Real-world effectiveness and safety of zilucoplan in patients with anti-AChR myasthenia gravis: A retrospective cohort study in France

Abstract

Objectives

To evaluate the effectiveness and safety of zilucoplan in the real-world treatment setting in France.

Methods

This retrospective cohort study evaluated patients with generalized anti-AChR myasthenia gravis (MG) failing current therapy enrolled in the French early access program (EAP) for zilucoplan. Patients were evaluated at enrollment and at Months 1, 3 and 6 with the MG-ADL score, the Myasthenic Muscle Score (MMS-Garches), and the MG-quality of life questionnaire (MG-QoL15r). MG crises and on-treatment adverse events were documented. MG medication use was compared between the six months before and after enrollment.

Results

Forty-eight patients were enrolled and treated with zilucoplan (mean age: 56.2 years; 50.9% men). Thirty patients achieved six months follow-up before the EAP ended. Three patients discontinued zilucoplan due to lack of efficacy. Mean MG-ADL score decreased from 7.4 ± 4.4 to M0 to 2.5 ± 2.7 at M6 (p < 0.0001). 9/43 patients achieved minimal symptom expression at M3 and 12/30 at M6. Mean MMS-Garches score was 67.5 ± 20.0 at M0 and 87.5 ± 13.2 at M6 (p < 0.0001). Mean MG-QoL15r score was 18.2 ± 8.6 at M0 and 8.7 ± 8.3 at M6 (p = 0.0156). 15 patients experienced adverse events, leading to discontinuation in four cases. The mean oral corticosteroid dose decreased from 28.8 ± 11.8 mg to 17.9 ± 11.8 (p = 0.001). Six patients experienced MG crises on treatment, compared to 22 in the six months preceding enrollment. treatment.

Discussion

Following initiation of zilucoplan treatment, we observed an improvement in MG symptoms and a reduction in MG crises and in exposure to oral corticosteroids. Overall, zilucoplan was well-tolerated with no major adverse events reported.

Trial registration information

The study was registered in the clinicaltrials.gov trial registry under the number NCT06815133 (https://clinicaltrials.gov/study/NCT06815133) on February 4^th, 2025.

Keywords

myasthenia gravis zilucoplan effectiveness quality of life safety corticosteroids real-world evidence

Introduction

Generalized myasthenia gravis (gMG) is a rare autoimmune disease in which antibodies targeting the neuromuscular junction impair normal synaptic transmission, resulting in muscular weakness which is aggravated by sustained effort.¹ In the majority of cases (∼80%), the specific target of the pathogenic antibodies is the nicotinic acetylcholine receptor (AChR). In a minority of cases, the target is the muscle-specific receptor tyrosine kinase (MuSK) or lipoprotein receptor-related protein 4 (LRP4).² In a small percentage of patients, the antibody is not detected by routine testing (seronegative MG).³ Apart from in anti-MUSK related MG, binding of the antibody leads to complement-mediated damage of the post-synaptic membrane.^4,5

For many decades, gMG was managed by symptomatic treatment with acetylcholinesterase inhibitors (AChEIs) and disease-modifying therapies such as oral corticosteroids (OCS) and non-steroidal immunosuppressant drugs.⁶ Myasthenic crises are treated by intravenous immunoglobulins (IVIG) or plasma exchange (PLEX).^7,8 Although these therapies are effective in many patients, a minority fail to respond and there is thus a need for alternative treatments. Since 2020, several new treatments for gMG have been introduced which target disease mechanisms.^9,10 These include zilucoplan, a macrocyclic peptide a macrocyclic peptide which binds to complement factor 5 (C5) preventing its cleavage, and thus inhibiting assembly of the membrane attack complex.^11,12 A Phase II study¹³ and subsequent larger Phase III studies (RAISE and MG0017),^9,14,15 have demonstrated that zilucoplan can improve muscle weakness and disease symptoms, measured with the MG Activities of Daily Living Score (MG-ADL), with a rapid onset of action and sustained efficacy over time. Zilucoplan offers certain advantages over recent antibody-based or intravenously-administered treatments for gMG. As a self-administered, subcutaneous drug, reduces the need for programed hospital visits, still required in most cases for the administration of intravenous treatments, empowering the patient with independence and flexibility in the management their treatment. Compared with OCS and non-steroidal immunosuppressants, zilucoplan seems better tolerated.¹⁶ The most frequently reported adverse events are injection site reactions (and upper respiratory tract infections. Moreover, zilucoplan may increase susceptibility to infections by Neisseria meningitidis, and vaccination against this pathogen before initiating zilucoplan is mandatory.

The positive findings of these studies led to the approval of zilucoplan as an add-on to standard therapy for the treatment of anti-AChR positive gMG in adult patients in the United States and in the European Union in 2023. Following approval of zilucoplan in France, an early access program (EAP) was set up in order to provide zilucoplan to patients in need before it became commercially available. In France, EAPs are available for innovative therapies under certain conditions, such as for the treatment of rare or disabling diseases, or when implementation of treatment cannot be postponed, at the discretion of the national health authorities. Neurologists could apply for inclusion of eligible patients in the program and, once the application had been approved, the patient would receive zilucoplan.

