Novartis' Ilaris Gets Thumbs Down As Gout Treatment

From BioWorld Today (June 22, 2011)

Novartis AG may have proven the efficacy of its Ilaris to treat gouty arthritis attacks, but it couldn't overcome the safety concerns.

The FDA's Arthritis Drugs Advisory Committee voted 11-1 Tuesday that the IL-1 beta inhibitor showed efficacy in treating the attacks in patients who haven't found relief from nonsteroidal anti-inflammatory drugs or colchicine. However, only one member voted to recommend approval.

While the panel voted 8-4 that the data demonstrated Ilaris' (canakinumab) efficacy in extending the time to next attack and reducing the frequency of subsequent attacks, it unanimously opposed recommending approval for that part of the indication.

In both instances, the committee said the safety profile just didn't support approval. While the FDA doesn't have to follow the committee's recommendation, Tuesday's vote doesn't bode well for the Basel, Switzerland-based company's supplemental biologic license application.

The committee's recommendations were not a big surprise. Going into the meeting, the FDA raised concerns about the monoclonal antibody's "complicated" benefits-risk profile, citing its long half-life and extended pharmacodynamic effects. Those characteristics, not typical for an acute treatment, can be both good and bad.

The data from Novartis' clinical development suggested the effects of even a single subcutaneous 150-mg injection of Ilaris may be protracted. For instance, a median time to new flare-up following a single injection, one of the primary endpoints, couldn't be determined in the two Phase III studies and their extensions because not enough subjects receiving Ilaris experienced a new flare within the study period.

In contrast, the median time for a new flare-up for triamcinoclone, an injectable steroid that served as the control, was 119 days in one trial and 146 days in the other trial.

The data also showed a statistically significant decrease in pain as measured by the Visual Analogue Scale at 72 hours after dosing with Ilaris ?? the second primary endpoint of both studies.

On the risk side, however, the extended pharmacodynamics effects raised a few flags. A single injection of Ilaris resulted in:

twice the proportion of serious adverse events (7 percent for Ilaris vs. 3 percent for triamcinoclone);

a higher proportion of patients experiencing at least one adverse event (62 percent vs. 51 percent);

a higher proportion of patients experiencing infections (19 percent vs. 13 percent) and serious infections (2 percent vs. 0 percent).

Except for the infections, the types of adverse events observed were generally consistent with the patient population, which tends to have comorbidities such as obesity, hypertension, diabetes and cardiovascular disease.

But given that Ilaris, in this indication, would primarily provide a symptomatic benefit, the FDA wondered whether the risk of infection outweighed the clinical benefits. The U.S. labeling for Ilaris, which is approved in 45 countries to treat cryopyrin-associated periodic syndrome (CAPS) in children and adults, includes a warning about an increased risk of serious infections.

The agency had a few other concerns about using Ilaris for gout. "Canakinumab treatment also appeared to be associated with an increase in a number of findings, which together, could ultimately result in a negative impact in gout patients ?? namely decline in renal function, hypertriglyceridemia and serum uric acid elevation," the agency said in its briefing documents.

While those differences weren't of great magnitude, the FDA said they raised questions about the biologic's net impact on gout patients with comorbidities.

Novartis also filed for approval for the gout indication in the European Union last year and in Canada and Switzerland the first quarter of this year. The company is still waiting to hear on those submissions, Novartis spokesman Eric Althoff told BioWorld Today.

Meanwhile, the company is studying Ilaris in other diseases in which IL-1 beta plays a key role in causing inflammation, such as systemic juvenile idiopathic arthritis and cardiovascular disease.

IL-1 is a target that has generated a great deal of interest for a number of indications, but few viable candidates. Thousand Oaks, Calif.-based Amgen Inc. has an IL-1 blocker, Kineret (anakinra), for rheumatoid arthritis, but it has not been very successful on the market. Results from a clinical study of Kineret in gout were published in 2007. (See BioWorld Today, March 24, 2011.)

Earlier this year, Berkeley, Calif.-based XOMA Ltd.'s IL-1 inhibitor, XOMA 052, missed its primary endpoint in a Phase IIb trial in Type II diabetes.

Ilaris itself stems from an old collaboration Novartis had with Tarrytown, N.Y.-based Regeneron Pharmaceuticals Inc. to develop another IL-1 blocker, Arcalyst (rilonacept). Like Ilaris, Arcalyst is approved for CAPS. In a recent Phase III trial in gout, Arcalyst met all of its endpoints. (See BioWorld Insight, Jan. 10, 2010, and June 20, 2011.)


 

Posted: June 2011


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