Summary Basis of Decision (SBD) for Amvuttra

Clinical Pharmacology

The medicinal ingredient in Amvuttra, vutrisiran, is a ribonucleic acid interference (RNAi) therapeutic. Through the natural process of RNAi, vutrisiran causes the catalytic degradation of transthyretin messenger ribonucleic acid (TTR mRNA) in the liver, resulting in a reduction of serum TTR protein. Vutrisiran is a conjugate of a chemically modified double-stranded small-interfering ribonucleic acid (siRNA) and a trivalent N-acetylgalactosamine (GalNAc) ligand. The siRNA molecule specifically targets variant and wild-type TTR mRNA, whereas the GalNAc ligand enables delivery of the siRNA to the liver. The physicochemical characteristics of the GalNAc-siRNA conjugate lead to its enhanced metabolic stability and prolonged liver residence time, allowing for less frequent dosing.

The pharmacokinetics of vutrisiran after subcutaneous administration was characterized in healthy volunteers in a Phase I study evaluating single ascending doses (from 5 to 300 mg) and in patients with hereditary transthyretin-mediated amyloidosis (hATTR) who received 25 mg of vutrisiran once every 3 months in the pivotal Phase III study HELIOS-A (described in the Clinical Efficacy section).

Vutrisiran exhibited similar pharmacokinetic profiles and exposures in healthy subjects and patients with hATTR with polyneuropathy.

A dose-proportional increase in the maximum plasma concentration C_max of vutrisiran and a slightly greater than dose-proportional increase in the area under the concentration-time curve (AUC) were observed after single subcutaneous doses across the dose range evaluated (5 to 300 mg).

Vutrisiran was rapidly absorbed after subcutaneous administration, with a median time to C_max (t_max) of 3 hours (range: 2 to 6.5 hours). Plasma protein binding of vutrisiran was approximately 80%, and the apparent central compartment volume of distribution of vutrisiran in humans was estimated to be 10.07 L. Based on non-clinical data, vutrisiran is expected to be distributed predominantly to the liver in humans, and the plasma exposure was predicted to be predominantly driven by liver uptake. A dedicated human study to characterize the absorption, distribution, metabolism, and excretion of vutrisiran was not conducted due to the risks associated with prolonged exposure to radioactivity in the liver. Based on pharmacokinetic and pharmacodynamic modelling, the half-life of vutrisiran in human liver was estimated to be approximately 55 days.

Vutrisiran was shown to be metabolized via nuclease-mediated hydrolysis in animals. In humans, no major circulating metabolites were observed. Vutrisiran was not a substrate of and did not inhibit any of the major cytochrome P450 enzymes. No plasma accumulation of vutrisiran was detected following repeat daily dosing, as expected based on the population estimate for the mean elimination half-life of 6.29 hours in humans.

Limited information is available regarding the potential impact of intrinsic and extrinsic factors on the pharmacokinetics of vutrisiran. Small numbers of patients with mild hepatic impairment and patients with mild or moderate renal impairment were included in the clinical studies. Vutrisiran has not been studied in patients with severe renal impairment or end-stage renal disease, in patients with moderate or severe hepatic impairment, or in patients who have undergone liver transplantation. A population pharmacokinetic evaluation concluded that there was no impact of mild hepatic impairment and mild or moderate renal impairment on the exposure to vutrisiran or the reduction in serum TTR levels.

The pharmacodynamic effects of 25 mg of vutrisiran administered subcutaneously once every 3 months were evaluated in patients with hATTR in the pivotal Phase III study HELIOS-A. After 9 and 18 months of treatment, mean reductions of serum TTR were 83% and 88%, respectively. The median percent reduction in serum TTR levels in the vutrisiran group was non-inferior to the within-study patisiran reference group through Month 18, with a difference of 5.3% (95% CI: 1.2%, 9.3%).

The submitted clinical pharmacology data support the use of Amvuttra for the specified indication.

For further details, please refer to the Amvuttra Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Amvuttra in the treatment of the polyneuropathy in adults with hATTR was evaluated in a single pivotal, randomized, open-label, Phase III study (HELIOS-A). In total, 164 patients were randomized in a ratio of 3:1 to receive 25 mg of Amvuttra subcutaneously once every 3 months (122 patients) or 0.3 mg/kg patisiran intravenously every 3 weeks (42 patients), as a reference comparator, for 18 months. The placebo group (77 patients) of the APOLLO study, the pivotal Phase III study of patisiran, was used as an external placebo control for the efficacy endpoints.

