Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Various alimentary tract and metabolism products, ATC code: A16AX18.

Mechanism of action
Lumasiran is a double-stranded small interfering ribonucleic acid (siRNA) that reduces levels of glycolate oxidase (GO) enzyme by targeting the hydroxyacid oxidase 1 (HAO1) gene messenger ribonucleic acid (mRNA) in hepatocytes through RNA interference. Decreased GO enzyme levels reduce the amount of available glyoxylate, a substrate for oxalate production. This results in reduction of urinary and plasma oxalate levels, the underlying cause of disease manifestations in patients with PH1. As the GO enzyme is upstream of the deficient alanine: glyoxylate aminotransferase (AGT) enzyme that causes PH1, the mechanism of action of lumasiran is independent of the underlying AGXT gene mutation.

Clinical efficacy

The efficacy of lumasiran was studied in a randomised, double-blind, placebo-controlled clinical study in patients 6 years and older with PH1 (ILLUMINATE-A) and in a single-arm clinical study in patients less than 6 years of age with PH1 (ILLUMINATE-B).

ILLUMINATE-A
A total of 39 patients with PH1 were randomised 2:1 to receive subcutaneous doses of lumasiran or placebo during the 6-month double-blind, placebo-controlled period. Patients 6 years and older with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 were enrolled, and received 3 loading doses of 3 mg/kg lumasiran or placebo administered once monthly, followed by quarterly maintenance doses of 3 mg/kg lumasiran or placebo (see section 4.2). After the 6-month double-blind treatment period, patients, including those originally assigned to placebo, entered an extension period with administration of lumasiran.

During the 6-month double-blind, placebo-controlled period, 26 patients received lumasiran, and 13 received placebo. The median age of patients at first dose was 14.9 years (range 6.1 to 61.0 years), 66.7% were male, and 76.9% were white. The median 24-hour urinary oxalate excretion corrected for body surface area (BSA) at baseline was 1.72 mmol/24 h/1.73 m2, the median spot urinary oxalate: creatinine ratio at baseline was 0.21 mmol/mmol, and the median plasma oxalate level at baseline was 13.1 µmol/L. Overall, 33.3% of patients had normal renal function (eGFR ≥90 mL/min/1.73 m2), 48.7% had mild renal impairment (eGFR of 60 to <90 mL/min/1.73 m2), and 18% had moderate renal impairment (eGFR of 30 to <60 mL/min/1.73 m2). Of the patients enrolled in the study, 84.6% reported a history of symptomatic renal stone events and 53.8% reported a history of nephrocalcinosis at baseline. The treatment arms were balanced at baseline with respect to age, urinary oxalate level, and eGFR.

The primary endpoint was the percent reduction from baseline in 24-hour urinary oxalate excretion corrected for BSA averaged over months 3 through 6. Lumasiran was associated with a statistically significant reduction of 65.4% in 24-hour urinary oxalate corrected for BSA, as compared to 11.8% in the placebo group, representing a difference of 53.5% (95% CI: 44.8, 62.3; p<0.0001). Consistent with the primary endpoint, a reduction of 60.5% was observed at month 6 in spot urinary oxalate: creatinine ratio in the lumasiran arm compared to an 8.5% increase in the placebo arm. Furthermore, patients treated with lumasiran had a rapid and sustained decrease in 24-hour urinary oxalate corrected for BSA, as shown in Figure 1.
Figure 1: ILLUMINATE-A: Percent change from baseline in 24-hour urinary oxalate corrected for BSA by month



Abbreviations: BL = baseline; BSA = body surface area; M = month; SEM = standard error of mean.
Results are plotted as mean (±SEM) of percent change from baseline.

At month 6, a higher proportion of lumasiran-treated patients achieved normal or near-normal levels of 24-hour urinary oxalate corrected for BSA (≤1.5×ULN) compared to placebo-treated patients, as shown in Table 3.

