----------------------------CONTRAINDICATIONS----------------------------------

HIGHLIGHTS OF PRESCRIBING INFORMATION

VYVGART HYTRULO is contraindicated in patients with serious
These highlights do not include all the information needed to use
hypersensitivity to efgartigimod alfa products, to hyaluronidase, or to
VYVGART HYTRULO safely and effectively. See full prescribing
any of the excipients of VYVGART HYTRULO. (4)
information for VYVGART HYTRULO.
------------------------WARNINGS AND PRECAUTIONS-----------------------
VYVGART® HYTRULO (efgartigimod alfa and hyaluronidase-qvfc)
injection, for subcutaneous use  Infections: Delay administration of VYVGART HYTRULO to patients
Initial U.S. Approval: 2023 with an active infection. Monitor for signs and symptoms of infection
in patients treated with VYVGART HYTRULO. If serious infection
occurs, administer appropriate treatment and consider withholding
-----------------------------RECENT MAJOR CHANGES------------------------- VYVGART HYTRULO until the infection has resolved. (5.1)
Indications and Usage (1) 6/2024  Hypersensitivity Reactions: Anaphylaxis, hypotension leading to
Dosage and Administration (2.1) 8/2024 syncope, angioedema, dyspnea, rash, and urticaria have occurred
Dosage and Administration (2.4) 6/2024 in patients treated with VYVGART HYTRULO or intravenous
Contraindications (4) 12/2023 efgartigimod alfa-fcab product. If a hypersensitivity reaction
Warnings and Precautions (5.1) 8/2024 occurs, the healthcare professional should institute appropriate
Warnings and Precautions (5.2, 5.3) 12/2023 measures if needed or the patient should seek medical attention.
(4, 5.2)
 Infusion-Related Reactions: If a severe infusion-related reaction
-----------------------------INDICATIONS AND USAGE--------------------------- occurs, initiate appropriate therapy; consider the risks and benefits of
VYVGART HYTRULO is a combination of efgartigimod alfa, a readministering. If a mild to moderate infusion-related reaction
neonatal Fc receptor blocker, and hyaluronidase, an endoglycosidase, occurs, may rechallenge with close clinical observation, slower
indicated for the treatment of adult patients with: infusion rates, and pre-medications. (5.3)
 generalized myasthenia gravis (gMG) who are anti-acetylcholine
receptor (AChR) antibody positive (1) -------------------------------ADVERSE REACTIONS------------------------------
 chronic inflammatory demyelinating polyneuropathy (CIDP) (1) The most common adverse reactions (≥ 10%) in patients with gMG
treated with efgartigimod alfa-fcab were respiratory tract infections,
------------------------DOSAGE AND ADMINISTRATION----------------------- headache, and urinary tract infection.
 See Full Prescribing Information for instructions on dosage,
preparation, and administration. (2.1, 2.2, 2.3, 2.4, 2.5) Injection site reactions were common (≥ 15%) in patients with gMG and
 Evaluate the need to administer age-appropriate vaccines according CIDP who were treated with VYVGART HYTRULO. (6.1)
to immunization guidelines before initiation of a new treatment cycle
with VYVGART HYTRULO. (2.1) To report SUSPECTED ADVERSE REACTIONS, contact argenx at
1-833-argx411 or FDA at 1-800-FDA-1088 or
 Administer by a healthcare professional only. (2.2) www.fda.gov/medwatch.
 Administer with a winged infusion set subcutaneously over 30 to 90
seconds. (2.2, 2.3, 2.4) ------------------------------DRUG INTERACTIONS--------------------------------
 gMG: The recommended dosage is 1,008 mg / 11,200 units (1,008 Closely monitor for reduced effectiveness of medications that bind to
mg efgartigimod alfa and 11,200 units hyaluronidase) in cycles of the human neonatal Fc receptor. When concomitant long-term use of
once weekly injections for 4 weeks. Administer subsequent such medications is essential for patient care, consider discontinuing
treatment cycles based on clinical evaluation; safety of initiating VYVGART HYTRULO and using alternative therapies. (7)
subsequent cycles sooner than 50 days from the start of the
previous treatment cycle has not been established. (2.3) See 17 for PATIENT COUNSELING INFORMATION
 CIDP: The recommended dosage is 1,008 mg / 11,200 units (1,008
mg efgartigimod alfa and 11,200 units hyaluronidase) as once Revised: 8/2024
weekly injections. (2.4)

---------------------DOSAGE FORMS AND STRENGTHS----------------------

Injection: 1,008 mg efgartigimod alfa and 11,200 units hyaluronidase
per 5.6 mL (180 mg/2,000 units per mL) in a single-dose vial. (3)
FULL PRESCRIBING INFORMATION: CONTENTS* 8 USE IN SPECIFIC POPULATIONS
1 INDICATIONS AND USAGE 8.1 Pregnancy
2 DOSAGE AND ADMINISTRATION 8.2 Lactation
2.1 Recommended Vaccination 8.4 Pediatric Use
2.2 Important Dosage and Administration Instructions 8.5 Geriatric Use
2.3 Recommended Dosage for gMG 8.6 Renal Impairment
2.4 Recommended Dosage for CIDP 11 DESCRIPTION
2.5 Preparation and Administration Instructions 12 CLINICAL PHARMACOLOGY
3 DOSAGE FORMS AND STRENGTHS 12.1 Mechanism of Action
4 CONTRAINDICATIONS 12.2 Pharmacodynamics
5 WARNINGS AND PRECAUTIONS 12.3 Pharmacokinetics
5.1 Infections 12.6 Immunogenicity
5.2 Hypersensitivity Reactions 13 NONCLINICAL TOXICOLOGY
5.3 Infusion-Related Reactions 13.1 Carcinogenesis, Mutagenesis, Impairment
6 ADVERSE REACTIONS of Fertility
6.1 Clinical Trials Experience 14 CLINICAL STUDIES
6.2 Postmarketing Experience 14.1 Generalized Myasthenia Gravis
7 DRUG INTERACTIONS 14.2 Chronic Inflammatory Demyelinating Polyneuropathy
7.1 Effect of VYVGART HYTRULO on Other Drugs 16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full

prescribing information are not listed.
FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

