Leaflet VYVGART 1000mg 200mg / ml solution for injection in pre-filled syringe

Vyvgart 1 000 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 1 000 mg of efgartigimod alfa in 5 mL (200 mg/mL).

Efgartigimod alfa is a human recombinant immunoglobulin G1 (IgG1)-derived Fc fragment producedin Chinese hamster ovary (CHO) cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Solution for injection

Yellowish, clear to opalescent, pH 6.0.

Vyvgart is indicated as

- an add-on to standard therapy for the treatment of adult patients with generalised Myasthenia

Gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody positive.

- monotherapy for the treatment of adult patients with progressive or relapsing active chronicinflammatory demyelinating polyneuropathy (CIDP) after prior treatment with corticosteroidsor immunoglobulins.

Treatment must be initiated and supervised by a physician experienced in the management of patientswith neuromuscular disorders.

Generalised myasthenia gravis

The first treatment cycle and first administration of the second treatment cycle must be administeredeither by or under the supervision of a healthcare professional. Subsequent treatment should beadministered by a healthcare professional or may be administered at home by a patient or caregiverafter adequate training in the subcutaneous injection technique.

The recommended dose is 1 000 mg to be administered subcutaneously in cycles of once weeklyinjections for 4 weeks. Subsequent treatment cycles should be administered according to clinicalevaluation. The frequency of treatment cycles may vary by patient (see section 5.1).

In the clinical development program, the earliest time to initiate a subsequent treatment cycle was7 weeks from the initial infusion of the previous cycle.

For patients currently receiving efgartigimod alfa intravenously, the solution for subcutaneousinjection may be used as an alternative. It is recommended to switch between formulations at the startof a new treatment cycle. No safety and efficacy data in patients switching formulations during thesame cycle is available.

Chronic inflammatory demyelinating polyneuropathy

The first 4 injections must be administered either by or under the supervision of a healthcareprofessional. Subsequent injections should be administered by a healthcare professional or may beadministered at home by a patient or caregiver after adequate training in the subcutaneous injectiontechnique.

The recommended dose is 1 000 mg administered subcutaneously as once-weekly injections.

Treatment is initiated with a weekly dose regimen and may be adjusted to every other week basedon clinical evaluation. In case of worsening of symptoms, administration of once-weekly injectionsshould be resumed.

For those patients transitioning from their current CIDP therapies, Vyvgart treatment shouldpreferably be initiated before the clinical effect of these prior therapies starts to decrease.

Clinical response is usually achieved within 3 months of initiation of treatment with efgartigimod alfasubcutaneous. Clinical evaluation should be considered 3 to 6 months after treatment initiation toassess the treatment effect and at regular intervals thereafter.

An interval of at least 3 days should be observed between two consecutive administrations. Whenadministrations cannot be done at the scheduled time point, they should be performed as soon aspossible and at least 3 days ahead of the following administration. If there are less than 3 days to thenext administration, the missed dose should be skipped and the next dose should be administered atthe scheduled time point.

No dose adjustment is required in patients aged 65 years and older (see section 5.2).

Limited safety and efficacy data in patients with mild renal impairment is available, no doseadjustment is required for patients with mild renal impairment. There is very limited safetyand efficacy data in patients with moderate or severe renal impairment (see section 5.2).

No data in patients with hepatic impairment are available. No dose adjustment is required in patientswith hepatic impairment (see section 5.2).

The safety and efficacy of efgartigimod alfa in paediatric population have not yet been established.

No data are available.

This medicinal product should only be administered via subcutaneous injection. Do not administerintravenously.

After removing the pre-filled syringe from the refrigerator, wait for at least 30 minutes before injectingto allow the solution to reach room temperature. A safety needle, which is not included in the carton,should be connected to the pre-filled syringe. Use aseptic technique when handling the pre-filledsyringe and during administration. Do not shake the pre-filled syringe.

During the initial administrations of efgartigimod alfa (see section 4.2), appropriate treatment forinjection and hypersensitivity-related reactions should be readily available (see section 4.4). Therecommended injection sites (abdomen) should be rotated and injections should never be given intomoles, scars, or areas where the skin is tender, bruised, red or hard. The medicinal product should beinjected for approximately 20 to 30 seconds. The injection may be slowed if the patient experiencesdiscomfort.

The first self-administration must always be conducted under the supervision of a healthcareprofessional. After adequate training in subcutaneous injection technique, patients or caregivers mayinject the medicinal product at home if a healthcare professional determines that it is appropriate.

Patients or caregivers should be instructed to inject Vyvgart according to the directions provided in thepackage leaflet.