A recent study of a cohort of patients enrolled in the Italian EAP for zilucoplan,¹⁷ reported findings with respect to the effectiveness and safety of this drug in the real world setting which were consistent with those reported in the Phase III RAISE study.¹⁵ Apart from this study and a few case-reports,^18–20 little information is available on the impact of zilucoplan with respect to its benefits and risks in everyday clinical practice, and further studies in the real-world treatment setting are necessary. To collect more data concerning the potential benefits and risks of zilucoplan in the real-world setting, we now report a retrospective study of the French cohort of patients with anti-AChR gMG included in the EAP, following closure of the program. The study aimed to investigate and report the impact of zilucoplan in a real-world treatment setting, by the evaluation of MG-ADL, Myasthenic Muscle Score (Garches Score; MMS-Garches), revised 15-item MG quality of life score (MG-QoL15r), occurrence of adverse events and comedication use.

Methods

This multicenter, retrospective study enrolled adult patients with anti-AChR gMG followed in sixteen neuromuscular disease reference centers in French University Hospitals. The study was open to all patients enrolled in the EAP, which was active from the date when zilucoplan was approved by the European Medicines Agency (March 9^th 2023) up to the date the manufacturer received the marketing authorization from the French Health Authorities (February 7^th 2025). Inclusion of each patient was discussed and approved according to the treatment protocols in place in each center. The date of termination of the EAP was not foreseeable in advance and was at the discretion of the French Health Authorities. At this time, patients left the EAP and were thereafter prescribed zilucoplan directly by the neurologist as in routine clinical practice. The first patient was enrolled in the zilucoplan Early Access Plan on March 9^th 2023.

The present study was initiated once the EAP had closed, which meant that all patients were included retrospectively. The index date for the present study was the date of enrollment into the zilucoplan EAP. We collected patient data up for at least six months after EAP enrollment or until the end of the EAP, if the EAP was closed before six months follow-up had been completed. We retrieved data from the patients’ medical records relating to clinical evaluations performed at the index date (M0) and one, three and six months thereafter (M1, M3 and M6). Since the study was performed under real-world conditions, not all patients attended all three follow-up visits, and the visits did not always fall exactly on these time points. The closest visit within one month of the expected date was chosen. If the interval exceeded one month, we considered the evaluation as missing for that visit. In addition, we searched the patient's medical records for six months before the index date for information on MG crises and medications prescribed for MG. The study design is illustrated in Figure 1.

Figure 1.

Study design. MG: myasthenia gravis.

Patients

Adult patients (≥18 years) with anti-AChR gMG could enter the EAP and receive zilucoplan in combination with standard therapy if they fulfilled the following eligibility criteria: diagnosis of symptomatic gMG, severity classes IIa to IVb according to the Myasthenia Gravis Foundation of America (MGFA) clinical classification,²¹ and ineligibility for, or failure to respond to or intolerance to currently available therapies, as evaluated by the investigators. In addition, patients with recent thymectomy, defined as thymectomy within 12 months before baseline or scheduled to have one, as well as patients participating in clinical trials, were excluded from the EAP at the request of the French health authorities. Patients with recent thymectomy were not included in the Phase III pivotal trials of zilucoplan¹⁵ and safety in this group of patients had not been evaluated; this was the reason for their exclusion from the EAP. All patients entering the EAP were required to receive anti-meningococcal vaccination before receiving zilucoplan and/or antibiotic prophylaxis throughout treatment.

Data collection, study outcome and endpoints

Data were extracted retrospectively from medical records and imported into SAS for analysis.

At baseline (M0), we collected data on demographic and clinical characteristics (age, sex, weight, comorbidities, age at diagnosis of gMG, history of thymectomy, MGFA class, hospitalizations). We classified patients into four groups based on age at disease onset (<18 years: juvenile onset; 18–49 years: early onset; 50–64 years: late onset; ≥65years: very late onset).^22,23 MG-ADL,²⁴ MMS-Garches and MG-QoL-15r²⁵ scales were assessed at M0 and then at M1, M3 and M6 following zilucoplan initiation. We assessed the change from baseline in these scores at each study visit. Patients who showed an improvement of ≥2 points since baseline were considered to be responders. We also determined the number of patients who achieved minimal symptoms expression (MSE), defined as an MG-ADL score ≤1 achieved at any study visit and sustained thereafter.²⁶ Patients experiencing an MG crisis, defined as respiratory failure requiring invasive or non-invasive ventilatory support,^8,26 were documented over a six-month period before M0, and throughout the follow-up period.

We documented prior and concomitant treatments, including AChEIs, OCS, non-steroidal immunosuppressants, IVIg and PLEX, for the six-month period up to M0 and M6. In the case of OCS, the dose prescribed was documented as prednisone dose equivalents. Adverse events were documented throughout follow-up to evaluate safety.

