Summary Basis of Decision for Takhzyro

 

Clinical Pharmacology

Lanadelumab, the medicinal ingredient in Takhzyro, is a fully human monoclonal antibody (immunoglobulin G subclass 1 [IgG1]/ kappa [κ]-light chain) that binds plasma kallikrein and inhibits its proteolytic activity. Plasma kallikrein is a protease that cleaves high-molecular-weight-kininogen (HMWK) to generate cleaved HMWK (cHMWK) and bradykinin, a potent vasodilator that increases vascular permeability resulting in swelling and pain associated with hereditary angioedema (HAE). In patients with HAE due to C1-inhibitor (C1-INH) deficiency or dysfunction, uncontrolled increase in plasma kallikrein activity results in angioedema attacks. Lanadelumab decreases plasma kallikrein activity to control bradykinin generation in patients with HAE.

The pharmacological properties of Takhzyro were characterized based on two Phase I studies, one Phase III (pivotal) study, and one open-label extension study. The pharmacokinetics of Takhzyro was approximately dose proportional in the dose range of 150 mg every 4 weeks (q4wks), 300 mg q4wks, and 300 mg every two weeks (q2wks). Following administration of a single dose, complete drug absorption was expected in 8 days. Steady state was expected to be achieved in approximately 70 days. The typical clearance and elimination half-life values were 0.0249 L/h and 14.8 days, respectively. Concentration dependent inhibition of plasma kallikrein, measured as reduction of cHMWK levels, was demonstrated after subcutaneous administration of Takhzyro 150 mg q4wks, 300 mg q4wks, and 300 mg q2wks in patients with HAE.

The 300 mg q2wks dose regimen was shown to result in the highest response based on the exposure response models. A dosing interval of q4wks may be considered if the patient is well controlled (e.g., attack free) for more than 6 months. Body weight was identified as a significant covariate describing the variability of clearance and volume of distribution. In addition, the overall drug exposure in adolescents (12 to 17 years of age) was approximately 37% higher relative to that in adults. Yet, dose adjustment is not required based on consistent efficacy and safety observed across the entire study population.

Overall, the clinical pharmacological data support the use of Takhzyro for the recommended indication.

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

Clinical Efficacy

The efficacy of Takhzyro in preventing acute attacks in patients with Type I or Type II HAE was supported primarily by the results of one pivotal, multicentre, randomized, double-blind, placebo-controlled Phase III study (DX-2930-03). Additional efficacy results were obtained from the pivotal study's open label extension (DX-2930-04).

Study DX-2930-03

In study DX-2930-03, 115 adults and 10 adolescents with Type I or Type II HAE were randomized in a 3:2:2:2 ratio (placebo, Takhzyro 150 mg q4wks, Takhzyro 300 mg q4wks, or Takhzyro 300 mg q2wks; all administered by subcutaneous injection) for a 26-week treatment period. Randomization was stratified by baseline attack rate observed during the run-in period into the following groups: 1 to <2 attacks per 4 weeks, 2 to <3 attacks per 4 weeks, and ≥3 attacks per 4 weeks. Patients were required to discontinue other long-term prophylactic HAE treatments prior to the study run-in period. The use of rescue medications for treatment of acute HAE attacks, including C1 esterase inhibitors, were allowed during the study.

During the study, patients (or caregivers in the circumstance that a patient was <18 years of age) were instructed to notify and report details of an attack to the study site within 72 hours of the onset of an HAE attack. Patients were asked to provide specific details characterizing the attack, including severity and whether the attack required acute treatment.

The primary efficacy endpoint was the number of investigator-confirmed HAE attacks during the treatment period (Day 0 through Day 182). Key secondary endpoints included the number of investigator-confirmed HAE attacks requiring acute treatment during the treatment period (Day 0 through Day 182), and the number of moderate to severe investigator-confirmed HAE attacks during the treatment period (Day 0 through Day 182). Additional exploratory endpoints that are clinically relevant included a responder analysis (e.g., the proportion of patients who achieved a ≥50% reduction in HAE attack rate), proportion of patients that were attack-free (e.g., the proportion of patients with a 100% reduction in HAE attack rate), and the proportion of patients who achieved an improvement in quality of life as measured by the Angioedema Quality of Life questionnaire (AE-QoL).

