Summary Basis of Decision for Onpattro

 

Clinical Pharmacology

Patisiran, the medicinal ingredient in Onpattro, is a double-stranded small interfering ribonucleic acid (siRNA) molecule that specifically targets a genetically conserved sequence in the 3' untranslated region of all mutant and wild-type transthyretin (TTR) messenger ribonucleic acid (mRNA). In patients with hereditary transthyretin amyloidosis (hATTR), mutant and wild-type TTR proteins form amyloid deposits in tissues, leading to progressive polyneuropathy and cardiomyopathy.

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, resulting in reduced serum TTR protein. In animal studies, patisiran-mediated reductions in TTR mRNA resulted in reduced serum TTR protein.

Absorption, distribution, metabolism and elimination properties of the siRNA and the two novel lipid nanoparticle excipients (DLin-MC3-DMA and PEG₂₀₀₀-C-DMG) were determined in pharmacokinetic studies conducted in healthy subjects and patients with hATTR. Patisiran plasma exposure increased proportionally with dose over the dose range evaluated in the clinical studies (0.01 to 0.5 mg/kg). More than 95% of patisiran in the circulation was associated with lipid nanoparticles. At the recommended dose regimen of 0.3 mg/kg administered via intravenous infusion every three weeks, steady state was reached within 24 weeks of initiating treatment.

At the recommended dose regimen, mean ± standard deviation (SD) steady-state volume of distribution (Vss) of patisiran was 0.26 ± 0.20 L/kg, while the mean ± SD Vss of DLin-MC3-DMA and of PEG₂₀₀₀-C-DMG was 0.47 ± 0.24 L/kg and 0.13 ± 0.05 L/kg, respectively.

Less than 1% of the administered dose of siRNA was recovered in the urine. Approximately 5.5% of DLin-MC3-DMA was recovered after 96 hours as its metabolite 4-dimethylaminobutyric acid (DMBA) in urine. The excretion of PEG₂₀₀₀-C-DMG was not measured in humans.

A Phase II study demonstrated that the dose of 0.3 mg/kg every third week was the most effective of the doses evaluated at reducing TTR protein. This dose was well tolerated (based on exposure to one or two patisiran doses). In addition, a Phase II open-label extension study utilizing similar endpoints as the pivotal Phase III study (the latter is described in the Clinical Efficacy section) suggested that the selected dosing was effective and had an acceptable safety profile.

The clinical pharmacology data support the use of Onpattro for the recommended indication.

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

Clinical Efficacy

Onpattro was studied in a comprehensive clinical program which comprised six clinical studies, including a randomized, double-blind, placebo-controlled, pivotal Phase III trial, and two supportive long-term extension studies in patients with hATTR with polyneuropathy (hATTR-PN). The patients enrolled were recruited in 19 countries, carried 39 different TTR mutations, and exhibited a range of neuropathy severities, from mild sensory abnormalities to severe motor, sensory, and autonomic abnormalities, requiring two walking sticks to ambulate.

Key efficacy data were derived from the pivotal Phase III trial (the APOLLO study), conducted in 225 patients with hATTR-PN. All patients had a demonstrated TTR mutation. Forty-six percent of the 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). Overall, 56% of the patients in the pivotal trial met the predefined echocardiographic criteria for cardiac involvement at baseline.

Patients were randomized in a 2:1 ratio to receive Onpattro 0.3 mg/kg (148 patients) or placebo (77 patients) via intravenous infusion once every three weeks. Since Onpattro reduces serum levels of TTR, a carrier protein for vitamin A, all patients received daily vitamin A supplementation to prevent possible vitamin A deficiency. All patients were pre-treated with acetaminophen and intravenous corticosteroids and histamine receptor (H1 and H2) blockers at least 60 minutes before each Onpattro infusion, as prophylaxis against infusion-related reactions.

The primary efficacy endpoint of the study was the change from baseline to 18 months in the modified Neurologic Impairment Score +7 (mNIS+7). 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. A higher score indicates a worse outcome.

The key secondary endpoint was the change from baseline to 18 months in the Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) total score, a patient-reported score that assesses a comprehensive set of neuropathy parameters, including autonomic nerve function and activities of daily living.

Treatment with Onpattro resulted in an improvement of 34.0 points in the mNIS+7 score relative to placebo (p<0.001), with a mean improvement from baseline of -6.0 points, compared to a worsening of 28.0 points with placebo treatment at 18 months. The improvement was observed after 9 months of treatment, the first post-baseline assessment in the study. In addition, Onpattro treatment resulted in an improvement of 21.1 points in the Norfolk QoL-DN score relative to placebo (p<0.001), with an improvement from baseline of -6.7 points compared to a worsening of 14.4 points with placebo at 18 months. The improvement was evident after 9 months of therapy.