Table 3:     ILLUMINATE-A: Secondary endpoint results over the 6-month double-blind, placebo-controlled period
Endpoints                         Lumasiran              Placebo       Treatment difference       p-value (N=26)                (N=13)             (95% CI)
Proportion of patients with    0.52 (0.31, 0.72)§       0 (0, 0.25)§     0.52 (0.23, 0.70)¶        0.001# 24-hour urinary oxalate levels at or below ULN‡

Endpoints                         Lumasiran              Placebo        Treatment difference     p-value (N=26)                (N=13)              (95% CI)
Proportion of patients with     0.84 (0.64,0.95)§       0 (0, 0.25)§       0.84 (0.55, 0.94)¶    <0.0001# 24-hour urinary oxalate levels at or below
1.5×ULN‡
Percent reduction in plasma        39.8 (2.9)†          0.3 (4.3)†         39.5 (28.9, 50.1)     <0.0001 oxalate from baseline*Þ
Abbreviations: ULN = upper limit of normal; SEM = Standard Error of Mean Results are based on liquid chromatography tandem mass spectrometry (LC-MS/MS) assay.
*The estimate based on the average of the least square mean of percent reduction at Months 3, 4, 5, and 6 using a mixed model for repeated measures.
†
LS Mean (SEM).
‡
ULN=0.514 mmol/24 hr/1.73 m2 for 24-hour urinary oxalate corrected for BSA.
§
95% CI based on Clopper Pearson Exact confidence interval.
¶
Calculated using the Newcombe Method based on the Wilson Score.
# p-value is based on Cochran–Mantel–Haenszel test stratified by baseline 24-hour urinary oxalate corrected for BSA (≤1.70 vs >1.70 mmol/24 hr/1.73 m2).
Þ
Analysed in 23 lumasiran and 10 placebo patients who had baseline levels that allowed for reduction to occur.

Reduction in 24-hour urinary oxalate corrected for BSA from baseline in patients with PH1 receiving lumasiran compared to placebo was similar across all pre-specified subgroups, including age, sex, race, renal impairment, baseline pyridoxine (vitamin B6) use, and history of symptomatic renal stone events (Figure 2).
Figure 2: ILLUMINATE-A: Percent change from baseline in 24-hour urinary oxalate corrected for BSA, subgroup analysis



Reduced oxalate levels observed in the double-blind period were maintained with continued lumasiran treatment through 24 months during the extension period of study.
 eGFR and renal stone events (reported by events per person-year) were assessed through the 6-month double-blind and extension periods for a total of 24 months. eGFR remained stable in patients administered lumasiran.


The rate of renal stone events per person-year reported in patients treated with lumasiran in ILLUMINATE-A are presented in Table 4.

Table 4:           Rate of Renal Stone Events per Person-Year Reported in the Lumasiran Group 
Treatment                               Time Period                             Rate (95% CI) No treatment                             12 months prior to consent                      3.19 (2.57, 3.96) Lumasiran                                6-month double-blind period                     1.09 (0.63, 1.88) Month 6 to month 12                             0.87 (0.47, 1.62)
Month 12 to month 18                            0.56 (0.25, 1.24)
Month 18 to month 24                            0.63 (0.30, 1.33)


The rate of renal stone events per person-year reported in patients treated with placebo in ILLUMINATE-A are presented in Table 5. The patients in the placebo group were initially randomised to placebo for the 6-month double-blind period and subsequently treated with lumasiran in the extension periods: month 6 to month 12, month 12 to month 18, and month 18 to month 24.


Table 5:           Rate of Renal Stone Events per Person-Year Reported in the Placebo Group 
Treatment                               Time Period                             Rate (95% CI) No treatment                             12 months prior to consent                      0.54 (0.26, 1.13) Placebo                                  6-month double-blind period                     0.66 (0.25, 1.76) Lumasiran                                Month 6 to month 12                             0.16 (0.02, 1.17) Month 12 to month 18                            0.67 (0.25, 1.78)
Month 18 to month 24                            0.00 (0.00, 0.62)


Medullary nephrocalcinosis results, assessed by renal ultrasound, at month 6 and month 12 relative to baseline are presented in Table 6.

