 1.95) with LSM difference from placebo was − 9.56 (97.5% confidence interval: −15.25, −3.87); 10 mg/kg, −6.45 (−11.03, −1.86) [24]. Post-hoc analyses dedicated to the assessment of muscle weakens and fatigability with the use of MG symptom PRO indicated that muscle weakness fatigability at day 43 improved by 46.9% in the 7 mg/kg group, 56.5% in the 10 mg/kg group, compared to 28.1% in the placebo group [25].

Autoantibody levels were also assessed, revealing significant least squares mean differences from placebo for AChR autoantibody-positive patients: −1.94 (97.5% CI: −3.06 to − 0.81) for the 7 mg/kg group and − 2.26 (97.5% CI: −3.39 to − 1.13) for the 10 mg/kg group. For MuSK autoantibody-positive patients, the least squares mean differences from placebo were − 9.56 (97.5% CI: −15.25 to − 3.87) for the 7 mg/kg group and − 6.45 (97.5% CI: −11.03 to − 1.86) for the 10 mg/kg group [23].

Subsequent open-label extension studies, MG0004 and MG0007, further evaluated the long-term efficacy of rozanolixizumab. In MG0004, patients were randomized to receive either 7 mg/kg or 10 mg/kg weekly for 52 weeks, followed by an 8-week observation period. Once the patient reached ≥ 6 visits, patients could then roll over into MG0007/NCT04650854, which permitted on-demand infusion depending on the investigator’s discretion (such as MG-ADL increase ≥ 2, QMG increase. ≥3 and “symptom-driven cycles”). Post-hoc analyses of these studies revealed sustained clinical improvements in mean MG-ADL with reductions ranging from − 2.7 to − 3.1 for 7 mg/kg and − 3.4 to − 4.1 for 10 mg/kg, and for QMG, reductions of − 2.6 to − 5.4 for 7 mg/kg and − 4.2 to − 6.2 points for 10 mg/kg with a stable improvement over time [22]. Moreover, minimal symptom expression scores (MG-ADL of ≤ 1) also improved across six cycles [26].

As of the latest update, an ongoing clinical trial (MG0020/NCT016149559) is evaluating the efficacy and safety of rozanolixizumab in pediatric patients aged 2 to less than 18 years with moderate to severe generalized MG (roMyG), with an expected completion date in August 2026 [27].

In these studies, rozanolixizumab was infused with the use of an infusion pump. A phase 3 (NCT05681715) open-label crossover study was done to evaluate the self-administered rozanolixizumab with push or infusion pump in gMG patients. This study was completed in April 2024, and results have not yet been published, but posters at international meetings reported high patient satisfaction and safety with both infusion methods [28]. Table 1 summarizes the clinical trials on rozanolixizumab in MG.

Table 1.

Clinical trials of Rozanolixizumab in Myasthenia Gravis.

Drugs	Indication	Phase	Status	Location	Identifier
UCB 7665 (Intravenous, Subcutaneous)	Healthy Subjects	I	Completed	United Kingdom	NCT02220153 Eudra 2013 -005,469-38
Rozanolixizumab SC (7 mg/kg, 10 mg/kg, placebo)	Myasthenia gravis	II	Completed	Multinational	NCT03052751 Eudra 2016 -002,698-36 MG002
Rozanolixizumab SC (7 mg/kg, 10 mg/kg, placebo)	Myasthenia gravis	III MycarinG	Completed	Multinational	NCT03971422 Edura 2019 -000,968-18 MG003
Rozanolixizumab SC	Myasthenia gravis	III (open label)	Completed	Multinational	NCT04124965 Eudra 2019 -000,969-21 MG004
Rozanolixizumab SC	Myasthenia gravis	III (open label)	Completed	Multinational	NCT04650854 Eudra 2020 -003,230-20 MG007
Rozanolixizumab SC	Myasthenia gravis	III (open label)	Completed	Multinational	NCT05681715 Eudra 2022 -003,870-21 MG0020
Rozanolixizumab SC	Myasthenia gravis	III roMyG	Ongoing	Multinational	NCT06149559 Eudra 2022 -502,074-16-00 MG006

2.2. Safety

Based on phase II, III, and open-label extension studies, subcutaneous rozanolixizumab has shown to be fairly safe and well-tolerated in patients with generalized MG. Most adverse events reported were mild to moderate in severity. However, between 7 mg/kg and 10 mg/kg, there are higher TAES seen in the rozanolixizumab 10 mg/kg group than those who received 7 mg/kg [21,23].

In the phase I study of rozanolixizumab, subcutaneous infusion was proven to have lower concentration after infusion compared to IV but was proven to have favorable safety and tolerability profile compared with intravenous infusion [6].

