14 CLINICAL STUDIES

14.1 Treatment of Primary Humoral Immunodeficiency (PI)

Study 1: In a prospective, open-label, single-arm, multicenter study in 51 children and adults with PI, subjects received PANZYGA at a dose between 200 to 800 mg/kg body weight every 3 or 4 weeks. Subjects participated in the study for a mean of 360 days. Infusions were initiated at a rate of 1 mg/kg/min for the first 30 minutes, and, if tolerated, could be advanced to a maximum tolerated rate not exceeding 8 mg/kg/min. The mean age of subjects was 26.8 years (range: 2 to 65 years).

The primary efficacy endpoint was the number of episodes of serious bacterial infections per patient per year. Serious infection included pneumonia, bacteremia or sepsis, osteomyelitis/septic arthritis, visceral abscesses, or bacterial meningitis. Secondary efficacy variables included: occurrence of any infection of any kind or seriousness; time to resolution of infections; use of antibiotics; the number of days of work/school missed; the number and days of hospitalizations; and the number of episodes of fever.

For the primary endpoint, the observed rate was 0.08 serious bacterial infections per patient per year (4 infections over 50.2 patient-years).

Only 1 adult patient was hospitalized due to an infection for 4 days (overall rate of days in hospital per person-year: 0.080). Episodes of fever were observed for less than 25% of all patients. The mean resolution time was 14 days for serious bacterial infections and 18 days for other infections. Approximately 50% of all patients missed at least 1 day of work or school due to infections, with an annual rate of less than 4 days/person-year.

Table 7 summarizes the efficacy results for all 51 subjects.

Table 7: Study 1 – Summary of Efficacy Results for subjects with PI

Category	Result	Unit
Number of subjects	51	Subjects
Total number of subject days	18,349	Days
Annual rate of confirmed serious bacterial infections (SBIs)*	0.080	SBIs/person-year **
Annual rate of other infections	3.682	Inf./person-year
Number of subjects (%) with use of antibiotics	42 (82.4%)	Subjects(%)
Annual rate of use of antibiotics	87	Days/person-year
Absences from work or school due to Infection, number of days (%)	183 (1.0%)	Days (%)
Annual rate of absences from work or school due to infection	3.6	Days/person-year
Hospitalization due to infection, number of days	4	Days
Annual rate of hospitalizations due to infection	0.1	Day/person-year

* Defined as bacteremia/sepsis, bacterial meningitis, osteomyelitis/septic arthritis, bacterial pneumonia and visceral abscess

** Upper 1-sided 99% confidence interval: 0.503

Throughout the entire study, the serum IgG trough levels were nearly constant for both treatment schedules and were above the required trough levels of about 5-6 g/L. The calculated pharmacokinetic parameters showed that the minimum concentration of IgG was at least 6.8 g/L for both treatment intervals.

14.2 Treatment of Chronic Immune Thrombocytopenia (ITP) in Adults

A prospective, open-label, single-arm, multicenter study assessed the efficacy, safety, and tolerability of PANZYGA in 40 subjects with chronicITP and a platelet count of 20 x 109/L or less. Subjects ranged in age from 18 to 72 years (median: 32 years); 43% were female and 57% were male. Ninety percent of the subjects were Caucasian and 10% were Asian.

Subjects received a 2 g/kg dose of PANZYGA administered as two daily 1 g/kg intravenous doses, given on 2 consecutive days. All but one patient received the maximum infusion rate of 8 mg/kg/minute, starting at 1 mg/kg/minute. Platelet counts were measured on Days 1 to 8, 15, and 22.

The study was designed to determine the response rate, defined as the percentage of subjects with an increase in platelet count to at least 50 x 109/L within 7 days after the first infusion (responders). Additionally, maximum platelet count, the time to reach a platelet count of at least 50 x 109/L within the first 7 days, the duration of that response (i.e., the number of days the platelet count remained in excess of 50 x 109/L), and the regression of hemorrhages in subjects who had bleeding at baseline were observed.

