Rilonacept

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According to Wikipedia:
Rilonacept (marketed under the trade name Arcalyst), is a dimeric fusion protein for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease.

It was given an "Orphan Drug" status by the United States Food and Drug Administration. It was approved by the FDA on February 2008.

Clinical trials of Rilonacept in gout:
Study Utilizing Rilonacept in Gout Exacerbations (SURGE) (http://www.goutonline.net/showthread.php?t=68)
Review of Safety Using Rilonacept in Preventing Gout Exacerbations (RE-SURGE) (http://www.goutonline.net/showthread.php?t=65)

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Press Release:
Regeneron's ARCALYST(R) (rilonacept) Reduced Incidence of Gout Flares by 81 Percent in a Phase 2 Study in Gout Patients Initiating Urate-Lowering Therapy
Proportion of patients experiencing gout flares reduced from 45.2 percent to 14.6 percent
TARRYTOWN, N.Y--Sept. 3, 2008--Regeneron Pharmaceuticals, Inc. (Nasdaq: REGN) today announced that treatment with ARCALYST(R) (rilonacept), also known as IL-1 Trap, in a Phase 2 study of gout patients initiating therapy with allopurinol to lower their uric acid levels, produced a statistically significant reduction versus placebo in the incidence of gout flares. In this 83-patient, double-blind, placebo-controlled study, the mean number of flares per patient over the first 12 weeks of urate-lowering therapy was 0.79 with placebo and 0.15 with ARCALYST (p=0.0011), an 81 percent reduction. This was the primary endpoint of the study. All secondary endpoints also were met with statistical significance.

In the first 12 weeks of treatment, 45.2 percent of patients treated with placebo experienced a gout flare and, of those, 47.4 percent had more than one flare. Among patients treated with ARCALYST, only 14.6 percent experienced a gout flare (p=0.0037 versus placebo) and none had more than one flare. No serious drug-related adverse events were reported in patients receiving ARCALYST treatment. Injection-site reaction was the most commonly reported adverse event with ARCALYST treatment. Detailed data from the study will be presented at a future scientific conference.

This Phase 2 study evaluated the efficacy and safety of ARCALYST versus placebo in the prevention of gout flares induced by the initiation of uric acid-lowering drug therapy that is used to control gout. ARCALYST patients received an initial 320 milligram (mg) dose, followed by weekly doses of 160 mg. Gout is characterized by high blood levels of uric acid, a bodily waste product normally excreted by the kidneys. The uric acid can form crystals in the joints of the toes, ankles, knees, wrists, fingers, and elbows. Chronic treatment with uric acid-lowering medicines, such as allopurinol, is prescribed to eliminate the uric acid crystals and prevent reformation. During the first months of allopurinol therapy while uric acid blood levels are being reduced, the break up of the uric acid crystals can result in stimulation of inflammatory mediators, including interleukin-1 (IL-1), resulting in acute flares of joint pain and inflammation. These painful flares generally persist for at least five days. In this study a gout flare was defined as patient-reported acute joint pain that was deemed by the patient and/or investigator to require rescue treatment with an anti-inflammatory drug.

"These findings could be significant in the future management of patients with gout in that they address an impediment to successful long-term treatment. Allopurinol therapy is an important approach to lowering patients' high uric acid levels, which is the cause of their gout. However, the increased risk of painful gout flares over the first few months of initiation of uric acid-lowering therapy makes it difficult for patients to stick with treatment," said John Sundy, M.D., Ph.D., Division of Rheumatology, Department of Medicine, Duke University Medical Center. "Currently, colchicine or anti-inflammatory drugs are recommended for use to reduce the risk of gout flares in patients taking allopurinol, but these drugs may cause side effects and some patients do not tolerate them. The results from this study suggest that concomitant use of rilonacept during the first several months of allopurinol therapy may help avoid gout flares, which could, in turn, improve patient outcomes."

