Summary Basis of Decision (SBD) for Nduvra

Clinical Pharmacology

Tapinarof is an aryl hydrocarbon receptor (AhR) agonist. The specific mechanisms by which tapinarof exerts its therapeutic action in patients with psoriasis are unknown.

The clinical pharmacology package demonstrated that once daily topical applications of tapinarof 1% cream resulted in minimal systemic absorption of tapinarof and did not lead to systemic accumulation. The plasma concentration of tapinarof was below the quantitation limits of 50 pg/mL in the majority of the samples in the Phase II maximal use study and also in the two pivotal Phase III PSOARING 1 and PSOARING 2 studies described in the Clinical Efficacy section.

Under maximum usage conditions, tapinarof 1% cream did not have a clinically relevant effect on the QT interval and heart rate within the observed tapinarof plasma concentration range of up to approximately 4,600 pg/mL. Effects of tapinarof on heart rate were minimal, with a mean change in heart rate ranging from -2.6 bpm (3 hours post dose) to 5.0 bpm (8 hours post dose).

The key treatment-related safety findings were mild to moderate cases of folliculitis, contact dermatitis, and headache. The majority of these adverse events resolved on their own. These adverse events are adequately captured in the Product Monograph for Nduvra.

The clinical pharmacology data presented in the Phase II maximal use study and in the pivotal Phase III studies were derived from adult populations of mainly white males.

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

Clinical Efficacy

The clinical efficacy of Nduvra for the treatment of plaque psoriasis in adults was primarily derived from PSOARING 1 and PSOARING 2, two identical, Phase III, pivotal, 12-week, double-blind, randomized, vehicle-controlled, multicentre studies. In the intention-to-treat population, 1,025 adult patients with plaque psoriasis from PSOARING 1 (number of patients [n] = 510) and PSOARING 2 (n = 515) were randomized 2:1 to receive Nduvra 1% cream or vehicle cream once daily for 12 weeks.

Other than the restrictions limiting patients with mild and severe psoriasis to 10% each of the randomized population, overall, the demographic and baseline characteristics in the pivotal studies pool were generally balanced between the two treatment arms and reflective of the target population. The median age was 51.0 years and the majority of patients were male (57.5%), Caucasian (84.9%), and not Hispanic (84.6%).

Primary endpoint

In PSOARING 1 and PSOARING 2, the primary endpoint was defined as the proportion of patients who achieved a Physician Global Assessment (PGA) score of clear (0) or almost clear (1) with a minimum 2-grade improvement from baseline at Week 12 (i.e., PGA treatment success). Both studies met their respective primary endpoints as Nduvra was superior to vehicle cream in achieving PGA treatment success at Week 12. The mean PGA treatment success at Week 12 in PSOARING 1 and PSOARING 2 was 35.4% and 40.2% in the Nduvra arm compared to 6.0% and 6.3% in the vehicle cream arm, respectively. The treatment effect of Nduvra compared to vehicle cream in PSOARING 1 and PSOARING 2 was statistically significant (both p<0.0001) with a relative risk (RR) of 5.8 (95% confidence interval [CI]: 2.9, 11.6) and 6.1 (95% CI: 3.3, 11.4), respectively. The sensitivity analyses (observed cases [OC] and treatment failures [TF]) and the supportive analyses (last observation carried forward [LOCF] and per protocol for OC only) were all consistent and corroborated the findings of the primary endpoint (all analyses had p<0.0001).

The subgroups analyses were generally consistent with the primary endpoint findings with the exception of the subgroup related to baseline PGA score, where the difference in PGA treatment success at Week 12 between the Nduvra arm and the vehicle arm was numerically lower in the subgroup of patients with a baseline PGA of 2 (15.4% in PSOARING 1; 17.9% in PSOARING 2) than in patients with a baseline PGA of 3 (35.2% in PSOARING 1; 37.3% in PSOARING 2) or a baseline PGA of 4 (35.1% in PSOARING 1; 31.8% in PSOARING 2).

