Summary Basis of Decision (SBD) for Vyvgart

As outlined in the What steps led to the approval of Vyvgart? section, the clinical review of the New Drug Submission for Vyvgart was conducted as per Methods 2 and 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada .

Clinical Pharmacology

Efgartigimod alfa (the medicinal ingredient in Vyvgart) is a human immunoglobulin G1 (IgG1) antibody fragment that binds to the neonatal Fc receptor (FcRn) and inhibits its interaction with immunoglobulin G (IgG). This results in increased degradation of IgG and reduction of circulating IgG and pathological IgG autoantibodies.

The pharmacokinetics of efgartigimod alfa was characterized after single or multiple intravenous doses (once every 4 or 7 days) in healthy subjects and in patients with generalized myasthenia gravis (gMG). The results of a noncompartmental analysis in healthy subjects showed that after a single dose (at 2.0, 10, 25, or 50 mg/kg), the exposure of efgartigimod alfa, as measured by the area under the concentration-time curve (AUC_0-inf) increased dose-proportionally. The estimated mean clearance was 0.122 to 0.163 L/h, the volume of distribution was 15 to 20 L, and the mean elimination half‑life (t_½) was 80 to 120 hours (3 to 5 days).

In patients with gMG who received 4 weekly doses of 10 mg/kg efgartigimod alfa, steady state exposure was reached by the fourth dose, with minimal accumulation. A population pharmacokinetic analysis was conducted using serum concentration data from 84 patients with gMG treated with a treatment cycle of 4 weekly intravenous doses of efgartigimod alfa. The estimated clearance was 0.108 L/h, which was slightly lower than the rates observed in healthy subjects. Body weight and estimated glomerular filtration rate (eGFR; a measure of renal function) were identified as significant covariates for clearance. The exposure, as measured by the maximum plasma concentration (C_max) and the AUC, was similar for patients with gMG weighing more than 120 kg given the capped dose at 1,200 mg, as compared to gMG patients with BW less than 120 kg dosed at 10 mg/kg. Compared to patients with normal renal function, a 22% increase in exposure (90% confidence interval [CI]: 1.19, 1.37) was estimated for patients with mild renal impairment (defined as an eGFR of 60 to 89 mL/min/1.73 m²). However, no dose adjustment is required in patients with mild renal impairment. The impact of moderate renal impairment (defined as an eGFR of less than 60 mL/min/1.73 m²) on exposure could not be assessed since the number of patients (total number [n] = 3) was too small. No dedicated pharmacokinetics study has been conducted in patients with hepatic impairment. Hepatic impairment is not expected to affect the pharmacokinetics of efgartigimod alfa.

Dose-dependent decreases of IgG levels were observed following a single infusion of efgartigimod alfa in healthy subjects at a dose up to 50 mg/kg. The maximum levels of pharmacodynamic effects (i.e., reduction in total IgG and in IgG subtypes IgG1, IgG2, IgG3, and IgG4) were achieved at a dose of 10 mg/kg. Following 4 weekly 10 mg/kg infusions in patients with gMG, the decrease in levels of total IgG and IgG subtypes reached its maximum (61% reduction from baseline levels) one week after the last infusion, and returned to baseline by Week 12 (9 weeks after the last infusion). The reduction of antiAChR antibodies followed a similar pattern. Antidrug antibodies (ADA) were detected in 17 of 83 patients with gMG (21%) after receiving 4 weekly intravenous doses at 10 mg/kg. Neutralizing antibodies were detected in 6 of the 17 patients. Although the results of impact analyses did not reveal significant effects of the ADAs or neutralizing antibodies on the pharmacokinetics, pharmacodynamics, efficacy, or safety of efgartigimod alfa, definitive conclusions cannot be drawn given the small number of subjects.