Table 6:           ILLUMINATE-A: Patients with Medullary Nephrocalcinosis at Month 6 and Month 12 Relative to Baseline*

Timepoint               Treatment (n)              Improvement             No Change           Worsening Month 6                  Lumasiran (n=23)
3                    20                  0
Placebo
0                    11                  1
(n=12)
Month 12                     Lumasiran
11                    4                  3
(n=18)
Placebo/Lumasiran**
1                     9                      1
(n=11)

* Patients with renal ultrasounds at baseline and the relevant timepoint were assessed.
** Patients received placebo for 6 months followed by lumasiran treatment for 6 months.



ILLUMINATE-B
A total of 18 patients were enrolled and treated with lumasiran in an ongoing multi-center, single-arm study in patients with PH1 (ILLUMINATE-B). The study enrolled patients less than 6 years of age with an eGFR >45 mL/min/1.73 m2 in patients 12 months of age and older, and normal serum creatinine in patients less than 12 months of age. In the 6-month primary analysis, at first dose, 3 patients were less than 10 kg, 12 were 10 kg to less than 20 kg, and 3 were 20 kg and above. The median age of patients at first dose was 51.4 months (range 4.0 to 74.0 months), 55.6% were female, 

and 88.9% were white. The median spot urinary oxalate: creatinine ratio at baseline was 0.47 mmol/mmol.

At month 6, patients treated with lumasiran achieved a reduction of 72.0% (95% CI: 66.4, 77.5) in spot urinary oxalate: creatinine ratio from baseline (averaged over months 3 through month 6), the primary endpoint. Lumasiran was associated with rapid, and sustained reductions in spot urinary oxalate: creatinine ratio (Figure 3), which were similar across all weight strata. The percent reduction in urinary oxalate excretion was consistent with data from ILLUMINATE-A.
Figure 3: ILLUMINATE-B: Percent change in spot urinary oxalate: creatinine ratio from baseline by month



At month 6,nine of 18 patients achieved near normalisation (≤1.5×ULN), including 1 patient who achieved normalisation (≤ULN), in spot urinary oxalate: creatinine ratio. At month 12, ten of 18 patients achieved near normalization (≤1.5×ULN), including 2 patients who achieved normalization (≤ULN), in spot urinary oxalate: creatinine ratio.


Furthermore, from baseline to month 6 (average of month 3 to month 6), a mean plasma oxalate reduction of 31.7% (95% CI: 23.9, 39.5) was observed. Reduced plasma oxalate levels observed in the primary analysis period were maintained with continued lumasiran treatment. The eGFR remained stable in all patients with continued dosing.

The rate of renal stone events per person-year reported in the 12-month period prior to consent and during the 6-month primary analysis period was 0.24 (95% CI: 0.09, 0.63) and 0.24 (95% CI: 0.06, 0.96), respectively. The rate of events from month 6 to month 12 was 0.12 (95% CI: 0.02, 0.84).

Medullary nephrocalcinosis results, assessed by renal ultrasound, at month 6 and month 12 relative to baseline are presented in Table 7.

Table 7:            ILLUMINATE-B: Patients with Medullary Nephrocalcinosis at Month 6 and Month 12 Relative to Baseline*

Timepoint                           Improvement (n)                     No Change        Worsening Month 6
8                              10              0
(n=18)
Month 12
11                               6              0
(n=17)
* Patients with renal ultrasounds at baseline and the relevant timepoint were assessed.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Absorption

Following subcutaneous administration, lumasiran is rapidly absorbed with a median (range) time to reach maximum plasma concentration (tmax) of 4.0 (0.5 to 12.0) hours. In children and adults with PH1 ≥20 kg, the peak plasma concentration of lumasiran (Cmax) and area under the concentration curve from time zero to the last measurable concentration after dosing (AUC0-last) following the recommended lumasiran dose of 3 mg/kg were 529 (205 to 1130) ng/mL and 7400 (2890 to 10700) ng·h/mL, respectively. In children less than 20 kg, Cmax and AUC0-last of lumasiran following the recommended lumasiran dose of 6 mg/kg were 912 (523 to 1760) and 7960 (5920 to 13300). Lumasiran concentrations were measurable, up to 24 to 48 hours post-dose.