In the pooled analysis of the integrated summary of efficacy, the difference in PGA treatment success was also numerically lower in the subgroup of patients with baseline mild psoriasis (14.2%; RR 3.5 [95% CI: 0.8, 14.7]) compared to patients with moderate disease (33.8%; RR 6.4 [95% CI: 3.8, 10.6]) or severe disease (31.6%; RR 8.3 [95% CI: 1.2, 55.5]). Notably, the 95% CI of the subgroup of patients with baseline mild psoriasis was inclusive of 1, suggesting that there may not be a difference in efficacy between Nduvra and vehicle cream in this subgroup.

Secondary endpoints

There were four secondary endpoints in PSOARING 1 and PSOARING 2, tested sequentially in the following pre-specified order: the proportion of patients with a 75% or greater improvement in Psoriasis Area Severity Index (PASI) score from baseline at Week 12 (PASI75); the proportion of patients with a PGA score of 0 or 1 at Week 12; the mean change in percent body surface area affected from baseline at Week 12; and the proportion of patients with a 90% or greater improvement in PASI score from baseline to Week 12 (PASI90). The second secondary endpoint of the proportion of patients with a PGA score of 0 or 1 at Week 12 was not considered clinically meaningful as patients with a 2- and 1-grade improvement from baseline would be deemed a treatment success in contrast to the primary endpoint where a minimum 2-grade improvement would be required. Accordingly, this endpoint was not included in the Product Monograph for Nduvra.

All of the secondary endpoints were supportive and consistent with the findings of the primary endpoint. Nduvra demonstrated statistically significant superiority to vehicle cream in all the secondary endpoints measured. In PSOARING 1, the mean PASI75 response rate was 36.1% versus (vs) 10.2% (p<0.0001); the mean PGA success rate (score of 0 or 1) was 37.8% vs 9.9% (p = 0.0001); the mean change from baseline in percent body surface area affected was -3.47 vs -0.37 (p<0.0001); and the mean PASI90 response rate was 18.8% vs 1.6% (p = 0.0005). In PSOARING 2, the mean PASI75 response rate was 47.6% vs 6.9% (p<0.0001); the mean PGA success rate (score of 0 or 1) was 43.6% vs 8.1% (p<0.0001); the mean change from baseline in percent body surface area affected was -4.31 vs 0.28 (p<0.0001); and the mean PASI90 response rate was 20.9% vs 2.5% (p<0.0001).

The sensitivity and supportive analyses (i.e., OC, TF, LOCF, and per protocol for OC) of the secondary endpoints were all consistent and corroborated the secondary endpoint findings.

The subgroup analyses were generally consistent with the secondary endpoint findings with the exception of the subgroup related to baseline PGA score, where it was noted that the background event rate of the vehicle control arm varied greatly (i.e., ranging from 0% to 36.8%). Consequently, there were some inconsistencies in the results between PSOARING 1 and PSOARING 2. For instance, in the subgroup of patients with a baseline PGA of 2, the difference in PASI75 response rate at Week 12 between Nduvra and vehicle cream was -0.6% in PSOARING 1 compared to 38.7% in PSOARING 2. For the same subgroup, the difference between Nduvra and vehicle cream in percent body surface area affected was -0.16 in PSOARING 1 and -2.71 in PSOARING 2.

In the pooled analyses of the integrated summary of efficacy, the differences between Nduvra and vehicle cream for each of the four secondary endpoints were numerically lower in the subgroup of patients with baseline mild psoriasis (PGA of 2) than that observed for the subgroups of patients with moderate disease (PGA of 3) or severe disease (PGA of 4). The 95% CI of the relative risk for the subgroup of patients with baseline PGA of 2 was inclusive of 1 for the secondary endpoints where it was measured (i.e., PASI75, PGA score 0 or 1, and PASI90), suggesting that there may not be a difference in efficacy between Nduvra and vehicle cream in this subgroup. However, the 95% CI of the least squares mean difference for the change in percent body surface area affected did not include 0, indicating a treatment difference between Nduvra and vehicle cream for this particular outcome.

