Summary Basis of Decision for Redemplo

Clinical Pharmacology

Plozasiran is an N-acetylgalactosamine (GalNAc) conjugated double-stranded small interfering ribonucleic acid (siRNA) targeted against apolipoprotein C3 (APOC3) mRNA. Through its conjugation to GalNAc, plozasiran undergoes uptake by asialoglycoprotein receptors at the surface of hepatocytes. In hepatocytes, plozasiran selectively causes the degradation of APOC3 mRNA through the RNA interference mechanism, resulting in reduced levels of hepatic and serum APOC3 protein. This in turn enhances the activity of lipoprotein lipase and hepatocyte uptake of triglyceride-rich lipoprotein remnants, leading to decreases in serum triglycerides.

Following subcutaneous administration, plozasiran is quickly absorbed into circulation, with a median time to maximal concentration (T_max) of 4.1 hours. In healthy participants, plozasiran exhibited linear and time-invariant pharmacokinetics within the 10 mg to 100 mg dose range. At the therapeutic dose of 25 mg, a mean peak concentration (C_max) of 110 ng/mL and a mean total exposure (as measured by the area under the concentration-time curve from zero to time infinity [AUC_0-inf]) of 1,080 h*ng/mL were observed.

Plozasiran is plasma protein bound by as much as 78%, distributing mainly to the liver (primary site of action) and the kidneys (primary excretory organ). Distribution to other organs is expected to have no clinical significance, but was observed in non-clinical studies at levels >100-fold lower than in the liver. No dedicated mass balance study was performed; this omission is considered acceptable in the context of the targeted patient population being those with familial chylomicronemia syndrome. Plozasiran, which is primarily metabolized by ribonucleases to shorter oligonucleotides of varying lengths, is not a substrate of cytochrome P450 enzymes or traditional small molecule transporters. No dedicated clinical drug interaction studies were performed.

Population pharmacokinetic and pharmacokinetic-pharmacodynamic models identified body weight and body mass index as significant covariates. Age, sex, ethnic origin, and hepatic or renal insufficiency were not identified as covariates. No dedicated hepatic or renal impairment studies were performed and a reduced number of participants with hepatic or renal impairment were enrolled in the clinical development programme, limiting the adequate assessment of its impact on the pharmacokinetics or pharmacodynamics of plozasiran. However, the risk is considered acceptable in the context of the target population being those with familial chylomicronemia syndrome, and administration to patients with mild hepatic impairment or mild to moderate renal impairment is considered acceptable without changes in dosing.

A dedicated QT/corrected QT Interval (QTc) study using a supratherapeutic dose of 100 mg plozasiran showed no clinically significant changes in QT interval or any electrocardiogram parameters.

Overall, the clinical pharmacology data support the use of Redemplo for the recommended indication.

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

Clinical Efficacy

The clinical efficacy of Redemplo was demonstrated in the single pivotal, multicentre, randomized, double‑blind, placebo‑controlled Phase III Study AROAPOC3-3001. Seventy-five adult patients with genetically confirmed or phenotypical familial chylomicronemia syndrome were randomized to Redemplo 25 mg (26 patients), Redemplo 50 mg (24 patients), or placebo (25 patients), subcutaneously injected every 3 months. The sponsor did not request market authorization for the 50 mg dose. The study included a 12-month randomized treatment period, followed by a 24-month open-label extension period (65 patients). Eligible participants were 18 years of age and older with triglyceride levels of at least 10 mmol/L despite dietary restriction (20 grams of fat per day or less) and evidence of familial chylomicronemia syndrome by known genotypes, evidence of low LPL activity, or phenotypical FCS. For patients with phenotypical familial chylomicronemia syndrome, inclusion criteria required one of more of the following: recurrent episodes of acute pancreatitis not caused by alcohol or cholelithiasis; recurrent hospitalizations for severe abdominal pain without other explainable cause; childhood pancreatitis; or family history of hypertriglyceridemia-induced pancreatitis.

The study population was balanced across treatment groups; the mean age was 46.0 years, 49% of patients were male, and baseline triglyceride levels averaged 28.2 mmol/L. Nearly 90% of patients had a prior history of pancreatitis. In all patients, comorbidities included diabetes (21.3%) and hypertension (33.3%). Genetic confirmation of familial chylomicronemia syndrome was present in 54.7% of patients, most commonly due to lipoprotein lipase (LPL) variants. The other 45.3% of patients met the clinical criteria for familial chylomicronemia syndrome but lacked confirmed known pathogenic genotypes.

