Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Alnylam Netherlands B.V., Antonio Vivaldistraat 150, 1083 HP Amsterdam, Netherlands
Pharmacotherapeutic group: Other nervous System Drugs
ATC code: N07XX12
Onpattro contains patisiran, a double-stranded small interfering ribonucleic acid (siRNA) that specifically targets a genetically conserved sequence in the 3' untranslated region of all mutant and wild-type TTR mRNA. Patisiran is formulated as lipid nanoparticles to deliver the siRNA to hepatocytes, the primary source of TTR protein in the circulation. Through a natural process called RNA interference (RNAi), patisiran causes the catalytic degradation of TTR mRNA in the liver, resulting in a reduction of serum TTR protein.
Mean serum TTR was reduced by approximately 80% within 10 to 14 days after a single dose with 300 micrograms per kg Onpattro. With repeat dosing every 3 weeks, mean reductions of serum TTR after 9 and 18 months of treatment were 83% and 84%, respectively. Serum TTR reduction was maintained with continued dosing.
Serum TTR is a carrier of retinol binding protein, which facilitates transport of vitamin A in the blood. Mean reductions in serum retinol binding protein of 45% and serum vitamin A of 62% were observed over 18 months (see sections 4.4 and 4.5).
The efficacy of Onpattro was studied in a randomised, double-blind, placebo-controlled study in 225 hATTR amyloidosis patients with a TTR mutation and symptomatic polyneuropathy. Patients were randomised 2:1 to receive 300 micrograms per kg Onpattro or placebo via intravenous infusion once every 3 weeks for 18 months. All patients received premedication with a corticosteroid, paracetamol, and H1 and H2 blockers.
In the study, 148 patients received Onpattro and 77 patients received placebo. The median patient age at baseline was 62 (range, 24 to 83) years and 74% of patients were male, 26% were female. Thirtynine (39) different TTR mutations were represented; the most common (≥5%) were V30M (43%), A97S (9%), T60A (7%), E89Q (6%), and S50R (5%). Approximately 10% of patients had the V30M mutation and early onset of symptoms (<50 years of age). At baseline, 46% of patients had stage 1 disease (unimpaired ambulation; mostly mild sensory, motor and autonomic neuropathy in the lower limbs), and 53% had stage 2 disease (assistance with ambulation required; mostly moderate impairment progression to the lower limbs, upper limbs, and trunk). Approximately half (53%) of patients had prior treatment with tafamidis meglumine or diflunisal. Forty-nine percent (49%) and 50% of patients had a New York Heart Association (NYHA) Class of I or II, respectively.
Approximately half of patients (56%) met pre-defined criteria for cardiac involvement (defined as baseline LV wall thickness ≥13 mm with no history of hypertension or aortic valve disease). Patient demographics and baseline characteristics were balanced between treatment groups, except that a higher proportion of patients in the Onpattro group had a non-V30M mutation (62% vs. 48%). Ninetythree percent (93%) of Onpattro-treated and 62% of placebo-treated patients completed 18 months of the assigned treatment.
The primary efficacy endpoint was the change from baseline to 18 months in modified Neuropathy Impairment Score +7 (mNIS+7). This endpoint is a composite measure of motor, sensory, and autonomic polyneuropathy including assessments of motor strength and reflexes, quantitative sensory testing, nerve conduction studies, and postural blood pressure, with the score ranging from 0 to 304 points, where an increasing score indicates worsening impairment.
A statistically significant benefit in mNIS+7 with Onpattro relative to placebo was observed at 18 months (Table 2). Benefits relative to placebo were also observed across all mNIS+7 components. Changes were also seen at 9 months, the first post-baseline assessment in the study, where treatment with Onpattro led to a 16.0-point treatment difference, with a mean change from baseline of -2.0 points, compared to an increase of 14.0 points with placebo. In a threshold analysis of mNIS+7 (change from baseline of <0 points), 56.1% of Onpattro-treated patients versus 3.9% of placebotreated patients experienced improvement in mNIS+7 (p<0.001).
Patients treated with Onpattro experienced statistically significant benefits in all secondary endpoints compared to patients who received placebo (all p<0.001) (Table 2).