Statistical analysis

The statistical analysis was exploratory and no formal statistical hypotheses were tested; no target population size was set a priori. We analyzed all patients fulfilling the eligibility criteria who were treated with zilucoplan at least once and missing data were not replaced. We compared score distributions on the MG rating scales between M0 and M1, M0 and M3 and between M0 and M6 using the Wilcoxon signed rank test, and the mean change in score calculated with its 95% confidence interval. These statistical comparisons should be considered as exploratory. A two-tailed probability threshold of 0.05 was taken to be statistically significant. Analyses were conducted using SAS Enterprise 9.4.

Ethics

The study was submitted to the Delegation for the Protection of Persons of the Nice University Hospital (CHU de Nice), which granted authorization for its conduct. The research was compliant with Reference Methodology MR-004 and was registered in the data processing registry under the number 2025-R004-02. A corresponding declaration was also filed on the Health Data Hub under the identifier 22833351. Prior to inclusion in the EAP, physicians provided potential participants with a general information sheet and an individual information notice, which specified that their data could be used for research purposes. Patients who did not object to such use of their data provided oral consent to the use of their data. According to current French legislation on medical research, oral consent is sufficient for historical studies with retrospective data collection, in which study participation cannot influence the provision of care.

Results

Study population

Overall, 53 patients were enrolled in the zilucoplan EAP during the inclusion period. Of these, two never received zilucoplan (of whom one died and the other left the treatment center before treatment initiation) and three were concomitantly participating in a clinical trial. The remaining 48/53 patients made up the study population. 30/48 patients (62.5%) remained under treatment in the EAP for at least six months. Nine patients (18.8%) did not complete the planned six months of follow-up because of the prior termination of EAP program (on 7^th February 2025). Assuming that all patients completing the planned six months of follow-up who were not explicitly documented to have discontinued treatment remained under treatment throughout the study, whether they attended planned assessment visits or not, the mean duration of exposure to zilucoplan was 4.9 ± 1.7 months (median [IQR]: 6 [4–6] months).

Nine of these 48 patients (18.8%) subsequently discontinued zilucoplan treatment, in three cases for perceived lack of efficacy, and in four cases due to the occurrence of adverse events; in the remaining two cases, the reason for zilucoplan discontinuation was not documented. An additional patient interrupted zilucoplan because he no longer presented MG symptoms but needed to restart treatment one month later due to symptom recurrence.

Given the real-world setting and the retrospective nature of the study, not all patients were evaluated at each study visit. At least one follow-up data was available for 44/48 patients at M1 (91.7%), for 35/43 at M3 (81.4%) and for 24/30 at M6 (80%). Unfortunately, due to the retrospective nature of the study, not all patients underwent all examinations at every follow-up. In particular, regarding M6, we had data from 24 patients for MG-ADL, 19 for MMS-Garches score and, 11 for MG-QoL15r questionnaire. A patient flow diagram is presented in Figure 2. The time-course of participation for individual patients is illustrated in Supplementary Figure 1.

Figure 2.

Patient flow diagram. EAP: Early access program.

The characteristics of the patients at M0 are presented in Table 1. The mean age was 56.2 years and the mean disease duration 11.6 years. Patients most frequently presented with early onset MG (18–49 years; 41.5% of patients) and the majority (62.2%) were classified as MGFA Class III. Twenty-four patients (45.3%) had undergone thymectomy.

Table 1.

Patient characteristics at baseline.

Age (mean ± SD; years)	56.2 ± 19.6
Sex (male ; n (%))	27 (50.9%)
Weight (mean ± SD; kg)	78.9 ± 20.5
Disease duration (mean ± SD; years)	11.6 ± 11.0
Age at symptom onset (mean ± SD; years)	46.4 ± 21.7
Juvenile MG (<18 years at MG onset)	6 (11.3%)
Early-onset MG (18–49 years at MG onset)	22 (41.5%)
Late-onset MG (50–64 years at MG onset)	12 (22.6%)
Very late-onset MG (≥65 years at MG onset)	13 (24.5%)
History of thymectomy (n, %)	24 (45.3%)
MGFA Class
IIa	5 (14.3%)
IIb	2 (5.7%)
IIIa	11 (31.1%)
IIIb	11 (31.1%)
IVa	1 (2.9%)
IVb	5 (14.3%)
MG-ADL score	N = 40
Mean ± SD	7.4 ± 4.4
Median [IQR]	7 [4–10]
MMS-Garches	N = 43
Mean ± SD	67.5 ± 20.0
Median [IQR]	70 [57–80]
MG-QoL15r score	N = 33
Mean ± SD	18.2 ± 8.6
Median [IQR]	19 [12–23]

IQR: interquartile range; MG: myasthenia gravis; MG-ADL: myasthenia gravis activities of daily living profile score; MG-QoL15r: 15-item myasthenia gravis quality of life scale (revised) score; MMS-Garches: myasthenic muscle score/Garches score; SD: standard deviation.