The duration of disease control while off therapy (i.e., remittive effect) was an efficacy parameter measured in a long-term extension study, PSOARING 3, which evaluated the long-term safety of Nduvra in the treatment of plaque psoriasis (see Clinical Safety section). Patients entering PSOARING 3 with a PGA of 0 had Nduvra discontinued and were followed for worsening of disease (i.e., a PGA of 2 or greater). Of the 74 patients entering the PSOARING 3 study with a PGA of 0 following treatment with Nduvra in PSOARING 1 and PSOARING 2, the median time to first worsening of disease was 115 days with a 95% CI ranging from 85 to 162 days. Limitations to the interpretation of the efficacy data from the PSOARING 3 study included its single-arm, open-label design and the lack of statistical testing.

Indication

The New Drug Submission for Nduvra was filed by the sponsor with the following proposed indication, which Health Canada subsequently approved:

Nduvra (tapinarof cream) is indicated for the topical treatment of plaque psoriasis in adults.

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

Clinical Safety

The clinical safety of Nduvra for the treatment of plaque psoriasis in adults was primarily derived from PSOARING 1 and PSOARING 2, described in the Clinical Efficacy section. In the pooled safety population from PSOARING 1 and PSOARING 2 (pivotal studies pool), 683 patients received Nduvra and 342 patients received vehicle cream. The long-term safety of Nduvra in the treatment of plaque psoriasis was assessed via PSOARING 3, a Phase III, 40-week, open-label, single-arm, multicentre, long-term extension study in 763 patients who completed treatment with either Nduvra or vehicle cream in PSOARING 1 or PSOARING 2. The median number of days exposed, the median number of doses administered, and the median treatment compliance were 84.0 days, 83.0 doses, 100%, respectively, in the pooled studies of PSOARING 1 and PSOARING 2 and 224 days, 192 doses, 98.5%, respectively, in PSOARING 3.

The safety profile of Nduvra was similar between PSOARING 1 and PSOARING 2. In the pivotal studies pool, the overall incidences of treatment-emergent adverse events (TEAEs), severe TEAEs, treatment-related adverse events (AEs), adverse events of special interest (AESI), serious adverse events (SAEs), TEAEs leading to study drug discontinuation, and TEAEs leading to study discontinuation were higher in the Nduvra arm compared to the vehicle arm.

In the pivotal studies pool, there was a higher proportion of patients in the Nduvra arm that had at least one TEAE compared to vehicle cream (52.4% vs 24.3%). At least one TEAE was reported in 62.1% of patients in PSOARING 3. In PSOARING 3, the proportion of TEAEs were similar in the patients previously treated with Nduvra or vehicle cream.

The majority of events across the pivotal studies pool and PSOARING 3 were of Grade 1 or 2 severity. In the pivotal studies pool, events of Grade 3 or 4 severity were reported in 3.2% of patients in the Nduvra arm and no patients in the vehicle cream arm. Events of Grade 3 or 4 severity were reported in 3.1% of patients in PSOARING 3.

The most commonly reported TEAE was folliculitis (20.2% in the Nduvra arm vs 0.9% in the vehicle cream arm of the pivotal studies pool; 22.7% in PSOARING 3). Other TEAEs reported with a 2% or greater incidence in the Nduvra arm of the pivotal studies pool, with corresponding incidence in the vehicle arm, by preferred term included nasopharyngitis (5.7% vs 4.4%), contact dermatitis (4.8% vs 0.3%), headaches (3.4% vs 1.2%), upper respiratory tract infection (2.5% vs 3.5%), and pruritus (2.2% vs 0.6%). No new safety signals emerged from the common TEAEs observed in PSOARING 3.

Treatment-related AEs were reported in 24.5% of patients in the Nduvra arm and 2.9% of patients in the vehicle cream arm of the pivotal studies pool, and in 27.5% of patients in PSOARING 3. The most common treatment-related AEs were folliculitis and contact dermatitis. The incidence of SAEs was low (2.3% in the Nduvra arm of the pivotal studies pool; 2.5% in PSOARING 3) and none of the SAEs were related to study drug.

Treatment-emergent adverse events leading to treatment discontinuation were reported in 8.6% of patients in the Nduvra arm and 0.3% of patients in the vehicle cream arm of the pivotal studies pool, and in 5.6% of patients in PSOARING 3. The most commonly reported TEAEs that led to treatment discontinuation were folliculitis (2.8% in the Nduvra arm of the pivotal studies pool; 1.2% in PSOARING 3) and contact dermatitis (2.3% in the Nduvra arm of the pivotal studies pool; 1.7% in PSOARING 3).

