Hizentra for the treatment of primary immunodeficiency

Figures & data

Table 1. Composition of Hizentra^®.

Property	Value
Protein	≥98% IgG
IgA, μg/ml	≤50
l-Proline, mmol/l	250 (210–290)
Polysorbate 80, mg/l	8–30
Sodium	Trace
pH	4.6–5.2

Figure 1. Steps in the manufacturing process of Hizentra.

Figure 2. Pharmacokinetic simulation of steady-state concentration profiles for IgG following Hizentra weekly or biweekly dosing or Privigen monthly dosing. Total monthly sc. doses are 1.53-fold higher than iv. doses.

Table 2. Published studies of Hizentra in patients with primary immunodeficiency disease: mean dose, IgG levels and acute serious bacterial infections.

Study (year), country	Study details	Patients (n)	Mean age, years (SD)	Mean Hizentra weekly dose, mg/kg	aSBIs, n (% of subjects)	Annual aSBI rate per patient (upper 99% CL)	Pre-study IgG level (SD), mg/dl	Hizentra IgG level (SD), mg/dl	Ref.
Hagan et al. (2010) USA	12-month, prospective, multicenter, open-label single-arm Phase III study	38^†	36.3 (19.62)	213.2	0	0 (0.132)	1010 (257)	1253 (321)	[56]
Jolles et al. (2011) EU	40-week, prospective, multicenter, open-label single-arm Phase III study	46	21.5 (15.60)	118.7	0^‡	0 (0.192)	749 (157)	810 (134)	[29]
Kanegane et al. (2014) Japan	12-week, prospective, multicenter, open-label single-arm Phase III study	24	20.5 (13.5)	87.8	0	NR	653 (140)	715 (151)	[57]
Jolles et al. (2014)	US extension study up to 104 weeks	21	42.4 (18.53)	193.2	2 (9.5)	0.06 (0.257)	NR	1198 (365)	[58]
	EU extension study up to 166 weeks	40	21.6 (15.31)	116.0	5 (12.5)	0.048 (0.1252)	NR	797 (117)

^†Patients who received 20% SCIG during the efficacy period.

^‡Data from the efficacy period; 1 patient experienced an SBI (pneumonia) during the wash-in/wash-out period.

aSBI: Acute serious bacterial infection; CL: Confidence limit; NR: Not reported; PIDD: Primary immunodeficiency disease.

Table 3. Secondary efficacy end points in Hizentra studies.

Parameter	Hagan et al. (2010) [56]	Jolles et al. (2011) [29]	Kanegane et al. (2014) [57]	Jolles et al. (2014) [58]
				USA	EU
Patients (n)	38	46	21	21	40
Patient years	34.8	24.2	5.0	32.7	104.6
Infections (n)	96	124	15	78	349
Patients (n) (%)	31 (81.6)	36 (78.3)	11 (52.4)	20 (95.2)	38 (95.0)
Annual rate of infections/patient/year (CI)	2.76 (2.235–3.370)	5.18 (4.305–6.171)	2.98	2.38 (1.883–2.973)	3.33 (2.993–3.703)
Days off work/school (n)	71^†	198	19^§	140	706
Patients (n) (%)	12 (31.6)	20 (43.5)	7 (33.3)	9 (49.2)	27 (67.5)
Days off work/school/patient/ year	2.06^†	8.0	3.48^§	4.28	6.77
Days hospitalized due to infection	7^†	86	3^§	18	110
Patients (n) (%)	1 (2.6%)	4 (8.7)	1 (4.8)	2 (9.5)	7 (17.5)
Hospital days/patient/year	0.2^‡	3.48	0.55^†	0.55	1.06
Days on antibiotics^§	1688	1743	844	2746	7551
Patients (n) (%)	27 (71.1)	32 (69.6)	16 (76.2)	19 (90.5)	36 (90.0)
Antibiotic days/ patient/year	48.5	72.75	167.42	83.87	72.13

^†Based on 1990 patient diary days.

^‡Based on 12,605 patient diary days.

^§Used for prophylaxis or treatment.

Table 4. Summary of adverse events and adverse event rates in Hizentra efficacy studies.

AE category	Hagan et al. (2010) [56]		Jolles et al. (2011) [29]		Kanegane et al. (2014) [57]		Jolles et al. (2014) [58]
	No. (%) of subjects (n = 49)	No. (rate) of events (n = 2264)	No. (%) of subjects (n = 51)	No. (rate) of events (n = 1831)	No. (%) of subjects (n = 25)	No. (rate) of events (n = 584)	USA extension		EU extension
							No. (%) of subjects (n = 21)	No. (rate) of events (n = 1735)	No. (%) of subjects (n = 40)	No. (rate) of events (n = 5405)
AEs	49 (100)	1749 (0.773)	50 (98)	527 (0.288)	24 (96)	269 (0.461)	21 (100)	1147 (0.661)	39 (97.5)	506 (0.094)
Mild AEs	N/A (99)		N/A (98.7)		21 (84)	264 (N/A)	21 (100)	998 (0.575)	39 (97.5)	370 (0.069)
Moderate  AEs					3 (12)	5 (0.009)	18 (85.7)	132 (0.076)	25 (62.5)	125 (0.023)
At least possibly related AEs	49 (100)	1436 (0.634)	31 (60.8)	194 (0.106)	21 (84)	175 (0.300)	21 (100)	909 (0.524)	8 (20.0)	14 (0.003)
At least  possibly  related local  reaction	49 (100)	1313 (0.580)	25 (49.0)	110 (0.058)	20 (80)	160 (0.274)	19 (90.5)	867 (0.500)	6 (15)	7 (0.001)
At least  possibly  related  temporally  local reaction	49 (100)	1297 (0.573)	24 (47.1)	102 (0.056)	20 (80)	156 (0.267)	19 (90.5)	863 (0.497)	NR	NR
Serious AEs	7 (14.3%)	10	5 (9.8)	7	1	1 (0.002)	4 (19.0)	5 (0.003)	14 (35.0)	18 (0.003)
At least possibly related SAEs	0	0	0	0	0	0	0	0	0	0
Treatment-related AEs leading to discontinuation	2 (4.15)		3 (5.9)	7	0	0	0	0	0	0
AEs leading to death	0	0	0	0	0	0	0	0	1 (2.5)	1 (0.0002)

AE: Adverse event; N/A: Not available; NR: Not reported; SAE: Serious adverse event.

Table 5. Summary of related adverse events, excluding local reactions, in >5% of patients in Hizentra primary efficacy studies.

Adverse event	Hagan et al. (2010) [56]		Jolles et al. (2011) [29]		Kanegane et al. (2014) [57]
	No. (%) of subjects (n = 49)	No. (rate) of events (n = 2264)	No. (%) of subjects (n = 51)	No. (rate) of events (n = 1831)	No. (%) of subjects (n = 25)	No. (rate) of events (n = 584)
Headache	12 (24.5)	36 (0.016)	6 (11.8)	13 (0.007)
Skin and subcutaneous tissue disorders					2 (8.0)	9 (0.015)
Injection-site bruising	5 (10.2)	19 (0.008)
Pruritus			4 (7.8)	14 (0.008)
Vomiting	3 (6.1)	3 (0.001)
Pain	3 (6.1)	4 (0.002)
Fatigue	3 (6.1)	3 (0.001)	3 (5.9)	5 (0.003)
Pyrexia			3 (5.9)	3 (0.002)

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