Ilaris: FDA Asks if Gout Symptom Relief Is Worth Infection Risks

The Food and Drug Administration is questioning whether the "primarily symptomatic relief" of gout provided by the injectable biologic canakinumab outweighs an increased risk of serious infections.

At a June 21 meeting, the FDA will ask its Arthritis Advisory Committee about acute, recurrent use of canakinumab (Ilaris, Novartis) in gout and the risk of infections and laboratory value abnormalities, according to agency briefing documents.

The committee will be asked to vote on whether canakinumab should be approved merely for second-line treatment of gouty attacks or whether efficacy and safety data support adding a claim for extending the time to next attack and reducing the frequency of subsequent attacks.

"Determining the benefit-risk profile of canakinumab for the treatment of acute gout flares in light of its extended pharmacodynamic effects, both desirable and undesirable, is complicated and will underlie the questions for discussion" at the committee meeting, Dr. Sarah Yim, medical team leader, division of pulmonary, allergy, and rheumatology products, wrote in a memo.

The agency also will ask the panel whether Novartis should explore lower doses of canakinumab and obtain additional data on repeated dosing over time.

"Although a fairly wide range of doses were studied early on, only the 150 mg dose of canakinumab was studied further in the gout clinical development program," Dr. Yim wrote. "Given that some of the safety findings suggest a dose-response, it would have been useful to have additional data from a lower dose, to assess whether adequate efficacy could have been provided with less undesirable effects on susceptibility to infection and laboratory abnormalities. However these data are not available."

Canakinumab, an interleukin-1 beta-inhibitor, won FDA approval 2 years ago for treatment of cryopyrin-associated periodic syndrome, an orphan indication. Canakinumab, also in clinical development for systemic juvenile idiopathic arthritis and cardiovascular disease, has hit snags in clinical evaluations in rheumatoid arthritis and diabetes.

By selectively binding and neutralizing IL-1B, canakinumab interrupts the signaling pathway for crystal-induced inflammation in gouty arthritis, Novartis said in its advisory committee briefing document.

Gout attacks are currently treated with anti-inflammatories such as colchicine (Colcrys, Mutual Pharmaceuticals), NSAIDs, and corticosteroids. The underlying pathology is treated by controlling hyperuricemia with urate-lowering therapies, such as allopurinol, probenecid, febuxostat (Uloric, Takeda Pharmaceuticals), and pegloticase (Krystexxa, Savient Pharmaceuticals).

Novartis is pursuing a second-line gout indication that canakinumab has been shown "to extend the time to next attack and reduce the frequency of subsequent attacks." The proposed indication is for treatment of gouty arthritis attacks in patients who do not respond to NSAIDs and colchicine. In its briefing document, Novartis says the targeted patient population is less than 10% of the approximately 300,000 U.S. patients who receive treatment for gouty arthritis. The second-line indication and the narrow population targeted could help turn the risk/benefit equation by demonstrating that the biologic’s potential adverse events are outweighed by the symptomatic and disease relief benefit it brings to patients who fail on first-line therapy.

Pain Reduction With Reduced Risk of New Flares

The supplemental biologics license application is supported by data from two identically designed phase III trials encompassing 454 patients who were intolerant of, or refractory to, NSAIDS or colchicine. Half of the patients in one study, and one-third in the other, were on urate-lowering therapy.

The studies measured two co-primary end points: mean difference in patient assessment of gout pain from baseline to 72 hours post dose using the Visual Analog Scale, and time to new gout flare. Patients were randomized to a single dose of either canakinumab 150 mg or the corticosteroid triamcinolone 40 mg on day 1 and followed for 12 weeks.

"Overall, both trials ... demonstrated statistically significant decreases in pain intensity measured on VAS for canakinumab, compared to triamcinolone, and statistically significant differences between treatment groups (favoring canakinumab) for the risk of a new gout flare," Dr. Yim wrote.

"Subgroup analyses of the co-primary efficacy endpoints were generally consistent with the overall efficacy results, including results for the subgroup of patients intolerant to, with contraindications for, or lack of efficacy from NSAIDs and/or colchicine; however, differences in the magnitude of the treatment effect in the subgroup of patients taking urate-lowering therapy versus those not taking urate therapy [were] observed."