Before the initiation of zilucoplan, nine patients (18.8 %) had received an anti-FcRn therapy (eight with efgartigimod alfa and one with rozanolixizumab), while five patients (10 %) were treated with another anti-C5 therapy (ravulizumab); all patients switched to zilucoplan except for one patient treated with rozanolixizumab and one treated with efgartigimod, who continued to receive their previous anti Fc-Rn treatment with add-on zilucoplan.

Effectiveness outcomes

The mean MG-ADL score was 7.4 ± 4.4 at M0 and declined to 2.5 ± 2.7 at M6 (Figure 3). At each of the follow-up assessments, the score distribution differed from that observed at M0 (p < 0.0001 in each case). The mean change in MG-ADL score between M0 and M6 was −5.57 ± 4.56. During the treatment period, 14 patients (29.2%) achieved MSE (MG-ADL score ≤ 1). This was the case for 9/43 patients assessed at M3 (20.9%) and 12/30 assessed at M6 (40.0%), corresponding to 50% of the patients, when the number of the effective evaluations is considered (12/24). MSE was sustained over the remainder of follow-up, with the exception of the patient who temporarily discontinued treatment, and whose MG-ADL score subsequently increased to 9. On reintroduction of zilucoplan, this patient recovered MSE at the next assessment. Of the 23 patients with a valid MG-ADL measure at M6, seventeen were considered to be responders (73.9%). Of the remaining patients, five (21.7%) scored <2 at the first assessment and remained well-controlled below this threshold throughout zilucoplan treatment, and two were non-responders, with a baseline MG-ADL score of ≥2 which failed to change by ≥2 on treatment. Of the nine patients who did not complete six months of treatment due to the end of the EAP, two were non-responders at the time they left the study, four achieved MSE at their last assessment and the remaining three were responders. Of the six patients who discontinued treatment due to adverse events or for undisclosed reasons, two were non-responders at the time they left the study, and the remaining four were responders.

Figure 3.

Effectiveness outcome measures over the course of the study. Data are presented as mean scores with their standard deviations at inclusion (M0), and at study visits at Months 1 (M1), 3 (M3) and 6 (M6). MG-ADL: myasthenia activities of daily living scale; MMS-Garches: myasthenic muscle score/Garches score; MG-QoL15r: 15-item myasthenia gravis quality of life profile (revised version). Median sores [interquartile range] were 7 [4–10] at M0, 2 [1–5] at M1, 3 [1–5] at M3 and 2 [0–4] at M6 for the MG-ADL, 70 [57–80], 80 [65–90], 84 [74–94] and 90 [83–100] respectively for the MMS-Garches score and 19 [12–23], 12 [4–21], 11 [3–14 ] and 7 [2–12] respectively for the MG-QOL15r.

Figure 4 shows a breakdown of patients classified as responders and non-responders at M3 and M6, as well as a representation of the degree of response based on MG-ADL data.

Figure 4.

Breakdown of patients at M3 and M6. A: Breakdown of patients classified as responders or non-responders at M3 and M6 and discontinuation of therapy. B: Classification of responder patients based on MG-ADL score at M3 and M6, with a graphical representation of the decrease in MG-ADL score from M0. MG-ADL: myasthenia activities of daily living scale.

With respect to patients switching from an anti FcRn or another anti-C5 to zilucoplan, none of the five patients previously exposed to ravulizumab showed any improvement (MG-ADL score) at the last available follow-up. For the seven patients switched from efgartigimod alfa to zilucoplan, data was unavailable beyond M1 in two patients; in the remaining five, a decrease in MG-ADL score ≥2 was observed in all but one patient following the switch and one patient achieved MSE. Two patients continued rozanolixizumab or efgartigimod in association with zilucoplan. In these two patients, the mean MG-ADL score decreased from 10 and 15 at M0 to 1 and 4 respectively at M1 and the patients achieved and sustained MSE throughout all further follow-up visits.

At M0, the MMS-Garches score was 67.5 ± 20.0, and improved progressively to 87.5 ± 13.2 at M6 (Figure 3). At each of the follow-up assessments, the score distribution differed from that observed at M0 (p < 0.0001 at each assessment). The mean change in MMS-Garches score between M0 and M6 was 10.9 ± 25.0.

At M0, the MG-QoL15r score was 18.2 ± 8.6, and declined progressively to 8.7 ± 8.3 at M6 (Figure 3). At each of the follow-up assessments, the score distribution differed from that observed at M0 (p = 0.0028 at M1, p = 0.0199 at M3 and p = 0.0156 at M6). The mean change in MG-QoL15r score between M0 and M6 was −10.8 ± 9.5.

MG crises

Over the six months preceding the M0 assessment, 25 patients (47.2%) did not experience an MG crisis, 13 experienced a single crisis (24.5%) and 9 experienced ≥2 crises (17.0%). Over the treatment period, 42 patients (87.5%) did not experience an MG crisis, 2 experienced a single crisis (4.2%) and 4 experienced ≥2 crises (8.3%).