The key secondary endpoint was the change from baseline to 18 months in Norfolk Quality of LifeDiabetic Neuropathy (QoL-DN) total score. The Norfolk QoL-DN questionnaire (patient-reported) includes domains relating to small fibre, large fibre, and autonomic nerve function, symptoms, and activities of daily living, with the total score ranging from -4 to 136, where an increasing score indicates worsening quality of life. At 18 months, a benefit with Onpattro to placebo was observed across all domains of Norfolk QoL-DN, and 51.4% of Onpattro-treated patients experienced an improvement in quality of life (Norfolk QoL-DN change from baseline of <0 points) compared to 10.4% of placebo-treated patients. Improvement was observed at 9 months, the first post-baseline assessment in the study.
Table 2. Clinical Efficacy Results from the Placebo-Controlled Study:
| Endpointa | Baseline, Mean (SD) | Change from Baseline at 18 months, LS Mean (SEM) | (Onpattro – Placebo) Treatment Difference, LS Mean (95% CI) | p-value | ||
|---|---|---|---|---|---|---|
| Onpattro N=148 | Placebo N=77O | Onpattro | Placebo | |||
| Primary | ||||||
| mNIS+7b | 80.9 (41.5) | 74.6 (37.0) | −6.0 (1.7) | 28.0 (2.6) | −34.0 (−39.9, −28.1) | p<0.001 |
| Secondary | ||||||
| Norfolk QoL-DNb | 59.6 (28.2) | 55.5 (24.3) | −6.7 (1.8) | 14.4 (2.7) | −21.1 (−27.2, −15.0) | p<0.001 |
| NIS-Wb | 32.7 (25.2) | 29.0 (23.0) | 0.05 (1.3) | 17.9 (2.0) | −17.9 (−22.3, −13.4) | p<0.001 |
| R-ODSc | 29.7 (11.5) | 29.8 (10.8) | 0.0 (0.6) | −8.9 (0.9) | 9.0 (7.0, 10.9) | p<0.001 |
| 10-metre walk test (m/sec)c | 0.80 (0.40) | 0.79 (0.32) | 0.08 (0.02) | -0.24 (0.04) | 0.31 (0.23. 0.39) | p<0.001 |
| mBMId | 970 (210) | 990 (214) | −3.7 (9.6) | -119 (14.5) | 116 (82, 149) | p<0.001 |
| COMPASS 31b | 30.6 (17.6) | 30.3 (16.4) | −5.3 (1.3) | 2.2 (1.9) | −7.5 (−11.9, −3.2) | p<0.001 |
SD, standard deviation; LS mean, least squares mean; SEM, standard error of the mean; CI, confidence interval, NIS-W, NIS-weakness (motor strength); R-ODS, Rasch-Built Overall Disability (patient reported ability to perform activities of daily living); 10-metre walk test (gait speed); mBMI, modified body mass index (nutritional status); COMPASS 31, Composite Autonomic Symptom Score 31 (patient reported symptom score)
a All endpoints analysed using the mixed-effect model repeated measures (MMRM) method.
b A lower number indicates less impairment/fewer symptoms.
c A higher number indicates less disability/less impairment.
d mBMI: body mass index (BMI; kg/m²) multiplied by serum albumin (g/L); a higher number indicates better nutritional status; nutritional status favoured Onpattro as early as 3 months.
Patients receiving Onpattro experienced similar benefits relative to placebo in mNIS+7 and Norfolk QoL-DN score across all subgroups including age, sex, race, region, NIS score, V30M mutation status, prior tafamidis meglumine or diflunisal use, disease stage, and patients with pre-defined cardiac involvement. Patients experienced benefit across all TTR mutations and the full range of disease severity studied.
In patients with pre-defined cardiac involvement, centrally-assessed echocardiograms showed decreases in LV wall thickness (LS mean difference: −0.9 mm [95% CI −1.7, −0.2]) and longitudinal strain (LS mean difference: −1.37% [95% CI -2.48, -0.27]) with Onpattro treatment relative to placebo. N-terminal pro-B type natriuretic peptide (NT-proBNP) was 727 ng/L and 711 ng/L at baseline (geometric mean) in Onpattro-treated and placebo-treated patients, respectively. At 18 months, the adjusted geometric mean ratio to baseline was 0.89 with Onpattro and 1.97 with placebo (ratio, 0.45; p<0.001), representing a 55% difference in favour of Onpattro.