The primary efficacy endpoint was the percent change from baseline in fasting triglyceride levels at Month 10. At Month 10, median fasting triglyceride levels were reduced by 80.1% in the Redemplo 25 mg group compared with 17.1% in the placebo group, with a between‑group difference of -58.7% (95% confidence interval [CI]: -89.6, -27.9; p<0.0001).

For the key secondary endpoint of the percent change from baseline in fasting triglyceride levels averaged across months 10 and 12, treatment with Redemplo 25 mg resulted in an average decrease of 77.7% versus (vs.) 2.6% in the placebo group, with a between-group difference of -59.6% (95% CI: -91.6, -27.5; p<0.0001). For the key secondary endpoint of percent change from baseline in fasting APOC3 at Month 10, APOC3 levels decreased by 93.0% following treatment with Redemplo 25 mg compared with 1.3% following treatment with placebo, with a between-group difference of -90.5% (95% CI: -108.3, -72.7); p<0.0001). Finally, for the key secondary endpoint of the incidence of positively adjudicated events of acute pancreatitis during the randomized treatment period, the incidence of acute pancreatitis over 12 months of treatment was numerically lower in patients treated with Redemplo 25 mg compared with patients treated with placebo (7.7% vs. 20.0%, respectively).

Indication

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

Redemplo (plozasiran injection) is indicated as an adjunct to diet to reduce triglyceride levels for adult patients with genetically confirmed or clinically diagnosed familial chylomicronemia syndrome (FCS) for whom standard triglyceride lowering therapies have been inadequate.

Health Canada approved the following indication:

Redemplo (plozasiran injection) is indicated as an adjunct to diet to reduce triglyceride levels for adult patients with familial chylomicronemia syndrome (FCS) for whom standard triglyceride lowering therapies have been inadequate.

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

Clinical Safety

The clinical safety of Redemplo was assessed in the pivotal Phase III Study AROAPOC3-3001 (described in the Clinical Efficacy section), a completed, double-blind, placebo-controlled, 12-month study in 75 patients with familial chylomicronemia syndrome. Supportive longer-term data is provided by an ongoing open-label extension (65 patients) of Study AROAPOC3-3001. Additional supportive safety data was provided by two randomized, double-blind, placebo-controlled Phase IIb studies: Study AROAPOC3-2001 in patients with severe hypertriglyceridemia (226 patients) and Study AROAPOC3-2002 in patients with moderate hypertriglyceridemia and mixed dyslipidemia (353 patients). Long-term safety was further evaluated in the dedicated open-label extension Study AROAPOC3-2003, which enrolled 418 patients from the Phase IIb studies.

In total, 654 patients were included in the clinical program, with 148 patients receiving Redemplo 25 mg during the placebo-controlled phases and 472 patients receiving Redemplo 25 mg in the open-label extension periods. In the pivotal Study AROAPOC3-3001, the median exposure to Redemplo 25 mg was 11.8 months. In the Phase II studies, AROAPOC3-2001, and AROAPOC3-2002, patients received two doses over a 12-week treatment period. In the combined randomized and open-label extension periods, the Redemplo 25 mg group had a median cumulative treatment exposure of 26.2 months; 121 patients (25.7%) had between 25 and 28 months of exposure and 66 patients (14.0%) were treated for more than 31 months.

During the 12-month placebo-controlled period of the pivotal Study AROAPOC3-3001, common adverse drug reactions (occurring 10% or more of patients and occurring >5% more frequently than in the placebo group) in Redemplo-treated patients (vs. placebo-treated patients) included nasopharyngitis (19.2% vs. 12.0%), hyperglycemia (19.2% vs. 8.0%), nausea (15.4% vs. 8.0%), injection site reactions (15.4% vs. 4.0%), and palpitations (11.5% vs. 0%). Less frequent adverse reactions included constipation, abdominal pain, increases in alanine aminotransferase (ALT), procedural pain, dysgeusia, dizziness, headache, pruritus, and urticaria. Discontinuations due to adverse events occurred in 2 patients (7.7%) treated with Redemplo 25 mg and in 0 patients in the placebo group. The reasons for treatment discontinuation were hyperglycemia and urticaria.