Other MG medications before and during zilucoplan treatment

Prescription of AChEIs remained relatively stable over the follow-up period, with the proportion of patients prescribed these agents increasing from 72.9% (35 patients) in the six months before initiation of zilucoplan to 85.4% (41 patients) in the following six months under zilucoplan. This increase was not statistically significant.

After initiation of zilucoplan, the mean dose of OCS prescribed decreased from 28.8 ± 18.8 mg to 17.9 ± 11.8 (p = 0.001). By M6, twenty patients had discontinued OCS completely, no patients were receiving an OCS dose >50 mg/day and half those still receiving OCS were treated with a dose ≤10 mg/day. The distribution of OCS doses at M0, M1, M3 and M6 is provided in Table 2.

Table 2.

Oral corticosteroid dose at consecutive assessments.

	M0 (N = 48)	M1 (N = 47)	M3 (N = 41)	M6 (N = 28)
No oral corticosteroid use	3 (6.3%)	4 (7.8%)	4 (9.8%)	9 (32.1%)
Total patients prescribed oral corticosteroids	33 (68.8%)	29(61.7%)	25 (61.0%)	16 (57.1%)
≤ 10 mg	6 (2.5%)	7 (14.9%)	7 (17.1%)	8 (28.6%)
11–20 mg	10 (20.8%)	9 (19.1%)	10 (24.3%)	4 (14.3%)
21–50 mg	15 (31.3%)	12 (25.5%)	7 (17.1%)	4 (14.3%)
> 50 mg	2 (15.6%)	1 (2.1%)	1 (2.4%)	0
Oral corticosteroid dose (mg/day ; mean ± SD)	28.8 ± 11.8	21.9 ± 13.6	20.7 ± 13.3	17.9 ± 11.8

SD: standard deviation.

We also observed a decrease of at least twofold in the proportion of patients receiving conventional non-steroidal immunosuppressants, IVIG and PLEX following initiation of zilucoplan (Figure 5).

Figure 5.

Other myasthenia gravis treatments. Note: Data on prior treatments during the historical period was unavailable for four patients.

Regarding patients taking other concomitant innovative gMG treatments, two patients received zilucoplan with an anti-FcRn therapy, including one patient already receiving rozanolixizumab and one already receiving efgartigimod during the study.

Safety: adverse events

During the course of follow-up, we documented 53 adverse events in 15 (31.3%) patients (Table 3). The most frequent individual medical events were headache (5 events), nausea (4 events) and injection site pain (4 events) and metallic taste (2 events). One patient developed morphea, which was treated with 10 mg/day corticosteroids and did not require discontinuation of zilucoplan. No other medical event was reported more than once. In addition, nine abnormal laboratory findings were reported (4 cases of hypereosinophilia, 4 cases of elevated lipase and one of lymphopenia). None of these adverse events required hospitalization and no patients died. Most of the adverse events were mild to moderate in severity and no serious adverse events were reported. In three patients, the neurologist stopped zilucoplan because of adverse events, in one case due to injection site pain, in the second due to headaches and, in the third, due to elevated lipases and abdominal pain. A fourth patient decided to stop zilucoplan after one month of treatment due to abdominal pain without medical advice. No cases of meningococcal infections were documented.

Table 3.

Adverse events during follow-up.

	Patients (n)	Events (n)
All events	15	53
Gastrointestinal disorders	5	10
Nausea	2	4
Metallic taste	1	2
Abdominal pain	1	1
Mild diarrhea	1	1
Hepatic colic	1	1
Gastroesophageal reflux	1	1
Pain	5	10
Headache	2	5
Injection site pain	2	4
Bilateral polyarthralgia	1	1
Abnormal biological markers	4	9
Hypereosinophilia	1	4
Elevated lipase	2	4
Lymphopenia	1	1
Infections	4	4
Non-necrotizing dermohypodermitis (right upper limb)	1	1
Mycoses (oral, vaginal, anal)	1	1
Conjunctivitis	1	1
Herpes labialis	1	1
Dermatological disorders	3	3
Morphea	1	1
Pruritus	1	1
Urticaria	1	1
Metabolic and endocrine disorders	1	1
Weight gain	1	1

Discussion

This observational retrospective cohort study evaluated effectiveness and safety outcomes following initiation of zilucoplan in 48 patients with anti-AChR gMG in France who were non responders, ineligible or intolerant to other available therapeutic options. One month after starting treatment with zilucoplan, we observed significant improvements on all domains evaluated, which were sustained up to six months. Under zilucoplan treatment, around one-third of patients achieved minimal symptom expression following initiation of zilucoplan and almost 90% remained crisis-free. Zilucoplan was generally well-tolerated, and we observed a reduction in exposure to OCS during zilucoplan treatment.

Our cohort was similar to the RAISE study population in terms of age at enrollment, age at disease onset and disease duration. In our cohort, the improvement observed on the MG-ADL and the MG-QoL15r after three months was similar to that demonstrated in the randomized clinical trials of zilucoplan,^13,15 and at six months in the RAISE long-term extension trial (RAISE-XT).²⁷ In addition, the proportion of patients continuously treated with zilucoplan who achieved MMS at M6 in our study was 29%, consistent with the 31% reported in the RAISE-XT study.²⁷ One patient who achieved MSE, and who discontinued zilucoplan for this reason, experienced rapid symptom recurrence, which resolved after reintroduction of zilucoplan.

