Summary Basis of Decision for Wainua

As outlined in the What steps led to the approval of Wainua? section, the clinical review of the New Drug Submission for Wainua was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada .

Clinical Pharmacology

Eplontersen, the medicinal ingredient in Wainua, is a 20-mer antisense oligonucleotide (ASO) that specifically targets variant and wild-type transthyretin (TTR) messenger ribonucleic acid (mRNA). It is identical in sequence to inotersen (Tegsedi), approved for the treatment of hereditary transthyretin-mediated amyloidosis (hATTR) in adults. However, eplontersen has a mixed phosphorothiate/phosphodiester backbone and an additional three N-acetylgalactosamine (GalNAc) residue conjugate. The incorporation of a mixed backbone of phosphorothioate and phosphodiester internucleotide linkages reduces nonspecific protein binding, while the addition of a GalNAc3 complex facilitates targeted delivery to hepatocytes. Together, these modifications are designed to improve tolerability and increase potency. Eplontersen is rapidly distributed to the liver (the primary source of TTR), where it binds to and degrades TTR mRNA thereby inhibiting TTR protein synthesis with the goal of reducing amyloid deposition.

The pharmacokinetics (PK) of eplontersen were determined in two Phase I clinical studies in healthy volunteers as well as in the pivotal Phase III NEURO-TTRansform (ION-682884-CS3) study in patients with hATTR amyloidosis. Eplontersen PK profiles and exposures were similar in healthy subjects and patients. A comprehensive understanding of eplontersen pharmacokinetics is derived from a combination of non-clinical, clinical, and population PK studies.

Following subcutaneous injection, eplontersen is rapidly absorbed, with a time to maximum plasma concentration (T_max) of approximately 2 hours post dose. The mean maximum concentration (C_max) and area under the concentration-time curve (AUC) were slightly greater than dose-proportional across the range of doses tested (45 mg to 120 mg).

Eplontersen undergoes an initial rapid distribution phase (mean residence time from 0 to 48 h [MRT_0-48h] of 2 to 7 hours), distributing mainly to the liver and kidney cortex, as demonstrated by non-clinical studies. Tissue levels of eplontersen were not studied in humans. Plasma protein binding was approximated to be greater than 98%, and the apparent volume of distribution in humans was estimated at 12.2 L for the central compartment and 11,100 L for the peripheral compartment.

Eplontersen has an apparent terminal elimination half-life of 3 to 4 weeks. It undergoes rapid hydrolysis of the GalNAc conjugate in the liver, immediately upon tissue uptake, followed by a slower metabolism of the unconjugated oligonucleotide by endo-and exonucleases. Oligonucleotide metabolites are then excreted in urine. There were no oligonucleotide metabolites detected in human plasma and only 0.1% of oligonucleotides in urine were intact eplontersen, while the majority were shortmers and linker metabolites. Eplontersen was not a substrate of and did not inhibit any of the major cytochrome P450 enzymes or transporters.

There was no increase in C_max or AUC with repeated dosing every four weeks. There was, however, an increase in trough concentration (C_trough) levels, reflective of tissue accumulation. The time to steady-state was estimated by population PK analysis to be approximately 169 days. Population PK analyses showed eplontersen plasma PK exposure is not significantly affected by body weight, sex, age, race, or Val30Met mutation (valine at amino acid 30 to methionine, the most common mutation of the TTR gene) status.

Eplontersen treatment resulted in dose-dependent reductions in serum TTR levels. In the pivotal Phase III study, eplontersen treatment (45 mg every four weeks) resulted in an 82% reduction in serum TTR levels in hATTR patients at 35 weeks that was relatively consistent across all subgroups examined (Val30Met TTR mutation status, age, sex, race, region, previous treatment, disease stage, familial amyloid cardiomyopathy, and cardiomyopathy). Although change from baseline in serum TTR levels was listed as a co-primary efficacy endpoint in the pivotal Phase III clinical study, it is considered a pharmacodynamic endpoint, indicative of target engagement and confirmatory of the proposed mechanism of action.

