Single-Dose Prefilled Syringe

VYVGART HYTRULO prefilled syringe may be administered by patients and/or caregivers after proper instruction in subcutaneous injection technique [see Instructions for Use].

Single-Dose Vial

VYVGART HYTRULO vial is to be administered with a winged infusion set by a healthcare professional only [see Dosage and Administration (2.4)].

Single-Dose Prefilled Syringe

The recommended dosage of VYVGART HYTRULO prefilled syringe is 1,000 mg / 10,000 units (1,000 mg efgartigimod alfa and 10,000 units hyaluronidase) administered subcutaneously over approximately 20 to 30 seconds in cycles of once weekly injections for 4 weeks.

Single-Dose Vial

The recommended dosage of VYVGART HYTRULO vial 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.

General Dosage Considerations

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.

Single-Dose Prefilled Syringe

The recommended dosage of VYVGART HYTRULO prefilled syringe is 1,000 mg / 10,000 units (1,000 mg efgartigimod alfa and 10,000 units hyaluronidase) administered subcutaneously over approximately 20 to 30 seconds as once weekly injections.

Single-Dose Vial

The recommended dosage of VYVGART HYTRULO vial 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.

General Dosage Considerations

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.

Single-Dose Prefilled Syringe

• Take the VYVGART HYTRULO prefilled syringe out of the refrigerator at least 30 minutes before injecting to allow it to reach room temperature [see How Supplied/Storage and Handling (16)]. Do not use external heat sources to bring the syringe to room temperature.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Visually inspect that the prefilled syringe solution is yellowish, clear to opalescent and devoid of particulate matter. Do not use if visible particles are present.
• Each prefilled syringe is for one-time use only.
• To administer VYVGART HYTRULO prefilled syringe, use a safety needle that is 25G, 5/8 inches in length, and thin wall type. The safety needle is not included in the carton.
• Choose an injection site on the abdomen (at least 2 inches away from the navel).
  • Do not inject on areas where the skin is irritated, red, bruised, infected, tender, hard, or into areas where there are moles or scars.
  • Rotate injection sites for subsequent administrations.
• Inject VYVGART HYTRULO prefilled syringe subcutaneously into a pinched skin area at an angle of 45 to 90 degrees for approximately 20 to 30 seconds.
• Discard any unused portions of medicine remaining in the syringe.
• Localized injection site reactions may occur after VYVGART HYTRULO is administered [see Adverse Reactions (6.1)].
• Monitor for clinical signs and symptoms of hypersensitivity reactions for at least 30 minutes after administration. If a hypersensitivity reaction occurs, the patient should seek medical attention and the healthcare professional should institute appropriate measures, if needed [see Warnings and Precautions (5.2)].

For detailed instructions on the preparation and administration of VYVGART HYTRULO prefilled syringe see INSTRUCTIONS FOR USE.

Single-Dose Vial

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

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.

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)].

Clinical Experience in Patients with CIDP

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

Data

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.

Absorption

The rate and extent of absorption from a single-dose prefilled syringe and single-dose vial are similar.

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

Drug Interaction Studies

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

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.

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:

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

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

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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

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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.

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

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.

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.