"We are encouraged about the potential role of ARCALYST(R) (rilonacept) therapy in the treatment of gout. The results of this study, together with the findings of a previous small study of ARCALYST in patients with chronic, active gout, suggest that ARCALYST may provide utility in a number of different gout patient populations," stated George D. Yancopoulos, M.D., Ph.D., President of Regeneron Research Laboratories. "Based upon these results, we plan to initiate a Phase 3 clinical development program early next year with ARCALYST in the prevention of gout flares in patients initiating urate-lowering drug therapy. Studies in other gout settings are also planned."

[Admin]

Press Release:

Regeneron Announces Initiation of Phase 3 Gout Program with ARCALYST® (rilonacept)
Regeneron Pharmaceuticals, Inc. (Nasdaq: REGN) today announced that patient enrollment has been initiated in the Phase 3 program evaluating the efficacy and safety of ARCALYST® (rilonacept), also known as IL-1 (interleukin-1) Trap, in the prevention of gout flares associated with the initiation of urate-lowering drug therapy and in the treatment of acute gout attacks. ARCALYST is approved in the U.S. for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including Familial Cold Auto-inflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS) in adults and children 12 and older.

This Phase 3 program with ARCALYST in gout was designed following discussions with the United States Food and Drug Administration. It will consist of four clinical studies. The North American-based PRE-SURGE 1 (PREventative Study against URate-lowering drug-induced Gout Exacerbations) study and the global PRE-SURGE 2 study are each evaluating the number of gout flares per patient over the first 16 weeks of initiation of allopurinol therapy. Allupurinol is used to reduce serum uric acid levels in patients with gout. 240 patients will be randomized on a 1:1:1 basis to receive one of the following treatment regimens:

ARCALYST 160 milligrams (mg) as an initial loading dose, followed by weekly 80 mg subcutaneous injections
ARCALYST 320 mg as an initial loading dose, followed by weekly 160 mg subcutaneous injections
Weekly placebo injections
The global SURGE (Study Utilizing Rilonacept in Gout Exacerbations) study in patients experiencing an acute gout attack is evaluating pain during the initial 72 hours of treatment. 225 patients will be randomized on a 1:1:1 basis to receive one of the following treatment regimens:

ARCALYST 320 mg administered by subcutaneous injection on day 1 plus oral placebo taken for 12 days
ARCALYST 320 mg administered by subcutaneous injection on day 1 plus oral indomethacin (an anti-inflammatory drug currently indicated for the treatment of gout) taken for 12 days
Placebo administered by subcutaneous injection on day 1 plus oral indomethacin taken for 12 days
The last of the four studies, the global RE-SURGE (REview of Safety Using Rilonacept in preventing Gout Exacerbations) study, is evaluating the safety of ARCALYST versus placebo over 16 weeks in patients who are at risk for gout flares because they are taking urate-lowering drug treatment. 300 patients will receive placebo and 900 patients will receive ARCALYST dosed at 320 mg as an initial loading dose, followed by weekly 160 mg subcutaneous injections. Patients can be taking any of four urate-lowering drugs, allopurinol, febuxostat, probenecid, or sulfinpyrizone, with no requirements in the study design as to the total number of patients taking each.

“Nearly one and a half million Americans are treated for gout each year, but significant unmet medical needs persist,” said George D. Yancopoulos, M.D., Ph.D., President of Regeneron Research Laboratories. “Although chronic urate-lowering therapy is generally effective in achieving long-term gout symptom control, many patients discontinue treatment because they cannot tolerate painful gout flares that occur during the first few months of therapy. In the acute gout setting, treatment with available anti-inflammatory drugs is limited by inadequate pain relief or safety concerns in many patients. This comprehensive Phase 3 program reflects our enthusiasm for the potential role of ARCALYST® (rilonacept) therapy in these two gout patient populations. Initial data from this program are expected next year.”