For comprehensive instructions for the administration of the medicinal product, please refer to the

Instructions for Use in the package leaflet.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Myasthenia Gravis Foundation of America (MGFA) Class V patients

Treatment with efgartigimod alfa in patients with MGFA Class V (i.e. myasthenic crisis), defined asintubation with or without mechanical ventilation except in the setting of routine postoperative care,has not been studied. The sequence of therapy initiation between established therapies for MG crisisand efgartigimod alfa, and their potential interactions, should be considered (see section 4.5).

As efgartigimod alfa causes transient reduction in IgG levels the risk of infections may increase(see sections 4.8 and 5.1). The most common infections observed in clinical trials were upperrespiratory tract infections and urinary tract infections (see section 4.8). Patients should be monitoredfor clinical signs and symptoms of infections during treatment with Vyvgart. In patients with an activeinfection, the benefit-risk of maintaining or withholding treatment with efgartigimod alfa should beconsidered until the infection has resolved. If serious infections occur, delaying treatment withefgartigimod alfa should be considered until the infection has resolved.

Injection reactions and hypersensitivity reactions

Injection reactions such as rash or pruritus were reported in the clinical trials (see section 4.8). Thesewere mild to moderate. Cases of anaphylactic reaction have been reported with efgartigimod alfaintravenous in the post-marketing setting. The first administrations of Vyvgart must be performedunder the supervision of a healthcare professional (see section 4.2). Patients should be monitored for30 minutes after administration for clinical signs and symptoms of injection reactions. Should areaction occur and based on the severity of the reaction, appropriate supportive measures should beinitiated. Subsequent injections may be cautiously administered, based on clinical evaluation.

If an anaphylactic reaction is suspected, administration of Vyvgart should be immediatelydiscontinued and appropriate medical treatment initiated. Patients should be informed of the signsand symptoms of hypersensitivity and anaphylactic reactions and advised to contact their healthcareprofessional immediately should they occur.

All vaccines should be administered according to immunisation guidelines.

The safety of immunisation with live or live-attenuated vaccines and the response to immunisationwith these vaccines during treatment with efgartigimod alfa are unknown. For patients that are beingtreated with efgartigimod alfa, vaccination with live or live-attenuated vaccines is generally notrecommended. If vaccination with live or live-attenuated vaccines is required, these vaccines shouldbe administered at least 4 weeks before treatment and at least 2 weeks after the last dose ofefgartigimod alfa.

Other vaccines may be administered as needed at any time during treatment with efgartigimod alfa.

In the active-controlled study ARGX-113-2001, pre-existing antibodies that bind to efgartigimod alfawere detected in 12/110 (11%) patients with gMG. Anti-efgartigimod alfa antibodies were detected in19/55 (35%) patients treated with efgartigimod alfa subcutaneous compared to 11/55 (20%) patientstreated with the intravenous formulation. Neutralising antibodies were detected in 2 (4%) patientstreated with efgartigimod alfa subcutaneous and 2 (4%) patients treated with efgartigimod alfaintravenous.

In study ARGX-113-1802, pre-existing antibodies that bind to efgartigimod alfa were detected in13/317 (4.1%) patients with CIDP. Anti-efgartigimod alfa antibodies were detected in 20/317 (6.3%)of patients treated in the open-label part of the study (Stage A), and in 2/111 (1.8%) of patients treatedin the placebo-controlled part (Stage B). Neutralising antibodies were detected in 1 (0.3%) patient inthe open-label part of the study only (see section 5.1).

The impact of antibodies to efgartigimod alfa on clinical efficacy or safety, pharmacokinetics andpharmacodynamic cannot be assessed given the low incidence of neutralizing antibodies.

When non-steroidal immunosuppressants, corticosteroids and anticholinesterase therapies aredecreased or discontinued, patients should be monitored closely for signs of disease exacerbation.

This medicinal product contains less than 1 mmol sodium (23 mg) per pre-filled syringe, that is to sayessentially ‘sodium-free’.

Polysorbates

This medicinal product contains 2.1 mg of polysorbate 80 in each syringe which is equivalent to0.4 mg/mL. Polysorbates may cause allergic reactions.

No interaction studies have been performed.

Efgartigimod alfa may decrease concentrations of compounds that bind to the human neonatal Fc

Receptor (FcRn), i.e., immunoglobulin products, monoclonal antibodies, or antibody derivativescontaining the human Fc domain of the IgG subclass. If possible, it is recommended to postpone theinitiation of treatment with these products to 2 weeks after the last dose of Vyvgart. As a precaution,patients receiving Vyvgart while on treatment with these products should be closely monitored for theintended efficacy response of those products.

Plasma exchange, immunoadsorption, and plasmapheresis may reduce circulating levels ofefgartigimod alfa.

All vaccines should be administered according to immunisation guidelines.

The potential interaction with vaccines was studied in a nonclinical model using Keyhole limpethemocyanin (KLH) as the antigen. The weekly administration of 100 mg/kg to monkeys did notimpact the immune response to KLH immunisation.