Do Adverse Events Trump Symptom Relief?

While FDA reviewers describe the benefits as primarily symptomatic and question whether they outweigh the risks of infection and other side effects, particularly since the agent is expected to be used on a recurring basis.

Ilaris’ current labeling includes a warning about the risk of serious infections and says physicians should exercise caution when giving the biologic to patients with infections, a history of recurring infections or underlying conditions that may predispose them to infections.

In gout patients, compared to triamcinolone 40 mg, canakinumab 150 mg was associated with a higher proportion of serious adverse events, at least one adverse event, infection and serious infections.

"The types of adverse events and serious adverse events observed were generally consistent with the underlying patient population, with the exception of infections," Dr. Yim noted. "However, the increase in these (adverse events) is particularly notable in light of the fact that they were observed after a single injection of canakinumab."

FDA reviewers also raised concerns about laboratory abnormalities associated with canakinumab use that could negatively affect gout patients over the long term. These include declines in renal function values, increased triglyceride levels, and elevations in serum uric acid levels.

Although small increases in serum uric acid should be manageable with adequate doses of urate-lowering therapy, "one could also imagine that for certain patients whose serum uric acid is not adequately controlled that a further increase might enhance tophi formation," Dr. Yim commented. "In any case, this finding, as with hypertriglyceridemia and creatinine elevation, raises questions regarding the net impact that canakinumab treatment could have on gout patients and their comorbidities."

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Administration is questioning whether the "primarily symptomatic relief" of gout provided by the injectable biologic canakinumab outweighs an increased risk of serious infections.

At a June 21 meeting, the FDA will ask its Arthritis Advisory Committee about acute, recurrent use of canakinumab (Ilaris, Novartis) in gout and the risk of infections and laboratory value abnormalities, according to agency briefing documents.

The committee will be asked to vote on whether canakinumab should be approved merely for second-line treatment of gouty attacks or whether efficacy and safety data support adding a claim for extending the time to next attack and reducing the frequency of subsequent attacks.

"Determining the benefit-risk profile of canakinumab for the treatment of acute gout flares in light of its extended pharmacodynamic effects, both desirable and undesirable, is complicated and will underlie the questions for discussion" at the committee meeting, Dr. Sarah Yim, medical team leader, division of pulmonary, allergy, and rheumatology products, wrote in a memo.

The agency also will ask the panel whether Novartis should explore lower doses of canakinumab and obtain additional data on repeated dosing over time.

"Although a fairly wide range of doses were studied early on, only the 150 mg dose of canakinumab was studied further in the gout clinical development program," Dr. Yim wrote. "Given that some of the safety findings suggest a dose-response, it would have been useful to have additional data from a lower dose, to assess whether adequate efficacy could have been provided with less undesirable effects on susceptibility to infection and laboratory abnormalities. However these data are not available."

Canakinumab, an interleukin-1 beta-inhibitor, won FDA approval 2 years ago for treatment of cryopyrin-associated periodic syndrome, an orphan indication. Canakinumab, also in clinical development for systemic juvenile idiopathic arthritis and cardiovascular disease, has hit snags in clinical evaluations in rheumatoid arthritis and diabetes.

By selectively binding and neutralizing IL-1B, canakinumab interrupts the signaling pathway for crystal-induced inflammation in gouty arthritis, Novartis said in its advisory committee briefing document.

Gout attacks are currently treated with anti-inflammatories such as colchicine (Colcrys, Mutual Pharmaceuticals), NSAIDs, and corticosteroids. The underlying pathology is treated by controlling hyperuricemia with urate-lowering therapies, such as allopurinol, probenecid, febuxostat (Uloric, Takeda Pharmaceuticals), and pegloticase (Krystexxa, Savient Pharmaceuticals).

Novartis is pursuing a second-line gout indication that canakinumab has been shown "to extend the time to next attack and reduce the frequency of subsequent attacks." The proposed indication is for treatment of gouty arthritis attacks in patients who do not respond to NSAIDs and colchicine. In its briefing document, Novartis says the targeted patient population is less than 10% of the approximately 300,000 U.S. patients who receive treatment for gouty arthritis. The second-line indication and the narrow population targeted could help turn the risk/benefit equation by demonstrating that the biologic’s potential adverse events are outweighed by the symptomatic and disease relief benefit it brings to patients who fail on first-line therapy.

