Safety and Pharmacokinetics of 120 mg/kg versus 60 mg/kg Weekly Intravenous Infusions of Alpha-1 Proteinase Inhibitor in Alpha-1 Antitrypsin Deficiency: A Multicenter, Randomized, Double-Blind, Crossover Study (SPARK)

Figures & data

Figure 1.  Study design. Following an initial screening phase, subjects were enrolled into this crossover study, which involved two treatment periods (1 and 2), each consisting of two treatments (60 or 120 mg/kg weekly IV alpha₁-PI (Prolastin-C®), separated by a washout period. Time points for serial samples for pharmacokinetic (PK) analysis are indicated.

Figure 2.  Subject flow. ^aSubject had previously received gene therapy for alpha₁-PI in a research study.

Table 1.  Demographics and disease characteristics of the study population

	Alpha1-PI treatment sequence
Characteristic	60 mg/kg–120 mg/kg	120 mg/kg–60 mg/kg	Total
	n = 15	n = 15	n = 30
Male gender, n (%)	7 (46.7)	7 (46.7)	14 (46.7)
Female gender, n (%)	8 (53.3)	8 (53.3)	16 (53.3)
Mean age, years (SD)	59.7 (6.89)	57.4 (6.34)	58.6 (6.62)
Ethnicity, n (%)
Hispanic/Latino	1 (6.7)	1 (6.7)	2 (6.7)
Not Hispanic/Latino	14 (93.3)	14 (93.3)	28 (93.3)
Mean height, cm (SD)^a	171.9 (10.66)	171.4 (10.93)	171.6 (10.61)
Mean weight, kg (SD)^a	80.1 (16.96)	90.6 (17.97)	85.4 (17.97)
Median time since diagnosis, years (range)	7.0 (3.0–25.0)	7.5 (1.0–22.0)^b	7.0 (1.0–25.0)
Genotype, n (%)
PI*ZZ	13 (86.7)	15 (100.0)	28 (93.3)
PI*Z(null)	1 (6.7)	0	1 (3.3)
PI*ZMmalton	1 (6.7)	0	1 (3.3)
Mean alpha1-PI level at time of diagnosis (μM)	5.24 (1.50)	4.61 (0.94)^b	4.93 (1.28)
Mean baseline alpha1-PI concentration (μM),^c naïve subjects
n	2	2	4
Mean (SD)	5.65 (2.08)	7.46 (0.16)	6.55 (1.58)
Mean baseline alpha1-PI concentration (μM),^c non-naïve subjects
n	13	13	26
Mean (SD)	7.68 (3.07)	7.46 (2.26)	7.68 (2.64)
Mean% predicted FEV1 (SD)	54 (14.5)	49 (12.4)	52 (13.5)

^aBaseline values are taken from screening visit.

^bFor time since diagnosis and AAT level at time of diagnosis n = 14; verification was not provided for one subject and therefore this information for the subject was not included in the database.

^cBaseline AAT concentration is trough concentration at week 1 prior to the start of the first alpha₁-PI infusion. AAT concentration was converted from mg/mL to μM using the conversion factor of 22.6 based on the protein-only molecular weight of 44.3 KDa for AAT.

AAT, alpha-1 antitrypsin; FEV₁, forced expiratory volume in 1 second; SD, standard deviation.

Table 2.  Adverse events

	Dose
	60 mg/kg alpha1-PI	120 mg/kg alpha1-PI
	n = 30	n = 30
Subjects with TEAE(s), n (%)	23 (76.7)	18 (60.0)
Total number of TEAEs	69	43
Subjects with drug-related TEAE(s), n (%)	3 (10.0)	1 (3.3)
Total number of drug-related TEAEs	5	1
Subjects with exacerbations, n (%)	7 (23.3)	5 (16.7)
Total number of exacerbations	9	6
Subjects with SAE(s), n (%)	0	0
Subjects withdrawn due to an AE(s)	0	0
TEAEs occurring in ≥5% of subjects, n (%)
COPD exacerbation	7 (23.3)	5 (16.7)
Urinary tract infection	3 (10.0)	0
Contusion	1 (3.3)	2 (6.7)
Thrombocytopenia	2 (6.7)	0
Proteinuria	2 (6.7)	1 (3.3)
Blood creatinine increased^a	0	2 (6.7)
Blood glucose increased^a	0	2 (6.7)

AE, adverse event; SAE, serious adverse event; TEAE, treatment-emergent adverse event.

