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Rilonacept for Cryopyrin associated periodic syndromes

Source agency:

NHSC

Date of Submission:

05/11/2009

Date of Printing:

05/02/2012

Disclaimer:

This report is work in progress and should not be used for external distribution without permission from the originating agency. Users should be aware that reports are based on information available at the time of research and often on a limited literature search.

Technology, Company & Licensing

Technology name:

Rilonacept

Technology - description:

Rilonacept (Arcalyst, IL-1 Trap) is a dimeric fusion protein made up of the extracellular domains of both of the interleukin-1 (IL-1) receptor components: IL-1 receptor type 1 and IL-1 receptor accessory protein linked to a portion of human immunoglobulin G. Rilonacept binds to IL-1 blocking its interaction with cell surface receptors. It is administered by subcutaneous injection (SC) at 160mg per week.

The company state that rilonacept should not be administered to people with an active or chronic infection, and serious life-threatening infections have been reported with its use. Taking rilonacept with tumour necrosis factor inhibitors is not recommended because this may increase the risk of serious infections.

Rilonacept is also in phase III clinical trials for gout.

Company or developer:

Regeneron Pharmaceuticals Inc.

Reason for database entry:

There is currently no licensed treatment for CAPS in Europe. Rilonacept will be one of the first licensed treatments for this indication.

Technology - stage in early warning process:

Assessment complete

Technology - stage of development:

Investigational - phase III

Licensing, reimbursement and other approval:

 

Technology - type(s):

Drug

Technology - use(s):

Therapeutic

Patient Indication & Setting

Patient indications:

Cryopyrin associated periodic syndromes (CAPS) in people aged 12 and over with severe symptoms of:
• Muckle-Wells Syndrome (MWS).
• Familial cold autoinflammatory syndrome (FCAS) also known as familial cold uriticaria (FCU).

Disease description and associated mortality and morbidity:

CAPS is a family of three autoinflammatory syndromes MWS, FCAS and chronic infantile neurological, cutaneous, and articular syndrome (CINCA). These syndromes have been linked to mutations in the gene (CIAS-1) encoding cryopyrin (NALP3), an immune system regulatory protein. Symptoms include varying severity of fever, fatigue, skin rashes, conjunctivitis, painful joints and muscles, headaches and aseptic meningitis, often in response to exposure to cool ambient temperatures. Skeletal and neurological abnormalities during growth and development are quite common, and include distortion of the face, deafness and sometimes blindness. Features of the disease generally become evident shortly after birth, and those relating to acute inflammation persist in a fluctuating manner for the remainder of the patient’s life. About 25% of patients develop systemic amyloid associated (AA) amyloidosis as a result of the chronic inflammation, typically in early adult life and resulting in renal failure, dialysis dependence and death within 5-10 years.

Number of Patients:

There are an estimated 500 people with CAPS in the EU (1).

Technology - specialities(s):

Paediatrics & neonatology

Technology - setting(s):

None

Setting - further information:

 

Impact

Alternative and/or complementary technology:

 

Current Technology:

There is no standard therapy for CAPS within the EU. Severe flares are managed symptomatically with anti-inflammatory products. Daily anakinra (Kineret, unlicensed) an IL-1 receptor antagonist, has been reported to be effective in anecdotal case reports.

Health Impact:

 

Diffusion:

 

Cost, infrastructure and economic consequences:

 

Ethical, social, legal, political and cultural impact:

 

Evidence & Policy

Clinical evidence and safety:

