FDA is questioning whether the "primarily symptomatic relief" provided by Novartis' Ilaris (canakinumab) in treating gout attacks and delaying flares outweighs the risk of serious infections and other adverse events that could potentially worsen gout patients' condition.

At a June 21 meeting, FDA will ask its Arthritis Advisory Committee about the potential risk of using canakinumab on an acute recurrent basis and the safety implications related to the risk of infections and laboratory value abnormalities seen in the clinical development program, according to agency briefing documents released on June 17.

The committee also will be asked to vote on whether Ilaris 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, Division of Pulmonary, Allergy and Rheumatology Products Medical Team Leader Sarah Yim writes 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.

Second Indication, Larger Population

Canakinumab, an interleukin-1 beta inhibitor, won FDA approval two years ago for treatment of cryopyrin-associated periodic syndrome, an ultra orphan indication (Also see "Novartis Ilaris Approved For Rare Autoinflammatory Disorder; Filings For More Common Diseases Planned" - Pink Sheet, 18 June, 2009.).

The strategy of starting with a very narrow indication for Ilaris follows the approach adopted by Novartis' Institute for Biomedical Research. The R&D model is based on identifying a molecule's pathway and method of action, and then pursuing a small, clear, targeted indication in an accelerated clinical program while also moving forward on indications encompassing larger populations (Also see "Novartis Has Proof Of Concept For New R&D Model, And NMEs To Show It" - Pink Sheet, 8 December, 2008.). The biologic is also in clinical development for systemic juvenile idiopathic arthritis and cardiovascular disease. It has hit snags in rheumatoid arthritis and diabetes.

Gout is a metabolic disorder characterized by reduced clearance or over-production of uric acid leading to hyperuricemia, which can result in the formation of crystals around the joints and soft tissues, urate nephropathy and nephrolithiasis.

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 Mutual Pharmaceutical's Colcrys (colchicine), NSAIDs or corticosteroids. The underlying pathology is treated by controlling hyperuricemia with urate-lowering therapies, such as allopurinol, probenecid, Takeda Pharmaceuticals' Uloric (febuxostat) and Savient Pharmaceuticals' Krystexxa (pegloticase).

Novartis is pursuing a second-line gout indication for Ilaris that verges on crossing the treatment line over into prophylaxis.

The proposed indication is for treatment of gouty arthritis attacks in patients who cannot obtain response with NSAIDS and colchicine. The sponsor also seeks a claim that Ilaris has been shown "to extend the time to next attack and reduce the frequency of subsequent attacks."

In its briefing document, Novartis says the targeted patient population is less than 10%(approximately 300,000) of U.S. patients who receive treatment for gouty arthritis. The second-line indication and the narrow population targeted could help Novartis turn the risk/benefit equation in its favor by demonstrating that the biologic's potential adverse events are outweighed by the symptomatic and disease relief it brings to patients who fail on first-line therapy.

Pain Reduction With Reduced Risk Of New Flares

The sBLA is supported by data from two identically designed Phase III trials encompassing 454 patients who were intolerant of, or refractory to, NSAIDS and/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 endpoints: mean difference in patient assessment of gout pain from baseline to 72 hours post-dose using the Visual Analogue 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," Yim writes.

"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 appear to take no major issue with the biologic's efficacy, they question whether its benefits, which Yim describes as primarily symptomatic, 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.

Across the gout clinical program, canakinumab 150 mg was associated with a higher proportion of subjects who experienced serious adverse events, at least one adverse event, infection or serious infections when compared to triamcinolone 40 mg.

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

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

Although small serum uric acid increases 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," Yim comments. "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 co-morbidities."

Novartis Dose-Finding Practices Face Scrutiny, Again

FDA also seeks the panel's views on whether Novartis has done enough work to find the optimal dose of canakinumab in gout.

"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," Yim says. "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."

The canakinumab meeting will mark the second time in three months that the Division of Pulmonary, Allergy and Rheumatology Products has publicly discussed concerns about the adequacy of Novartis' dose exploration strategy for drugs in development.

At a March meeting of the Pulmonary-Allergy Drugs Advisory Committee, the agency questioned whether Novartis had determined the optimal dose for the chronic obstructive pulmonary disease treatment Arcapta Neohaler (indacaterol). The committee agreed with the agency's concerns, voting to recommend approval of a 75 mcg dose but not Novartis' preferred 150 mcg dose (Also see "Arcapta Quality Of Life Data For High Dose Cannot Overcome Efficacy Questions" - Pink Sheet, 8 March, 2011.).

-Sue Sutter (s.sutter@elsevier.com)

Novartis' Ilaris For Gout: FDA Questions Whether Symptom Relief Is Worth Risks

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