The patients enrolled were representative of the overall population of patients with hATTR with polyneuropathy. The demographic and disease characteristics of patients in the Amvuttra group were relatively comparable to those of patients in the external placebo group. Baseline values for most efficacy endpoints were indicative of a slightly greater severity of the disease in the external placebo group when compared to the Amvuttra group. A lower percentage of patients with pre-existing evidence of cardiac amyloid involvement was included in HELIOS-A as compared to the APOLLO study.

In the Amvuttra group, the median patient age at baseline was 60 years and 65% of patients were male. Seventy percent of patients were Caucasian, 17% were Asian, 3% were Black, and 9% were reported as “other”. Twenty-two different TTR gene variants were documented. The most common disease-causing TTR gene variant contains a point mutation leading to replacement of valine by methionine at position 30 (V30M) of the mature TTR protein; this variant was present in 44% of patients in the Amvuttra group. Sixty-nine percent of patients in the Amvuttra group had stage 1 polyneuropathy (unimpaired ambulation; mild sensory, motor and autonomic neuropathy in the lower limbs), and 31% had stage 2 polyneuropathy (assistance with ambulation required; moderate impairment of the lower limbs, upper limbs, and trunk).

The primary efficacy endpoint of the HELIOS-A study was the change from baseline in the modified Neurologic Impairment Score +7 (mNIS+7) compared to the external placebo control at Month 9. The mNIS+7 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. The minimum and maximum values are 0 and 304, respectively. Higher scores indicate worsening of neuropathy.

The key secondary endpoint was the change from baseline in total score on the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) questionnaire compared to the external placebo control at Month 9. This questionnaire is a tool to obtain patient-reported assessment of a comprehensive set of neuropathy parameters, including autonomic nerve function and activities of daily living. The total score ranges from -4 to 136, and higher scores indicate worse quality of life.

Efficacy assessments were performed prior to the first dose, at Month 9 (the point of primary efficacy analysis), and at Month 18.

At Month 9, an improvement in neuropathy (a least squares mean change from baseline of -2.2 points in mNIS+7) was observed in the Amvuttra group, whereas the placebo group showed a worsening of neuropathy (a least squares mean change from baseline of 14.8 points in mNIS+7). This represents a statistically significant improvement in neuropathy in patients in the Amvuttra group compared to the external placebo group, with a least squares mean difference in the mNIS+7 change from baseline to Month 9 of ‑17 points (95% confidence interval [CI]: -21.8, -12.2; p<0.0001).

The efficacy of Amvuttra was also supported by the results of the key secondary endpoint. Compared to the external placebo control group, the least squares mean difference in the change from baseline in Norfolk QoL-DN total score at Month 9 was ‑16.2 points (95% CI: -21.7, -10.8; p<0.0001).

Furthermore, for both endpoints, the efficacy of Amvuttra was sustained after 18 months of treatment. Compared to the external placebo group, there were statistically significant improvements of 28.6 and 21.0 points in mNIS+7 and Norfolk QoL-DN questionnaire total score, respectively (p<0.0001). Similarly, statistically significant improvements with Amvuttra compared to the external placebo group were observed for other secondary endpoints, including the 10-meter walk test at Month 9 and Month 18, the modified body mass index at Month 18, and the Rasch-built Overall Disability Scale (R-ODS) score at Month 18.

Indication

The New Drug Submission for Amvuttra was filed by the sponsor with the following proposed indication:

Amvuttra (vutrisiran) is indicated for the treatment of hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) in adults.

Health Canada revised the proposed indication to reflect the patient population in the pivotal Phase III study HELIOS-A. As no patients with polyneuropathy stage 3 were included in the HELIOS-A study, the indication was limited to patients with hATTR with polyneuropathy stage 1 or stage 2. Accordingly, Health Canada approved the following indication:

Amvuttra (vutrisiran injection) is indicated for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis).