Trial: NCT00288704; FCAS and MWS; rilonacept vs placebo; phase III (stage 1).
Sponsor: Regeneron.
Status: Published (2).
Location: USA.
Design: Randomised, double blind, controlled, stratified by disease activity.
Participants and schedule: n=47; adults; FCAS (n=44) or MWS (n=3).
Randomised to loading dose rilonacept 320mg
then rilonacept 160mg per week or placebo for 6 wks.
Follow-up: 6 weeks treatment period.
Primary outcomes: Patient assessed disease activity (key symptoms).
Secondary outcomes: Response: 30, 50 or 70% response in key symptoms, multi- and single symptom disease flare days, physicians assessment of disease activity, limitations in daily activities, C-reactive protein and serum amyloid A (SAA), safety.
Key results: Mean change in key symptom score -2.6 with rilonacept and -0.3 with placebo (p=0.0001).
Rilonacept reduced the number of multi-symptom (rilonacept
-8.5, placebo -1.2) and single-symptom (rilonacept -12.1, placebo -1.2) flare days (p<0.0001), and significantly improved the physician’s global assessment of health (p<0.0001) and all other secondary outcomes.
Adverse effects (AEs): 74% of the rilonacept and 54% of placebo group experienced treatment emergent AEs. The most common AEs with rilonacept was injection site reaction (48%) and upper respiratory tract infection (26%). 1 discontinuation due to pre-existing hepatitis C virus infection.

Trial: NCT00288704; FCAS and MWS; rilonacept vs placebo; phase III (stage 2).
Sponsor: Regeneron.
Status: Published (2).
Location: USA.
Design: Single blind extension, then randomised, controlled, withdrawal trial.
Participants and schedule: n=46 completing NCT00288704 (stage 1); all participants received rilonacept 160mg per week for 9 weeks, then randomised to rilonacept 160mg per week or placebo for 9 weeks.
Follow-up: 18 weeks treatment period.
Primary outcomes: Patient assessed disease activity (key symptoms).
Secondary outcomes: Response: 30, 50 or 70% response in key symptoms, multi- and single symptom disease flare days, physicians assessment of disease activity, daily activities, C-reactive protein and serum amyloid A (SAA), safety.
Key results: 9 week extension: patients on rilonacept from stage 1 maintained benefits; patients on placebo in stage 1 had rapid improvement in symptoms.
Withdrawal study: rilonacept maintained low key symptom scores vs. placebo (+0.1 vs. +1.0, p=0.0002). Also significantly better at maintaining low multi- and single symptom flare days, and physician’s global assessment of health.
Adverse effects (AEs): The most common AEs were injection site reaction (rilonacept 36%, placebo 13%). Other common AEs with rilonacept included headache, arthralgia and diarrhoea.

Trial: NCT00288704 extension; FCAS and MWS.
Sponsor: Regeneron.
Status: Abstract (3).
Location: USA.
Design: Open-label extension.
Participants and schedule: n=56; completing NCT00288704 and 12 new patients.
Received rilonacept 160mg per week.
Follow-up: 24 weeks additional treatment period.
Primary outcomes: Patient assessed disease activity (key symptoms).
Secondary outcomes: Disease flare days, C-reactive protein and serum amyloid A (SAA), safety.
Key results: The efficacy of rilonacept was sustained over the additional 24 week period.
Adverse effects (AEs)

Economic evaluation:

 

Ongoing research:

 

Ongoing or planned HTA:

 

Web link:

http://www.nhsc-healthhorizons.org.uk/outputs/specialties/

References and sources:

European Medicines Agency (EMEA). Pre-authorisation evaluation of medicines for human use. Committee
for orphan medicinal products. Public summary of positive opinion for orphan designation of rilonacept for the
treatment of cryopyrin-associated periodic syndromes (familial cold urticaria syndrome (FCUS), Muckle - Wells syndrome (MWS), and neonatal onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurological cutaneous articular syndrome CINCA). 29th July 2008.
http://www.emea.europa.eu/pdfs/human/comp/opinion/17086808en.pdf Accessed 6th July 2009.
Hoffman HM, Throne ML, Amar NJ, et al. Efficacy and safety of rilonacept (Interleukin-1 Trap) in patients
with cryopyrin associated periodic syndromes. Arthritis & Rheumatism 2008;58:2443-2452.
Hoffman H, Wolfe F, Kavanaugh A et al. Sustained efficacy of rilonacept (IL-1 Trap) in patients with cryopyrin-associated periodic syndromes (CAPS). American Collage of Rheumatology 2007 Annual Scientific Meeting. Abstract 1291.

Notes: