New Gout Drug Lesinurad (ZURAMPIC) Too Dangerous

On Dec. 22, 2015, the Food and Drug Administration (FDA) approved lesinurad (ZURAMPIC) for the treatment of gout.[1] The approval came despite serious safety concerns and limited evidence of benefits, representing another example of the agency’s reckless approach to the oversight of prescription drugs.

Lesinurad is approved only for treating gout patients who have not been adequately treated with one of the older gout drugs known as xanthine oxidase inhibitors (XOIs).[2] Allopurinol (LOPURIN, ZYLOPRIM), the oldest XOI, is the first-choice drug for gout. Lesinurad is approved for use only in combination with an XOI and only at a maximum daily dose of 200 milligrams (mg).

Patients should not use lesinurad because its substantial risks far outweigh its benefits.

What is gout?

Gout develops in some patients who have high blood levels of the bodily waste product uric acid. The condition can be caused by the body producing too much uric acid or by the kidneys removing too little of it. Gout affects more than 8 million adults in the U.S.;[3] most of them are middle-aged and older men and postmenopausal women.[4]

Acute gout attacks occur when uric acid levels in the blood rise to the point that uric acid crystals form in joints and surrounding tissues, resulting in severe joint pain, swelling and redness. Gout attacks usually affect a single joint, such as the big toe, ankle or knee; last several days; and occur intermittently. Standard treatments for acute gout attacks include nonsteroidal anti-inflammatory drugs and colchicine (COLCRYS, MITI-GARE).

Some gout patients develop large uric acid deposits, called tophi, over joints, tendons and bones. Tophi appear as hard bumps under the skin. Patients also may experience kidney damage and kidney stones caused by uric acid crystals forming in the kidneys and urine.

Drugs that lower uric acid levels help prevent acute gout attacks, tophi formation, and, in some cases, kidney damage. XOIs work by blocking the body’s production of uric acid. For patients who experience an inadequate response to an XOI, a second drug that increases the removal of uric acid by the kidneys — known as a uricosuric — can be added to further decrease uric acid levels. Probenecid (PROBALAN), initially approved by the FDA in 1951, and lesinurad are the only uricosurics currently available in the U.S.[5]

Lesinurad’s meager benefits

The FDA’s conclusion that lesinurad was effective was based on the results of three clinical trials in gout patients who had not achieved adequate reductions in uric acid levels with an XOI alone.[6] For each trial, several hundred subjects were randomly assigned to receive either lesinurad — at a daily dose of 200 or 400 mg — or a placebo for one year. All subjects also received allopurinol (in two trials) or febuxostat (ULORIC), a newer XOI that we are currently evaluating (in one trial).

For all three trials, the FDA found that subjects in the lesinurad group had only modest reductions in blood uric acid levels compared to subjects in the placebo group.[7] More importantly, subjects treated with lesinurad fared no better than those treated with a placebo with respect to the frequency of acute gout attacks, decreases in the size of tophi and degree of physical disability.[8] Thus, the slight reductions in uric acid levels did not translate into any significant benefits during one year of treatment.

Alongside these minimal benefits, the drug is associated with a number of serious, potentially fatal risks.

Kidney toxicity

Lesinurad’s most troubling adverse effect is kidney damage. Initial evidence that lesinurad is harmful to the kidneys came from studies done with rats. The data clearly showed that the drug, given at very high doses, is directly toxic to rat kidneys.[9]

More importantly, data from the three key trials used to support approval provided definitive evidence that the drug causes acute kidney damage in humans.[10] Even at 200 mg — the minimum dose tested in the trials — subjects receiving lesinurad experienced more sudden decreases in kidney function than subjects given placebos. The number of adverse kidney events increased further at the 400 mg dose. Such a correlation between increasing toxicity and increasing dosage provides strong evidence that the drug causes kidney injury.

When the FDA approved lesinurad, the agency required that the drug’s label include a black-box warning about the risk of acute kidney failure.[11]

Cardiovascular safety concerns

The same clinical trials also revealed that lesinurad may increase the risk of serious adverse cardiovascular events, including heart attacks and heart failure.[12] Although the number of these events seen in the trials was small, more lesinurad-treated subjects than placebo-treated subjects experienced such events. In addition, an FDA analysis showed that as the dose of lesinurad increased from 200 to 400 mg, the occurrence rate for the most serious adverse cardiovascular events also increased.

Finally, five subjects receiving lesinurad died — four from an adverse cardiovascular event — whereas no placebo-treated subjects died.[13]

Although the data on lesinurad’s cardiovascular risk are not definitive, these warning signals should be taken seriously, particularly for a drug that is not a breakthrough treatment for a life-threatening disease.

