New results from a one-year phase-III study have confirmed that the investigational biological therapy Ilaris (canakinumab, formerly ACZ885) produced rapid and sustained remission of symptoms in the majority of children and adults with a rare and potentially life-threatening auto-inflammatory disease called cryopyrin-associated periodic syndrome (CAPS).

The study showed that more than 90 of CAPS patients treated with Ilaris (28 out of 31) remained in remission at the end of the final four-month phase of the study. This finding supported interim data from earlier phases showing efficacy in 97 to 100 per cent of patients. The full results have now been published in The New England Journal of Medicine.

"This study represents an important step forward for the rare disease community, as canakinumab treats the underlying causes of CAPS rather than just the symptoms," said Helen J Lachmann of the UK National Amyloidosis Centre at the Royal Free and University College Medical School in London, UK. "In the study, patients experienced a benefit within hours after receiving a single dose of canakinumab and only needed further treatment every two months to control their symptoms. This may give canakinumab a significant advantage over current therapies in an area of unmet medical need."

CAPS includes a number of lifelong diseases associated with a gene mutation and characterized by the overproduction of interleukin 1-ß (IL-1ß), a protein (or cytokine) that has a pivotal role in driving inflammation and tissue destruction. The clinical benefits of Ilaris, a fully human monoclonal antibody, are due to its selective and long-lasting blockade of IL-1ß1. By neutralizing IL-1ß for a sustained period, Ilaris switches off all symptoms of inflammation in CAPS, as demonstrated in new research published in The Journal of Experimental Medicine.

The success in treating CAPS led Ilaris to be investigated also in other rare diseases such as systemic juvenile idiopathic arthritis (SJIA), or more common ones such as some forms of gout, chronic obstructive pulmonary disorder (COPD), rheumatoid arthritis and type-2 diabetes.

The Novartis research and development strategy for Ilaris involves using proof-of-concept studies which are small-scale phase-I clinical trials in genetically well-defined diseases to determine how genes interact in molecular or 'signalling' pathways10. The resulting clinical and biomarker data are then subjected to state-of-the-art modelling and simulation to yield new insights into the regulation of IL-1ß in patients.

"Ilaris is the outcome of our highly innovative approach to research and development that is designed to bring more and better targeted medicines to patients in the shortest possible time," said Trevor Mundel, head of Global Development at Novartis Pharma AG. "We are extremely excited about the efficacy shown by Ilaris in patients with CAPS, and we hope to be able to extend these benefits to many more patients with other inflammatory diseases which are more widespread, and often equally debilitating."

CAPS comprises three syndromes of increasing severity: familial cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID). Patients with CAPS experience debilitating fatigue, fever and chronic anemia from infancy. Inflammation can affect the skin, eyes and bones causing rashes, conjunctivitis and destructive arthritis. Other severe complications of CAPS include progressive hearing loss, visual and intellectual impairment, and amyloidosis, a condition in which the build-up of proteins can cause vital organs to fail. About 25 per cent of CAPS patients develop systemic amyloidosis resulting in renal failure, and usually in death within five to 10 years.

The phase-III clinical trial in CAPS was a multinational, randomized, double-blind and placebo-controlled study designed to assess the efficacy, safety and tolerability of Ilaris. The 48-week study involved 35 patients aged nine to 74 years old and was divided into three parts1. First interim results were presented at the American Rheumatology College meeting in October 20085, while full one-year results are now published for the first time in The New England Journal of Medicine1.

In the first part of the study lasting eight weeks, 35 patients received a single dose of Ilaris (150 mg by subcutaneous injection). All but one patient (97 per cent) showed a rapid and complete response. After this, 31 patients who maintained their response proceeded to part two, a randomized 24-week, double-blind placebo-controlled phase. Patients were treated every eight weeks with either Ilaris or placebo and if a relapse occurred, they entered part three.

Part two of the study included the primary endpoint, a comparison between the number of patients treated every eight weeks with Ilaris who experienced disease relapse or 'flares' vs. those on placebo. Results showed that no patients in the Ilaris group experienced a disease flare compared to 13 out 16 patients in the placebo group (0% vs. 81%, p<0.001).

Following either completion of part two or occurrence of a disease flare, patients proceeded to part three which involved at least two further doses of Ilaris for a minimum of 16 weeks. Out of 31 patients who entered part three, 28 completed this phase of the study without suffering a relapse (90 per cent). One patient suffered a relapse on the last day of the study, i.e. 62 days after receiving their last dose of Ilaris. In addition, one patient discontinued the study due to a perceived lack of therapeutic response, and one discontinued because of a urinary tract infection.

Ilaris was generally well tolerated, with no consistent pattern of adverse events beyond an increase in all suspected infections. Two patients experienced serious adverse events but there were no deaths or life-threatening adverse events during the study.

Ilaris has orphan drug status in the EU, US, Switzerland and Australia for the treatment of CAPS and is currently under priority review by the regulatory authorities in US, Switzerland and Australia. Regulatory review is also underway in the EU.