The clinical pharmacology data support the use of Wainua for the recommended indication. For further details, please refer to the Wainua Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Wainua for the treatment of the polyneuropathy in patients with stage 1 and stage 2 hATTR amyloidosis was supported by the ongoing, open-label, Phase III NEURO-TTRansform study with a concurrent reference arm (inotersen) and an external placebo group from the NEURO-TTR study. The NEURO-TTR study was a randomized, double-blind, placebo-controlled, multicentre clinical study conducted in adult patients with hATTR with polyneuropathy. The pivotal NEURO-TTRansform study included 168 patients randomized to one of two arms: 45 mg eplontersen (Wainua; number of patients [n] = 144) administered subcutaneously every 4 weeks (Q4W) until Week 81 or 300 mg inotersen (n = 24) administered subcutaneously once per week (Q1W) until week 34, followed by eplontersen until Week 81. All efficacy endpoints were measured against the 60 patients included in the external placebo group. Efficacy was only assessed at 35 weeks.

In general, patients were representative of the overall population of patients with the disease, and demographic characteristics, including baseline disability, were relatively comparable across groups. Key imbalances in the characteristics of the Wainua and external placebo groups were accounted for during the analysis. Of the patients who received Wainua, the median patient age at baseline was 51.5 years and 69% of patients were male. Seventy eight percent (78%) of patients were Caucasian, 15% were Asian, 4% were Black, and 2% were reported as other. Patients were from North America (15%), Europe (38%), and South America/Australia/New Zealand/Asia (48%). Twenty-two different TTR variants were represented in total.

A planned interim analysis was conducted after all patients completed Week 35 assessments. The primary efficacy endpoint assessed at the time of the interim analysis was the change from baseline to Week 35 in the modified Neuropathy Impairment Scale+7 (mNIS+7) composite score. The mNIS+7 is an objective assessment of neuropathy and comprises the NIS and Modified +7 composite scores. In the validated version of the mNIS+7 used in the study, the NIS objectively measures deficits in cranial nerve function, muscle strength, reflexes, and sensations, and the Modified +7 composite score assesses heart rate response to deep breathing, quantitative sensory testing (touch-pressure and heat-pain), and peripheral nerve electrophysiology. The mNIS+7 score had a range of -22.3 to 346.3 points, with higher scores representing a greater severity of disease.

The clinical meaningfulness of effects on the mNIS+7 was assessed by the key secondary endpoint: the change from baseline to Week 35 in the Norfolk Quality of Life – Diabetic Neuropathy (QoL-DN) questionnaire total score. The Norfolk QoL-DN scale is a patient-reported assessment that evaluates the subjective experience of neuropathy in the following domains: physical functioning/large fiber neuropathy, activities of daily living, symptoms, small fiber neuropathy, and autonomic neuropathy. The version of the Norfolk QoL-DN used in the study had a range from -4 to 136 points, with higher scores representing greater impairment.

Overall, the primary efficacy endpoint was met. In hATTR patients, at the recommended dose, Wainua slowed or halted progression of polyneuropathy disability and improved quality of life. A larger percentage of patients receiving Wainua showed an improvement (negative change from baseline) in the mNIS+7 total score at Week 35 than in the external placebo group (p <0.001). At Week 35, mNIS+7 scores in placebo-treated subjects declined by 9 points, consistent with ongoing progression of polyneuropathy disability, while Wainua-treated subjects remained stable. These differences were statistically significant and clinically meaningful.

With respect to the key secondary endpoint, Wainua was superior to placebo with statistically significant results in quality of life, as assessed by the Norfolk QoL-DN total score. At Week 35, there was a greater mean reduction in the change in Norfolk QoL-DN, with Wainua-treated patients improving by 3.1 points, compared to a decline of 8.7 points in the external placebo group (p <0.001). However, the subjective nature of the Norfolk QoL-DN, in the context of an open-label study, may have increased the risk of bias. Efficacy findings did not differ significantly across subgroups (Val30Met mutation, sex, age, race, region, previous treatment, disease stage, familial amyloid cardiomyopathy, and cardiomyopathy). Longer-term efficacy data was not available at the time of review.

The formulation and presentation of the drug product used in the clinical studies differ from those of the proposed commercial product. Therefore, the sponsor provided the results of Study ION-682884-CS21, a pivotal bridging study comparing the bioavailability of the two formulations. The study used a three-sequence, three-period cross-over design, in which healthy adult subjects were administered single abdominal subcutaneous doses of 45 mg of the clinical study and commercial products. The results of the study met the Health Canada standard for bioequivalence between the clinical study and proposed commercial formulations.