Treatment-emergent adverse events leading to study discontinuation were reported in 5.7% of patients in the Nduvra arm and 0.3% of patients in the vehicle cream arm in the pivotal studies pool, and in 5.4% of patients in PSOARING 3. The most common TEAEs leading to study discontinuation were contact dermatitis (1.5% in the Nduvra arm of the pivotal studies pool; 1.0% in PSOARING 3) and folliculitis (1.3% in the Nduvra arm of the pivotal studies pool; 1.2% in PSOARING 3).

There were no deaths in PSOARING 1 and PSOARING 2. There was one death unrelated to study drug treatment in PSOARING 3. The death was secondary to a myocardial infarction in a 73-year-old male patient with a history of cardiovascular disease.

The identified AESI for Nduvra included folliculitis, contact dermatitis, and headaches. Adverse events of special interest were reported in 27.2% of patients in the Nduvra arm compared to 2.6% of patients in the vehicle cream arm of the pivotal studies pool, and in 28.8% patients in PSOARING 3. Most AESIs reported were folliculitis (20.6% in the Nduvra arm and 0.9% in the vehicle cream arm of the pivotal studies pool; 24.0% in PSOARING 3) followed by contact dermatitis (5.4% in the Nduvra arm vs 0.3% in the vehicle cream arm of the pivotal studies pool; 5.9% in PSOARING 3) and the majority of events were considered related to treatment. The majority of AESI reported as headaches were not considered related to study treatment.

No clinically important changes were observed in clinical laboratory evaluations or vital signs in all three Phase III studies.

Both the patients and the investigator conducted overall assessments of the local tolerability of Nduvra using 5-point local tolerability scales. At all time points measured across all three Phase III studies, most patients reported no, slight, or mild irritation when assessing the presence and degree of burning/stinging and itching. Similarly, in most patients, the investigator reported no irritation when assessing the presence and degree of dryness, erythema, and peeling.

Overall, the safety profile of Nduvra was considered acceptable and manageable. Appropriate warnings and precautions are in place in the approved Product Monograph for Nduvra to address the identified safety concerns.

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

Tapinarof, the medicinal ingredient of Nduvra, showed potent activation of the human aryl hydrocarbon receptor (AhR) in vitro, with a half maximal effective concentration (EC₅₀) of 12.5 nM, and increased cytochrome P450 (CYP)1A1 expression, a known effect of AhR activation. Activation of nuclear factor erythroid 2-related factor (NRF2) was also observed.

Tapinarof altered expression of proinflammatory cytokines and skin barrier proteins in vitro. In pre-clinical mouse models of psoriasis, tapinarof resulted in the downregulation of the proinflammatory cytokines, interleukin (IL)-17A and IL-17F, and led to improvement in psoriasiform clinical disease. This was not observed in AhR-deficient mice.

Tapinarof also showed cytotoxic or anti-proliferative effects to many cell types at relatively high concentrations (3 μM or greater, approximately 15,000-fold greater than the maximum observed tapinarof free plasma concentration).

When screened for off-target effects, tapinarof exhibited potent activation (EC₅₀ less than or equal to 1 μM) of the cannabinoid receptor 2 (CB2). Tapinarof also had potent inhibitory activity against monoamine oxidase B (MAO-B), CYP2C9, CYP2D6, and CYP1A2. Based on the highest tapinarof free plasma concentration from clinical studies, the potential for systemic off-target effects is low and any effects would likely be limited to the site of dermal application where the concentration would be highest.

The totality of evidence from safety pharmacology studies did not identify concerns with respect to vital functions (cardiovascular system, central nervous system, and respiratory system). Tapinarof inhibited the human ether-a-go-go-related gene (hERG) channel in vitro with a half-maximal inhibitory concentration (IC₅₀) of approximately 4 μM; however, this is approximately 20,000-fold above the highest observed human tapinarof free plasma concentration.

The cardiovascular no-observed-adverse-effect level (NOAEL) was tapinarof 6% when applied topically in guinea pigs. With tapinarof 6% cream, there were slight changes noted at 4 or 6 hours that were not considered adverse, including changes in heart rate (up to 16%) coupled with slight, non-dose-dependent reductions in PR interval, uncorrected QT interval (6%), and corrected mean QT interval.