Pain Reduction With Reduced Risk of New Flares

The supplemental biologics license application is supported by data from two identically designed phase III trials encompassing 454 patients who were intolerant of, or refractory to, NSAIDS or colchicine. Half of the patients in one study, and one-third in the other, were on urate-lowering therapy.

The studies measured two co-primary end points: mean difference in patient assessment of gout pain from baseline to 72 hours post dose using the Visual Analog Scale, and time to new gout flare. Patients were randomized to a single dose of either canakinumab 150 mg or the corticosteroid triamcinolone 40 mg on day 1 and followed for 12 weeks.

"Overall, both trials ... demonstrated statistically significant decreases in pain intensity measured on VAS for canakinumab, compared to triamcinolone, and statistically significant differences between treatment groups (favoring canakinumab) for the risk of a new gout flare," Dr. Yim wrote.

"Subgroup analyses of the co-primary efficacy endpoints were generally consistent with the overall efficacy results, including results for the subgroup of patients intolerant to, with contraindications for, or lack of efficacy from NSAIDs and/or colchicine; however, differences in the magnitude of the treatment effect in the subgroup of patients taking urate-lowering therapy versus those not taking urate therapy [were] observed."

Do Adverse Events Trump Symptom Relief?

While FDA reviewers describe the benefits as primarily symptomatic and question whether they outweigh the risks of infection and other side effects, particularly since the agent is expected to be used on a recurring basis.

Ilaris’ current labeling includes a warning about the risk of serious infections and says physicians should exercise caution when giving the biologic to patients with infections, a history of recurring infections or underlying conditions that may predispose them to infections.

In gout patients, compared to triamcinolone 40 mg, canakinumab 150 mg was associated with a higher proportion of serious adverse events, at least one adverse event, infection and serious infections.

"The types of adverse events and serious adverse events observed were generally consistent with the underlying patient population, with the exception of infections," Dr. Yim noted. "However, the increase in these (adverse events) is particularly notable in light of the fact that they were observed after a single injection of canakinumab."

FDA reviewers also raised concerns about laboratory abnormalities associated with canakinumab use that could negatively affect gout patients over the long term. These include declines in renal function values, increased triglyceride levels, and elevations in serum uric acid levels.

Although small increases in serum uric acid should be manageable with adequate doses of urate-lowering therapy, "one could also imagine that for certain patients whose serum uric acid is not adequately controlled that a further increase might enhance tophi formation," Dr. Yim commented. "In any case, this finding, as with hypertriglyceridemia and creatinine elevation, raises questions regarding the net impact that canakinumab treatment could have on gout patients and their comorbidities."

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Administration is questioning whether the "primarily symptomatic relief" of gout provided by the injectable biologic canakinumab outweighs an increased risk of serious infections.

At a June 21 meeting, the FDA will ask its Arthritis Advisory Committee about acute, recurrent use of canakinumab (Ilaris, Novartis) in gout and the risk of infections and laboratory value abnormalities, according to agency briefing documents.

The committee will be asked to vote on whether canakinumab should be approved merely for second-line treatment of gouty attacks or whether efficacy and safety data support adding a claim for extending the time to next attack and reducing the frequency of subsequent attacks.

"Determining the benefit-risk profile of canakinumab for the treatment of acute gout flares in light of its extended pharmacodynamic effects, both desirable and undesirable, is complicated and will underlie the questions for discussion" at the committee meeting, Dr. Sarah Yim, medical team leader, division of pulmonary, allergy, and rheumatology products, wrote in a memo.

The agency also will ask the panel whether Novartis should explore lower doses of canakinumab and obtain additional data on repeated dosing over time.

"Although a fairly wide range of doses were studied early on, only the 150 mg dose of canakinumab was studied further in the gout clinical development program," Dr. Yim wrote. "Given that some of the safety findings suggest a dose-response, it would have been useful to have additional data from a lower dose, to assess whether adequate efficacy could have been provided with less undesirable effects on susceptibility to infection and laboratory abnormalities. However these data are not available."