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

Clinical Efficacy

The results of the pivotal Study 1704 provided evidence of the clinical efficacy of Vyvgart for the treatment of adult patients with gMG who are anti‑AChR antibody positive. Study 1704 was a 26‑week, double-blind, ‑placebo-controlled study that enrolled 167 patients with gMG who were on stable background therapy. Patients were randomized in a 1:1 ratio to receive either 10 mg/kg Vyvgart or placebo. Each treatment cycle consisted of a 3‑week treatment period in which patients received either Vyvgart or placebo every 7 days (4 infusions in total), followed by at least a 5-week follow-up period, dependent on each patient’s clinical response. The total study duration was up to 28 weeks, including a 2-week screening period, an initial treatment cycle of at least 8‑weeks, and an intertreatment cycle period. Between treatment cycles (during the intertreatment cycle period), patients received only their stable concomitant gMG (standard) treatment. The length of this period and the need for subsequent treatment cycles were dependent on each patient's clinical response to Vyvgart. The efficacy of Vyvgart was measured using the Myasthenia Gravis Specific Activities of Daily Living (MG‑ADL) scale. This scale assesses the impact of gMG on 8 specific functions and symptoms that are typically affected in gMG. Each item is assessed on a 4‑point scale, where a score of 0 represents normal function and a score of 3 represents loss of ability to perform that function. A total score ranges from 0 to 24, with higher scores indicating more impairment. Efficacy was assessed 8 weeks after treatment initiation (at the end of the first treatment cycle).

The primary efficacy endpoint in Study 1704 was the percentage of MG‑ADL responders during the first treatment cycle in the anti‑AChR antibody positive population. An MG‑ADL responder was defined as a patient with a 2‑point or greater reduction in the MG‑ADL total score relative to baseline, for at least four consecutive weeks, with the first reduction occurring no later than one week after the last infusion of the product in Cycle 1.

The efficacy of Vyvgart was also measured using the Quantitative Myasthenia Gravis (QMG) total score, a 13‑item categorical grading system that assesses muscle weakness. Each item is assessed on a 4-point scale, where a score of 0 represents no weakness and a score of 3 represents severe weakness. A total score ranges from 0 to 39, where higher scores indicate more severe impairment. The key secondary efficacy endpoint in Study 1704 was the percentage of QMG responders during Cycle 1 in the anti‑AChR antibody positive population. A QMG responder was defined as a patient with a 3‑point or greater reduction in the total QMG score relative to baseline, for at least 4 consecutive weeks, with the first reduction occurring no later than one week after the last infusion of the product in Cycle 1.

The results indicated that Vyvgart was superior to placebo with respect to the primary and key secondary endpoints. These results were found to be clinically meaningful. A higher percentage of MG-ADL responders was observed in the anti-AChR antibody positive group that received Vyvgart (67.7%) than in the placebo group (29.7%). This difference was statistically significant (p<0.0001). A higher percentage of QMG responders was also observed in the group that received Vyvgart (63.1%) than in the placebo group (14.1%). This difference was also statistically significant (p<0.0001). Although both anti-AChR antibody positive and anti-AChR antibody negative patients were enrolled in this study, the treatment effect for the primary endpoint in the overall population was driven by the anti-AChR antibody positive group.

Retreatment criteria were specific to the design of this clinical study. In clinical practice, the frequency of Vyvgart treatment cycles is to be based on clinical evaluation and may vary by patient.

Indication

Sponsor's proposed indication	Health Canada-approved indication
Vyvgart (efgartigimod solution, for intravenous use) is indicated for the treatment of adult patients with generalized myasthenia gravis (gMG).	Vyvgart (efgartigimod solution, for intravenous use) is indicated for the treatment of adult patients with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody positive.

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

Clinical Safety

The database used to evaluate the clinical safety of Vyvgart included data from 162 patients with gMG who received at least one dose of Vyvgart in either the pivotal study (Study 1704, described in the Clinical Efficacy section), an ongoing open‑label extension study (Study 1705), or a supportive Phase II study (Study 1602). The frequency of Vyvgart treatment cycles received varied by patient. The minimum time to initiation of a subsequent treatment cycle was 4 weeks from the last infusion of the previous treatment cycle (per protocol). Therefore, the safety of initiating subsequent treatment cycles any earlier has not been established.

Eighty‑five of the 162 patients received at least 6 treatment cycles with Vyvgart. A maximum of 14 treatment cycles were administered (for two patients). The clinical safety of Vyvgart was evaluated primarily in the placebo‑controlled pivotal study, in which 84 patients received Vyvgart and 83 patients received placebo. Placebo‑controlled data are available for a maximum of 3 treatment cycles.

In the pivotal study, the most common treatment‑emergent adverse events (TEAEs) (reported in at least 5% of patients and at a higher rate [at least 3 patients more] in the Vyvgart group than in the placebo group) were: upper respiratory tract infection, urinary tract infection, bronchitis, myalgia, and procedural headache. The majority of TEAEs were mild or moderate in severity. Serious TEAEs were reported in 5% of patients treated with Vyvgart and 8% of patients who received placebo. The proportion of patients who discontinued treatment due to TEAEs was similar in both groups (4% each). Treatment‑emergent adverse events belonging to the Infections and infestations system organ class (SOC) were the most commonly reported in the pivotal study, with 46% of patients treated with Vyvgart and 37% of patients treated with placebo reporting these events.