The pharmacokinetic programs consisted of absorption, distribution, metabolism, excretion, and drug-drug interaction potential studies in mice, rats, rabbits, and minipigs by subcutaneous, oral, intravenous, and/or dermal routes of administration. In general, no marked sex differences were observed in terms of systemic exposure and no substantial accumulation of tapinarof was observed.

Tapinarof was shown to have high passive membrane permeability (670 nm/s at pH 7.4) in Madin-Darby canine kidney (MDCKII-MDR1) cells in the presence of a P-glycoprotein (P-gp) inhibitor.

Tapinarof was highly protein bound (approximately 99%) in human plasma in vitro. Levels of plasma protein binding were similar in all species tested (rat, mouse, rabbit, minipig, and human). The administration of radiolabeled tapinarof ([14C]-tapinarof) via subcutaneous injection in rats demonstrated that tapinarof is widely distributed throughout all tissues of the body. Compared to whole blood, the majority of tissues were more highly exposed to tapinarof.

In human hepatocytes, the metabolites of tapinarof were the products of oxidation, sulfation, and glucuronidation, alone or in combination, and all metabolites were observed in at least one of the non-clinical species tested.

In rats dosed subcutaneously with [¹⁴C]-tapinarof, biliary secretion into the feces appeared to be the major route of elimination, followed by urinary elimination. Elimination following subcutaneous administration was rapid, with the majority of the dose being recovered by 24 hours post dose. Following a single dermal administration in minipigs, less than 1% of the administered material was recovered in excreta, suggesting minimal absorption.

Tapinarof is not expected to inhibit CYP2B6, CYP2C8, CYP2C9, CYP2C19, CRP2D6 or CYP3A4/5 nor induce CYP1A2, CYP2B6 or CYP3A4 under conditions of clinical use. Tapinarof is not expected to inhibit breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug and toxic compound extrusion (MATE)1, MATE-2K, organic anion transporter (OAT)1, OAT3, OATP1B1, OATP1B3, organic cation transporter (OCT)1, OCT2, or P-gp under conditions of clinical use. Tapinarof is not a substrate for BCRP, OATP1B1, OATP1B3, or P-gp.

Single- and repeat-dose toxicity studies were conducted in rats, mice, rabbits, and minipigs; dermal toxicity studies were performed in all of these species, while subcutaneous repeat-dose studies were conducted in the rat only. Tapinarof was evaluated in repeat-dose dermal toxicity studies of up to 13 weeks in mice and rats, up to 28 days in rabbits, and up to 39 weeks in minipigs; these studies utilized multiple formulations of tapinarof cream. Repeat-dose subcutaneous toxicity studies of up to 26 weeks were also conducted in rats with the purpose of increasing systemic exposure. Additionally, the carcinogenic potential following dermal and systemic administration of tapinarof has been assessed in lifetime dermal mouse and subcutaneous injection rat carcinogenicity studies.

The principal test article-related findings observed in repeat-dose dermal and systemic studies were related to the liver, skin, kidney, and thymus, with associated secondary clinical pathological findings. An NOAEL was identified in each of the non-clinical species administered tapinarof by dermal or subcutaneous routes. For each NOAEL that was determined in the completed toxicity studies with tapinarof, there are modest (dermal studies) to large (subcutaneous studies) safety margins when systemic tapinarof exposure is compared between animals and the observed and anticipated systemic exposure in humans. At the proposed human dose to treat patients with plaque psoriasis (tapinarof 1% cream once daily), the systemic exposure (as measured by the area under the concentration-time curve [AUC]) ratios of tapinarof at the animal NOAELs in dermal and subcutaneous toxicity studies were up to 64-fold in mice, 13-fold in minipigs (in dermal studies, gender averaged), and 410-fold (in rats dosed subcutaneously, gender averaged) above the observed average human AUC from 0 to 24 hours (AUC_0-24) value of 8.0 ng•h/mL detected in the completed clinical studies. It is unlikely that exposure levels greater than those obtained at the subcutaneous injection NOAELs in rats will be achieved from the topical administration of tapinarof cream in humans.