VYVGART HYTRULO is indicated for the treatment of adult patients with:
 generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody
positive
 chronic inflammatory demyelinating polyneuropathy (CIDP)

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Vaccination

Evaluate the need to administer age-appropriate vaccines according to immunization guidelines

before initiation of a new treatment cycle with VYVGART HYTRULO. Because VYVGART
HYTRULO causes transient reduction in IgG levels, vaccination with live vaccines is not
recommended during treatment with VYVGART HYTRULO [see Dosage and Administration (2.3)
and Warnings and Precautions (5.1)].

2.2 Important Dosage and Administration Instructions

VYVGART HYTRULO is to be administered by a healthcare professional only.

VYVGART HYTRULO is for subcutaneous use only and administered with a winged infusion set
[see Dosage and Administration (2.4)]. Do not administer intravenously.

Do not dilute VYVGART HYTRULO.

2.3 Recommended Dosage for gMG

The recommended dosage of VYVGART HYTRULO is 1,008 mg / 11,200 units (1,008 mg

efgartigimod alfa and 11,200 units hyaluronidase) administered subcutaneously over
approximately 30 to 90 seconds in cycles of once weekly injections for 4 weeks.

Administer subsequent treatment cycles according to clinical evaluation. The safety of initiating
subsequent cycles sooner than 50 days from the start of the previous treatment cycle has not
been established.

If a scheduled dose is missed, VYVGART HYTRULO may be administered up to 3 days after the
scheduled time point. Thereafter, resume the original dosing schedule until the treatment cycle is
completed.
2.4 Recommended Dosage for CIDP

The recommended dosage of VYVGART HYTRULO is 1,008 mg / 11,200 units (1,008 mg efgartigimod
alfa and 11,200 units hyaluronidase) administered subcutaneously over approximately 30 to 90 seconds
as once weekly injections.

If a scheduled injection is missed, VYVGART HYTRULO may be administered up to 3 days after the
scheduled time point. Thereafter, resume the original dosing schedule.

2.5 Preparation and Administration Instructions

Use aseptic technique when preparing and administering VYVGART HYTRULO. Do not shake the
vial. Each vial is for one time use only. Avoid exposure to direct sunlight.

Preparation

 Take the VYVGART HYTRULO vial out of the refrigerator at least 15 minutes before
injecting to allow it to reach room temperature [see How Supplied/Storage and Handling
(16)]. Do not use external heat sources.
 Check that the VYVGART HYTRULO solution is yellowish, clear to opalescent.
 Parenteral medicine products should be inspected visually for particulate matter prior to
administration, whenever solution and container permit. Do not use if opaque particles or
other foreign particles are present.
 Withdraw the entire content of VYVGART HYTRULO from the vial using a polypropylene
syringe and an 18G stainless steel transfer needle.
 Remove large air bubbles, if present.
 Each vial contains overfill to compensate for liquid loss during preparation and to
compensate for the priming volume of the winged infusion set.
 VYVGART HYTRULO does not contain preservatives. Administer immediately after
preparation.

Administration

 To administer VYVGART HYTRULO use a winged infusion set made of polyvinyl chloride
(PVC), 25G, 12 inches tubing, maximum priming volume of 0.4 mL.
 Remove the transfer needle from the syringe and connect the syringe to the winged
infusion set.
 Prior to administration, fill the tubing of the winged infusion set by gently pressing the
syringe plunger until the plunger is at 5.6 mL. There should be solution at the end of the
winged infusion set needle.
 Choose an injection site on the abdomen (at least 2 to 3 inches away from the navel).
o Do not inject on areas where the skin is red, bruised, tender, hard, or into areas where
there are moles or scars.
o Rotate injection sites for subsequent administrations.
 Inject VYVGART HYTRULO subcutaneously into a pinched skin area at an angle of about
45 degrees over 30 to 90 seconds.
 Localized injection site reactions may occur after VYVGART HYTRULO is administered.
 [see Adverse Reactions (6.1)].
 Discard any unused portions of medicine remaining in the vial, the syringe and the winged
infusion set.
 Healthcare professionals should monitor for clinical signs and symptoms of hypersensitivity
reactions for at least 30 minutes after administration. If a hypersensitivity reaction occurs,
the healthcare professional should institute appropriate measures if needed or the patient
should seek medical attention [see Warnings and Precautions (5.2)].

3 DOSAGE FORMS AND STRENGTHS

Injection: 1,008 mg efgartigimod alfa and 11,200 units hyaluronidase per 5.6 mL (180 mg/2,000
units per mL) as yellowish, clear to opalescent solution, in a single-dose vial.

4 CONTRAINDICATIONS
VYVGART HYTRULO is contraindicated in patients with serious hypersensitivity to efgartigimod alfa
products, to hyaluronidase, or to any of the excipients of VYVGART HYTRULO. Reactions have included
anaphylaxis and hypotension leading to syncope [see Warnings and Precautions (5.2)].