For more information, refer to the Amvuttra Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety of Amvuttra was evaluated in 122 patients with hATTR with polyneuropathy in the pivotal Phase III study HELIOS-A (described in the Clinical Efficacy section) and in 60 healthy volunteers in a Phase I study. Of the 122 patients, 119 were exposed to Amvuttra for at least 12 months. The mean duration of treatment was 18.8 months (range: 1.7 to 19.4 months). Taking into consideration that hATTR is a rare and life-threatening disease, the number of subjects exposed to Amvuttra was deemed acceptable for assessing the safety profile of Amvuttra. Nevertheless, the occurrence and frequency of uncommon adverse events remain uncertain.

In healthy volunteers and patients with hATTR with polyneuropathy, Amvuttra was generally safe and well tolerated.

In the HELIOS-A study, the most frequently reported adverse events in the Amvuttra-treated patients were pain in extremities (in 14.8% of patients) and arthralgia (in 10.7% of patients). Mild and transient injection-site reactions were observed in 4.1% of patients treated with Amvuttra. Of note, initially, in the Phase I study and the first half of the HELIOS-A study, Amvuttra was administered from a vial, which was subsequently replaced with a to-be-marketed prefilled syringe with passive needle safety system. One hundred and nineteen patients received at least one dose and 93 patients received three doses via the prefilled syringe presentation. The rate of adverse events was comparable before and after introduction of the prefilled syringe.

Given that patients with hATTR often have cardiac involvement, the assessment of cardiac adverse events is confounded by the underlying disease cardiac manifestations. There were no significant differences in the incidence or nature of cardiac adverse events and cardiac serious adverse events between the Amvuttra group and the external placebo group. Adverse events possibly related to cardiac disorders were reported in 30.3% of patients treated with Amvuttra and 23.8% in patients receiving patisiran. Considering the smaller sample size of the patisiran group (42 patients) and the underlying cardiac involvement, the incidence of these adverse events in the Amvuttra group was not high enough to be considered a cardiovascular safety concern related to the drug. In the Phase I study, Amvuttra had no effect on the corrected QT (QTc) interval in healthy subjects who received doses up to 300 mg. A dedicated thorough QT study was not conducted with Amvuttra.

As Amvuttra is selectively delivered to the liver and exhibits prolonged liver residence time, hepatic adverse events were considered an issue of particular concern in the clinical development program of Amvuttra. All hepatic adverse events in the Amvuttra group were mild or moderate in severity, and none of the events led to discontinuation of study drug. Transient, low-level elevations of alanine aminotransferase and aspartate aminotransferase were noted in some patients treated with Amvuttra.

A decrease in serum levels of vitamin A is a known secondary pharmacodynamic effect of reducing serum TTR levels, because the protein serves as a carrier for vitamin A. In the HELIOS-A study, despite concomitant vitamin A supplementation, serum vitamin A levels were reduced in the Amvuttra-treated patients (mean steady-state peak and trough reductions were 70% and 63%, respectively). While no regular ophthalmological examinations were performed in the study, 28.7% of Amvuttra-treated patients reported adverse events denoted by preferred terms within the System Organ Class Eye disorders (as per the Medical Dictionary for Regulatory Activities, MedDRA).

The clinical consequences of vitamin A deficiency, including ocular symptoms (e.g., night blindness) and the potential teratogenic risk arising from unbalanced vitamin A levels during pregnancy are highlighted in the Warnings and Precautions section of the Amvuttra Product Monograph, along with relevant recommendations. Supplementation at the recommended daily allowance of vitamin A is advised for all patients taking Amvuttra. In addition, it is recommended that women of childbearing potential use effective contraception during treatment with Amvuttra. Furthermore, the use of Amvuttra is not recommended during pregnancy.

The incidence of anti-drug antibodies (ADAs) was low (3.3%) in patients treated with Amvuttra in the HELIOS-A study, and the presence of ADAs did not appear to impact the pharmacokinetics, pharmacodynamics, efficacy or safety of Amvuttra.