For patients that are being treated with efgartigimod alfa, vaccination with live or live-attenuatedvaccines is generally not recommended. If vaccination with live or live-attenuated vaccines isrequired, these vaccines should be administered at least 4 weeks before treatment and at least 2 weeksafter the last dose of efgartigimod alfa (see section 4.4).

There is no available data on the use of efgartigimod alfa during pregnancy. Antibodies includingtherapeutic monoclonal antibodies are known to be actively transported across the placenta (after30 weeks of gestation) by binding to FcRn.

Efgartigimod alfa may be transmitted from the mother to the developing foetus. As efgartigimod alfais expected to reduce maternal antibody levels, and is also expected to inhibit the transfer of maternalantibodies to the foetus, reduction in passive protection to the newborn is anticipated. Therefore, risksand benefits of administering live/live-attenuated vaccines to infants exposed to efgartigimod alfain utero should be considered (see section 4.4).

Treatment of pregnant women with Vyvgart should only be considered if the clinical benefitoutweighs the risks.

There is no information regarding the presence of efgartigimod alfa in human milk, the effects on thebreastfed child or the effects on milk production. Animal studies on the transfer of efgartigimod alfainto milk have not been conducted, and therefore, excretion into maternal milk cannot be excluded.

Maternal IgG is known to be present in human milk. Treatment of lactating women with efgartigimodalfa should only be considered if the clinical benefit outweighs the risks.

There is no available data on the effect of efgartigimod alfa on fertility in humans. Animal studiesshowed no impact of efgartigimod alfa on male and female fertility parameters (see section 5.3).

Vyvgart has no or negligible influence on the ability to drive and use machines.

The most frequently observed adverse reactions were injection site reactions (33%), upper respiratorytract infections (10.7%) and urinary tract infections (9.5%).

The overall safety profile of Vyvgart subcutaneous for both cyclic and continuous dose regimens wasconsistent with the known safety profile of the intravenous formulation.

Adverse reactions described in this section were identified in clinical trials and from post-marketingreports. These reactions are presented by system organ class and preferred term. Frequency categoriesare defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to< 1/100), rare (≥ 1/10 000 to < 1/1 000) or not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse reactions

System organ class Adverse reaction Frequency category

Infections and infestations* Upper respiratory tract infections Very common

Urinary tract infections Common

Bronchitis Common

Immune system disorders Anaphylactic reaction a Not known

Gastrointestinal disorders Nausea b Common

Musculoskeletal and connective

Myalgia Commontissue disorders

General disorders and

Injection site reactions c, d Very commonadministration site conditions*

Injury, poisoning and

Procedural headache e Commonprocedural complications*

* See paragraph “Description of selected adverse reactions”a From spontaneous post-marketing reporting with intravenous route of administrationb From spontaneous post-marketing reporting.

c Subcutaneous administration only.d (e.g. injection site rash, injection site erythema, injection site pruritus, injection site pain)e Intravenous administration only.

In the pooled dataset from two clinical studies in gMG with efgartigimod alfa subcutaneous (n = 168),all injection site reactions were mild to moderate in severity and did not lead to treatmentdiscontinuation. 44.0% (n = 74)) of patients experienced an injection site reaction. Injection sitereactions occurred within 24 hours after administration in 78.4% (58/74) of patients and resolvedwithout treatment in 85.1% (63/74) of the patients. The incidence of injection site reactions was thehighest in the first treatment cycle, reported in 36.3% (61/168) of patients during the first treatmentcycle and decreased to 20.1% (30/149), 15.4% (18/117) and 12.5% (10/80) of patients with thesecond, third and fourth treatment cycle. In a pooled dataset from 2 clinical studies in patients with

CIDP who received continuous administration of efgartigimod alfa subcutaneous the incidence ofinjection site reactions was 26% (61/235). Analysis by 3-month intervals showed that the percentageof participants with injection-site reactions was highest in the first 3 months of treatment (73 [22.2%]participants) and decreased in subsequent 3-month intervals (range: 0 to 17 [6.8%] participants).

In the gMG ARGX-113-1704 placebo-controlled study with efgartigimod alfa intravenous, the mostfrequently reported adverse reactions were infections, and the most reported infections were upperrespiratory tract infections (10.7% [n = 9] of patients treated with efgartigimod alfa intravenous and4.8% [n = 4] of patients treated with placebo) and urinary tract infections (9.5% [n = 8] of patientstreated with efgartigimod alfa intravenous and 4.8% [n = 4] of patients treated with placebo). Theseinfections were mild to moderate in severity in patients who received efgartigimod alfa intravenous(≤ Grade 2 according to the Common Terminology Criteria for Adverse Events). Overall, treatmentemergent infections were reported in 46.4% (n = 39) of patients treated with efgartigimod alfaintravenous and 37.3% (n = 31) of patients treated with placebo. The median time from treatmentinitiation to emergence of infections was 6 weeks. Incidence of infections did not increase withsubsequent treatment cycles. Treatment discontinuation or temporary interruption of treatment due toan infection occurred in less than 2% of patients. In the placebo-controlled part of the

ARGX-113-1802 study in patients with CIDP, continuous administration of efgartigimod alfasubcutaneous was not associated with any increase in the incidence of infections (31.5% [35/111] inthe efgartigimod alfa subcutaneous group and 33.6% [37/110] in the placebo group) (see section 5.1).

