Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Various alimentary tract and metabolism products, ATC code: A16AX16 
Mechanism of action

Givosiran is a double-stranded small interfering ribonucleic acid (siRNA) that causes degradation of aminolevulinic acid synthase 1 (ALAS1) messenger ribonucleic acid (mRNA) in hepatocytes through RNA interference, resulting in a reduction of induced liver ALAS1 mRNA towards normal. This leads to reduced circulating levels of neurotoxic intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG), the key causal factors of attacks and other disease manifestations of AHP.

Pharmacodynamic effects

In the placebo-controlled study in patients with AHP receiving givosiran 2.5 mg/kg once monthly (ENVISION), median reductions from baseline in urinary ALA and PBG of 83.7 % and 75.1 %, respectively, were observed 14 days after the first dose. Maximal reductions in ALA and PBG levels were achieved around month 3 with median reductions from baseline of 93.8 % for ALA and 94.5 % for PBG, and were sustained with repeated once monthly dosing.

Observed data and modelling demonstrated that once monthly dosing with 2.5 mg/kg givosiran resulted in a greater reduction and less fluctuation in ALA levels compared with doses less than 2.5 mg/kg or dosing once every 3 months.

Clinical efficacy

The efficacy of givosiran was evaluated in a randomised, double-blind, placebo-controlled, multinational study (ENVISION).

ENVISION
A total number of 94 patients with AHP (89 patients with acute intermittent porphyria (AIP), 2 patients with variegate porphyria (VP), 1 patient with hereditary coproporphyria (HCP), and 2 patients with no identified mutation in a porphyria-related gene) were randomised 1:1 to receive once monthly subcutaneous injections of givosiran 2.5 mg/kg or placebo during the 6-month double-blind period.
Patients randomised to givosiran included 46 patients with AIP, 1 patient with VP, and 1 patient with HCP. In this study, inclusion criteria specified a minimum of 2 porphyria attacks requiring hospitalisation, urgent healthcare visit, or intravenous (IV) hemin administration at home in the 6 months prior to study entry. Hemin use during the study was permitted for the treatment of acute porphyria attacks. The median age of patients in the ENVISION study was 37.5 years (range 19 to 65 years); 89.4 % of patients were female, and 77.7 % were white. The treatment arms were balanced with respect to historical annualised porphyria attack rate (overall median baseline rate of 8 per year), prior hemin prophylaxis, use of opioid medicinal products, and patient-reported measures of chronic symptoms between attacks.

The major efficacy measure was the annualised attack rate (AAR) of composite porphyria attacks during the 6-month double-blind period and consisted of three components: attacks requiring hospitalisation, urgent healthcare visit, or IV hemin administration at home. This composite efficacy measure was evaluated as the primary endpoint in patients with AIP, and as a secondary endpoint in the overall population of patients with AHP. Treatment with this medicinal product resulted in a significant reduction of the AAR of composite porphyria attacks, compared with placebo, of 74 % in patients with AIP (Table 2). Comparable results were seen in patients with AHP, with a reduction of 73 %. Consistent results were observed for each of the 3 components of the composite porphyria attack endpoint.

The results observed over 6 months were maintained through Month 12, with a median AAR (Q1, Q3) of 0.0 (0.0, 3.5) observed for patients with continued dosing with the medicinal product during the open-label extension period.

Givosiran reduced porphyria attacks compared to placebo in patients with AHP across all pre-specified subgroups, including age, sex, race, region, baseline body mass index (BMI), prior hemin prophylaxis use, historical attack rate, prior chronic opioid use when not having attacks, and the presence of prior chronic symptoms when not having attacks.

Additional clinical efficacy endpoints were studied in AIP patients and are summarised in Table 2.