Of the 36 subjects in the full analysis set, 29 (81%: 95% CI: 64%- 92%).) responded to PANZYGA with a rise in platelet count to at least 50 x 109/L within 7 days after the first infusion. The lower bound of the overall 95% confidence interval for the response rate in all 36 subjects (64%) is above the predefined response rate of 60%.

Table 8 shows the median and mean of the maximum platelet count.

Table 8: Maximum Platelet Count (x109/L)

	ITP subjects (n=36)
Median and range	196 (8 to 1067)
Mean ± standard deviation	237 ± 205

Table 9 shows the median and mean of the time to and duration of platelet response.

Table 9: Time to and Duration of Platelet Response (Responders Only).

	Time to Platelet Response (at least 50x109/L) (Days)	Duration of Platelet Response (Days)
	ITP Subjects Responders (n=29)	ITP Subjects Responders (n=29)
Median and range	2 (1 to 4)	14 (1 to 20)
Mean ± standard deviation	1.8 ± 0.8	12.4 ± 5.8

Of the 36 subjects, 23 (64%) subjects had bleeding at baseline. Bleeding was minor in 14 subjects (39%), mild in 2 subjects (6%) and moderate in 7 subjects (19%). On Day 7, only 14% of subjects were bleeding (5/36). Persistent bleeding was mild in 1 and minor in 2 subjects. Information regarding bleeding resolution was missing in 2 subjects with moderate bleeding.

14.3 Treatment of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in Adults

The efficacy of PANZYGA in adults with CIDP was evaluated in a prospective, double-blind, randomized, multicenter study that enrolled 142 adult subjects (between 18 and 83 years of age) with CIDP who deteriorated in the Wash-out Phase, during which the current medication (immunoglobulins or corticosteroids) was reduced gradually. Subjects were randomized 1:2:1 to receive first a loading dose of 2 g/kg, and then 0.5 g/kg, 1.0 g/kg or 2.0 g/kg PANZYGA according to their respective dose armfor 7 maintenance infusions at 3-week intervals during the 24-week Dose-evaluation Phase. Subjects in the 0.5 g/kg and 1.0 g/kg arms had the option of rescue treatment with two consecutive infusions of 2.0 g/kg Panzygaat 3-week intervals if criteria were met [CLINICAL PHARMACOLOGY (12.3)].

Efficacy was based on the proportion of responders in the 1.0 g/kg PANZYGA arm at Week 24 relative to Baseline (Week 0). A responder was defined as a subject with a decrease of at least 1 point in the adjusted 10-point Inflammatory Neuropathy Cause and Treatment (INCAT) disability score at Week 24 relative to Baseline. The proportion of responders in the 1.0 g/kg arm was 79.71% (95% CI: 68.8, 87.5), with 55 out of 69 subjects classified as responders. Efficacy was supported by the proportion of responders in the 2.0 g/kg dose arm in the adjusted INCAT disability score, and the proportion of responders in the 1.0 g/kg and 2.0 g/kg dose arms in the grip strength, inflammatory Rasch-built Overall Disability Scale (I-RODS) and Medical Research Council (MRC) sum scores (Table 10).

Table 10: Responder rates for different efficacy scores and dose arms

	1.0 g/kg N=69	2.0 g/kg N=36
Adjusted INCAT Disability Score
Number (%) of responders	55 (79.7%)	33 (91.7%)
95% CI	68.8; 87.5	78.2; 97.1
I-RODS
Number (%) of responders	38 (55.1%)	26 (72.2%)
95% CI	43.4; 66.2	56; 84.2
Grip Strength
Number (%) of responders	45 (65.2%)	30 (83.3%)
95% CI	53.4; 75.4	68.1; 92.1
MRC Sum Score
Number (%) of responders	50 (72.5%)	31 (86.1%)
95% CI	61; 81.6	71.3; 93.9