Study ION-682884-CS21 successfully bridges the proposed commercial product to the formulation that was used in the pivotal clinical safety and efficacy studies.

Indication

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

Wainua (eplontersen injection) is indicated for the treatment of adult patients with polyneuropathy associated with hereditary transthyretin-mediated amyloidosis (ATTRv).

Health Canada revised the proposed indication to specify stage 1 and stage 2 polyneuropathy in adult patients with hATTR as no patients with stage 3 hATTR were included in the clinical studies. Accordingly, Health Canada approved the following indication:

Wainua (eplontersen injection) is indicated for the treatment of polyneuropathy associated with stage 1 or stage 2 hereditary transthyretin-mediated amyloidosis (hATTR) in adults.

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

Clinical Safety

The clinical safety of Wainua was primarily evaluated using data from the pivotal Phase III NEURO-TTRansform clinical study and the open-label extension trial (Study ION-682884-CS13) and, to a lesser extent, by three Phase I studies (ION-682884-CS1, -CS20, and -CS21) in healthy volunteers. At the time of data cutoff, including the 120-Day Safety Update, 137 patients completed 12 months or more of Wainua treatment, with a mean duration of exposure of 500 days and a median of 11 to 20 doses. Twenty additional participants received at least five doses of Wainua, following the switch from inotersen, at Week 37. Limited data was available to address the longer-term safety of Wainua, but will be available upon study completion.

The overall safety profile of Wainua is considered favourable. The most common treatment-emergent adverse events (TEAEs) (frequency of 5% or more and a difference in incidence of 3% or more compared to the external placebo) included vitamin A deficiency (11.1% versus [vs.] 0%), vomiting (9% vs. 5%), injection site reactions (5.6% vs. 0%), proteinuria (9.7% vs. 3.3%), blurred vision (5.6% vs. 1.7%), and cataract (5.6% vs. 1.7%). All of the most common TEAEs occurred more frequently in females than males. In addition, some TEAEs, reported as less common in the overall population, were common in females. These included anemia (11.4%), atrioventricular (AV) block (9.1%), peripheral edema (13.6%), myalgia (9.1%), syncope (6.8%), rash (9.1%), hypotension (11.4%), alopecia (6.8%), and renal impairment (11.4%). Most TEAEs were mild or moderate in severity. The incidence of patients with severe TEAEs was lower in the Wainua group (9.7%), compared to the external placebo (23.3%), historical inotersen (27.7%), and concurrent inotersen (12.5%) groups. There were no TEAEs reported at a higher frequency in the Wainua group than in the historic inotersen group. Overall, TEAEs did not increase in occurrence with increasing duration of Wainua treatment. Serious TEAEs were experienced by a lower proportion of patients treated with Wainua (18.1%) than patients in the external placebo group (21.7%) or in the historical inotersen (32.1%) group. This included serious events of urinary tract infection, nausea, vomiting, renal impairment, AV block, and syncope, none of which were considered related to the study treatment. The incidence of discontinuations due to TEAEs was low in the Wainua-treated group (3.5 %) and comparable to the external placebo group (3.3 %). There were three deaths (cerebral hemorrhage, cardiac arrhythmia, cardiac arrest) but none were considered related to the study drug.

A subgroup analysis found the safety of Wainua did not vary, overall, by age, sex, region, polyneuropathy disability (PND) score at baseline, Val30Met TTR genotype, previous treatment with Vyndaqel (tafamidis) or diflunisal, disease stage, familial amyloid cardiomyopathy clinical diagnosis, cardiomyopathy subgroup, or estimated glomerular filtration rate (eGFR) at baseline. However, the study was not sufficiently powered for accurate subgroup analyses. In addition to observed differences in the frequency of some TEAEs in females, those patients 75 years of age and older had a higher overall incidence of most of the TEAEs, as compared to those 65 to 74 years of age and had a higher incidence of severe AEs than those in the external placebo group (37.5% vs. 22.2%).