5 WARNINGS AND PRECAUTIONS

5.1 Infections

VYVGART HYTRULO may increase the risk of infection. The most common infections observed in
Study 1 were urinary tract infection (10% of efgartigimod alfa-fcab-treated patients compared to
5% of placebo-treated patients) and respiratory tract infections (33% of efgartigimod alfa-fcab-
treated patients compared to 29% of placebo-treated patients) [see Adverse Reactions (6.1) and
Clinical Studies (14)]. A higher frequency of patients who received efgartigimod alfa-fcab
compared to placebo were observed to have below normal levels for white blood cell counts (12%
versus 5%, respectively), lymphocyte counts (28% versus 19%, respectively), and neutrophil
counts (13% versus 6%, respectively). The majority of infections and hematologic abnormalities
were mild to moderate in severity. Delay VYVGART HYTRULO administration in patients with an
active infection until the infection is resolved. During treatment with VYVGART HYTRULO, monitor
for clinical signs and symptoms of infections. If serious infection occurs, administer appropriate
treatment and consider withholding VYVGART HYTRULO until the infection has resolved.

Immunization
Evaluate the need to administer age-appropriate vaccines according to immunization guidelines
before initiation of a new treatment cycle with VYVGART HYTRULO. The safety of immunization with
live vaccines and the immune response to vaccination during treatment with VYVGART HYTRULO
are unknown. Because VYVGART HYTRULO causes a reduction in IgG levels, vaccination with live
vaccines is not recommended during treatment with VYVGART HYTRULO.

5.2 Hypersensitivity Reactions

In clinical trials, hypersensitivity reactions, including rash, angioedema, and dyspnea were
observed in patients treated with VYVGART HYTRULO or intravenous efgartigimod alfa-fcab.
Urticaria was also observed in patients treated with VYVGART HYTRULO. Hypersensitivity
reactions were mild or moderate, occurred within one hour to three weeks of administration.
Anaphylaxis and hypotension leading to syncope have been reported in postmarketing experience with
intravenous efgartigimod alfa-fcab. Anaphylaxis and hypotension occurred during or within an hour of
administration and led to infusion discontinuation and in some cases to permanent treatment
discontinuation.
Healthcare professionals should monitor for clinical signs and symptoms of hypersensitivity
reactions for at least 30 minutes after administration [see Dosage and Administration (2.4)]. If a
hypersensitivity reaction occurs, the healthcare professional should institute appropriate measures
if needed or the patient should seek medical attention. VYVGART HYTRULO is contraindicated in
patients with a history of serious hypersensitivity to efgartigimod alfa products, to hyaluronidase, or
to any of the excipients of VYVGART HYTRULO [see Contraindications (4)].

5.3 Infusion-Related Reactions

Infusion-related reactions have been reported with intravenous efgartigimod alfa-fcab in

postmarketing experience. The most frequent symptoms and signs were hypertension, chills,
shivering, and thoracic, abdominal, and back pain. Infusion-related reactions occurred during or
within an hour of administration and led to infusion discontinuation. If a severe infusion-related
reaction occurs, initiate appropriate therapy. Consider the risks and benefits of readministering
VYVGART HYTRULO following a severe infusion-related reaction. If a mild to moderate infusion-
related reaction occurs, patients may be rechallenged with close clinical observation, slower
infusion rates, and pre-medications.

6 ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:

 Infections [see Warnings and Precautions (5.1)]

 Hypersensitivity Reactions [see Warnings and Precautions (5.2)]
 Infusion-Related Reactions [see Warnings and Precautions (5.3)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of
another drug and may not reflect the rates observed in practice.

Clinical Experience in Patients with gMG

The safety of efgartigimod alfa in patients with gMG was established in a double blinded placebo-
controlled study with efgartigimod alfa-fcab administered intravenously (Study 1) and its open-
label extension, and in an active-controlled study of VYVGART HYTRULO administered
subcutaneously (Study 2) and its open-label extension [see Clinical Studies (14.1)].

Adverse Reactions with Efgartigimod Alfa-fcab Intravenous in Patients with gMG

In clinical studies, the safety of efgartigimod alfa-fcab administered intravenously has been
evaluated in 246 patients with gMG who received at least one dose of efgartigimod alfa-fcab,
including 57 patients exposed to at least 7 treatment cycles and 8 patients exposed to at least 10
treatment cycles.

In a placebo-controlled study (Study 1) in patients with gMG, 84 patients received efgartigimod

alfa-fcab 10 mg/kg [see Clinical Studies (14)]. Of these 84 patients, approximately 75% were
female, 82% were White, 11% were Asian, and 8% were of Hispanic or Latino ethnicity. The mean
age at study entry was 46 years (range 19 to 78).

The minimum time to initiate a subsequent cycle, specified by study protocol, was 50 days from
the start of the previous treatment cycle. On average, efgartigimod alfa-fcab-treated patients
received 2 cycles in Study 1. The mean and median times to the second treatment cycle were 94
days and 72 days from the initial infusion of the first treatment cycle, respectively, for efgartigimod
alfa-fcab-treated patients.

Adverse reactions reported in at least 5% of patients treated with efgartigimod alfa-fcab and more
frequently than placebo are summarized in Table 1. The most common adverse reactions
(reported in at least 10% of efgartigimod alfa-fcab-treated patients) were respiratory tract infection,
headache, and urinary tract infection.