Of 218 patients who completed one of the two parent studies with patisiran (18-month placebo-controlled study [Study 004] or 2-year open-label study [Study 003]), 211 patients (25 prior patisiran from Study 003, 49 prior placebo and 137 prior patisiran from Study 004) enrolled in a global open-label extension study (Study 006). All patients in Study 006 received 300 micrograms per kg of patisiran via IV infusion once every 3 weeks. At Study 006 baseline, for the prior (Study 004) patisiran and placebo groups, 42.3% and 28.6% had stage 1 disease, 51.8% and 55.1% had stage 2 disease and 5.8% and 16.3% had stage 3 disease, respectively.
After initiation of patisiran in Study 006, clinical benefit was observed in patients who previously received placebo as demonstrated by stable measures of disease manifestations. Although these patients achieved stabilisation of their disease, measures of disease manifestations remained worse compared to the prior patisiran group, supporting the early initiation of patisiran treatment after the onset of symptoms. Continued treatment with patisiran through Year 3, across a range of disease stages, resulted in continued benefit.
In an open-label study, 23 patients with hATTR amyloidosis and polyneuropathy progression after receiving a liver transplant were treated with patisiran at a dose of 300 micrograms per kg via IV infusion once every 3 weeks. Median time from transplant to first patisiran dose was 9.4 years and median duration of patisiran treatment was 13.1 months. All patients received concomitant immunosuppressants. The study demonstrated a statistically significant median reduction in serum TTR levels from baseline of 91% (p<0.001). Patients also showed stable or improved efficacy endpoints at Month 12 compared to baseline. This was consistent with the findings in the placebo-controlled patisiran study.
The European Medicines Agency has waived the obligation to submit the results of studies with Onpattro in all subsets of the paediatric population in hATTR amyloidosis (see section 4.2 for information on paediatric use).
The pharmacokinetic properties of Onpattro were characterised by measuring the plasma concentrations of patisiran and the lipid components DLin-MC3-DMA and PEG2000-C-DMG.
Greater than 95% of patisiran in the circulation is associated with lipid nanoparticles. At the dose regimen of 300 micrograms per kg every 3 weeks, steady state was reached by 24 weeks of treatment. The estimated patisiran mean ± SD steady-state peak concentration (Cmax), trough concentration (Ctrough), and area under the curve (AUCτ) were 7.15 ± 2.14 µg/mL, 0.021 ± 0.044 µg/mL, and 184 ± 159 µg·h/mL, respectively. The accumulation of AUCτ was 3.2-fold at steady-state compared to the first dose.
The estimated DLin-MC3-DMA mean ± SD steady-state Cmax, Ctrough and AUCτ were 40.2 ± 11.5 µg/mL, 1.75 ± 0.698 µg/mL, and 1403 ± 105 µg·h/mL, respectively. The accumulation of AUCτ was 1.76-fold at steady-state compared to the first dose.
The estimated PEG2000-C-DMG mean ± SD steady-state Cmax, Ctrough and AUCτ were 4.22 ± 1.22 µg/mL, 0.0236 ± 0.0093 µg/mL, and 145 ± 64.7 µg·h/mL, respectively. There was no accumulation of AUCτ at steady-state compared to the first dose.
Plasma protein binding of Onpattro is low, with ≤2.1% binding observed in vitro with human serum albumin and human α1-acid glycoprotein. At the dose regimen of 300 micrograms per kg every 3 weeks, the mean ± SD steady-state volume of distribution (Vss) of patisiran, DLin-MC3-DMA and PEG2000-C-DMG was 0.26 ± 0.20 L/kg, 0.47 ± 0.24 L/kg and 0.13 ± 0.05 L/kg, respectively.
Patisiran is metabolized by nucleases to nucleotides of various lengths. DLin-MC3-DMA is primarily metabolised to 4-dimethylaminobutyric acid (DMBA) by hydrolysis. There is little to no metabolism of PEG2000-C-DMG.
At the dose regimen of 300 micrograms per kg every 3 weeks, mean ± SD steady state plasma clearance (CLss) of patisiran was 3.0 ± 2.5 mL/h/kg. The mean ± SD terminal elimination half-life (t1/2β) of patisiran was 3.2 ± 1.8 days. Less than 1% of patisiran in the administered dose was recovered intact in urine.