Procedural headache

Procedural headache was reported in 4.8% of the patients treated with efgartigimod alfa intravenousand 1.2% of patients treated with placebo. Procedural headache was reported when a headache wasjudged to be temporally related to the intravenous infusion of efgartigimod alfa. All were mild ormoderate except one event which was reported as severe (Grade 3).

All other adverse reactions were mild or moderate with the exception of one case of myalgia (Grade 3).

Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There are no known specific signs and symptoms of overdose with efgartigimod alfa. In the event ofan overdose the adverse events that may occur are not expected to be different from those that may beobserved at the recommended dose. Patients should be monitored for adverse reactions, andappropriate symptomatic and supportive treatment initiated. There is no specific antidote for overdosewith efgartigimod alfa.

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants, ATC code:

L04AA58

Efgartigimod alfa is a human IgG1 antibody fragment engineered for increased affinity to the neonatal

Fc Receptor (FcRn). Efgartigimod alfa binds to FcRn, resulting in a reduction in the levels ofcirculating IgG including pathogenic IgG autoantibodies. Efgartigimod alfa does not affect the levelsof other immunoglobulins (IgA, IgD, IgE or IgM), and does not reduce those of albumin.

IgG autoantibodies are the underlying cause of the pathogenesis of IgG mediated autoimmunediseases.

In MG these impair neuromuscular transmission by binding to acetylcholine receptors (AChR),muscle-specific tyrosine kinase (MuSK) or low-density lipoprotein receptor-related protein 4 (LRP4).

In CIDP, several lines of evidence point to the key role of IgG autoantibodies in the pathogenesis ofthis disease. This includes the demonstration of autoreactive IgG antibodies against components ofmyelinated nerves, passive transfer of CIDP symptoms to animal models using sera or IgG’s frompatients with CIDP, and the therapeutic effect of plasma exchange and immunoadsorption for treatingpatients with CIDP.

Intravenous formulation

In the ARGX-113-1704 double-blind placebo-controlled study in gMG patients, efgartigimod alfa10 mg/kg administered once weekly for 4 weeks decreased serum IgG levels and AChR autoantibody(AChR-Ab) levels. Maximum mean percentage decrease in total IgG levels compared to baselinereached 61% one week after the last infusion of the initial treatment cycle and returned to baselinelevels 9 weeks after the last infusion. Similar effects were also observed for all subtypes of IgG.

Decrease in AChR-Ab levels followed a similar time course with maximum mean percentage decreaseof 58% one week after the last infusion and return to baseline levels 7 weeks after the last infusion.

Similar changes were observed during the second cycle of the study.

Subcutaneous formulation

In the ARGX-113-2001 study, decreases in AChR-Ab levels followed a comparable time course astotal IgG levels and were similar between the efgartigimod alfa subcutaneous and intravenous groups.

Maximum mean percentage decreases in AChR-Ab levels of 62.2% and 59.6% were observed oneweek after the last administration in the efgartigimod alfa subcutaneous and intravenous groups,respectively. For both the efgartigimod alfa subcutaneous and intravenous groups, decrease in total

IgG and AChR-Ab levels were associated with a clinical response, as measured by the change frombaseline in MG-ADL total score (see figure 1).

Figure 1. Relationship between total IgG and AChR-Ab and MG-ADL total score in AChR-

Ab seropositive population treated with efgartigimod alfa subcutaneous (1A) andefgartigimod alfa intravenous (1B) (study ARGX-113-2001)

In the ARGX-113-1802 study in patients with CIDP receiving continuous once-weekly administrationof efgartigimod alfa subcutaneous at 1 000 mg, the mean percent change from baseline in total IgGlevels was sustained from Week 4 throughout the treatment period (mean percentage reduction frombaseline ranging between 66.8 to 71.6%).

Generalised Myasthenia Gravis

Intravenous formulation

Efficacy of efgartigimod alfa for the treatment of adults with generalised Myasthenia Gravis (gMG)was studied in a 26-week, multicentre randomised double-blind placebo-controlled trial(ARGX-113-1704).