Uncertainties remain with respect to the safety of Amvuttra in patients with moderate or severe hepatic impairment, patients who have undergone liver transplantation, patients with severe renal impairment or end-stage renal disease, and pregnant or breastfeeding women. Similarly, the safety of Amvuttra in patients who switch from treatment with another TTR-lowering agent to treatment with Amvuttra has not been assessed, as prior TTR-lowering therapy was an exclusion criterion in the HELIOS-A study. Notably, limited data are available regarding the long-term safety of Amvuttra beyond 18 months of treatment. However, the sponsor is expected to provide Health Canada with the results of the 42-month randomized extension period of the HELIOS-A study upon its completion.

Appropriate warnings and precautions are in place in the approved Amvuttra Product Monograph to address the identified safety concerns.

For more information, refer to the Amvuttra Product Monograph, approved by Health Canada and available through the Drug Product Database.

Vutrisiran, the medicinal ingredient in Amvuttra, is a chemically modified double-stranded small-interfering ribonucleic acid (siRNA) molecule that specifically targets variant and wild-type transthyretin messenger ribonucleic acid (TTR mRNA) and is covalently linked to a ligand containing three N-acetylgalactosamine (GalNAc) residues to enable delivery of the siRNA to hepatocytes. Through a natural process called RNA interference, vutrisiran causes the catalytic degradation of TTR mRNA in the liver, resulting in a reduction of serum TTR protein levels and TTR protein deposits in tissues.

Due to species differences in the targeted TTR mRNA sequence, vutrisiran is pharmacologically active in humans and cynomolgus monkeys but not in rodents or rabbits, limiting applicability of the results from studies in these species.

Non-clinical pharmacodynamic findings confirmed that vutrisiran potently and selectively reduced TTR mRNA expression and had a low potential off-target activity at the recommended therapeutic dose.

In a safety pharmacology study, no effects on cardiovascular function (heart rate, blood pressure, electrocardiogram findings), body temperature, or respiration rate were observed in male telemetered cynomolgus monkeys administered subcutaneously single vutrisiran doses of up to 300 mg/kg.

Non-clinical pharmacokinetic findings demonstrated that after subcutaneous dosing vutrisiran is rapidly and specifically distributed to the liver. Exposures to vutrisiran were similar in males and females. Vutrisiran is eliminated principally by renal and biliary excretion. In vitro and in vivo metabolism studies confirmed that vutrisiran is relatively stable and did not accumulate in the plasma after monthly dosing in rats and cynomolgus monkeys.

Vutrisiran is primarily metabolized by endo- and exonucleases to short nucleotide fragments of varying sizes within the liver. Metabolites were similar across species and sexes. There was no evidence of accumulation of metabolites in the plasma or liver in rats and cynomolgus monkeys.

In repeat-dose toxicity studies in rats and cynomolgus monkeys, non-adverse drug-related histological findings were observed in the liver (in both species), kidneys (in rats), lymph nodes (in monkeys) and injection sites (in both species), reflecting the principal distribution and accumulation of vutrisiran. The no-observed-adverse-effect levels (NOAELs) were the high doses of 150 mg/kg/month and 300 mg/kg/month in rats and monkeys, respectively. Exposures at the NOAELs correspond to more than 1,000- and 3,000-fold the exposures at the maximum recommended human dose of vutrisiran, normalized to the recommended dosing schedule (25 mg administered every 3 months).

Based on genotoxicity and carcinogenicity studies, vutrisiran was not considered genotoxic or carcinogenic.

In reproductive and developmental toxicity studies, no direct effects associated with vutrisiran exposure were reported. However, some adverse effects were observed in the rat embryo-fetal development study, which were likely secondary to maternal toxicity or stress caused by the once-daily dosing schedule during gestation. The impact of vutrisiran-induced reduction in TTR and vitamin A levels could not be fully assessed using this model.

In animals with an anti-drug antibody response, there were no apparent effects of anti-drug antibodies on the pharmacodynamics, toxicokinetics or toxicity of vutrisiran.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Amvuttra Product Monograph. In view of the intended use of Amvuttra, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.

For more information, refer to the Amvuttra Product Monograph, approved by Health Canada and available through the Drug Product Database.

The chemistry and manufacturing information submitted for Amvuttra has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored at 2 ºC to 30 ºC.

Proposed limits of drug-related impurities are considered adequately qualified, i.e., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) limits and/or qualified from toxicological studies.

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations. In addition, no excipients of human or animal origin are used in the formulation of Amvuttra.