Tapinarof showed no evidence of genotoxicity in a bacterial reverse mutation test, an in vitro mammalian chromosomal aberration assay, an in vitro mouse lymphoma assay, and an in vivo rat bone marrow micronucleus assay.

In a subcutaneous rat study, tapinarof was not carcinogenic in females up to 1 mg/kg/day when treated for up to 83 weeks (8 times the maximum recommended human dose [MRHD] based on AUC comparison). In a dermal mouse study, tapinarof was not carcinogenic following administration of up to 3% cream in mice for 102 weeks in males and 98 weeks in females (44 times the MRHD based on AUC comparison). There was an increased incidence of benign squamous cell papilloma in males treated with tapinarof at concentrations of 1.5% and higher and in females treated with tapinarof 3%, which was considered secondary to tapinarof-related skin irritation. This has been appropriately labelled in the Product Monograph for Nduvra to mitigate any potential risk of benign squamous cell papilloma.

In a 4-week subcutaneous rat study, there were no changes considered related to tapinarof administration in the stage-dependent evaluation of spermatogenesis at subcutaneous doses of up to 30 mg/kg/day. Given that tapinarof is a topical product with limited systemic exposure, the effects of this product on male fertility are considered most likely negligible under conditions of clinical use.

Tapinarof increased the incidence of skeletal variations (incomplete ossification of nasal bones) at the dose of 34 mg/kg/day in an embryofetal development study in rats. This dose corresponds to 268 times the MRHD based on AUC comparisons. The subcutaneous NOAEL for rat embryo-fetal development in this study is 6.9 mg/kg/day (a 45-fold safety margin).

In an embryofetal development study in rabbits, tapinarof was administered by continuous subcutaneous infusion to pregnant animals at doses of 1, 2 and 3 mg/kg/day during the period of organogenesis. Tapinarof was not associated with embryofetal lethality or fetal malformations at doses up to 3 mg/kg/day (20 times the MRHD based on AUC comparison).

In a prenatal and postnatal development study conducted in rats, the NOAEL for effects on the development of the offspring was 1 mg/kg/day. There was a test article-related decrease in first filial generation (F1) pup survival and viability from 6 mg/kg/day that resulted in reduced litter sizes and decreased pup weights. The dose of 6 mg/kg/day is equivalent to 45 times the MRHD based on AUC comparisons. Quantifiable tapinarof exposures were detected in the 6 and 30 mg/kg/day F1 groups, confirming that tapinarof was present in maternal milk.

In a juvenile animal toxicity study, renal pelvic dilatation was observed at doses of tapinarof greater than or equal to 15 mg/kg/day (NOAEL of 1 to 1.5 mg/kg/day). The dose of 15 mg/kg/day is equivalent to 165 times the MRHD based on AUC comparisons. Tapinarof is only indicated in adults, and the doses used in the reproductive and developmental studies are several times higher than the MRHD.

Following single-dose dermal administration, tapinarof cream up to 8% was not associated with dermal irritation (in rats or rabbits), skin sensitization (in guinea pigs), or phototoxicity (in hairless mice). Tapinarof cream up to 4% was not associated with skin sensitization in mice. Tapinarof 8% cream was found to be practically non irritating upon application to the rabbit eye. These studies were conducted with earlier formulations which are not the final commercial formulation.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph for Nduvra. In view of the intended use of Nduvra, 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 Nduvra, approved by Health Canada and available through the Drug Product Database.

The quality (chemistry and manufacturing) information submitted for Nduvra 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 36 months for the 60 g aluminium barrier laminate tube presentation is acceptable when the drug product is stored at 15 ºC to 25 ºC, and the proposed shelf life of 24 months for the 2g aluminium tube presentation is acceptable when the drug product is stored at 2 ºC to 25 ºC.

During the review of the initially submitted quality (chemistry and manufacturing) data package for Nduvra, Health Canada identified major deficiencies with respect to the classification and evaluation of identified extractable/potential leachable impurities. A Notice of Non-Compliance (NON) was previously issued on March 12, 2024 by Health Canada. In response to the NON, the sponsor provided additional supportive toxicological data, which was considered acceptable and resolved this issue. Therefore, 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 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 Nduvra is of human or animal origin.