Table 1: Adverse Reactions in at least 5% of Patients with gMG Treated with Efgartigimod
Alfa-fcab Intravenously (EFG IV) and More Frequently than in Placebo-Treated Patients
in Study 1 (Safety Population)

Adverse reaction EFG IV Placebo

(N=84) (N=83)
% %
Respiratory tract infection 33 29
Headache* 32 29
Urinary tract infection 10 5
Paraesthesia† 7 5
Myalgia 6 1
*Headache includes migraine and procedural headache.
†
Paresthesia includes oral hypoesthesia, hypoesthesia, and hyperesthesia.

Adverse Reactions with VYVGART HYTRULO in Patients with gMG

In an active-controlled study in patients with gMG (Study 2), 110 patients were randomized and
received one cycle of once weekly administrations for 4 weeks (4 administrations total), of either
VYVGART HYTRULO subcutaneously (n=55) or efgartigimod alfa-fcab intravenously (n=55) at
recommended doses [see Dosage and Administration (2.2)]. The open-label extension of Study 2
included some patients who switched from efgartigimod alfa-fcab IV to VYVGART HYTRULO.

The most common adverse reactions (reported in at least 10% of VYVGART HYTRULO-treated
patients) were injection site reactions and headache.

In Study 2, injection site reactions occurred in 38% of patients receiving VYVGART HYTRULO.
These were injection site rash, erythema, pruritus, bruising, pain, and urticaria.
In Study 2 and its open-label extension (n = 168), all injection site reactions were mild to moderate
in severity and did not lead to treatment discontinuation. The majority occurred within 24 hours
after administration and resolved spontaneously. Most injection site reactions occurred during
the first treatment cycle, and the incidence decreased with each subsequent cycle.

Clinical Experience in Patients with CIDP

Adverse Reactions with VYVGART HYTRULO in Patients with CIDP

In a placebo-controlled study in patients with CIDP (Study 3, stage B), 221 patients were
randomized to receive once-weekly administration of either VYVGART HYTRULO 1,008 mg /11,
200 units subcutaneously (n=111) or placebo (n=110) [see Clinical Studies (14.2)]. The mean
duration of treatment with VYVGART HYTRULO in stage B was 25 weeks. The overall safety
profile observed in patients with CIDP treated with VYVGART HYTRULO was consistent with the
known safety profile of VYVGART HYTRULO and of efgartigimod alfa-fcab administered
intravenously.

In Study 3, injection site reactions occurred in 15% of patients treated with VYVGART HYTRULO
compared to 6% of patients who received placebo. The most common of these injection site
reactions were injection site bruising and injection site erythema. All injection site reactions were
mild to moderate in severity. Most injection site reactions occurred during the first 3 months of
treatment.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of efgartigimod alfa
products. Because these reactions are reported voluntarily from a population of uncertain size, it is
not always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure.

Immune System Disorders: Hypersensitivity reactions including anaphylaxis and hypotension, and
infusion-related reactions [see Warnings and Precautions (5.2, 5.3)].

7 DRUG INTERACTIONS
7.1 Effect of VYVGART HYTRULO on Other Drugs

Concomitant use of VYVGART HYTRULO with medications that bind to the human neonatal Fc
receptor (FcRn) (e.g., immunoglobulin products, monoclonal antibodies, or antibody derivates
containing the human Fc domain of the IgG subclass) may lower systemic exposures and reduce
effectiveness of such medications. Closely monitor for reduced effectiveness of medications that
bind to the human neonatal Fc receptor. When concomitant long-term use of such medications is
essential for patient care, consider discontinuing VYVGART HYTRULO and using alternative
therapies.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to
VYVGART HYTRULO during pregnancy. Healthcare providers and patients may call 1-855-272-6524 or
go to https://www.Vyvgartpregnancy.com to enroll in or to obtain information about the registry.

Risk Summary

There are no available data on the use of VYVGART HYTRULO or efgartigimod alfa containing
products during pregnancy. There was no evidence of adverse developmental outcomes following
the intravenous administration of efgartigimod alfa at up to 100 mg/kg/day in rats and rabbits (see
Data).

The background rate of major birth defects and miscarriage in the indicated population is
unknown. In the U.S. general population, the estimated background rate of major birth defects and
miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses,
with the largest amount transferred during the third trimester. Therefore, efgartigimod alfa may be
transmitted from the mother to the developing fetus.

As VYVGART HYTRULO is expected to reduce maternal IgG antibody levels, reduction in passive
protection to the newborn is anticipated. Risk and benefits should be considered prior to
administering live vaccines to infants exposed to VYVGART HYTRULO in utero [see Warnings
and Precautions (5.1)].

Data

Animal Data
VYVGART HYTRULO for subcutaneous injection contains efgartigimod alfa and hyaluronidase
[see Description (11)].

Efgartigimod alfa:
- Intravenous administration of efgartigimod alfa (0, 30, or 100 mg/kg/day) to pregnant rats and
rabbits throughout organogenesis resulted in no adverse effects on embryofetal development
in either species. Maternal efgartigimod alfa exposures at the highest no-effect doses were
approximately 8 and 62 times, respectively, that in humans at the recommended human dose
(RHD) of 1008 mg.
- Intravenous administration of efgartigimod alfa (0, 30, or 100 mg/kg/day) to rats throughout
gestation and lactation resulted in no adverse effects on pre- or postnatal development.
Maternal exposures at the highest no-effect dose were approximately 13 times that in humans
at the RHD.