In this study, patients had to meet the following main criteria at screening:

* Myasthenia Gravis Foundation of America (MGFA) clinical classification class II, III or IV;

* Patients with either positive or negative serologic tests for antibodies to AChR;

* MG-Activities of Daily Living (MG-ADL) total score of ≥ 5;

* On stable doses of MG therapy prior to screening, that included acetylcholinesterase (AChE)inhibitors, steroids or non-steroidal immunosuppressive therapy (NSIST), either in combinationor alone [NSISTs included but were not limited to azathioprine, methotrexate, cyclosporine,tacrolimus, mycophenolate mofetil, and cyclophosphamide];

* IgG levels of at least 6 g/L.

Patients with MGFA Class V gMG; patients with documented lack of clinical response to PLEX;patients treated with PLEX, IVIg one month and monoclonal antibodies six months prior to startingtreatment; and patients with active (acute or chronic) hepatitis B infection, hepatitis C seropositivity,and diagnosis of AIDS, were excluded from the trials.

A total of 167 patients were enrolled in the study and were randomised to either efgartigimod alfaintravenous (n = 84) or placebo (n = 83). Baseline characteristics were similar between treatmentgroups, including median age at diagnosis [45 (19-81) years], gender [most were female; 75%(efgartigimod alfa) versus 66% (placebo)], race [most patients were white; 84.4%] and median timesince diagnosis [8.2 years (efgartigimod alfa) and 6.9 years (placebo)].

The majority of patients (77% in each group) tested positive for antibodies to AChR (AChR-Ab) and23% of patients tested negative for AChR-Ab.

During the study, over 80% of patients in each group received AChE inhibitors, over 70% in eachtreatment group received steroids, and approximately 60% in each treatment group received NSISTs,at stable doses. At study entry, approximately 30% of patients in each treatment group had no previousexposure to NSISTs.

Median MG-ADL total score was 9.0 in both treatment groups, and median Quantitative Myasthenia

Gravis (QMG) total score was 17 and 16 in the efgartigimod alfa and placebo groups, respectively.

Patients were treated with efgartigimod alfa intravenous 10 mg/kg administered once weekly for4 weeks and received a maximum of 3 treatment cycles.

The efficacy of efgartigimod alfa was measured using the Myasthenia Gravis-Specific Activities of

Daily Living scale (MG-ADL) which assesses the impact of gMG on daily functions. A total scoreranges from 0 to 24 with the higher scores indicating more impairment. In this study, an MG-ADLresponder was a patient with ≥ 2-point reduction in the total MG-ADL score compared to the treatmentcycle baseline, for at least 4 consecutive weeks with the first reduction occurring no later than 1 weekafter the last infusion of the cycle.

The efficacy of efgartigimod alfa was also measured using the QMG total score which is a gradingsystem that assesses muscle weakness with a total possible score of 0 to 39 where higher scoresindicate more severe impairment. In this study, a QMG responder was a patient who had a ≥ 3-pointreduction in the total QMG score compared to the treatment cycle baseline, for at least 4 consecutiveweeks with the first reduction occurring no later than 1 week after last infusion of the cycle.

The primary efficacy endpoint was the comparison of the percentage of MG-ADL responders duringthe first treatment cycle (C1) between treatment groups in the AChR-Ab seropositive population.

A key secondary endpoint was the comparison of the percentage of QMG responders during C1between both treatment groups in the AChR-Ab seropositive patients.

Table 2. MG-ADL and QMG responders during cycle 1 in AChR-Ab seropositive population(mITT analysis set)

Population Efgartigimod Placebo P-value Differencealfa n/N (%) Efgartigimod alfa-n/N (%) Placebo (95% CI)

MG-ADL AChR-Ab seropositive 44/65 (67.7) 19/64 (29.7) < 0.0001 38.0 (22.1; 54.0)

QMG AChR-Ab seropositive 41/65 (63.1) 9/64 (14.1) < 0.0001 49.0 (34.5; 63.5)

AChR-Ab = acetylcholine receptor-antibody; MG-ADL = Myasthenia Gravis Activities of Daily Living;

QMG = Quantitative Myasthenia Gravis; mITT = modified intent-to-treat; n = number of patients for whom theobservation was reported; N = number of patients in the analysis set; CI = confidence interval;

Logistic regression stratified for AChR-Ab status (if applicable), Japanese/Non-Japanese and standard of care,with baseline MG-ADL as covariate/QMG as covariates

Two-sided exact p-value

Analyses show that during the second treatment cycle MG-ADL responder rates were similar to thoseduring the first treatment cycle (see Table 3).

Table 3. MG-ADL and QMG responders during cycle 2 in AChR-Ab seropositive population(mITT analysis set)

Population Efgartigimod alfa Placebon/N (%) n/N (%)

MG-ADL AChR-Ab seropositive 36/51 (70.6) 11/43 (25.6)

QMG AChR-Ab seropositive 24/51 (47.1) 5/43 (11.6)

AChR-Ab = acetylcholine receptor-antibody; MG-ADL = Myasthenia Gravis Activities of Daily Living;

QMG = Quantitative Myasthenia Gravis; mITT = modified intent-to-treat; n = number of patients for whom theobservation was reported; N = number of patients in the analysis set.

