Recognition that three unrelated rare fever syndromes are all mediated by a single interleukin opened a new approach for controlling flares in the diseases.

A clinical trial including cohorts of patients who have colchicine-resistant familial Mediterranean fever (crFMF), mevalonate kinase deficiency, or the tumor necrosis factor receptor–associated periodic syndrome (TRAPS) confirmed that the interleukin 1β inhibitor canakinumab (Ilaris, Novartis) effectively controlled or prevented flares in all three diseases, researchers reported.

The phase 3 data, published online May 17 in the New England Journal of Medicine, were from the Canakinumab Pivotal Umbrella Study in Three Hereditary Periodic Fevers (CLUSTER) study.

The three monogenic autoinflammatory syndromes are all characterized by recurrent fevers lasting days or weeks, as well as by debilitating joint and muscle pain. Colchicine is standard treatment for familial Mediterranean fever, but is ineffective or associated with unacceptable adverse effects in 5% to 10% of patients.

Until the FDA approved canakinumab in September 2016 for familial Mediterranean fever, mevalonate kinase deficiency, and TRAPS, there had been no approved therapies for the latter two disorders.

"At this moment, we do not have other promising medications which may be useful in the most difficult-to-treat patients with familial Mediterranean fever. Many anecdotal reports suggested that canakinumab could be a fruitful option in cases nonresponsive to the daily prophylactic administration of colchicine. Now we have a proof of canakinumab working for these patients," Donato Rigante reported.

CLUSTER Clinical Trial Design

The trial was designed to determine whether canakinumab is effective and comprises three groups of patients with severe recurrent fever disorders: crFMF, mevalonate kinase deficiency, and TRAPS.

This required a clinical trial design that would encompass the different frequencies and durations of fever episodes in the 3 diseases, different clinical presentations, the rarity of these diseases, the wide age range of affected patients, and the need for a randomized controlled trial. The upside of the complicated trial design is that it produced a larger safety database, the authors note.

Study Viewed as Breakthrough for These Syndromes

Rigante commented, "The study of De Benedetti et al. has had a difficult gestation, but today, with its global diffusion, it appears as a very important message and exciting instrument for clinicians involved in the management of patients with hereditary periodic fevers, as it ascertains the beneficial effects that canakinumab might have for managing complex cases of patients with autoinflammatory syndromes.

This is true, of course, for patients with [crFMF], mevalonate kinase deficiency, and tumor necrosis factor receptor–associated periodic syndrome, which are the most relevant hereditary causes of periodic fever in the world.

Schulert said that the key unanswered questions are why some patients have an excellent response to treatments such as canakinumab, but others do not, and what would be the best treatment for those patients?

Canakinumab was approved by the US Food and Drug Administration in September 2016 for use in FMF, mevalonate kinase deficiency, and TRAPS. Canakinumab had been approved previously for treatment of Cryopyrin-Associated Periodic Syndromes, Familial Cold Autoinflammatory Syndrome, and Muckle-Wells Syndrome.