In the pivotal Study AROAPOC3-3001, serious adverse events were reported in 5 patients (19.2%; 6 events) in the Redemplo 25 mg group compared with 7 patients (28.0%; 11 events) in the placebo group, with pancreatitis accounting for most events (2 patients [7.7%] in the Redemplo 25 mg group vs.7 patients [28.0%] in the placebo group). Other serious adverse events, which occurred as single cases and were assessed as unrelated to study drug, included overdose, coronary artery disease vascular graft occlusion, ST elevation myocardial infarction in the Redemplo 25 mg group, and coronary artery stenosis prostatitis, anaphylaxis, and large intestinal polyp removal in the placebo group. No deaths occurred in the pivotal study. Within the overall clinical studies, 6 deaths were reported (4 in Study AROAPOC3-2002 and 2 in the open label extension studies), with causes including aortic rupture, pneumonia/empyema with cardiac arrest, suicide, septic shock/multiorgan failure, sudden cardiac death, and cholangiocarcinoma with postoperative sepsis. None were assessed as being related to treatment with Redemplo, although causality could not be definitively excluded in the case of sudden cardiac death.

In the pivotal Study AROAPOC3-3001, laboratory findings included treatment-emergent adverse events (TEAEs) related to hyperglycemia in 23.1% of patients receiving Redemplo 25 mg, 20.8% in those receiving Redemplo 50 mg, and 8.0% of patients receiving placebo. Increased hemoglobin A1C (HbA1c) was the most frequent TEAE by preferred term (11.5% of patients receiving Redemplo 25 mg, 12.5% of patients receiving Redemplo 50 mg, and 0% of patients receiving placebo). Among patients with baseline diabetes, worsening glycemia was reported in 60.0% of patients receiving Redemplo 25 mg and in 75.0% of patients receiving Redemplo 50 mg compared with 11.1% of those in the placebo group. In pre-diabetic patients, new-onset diabetes occurred in 33.3% of patients in the Redemplo 25 mg group compared with none in the placebo group.

At Month 12 in the pivotal Study AROAPOC3-3001, modest mean increases in aspartate aminotransferase (AST; +6.1 U/L in the Redemplo 25 mg group vs. +3.9 U/L in the placebo group) and ALT (+11.8 U/L in the Redemplo 25 mg group vs. +1.3 U/L in the placebo group) were observed. No cases of ALT or AST elevations 3 times the upper limit of normal or higher were reported in this study. In contrast, in Study AROAPOC3-2001, elevations 3 times the upper limit of normal or higher occurred in 3 patients (5.45%) treated with Redemplo 25 mg and in 1 patient (1.6%) receiving placebo. These enzyme elevations were not accompanied by bilirubin increases. No cases met Hy’s Law criteria, and no cholestatic drug induced liver injury was identified.

In the pivotal Study AROAPOC3-3001, increases in low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (ApoB) were observed during treatment with Redemplo 25 mg. Levels of LDL‑C rose from 0.62 mmol/L at baseline to 1.27 mmol/L at Month 12 in patients treated with Redemplo 25 mg, compared with an increase from 0.73 mmol/L to 0.93 mmol/L in patients in the placebo group. The mean percent change from baseline to Month 12 in LDL-C was an increase of 136.9% in the Redemplo 25 mg group and 20.5% in the placebo group. A larger proportion of Redemplo‑treated patients shifted post-baseline to a higher LDL‑C category, with 46.0% moving upward compared to 16.0% in the placebo group. Despite these shifts, mean LDL‑C values at Month 12 remained less than 1.40 mmol/L across treatment groups (1.27 mmol/L in the Redemplo 25 mg group vs. 0.93 mmol/L in the placebo group). However, in the phenotypical familial chylomicronemia syndrome subgroup treated with Redemplo 25 mg, LDL‑C values exceeded 1.40 mmol/L, reaching 1.53 mmol/L at Month 10 and 1.69 mmol/L at Month 12.

Levels of ApoB also increased following treatment with Redemplo; the mean percent change from baseline to Month 12 was an increase of 34.0% in the Redemplo 25 mg group and 10.4% in the placebo group. The proportion of patients exceeding the ApoB threshold of 130 mg/dL at any time post-baseline was 34.6% in the Redemplo 25 mg group and 24.0% in the placebo group.

Eight cardiac events were reported in 6 patients. Four events (acute myocardial infarction, left bundle branch block, coronary artery disease, and coronary artery stenosis) could have met adjudicated major adverse cardiovascular events criteria but were assessed as not related to study drug. Palpitations was the only cardiac event considered possibly related to treatment, occurring in 3 patients (11.5%) in the Redemplo 25 mg group. All other cardiac events occurred once each.

