Summary Basis of Decision for Firazyr

 

Clinical Pharmacology

Hereditary angioedema (HAE) types I and II are caused by the absence or dysfunction of C1-esterase-inhibitor, a key regulator of the Factor XII/kallikrein proteolytic cascade, that leads to bradykinin production. Bradykinin is a vasodilator which is the key mediator of the characteristic HAE symptoms of localized swelling, inflammation and pain. Icatibant, the active ingredient of Firazyr, is a selective competitive antagonist for the bradykinin B2 receptor, with an affinity similar to bradykinin and thereby treats the clinical symptoms of an acute, episodic attack of HAE.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. The clinical pharmacological data support the use of Firazyr for the specified indication.

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

Clinical Efficacy

The efficacy of Firazyr for the treatment of acute HAE attacks was supported by the results of one pivotal randomized, placebo-controlled, parallel-group Phase III study (Study 1 or FAST 3) and two supporting randomized, double-blind, controlled Phase III studies (Studies 2 and 3 or FAST 1 and FAST 2, respectively). Additional efficacy results were obtained from a self-administration uncontrolled study and an escalating dose, Phase II proof-of-concept study. In the Phase III studies, patients were enrolled if their attack involved the cutaneous, abdominal and/or laryngeal areas; the cutaneous or abdominal attacks were at least moderate in severity and the laryngeal attacks were at least mild in severity, as determined by the investigator. The study drug was administered within 6 hours of the attack severity becoming at least mild (laryngeal) or moderate (non-laryngeal), but not more than 12 hours after the onset of the attack. The Phase III clinical studies used endpoints that were specifically developed to assess the response to therapy in patients with acute HAE attacks. These endpoints were deemed acceptable to demonstrate efficacy of Firazyr for the specified indication.

In Study 1, 98 adult HAE type I or type II patients (mean age 37.0 years, 88.8% white, 86.7% HAE type I, 3.1% >65 years of age) were randomized to receive a single dose of either Firazyr 30 mg or placebo by subcutaneous (SC) injection. Patients with severe laryngeal attacks of HAE were not randomized and received open-label Firazyr 30 mg SC. In the open-label extension phase of the study, patients were eligible for treatment of subsequent attacks with Firazyr 30 mg SC and could receive up to 3 doses at least 6 hours apart for each attack.

The primary endpoint of the pivotal study was the "Time to onset of symptom relief" (TOSR). The TOSR in the non-laryngeal intent-to-treat (ITT) population was 2.0 hours in the Firazyr group compared to 19.8 hours in the placebo group. This difference was statistically significant (p<0.001) and clinically meaningful for patients with acute non-laryngeal HAE attacks.

The key secondary endpoint of the pivotal study was"Time to onset of primary symptom relief" (TOSR-P). The TOSR-P in the non-laryngeal ITT population was 1.5 hours in the Firazyr group and 18.5 hours in the placebo group. This difference was statistically significant (p<0.001) and clinically meaningful. The time to almost complete symptom relief was 8.0 hours in the Firazyr group compared to 36.0 hours in the placebo group, suggesting a smaller duration of the attacks in patients treated with Firazyr. In addition, patients treated with Firazyr used less rescue medication prior to the onset of symptom relief (0% in the Firazyr group versus 35.6% in the placebo group). The results of other secondary and exploratory endpoints also supported the efficacy of Firazyr for the treatment of patients with acute non-laryngeal HAE attacks.

Due to the small number of patients with laryngeal attacks in the double-blind phase of the pivotal study, the efficacy of Firazyr for the treatment of laryngeal attacks was demonstrated through post-hoc analyses. These analyses included all patients with laryngeal attacks treated with Firazyr during the double-blind phase and the open-label phase of the study. Comparison with a control group was therefore not available. The median time to onset of symptom relief was 2.0 hours. The median time to almost complete symptom relief was 6.4 hours. According to previously published literature, the mean time from onset of symptoms to maximum development of laryngeal edema has been observed between 8 and 12 hours in 67.2% patients based on analysis of retrospective data from 61 patients with 595 laryngeal attacks. However, the interval between onset of laryngeal edema and asphyxiation has been observed to be as short as 20 minutes, indicating that airway compromise can also occur quickly and be fatal. Since the asphyxiation may occur rapidly after the onset of a laryngeal attack, the impact of Firazyr on survival is unclear since the median time to the onset of symptom relief is 2.0 hours. No formal studies have been conducted to determine if Firazyr treatment can reduce the risk of suffocation and mortality in HAE patients with laryngeal attacks. Because laryngeal attacks can be lethal, it is recommended that patients with laryngeal symptoms or any swelling causing breathing difficulties should seek medical attention immediately after administration of Firazyr and need to be managed in an appropriate medical institution after injection until the physician considers discharge to be safe.