Exploratory data shows that onset of response was observed within 2 weeks of initial infusion in 37/44(84%) patients treated with efgartigimod alfa intravenous in the AChR-Ab seropositive MG-ADLresponders.

In the double-blind placebo-controlled study (ARGX-113-1704), the earliest possible time to initiatingthe subsequent treatment cycle was 8 weeks after the initial infusion of the first treatment cycle. In theoverall population the mean time to the second treatment cycle in the efgartigimod alfa intravenousgroup was 13 weeks (SD 5.5 weeks) and the median time was 10 weeks (8-26 weeks) from the initialinfusion of the first treatment cycle. In the open-label extension study (ARGX-113-1705) the earliestpossible time of initiation of the subsequent treatment cycles was 7 weeks.

In patients that responded to treatment, the duration of clinical improvement was 5 weeks in5/44 (11%) patients, 6-7 weeks in 14/44 (32%) of patients, 8-11 weeks in 10/44 (23%) patients and12 weeks or more in 15/44 (34%) patients.

Subcutaneous formulation

A 10-week, randomised, open-label, parallel-group, multicentre study (ARGX-113-2001) wasconducted in adult patients with gMG to evaluate the non-inferiority of the pharmacodynamic effectof efgartigimod alfa subcutaneous compared to efgartigimod alfa intravenous. The main inclusion andexclusion criteria were the same as in study ARGX-113-1704.

A total of 110 patients were randomised and received one cycle of once weekly administrations for4 weeks, of either efgartigimod alfa subcutaneous 1 000 mg (n = 55) or efgartigimod alfa intravenous10 mg/kg (n = 55). The majority of patients were positive for antibodies to AChR (AChR-Ab):

45 patients (82%) in efgartigimod alfa subcutaneous group and 46 patients (84%) in efgartigimod alfaintravenous group. All patients were on stable doses of MG therapy prior to screening, that included

AChE inhibitors, steroids or NSISTs, either in combination or alone.

Baseline characteristics were similar between treatment groups.

During the study, over 80% of patients in each group received AChE inhibitors, over 60% of patientsin each group received steroids and about 40% in each treatment group received NSISTs, at stabledoses. At study entry, approximately 56% of patients in each treatment group had no previousexposure to NSISTs.

The primary endpoint was the comparison of the percent reduction in total IgG levels from baseline atday 29 between treatment groups in the overall population. The results in the AChR-Ab seropositivepopulation demonstrates non-inferiority of efgartigimod alfa subcutaneous compared to efgartigimodalfa intravenous (see Table 4).

Table 4. ANCOVA analysis of percent change from baseline in total IgG level at day 29 in

AChR-Ab seropositive population (mITT analysis set)

Efgartigimod alfa SC Efgartigimod alfa IV Difference

Efgartigimod alfa SC-

Efgartigimod alfa IV

N LS Mean 95% CI N LS Mean 95% CI LS of 95% CI p-value

Meandifference41 -66.9 -69.78, -64.02 43 -62.4 -65.22, -59.59 -4.5 -8.53, -0.46 < 0.0001

AChR-Ab = acetylcholine receptor-antibody; ANCOVA = analysis of covariance; CI = confidence interval;

SC = subcutaneous; IV = intravenous; LS = least squares; mITT = modified intent-to-treatment analysis set;

N = number of patients per group that were included in the ANCOVA analysis

Efficacy secondary endpoints were comparisons of the percentage of MG-ADL and QMG responders,as defined in study ARGX-113-1704, between both treatment groups. The results in AChR-Abseropositive population are presented in Table 5.

Table 5. MG-ADL and QMG responders at day 29 in AChR-Ab seropositive population(mITT analysis set)

Efgartigimod alfa SC Efgartigimod alfa IV Differencen/N (%) n/N (%) Efgartigimod alfa SC-

Efgartigimod alfa IV (95% CI)

MG-ADL 32/45 (71.1) 33/46 (71.7) -0.6 (-19.2 to 17.9)

QMG 31/45 (68.9) 24/45 (53.3) 15.6 (-4.3 to 35.4)

AChR-Ab = acetylcholine receptor-antibody; MG-ADL = Myasthenia Gravis Activities of Daily Living;

QMG = Quantitative Myasthenia Gravis; SC = subcutaneous; IV = intravenous; mITT = modified intent-to-treat;n = number of patients for whom the observation was reported; N = number of patients in the analysis set;

CI = confidence interval

Exploratory data shows that onset of response was observed within 2 weeks of initial administration in28/32 (88%) patients treated with efgartigimod alfa subcutaneous and 27/33 (82%) patients treatedwith efgartigimod alfa intravenous in the AChR-Ab seropositive MG-ADL responders.