In our study, we collected information on effectiveness out to six months and observed that the improvement was sustained over time, both in terms of the extent of symptom improvement, evaluated as the difference in score from baseline, and persistent MSE. This is consistent with findings from the open-label extension phase of the RAISE trial, which provided no evidence for loss of efficacy over time in patients followed out to five years of zilucoplan treatment.²⁷ However, unlike the patients studied in the clinical trials, the eligibility criteria of the EAP for zilucoplan limited inclusion to symptomatic patients who were ineligible, or non-responders or intolerant to all conventional therapies, and our findings are indicative of the effectiveness of zilucoplan in this category of patients.

We observed a reduction in the use of OCS following initiation of zilucoplan. At the last follow-up, around half the patients were no longer prescribed any OCS, none were receiving a high dose of >50 mg prednisone equivalents and around one quarter were receiving a low dose (≤10 mg) of OCS. These findings are in agreement with those of the RAISE-XT study, which reported that 61.1% of patients had reduced or discontinued OCS five years after starting zilucoplan.²⁸ This is an important clinical benefit, since long-term OCS use increases the risk of potentially serious adverse events, including osteoporotic fracture, hypertension, diabetes and thromboembolism.^29–31 A recent Japanese study in patients with gMG has shown that reducing exposure to OCS is associated with a reduction in the frequency of new-onset diabetes and of osteoporotic fractures.³² In addition, the use of non-steroidal immunosuppressants was also reduced in our cohort following zilucoplan initiation, as has previously been reported in the RAISE-XT trial.²⁸

In addition, the percentage of patients in our cohort experiencing at least one MG crisis under treatment decreased compared to baseline data (around 10% vs 50% in the six months before starting zilucoplan). Consistent with this, we observed a reduction in the percentage of patients undergoing PLEX or receiving IVIG during follow-up.

Nonetheless, taken together, our results on improvement of MG-symptoms, modifications in concomitant treatments, and side effects are largely consistent with the data from the pivotal Phase III RAISE trial.^15,27 Our results can also be compared with a recent observational study of 54 patients included in the Italian zilucoplan EAP.¹⁷ This study reported responder rates of 75.6% at M3 and 82.9% at M6, and the proportion of patients achieving MSE of 28.9% and 55.6% respectively. The Italian study also reported a reduction in exposure to OCS and in hospitalization for an MG crisis, whereas no serious adverse events were described. The findings of the Italian and French studies are thus very comparable, supporting the effectiveness and good safety profile of zilucoplan.

Regarding other real-world studies of the efficacy of novel treatments, one study performed in 24 patients with gMG treated with ravulizumab reported a responder rate of 81% at Week 26, with 37.5% achieving MSE at the end of follow-up, as well as a reduction in use of OCS and non-steroidal immunosuppressants.³³ One patient developed Steven-Johnson syndrome following infusion of ravulizumab. Short-term effectiveness and a favorable safety profile have also been demonstrated for the anti-FcRn treatments, intravenous or subcutaneous efgartigimod alfa and rozanolixizumab, although both studies noted that treatment responses varied between patients and were sometimes not sustained.^34,35 Taken together, the available information highlights the importance of these innovative therapies for MG, which are well tolerated and have a rapid onset of action, in the management of MG and in controlling the risk MG crises.⁹ However, it should be emphasized that evaluation over longer follow-up durations will be critical to confirm the effectiveness of zilucoplan and all other novel MG therapies in reducing MG crises and exacerbations over the long-term.

A small number of patients in our cohort had previously received another innovative MG treatment, such as ravolizumab, efgartigimod alfa and rozanolixizumab, before initiation of zilucoplan. Specifically, patients who switched from ravolizumab, another anti-C5, to zilucoplan, did not show any improvement in MG-ADL, whereas the majority of patients switching from egartigimod alfa showed an improvement in MG-ADL scores, consistent with the complementary mechanisms of action of zilucoplan and anti-FcRn agents. Following initiation of zilucoplan, two patients continued previous anti FcRn therapy, one with rozanolixizumab and the other with efgartigimod alfa, with substantial improvement inn MG-ADL score for both patients, which was sustained over the 6 months follow-up.

With regard to safety, the incidence of adverse events was low, none were serious or reported in >10% of patients. No signal of any unexpected safety issue was identified. Headache, nausea, diarrhea, elevated lipase and injection site reactions have been reported as adverse events in clinical trials of zilucoplan.^15,27 Injection site reactions, elevated lipases, eosinophilia and morphea are all listed adverse events for zilucoplan. No patients developed meningococcal infections. No serious adverse events were documented, and only four patients discontinued zilucoplan due to safety issues.