In the Phase II study of rozanolixizumab for MG patients, headache was identified as the predominant treatment-emergent adverse event (TEAE) among those receiving rozanolixizumab at a dose of 7 mg/kg subcutaneously. Notably, no serious treatment-related side effects were reported. Despite a reduction in IgG levels by approximately 68% in this Phase II study, there was no significant difference in infection rates compared to the placebo group, nor were there any serious or opportunistic infections documented [21].

In the Phase III study, the most frequently reported TEAEs included were headache (affecting 45% in the 7 mg/kg rozanolixizumab group, 38% in the 10 mg/kg group, and 9% in the placebo group), diarrhea (reported 25% in the 7 mg/kg group, 16% in the 10 mg/kg group, and 13% in the placebo group), as well as pyrexia and nausea. The incidence of severe TEAEs was highest in the 10 mg/kg rozanolixizumab group (19%) compared to the 7 mg/kg group (5%) and the placebo group (4%). Serious TEAEs were reported in 8% of patients receiving rozanolixizumab 7 mg/kg, 10% of those receiving 10 mg/kg, and 9% of those in the placebo group. Importantly, no deaths, severe infections, or opportunistic infections were reported [23].

The long-term safety and tolerability of rozanolixizumab in patients with generalized MG were further assessed in an open-label trial (NCT04124965) and (NCT04650854). These studies indicated that there were only mild to moderate intensity adverse events and the most frequent was headache, followed by infection. Other reported adverse events included diarrhea, nausea, and pyrexia. It was also found out that subsequent cyclic treatments did not worsen these adverse events. No fatalities were recorded in this trial [22,29].

3. Compared with other FcRn medications in MG

Due to the advent of novel targeted therapies, there have been multiple FcRn blocking agents that have been developed for gMG aside from rozanolixizumab (UCB-7655), which include efgartigimod (ARGX-113), batoclimab (HMB9161) and nipocalimab (M281) [30]. Efgartigimod (ARGX-113) is an engineered Fc domain derived from human IgG1, administered via intravenous infusion at a dosage of 10 mg/kg weekly for 4 weeks, with subsequent cycles repeated at varying intervals based on the recurrence of symptoms. Clinical trials have indicated that efgartigimod significantly enhances the MG-ADL score within four weeks, reduces total IgG levels by 60–70%, and diminishes AChR antibody levels by 40–70% [9]. The U.S. Food and Drug Administration (FDA) approved efgartigimod in 2021 as a therapeutic option for patients with gMG who are AChR antibody-positive [31]. Currently, efgartigimod and rozanolixizumab are the only FcRn-blocking agents approved by the FDA, with rozanolixizumab being also approved for the treatment of MuSK-positive MG patients. The result of the phase III study (Vivacity-MG3) of Nipocalimab, a fully human IgG1 monoclonal antibody FcRn, administered intravenously at a dose of 60 mg/kg every two weeks showed statistically significant improvement from baseline MG-ADL and QMG compared to placebo in a 24-week period among broad antibody-positive population (including AChR+, MuSK+ and LRP4+) [32]. Other FcRn-blocking agents under investigation for gMG include batoclimab (RVT-1401), which is an IgG1 monoclonal antibody, and a phase 3 clinical trial is currently underway [30]. Moreover, nipocalimab is also being evaluated in the pediatric age group [33].

A published meta-analysis looked into the efficacy and safety of FcRn blocking agents in gMG with six articles (four phase II and 2 phase III studies) pooling 532 participants. Overall, this study showed that compared to placebo, the FcRn inhibitors were more efficacious in terms of MG-ADL (mean difference [MD]: −1.69 [−2.35, −1.03], p < 0.00001), MG-ADL responders (RR = 2.01 [1.62–2.48], p < 0.00001), QMG (MD = −2.45 [−4.35, − 0.55], p = 0.01), MGC (MD = − 2.97 [−4.27, − 1.67], p < 0.00001) and Myasthenia Gravis Quality of Life (MGQoL15r) (MD = − 2.52 [−3.54, − 1.50], p < 0.00001), without increasing the risk of safety. A subgroup analysis showed that efgartigimod was more effective than the placebo in terms of MG-ADL responders, while rozanolixizumab was more effective than the placebo in all parameters except in QMG and batoclimab was more effective than placebo except in MG – ADL. However, except for rozanolixizumab, all drugs showed non-inferior safety profiles to placebo [34].

Another systematic review and network meta-analysis comparing complement and FcRn-targeted therapies further supported the efficacy of these treatments. It found that rozanolixizumab was among the medications associated with significant clinical improvement within 1 to 4 weeks post-initiation, compared to placebo [35].