Firazyr continued to demonstrate efficacy across repeated treatments for up to 15 subsequent HAE attacks. Most of the patients required only one Firazyr injection per HAE attack.

Results of Study 3 were supportive of the efficacy of Firazyr for the specified indication. However, the results of the other supporting study, Study 2, failed to demonstrate the efficacy of Firazyr in the treatment of patients with acute attacks of HAE. Study 2 was a randomized, double-blind, placebo-controlled study. The median time to onset of symptom relief was 2.5 hours in the Firazyr group, and 4.6 hours in the placebo group. However, the difference was not statistically significant for this primary endpoint. The sponsor attributes the lack of statistical significance to the higher use of rescue medication in the placebo group. When patients that received rescue medication were censored, the median time to the onset of symptom relief increased to 9 hours in the placebo group, but remained 2.5 hours in the Firazyr group. This difference was statistically significant in favour of Firazyr (p = 0.024).

There were no patients with type III HAE enrolled in the Phase III studies. Therefore, no efficacy data were available for this subpopulation of HAE patients (HAE patients without a C1-esterase inhibitor deficiency). The indication was revised to specify that Firazyr is for the treatment of acute HAE attacks in adults with C1-esterase-inhibitor deficiency.

In an open-label study, the efficacy and the safety profile of Firazyr in patients who self-administered Firazyr were similar to those of patients whose therapy was administered by healthcare professionals. Patients who self-administered Firazyr during an acute attack of HAE had results similar to those seen after administration by a healthcare professional in the controlled Phase III studies.

Overall, the efficacy data demonstrated that Firazyr can significantly improve the time to onset of symptom relief during acute attacks of HAE in adults with C1-esterase inhibitor deficiency. The recommended dose and schedule are fully supported by the pivotal study data. The efficacy findings are statistically significant and clinically relevant for the revised indication and the targeted clinical population.

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

Clinical Safety

In the Phase III study safety population, 113 patients received Firazyr, 38 received tranexamic acid, and 75 received placebo.

The mean number of Firazyr-treated HAE attacks per patient was 5.7, ranging from 0 attacks to 142 attacks. No trends in the type or severity of the HAE attacks were observed by attack number. Adverse reactions occurring within 14 days of study drug administration were collected. Based on pharmacokinetic analyses, a single subcutaneous dose of 30 mg/kg icatibant (the active ingredient of Firazyr) exhibits a short terminal half-life (mean 1.4 ± 0.4 hours). The pharmacodynamic effect of icatibant lasts approximately 6 to 12 hours, therefore the important events are those reported within the first 24 hours after the Firazyr dose [that is (i.e.) acute adverse events], in order to evaluate a temporal association and potential causality with Firazyr.

No deaths were reported in Firazyr-treated patients in the clinical program. The most common clinically significant adverse reactions (frequency of >2%) in Firazyr-treated patients include injection site reactions (erythema, swelling, pruritus, burning sensation, warm sensation, itching and/or cutaneous pain), HAE, dizziness, headache, nausea, rash, pyrexia and increased liver enzymes [alanine transaminase (ALT) and aspartate transaminase (AST)]. These reactions occurred at a higher frequency in the Firazyr group versus the placebo-treated population.

Rare Grade 3 increases in liver transaminases (not Hy's Law cases) occurred in Firazyr-treated patients, but without experiencing any signs or symptoms, thus the clinical significance of these laboratory abnormalities is not known. Frequencies and types of adverse reactions were similar between the controlled phase and open-label phase.