Chronic Inflammatory Demyelinating Polyneuropathy

The efficacy of efgartigimod alfa subcutaneous for the treatment of adults with CIDP was studied in aprospective, multicentre study ARGX-113-1802 conducted in 2 treatment stages: an open-label Stage

A and a randomized-withdrawal, double-blinded, placebo-controlled Stage B.

Patients had been either on or off CIDP treatment during the 6 months prior to study entry. Those onprior CIDP treatment as well as those off CIDP treatment with no documented evidence of recent

CIDP deterioration, entered a treatment-free run-in period, and patients who demonstrated evidence ofclinically meaningful deterioration then entered Stage A of the study. Those off CIDP treatment whohad recent documented evidence of CIDP deterioration, skipped the run-in period and entered straightinto Stage A.

A total of 322 patients were enrolled in Stage A. Patients received up to 12 once weekly injections ofefgartigimod alfa subcutaneous 1 000 mg until evidence of clinical improvement (ECI) occurred at2 consecutive study visits. Subsequently, the patients with confirmed ECI entered Stage B of the studyand were randomised to receive weekly administrations of either efgartigimod alfa subcutaneous(111 patients) or placebo (110 patients). ECI was defined as clinical improvement on adjusted

Inflammatory Neuropathy Cause and Treatment (aINCAT) or improvement on Inflammatory Rasch-built Overall Disability Scale (I- RODS)/Grip Strength in patients who deteriorated on these scalesonly prior to Stage A.

In Stage A, patients had a median age of 54 years (range: 20 to 82 years), a median time since CIDPdiagnosis of 2.8 years and median INCAT score of 4.0. Sixty-five percent were male and 66% were

White. In Stage B, patients had a median age of 55 years (range: 20 to 82 years), a median time since

CIDP diagnosis of 2.2 years and median INCAT score of 3.0. Sixty-four percent were male and 65%were White. Baseline characteristics of Stage B were similar between treatment groups.

In Stage A, the primary endpoint was the percentage of responders defined as patients achievingconfirmed ECI. The primary endpoint was met in 66.5% of patients; further details are presented in

Table 6.

A secondary endpoint in Stage A was the time to the first confirmed ECI. Week 4 was the earliest timepoint at which ECI criteria could be met. At that time point, up to 40% of patients achieved ECI.

Based on an additional pre-specified analysis, 25% of patients showed clinically relevant improvementafter 9 days in at least one of 3 parameters (aINCAT, I-RODS or Grip Strength).

The majority of patients achieved confirmed ECI across all prior CIDP medication groups.

Table 6. Evidence of clinical improvement in patients with CIDP in ARGX-113-1802 Stage A

Stage A

ECI responders and time to initial confirmed ECI Efgartigimod alfa SC(N = 322)

ECI Responders (patients with confirmed clinical improvement) 214/322 (66.5%)n/N (%) (95% CI) (61.0; 71.6)

Time to initial confirmed ECI in days 43.0median (95% CI) (31.0; 51.0)n = number of patients for whom the observation was reported; N = number of patients in the analysis set

In Stage B, the primary endpoint was defined as the time to the occurrence of the first evidence ofclinical deterioration (a 1-point increase in aINCAT compared to Stage B baseline, which wasconfirmed at a consecutive visit after the first 1-point increase in aINCAT or, a ≥ 2-point increase inaINCAT compared to Stage B baseline). Patients who received efgartigimod alfa subcutaneousremained relapse-free (i.e., no clinical deterioration) significantly longer compared to patients whoreceived placebo, as demonstrated by a hazard ratio of 0.394 [95% CI (0.253; 0.614)]. 31/111 (27.9%)of patients who received efgartigimod alfa subcutaneous during Stage B of the study relapsedcompared to 59/110 (53.6%) of patients who received placebo. The results are presented in Table 7and Figure 2.

Table 7. First evidence of clinical deterioration in patients with CIDP in study ARGX-113-1802

Stage B

Stage B

Time to 1st aINCAT increase (clinical deterioration) Efgartigimod alfa SC Placebo(N = 111) (N = 110)0.394 (0.253; 0.614)

Hazard ratio (95% CI)p-value < 0.0001

Median time in days (95% CI) NC (NC; NC) 140.0 (75.0; NC)

NC = not calculated; N = number of patients in the analysis set; aINCAT = adjusted Inflammatory Neuropathy

Cause and Treatment

Figure 2. Time to the first aINCAT deterioration (Kaplan-Meier Curve) in patients with CIDPin study ARGX-113-1802 Stage B

The European Medicines Agency has deferred the obligation to submit the results of studies with

Vyvgart in one or more subsets of the paediatric population in treatment of myasthenia gravis(see section 4.2 for information on paediatric use).