Hyaluronidase:
- In a study in which hyaluronidase (human recombinant) was administered by subcutaneous
injection to pregnant mice throughout organogenesis, increased embryofetal mortality and
decreased fetal body weights were observed at the highest doses tested. The no-effect dose
for adverse effects on embryofetal development in the mouse was approximately 1800 times
the dose of hyaluronidase at the recommended human dose (RHD) of VYVGART HYTRULO
(1,008 mg efgartigimod alfa and 11,200 U hyaluronidase), on a U/kg basis.
- There were no adverse effects on pre- and postnatal development following subcutaneous
administration of hyaluronidase (human recombinant) to mice throughout gestation and
lactation at doses up to 5,000 times the dose of hyaluronidase at the RHD of VYVGART
HYTRULO, on a U/kg basis.

8.2 Lactation
Risk Summary

There is no information regarding the presence of efgartigimod alfa or hyaluronidase, from

administration of VYVGART HYTRULO, in human milk, the effects on the breastfed infant, or the
effects on milk production. Maternal IgG is known to be present in human milk.

The developmental and health benefits of breastfeeding should be considered along with the
mother’s clinical need for VYVGART HYTRULO and any potential adverse effects on the
breastfed infant from VYVGART HYTRULO or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of VYVGART HYTRULO did not include sufficient numbers of patients aged 65
and older to determine whether they respond differently from younger adult patients.

8.6 Renal Impairment

No dose adjustment of VYVGART HYTRULO is needed for patients with mild renal impairment.
There are insufficient data to evaluate 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 pharmacokinetic
parameters of VYVGART HYTRULO [see Clinical Pharmacology (12.3)].

11 DESCRIPTION
VYVGART HYTRULO is a coformulation of efgartigimod alfa and hyaluronidase (human
recombinant).

Efgartigimod alfa, a neonatal Fc receptor blocker, is a human immunoglobulin G1 (IgG1) -derived

Fc fragment (fragment, crystallized) of the za allotype, produced in Chinese hamster ovary (CHO)
cells. The efgartigimod alfa Fc fragment is a homodimer consisting of two identical peptide chains
each consisting of 227 amino acids linked together by two interchain disulfide bonds with affinity
for FcRn. The molecular weight of efgartigimod alfa is approximately 54 kDa.

Hyaluronidase (human recombinant) is an endoglycosidase used to increase the dispersion and

absorption of co-administered drugs when administered subcutaneously. Hyaluronidase (human
recombinant) is a glycosylated single-chain protein produced by Chinese hamster ovary cells
containing a DNA plasmid encoding for a soluble fragment of human hyaluronidase (PH20).
Hyaluronidase (human recombinant) has a molecular weight of approximately 61 kDa.

VYVGART HYTRULO (efgartigimod alfa and hyaluronidase-qvfc) injection is a sterile, preservative

free, yellowish, clear to opalescent solution supplied in a single-dose vial for subcutaneous
injection.

Each 5.6 mL single-dose vial of VYVGART HYTRULO contains 1,008 mg efgartigimod alfa and
11,200 units hyaluronidase (human recombinant). Each mL of solution contains 180 mg of
efgartigimod alfa, 2,000 units of hyaluronidase (human recombinant) and histidine (1.4 mg), L-
histidine hydrochloride monohydrate (2.2 mg), methionine (1.5 mg), polysorbate 20 (0.4 mg),
sodium chloride (5.8 mg), sucrose (20.5 mg), and water for injection, USP, at a pH of 6.0.

12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action

VYVGART HYTRULO is a coformulation of efgartigimod alfa and hyaluronidase.

Efgartigimod alfa is a human IgG1 antibody fragment that binds to the neonatal Fc receptor
(FcRn), resulting in the reduction of circulating IgG.

Hyaluronidase increases permeability of the subcutaneous tissue by depolymerizing hyaluronan.

This effect is transient and permeability of the subcutaneous tissue is restored within 24 to 48
hours.

12.2 Pharmacodynamics

In Study 1 [see Clinical Studies (14)], the pharmacological effect of efgartigimod alfa-fcab was
assessed by measuring the decrease in serum IgG levels and AChR autoantibody levels. In
patients testing positive for AChR antibodies and who were treated with efgartigimod alfa-fcab
intravenous, there was a reduction in total IgG levels relative to baseline. Decrease in AChR
autoantibody levels followed a similar pattern. A decrease in AChR-Ab was associated with a
clinical response in AChR-Ab positive patients, as measured by the change from baseline in MG-
ADL total score.
In Study 2, the pharmacological effect of VYVGART HYTRULO administered subcutaneously (SC)
at 1,008 mg / 11,200 Units was compared to efgartigimod alfa-fcab administered intravenously at
10 mg/kg (EFG IV) in gMG patients. The maximum mean reduction in AChR-Ab level was
observed at week 4, with a mean reduction of 62.2% and 59.7% in the VYVGART HYTRULO SC
and efgartigimod alfa-fcab IV arm, respectively. The decrease in total IgG levels followed a similar
pattern. The 90% confidence intervals for the geometric mean ratios of AChR-Ab reduction at day
29 and AUEC0-4w (area under the effect-time curve from time 0 to 4 weeks post dose) were within
the range of 80% to 125%, indicating no clinically significant difference between the two
formulations.

12.3 Pharmacokinetics

Efgartigimod alfa exposures were approximately dose-proportional up to the highest

subcutaneously tested dose of VYVGART HYTRULO (1750 mg, 1.75 times the recommended
dosage).

Distribution

The volume of distribution is 15 to 20L.