Serious adverse drug reactions were not observed during the Phase III studies. During the post-market period outside of Canada, one serious case each of acute myocardial infarction and chest pain were reported. There was also one case of serious AST/ALT increase reported in a patient with multi-organ failure due to sepsis.

Special Populations

No formal studies of the use of Firazyr in pregnant women have been conducted. The safety of Firazyr in nursing women has not been demonstrated. In addition, the submission did not contain sufficient evidence showing that there is no systemic absorption of icatibant after oral administration in infants.

The safety and efficacy of Firazyr in children and adolescents have not been evaluated.

Patients with evidence of coronary artery disease [for example (e.g.), unstable angina pectoris or severe coronary heart disease, and congestive heart failure (New York Heart Association class 3 and 4)] were not included in the studies. Therefore, there is no safety data for the use of Firazyr in that subset of patients. No cardio-vascular safety concerns were observed in the clinical studies. However, the size of these studies was relatively small. This may have prevented from detecting less common adverse events. Based on animal studies, the use of Firazyr in patients with acute ischemic heart disease or unstable angina pectoris could theoretically lead to a decrease in coronary blood flow and deterioration in cardiac function. In addition, there is a theoretical risk that the use of Firazyr in the weeks following a stroke could attenuate the positive late phase neuroprotective effects of bradykinin.

Patients >65 years of age are likely to have increased systemic exposure to Firazyr compared to younger patients. However, this is not expected to be clinically relevant for safety or efficacy, and no dose adjustment is necessary for elderly patients.

No dosage adjustment is required in patients with hepatic or renal impairment.

Formal drug-drug interaction studies have not been conducted with icatibant. Pharmacokinetic drug interactions involving cytochrome P450 enzymes are not expected.

In an open-label study, the efficacy and the safety profile of Firazyr in patients who self-administered Firazyr were similar to those of patients whose therapy was administered by healthcare professionals.

Immune Functions

Impairment of the acute inflammatory response via icatibant-mediated antagonism of the B2 receptor might be theorized to suppress host defense mechanisms. However, a convincing role of bradykinin or the B2 receptor in modulation of either the innate or adaptive immune system has not been demonstrated. Furthermore, the non-clinical studies suggest that icatibant is not immunotoxic (immunosuppressive). Analyses of the Clinical and Post-marketing safety database showed that Firazyr treatment does not seem to result in either an increase in the severity or prolongation of an ongoing infection. The clinical safety database does not suggest that Firazyr treatment is associated with an immunosuppressive effect.

Immunogenicity

Based on the clinical safety data, drug hypersensitivity and immunogenicity do not seem to incur any significant risks with icatibant.

Only one clinical case of potential hypersensitivity/immunogenicity was reported. Upon the eighth Firazyr-treated attack, a patient from the pivotal study experienced non-serious adverse events of generalized pruritus and generalized cutaneous burning sensation approximately 5 hours after injection with icatibant. The symptoms resolved after administration of the antihistamine levoceterizine. There was no associated rash, no respiratory symptoms or compromise, and no abnormalities in vital signs. There were no similar symptoms or other symptoms related to hypersensitivity during the initial seven attacks and the two subsequent attacks. There were no similar symptoms or other symptoms related to hypersensitivity during the patient's ninth Firazyr-treated attack. At the tenth treated attack, the patient experienced mild generalized pruritus following Firazyr administration, which resolved the same day. The events were deemed by the investigator to be possibly related to icatibant.

Conclusion

The risk profile of Firazyr for the treatment of acute attacks of HAE in adult patients is acceptable and the known risks are manageable through the final revised labelling. The use of Firazyr to treat HAE patients with laryngeal symptoms is of particular clinical relevance since laryngeal attacks resulting in swelling and blockage of the airway are potentially life-threatening. The revised labelling includes a statement advising patients with laryngeal symptoms to seek immediate medical attention after self-injection of Firazyr. In addition, because it is not known whether Firazyr treatment can minimize the risk of death, the revised labelling includes a statement to communicate this information to prescribers and patients.

Appropriate warnings and precautions are in place in the approved Firazyr Product Monograph to address the identified safety concerns.

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