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The New England Journal of Medicine reports that the anti-interleukin (IL)-1β monoclonal antibody canakinumab (Ilaris) was effective in the treatment of three distinct autoinflammatory recurrent fever syndromes (FMF, TRAPS, HIDS) with responses that were far superior to what was seen with placebo on almost every outcome measure, a randomized study found.
At week 16, significantly more patients with colchicine-resistant familial Mediterranean fever had a complete response to canakinumab treatment compared with placebo (61% versus 6%, P<0.001), according to Fabrizio De Benedetti, MD, PhD, of Ospedale Pediatrico Bambino Gesù in Rome, and colleagues.
Similarly, complete responses at 16 weeks were seen in 35% of patients with mevalonate kinase deficiency receiving canakinumab compared with 6% of those given placebo (P=0.003), and in 45% versus 8% (P=0.006) of those with tumor necrosis factor receptor-associated periodic syndrome (TRAPS).
These three monogenic diseases are characterized by recurrent fevers as well as involvement of the joints, skin, and serous membranes, and in all three, excessive IL-1β production has been observed. However, the precise molecular mechanisms leading to disease differ. In familial Mediterranean fever, mutations of MEFV lead to activation of the pyrin inflammasome and in TRAPS, the IL-1β production results from deposits of aberrant tumor necrosis factor receptor 1 proteins in the endoplasmic reticulum. Mevalonate kinase deficiency, also known as the hyperimmunoglobulinemia D syndrome, results from pyrin inflammasome activation and inflammatory responses from toll-like receptors.
Conventional treatment of familial Mediterranean fever is with colchicine, but this drug is ineffective or cannot be tolerated in 5-10% of patients. No standard treatments are available for the other two syndromes.
"The treatment of the hereditary periodic fever syndromes was revolutionized by the off-label use of the human recombinant IL-1 receptor antagonist anakinra [Kineret]," said Michael J. Ombrello, MD, head of the Translational Genetics and Genomics Unit of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, who was not involved in the study.
"In some patients, daily injections of anakinra rapidly aborted inflammatory episodes when used at the time of flare," he told MedPage Today. Although the treatment also reduced the frequency, severity, and duration of flares, "the administration of daily injections is an obstacle to its continuous use, particularly in young patients."
Canakinumab has been shown to be effective in systemic juvenile idiopathic arthritis and cryopyrin-associated periodic syndromes, and is administered subcutaneously every 4 to 8 weeks.
To examine the possible effects of canakinumab for these autoinflammatory diseases, De Benedetti and colleagues conducted the multicenter, international phase III Canakinumab Pivotal Umbrella Study in Three Hereditary Periodic Fevers (CLUSTER) trial, which was supported by Novartis.
"The design of our trial was chosen to address the rarity of the diseases, the wide age range, and the need for a randomized, controlled trial, while exploiting the hypothesis of a key common mediator. It also allowed the creation of a larger safety database," the team explained.
Study and Patients
Patients were enrolled at the time of a flare, and were randomly assigned to receive subcutaneous canakinumab, 150 mg or 2 mg/kg for patients weighing 40 kg or less, or placebo every 4 weeks. A flare was defined as a level of C-reactive protein (CRP) above 10 mg/L and a physician's global assessment of 2 or above.
Patients whose baseline flare persisted through days 8 to 14 or whose flare had not resolved by day 15 could have a blinded dose increase of an additional 150 mg every 4 weeks.
Between weeks 16 and 40, patients who had met the primary endpoint of complete response at week 16 were re-randomized to have 150 mg canakinumab or placebo every 8 weeks, to assess the possibility of using this lower dose as maintenance. Those receiving placebo who had flare within 8 weeks switched to open-label treatment with 150 mg every 4 weeks, and those who flared after 8 weeks were given canakinumab 150 mg every 8 weeks.
The study cohort included 63 patients with colchicine-resistant familial Mediterranean fever whose mean age was 22 and whose mean disease duration was 16 years. Slightly more than half of the patients were male, and the number of episodes of fever in the previous year ranged from 21 to 28. Physician's global score was 3 or 4 for most of the patients, and CRP levels ranged from 118 to 164 mg/L.
The group with mevalonate kinase deficiency included 72 patients whose mean age was 13 and whose disease duration was 12 years. More than half were female, and the number of fever episodes in the previous year averaged 15. Most had a physician's global score of 3, and CRP levels ranged from 163 to 182 mg/L.
The TRAPS group included 46 patients whose mean age was 22 and whose disease duration was 14 years. The sexes were equally represented, and the mean number of episodes of fever in the previous year was 10. Most had physician's global scores of 2 or 3, and levels of CRP ranged from 133 to 183 mg/L.
Efficacy and Safety
During the first randomization period, the complete response rates for those who had a blinded dose increase to 300 mg every 4 weeks were 71% for those with familial Mediterranean fever, 57% for those with mevalonate kinase deficiency, and 73% for those with TRAPS (P< 0.001 versus placebo for all).
Canakinumab treatment also was associated with responses on various secondary endpoints at week 16. In the familial Mediterranean fever group, more patients in the active treatment group had a physician's global score less than 2 (65% versus 9%, P<0.001), as did patients in the mevalonate kinase deficiency group (46% versus 6%, P=0.001) and those with TRAPS (45% versus 4%, P=0.006). The percentages with CRP levels of 10 mg/L or less were 68% versus 6% (P<0.001), 41% versus 6% (P=0.002), and 36% versus 8% (P=0.03), respectively.
Among patients who had a complete response during the second randomization, an absence of flares was maintained through week 40 in 100% of the familial Mediterranean fever group, 82% of the mevalonate kinase deficiency group, and 83% of those with TRAPS.
The extended dosing period of every 8 weeks was adequate for disease control in 46% of patients with familial Mediterranean fever, 23% of those with mevalonate kinase deficiency, and 53% of those with TRAPS.
The most common adverse events were infections, with 12 considered serious. The investigators noted that adverse events and serious adverse events were significantly more common among canakinumab-treated patients during the placebo-controlled phase of the study.
Ombrello called the research "a pivotal study within the field of autoinflammation, because the data from this study were the basis for the FDA approval of canakinumab for the treatment of colchicine-resistant familial Mediterranean fever, hyperimmunoglobulinemia D periodic fever syndrome, and TRAPS in September 2016."
The study was supported by Novartis. The investigators reported financial relationships with Novartis, AbbVie, Hoffmann-La Roche, Novimmune, Pfizer, R-Pharm, Sanofi, Sobi, Chugai, Biovitrum, Baaristol-Myers Squibb, MedImmune, Novimmune, Neovii, Neopharm, and Servier; several of the co-authors were employees of Novartis.