Metabolism and Elimination

Efgartigimod alfa and hyaluronidase are expected to be degraded by proteolytic enzymes into
small peptides and amino acids.

The terminal half-life is 80 to 120 hours (3 to 5 days).

After a single intravenous dose of 10 mg/kg efgartigimod alfa-fcab in healthy subjects, less than
0.1% of the administered dose was recovered in urine.

Specific Populations

Age, Sex and Race

A population pharmacokinetics analysis assessing the effects of age, body weight, sex, and race
did not suggest any clinically significant impact of these covariates on efgartigimod alfa exposures.

Body Weight

A population pharmacokinetics analysis suggests that the influence of body weight on efgartigimod
alfa exposure after administration of VYVGART HYTRULO SC 1008 mg was limited and not
clinically relevant.

Patients with Renal Impairment

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

Population PK analyses of data from the VYVGART HYTRULO clinical studies indicated that
patients with mild renal impairment (eGFR 60-89 mL/min/1.73 m²) had 11 to 20% increase in
exposure relative to the exposure in patients with normal renal function [see Use in Specific
Populations (8.6)].

Patients with Hepatic Impairment

No dedicated pharmacokinetic study has been performed in patients with hepatic impairment.
Hepatic impairment is not expected to affect the pharmacokinetics of efgartigimod alfa.

Drug Interaction Studies

Clinical drug interactions studies have not been performed with efgartigimod alfa.

P450 Enzymes

Efgartigimod alfa is not metabolized by cytochrome P450 enzymes; therefore, interactions with
concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes
are unlikely.

Drug Interactions with Other Drugs or Biological Products

Efgartigimod alfa may decrease concentrations of compounds that bind to the human FcRn [see
Drug Interactions (7.1)].

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and
specificity of the assay. Differences in assay methods preclude meaningful comparisons
of the incidence of anti-drug antibodies in the studies described below with the
incidence of anti-drug antibodies in other studies, including those of VYVGART HYTRULO or of
other efgartigimod products.
In Study 2, in up to 10 weeks following the initiation of a treatment period with 4 weekly
administrations, the incidence of anti-efgartigimod alfa antibodies was 35% (19/55) following
treatment with VYVGART HYTRULO and 20% (11/55) in patients receiving intravenous
efgartigimod alfa-fcab. For both IV and SC arms, neutralizing anti-efgartigimod alfa antibodies were
detected in 4% (2/55) of patients.
In Study 3, in up to 12 weeks of treatment in stage A and 48 weeks in stage B, the incidence of anti-
efgartigimod alfa antibodies was 6% (20/317) in stage A and 2% (2/111) in stage B, following
treatment with VYVGART HYTRULO. Neutralizing anti-efgartigimod alfa antibodies were detected
in 0.3% (1/317) of patients in stage A and in no patient in stage B.
Some neutralizing antibodies may not be detected by the assay. The available data are too limited
to make definitive conclusions regarding immunogenicity and the effect on pharmacokinetics,
safety, or efficacy of VYVGART HYTRULO.

13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

VYVGART HYTRULO for subcutaneous injection contains efgartigimod alfa and hyaluronidase
[see Description (11)].

Carcinogenesis and Mutagenesis

No studies have been conducted to assess the carcinogenic potential of efgartigimod alfa.

No studies have been conducted to assess the genotoxic potential of efgartigimod alfa.

No carcinogenicity or genotoxicity studies were conducted for human recombinant hyaluronidase.

Impairment of Fertility

Intravenous administration of efgartigimod alfa (0, 30, or 100 mg/kg/day) to male and female rats
prior to and during mating and continuing in females through gestation day 7 resulted in no
adverse effects on fertility. Efgartigimod alfa exposures at the highest no-effect dose were
approximately 12 times that in humans at the recommended human dose of 1008 mg.
There were no effects on reproductive tissues in monkeys following subcutaneous administration
of hyaluronidase (human recombinant) doses up to approximately 1,200 times the dose of
hyaluronidase at the recommended human dose (RHD) of VYVGART HYTRULO (1,008 mg
efgartigimod alfa and 11,200 U hyaluronidase) on a U/kg basis for 39 weeks. No systemic
exposure to hyaluronidase was observed at doses up to approximately 120 times the dose of
hyaluronidase at the RHD of VYVGART HYTRULO, on a U/kg basis.

14 CLINICAL STUDIES
14.1 Generalized Myasthenia Gravis
Study 1 (described below) which established the effectiveness of efgartigimod alfa-fcab for the
treatment of generalized myasthenia gravis (gMG) in adults who are AChR antibody positive was
conducted with efgartigimod alfa-fcab intravenous formulation. In Study 2, VYVGART HYTRULO
demonstrated a comparable pharmacodynamic effect on AChR antibody reduction as compared to
the efgartigimod alfa-fcab intravenous formulation, which established the efficacy of VYVGART
HYTRULO [see Clinical Pharmacology (12.2)].

Study 1 (Efgartigimod Alfa-fcab Intravenous)

The efficacy of efgartigimod alfa-fcab intravenous (EFG IV) for the treatment of generalized
myasthenia gravis (gMG) in adults who are AChR antibody positive was established in a 26-week,
multicenter, randomized, double-blind, placebo-controlled trial (Study 1; NCT03669588).