This study has a number of limitations. First of all, due to the uncontrolled, retrospective, real-world nature of the study, it is not possible to ascribe causality to changes in disease manifestations documented after treatment initiation. Certain changes observed may represent regression to the mean; notably, crisis reduction and steroid-sparing may be highly susceptible to this phenomenon. In addition, given the real-world setting of the study, several patients were not evaluated at each study visit, and not all patients were evaluated with all the clinical scales. Missing data and attrition are thus substantial, especially at M6 (notably for MG-QoL15r), and discontinuations for inefficacy/adverse events may have biased observed improvements toward responders. Nonetheless, improvements were observed across all clinical outcome measures and in both completers and non-completers. This argues for the internal validity of the data, which are consistent with the effectiveness of zilucoplan expected from the findings of randomized clinical trials.

Another limitation relates to the relatively low number of patients included. For comparison, the Phase III RAISE study conducted across three continents included 174 patients over a two-year period.¹⁵ Our study was performed before zilucoplan was made commercially available and access to treatment was only possible through the EAP. The administrative burden of accessing zilucoplan in this way may have been a deterrent for physicians to enter their patients in the program. Moreover, at this time, EAPs were also in place in France for other novel gMG treatments. Nonetheless, the relatively low cohort size did not preclude the documentation of robust treatment effects. In addition, the EAP was closed following marketing authorization of zilucoplan in February 2025, before all patients had achieved six months of follow-up, and this resulted in substantial missing data at the M6 timepoint.

The involvement of a multidisciplinary panel of MG experts to advise on inclusion in the EAP could perhaps be considered outside the scope of “real-world” practice. However, it should be noted that French national guidelines for the management of MG recommend multidisciplinary decision-making in the choice of treatment (as in cancer).³⁶ Similarly, exclusion of patients with recent thymectomy, which was required by the health authorities, as it was an exclusion criteria in RAISE trial,¹⁵ may also be inconsistent with “real-world” practice. A dedicated study may be of interest to evaluate the safety of zilucoplan in this category of patients.

Data were also collected retrospectively from medical records and this may have compromised accuracy and completeness, for example with respect to documentation of adverse events. In addition, the follow-up period was limited to six months, and this may have been too short to capture fully certain adverse events, as morphea, which may only appear after several months of treatment, or to estimate the reduction of MG crises with precision or to identify the presence of late responders to treatment. A long-term follow-up is essential for this purpose, because it could help to fill the gap on safety and efficacy, and provide new insights into long-term outcomes of this emerging treatment. The strengths of the study included the fact that the patients were managed in reference centers for neuromuscular diseases, who share common care protocols and collect data in a consistent way for compilation in the French National Rare Diseases Registry.³⁷ This should ensure a low level of between-center variability in definitions or in the quality of data collected. Also, the multicentric nature of this study provides robustness of data collection and the findings would be expected to be representative of the real-world clinical setting in France.

In conclusion, the findings of this observational, retrospective study in the real-world treatment are supportive of the effectiveness of zilucoplan in patients with anti-AChR gMG, consistent with that observed in randomized trials of this treatment. Notably, after zilucoplan initiation, we observed a reduction of clinical and functional impairment, and on-treatment improvements of quality of life, as well as a substantial reduction in the frequency of MG crises and the need for concomitant MG medication (and notably for OCS), thus reducing the disease burden. In our cohort, the safety of zilucoplan was acceptable and no unexpected serious adverse events were identified. Our results support literature findings that zilucoplan can be used with confidence for the treatment of anti-AChR gMG who are symptomatic and non-responders to, intolerant of, or ineligible for, conventional therapies in routine clinical practice.

Supplemental Material

sj-docx-1-jnd-10.1177_22143602261437792 - Supplemental material for Real-world effectiveness and safety of zilucoplan in patients with anti-AChR myasthenia gravis: A retrospective cohort study in France

Supplemental material, sj-docx-1-jnd-10.1177_22143602261437792 for Real-world effectiveness and safety of zilucoplan in patients with anti-AChR myasthenia gravis: A retrospective cohort study in France by Giulia Tammam, Abderhmane Slioui, Diane Friedman, Blandine Acket, Michele Cavalli, Saskia Bresch, Emmeline Lagrange, Guilhem Sole, Jean-Baptiste Noury, Luce Barbat Du Closel, Clémence Marois, Aleksandra Nadaj Pakleza, Céline Tard, Emmanuelle Salort-Campana, Philippe-Edouard Merle, Djillali Annane, Shahram Attarian, Fanny Duval, Simon Frachet, Juliette Svahn, Antoine Pegat, Françoise Bouhour, Guillaume Taieb, Julien Praline, Angela Puma, Vincent Fabry, Luisa Villa, Stéphane Beltran, Anthony Behin, Pascal Cintas and Sabrina Sacconi in Journal of Neuromuscular Diseases

Footnotes

Acknowledgements

The participation of Sarah Ait Benamara and Laura Bouchareychas in collating the data from the various study centers is gratefully acknowledged. The authors would like to thank all patients or their participation in the study, and the staff of the various reference centers participating in the study.