The Phase 3 program in gout is supported by data from two previous studies of ARCALYST. In a Phase 2 study of gout patients initiating therapy with allopurinol to lower their uric acid levels, treatment with ARCALYST produced a statistically significant reduction versus placebo in the incidence of gout flares. In this 83-patient, double-blind, placebo-controlled study, the mean number of flares per patient over the first 12 weeks of urate-lowering therapy was 0.79 with placebo and 0.15 with ARCALYST (p=0.0011), an 81 percent reduction. In the first 12 weeks of treatment, 45.2 percent of patients treated with placebo experienced a gout flare and, of those, 47.4 percent had more than one flare. Among patients treated with ARCALYST, only 14.6 percent experienced a gout flare (p=0.0037 versus placebo) and none had more than one flare. No drug-related serious adverse events were reported in patients receiving ARCALYST treatment. Injection-site reaction was the most commonly reported adverse event with ARCALYST treatment.

In a Phase 1, single-blind study of 10 patients with chronic active gout, patients received placebo for two weeks and were then treated with ARCALYST. Treatment with ARCALYST resulted in a statistically significant reduction in patient pain scores, the key symptom measure in persistent gout. Mean patient pain scores were substantially reduced during blinded active treatment (-41 percent, p=0.025, during the first two weeks of active treatment, and -56 percent, p <0.004, after six weeks of active treatment), as compared to changes during the blinded two-week placebo run-in period (-13 percent, which was not statistically significant). After six weeks of ARCALYST treatment, 70 percent of patients achieved at least a 50 percent improvement in their pain scores; whereas none of the patients achieved a 50 percent improvement in their pain scores during the placebo run-in period. In this study, in which safety was the primary endpoint measure, treatment with ARCALYST was generally well tolerated with injection-site reaction being the only reported drug-related adverse event.

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The IL-1 inhibitor rilonacept in treatment of chronic gouty arthritis: results of a placebo-controlled, monosequence crossover, nonrandomized, single-blind pilot study.
Terkeltaub R, Sundy JS, Schumacher HR, Murphy F, Bookbinder S, Biedermann S, Wu R, Mellis S, Radin A.
Ann Rheum Dis. 2009 Jul 26. [Epub ahead of print] (http://www.ncbi.nlm.nih.gov/pubmed/19635719?dopt=Abstract)
OBJECTIVES: Recent studies suggest that blockade of the NLRP3 (cryopyrin) inflammasome IL-1beta pathway may offer a new treatment strategy for gout. This proof-of-concept study explored the potential utility of rilonacept (IL-1 Trap) in patients with chronic active gouty arthritis.

METHODS: This 14-week, multicenter, nonrandomized, single-blind, monosequence crossover study of 10 patients with chronic active gouty arthritis included a placebo run-in (2-weeks), active rilonacept treatment (6-weeks), and a 6 week post-treatment follow-up.

RESULTS: Rilonacept was generally well tolerated. No deaths and no serious AEs occurred during the study. One patient withdrew due to an injection-site reaction. Patients' self-reported median pain VAS scores significantly decreased from Week 2 (following placebo run-in) to Week 4 (2 weeks of rilonacept) (5.0 to 2.8; P < 0.049), with sustained improvement at Week 8 (1.3; P < 0.049); 5 of 10 patients reported at least a 75% improvement. Median symptom severity-adjusted joint scores were significantly decreased. hs-CRP levels fell significantly.

CONCLUSIONS: This proof-of-concept study demonstrated that rilonacept is generally well tolerated and may offer therapeutic benefit in reducing pain in patients with chronic refractory gouty arthritis, supporting the need for larger, randomized, controlled studies of IL-1 antagonism such as with rilonacept for this clinical indication.

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This clinical trial has just been registered:

PREventative Study Against URate-Lowering Drug-Induced Gout Exacerbations (PRE-SURGE 2)
(http://clinicaltrials.gov/ct2/show/NCT00958438)
The purpose of this clinical research study is to determine the safety and effectiveness of an experimental drug called rilonacept in subjects with gout who are beginning allopurinol treatment for gout. Subjects will participate in this study for approximately 22 weeks. Rilonacept is being studied for use in preventing allopurinol-induced gout flares.