One important identified potential risk of treatment with Wainua is vitamin A deficiency as TTR functions as a key transporter for retinol. Reductions in TTR are associated with reductions in serum levels of vitamin A. Wainua decreased vitamin A levels below the lower limit of normal in 96% of Wainua-treated patients, with a median percent reduction of 71% through Week 37. Vitamin A deficiency can lead to ophthalmological, dermatological, and immune impairment. Vitamin A also plays a critical role in reproduction and development, having potential implications for pregnant and breast-feeding mothers. To address this concern, a recommendation that patients taking Wainua also take the recommended daily allowance of vitamin A was included in the Wainua Product Monograph.

Ocular events are characteristic of both the underlying condition and vitamin A deficiency. The incidence of total events for ocular AEs (including cataract and blurred vision) potentially related to vitamin A deficiency was 28.5% in the Wainua group, 20.0% in the external placebo group, 20.5% in historical inotersen group, and 16.7% in the concurrent inotersen group. There were no reports of night blindness.

In hATTR patients, the incidence of treatment-emergent anti-drug antibody (ADA) during the interim 35‑week treatment period was 36.8% in the Wainua group. The patients who were ADA positive had higher C_trough that continued to rise over time, up to 10‑fold higher than that observed in ADA-negative patients. Study drug-related TEAEs were reported in a higher proportion of ADA-positive patients (47% vs. 25%). Furthermore, as C_trough is reflective of tissue accumulation, there is some uncertainty regarding the longer-term effect of Wainua on hepatic safety, in ADA-positive patients.

Although there was no dedicated thorough QT study conducted with Wainua, single doses up to 2.7-times the recommended dose had no effect on the QTc interval in healthy subjects. Overall, there is no sign of increased cardiac risk with Wainua, however, there were seven TEAEs of AV block in the Wainua-treated group, including three that were considered serious. A potential role for Wainua has not been ruled out.

Thrombocytopenia and glomerulonephritis, both life-threatening AEs associated with inotersen, were not identified as risk factors with Wainua.

A Human Factors Evaluation and Usability Engineering summary report showed the autoinjector to be safe and effective for the intended use (subcutaneous injection, at home, once monthly, by patient or caregiver).

Based on the data provided to Health Canada, Wainua is effective for the treatment of polyneuropathy associated with stage 1 and stage 2 hATTR in adult patients and has an acceptable safety profile. Due to the limited number of patients exposed to Wainua in the clinical studies, the occurrence and frequency of uncommon AEs remains uncertain. Outstanding uncertainties including longer-term safety, AV block causality, immunogenicity, and missing information in special populations (moderate to severe hepatic impairment, prior liver transplant, severe renal impairment or end-stage renal disease, pregnant or lactating women, stage 3 hATTR patients) have all been addressed through labelling and ongoing pharmacovigilance activities.

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

As outlined in the What steps led to the approval of Wainua? section, the review of the non-clinical component of the New Drug Submission for Wainua was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The nucleotide sequence and mechanism of action of eplontersen, the medicinal ingredient in Wainua, is identical to that of inotersen, the medicinal ingredient in Tegsedi. Eplontersen is structurally different however, as it has a mixed phosphorothioate/phosphodiester backbone to reduce non-specific effects, and an additional 3-N-acetylgalactosamine (3-GalNAc) moiety at its 5’-end, for specific liver targeting.

No safety signal was found in the non-clinical data submitted. The structural modifications of eplontersen render it 50‑fold more potent than inotersen in inhibiting transthyretin (TTR) messenger ribonucleic acid (mRNA) levels in human primary hepatocytes, and 28- and 15‑fold more potent than inotersen, in reducing hepatic TTR mRNA and plasma TTR, respectively in human TTR (hTTR) transgenic mice.

In pharmacokinetic studies in the rat, eplontersen was rapidly absorbed following a single 10 mg/kg subcutaneous (SC) dose, with a time to maximum plasma concentration (T_max) of approximately 1 h, followed by an initial rapid and extensive elimination phase, and subsequently a slower elimination phase with terminal half-life of 4.47 days. Elimination from tissues was relatively slow, with elimination half-lives of 16.5 and 2.85 days in the kidneys and liver, respectively.