The European Medicines Agency has waived the obligation to submit the results of studies with

Vyvgart in all subsets of the paediatric population in CIDP (see section 4.2 for information onpaediatric use).

Based upon population PK data analysis, the estimated bioavailability with efgartigimod alfa 1 000 mgsubcutaneous is 77%.

The mean Ctrough after 4 once weekly administrations with efgartigimod alfa 1 000 mg subcutaneousand efgartigimod alfa 10 mg/kg intravenous were 22.0 µg/mL (37% CV) and 14.9 µg/mL (43% CV),respectively. The AUC0-168h of efgartigimod alfa after administration of one treatment cycle with1 000 mg subcutaneous and 10 mg/kg intravenous were comparable.

In patients receiving continuous subcutaneous administration of efgartigimod alfa 1 000 mg onceweekly, mean Ctrough ranged from 14.9 to 20.1 µg/mL.

Based upon population PK data analysis in healthy subjects and patients the volume of distribution is 18 L.

Probability of No Adjusted INCAT Deterioration

Efgartigimod alfa is expected to be degraded by proteolytic enzymes into small peptides andamino acids.

The terminal half-life is 80 to 120 hours (3 to 5 days). Based upon population PK data analysis, theclearance is 0.128 L/h. The molecular weight of efgartigimod alfa is approximately 54 kDa, which isat the boundary of molecules that are renally filtered.

The pharmacokinetics profile of efgartigimod alfa is linear, independent of dose or time, with minimalaccumulation.

Age, gender, race and bodyweight

The pharmacokinetics of efgartigimod alfa were not affected by age (19-84 years), gender, race andbodyweight.

No dedicated pharmacokinetic studies have been performed in patients with renal impairment.

The effect of renal function marker estimated glomerular filtration rate [eGFR] as a covariate in apopulation pharmacokinetic analysis showed an increase in exposure (11% to 21%) in patients withmild renal impairment (eGFR 60-89 mL/min/1.73 m2). No specific dose adjustment is recommendedin patients with mild renal impairment.

There is insufficient data on the impact of moderate renal impairment (eGFR 30-59 mL/min/1.73 m2)and severe renal impairment (eGFR < 30 mL/min/1.73 m2) on efgartigimod alfa pharmacokineticparameters.

No dedicated pharmacokinetic study has been performed in patients with hepatic impairment.

The effect of hepatic function markers as covariates in a population pharmacokinetic analysis did notshow any impact on the pharmacokinetics of efgartigimod alfa.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology and repeated dose toxicity.

In reproduction studies in rats and rabbits, intravenous administration of efgartigimod alfa did notresult in adverse effects on fertility and pregnancy nor were teratogenic effects observed up to doselevels corresponding to 11-fold (rats) and 56-fold (rabbits) a human 10 mg/kg exposure basedon AUC.

Carcinogenicity and genotoxicity

No studies have been conducted to assess the carcinogenic and genotoxic potential ofefgartigimod alfa.

Hyaluronidase is found in most tissues of the human body. Non-clinical data for recombinant humanhyaluronidase reveal no special hazard for humans based on conventional studies of repeated dosetoxicity including safety pharmacology endpoints. Reproductive toxicology studies with rHuPH20revealed embryofoetal toxicity in mice at high systemic exposure, but did not show teratogenicpotential.

Recombinant human hyaluronidase (rHuPH20)

L-arginine hydrochloride

L-histidine

L-histidine hydrochloride monohydrate

L-methionine

Polysorbate 80 (E433)

Sodium chloride

Sucrose

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

2 years

Patients may store the unopened pre-filled syringe at room temperature in the original carton up to30 °C for a single period of up to 1 month after removing it from the refrigerator or by the expiry date,whichever occurs first.

From a microbial point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

Store in the original package in order to protect from light.

5 mL solution in a single-use pre-filled syringe (type I glass) with a rubber stopper and a rubber tipcap.

1 pre-filled syringe.

4 pre-filled syringes.

Not all pack sizes may be marketed.

Vyvgart comes as a ready-to-use solution in single-use pre-filled syringe. The medicinal product doesnot need to be diluted.

Visually inspect that the pre-filled syringe content has a yellowish, clear to opalescent colour, anddevoid of particulate matter. If visible particles are observed the pre-filled syringe must not be used.

After removing the pre-filled syringe from the refrigerator, wait for at least 30 minutes before injectingto allow the solution to reach room temperature (see section 4.2). After preparation for injection, itshould be administered immediately.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

argenx BV

Industriepark-Zwijnaarde 79052 Gent

Belgium

EU/1/22/1674/003

EU/1/22/1674/004

Date of first authorisation: 10 August 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.