The FDA’s reckless action

In October 2015, the FDA sought advice from one of its advisory committees about whether lesinurad was safe and effective, and whether it should be approved. In testimony before the committee, Public Citizen urged members to recommend that the FDA not approve lesinurad.[14]

When asked to vote on whether the drug had been shown to be safe, nearly half of the members (six of 14, with one abstaining) voted no.[15] Nevertheless, 10 of 14 members ultimately voted in favor of approval.

While most FDA scientists who reviewed the data on lesinurad favored approval, this position was not unanimous. One lead FDA statistician recommended against approving the drug, noting that there was “considerable uncertainty” about the drug’s benefit and expressing concern about the risks of kidney and heart toxicity.[16]

The FDA’s pharmacology reviewers also concluded that lesinurad should not be approved for patients who already had moderate to severe kidney failure — a condition common in gout patients — because the risks outweighed the benefits in those patients.[17]

Despite clear evidence that lesinurad’s risks exceed its meager benefits, the FDA opted to approve the drug, relying on warnings in the product label to address the drug’s serious risks.

The agency approved lesinurad even for patients with moderate kidney failure, who are at especially great risk. To further evaluate the risks involved, the FDA has required that the drug’s manufacturer conduct a large randomized clinical trial that includes many patients with moderate kidney failure.[18] The trial is scheduled to be completed in 2025. By that time, an epidemic of lesinurad- induced kidney disease will likely have occurred.

What You Can Do

You should avoid starting lesinurad if you are not currently taking it. If you are already taking it, consult with your doctor about switching to the older and safer uricosuric, probenecid.

If you have gout, you should avoid taking aspirin (ANACIN, BAYER ASPIRIN, ECOTRIN) and other salicylates, which decrease the kidneys’ ability to eliminate uric acid. You should also discuss with your doctor lifestyle modifications that can reduce your risk of acute gout attacks, including losing weight, reducing alcohol intake and making changes to your diet to lower blood uric acid levels.

References

[1] Parks MH. Food and Drug Administration letter approving NDA 207988 for Zurampic (lesinurad) tablets, 200 mg. December 22, 2015. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207988Orig1s000Approv.pdf. Accessed June 17, 2016.

[2] AstraZeneca. Label: lesinurad (ZURAMPIC). December 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207988lbl.pdf. Accessed June 17, 2016.

[3] Food and Drug Administration. Briefing document for the October 23, 2015, meeting of the Arthritis Advisory Committee for NDA 207988: Lesinurad for the proposed indication of treatment of hyperuricemia associated with gout in combination with a xanthine oxidase inhibitor. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM467942.pdf. Accessed June 17, 2016.

[4] Ibid.

[5] Neuner R. Food and Drug Administration clinical review of NDA 207988 for lesinurad for treatment of hyperuricemia associated with gout. September 17, 2015. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207988Orig1s000MedR.pdf. Accessed June 17, 2016.

[6] Food and Drug Administration. Briefing document for the October 23, 2015, meeting of the Arthritis Advisory Committee for NDA 207988: Lesinurad for the proposed indication of treatment of hyperuricemia associated with gout in combination with a xanthine oxidase inhibitor. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM467942.pdf. Accessed June 17, 2016.

[7] Ibid.

[8] Ibid.

[9] Ibid.

[10] Ibid.

[11] AstraZeneca. Label: lesinurad (ZURAMPIC). December 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207988lbl.pdf. Accessed June 17, 2016.

[12] Food and Drug Administration. Briefing document for the October 23, 2015, meeting of the Arthritis Advisory Committee for NDA 207988: Lesinurad for the proposed indication of treatment of hyperuricemia associated with gout in combination with a xanthine oxidase inhibitor. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM467942.pdf. Accessed June 17, 2016.

[13] Ibid.

[14] Carome MA. Public Citizen testimony before the FDA’s Arthritis Advisory Committee regarding new drug application 207988 for lesinurad: No unique benefits, but serious risks. October 23, 2015. http://www.citizen.org/documents/2279.pdf. Accessed June 17, 2016.

[15] Food and Drug Administration. Summary minutes of the Arthritis Advisory Committee meeting. October 23, 2015. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM475241.pdf. Accessed June 17, 2016.

[16] Levin GP. Food and Drug Administration statistical review and evaluation, clinical studies, NDA 207988 for lesinurad for treatment of hyperuricemia associated with gout. November 25, 2015. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207988Orig1s000StatR.pdf. Accessed June 17, 2016.

[17] Chen J, Ramamoorthy A, Grimstein C, et al. Food and Drug Administration clinical pharmacology review of NDA 207988 for lesinurad for treatment of hyperuricemia associated with gout. September 3, 2015. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207988Orig1s000ClinPharmR.pdf. Accessed June 17, 2016.

[18]Parks MH. Food and Drug Administration letter approving NDA 207988 for Zurampic (lesinurad) tablets, 200 mg. December 22, 2015. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207988Orig1s000Approv.pdf. Accessed June 17, 2016.