Other assessments of neuropathy progression included: measurement of motor strength (NIS-Weakness [NIS-W] score); patient-reported ability to perform activities of daily living and social participation such as eating, bathing, dressing, and standing (Rasch-built Overall Disability Scale [R-ODS] score); gait speed (10-meter walk test); nutritional status (modified body mass index [mBMI]); and patient-reported autonomic symptoms such as dizziness, constipation, diarrhea, nausea/vomiting, and incontinence (Composite Autonomic Symptom Score 31 [COMPASS 31]). All of these measures showed highly significant (p<0.001) improvement with Onpattro treatment compared to placebo at 18 months.

In the pivotal study, 56% of patients constituted a cohort with predefined echocardiographic criteria indicative of cardiac involvement (left ventricular wall thickness of 13 mm or more at baseline, with no history of hypertension or aortic valve disease). In this cohort, several cardiac parameters were assessed as exploratory endpoints. Decreases in left ventricle wall thickness and absolute longitudinal strain from baseline were noted with Onpattro treatment relative to the placebo treatment. Also, mean N-terminal pro-B type natriuretic peptide (NT-proBNP) levels decreased in Onpattro-treated patients and increased in placebo-treated patients. A brief description of these results is included in the Onpattro Product Monograph, where they are identified as exploratory in nature.

Overall, data from the pivotal trial demonstrated a consistent and highly significant sustained benefit of Onpattro to a wide range of measures of polyneuropathy progression in patients with hATTR-PN.

Results from the APOLLO study were supported by data from two open-label studies that showed maintenance of efficacy for up to 36 months.

Indication

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

• Onpattro (patisiran) is indicated for the treatment of hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) with polyneuropathy in adults.

Health Canada restricted the proposed indication to refer to the treatment of polyneuropathy in adult patients with hATTR amyloidosis, since the primary and secondary efficacy endpoints evaluated in the pivotal trial were neurological (including neurological quality-of-life endpoints), and patients were enrolled in the trial based on the polyneuropathy symptoms. Accordingly, Health Canada approved the following indication:

• Onpattro (patisiran) is indicated for the treatment of polyneuropathy in adult patients with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis).

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

Clinical Safety

The safety of Onpattro was evaluated in 224 patients with hATTR-PN treated with Onpattro for a median of 2.2 years. Of these patients, 186 patients received Onpattro for at least one year, 137 patients received Onpattro for at least 2 years, and 52 patients received Onpattro for at least 3 years.

In the pivotal APOLLO study (described in the Clinical Efficacy section), higher rates of treatment discontinuation and study withdrawal were observed in the placebo group, compared to the Onpattro-treated patients. This was attributed primarily to disease progression and adverse events likely associated with disease progression. There were 185 (82.2%) patients who completed study treatment, including 137 (92.6%) in the Onpattro group and 48 (62.3%) in the placebo group. Patients who discontinued study treatment could remain in the study and were considered to have completed the study if they completed the visit at 18 months. Overall, 193 (85.8%) patients completed the study, including 138 (93.2%) in the Onpattro group and 55 (71.4%) in the placebo group.

The most frequent adverse events observed with Onpattro treatment were peripheral edema reported with a frequency of 30%, compared to 22% in the placebo group, and infusion-related reactions reported with a frequency of 19% versus 9% in the placebo group. Other adverse events that occurred with a higher frequency in the Onpattro group relative to the placebo group included dyspepsia, muscle spasms, arthralgia, dyspnea, erythema, bronchitis, rhinitis, sinusitis, and vertigo.

Infusion-related reactions are known to be associated with lipid nanoparticle formulations. With the pre-treatment regimen used, infusion-related reactions reported in the APOLLO study were mild or moderate in severity and all resolved without sequelae, although one patient discontinued Onpattro due to an infusion-related reaction of moderate flushing. Most of the reported infusion-related reactions occurred during the first or second infusions of Onpattro. The identified risk of infusion-related reactions is highlighted in the Warnings and Precautions section of the Onpattro Product Monograh, along with the required premedication prior to Onpattro administration.

Rates of serious adverse events were comparable in patients treated with Onpattro and those treated with placebo (36.5% and 40.3%, respectively). There were no serious adverse events reported that occurred with a higher frequency in the Onpattro-treated patients relative to the placebo-treated patients. In the Onpattro group, 33.8% of patients had at least one hospitalization or death during the trial, compared to 39% of the placebo-treated patients. Overall, 4.7% of the Onpattro-treated patients died, compared to 7.8% of the placebo-treated patients.

The safety profile of Onpattro observed in the long-term open-label extension trials was consistent with the safety observations made in the APOLLO study. Important identified potential risks of Onpattro include vitamin A deficiency and severe hypersensitivity, although neither was observed in the clinical development program. All patients received daily vitamin A supplementation during Onpattro treatment. A recommendation for vitamin A supplementation is included in the Onpattro Product Monograph.

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

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