Date: 2018-09-21

Type of information: Granting of a Market Authorisation in Japan

Product name: Firazyr®

Compound: icatibant - synthetic decapeptide

Therapeutic area: Rare diseases - Genetic diseases

Action mechanism:

  • peptide. Icatibant is a specific bradykinin B2 receptor antagonist designed to block the effects of bradykinin, the key mediator of edema formation

Company: Shire (UK)


  • acute attacks of hereditary angioedema (HAE) in adult and paediatric patients

Latest news:

  • • On September 21, 2018,  Shire announced that the Ministry of Health, Labour and Welfare (MHLW) in Japan has granted manufacturing and marketing authorisation for Firazyr® (icatibant injection), for the acute treatment of hereditary angioedema (HAE) attacks in adult patients with HAE. The use of Firazyr® in Japanese patients was examined in an open-label, single-arm, Phase 3 study of 8 adult patients with a confirmed diagnosis of HAE who experienced angioedema attacks. During the study, 3 patients self-administered Firazyr® and 5 patients had Firazyr® administered by a physician. The primary efficacy endpoint was time to onset of symptom relief (TOSR), defined as a 50% reduction from baseline in patient Visual Analog Scale (VAS) score. The study showed that Firazyr® was well tolerated and demonstrated symptom relief during an acute HAE attack through a single injection. Overall, median TOSR was 1.75 hours, and TOSR was similar for patients who self-administered Firazyr® or who had Firazyr® administered by a physician. Symptom relief was attained as early as 1 hour after Firazyr® injection and all patients had symptom relief within 5 hours. The most common adverse events in patients treated with Firazyr® were injection site reactions such as erythema, or swelling, which were found to be mild to moderate in severity.
  • • On October 26, 2017, Shire announced that the European Commission (EC) has approved a label extension granting a new indication for Firazyr® (icatibant injection), broadening its use to adolescents and children aged 2 years and older, with hereditary angioedema (HAE) caused by C1-esterase-inhibitor (C1-INH) deficiency. Firazyr® has been approved in the European Union (EU) since 2008 for symptomatic treatment of acute attacks of HAE in adults with C1-INH deficiency. The use of Firazyr® in paediatric patients was studied in an open label, non-randomised single-arm study, involving 32 paediatric patients with HAE. The efficacy population consisted of 11 children and 11 adolescents with attacks. The primary efficacy endpoint was time to onset of symptom relief (TOSR) based on the investigator-assessed composite post-treatment symptom score, defined as earliest time post-treatment when 20% or more improvement in the composite symptom score was achieved, without worsening of any single component score. Overall, median TOSR was 1.0 hour, with no differences between children and adolescents. More than 70% of patients experienced symptom relief at 1.1 hours, and more than 90% by 2 hours post-treatment.
  • The majority of paediatric patients who were treated with subcutaneous  Firazyr® experienced injection site reactions such as erythema, swelling, burning sensation, skin pain and itching/pruritus; these were found to be mild to moderate in severity and consistent with reactions that have been reported in adults. The study showed Firazyr® was well tolerated and demonstrated rapid resolution of symptoms during an HAE attack through a single injection. The study that led to this approval is the first and only trial investigating a subcutaneous therapy in the HAE paediatric population.  Firazyr® will be available for use in paediatric patients in Europe beginning in Q4.
  • • On September 14, 2017, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending a change to the terms of the marketing authorisation for Firazyr®. The drug is now indicated for symptomatic treatment of acute attacks of hereditary angioedema (HAE) in adults, adolescents and children aged 2 years and older, (with C1-esterase-inhibitor deficiency).
  • • On June 23, 2011, Shire has announced that the Pulmonary-Allergy Drugs Advisory Committee to the FDA recommended, by a vote of twelve to one, that the efficacy and safety data provides substantial evidence to support approval of Firazyr® (icatibant) for the treatment of acute attacks of hereditary angioedema (HAE) in patients 18 years and older. In addition, by a vote of eleven to one, with one abstention, the Committee recommended self-administration of the drug by patients.
  • • On March 3, 2011, Shire announced that the European Commission has approved Firazyr® (icatibant) for self-administration after training in subcutaneous injection technique by a healthcare professional. Firazyr® is the first and only treatment for acute Type I and Type II hereditary angioedema (HAE) attacks licensed for self-administration in Europe. The European Commission approval of the Firazyr®  label change to include self-administration is valid in all of the 27 EU Member States plus Iceland, Liechtenstein and Norway. Firazyr® is currently approved in 37 countries worldwide, including the countries of the European Union.
  • • On February 28, 2011, Shire announced it has submitted a complete response to the not approvable letter issued by the FDA to Jerini in April 2008 regarding its New Drug Application for Firazyr® (icatibant) for the treatment of acute attacks of hereditary angioedema (HAE). Shire\'s complete response includes additional data requested by the agency regarding Firazyr®\'s efficacy and safety in treating HAE attacks. Shire conducted an additional Phase III clinical study (FAST-3), and in December 2010 reported positive efficacy and safety results. The Company's complete response is based primarily on recent results from the FAST-3 study and the ongoing self-administration study, as well as the previously published FAST-1 and FAST-2 studies.