Distribution

In healthy adult plasma samples, the protein binding of lumasiran is moderate to high (77 to 85%) at clinically relevant concentrations. For an adult patient with PH1, the population estimate for the apparent central volume of distribution (Vd/F) for lumasiran is 4.9 L. Lumasiran primarily distributes to the liver after subcutaneous dosing.

Biotransformation

Lumasiran is metabolised by endo- and exonucleases to oligonucleotides of shorter lengths. In vitro studies indicate that lumasiran does not undergo metabolism by CYP450 enzymes.

Elimination

Lumasiran is primarily eliminated from plasma by hepatic uptake, with only 7 to 26% of the administered dose recovered in urine as lumasiran in the pooled data from healthy adult subjects and patients with PH1 >6 years of age. The mean (%CV) terminal plasma half-life of lumasiran is 5.2 (47.0%) hours. The population estimate for apparent plasma clearance was 26.5 L/h for a typical 70-kg adult. The mean renal clearance of lumasiran was minor and ranged from 2.0 to 3.4 L/h in paediatric and adult patients with PH1.

Linearity/non-linearity

Lumasiran exhibited linear to slightly nonlinear, time-independent pharmacokinetics in plasma following single subcutaneous doses ranging from 0.3 to 6 mg/kg and multiple doses of 1 and 3 mg/kg once monthly or 3 mg/kg quarterly. There was no accumulation of lumasiran in plasma after repeated once monthly or quarterly dosing.

Pharmacokinetic/pharmacodynamic relationship(s)

Plasma concentrations of lumasiran do not reflect the extent or duration of the pharmacodynamic activity of lumasiran. Rapid and targeted uptake of lumasiran by the liver results in rapid decline in plasma concentrations. In the liver, lumasiran exhibits a long half-life leading to maintenance of pharmacodynamic effect over the monthly or quarterly dosing interval.

Interactions

In vitro studies indicate that lumasiran is not a substrate or an inhibitor of cytochrome P450 (CYP) enzymes. Lumasiran is not expected to inhibit or induce CYP enzymes or modulate the activities of drug transporters.


Special populations

Elderly
No studies have been conducted in patients ≥65 years of age. Age was not a significant covariate in the pharmacokinetics of lumasiran.

Gender and race
In clinical studies, there was no difference in the plasma exposure or pharmacodynamics of lumasiran based on gender or race.

Hepatic impairment
No studies have been conducted in patients with hepatic impairment (see section 4.2). Limited pharmacokinetic data in patients with mild and transient elevations in total bilirubin (total bilirubin >1.0 to 1.5×ULN) showed comparable plasma exposure of lumasiran and similar pharmacodynamics as patients with normal hepatic function. Published literature show lower expression of the asialoglycoprotein receptors in the liver, i.e. the receptors responsible for lumasiran uptake, in patients with hepatic impairment. Nonclinical data suggest that this may not influence liver uptake or pharmacodynamics at therapeutic doses. The clinical relevance of these data is unknown.

Renal impairment
Patients with mild renal impairment (eGFR 60 to <90 mL/min/1.73 m2) had comparable plasma exposure of lumasiran and similar pharmacodynamics as patients with normal renal function (eGFR ≥90 mL/min/1.73 m2). In patients with moderate renal impairment (eGFR 30 to <60 mL/min/1.73 m2) Cmax was similar to that in patients with normal renal function; AUC was 25% higher based on limited data. The effect of eGFR < 30 mL/min/1.73 m2 or dialysis on the pharmacokinetics of lumasiran is unknown.
Paediatric population
Data in children younger than 1 year of age are limited. In children <20 kg, lumasiran Cmax was 2-fold higher due to the nominally higher 6-mg/kg dose and faster absorption rate. The pharmacodynamics of lumasiran were comparable in paediatric patients (aged 4 months to 17 years) and in adults, despite the transiently higher plasma concentrations in children <20 kg, due to the rapid and predominant distribution of lumasiran to the liver.

Body weight
The recommended dosing regimens yielded up to 2-fold higher Cmax in children <20 kg while AUC was similar across the body weights studied (6.2 to 110 kg).