Canakinumab, an interleukin-1 beta-inhibitor, won FDA approval 2 years ago for treatment of cryopyrin-associated periodic syndrome, an orphan indication. Canakinumab, also in clinical development for systemic juvenile idiopathic arthritis and cardiovascular disease, has hit snags in clinical evaluations in rheumatoid arthritis and diabetes.

By selectively binding and neutralizing IL-1B, canakinumab interrupts the signaling pathway for crystal-induced inflammation in gouty arthritis, Novartis said in its advisory committee briefing document.

Gout attacks are currently treated with anti-inflammatories such as colchicine (Colcrys, Mutual Pharmaceuticals), NSAIDs, and corticosteroids. The underlying pathology is treated by controlling hyperuricemia with urate-lowering therapies, such as allopurinol, probenecid, febuxostat (Uloric, Takeda Pharmaceuticals), and pegloticase (Krystexxa, Savient Pharmaceuticals).

Novartis is pursuing a second-line gout indication that canakinumab has been shown "to extend the time to next attack and reduce the frequency of subsequent attacks." The proposed indication is for treatment of gouty arthritis attacks in patients who do not respond to NSAIDs and colchicine. In its briefing document, Novartis says the targeted patient population is less than 10% of the approximately 300,000 U.S. patients who receive treatment for gouty arthritis. The second-line indication and the narrow population targeted could help turn the risk/benefit equation by demonstrating that the biologic’s potential adverse events are outweighed by the symptomatic and disease relief benefit it brings to patients who fail on first-line therapy.

Pain Reduction With Reduced Risk of New Flares

The supplemental biologics license application is supported by data from two identically designed phase III trials encompassing 454 patients who were intolerant of, or refractory to, NSAIDS or colchicine. Half of the patients in one study, and one-third in the other, were on urate-lowering therapy.

The studies measured two co-primary end points: mean difference in patient assessment of gout pain from baseline to 72 hours post dose using the Visual Analog Scale, and time to new gout flare. Patients were randomized to a single dose of either canakinumab 150 mg or the corticosteroid triamcinolone 40 mg on day 1 and followed for 12 weeks.

"Overall, both trials ... demonstrated statistically significant decreases in pain intensity measured on VAS for canakinumab, compared to triamcinolone, and statistically significant differences between treatment groups (favoring canakinumab) for the risk of a new gout flare," Dr. Yim wrote.

"Subgroup analyses of the co-primary efficacy endpoints were generally consistent with the overall efficacy results, including results for the subgroup of patients intolerant to, with contraindications for, or lack of efficacy from NSAIDs and/or colchicine; however, differences in the magnitude of the treatment effect in the subgroup of patients taking urate-lowering therapy versus those not taking urate therapy [were] observed."

Do Adverse Events Trump Symptom Relief?

While FDA reviewers describe the benefits as primarily symptomatic and question whether they outweigh the risks of infection and other side effects, particularly since the agent is expected to be used on a recurring basis.

Ilaris’ current labeling includes a warning about the risk of serious infections and says physicians should exercise caution when giving the biologic to patients with infections, a history of recurring infections or underlying conditions that may predispose them to infections.

In gout patients, compared to triamcinolone 40 mg, canakinumab 150 mg was associated with a higher proportion of serious adverse events, at least one adverse event, infection and serious infections.

"The types of adverse events and serious adverse events observed were generally consistent with the underlying patient population, with the exception of infections," Dr. Yim noted. "However, the increase in these (adverse events) is particularly notable in light of the fact that they were observed after a single injection of canakinumab."

FDA reviewers also raised concerns about laboratory abnormalities associated with canakinumab use that could negatively affect gout patients over the long term. These include declines in renal function values, increased triglyceride levels, and elevations in serum uric acid levels.

Although small increases in serum uric acid should be manageable with adequate doses of urate-lowering therapy, "one could also imagine that for certain patients whose serum uric acid is not adequately controlled that a further increase might enhance tophi formation," Dr. Yim commented. "In any case, this finding, as with hypertriglyceridemia and creatinine elevation, raises questions regarding the net impact that canakinumab treatment could have on gout patients and their comorbidities."

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.