^aAbove the upper limit of the normal range.

Figure 3.  Mean steady-state serum alpha₁-PI concentration versus time curves. Serum concentrations of alpha₁-PI following the eighth weekly IV dose of 60 mg/kg and 120 mg/kg of alpha₁-PI were measured in blood samples. Linear scale (A); semi-logarithmic scale (B). ^aAt week 8, after receiving the 60 mg/kg dose, serum alpha₁-PI concentration hardly increased from the pre-dose level throughout the entire PK blood sampling period in one subject. This subject was excluded from PK data analysis.

Table 3.  Summary of steady-state PK parameters of serum alpha₁-PI following weekly intravenous infusion dose of 60 mg/kg and 120 mg/kg of alpha₁-PI

Parameter	Alpha1-PI 60 mg/kg	Alpha1-PI 120 mg/kg
	(n = 29^a)	(n = 30)
Mean AUC0-7days, mg*h/mL (%CV)	203.6 (10.1%)	344.8 (13.5%)
Mean Cmax, mg/mL (%CV)	2.47 (12.2%)	4.38 (16.1%)
Mean Cmax, μM (%CV)	55.8 (12.2%)	99.0 (16.1%)
Median adjusted tmax, hours range)	0.7 (0.3–2.4)	1.2 (0.3–8.8)
Mean t1/2, hours (%CV)	212.7 (13.4%)	184.3 (15.9%)
	Alpha1-PI 60 mg/kg	Alpha1-PI 120 mg/kg
	(n = 30)	(n = 30)
Mean trough, mg/mL (%CV)	0.77 (13.6%)	1.23 (13.5%)
Mean trough, μM (%CV)	17.3 (13.6%)	27.7 (13.5%)
Subjects with mean trough ≥11 μM, (%)	30 (100%)	30 (100%)

AUC_0-7days, area under the concentration versus time curve at steady state over the weekly dosing interval; C_max maximum serum alpha₁-PI concentration following drug infusion; CV, coefficient of variation; t_max, observed time to reach C_max; PK, pharmacokinetic; t_1/2, terminal half-life as determined for sampling period up to 504 hours’ post-infusion.

^a At week 8, after receiving the 60 mg/kg dose, serum alpha₁-PI concentration hardly increased from the pre-dose level throughout the entire PK blood sampling period in one subject. This subject was excluded from AUC_0-7days, C_max, t_max and t_1/2 analysis.

Table 4.  Statistical analysis of dose-normalized PK parameters of serum alpha₁-PI at steady-state following weekly intravenous infusion dose of 60 mg/kg and 120 mg/kg of alpha₁-PI

			Dose-normalized value(to 60 mg/kg dose)			GLSM ratio of dose normalized parameter (120 mg/kg versus 60 mg/kg)
PK parameter	Dose	N	Mean (%CV)	% diff^a	GLSM	Estimate	90% CI
AUC0-7days (hr*mg/mL)	120 mg/kg	30	172.4 (13.5%)	–15.33	170.9	0.85	(0.83, 0.88)
	60 mg/kg	29	203.6 (10.1%)		201.0
Cmax (mg/mL)	120 mg/kg	30	2.19 (16.1%)	–11.49	2.16	0.89	(0.85, 0.92)
	60 mg/kg	29	2.47 (12.2%)		2.43

^aDifference in the means of the dose-normalized PK parameters of alpha₁-PI (120 mg/kg –60 mg/kg).AUC_0-7days, area under the concentration versus time curve at steady state over the weekly dosing interval; CI, confidence interval; C_max maximum serum alpha₁-PI concentration following drug infusion; CV, coefficient of variation; GLSM, geometric least-squares mean; PK, pharmacokinetic.