A direct comparison of FcRn inhibitors was conducted, considering variations in efficacy endpoints by evaluating data at each trial’s primary assessment timepoint. Safety profiles were analyzed using network meta-analysis (NMA), which indicated that rozanolixizumab at both 7 mg/kg and 10 mg/kg doses was associated with a significantly higher incidence of headaches (mean difference in proportion [95% CrI]: 0.28 [0.10, 0.48] and 0.21 [0.03, 0.40], respectively). Additionally, cost-per-improved-outcome (CPIO) analysis revealed that the cost to achieve a ≥ 3-point reduction in QMG score from baseline was estimated at $1,839,110 for rozanolixizumab – higher than efgartigimod IV ($645,406) but notably lower than zilucoplan ($1,936,905) [36].

4. Role in other autoimmune conditions

Beyond its application in MG, the clinical efficacy of rozanolixizumab has been explored in various other autoimmune neurological disorders. These include chronic inflammatory demyelinating polyneuropathy (CIDP), myelin oligodendrocyte glycoprotein antibody-associated disease (MOG-AD), and leucine-rich glioma inactivated 1 (LGI-1) autoimmune encephalitis [37–39].

In the MyCIDP CHOICE study, rozanolixizumab did not demonstrate a significant change in the primary outcome measure, the inflammatory Rasch-built overall disability scale (iRODS) score. However, it was observed to reduce mean IgG levels by more than 80%, with no significant differences in treatment-emergent adverse events (TEAEs) reported [37]. Rozanolixizumab has also shown promising results in non-neurological autoimmune conditions. In the context of chronic primary immune thrombocytopenia (ITP), it elicited clinically relevant platelet responses (>50 × 10^9/L) and resulted in the lowest mean IgG levels. These changes were noted as early as Day 11 across multiple dose cohorts in a Phase II study [38]. Ongoing clinical trials are assessing the safety and efficacy of rozanolixizumab in a phase III study focusing on myelin oligodendrocyte glycoprotein antibody-associated disease, with an estimated completion date of February 2026 [39]. Lastly, a study of rozanolixizumab on LGI-1 Autoimmune Encephalitis was previously conducted, but due to enrollment challenges, this was terminated [40].

5. Regulation and approvals

Rozanolixizumab (UBC-7665) was granted an Orphan Drug Designation for the treatment of gMG by the U.S. Food and Drug Administration (FDA) in 2019 and by the European Commission in 2020 [39]. In January 2023, a Biologics License Application (BLA) for rozanolixizumab was submitted to the FDA, which subsequently granted Priority Review status for its use in adults with generalized MG who are positive for either AChR or MuSK antibodies [41]. On 27 June 2023, the FDA approved rozanolixizumab for the treatment of generalized MG for both AChR or MuSK antibodies [19]. In September 2023, the Japanese Ministry of Health, Labor and Welfare (MHLW) approved rozanolixizumab for this indication [42]. Additionally, the European Medicines Agency (EMA) granted approval for rozanolixizumab on 5 January 2024, as an add-on to standard therapy for the treatment of generalized MG with either AChR or MuSK autoantibody-positive disease [43]. On 7 March 2024, the United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA) also approved rozanolixizumab (marketed as Rystiggo) for the treatment of adults with generalized MG [44]. Rozanolixizumab is currently under review by the Center for Drug Evaluation of China (National Medical Products Administration), Australia (Therapeutic Goods Administration (TGA)), Canada (Health Canada), and Switzerland (Swissmedic) for the treatment of adults with generalized MG, responses from these regulatory agencies are expected within this year [15,43].

6. Future directions and clinical consideration

Although clinical trials provide essential data on the efficacy and safety of rozanolixizumab, there has been no published research on its real-world experience. Real-world experience articles are crucial for validating the drug’s effectiveness in everyday clinical settings, which often differ from controlled trial environments. These studies offer valuable insights into the drug’s performance across a more diverse patient population and reveal additional safety and efficacy information that may not be apparent in clinical trials. Furthermore, real-world studies can shed light on patient adherence to the treatment regimen and practical aspects of drug administration. As such, the absence of real-world data highlights a significant gap in our understanding of rozanolixizumab’s performance outside the clinical trial setting and underscores the need for future research to address these aspects.

