Type of information: Acceptation for review of a sNDA
Product name: Cinryze®
Compound: C1 esterase inhibitor
Therapeutic area: Rare diseases - Genetic diseases
- enzyme inhibitor/C1 esterase inhibitor. The C1 inhibitor protein is required to control the ‘complement’ and ‘contact’ systems, collections of proteins in the blood that fight against infection and cause inflammation. Patients with low levels of this protein have excessive activity of these two systems, which leads to the symptoms of angioedema. Cinryze® is used to replace the missing C1 inhibitor, correcting the deficiency and helping to prevent or treat angioedema attacks.
Company: Viropharma (USA), now Shire (UK - USA)
- treatment and prevention of angioedema attacks in children and adult patients with C1 inhibitor deficiency
- • On February 15, 2018, Shire announced that the FDA accepted the Cinryze® supplemental Biologics License Application (sBLA) to expand the currently approved indication to include children aged 6 years and older with hereditary angioedema (HAE). The FDA is expected to provide a decision on the expanded indication of Cinryze® by June 20, 2018, based on the Prescription Drug User Fee Act V action date.
- This sBLA for CINRYZE is supported by data from two open-label studies (LEVP 2006-1 and LEVP 2006-4) and two pediatric clinical studies (0624-203 and 0624-301).6,7,8,9 The pediatric studies used in this filing are the only clinical trials investigating a prophylactic therapy in the HAE pediatric population.
- • On March 16, 2017, the European Commission (EC) has approved a label extension granting three new indications for Cinryze® (C1 inhibitor [human]), broadening its use to children with Hereditary angiodema (HAE). Cinryze® is now indicated for routine prevention of angioedema attacks in children (ages 6 years and above) with severe and recurrent attacks of HAE who are intolerant to or insufficiently protected by oral preventions treatments, or patients who are inadequately managed with repeated acute treatment.
- It is the first and only HAE treatment with this indication in paediatric patients. Cinryze® has been approved since 2011 for these indications in adults and adolescents ages 12-17 years with HAE. The drug will be available for use in paediatric patients later in 2017 throughout Member States of the European Union (EU), as well the European Economic Area (EEA) in which Shire currently has a licence in the adult and adolescent population.
- • On 15 December 2016, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending a change to the terms of the marketing authorisation for Cinryze®. The extension to the existing indication is as follows:
- - “Treatment and pre-procedure prevention of angioedema attacks in adults, adolescents and children (2 years old and above) with hereditary angioedema (HAE)".
- - Routine prevention of angioedema attacks in adults, adolescents and children (6 years old and above) with severe and recurrent attacks of hereditary angioedema (HAE), who are intolerant to or insufficiently protected by oral prevention treatments, or patients who areinadequately managed with repeated acute treatment.”
• On March 8, 2013, Viropharma has announced that Cinryze® (C1 inhibitor [human]) is available in France for routine prevention, pre-procedure prevention and acute treatment of angioedema attacks.
- • On June 15, 2011, ViroPharma has announced that the European Commission has granted Centralized Marketing Authorization for Cinryze® (C1 inhibitor [human]) in adults and adolescents with hereditary angioedema (HAE) for routine prevention, pre-procedure prevention and acute treatment of angioedema attacks. The approval also includes a self administration option for appropriately trained patients included in the Summary of Product Characteristics (SPC). The approval of Cinryze follows the positive opinion adopted by the Committee for Medicinal Products for Human Use (CHMP) in March 2011. Cinryze is now approved throughout all the Member States of the European Union (EU) as well as in the European Economic Area (EEA), namely Norway, Iceland and Liechtenstein.
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
UE authorization: 2011-06-15/2017-03-16
Favourable opinion UE: 2011-03-17/2016-12-15
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE:
- • On,October 11, 2018, the Institute for Clinical and Economic Review (ICER) released an Evidence Report assessing the comparative clinical effectiveness and value of therapies for long-term prophylaxis against hereditary angioedema (HAE) attacks. The report reviews three therapies for the prevention of HAE attacks: lanadelumab (Takhzyro™, Shire Plc), and two C1 inhibitors (Haegarda®, CSL Behring ; and Cinryze®, Shire). ICER's earlier draft report also included an additional C1 inhibitor, Ruconest® (Pharming Healthcare,), which has since been removed from the assessment because the treatment is no longer under consideration for FDA approval for long-term prophylaxis.
- All three drugs reviewed reduced the number and severity of HAE attacks compared with no long-term prophylaxis, and available data suggest few harms. Haegarda and lanadelumab have the additional benefit of being subcutaneously administered, which may decrease the burden and complexity of administration and avoid complications due to repeated intravenous infusions. Evidence provides high certainty that Haegarda and Cinryze provide a substantial net benefit compared with no prophylaxis. Evidence on lanadelumab was considered promising but inconclusive because of concerns about long-term safety with a new therapy that was only studied in short-term trials and small numbers of patients. Evidence was insufficient to compare the net health benefits among the three treatments.
- Economic analyses assessing long-term cost-effectiveness found that all three treatments far exceed commonly cited thresholds of $50,000-$150,000 per quality-adjusted life year (QALY) gained, with $243,000 per QALY for Haegarda, $5,870,000 per QALY for Cinryze, and $1,020,000 per QALY for lanadelumab. To align costs with the added benefits for patients, discounts off the list price would need to be approximately 59% for Cinryze, 27% for Haegarda, and 33% for lanadelumab.
- However, because the overall cost-effectiveness of prophylactic treatment balances the high treatment cost of prophylaxis with the avoided high costs associated with on-demand treatment of acute attacks, the economic modeling results are highly sensitive to assumptions made about variables such as the baseline rate of acute attacks and the likelihood that patients will switch dosing schedules over time for prophylactic therapy.
- • On January 24, 2018, Shire announced that the FDA has granted approval for the technology transfer of Cinryze® (C1 esterase inhibitor [human]) drug product manufacturing process to its Vienna, Austria manufacturing site. Shire will begin commercial manufacturing of the product in Vienna in the first quarter of 2018. Cinryze will also continue to be produced by a third-party supplier, providing an additional supply source to meet patient demand.