Study 1 enrolled patients who met the following criteria at screening:

- Myasthenia Gravis Foundation of America (MGFA) clinical classification class II to IV

- MG-Activities of Daily Living (MG-ADL) total score of ≥ 5
- On stable dose of MG therapy prior to screening, that included acetylcholinesterase
(AChE) inhibitors, steroids, or non-steroidal immunosuppressive therapies (NSISTs),
either in combination or alone
- IgG levels of at least 6 g/L

A total of 167 patients were enrolled in Study 1 and were randomized to receive either EFG IV
10mg/kg (1200 mg for those weighing 120 kg or more) (n=84) or placebo (n=83). Baseline
characteristics were similar between treatment groups. Patients had a median age of 46 years at
screening (range: 19 to 81 years) and a median time since diagnosis of 7 years. Seventy-one
percent were female, and 84% were White. Median MG-ADL total score was 9, and median
Quantitative Myasthenia Gravis (QMG) total score was 16. The majority of patients (n=65 for EFG
IV; n=64 for placebo) were positive for AChR antibodies.

At baseline, over 80% of patients in each group received AChE inhibitors, over 70% in each
treatment group received steroids, and approximately 60% in each treatment group received
NSISTs, at stable doses.

Patients were treated with 10 mg/kg EFG IV administered as an intravenous infusion over one
hour once weekly for 4 weeks. In patients weighing 120 kg or more, EFG IV was administered as
1200 mg per infusion. Subsequent treatment cycles were administered based on clinical
evaluation, but no sooner than 50 days from the start of the previous treatment cycle.
The efficacy of EFG IV was measured using the Myasthenia Gravis-Specific Activities of Daily
Living scale (MG-ADL) which assesses the impact of gMG on daily functions of 8 signs or
symptoms that are typically affected in gMG. Each item is assessed on a 4-point scale where a
score of 0 represents normal function and a score of 3 represents loss of ability to perform that
function. A total score ranges from 0 to 24, with the higher scores indicating more impairment. In
this study, an MG-ADL responder was defined as a patient with a 2-point or greater reduction in
the total MG-ADL score compared to the treatment cycle baseline for at least 4 consecutive
weeks, with the first reduction occurring no later than 1 week after the last infusion of the cycle.

The primary efficacy endpoint was the comparison of the percentage of MG-ADL responders
during the first treatment cycle between treatment groups in the AChR-Ab positive population. A
statistically significant difference favoring EFG IV was observed in the MG-ADL responder rate
during the first treatment cycle [67.7% in the EFG IV-treated group vs 29.7% in the placebo-
treated group (p <0.0001)].

The efficacy of EFG IV was also measured using the Quantitative Myasthenia Gravis (QMG) total
score which is a 13-item categorical grading system that assesses muscle weakness. Each item is
assessed on a 4-point scale where a score of 0 represents no weakness and a score of 3
represents severe weakness. A total possible score ranges from 0 to 39, where higher scores
indicate more severe impairment. In this study, a QMG responder was defined as a patient who
had a 3-point or greater reduction in the total QMG score compared to the treatment cycle
baseline for at least 4 consecutive weeks, with the first reduction occurring no later than 1 week
after last infusion of the cycle.

The secondary endpoint was the comparison of the percentage of QMG responders during the
first treatment cycle between both treatment groups in the AChR-Ab positive patients. A
statistically significant difference favoring EFG IV was observed in the QMG responder rate during
the first treatment cycle [63.1% in the EFG IV-treated group vs 14.1% in the placebo-treated group
(p <0.0001)].

The results are presented in Table 2.

Table 2: MG-ADL and QMG Responders During Cycle 1 in AChR-Ab Positive Patients (mITT
Analysis Set)

EFG IV Placebo P-value Odds Ratio (95% CI)

n=65 n=64
% %
MG-ADL Responders 67.7 29.7 < 0.0001 4.951 (2.213, 11.528)
QMG Responders 63.1 14.1 < 0.0001 10.842 (4.179, 31.200)

EFG IV= Efgartigimod alfa-fcab intravenous; MG-ADL=Myasthenia Gravis Activities of Daily Living; QMG
=Quantitative Myasthenia Gravis; mITT=modified intent-to-treat; n=number of patients for whom the observation was
reported; 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

Figure 1 shows the mean change from baseline on the MG-ADL during cycle 1.
Figure 1: Mean Change in Total MG-ADL From Cycle 1 Baseline Over Time in AChR-Ab
Positive Patients (mITT Analysis Set)

Figure 2 shows the distribution of response on the MG-ADL and QMG during cycle 1, four weeks
after the first infusion with EFG IV.
Figure 2: Percentage of Patients with MG-ADL and QMG Total Score Change 4 Weeks Post
Initial Infusion of the First Cycle in AChR-Ab Positive Patients
14.2 Chronic Inflammatory Demyelinating Polyneuropathy

The efficacy of VYVGART HYTRULO for the treatment of adults with chronic inflammatory demyelinating
polyneuropathy (CIDP) was established in a two stage, multicenter study (Study 3; NCT04281472). Study
3 included an open-label period to identify VYVGART HYTRULO responders (stage A) who then entered
a randomized, double-blind, placebo-controlled, withdrawal period (stage B).

Study 3 enrolled male and female patients age 18 years and older, who at the time of screening, had a
documented diagnosis of definite or probable CIDP using the European Federation of Neurological
Societies/Peripheral Nerve Society (EFNS/PNS; 2010) criteria for progressing or relapsing forms.

