14 CLINICAL STUDIES

The efficacy of VYVGART 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 VYVGART 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 VYVGART; 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 VYVGART at the recommended dosage regimen [see Dosage and Administration (2.2)].

The efficacy of VYVGART 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 VYVGART was observed in the MG-ADL responder rate during the first treatment cycle [67.7% in the VYVGART-treated group vs 29.7% in the placebo-treated group (p <0.0001)].

The efficacy of VYVGART 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 VYVGART was observed in the QMG responder rate during the first treatment cycle [63.1% in the VYVGART-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)
	VYVGART n=65 %	Placebo n=64 %	P-value	Odds Ratio (95% CI)
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
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)

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 VYVGART.

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 Population