The majority of infections and hematology abnormalities were of mild to moderate intensity. Serious infections were not reported in patients treated with Vyvgart in the pivotal study, but were reported in the open‑label extension study. While no deaths were reported in the pivotal study, five deaths were reported in the open‑label extension study. Confounding factors and other underlying risk factors were present for all five deaths, however, two of the deaths occurred in the setting of infection. Considering the mechanism of action, Vyvgart as a potential contributing factor could not definitively be ruled out. The risk of infections, including the occurrence of serious infections in clinical studies, has been included in the Vyvgart Product Monograph. Serious infections will also be monitored post-market via enhanced pharmacovigilance activities. Based on the available information in the clinical safety database and the mechanism of action of Vyvgart, other risks include the potential for hypersensitivity, and infusion-related reactions. Appropriate risk mitigation guidelines have been included in the Product Monograph.

The safety database for Vyvgart was determined to be sufficient to support authorization in the intended population and using the intended dosing regimen. The safety data collected during the clinical studies supports a favourable benefit-risk profile for Vyvgart. However, the safety database has limitations due to a relatively small number of patients and minimal long‑term exposure data, which can be partly attributed to the rarity of the disease. The potential for serious infections and serious hypersensitivity reactions remains to be characterized when used in the post‑market setting. The risks identified for Vyvgart have been included in the labelling and a combination of routine and enhanced pharmacovigilance activities will be undertaken to monitor safety. In particular, uncertainties regarding adverse outcomes in pregnancy, risk of malignancy, reactivation of hepatitis B, and reactivation of latent tuberculosis will be monitored, characterized, and managed in the post‑market setting through post‑authorization safety studies and routine and enhanced pharmacovigilance activities.

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

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

A 4-week repeat-dose toxicity study was conducted in which rats were treated with placebo (0.9% sodium chloride solution) or intravenous injections of efgartigimod alfa at doses of 10, 30, or 100 mg/kg once every 2 days, for a total of 15 doses. Kupffer cell hypertrophy/hyperplasia was observed in the liver in male and female rats at the 100 mg/kg dose level. The relationship between this finding and the treatment remains uncertain. The no-observed-adverse-effect level (NOAEL) was established at 30 mg/kg, which is approximately three times the recommended human dose of 10 mg/kg on a body weight (mg/kg) basis.

In the pivotal 26-week toxicity study, cynomolgus monkeys received intravenous infusions of efgartigimod alfa at doses of 0 (vehicle control), 10, 30, and 100 mg/kg per week (total of 27 infusions). Signs of enterocolitis were detected in two monkeys that received a low-dose and one monkey that received a high-dose, with greater severity observed at the high-dose. Diarrhea was observed in a monkey that received the high dose, along with myeloid hyperplasia in the bone marrow of the sternum. The relationship between these findings and the treatment is uncertain. The NOAEL was established at 100 mg/kg (approximately ten times the recommended human dose of 10 mg/kg) on a body weight (mg/kg) basis.

No dedicated studies have been conducted to assess the carcinogenic or genotoxic potential of efgartigimod alfa.

Reproductive and developmental studies were conducted in rats and rabbits given an intravenous bolus injection of efgartigimod alfa once daily at doses of 0 (vehicle control), 30, or 100 mg/kg (approximately 3- and 10-times the recommended human dose on a body weight basis, respectively). For all studies, the NOAEL was established at 100 mg/kg on a body weight (mg/kg) basis. Efgartigimod alfa concentrations in maternal milk and in the sera of fetuses or F1 generation offspring were not assessed. The potential effect of efgartigimod alfa on neonatal fragment crystallizable (Fc) receptor (FcRn) mediated transfer of maternal antibodies to the fetus was also not assessed.

A fertility study was conducted in rats, in which male rats were dosed from 4 weeks before mating and up to Day 43 of the study, and female rats were dosed 2 weeks before mating and up to Day 7 of gestation. At doses three and ten times the recommended human dose of 10 mg/kg, efgartigimod alfa did not adversely affect male or female fertility.

An embryofetal development study was conducted in female rats and rabbits. Efgartigimod alfa was administered from Day 6 of gestation through 17 in rats and Day 6 of gestation through 28 in rabbits. There was no evidence of adverse developmental outcomes following the administration of efgartigimod alfa in rats. In rabbits only, abortions were reported (two in the low-dose group and one in the high-dose group) at an incidence comparable to historical control data of the test facility and were considered to be spontaneous occurrences. One maternal rabbit in the low-dose group presented with a contained liver lesion, where an infectious cause could not be excluded.