No new safety signals were observed in the supportive Phase IIb and extension studies and were consistent with what was seen in the pivotal study.

Overall, the benefit-harm-uncertainty profile is favourable when used under the conditions of use recommended in the approved Product Monograph for Redemplo. Appropriate warnings and precautions are in place in the approved Product Monograph for Redemplo to address the identified safety concerns.

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

Plozasiran reduced hepatic apolipoprotein C-III (APOC3) messenger ribonucleic acid (mRNA) levels dose-dependently, which correlated with reduced serum APOC3 protein and significant serum lipids in TgAPOC3 mice and in dyslipidemic rhesus monkeys. No plozasiran-related effects on QT interval or the central nervous, respiratory, or cardiovascular systems were observed at doses of up to 300 mg/kg.

Plozasiran was well tolerated in both rats and cynomolgus monkeys following the subcutaneous administration of up to 300 mg/kg. In rats administered up to 120 mg/kg once every 4 weeks for 24 weeks, plozasiran induced microscopic findings observed in the liver, spleen, kidneys, mandibular and mesenteric lymph nodes, and injection site. Hepatic findings of oval cell hyperplasia, individual hepatocyte necrosis, Kupffer cell pigment, karyocytomegaly/multinucleated hepatocytes, and foci of eosinophilic cellular alteration corresponding with decreased liver organ weights and higher alkaline phosphatase activity in males administered 30 mg/kg and in females administered 120 mg/kg were considered adverse. Therefore, in rats, the dose level of 15 mg/kg in males (7 times the maximum recommended human dose [MRHD]) and 30 mg/kg in females (14 times the MRHD) is considered the no-observed-adverse-effect level (NOAEL). In monkeys administered up to 180 mg/kg once every 4 weeks for 37 weeks (10 doses), findings were less prevalent than those observed in rats. Thus, 180 mg/kg (163 times the MRHD) is considered the NOAEL.

In vitro and in vivo studies showed that plozasiran was not cytotoxic nor mutagenic. In addition, a 26-week carcinogenicity study in transgenic mice demonstrated that plozasiran was not oncogenic at doses of up to 120 mg/kg. A 105-week carcinogenicity study in Sprague-Dawley rats showed that plozasiran, administered once every other month, was considered not oncogenic in males at up to 25 mg/kg/dose and in females administered 40 mg/kg/dose. Furthermore, plozasiran was shown to be teratogenic in rats when administered at 15 mg/kg or more daily during the period of organogenesis. As a risk mitigation measure, the Warnings and Precautions section of the Product Monograph for Redemplo highlights the need to discontinue Redemplo when pregnancy is recognized. Plozasiran was well tolerated in pregnant rabbits, with no adverse findings at doses of up to 180 mg/kg/day. In juvenile rats, plozasiran was well tolerated at doses of up to 120 mg/kg/week for 4 weeks beginning on postnatal Day 4. Plozasiran had no effects in the parental (F0) generation (with a maternal NOAEL of 80 mg/kg; 31 times the MRHD based on body surface area); however, an increase in the number of stillborn pups was observed. In addition, plozasiran affected the pups’ body weights at the maternal doses of 24 mg/kg or higher (9 times the MRHD based on body surface area), but had no effect on reflex or physical development at any dose level. Thus, the preweaning NOAEL for plozasiran was determined to be 8 mg/kg. During the postweaning phase, no adverse effects were observed in the first filial (F1) generation in both sexes at any dose level (with a postweaning NOAEL of 80 mg/kg).

Finally, in vitro studies demonstrated there is little or no potential for induction of the innate immune system (complement activation), mitochondrial toxicity/cytotoxicity, or platelet aggregation associated with plozasiran exposure at concentrations which far exceed the blood concentrations anticipated at the doses that are to be used clinically.

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

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

The quality (chemistry and manufacturing) information submitted for Redemplo has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development and supporting studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation (if any) made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months is acceptable when the drug product is stored between 2 ºC to 8 ºC, with an in-use period of 30 days when stored between 20 ºC to 25 ºC.

The proposed drug-related impurity limits are considered adequately qualified (e.g., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] limits and/or qualified from toxicological studies, as needed).

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

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

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations.

None of the excipients used in the formulation of Redemplo is of human or animal origin.