The Inflammatory Neuropathy Cause and Treatment disability score (INCAT) is a scale used to assess
the impact of CIDP on daily upper and lower limb function, and is composed of the arm score and leg
score (0 to 5 points for each). A total score on the INCAT ranges from 0 to 10 points with a higher number
representing more disability. The adjusted INCAT (aINCAT) disability score, identical to the INCAT
disability score but with changes in the upper limb function from 0 (normal) to 1 (minor symptoms)
excluded, was used to assess efficacy for VYVGART HYTRULO for the treatment of CIDP.

Stage A
In stage A, a total of 322 patients received up to 12 once weekly subcutaneous injections of VYVGART
HYTRULO 1008 mg / 11,200 units until evidence of improvement occurred at two consecutive study visits.
Improvement was defined as aINCAT improvement ≥1 point, I-RODS improvement ≥4 points, or mean
grip strength improvement ≥ 8 kPa. Stage A included 228 patients currently receiving standard-of-care
therapy and 94 patients who had either not received prior treatment for CIDP or were not treated with
standard-of-care therapy for at least 6 months before study entry. Sixty-nine percent of patients (n=221)
who had documented improvement at two consecutive visits during Stage A then entered Stage B.

Stage B
In stage B, a total of 221 patients were randomized to receive once weekly subcutaneous injections of
VYVGART HYTRULO 1008 mg / 11,200 units (n=111) or placebo (n=110).

Baseline characteristics of patients in stage B were similar between treatment groups. 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, 30% Asian, and 1%
African American.

Stage B included 146 patients currently receiving standard-of-care therapy and 75 patients who had either
not received prior treatment for CIDP or were not treated with standard-of-care therapy for at least 6
months before study entry.

The primary endpoint was the time to clinical deterioration defined as a 1-point increase in aINCAT at two
consecutive visits or a >1-point increase in aINCAT at one visit. Patients who had clinical deterioration or
completed week 48 in Stage B without clinical deterioration were withdrawn from the placebo-controlled
portion of the study. The study stopped when 88 events of clinical deterioration occurred for the primary
endpoint analysis.

Patients who received VYVGART HYTRULO experienced a longer time to clinical deterioration (i.e.,
increase of ≥1 point in aINCAT score) compared to patients who received placebo, which was statistically
significant, as demonstrated by a hazard ratio of 0.394 [95% CI (0.253; 0.614) p<0.0001]. The results are
presented in Table 3 and Figure 3.
Table 3: Time to First Increase of ≥1 Point in aINCAT Score In Patients With CIDP In Study 3 Stage B

Stage B
VYVGART Placebo
HYTRULO
(N=111) (N=110)
Time to 1st aINCAT increase (clinical deterioration) in days
Hazard ratio (95% CI) 0.394 (0.253; 0.614)
p-value <0.0001

N=number of patients in the analysis set; %: percentage; aINCAT: adjusted Inflammatory Neuropathy Cause and
Treatment
 Figure 3: Time To The First aINCAT Increase (Kaplan-Meier Curve) In Patients With CIDP In Study 3
Stage B

Note: The time to clinical deterioration is defined as the time in days from the first VYVGART HYTRULO or placebo
administration in Stage B to the first occurrence of either: an increase in aINCAT score of 1 point compared with Stage B
baseline if confirmed at the next visit or an increase in aINCAT score of >1 point compared with Stage B baseline.
16 HOW SUPPLIED/STORAGE AND HANDLING
VYVGART HYTRULO (efgartigimod alfa and hyaluronidase-qvfc) injection is a preservative free,
sterile, yellowish, clear to opalescent solution supplied as one single-dose vial per carton
containing 1,008 mg efgartigimod alfa and 11,200 units hyaluronidase per 5.6 mL (180 mg/2,000
units per mL): (NDC 73475-3102-3).

Store VYVGART HYTRULO vials refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to
protect from light until time of use. Do not freeze. Do not shake.

If needed, unopened vials may be stored in the original carton for up to 3 days at room
temperature at 20°C to 25°C (68°F to 77°F) for a single period before administration or returned to
refrigeration. Do not store the vial at room temperature more than one time. Record the date
removed from and the date returned to the refrigerator on the carton.

17 PATIENT COUNSELING INFORMATION

Infections

Instruct patients to communicate any history of infections to the healthcare provider and to contact
their healthcare provider if they develop any symptoms of an infection. Advise patients to complete
age-appropriate vaccines according to immunization guidelines prior to initiation of a new
treatment cycle with VYVGART HYTRULO. Administration of live vaccines is not recommended
during treatment with VYVGART HYTRULO [see Warnings and Precautions (5.1)].

Hypersensitivity Reactions

Inform patients that hypersensitivity reactions, including angioedema and anaphylaxis, have
occurred in patients who were treated with efgartigimod alfa products. Inform patients about the
signs and symptoms of these reactions, and advise patients to contact their healthcare provider
immediately if these occur [see Warnings and Precautions (5.2)].

Infusion-Related Reactions

Advise patients of the potential risk of infusion-related reactions, which can include hypertension,
chills, shivering, and chest, abdominal, and back pain [see Warnings and Precautions (5.3)].

Pregnancy Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to
VYVGART HYTRULO during pregnancy. Encourage participation and advise patients about how they
may enroll in the registry [see Use in Specific Populations (8.1)].

Manufactured by:

argenx BV
Industriepark 7
9052 Zwijnaarde, Belgium
U.S. License No. 2217

Halozyme Therapeutics, Inc.

12390 El Camino Real
San Diego, CA 92130
U.S. License No. 2187

Distributed by:

argenx US, Inc.

33 Arch Street
Boston, MA 02110

VYVGART HYTRULO is a trademark of argenx BV.

© 2024 argenx BV