Submission of marketing authorization application USA :

Submission of marketing authorization application UE:

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization: 2011-08-25

UE authorization: 2008-07-15/2017-10-26

Favourable opinion UE:

Favourable opinion USA: 2011-06-23

Orphan status USA: 2003-11-25

Orphan status UE: 2003-02-17

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

  • On November 15, 2018 , the Institute for Clinical and Economic Review (ICER) released a Final Evidence Report and Report-at-a-Glance assessing the comparative clinical effectiveness and value of therapies for long-term prophylaxis against hereditary angioedema (HAE) attacks.
  • In its report, ICER assessed three therapies for the prevention of HAE attacks: lanadelumab (Takhzyro™, Shire), and two C1 inhibitors (Haegarda®, CSL Behring ; and Cinryze®, Shire). ICER's report was reviewed at an October 2018 public meeting of the California Technology Assessment Forum (CTAF), one of ICER's three independent evidence appraisal committees. During the meeting, CTAF found that the evidence demonstrated a net health benefit for using the C1 inhibitors as long-term prophylaxis, but that the evidence was insufficient to distinguish between Cinryze and Haegarda. Because of concerns about risks with a new therapy, the committee also found that current evidence was not adequate to determine whether long-term prophylaxis with lanadelumab is superior to on-demand therapy alone.
  • Decision makers often give special considerations to therapies for ultra-rare diseases such as HAE, which may lead to coverage and funding decisions at higher thresholds for cost-effectiveness. During their deliberation, CTAF members underscored how HAE represents a particularly high lifetime burden of illness, and that all three prophylactic treatments may significantly improve both patients' and caregivers' ability to return to work or school. The panel recognized that Haegarda and lanadelumab offer simpler administration - subcutaneous injection - which may achieve better patient outcomes over a treatment like Cinryze, which is administered intravenously.
  • CTAF voted that both Cinryze and lanadelumab represent a low long-term value for money when compared to on-demand therapy. When evaluating the long-term value for money of Haegarda, the panel's majority vote was split evenly between low and intermediate value. All three prophylactic treatments, at current pricing, exceed commonly cited thresholds for cost-effectiveness. Following the voting session, a policy roundtable of experts - including a patient advocate, physician, drugmaker, and payer representative - convened to discuss the implications of the evidence for policy and practice. Key recommendations stemming from the roundtable discussion include:
  • Payers seeking to negotiate better prices may consider giving all market share to the two injectable treatments, Haegarda and lanadelumab, due to these therapies' simpler administration compared to intravenous drugs.
  • Prior authorization criteria should be based on clinical evidence with input from clinical experts and patient groups. Insurers crafting coverage policy may seek to confirm HAE through lab tests or physician attestation, determine the appropriateness of long-term prophylaxis based on the frequency and severity of attacks, and use a patient's weight to more precisely manage dosing of weight-based treatments. Specific options are described in greater detail within the full report.
  • There are currently no consensus criteria on when to consider starting long-term prophylaxis for patients with HAE. Specialists involved in the care of patients with HAE should convene and work with patients to develop a consensus statement to guide policymakers and payers on the appropriate use of long-term prophylaxis for patients with Type 1 or 2 HAE.

Is general: Yes