The estimated DLin-MC3-DMA mean ± SD steady-state CLss was 2.1 ± 0.8 mL/h/kg. Approximately 5.5% of DLin-MC3-DMA was recovered after 96 hours as its metabolite (DMBA) in urine.
The estimated PEG2000-C-DMG mean ± SD steady-state CLss was 2.1 ± 0.6 mL/h/kg. In rats and monkeys, PEG2000-C-DMG is eliminated unchanged in the bile. PEG2000-C-DMG excretion in humans was not measured.
Exposure to patisiran and the lipid components (DLin-MC3-DMA and PEG2000-C-DMG) increased proportionally with increase in dose over the range evaluated in clinical studies (10 to 500 micrograms per kg). Patisiran and the lipid components exhibit linear and time-independent pharmacokinetics with chronic dosing at the dose regimen of 300 micrograms per kg every 3 weeks.
Increasing the dose of patisiran resulted in greater TTR reduction, with maximal reductions plateauing at patisiran exposures obtained with 300 micrograms per kg every 3 weeks dosing.
The components of Onpattro are not inhibitors or inducers of cytochrome P450 enzymes or transporters, except for CYP2B6 (see Section 4.5). Patisiran is not a substrate of cytochrome P450 enzymes.
Clinical studies did not identify significant differences in steady state pharmacokinetic parameters or TTR reduction according to gender or race (non-Caucasian vs. Caucasian).
No data are available for patients weighing ≥110 kg.
In the placebo-controlled study, 62 (41.9%) patients treated with Onpattro were ≥65 years of age and 9 (6.1%) patients were ≥75 years of age. There were no significant differences in steady state pharmacokinetic parameters or TTR reduction between patients <65 years of age and ≥65 years of age.
Population pharmacokinetic and pharmacodynamic analyses indicated no impact of mild hepatic impairment (bilirubin ≤1 x ULN and AST >1 x ULN, or bilirubin >1.0 to 1.5 x ULN and any AST) on patisiran exposure or TTR reduction compared to patients with normal hepatic function. Onpattro has not been studied in patients with moderate or severe hepatic impairment.
In a clinical study in hATTR amyloidosis patients who had undergone prior liver transplant, steady state pharmacokinetic parameters and TTR reduction were comparable to those observed in patients without a liver transplant.
Population pharmacokinetic and pharmacodynamic analyses indicated no impact of mild or moderate renal impairment (eGFR ≥30 to <90 mL/min/1.73m²) on patisiran exposure or TTR reduction compared to subjects with normal renal function. Onpattro has not been studied in patients with severe renal impairment or end-stage renal disease.
Liver and spleen were the primary target organs of toxicity in both rats and monkeys. Intravenous administration of Onpattro led to increases in serum liver markers (ALT, AST, ALP, and/or total bilirubin) and histopathology findings in the liver (hepatocellular/single cell necrosis, inflammation, pigment deposition, and/or monocytic infiltration) at doses >100 micrograms per kg every 4 weeks and >1.0 mg/kg every 3 weeks in rats and monkeys, respectively. In spleen, lymphoid atrophy/necrosis and histiocytosis in the white pulp was observed in rats and hypocellularity of the red pulp was observed in monkeys.
In general, all findings observed at the end of dosing in the rat and monkey toxicity studies had either a full recovery or were observed with reduced severity at the end of the 60-90 day recovery period, indicating at least partial reversibility.
Onpattro did not exhibit a genotoxic potential in vitro and in vivo and was not carcinogenic in transgenic rasH2 mice.
In rats, while there were parental decreases in serum TTR (≥90%), thyroxine (≥66%) and vitamin A (≥75%) levels using a rat specific surrogate to patisiran, no effects were found on male or female fertility, embryo-foetal development, or pre-/post-natal development.
In rabbits, Onpattro generated spontaneous abortions, reduced embryo-foetal survival, and reduced foetal body weights at maternally toxic doses ≥1 mg/kg (HED 3.2 times the RHD). As patisiran is not pharmacologically active in rabbits, these effects are not due to reductions in TTR, thyroxine or vitamin A.
Intravenous administration of Onpattro had no effect on male reproductive assessments in sexually mature cynomolgus monkeys.
In lactating rats, patisiran was not present in milk, although small amounts of the lipid components DLin-MC3-DMA and PEG2000-C-DMG were present in milk (up to 7% of concomitant maternal plasma concentrations). There were no adverse effects on the pups.
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