Another factor that we should take into consideration is the cost of the medication. In the United States, the price of rozanolixizumab is around $6,050 per 2 ml vial (280 mg/2 mL), and how much the patient should pay depends on the health plan coverage. To date, there has been no cost-effectiveness study that has been conducted for rozanolixizumab. This kind of study may give valuable insights as to whether the drug benefit will justify its cost compared to existing treatments. This may further help in determining if the new drug provides value for money. Cost-effectiveness for efgartigimod and eculizumab for gMG was done and showed in gMG patients; weekly dosing efgartigimod had $692,700 total costs, 1.23 quality-adjusted life years gained and cost/QALY of 2,442,000 compared to conventional treatment. Also, based on this study, with the current price of eculizumab and efgartigimod, typical willingness-to-pay thresholds were exceeded, and this may result in limited patient access [45].

Lastly, future research should examine the safety and efficacy of rozanolixizumab in specific MG subgroups, including patients with thymoma, ocular MG, and those in MG crisis. Investigating the combination of rozanolixizumab with other treatments, such as complement inhibitors, and conducting head-to-head comparisons with these therapies would offer valuable information for MG patients and their healthcare providers.

7. Conclusion

Rozanolixizumab is a promising subcutaneous treatment for autoimmune diseases, selectively modulating IgG levels while sparing other immunoglobulins (IgA, IgM, IgE, and IgD). Clinical trials demonstrate its ability to reduce pathogenic IgG levels by up to 78%, comparable to plasma exchange (PLEX). Additionally, it has shown sustained efficacy in long-term open-label extension studies across multiple MG outcome measures (MG-ADL, MGC, QMG, and MG-PRO), with notable benefits for MuSK antibody-positive patients. Its safety profile remains favorable, with most treatment-emergent adverse events (TEAEs) being mild to moderate, headache being the most frequently reported. Despite these promising results, significant gaps remain in real-world data assessing its long-term efficacy, tolerability, and patient adherence. Future research should focus on large-scale observational studies to confirm its safety and effectiveness in routine clinical practice. Additionally, comparative studies against other FcRn inhibitors and standard therapies like IVIg and PLEX could clarify its positioning in treatment algorithms. Given its high cost (~$6,050 per vial), economic evaluations are essential to determine its cost-effectiveness and potential impact on healthcare systems. Studies exploring biomarkers for response prediction may also help identify patients who would benefit most from FcRn inhibition. Finally, research into optimal dosing strategies, combination therapies, and its effects on other IgG-mediated disorders could further expand its therapeutic potential.

Box 1.

Drug Summary.

Rozanolixizumab is a humanized IgG4 monoclonal antibody given subcutaneously that targets the neonatal Fc receptor (FcRn), thereby inhibiting the recycling of IgG and promoting its degradation. This results in a rapid reduction of up to 78% in circulating pathogenic IgG autoantibodies, offering efficacy comparable to plasma exchange. It has demonstrated clinical benefit in antibody-mediated diseases such as generalized myasthenia gravis (gMG) positive for anti-acetylcholine receptor (AChR) or anti-muscle-specific kinase (MuSK) antibodies. The recommended dosing is 7 mg/kg once weekly for six weeks, with clinical improvement seen two weeks after infusion. Common adverse effects include headache, diarrhea and fever, and upper respiratory tract infection. Rozanolixizumab has been approved in multiple countries for the treatment of generalized MG with AChR or MuSK autoantibody positivity.

Funding Statement

This review article was conducted without any external funding.

Article highlights

• Rozanolixizumab as a Novel Therapy: A subcutaneous FcRn inhibitor that selectively reduces pathogenic IgG levels without affecting other immunoglobulins.

• Comparable Efficacy to PLEX: Clinical trials demonstrate up to a 78% reduction in IgG levels, with improvements in MG outcome measures (MG-ADL, MGC, QMG, MG-PRO).

• Potential for MuSK-Positive MG: Shows significant benefits for MuSK antibody-positive patients, a subgroup with limited treatment options.

• Favorable Safety Profile: Most treatment-emergent adverse events (TEAEs) are mild to moderate, with headache being the most common.

• Future Research Directions: Investigations into optimal dosing, predictive biomarkers, combination therapies, and its role in other IgG-mediated diseases are necessary.

Declaration of interest

V Bril declares consultancy for Grifols, CSL, UCB, Argenx, Takeda, Alnylam, Octapharma, Pfizer, Powell Mansfield Inc, Akcea, Ionis, Immunovant, Sanofi, Momenta (J&J), Roche, Janssen, AZ-Alexion, NovoNordisk andJapan Tobacco; and research support from AZ-Alexion, Grifols, CSL, UCB, Argenx, Takeda, Octapharma, Akcea, Momenta (J&J) and Immunovant, Ionis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Author contributions

• Matic, A: Conceptualization, Literature Search, Data Curation, Writing – Original Draft

• Bril, V: Conceptualization, Writing – Review & Editing, Project administration