Ethics

Consent to participate

Prior to inclusion in the EAP, physicians provided potential participants with a general information sheet and an individual information notice, which specified that their data could be used for research purposes. Patients who did not object to such use of their data provided oral consent to the use of their data. According to current French legislation on medical research, oral consent is sufficient for historical studies with retrospective data collection, in which study participation cannot influence the provision of care.

Consent for publication

Not applicable.

Author contributions

G. Tammam, A. Slioui, P. Cintras and S. Sacconi were responsible for study conceptualization and design, interpretation of the data and preparing the first draft of the manuscript. A. Slioui performed the data analysis. All authors contributed to acquisition of the data and revising the manuscript for intellectual content.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded through a grant from Nice University Hospital.

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: D. Annane reports consultancy fees from Alexion and AstraZeneca Rare Disease. S. Attarian reports speaker fees from Alexion Pharmaceuticals Inc., Argenx, Sanofi, Pfizer, and LFB, honoraria from Alexion Pharmaceuticals Inc., UCB, Janssen, Sanofi, Pfizer, Biogen Inc., and consultancy fees from LFB. A. Béhin reports consultancy fees and fees for participating in training programmes from Alexion, Argenx, Johnson&Johnson, Novartis, Sanofi-Genzyme, UCB et Ultragenyx Pharmaceuticals and financial support for congress participation from Association Institut de Myologie (AIM), Argenx, Alexion, Johnson&Johnson, LFB, Sanofi-Genzyme, UCB and Ultragenyx Pharmaceuticals. S. Beltran reports financial support for congress and meeting participation from Biogen, Teva, Merck, Effik, Novartis, CSL Behring, Astrazeneca, UCB, Genzyme, Eisai, Bristol-Myers Squibb, Pfizer, Sanofi, Roche, Alexion, Argenx. S. Bresch reports consultancy fees from Alexion, Argenx, UCB, and Johnson & Johnson. M. Cavalli reports consultancy fees and financial support for congress participation from Alexion Pharmaceuticals, UCB Pharma, Takeda Pharmaceutical, Grifols. P. Cintas reports consultancy fees from Alexion, UCB and Argenx. F. Duval reports financial support for meeting participation from UCB. V. Fabry reports travel grants from Abbott, Effik, Novartis, LFB, Sanofi, Alylam, Argenx, CSL Behring and honoraria for lectures from UCB, Argenx and Alexion. S. Frachet reports financial support for congress and meeting participation from ALAIR, Alexion, Alnylam, Argenx, AstraZeneca, Coloplast, CSL Behring, Grifols, LFB, Pfizer, Sandoz, Sanofi, SOS Oxygène and UCB, and consultancy fees from Argenx and UCB. C. Marois reports fees for advisory board participation from Alexion and Novartis and research support from MATMUT-Fondation Paul Benneton. A. Nadaj-Pakleza reports being an investigator in the RAISE trial, sponsored by UCB and has received consultancy fees from UCB. J.-B. Noury reports fees for advisory board participation, financial support for congress participation and speaker's fees from Alexion, ArgenX, UCB, Johnson & Johnson, LFB, CSL. A. Pegat reports consultancy fees from UCB Pharma SA, Argenx, Alexion and Johnson & Johnson. A. Puma reports consultancy fees from UCB and Argenx, and has received congress travel support from UCB, Argenx, and CSL Behring. S. Sacconi reports speaker honoraria from Sanofi, LFB, Biogen, Alnylam, Dyne Therapeutics, Lupin, UCB Pharma, Argenx, Alexion, Fulcrum Therapeutics, and Takeda, and has received research funding from Sanofi, Biogen, Roche, Pfizer, Lupin, UCB Pharma, and Huma. E. Salort-Campana reports consultancy fees and financial support for meeting participation from Biogen, UCB, Sanofi-Genzyme, Argenx, Amicus, Lupin and Alexion. G. Solé reports fees for advisory board participation, financial support for congress participation from UCB. J. Svahn reports financial support for congress and meeting participation from UCB Pharma SA, Alexion Pharma France and Janssen Cilag. C. Tard reports consultancy fees and non-financial support from Argenx, UCB, Alexion, Amgen, Johnson and Johnson, Sanofi-Genzyme, Amicus, Akcea, Ultragenyx, Santhera, Janssen, Pfizer, Alnylam, Astrazeneca, Biogen, Roche, LFB, and CSL Behring. L. Villa reports consultancy fees from UCB and Argenx, and has received congress travel support from UCB, Argenx, and Sanofi. B. Acket, L. Barbat du Closel, F. Bouhour, D. Friedman, E. Lagrange, P.-E. Merle, J. Praline, A. Slioui, G. Taieb and G. Tammam report no relevant disclosures.

Data availability

The individual patient data can be made available to qualified researchers from relevant disciplines on request the corresponding author.

Supplemental material

Supplemental material for this article is available online.

ORCID iDs

Giulia Tammam

Abderhmane Slioui

Clémence Marois

Céline Tard

Djillali Annane

Simon Frachet

Julien Praline

Stéphane Beltran

Sabrina Sacconi

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Supplementary Material

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