Regarding patient demographics, 90.4% of patients enrolled in the study had Type I HAE. A history of laryngeal angioedema attacks was reported in 64.8% (81/125) of patients and 56.0% (70/125) were on prior long-term prophylaxis. During the study run-in period, attack rates of ≥3 attacks/month were observed in 52.0% (65/125) of patients overall.

The efficacy analysis was performed on the intention-to-treat (ITT) population, which included all randomized patients who received any exposure to the investigational product.

Results obtained from the DX-2930-03 study demonstrated Takhzyro 300 mg q2wks reduced the rate of investigator-confirmed HAE attacks by 86.9% (95% confidence interval [CI]; 76.2, 92.8) (rate ratio: 0.131 [95% CI; 0.072, 0.238]; p<0.001) compared to placebo following 26 weeks (182 days) of treatment in patients with Type I or Type II HAE who experienced at least one investigator-confirmed HAE attack per 4 weeks during the run-in period. Additionally, Takhzyro 300 mg q2wks reduced the rate of HAE attacks requiring acute treatment by 87.3% [95% CI; 75.2, 93.5] (rate ratio: 0.127 [95% CI; 0.065, 0.248]; p<0.001) and reduced the rate of HAE attacks categorized as moderate to severe by 83.4% ([95% CI; 67.1, 91.6] (rate ratio: 0.166 [95% CI; 0.084, 0.329]; p<0.001).

Regarding exploratory endpoints, the proportion of patients who achieved a ≥50% reduction in HAE attack rate over the 26 week treatment period (e.g., responder) was 100% of patients receiving Takhzyro 300 mg q2wks compared to 31.7% of patients receiving placebo. The proportion of patients who achieved a 100% reduction in HAE attack rate (i.e., attack-free) over the 26 week treatment period was 44.4% of patients receiving Takhzyro 300 mg q2wks compared to 2.4% of patients receiving a placebo. Additionally, the proportion of patients who achieved an improvement in quality of life as measured by the AE-QoL questionnaire (minimally important clinical difference ≥6 in the AE-QoL total score) was 80.8% for Takhzyro patients who received 300 mg q2wks and 36.8% for placebo patients.

Similar results were observed with Takhzyro 300 mg q4wks dosage regimen, although numerically less than results observed with the more frequent dosing posology. Pharmacokinetic and pharmacodynamic analysis indicates that exposure-response relationship (e.g., number of HAE attacks per month) plateaus by 6 months, with no notable difference in HAE attack rates between Takhzyro 300 mg q2wks and q4wks, respectively. A less frequent dosing interval of 300 mg q4wks may be considered by health care professionals if the patient is well-controlled (e.g., attack free) for more than 6 months on the recommended dose of 300 mg q2wks.

Patients who completed the treatment period in the DX-2930-03 study were then given the opportunity to enroll in the open-label extension study DX-2930-04. Patients who consented to participate in the DX-2930-04 study received their first open-label dose following the completion of all double-blind assessments scheduled on Day 182.

Study DX-2930-04

The DX-2930-04 study extension was an open-label, uncontrolled study designed to evaluate the long-term safety and efficacy of Takhzyro for prevention of HAE attacks in patients with Type I or Type II HAE. A total of 212 adult and adolescent (≥12 years) patients received at least one dose of 300 mg q2wks Takhzyro in the study extension, including 109 patients who entered as rollover patients from the original DX-2930-03 study. Rollover patients, regardless of randomization group in the DX-2930-03 study, received a single dose of Takhzyro 300 mg at study entry and did not receive additional treatment until the occurrence of an HAE attack. After the first HAE attack, all patients received open-label treatment with Takhzyro 300 mg q2wks. The majority of patients self-administered Takhzyro over 10 to 60 seconds (64.4% of 929 injections).

Results from the study extensions demonstrated at week 4 post-dose, 80.0% of patients who had been in the 300 mg q2wks treatment group (number of patients [n] = 25) in the DX-2930-03 study remained attack-free. These exploratory results should be interpreted with caution, however, as they reflect a select cohort that completed 26-weeks of exposure to Takhzyro and selectively enrolled in the open-label extension study.

