June 21, 2011

Testimony on ILARIS® (Canakinumab)

Testimony to the FDA’s Arthritis Advisory Committee on the Supplemental
Biologics Licensing Application (BLA) #125319, ILARIS® (Canakinumab)
Michael A. Carome, M.D., and Sidney Wolfe, M.D.
Public Citizen Health Research Group

View press release.

My name is Dr. Michael Carome, Deputy Director of the Health Research Group at Public Citizen. I am testifying on behalf of myself and Dr. Sidney Wolfe, Director of the Public Citizen Health Research Group. We have no financial conflicts of interest.

We oppose the Food and Drug Administration’s (FDA) approval of canakinumab, a potent immunosuppressant agent, for the treatment of patients with gouty arthritis attacks because the drug has serious, life-threatening risks that far outweigh the drug’s clinical benefits, which are limited primarily to relief of pain from acute gout flares in this patient population.

Pharmacokinetic Profile

The peak serum canakinumab concentration occurs at seven days after a dose, and its half-life is 26 days.[1] In this regard, the FDA noted the following:

Canakinumab has a long half-life and extended pharmacodynamic effects. These are not characteristics typical of an acute treatment, and both efficacy and safety data suggest the effects of even a single subcutaneous injection of canakinumab may be protracted.[2]

Benefit Assessment

The FDA noted that canakinumab “is expected to provide primarily a symptomatic benefit” in gout patients.

Risk Assessment

Even though the number of subjects in the gouty arthritis trials was relatively small and most received a single dose of canakinumab, the FDA identified multiple serious safety concerns. The overall percent of subjects experiencing at least one serious adverse event was more than two-fold higher in the pool of study subjects receiving canakinumab versus those receiving triamcinolone (see the Table below). Importantly, among the serious adverse events, the occurrence of serious infections was observed exclusively in the canakinumab treatment groups.[3]

Table: Overview of Adverse Events

	Canakinumab 150 mg N=253	Triamcinolone N=286
Number of Subjects with at Least 1 AE	158 (62.5%)	145 (50.7%)
Number of Subjects with at Least 1 Serious AE	18 (7.1%)	9 (3.1%)
Number of Subjects with at Least 1 Serious Infection	4 (1.6%)	0 (0.0%)

Given its mechanism of action as an immunosuppressant, canakinumab would be expected to increase the risk of all types of infections. The FDA expressed the following significant concern about this signal for serious infections:

Although the occurrence of infections would not be unexpected with an IL-1 inhibitor, the increased rate of the serious infections in gout patients after just a single injection of canakinumab is a unique and concerning observation in this development program.[4]

The inadequacy of the safety data base submitted as a basis for this approval contrasts sharply with the much larger amount of long-term safety data submitted prior to the FDA approving anakinra for treatment of rheumatoid arthritis. For that approval, data from a safety study with 875 patients given the drug daily for at least six months (study 990757), as well as data on several hundred additional subjects in randomized efficacy studies, were submitted to the FDA. For canakinumab, only 118 subjects with gout were treated with more than one injection of the proposed dose.

Immunosuppressive drugs, like canakinumab, can impair the body’s immunosurveillance and increase the risk of malignancies, particularly with repeated dosing. The duration and size of the studies involving subjects with gout did not allow for an adequate assessment of the malignancy risk posed by canakinumab to such patients. However, the FDA noted the following:

While the data show that the incidence of malignancies is not increased upon single injection treatment with canakinumab administered for gouty arthritis, the available data do not allow an estimation of the potential risk for malignancies upon chronic repetitive “on demand” canakinumab treatment in the gout population.[5]

Additional abnormalities that occurred more frequently in subjects treated with canakinumab versus subjects treated with triamcinolone included:[6]

– Leukopenia, neutropenia, and thrombocytopenia

– Declines in renal function

– Elevations in serum triglycerides and total cholesterol

– Elevations in serum uric acid

– Liver dysfunction

Novartis estimates that approximately 300,000 gout patients will be candidates for canakinumab if it is approved for this indication.[7] However, it is highly likely that off-label use will result in many more gout patients being treated with this drug. Even with approved use for acute gout attacks in a patient population of 300,000, repeated dosing with canakinumab will result in large numbers of serious infections and other life-threatening complications.     

Recommendation

The FDA review concludes that the question of whether the benefit-risk profile of canakinumab is acceptable for the treatment of acute flares of gout is “complicated.” We disagree – the assessment is not complicated. Like other immunosuppressing monoclonal antibodies, canakinumab is a potent and dangerous drug. While the risks of this drug are justified for patients with cryopyrin-associated periodic syndrome, these risks are not outweighed by the symptomatic benefit provided in patients with gout. Therefore, in the interests of protecting the public health, the FDA should not approve canakinumab for the treatment of gout.