Efgartigimod alfa was administered to female rats from Day 6 of gestation to Day 21 of lactation. Ataxia was observed in four pups from the F1 generation and one female in the high-dose group of the F0 generation. The relationship of this finding to the efgartigimod alfa administration is uncertain. Overall, the results indicated that efgartigimod alfa had no effect on the pregnancy of female rats, or on the development of both the pre- and postnatal F1 and F2 generation pups.

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

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

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

Characterization of the Drug Substance

Efgartigimod alfa is a recombinant protein which targets the neonatal fragment crystallizable (Fc) receptor (FcRn). It is an Fc fragment based on the structure of human immunoglobulin G1 (IgG1), and has been engineered to increase its affinity for FcRn at both pH 7.4 (neutral pH) and pH 6.0 conditions. The mechanism of action of efgartigimod alfa involves constitutive blockage of FcRn at pH 7.4 and pH 6.0, thereby outcompeting the binding of endogenous immunoglobulin G antibodies to FcRn and accelerating their degradation in the lysosomes.

Detailed characterization studies were performed to provide assurance that efgartigimod alfa consistently exhibits the desired characteristic structure and biological activity. Primary structure, higher order structure, and biological and physicochemical properties were all assessed.

Manufacturing Process of the Drug Substance and Drug Product and Process Controls

Efgartigimod alfa, the drug substance, is manufactured from recombinant Chinese hamster ovary (CHO) cells genetically engineered to express the protein. The upstream manufacturing process begins with the initiation of a cell culture from a vial from the working cell bank. The culture is transferred to progressively larger vessels as it expands, and is then used to inoculate a production bioreactor operated in fed-batch mode. The proteins are harvested by depth filtration when a defined cell viability or maximum culture time is reached. The downstream purification process includes multiple chromatography steps, a low pH treatment step, and a virus reduction filtration step. The drug substance is fully formulated and stored frozen.

The drug product manufacturing process involves thawing and pooling the drug substance, bioburden reduction filtration, and sterile filtration at the time of fill. Filled vials are crimped, visually inspected, packaged, and stored at 2 °C to 8 °C.

Changes to the manufacturing process made throughout the pharmaceutical development process are considered acceptable upon review. The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are validated and considered to be adequately controlled within justified limits.

None of the non-medicinal ingredients (excipients) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of efgartigimod alfa with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The control strategy for Vyvgart considers materials/excipients, critical steps within the manufacturing processes, and release and stability specifications. Process parameter ranges and in-process control limits are well defined and justified to ensure process and product consistency. Specification limits for compendial methods comply with those described in the relevant chapters. The limits for non-compendial methods, established on manufacturing experience and stability data, are appropriate to ensure product consistency. The non-compendial methods were appropriately validated and deemed suitable for their intended purpose. A two-tiered reference standard program has been developed and appropriately qualified.

Vyvgart is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs. For post-approval monitoring, Vyvgart has been assigned to Lot Release Group 4. It is considered a low-risk product, as efgartigimod alfa is well characterized and any significant issues from the submission have been resolved. The risk level associated with a drug product is determined by factors including the nature of the product, its indication and target patient population, and the manufacturer's production and inspection history.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 36‑month shelf life at 2 °C to 8 °C for Vyvgart is considered acceptable. The product must be protected from light until time of use and must not be frozen or shaken. Additional storage, reconstitution, and special handling instructions are included in the Vyvgart Product Monograph.

Facilities and Equipment

Based on risk assessments conducted by Health Canada, on‑site evaluations (OSEs) were not conducted for the drug substance or drug product manufacturing sites.

Factors considered in the risk assessments for the drug substance manufacturing sites include a risk determination score and previous OSE experience at the site. For one of the drug substance manufacturing sites, additional considerations included the manufacturer’s experience with recombinant proteins and findings from a United States Food and Drug Administration (FDA) pre-approval review of manufacturing site records.

An OSE was not recommended for the drug product manufacturing site based on its risk determination score.

Adventitious Agents Safety Evaluation

Scaled‑down viral clearance studies were conducted in line with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. The results demonstrated consistent clearance of four types of model viruses. The viral clearance studies were performed with material from both drug substance manufacturing sites.

Under worst-case settings, the proposed strategy was found to be capable of consistently reducing viral contamination to levels below the acceptable limits.