Following an SC injection of radiolabelled [3H] antisense oligonucleotide (ASO)‑eplontersen in rats ([3H] on the ASO), radioactivity was rapidly cleared from the blood and plasma (half-life [T_1/2] of 1.1 h), due to rapid uptake into the liver and kidneys with maximal tissue concentration observed at 8 h and 48 h post-dose, respectively. Radioactivity decreased more rapidly in liver (mean residence time from 0 to infinity [MRT_0-∞] of 126 h) than in the kidneys (MRT_0-∞ of 848 h). Excretion was slow, occurring primarily via urine. Eplontersen and unconjugated-eplontersen were the major component peaks at the 2 h time point in blood and plasma, and in liver and kidneys at 24 h post-dose. Shortmer metabolites were major components in urine, but minor components in blood, plasma, liver and kidneys. The metabolism of eplontersen to chain shortened oligonucleotides is consistent with nuclease-mediated metabolism. A difference in the composition of metabolites was observed in female and male urine, although this appeared to be without meaningful consequences on rats. In addition, high levels of eplontersen and non-conjugated eplontersen were still detected in kidneys, despite the presence of the GalNAc-3 linker for liver targeting.

The most abundant metabolites detected in the urine of all four species tested (mouse, rat, monkey, and human) were 3’- and 5’-exonuclease cleaved shortmers, followed by lower amounts of eplontersen without 1, 2, or 3, GalNAc sugar, 3’ deletion, as well as trace amounts of unconjugated eplontersen 3’-deletions in rat (n-8 to n-18) and human (n-11 to n-15).

No treatment-related effect on the central nervous system, cardiovascular system (heart rate, blood pressure, electrocardiogram, body temperature) or respiratory rate were observed in male cynomolgus monkeys administered single SC doses of 6 mg/kg or 24 mg/kg eplontersen. The doses tested were expected to provide approximately 14- and 56‑fold margins respectively, based on the predictive 90% effective dose (ED90) in human.

No effect of eplontersen was observed on the inhibition of the cardiac (human Ether-à-go-go-related gene [hERG]) potassium channels in stably transfected human embryonic kidney 293 (HEK-293) cells.

Eplontersen distributed mostly in the plasma compartment and was highly bound to plasma proteins (≥96.80%), in human, monkey and mouse. No drug-drug interaction was detected in vitro between eplontersen, and other highly plasma protein bound drugs, such as warfarin and ibuprofen.

The chronic toxicology assessment of eplontersen included two mouse studies (13 and 26 weeks in duration) and two monkey studies (13 weeks and 9 months in duration). In addition, an 18-week maximum tolerated dose study was conducted in mice, after the 13-week and 26-week studies were completed, in support of dose selection for a 6-month carcinogenicity study in TgRasH2 mice. The toxicological presentation was comparable between the two species.

In the monkey studies, one female from the high dose group (24 mg/kg/week) in the 13-week study presented with thrombocytopenia in the last few weeks of the treatment period. No other treatment-related effects were noted during the in-life period for any of the repeat‑dose studies in mice or monkeys.

Based on exposure, the 13-week monkey study provides a safety margin of 72.9 times the exposure at the maximum recommended human dose (MRHD), while the 9-month monkey study provides a safety margin of 123 times the exposure at the MRHD.

There was no evidence of genotoxicity identified in the three studies conducted with eplontersen.

There was no carcinogenic potential identified for eplontersen following administration to TgRasH2 mice for 26 weeks. On the basis of similarities between the toxicity and toxicokinetic profiles of inotersen and eplontersen and the fact that the carcinogenicity profile of inotersen has already been characterized, a 2-year carcinogenicity study in rats was not performed.

The administration of eplontersen to mice had no impact on fertility or embryo-fetal development. The potential carry over of eplontersen in breast milk wasn’t assessed, but was estimated based on studies performed with inotersen. Although the potential quantities of eplontersen carried over in breast milk are estimated to be very low, as no studies have been performed on eplontersen, a statement has been included in the Wainua Product Monograph indicating that a risk to the breastfed child cannot be excluded.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Wainua Product Monograph. In view of the intended use of Wainua, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product. For more information, refer to the Wainua Product Monograph, approved by Health Canada and available through the Drug Product Database.

The quality (chemistry and manufacturing) information submitted for Wainua 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 to 8 °C, protected from light. When in use, each single-use autoinjector may be stored unrefrigerated in the original container for up to 6 weeks, with protection from light.

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 Wainua is of human or animal origin.