Based on results derived from the pivotal clinical study (i.e., DX-2930-03) and supported by the extension study (i.e., DX-2930-04) Takhzyro 300 mg q2wks demonstrated the greatest numerical magnitude of efficacy compared to the other assessed dosing posologies. The robustness of these data supports a posology of Takhzyro 300 mg q2wks.

Indication

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

• Takhzyro (lanadelumab injection) is indicated for routine prevention of attacks and control of the symptoms of hereditary angioedema (HAE) in adolescents and adults.

To ensure safe and effective use of the product, Health Canada approved the following indication:

• Takhzyro (lanadelumab injection) is indicated for routine prevention of attacks of hereditary angioedema (HAE) in adolescents and adults.
• Takhzyro is not intended for acute treatment of HAE attacks.

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

Clinical Safety

The safety assessment of Takhzyro included pooled safety data from two Phase I studies in addition to two Phase III studies (DX-2930-03 and DX-2930-04) previously described in the Clinical Efficacy section. Further safety data was also consulted in reference to external assessments of pediatric data, electrocardiogram (ECG), and hepatic data from Phase III studies.

Overall, a total of 233 HAE patients and 24 healthy volunteers were exposed to Takhzyro at doses up to 400 mg during clinical development. The majority of doses (93.1%) were 300 mg. Of the 233 HAE patients enrolled in the Phase 1b and Phase III studies, 23 (10%) of these patients were adolescents 12 to 17 years old and 11 (5%) were 65 years of age and older. The majority of patients that participated in the primary Phase III studies continued their participation in the open-label extension with a length of exposure to Takhzyro of 19.6 months.

There were no deaths or serious adverse events (SAEs) determined by investigators to be related to study treatment with Takhzyro. There were 89.1% of patients that had treatment-emergent adverse events (TEAEs), 53.6% that had adverse drug reactions (ADRs), 5.0% with SAEs, 12.3% with severe TEAEs, and 2.7% that discontinued due to TEAEs. The most commonly observed adverse reactions associated with Takhzyro in patients with HAE were injection site reactions (ISR) including injection site pain, injection site erythema and injection site bruising. Most were of mild intensity and resolved within one day after onset. There were 11.4% of patients with anti-drug antibodies and 3.2% with neutralizing antibodies. There was no association seen between antibodies and safety profile.

There were 5.5% of patients that had adverse events of special interest (AESIs) of hypersensitivity reactions or disordered coagulation adverse events. There was an increase in activated partial thromboplastin time (aPTT) seen in Takhzyro patients which the sponsor attributes to the effect of plasma kallikrein inhibition on the assay. These elevations were not associated with bleeding events. There were several patients with hypersensitivity reactions, and while none were anaphylactic reactions, they did lead to discontinuation in three cases. There were two cases of severe elevations of liver enzymes seen in Takhzyro-treated patients that led to discontinuation. Review of reports detailing independent expert assessments of ECGs, pediatric data, and hepatic event data did not identify increased risk of such events with Takhzyro treatment.

Hereditary angioedema is a rare disease making clinical study enrolment relatively challenging. With a relatively limited number of patients enrolled in the pivotal study, which is common for such rare diseases, there exists a degree of uncertainty related to the safety of Takhzyro in the overall HAE patient population, including in various demographic subgroups. There were few adolescent (i.e., 12 to 17 years of age; Number of patients [n] = 23) and geriatric (i.e., ≥65 years of age; n = 11) patients enrolled in the Phase III clinical program; however, no pronounced safety signals were identified in these patients. Additionally, long-term safety data reflective of the intended chronic prophylaxis treatment remains limited. These limited data preclude robust conclusions regarding the safety of long-term treatment with Takhzyro in the HAE population, and in the incidence of rare and/or latent adverse events.

Overall, based on the data evaluated as part of this submission, Health Canada considers there to be sufficient evidence at this time to conclude that the benefit-risk profile of Takhzyro for the routine prevention of HAE attacks in adolescents and adults is favourable. The identified safety risks are considered sufficiently mitigated by product labelling and routine pharmacovigilance activities.

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