Table 2: Clinical Efficacy Results in Patients with AIP during the 6-Month Double-Blind Period of the ENVISION Study
Placebo                Givosiran
Endpoint
(N=43)                 (N=46)
Annualised attack rate of composite porphyria attacksa
Mean AAR (95 % CI)b                                        12.5 (9.4, 16.8)           3.2 (2.3, 4.6) b
Rate ratio (95 % CI) (givosiran/placebo)                   0.26 (0.16, 0.41) P-valueb                                                   < 0.001
Median AAR, (Q1, Q3)                                       10.7 (2.2, 26.1)           1.0 (0.0, 6.2) Number of patients with 0 attacks (%)                      7 (16.3)                   23 (50.0) Annualised days of hemin use
Mean (95 % CI)b                                            29.7 (18.4, 47.9)          6.8 (4.2, 10.9) b
Ratio (95 % CI) (givosiran/placebo)                        0.23 (0.11, 0.45) P-valueb                                                   < 0.001 c
Daily worst pain score
Baseline, median (Q1, Q3)                                  3.3 (1.9, 5.6)             2.2 (1.2, 4.5) Median of treatment difference (95 %)
−10.1 (−22.8, 0.9)
(givosiran-placebo)
P-value                                                    < 0.05 d
PCS of SF-12
Baseline, mean (SD)                                        38.4 (9.4)                 39.4 (9.6) Change from baseline at Month 6, LS mean
1.4 (−1.0, 3.9)            5.4 (3.0, 7.7)
(95 % CI)
LS mean difference (95 % CI) (givosiran-
3.9 (0.6, 7.3) placebo)
Nominal P-value                                            < 0.05
AAR, Annualised Attack Rate; AIP, Acute Intermittent Porphyria; CI, Confidence Interval; Q1, Quartile 1; Q3, Quartile 3; LS, Least Square; PCS, Physical Component Summary; SF-12, the 12-item Short-Form Health Survey a
Composite porphyria attacks includes three components: attacks requiring hospitalisation, urgent healthcare visits, or IV hemin administration at home.
b
Based on negative binomial regression model. A rate ratio < 1 represents a favourable outcome for givosiran.
c
Patients provided a daily self-assessment of their worst pain based on a 0 to 10 numerical rating scale (NRS).
A lower score indicates fewer symptoms. Median of treatment difference and CI were estimated using the Hodges-Lehmann method; p-value was based on Wilcoxon rank sum test, which was conducted post-hoc after data showed a significant deviation from normal distribution.
d
A higher score indicates improved health-related quality of life; analysed using the mixed-effect model repeated measures (MMRM) method. The endpoint was not formally tested for statistical significance; a nominal p-value was reported.

In addition to greater improvement from baseline in the SF-12 PCS score compared to patients treated with placebo at Month 6, there was consistent evidence of effect favouring this medicinal product in bodily pain, role-physical, and social functioning domains, but not in the general health, physical functioning, role-emotional, vitality, and mental health domains (Figure 1).


Figure 1: Change from Baseline to Month 6 in SF-12 Domain Scores in Patients with AIP Pbo   Givo    LS Mean
SF-12 Domain             Givosiran – Placebo                                 (n)    (n)   Difference   95 % Cl Physical Component
42     45      3.9       (0.6, 7.3)
Summary (PCS)
Mental Component
42     45      2.1       (−1.7, 5.8)
Summary (MCS)

Physical Functioning                                                              43     46      1.4       (−2.0, 4.7) 
Role Physical                                                                     43     46      4.4       (1.3, 7.5) 
Bodily Pain                                                                       43     46      7.2       (3.2, 11.2) 
General Health                                                                    42     46      3.3       (−0.7, 7.2) 
Vitality                                                                          42     45      1.7       (−2.0, 5.5) 
Social Functioning                                                                42     45      5.1       (1.6, 8.7) 
Role Emotional                                                                    43     46      1.4       (−2.5, 5.2) 
Mental Health                                                                     42     45      2.8       (−0.9, 6.4) 

Favours Placebo   Favours Givosiran
AIP, Acute Intermittent Porphyria; CI, Confidence Interval; Givo, givosiran; Pbo, placebo; LS, Least Square; MCS, Mental Component Summary; PCS, Physical Component Summary; SF-12, the 12-item Short-Form health survey version 2.

In a patient global assessment (Patient Global Impression of Change – PGIC) a larger proportion of patients with AIP treated with givosiran (61.1 %) than with placebo (20 %) rated their overall status as “very much improved” or “much improved” since the start of the study.