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Press Release:
Clinical trial demonstrates that rilonacept significantly reduces gout flares
Drug appears to be well tolerated by patients
A phase II clinical trial found that rilonacept, an inhibitor of the protein interleukin-1 (IL-1), significantly reduced acute gout flares that occur when initiating uric acid-lowering therapy. Results of the trial—the first placebo-controlled study investigating IL-1 targeted therapy in prevention of gout flares—show rilonacept to be generally well tolerated with no serious infections or treatment-related serious adverse events reported. Full findings are published in Arthritis & Rheumatism, a journal of the American College of Rheumatology (ACR).

Patients with gout—a type of inflammatory arthritis caused by the crystallization of urates in soft tissues—experience severe pain and swelling, often affecting the feet. A recent study also published in Arthritis & Rheumatism reported that doctor-diagnosed gout has risen over the past twenty years and now affects 8.3 million individuals in the U.S. Previous research shows that while gout attacks typically resolve spontaneously over several days, urate crystals remain in the joint, which can lead to recurrent attacks and if left untreated may permanently damage joints.

"To reduce deposits of crystals in the joints, we advise patients to initiate treatment with medications that lower levels of uric acid in the blood," said lead investigator Dr. H. Ralph Schumacher, Jr., Professor of Medicine at the University of Pennsylvania School of Medicine. The authors explain that in the early months of urate-lowering therapy, as crystal deposits are broken up, patients may experience gout attacks that are proposed to be due to the release of crystals from softened deposits. These urate crystals interact with cells that release interleukin-1 (IL-1) which can lead to a cascade of inflammation and acute joint pain flares.

Previous research has found that acute gout attacks brought on by uric acid-lowering therapy may make patients less likely to continue treatment. "Well tolerated drugs that reduce the risk of gout flares when initiating uric-acid lowering therapy could make patients more likely to continue important long-term treatments that control gout," added Dr. Schumacher.

Rilonacept—marketed under the brand name ARCALYST® to treat another disease—is designed to neutralize the protein IL-1 before it produces signals that can trigger inflammation. Thus, researchers looked to test the effectiveness of rilonacept in preventing gout flares and enrolled 83 patients at 27 study centers across the U.S. for a phase II clinical trial. Participants were 18 years of age or older and had gout, including a history of two or more gout flares within the prior year, as well as elevated blood levels of uric acid. Participants were randomized in a double blind fashion, with 41 administered rilonacept via subcutaneous injection (a double dose [320 mg], followed by (160 mg weekly for 16 weeks) and 42 administered weekly placebo. All patients were started on allopurinol (300mg/day) to reduce uric acid levels.

Trial results revealed a significantly lower number of gout flares in participants taking rilonacept with only 6 flares in the rilonacept arm compared with 33 in the placebo group. Researchers also observed fewer flares in patients treated with rilonacept as early as four weeks following the start of therapy. At the 12-week study point, only 15% of patients taking rilonacept had experienced gout flares compared to 45% of those in the placebo group. No deaths or serious infections occurred in either group. Common adverse events included infections reported in 15% of the rilonacept group compared with 26% with the placebo.

"This trial provides well-controlled evidence that this IL-1 blocker is effective in preventing acute gout flares in this setting," confirmed Dr. Schumacher. "Rilonacept appears safe and well tolerated and could increase patient adherence to long-term urate-lowering therapy." The authors recommend further evaluation of rilonacept in patients with gout.

Full citation:

"Rilonacept (IL-1 Trap) in the Prevention of Acute Gout Flares During Initiation of Urate-Lowering Therapy: Results of a Phase 2 Clinical Trial." H. R. Schumacher, Jr., John S. Sundy, Robert Terkeltaub, Howard R. Knapp, Scott J. Mellis, Neil Stahl, George D. Yancopoulos, Yuhwen Soo, Shirletta King-Davis, Steven P. Weinstein, Allen R. Radin on behalf of the 0619 Study Group. Arthritis & Rheumatism; Published Online: January 5, 2012 (DOI: 10.1002/art.33412). http://doi.wiley.com/10.1002/art.33412.