Ilaris "switches off" periodic syndromes in Phase III study

Novartis's injectable fully humanised monoclonal antibody, Ilaris (canakinumab) has been shown to send 90% of patients with cryopyrin-associated periodic syndromes (CAPS) into remission in a Phase III study, published in the NEJM online of June 4th.

"There are not many diseases that you can just switch off with a drug, and this is one of those rare and fantastic cases," said Dr Helen Lachmann of the University College Medical School in London, and lead author of the study.

"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."

Novartis has submitted marketing approvals for Ilaris in the US, EU, Switzerland and Australia, where it has orphan drug status.

The product is also in Phase III development for rheumatoid arthritis and in Phase II for hyperuricaemia, type 2 diabetes and chronic obstructive pulmonary disease (COPD).

Two other therapies are licensed to treat CAPS. The first is Regeneron's Arcalyst (rilonacept), a weekly dosed cytokine trap protein which blocks the activity of interleukin-1., It is not yet available in the EU.

The second is Amgen's Kineret (anakinra) – which according to Dr Lachmann revolutionised treatment of the syndromes because it was the first therapy to achieve a complete response. However, it is administered as a once-daily injection, which is unpopular with patients and can cause injection site reactions.

CAPS are rare inherited auto-inflammatory conditions, which include Muckle-Wells syndrome and familial cold auto-inflammatory disorder. They are associated with mutations the NLRP3 gene which encodes cryopyrin – a component of the interleukin-1 inflammasome that regulates the production of the pro-inflammatory cytokine interleukin-1β, which mediates local and systemic responses to infection and tissue injury.

Symptoms of CAPS include fever, fatigue, rash, joint and muscle pain and in severe cases, deafness, amyloidosis and disabilities of the central nervous system.

As with Kineret, Ilaris is an interleukin-1b antagonist that selectively blocks interleukin-1b, but has no cross-reactivity with interleukin-1 subtypes – which may minimise the risk of antigenicity. Kineret however is dosed once daily; Ilaris is administered once every eight weeks.

Phase III

The six-month CAPS Phase III study was divided into three parts. The first enrolled 35 patients who received a single dose of Ilaris by subcutaneous injection and were observed for the following two months. The company said 34 out of 35 patients showed a rapid and long-lasting clinical and biochemical response.

In part two, 31 of those patients continued on to a randomised, double-blind, placebo-controlled six-month study. The primary endpoint was a comparison between the patients treated every two months with ACZ885 who experienced a disease flare compared to those who received placebo.

The study was concluded with a four-month open-label, active-treatment period in which the patients received Ilaris every eight weeks, to provide further efficacy and safety data.

The patients enrolled were aged between four and 75 years old and weighed between 15kg and 100kg. Patients who had previously received treatment with Kineret, Arcalyst or Ilaris were eligible to participate after such treatment had been discontinued and their disease had relapsed.

The primary endpoint was the proportion of patients with a relapse of CAPS during Ilaris treatment, as compared with placebo.

A complete response to treatment was defined as a global assessment of no or minimal disease activity by a physician, an assessment of no or minimal rash, and a value for both serum C-reactive protein (CVRP), and serum amyloid A protein (SAA) that was within the normal range (<10mg per="" litre="" for="" both="" measures).="">

Relapse was defined as a value for CVRP or SAA of more than 30mg per litre, accompanied by a physician's assessment of global disease activity that was greater than minimal and accompanied by a rash that was assessed as more than minimal.

Of the 35 patients enrolled in part one, 34 (97%) had a complete response to treatment with a single dose of Ilaris. According to Novartis, symptoms of CAPS diminished within 24 hours in patients who had a response. A complete response was achieved by day eight in 25 patients, by day 15 in eight patients, and by day 29 in one patient.

Three patients who had a complete response in part one did not progress to part two. One patient withdrew because they were not satisfied with their therapeutic response and two others were withdrawn in order to avoid being randomised to placebo for part two.

During the double-blind part two phase, all 15 patients in the Ilaris group remained in remission and 13 of the 16 patients (81%) in the placebo group had a disease flare (p<0.001). at="" the="" end="" of="" part="" two,="" six="" of="" the="" 15="" patients="" (40%)="" in="" the="" ilaris="" group="" had="" a="" complete="" absence="" of="" symptoms,="" as="" compared="" with="" no="" patients="" in="" the="" placebo="">

All 31 patients progressed to part three, although two patients did withdraw during this phase – one had an unsatisfactory therapeutic response, and the other had a recurrent Escherichia coli urinary tract infection.

A total of 30 out of the 31 patients who had entered part three (97%) had no or minimal disease activity and the remaining patients had mild disease activity.

Two of the trial's participants had serious adverse events while receiving Ilaris. In addition to the case of the urinary tract infection, one patient had an episode of vertigo accompanied by acute-angel glaucoma, which was attributable to CAPS.

"The use of canakinumab was not associated with any clear pattern of adverse events other than an increase in the rate of suspected infections," said Dr Lachmann. "The incidences were not worrying, but will require to be monitored during post-marketing."