Pharmacokinetic Properties

5.2       Pharmacokinetic properties

Absorption
Following subcutaneous administration, givosiran is rapidly absorbed with a time to maximum plasma concentration (tmax) of 0.5 to 2 hours. At the 2.5 mg/kg once monthly dose, the steady-state peak plasma concentrations of givosiran (Cmax) and area under the curve from time of dosing up to 24 hours after dosing (AUC24) were 321 ± 163 ng/mL and 4130 ± 1780 ng·h/mL, respectively, and corresponding values for the active metabolite were 123 ± 79.0 ng/mL and 1930 ± 1210 ng·h/mL, respectively.

Distribution

Givosiran is greater than 90 % bound to plasma proteins over the concentration range observed in humans at the 2.5 mg/kg once monthly dose. The population estimate for the steady state apparent volume of distribution (Vd/F) for givosiran and for the active metabolite was 10.4 L. Givosiran and its active metabolite distribute primarily to the liver after subcutaneous dosing.

Biotransformation

Givosiran is metabolised by nucleases to oligonucleotides of shorter lengths. Active metabolite AS(N-1)3’ givosiran (with equal potency as that of givosiran) was a major metabolite in plasma with 45 % exposure (AUC0–24) relative to givosiran at the 2.5 mg/kg once monthly dose. In vitro studies indicate that givosiran does not undergo metabolism by CYP450 enzymes.

Elimination

Givosiran and its active metabolite are eliminated from plasma primarily by metabolism with an estimated terminal half-life of approximately 5 hours. The population estimate for apparent plasma clearance was 36.6 L/h for givosiran and 23.4 L/h for AS(N-1)3’ givosiran. After subcutaneous dosing, up to 14 % and 13 % of the administered givosiran dose was recovered in urine as givosiran and its active metabolite, respectively, over 24 hours. The renal clearance ranged from 1.22 to 9.19 L/h for givosiran and 1.40 to 12.34 L/h for the active metabolite.

Linearity/non-linearity

Givosiran and its active metabolite exhibited linear pharmacokinetics in plasma over the 0.35 to 2.5 mg/kg dose range. At doses greater than 2.5 mg/kg, plasma exposure increased slightly greater than dose-proportionally. Givosiran exhibited time-independent pharmacokinetics with chronic dosing at the recommended dose regimen of 2.5 mg/kg once monthly. There was no accumulation of givosiran or the active metabolite in plasma after repeated once monthly dosing.

Pharmacokinetic/pharmacodynamic relationship

Plasma concentrations of givosiran are not reflective of the extent or duration of pharmacodynamic activity. Since givosiran is a liver targeted therapy, concentrations in plasma decline rapidly due to uptake by the liver. In the liver, givosiran exhibits a long half-life leading to extended duration of pharmacodynamic effect maintained over the monthly dosing interval.

Special populations

Elderly
No studies have been conducted in patients aged > 65 years. Age was not a significant covariate in the pharmacokinetics of givosiran.

Gender and race
In clinical studies there was no difference in the pharmacokinetics or pharmacodynamics of givosiran based on gender or race.

Hepatic impairment
Adult patients with mild hepatic impairment (bilirubin ≤ 1×ULN and AST > 1×ULN, or bilirubin > 1×ULN to 1.5×ULN) had comparable plasma exposure of givosiran and its active metabolite and similar pharmacodynamics (percent reduction in urinary ALA and PBG) as patients with normal hepatic function. No studies have been conducted in patients with moderate or severe hepatic impairment (see sections 4.2 and 4.4).

Renal impairment
Adult patients with mild renal impairment (eGFR ≥ 60 to < 90 mL/min/1.73 m²), moderate renal impairment (eGFR ≥ 30 to < 60 mL/min/1.73 m²) or severe renal impairment (eGFR ≥ 15 to < 30 mL/min/1.73 m²) had comparable plasma exposure of givosiran and its active metabolite and similar pharmacodynamics (percent reduction in urinary ALA and PBG) as patients with normal renal function (eGFR ≥ to 90 mL/min/1.73 m²).Limited data are available in patients with severe renal impairment and GIVLAARI has not been studied in patients with end-stage renal disease (eGFR <15 mL/min/1.73 m2), or patients on dialysis (see sections 4.2 and 4.4).

Paediatric population
Available data suggest that body weight but not age was a significant covariate in the pharmacokinetics of givosiran. At the 2.5 mg/kg dose, a similar exposure is expected in adolescents aged 12 years or older, as in adults with the same body weight.