New relief for gout - Nature

n e w s f e at u r e

New relief for gout

After allopurinol “Allopurinol is a good drug, but it’s often underdosed,” says Terkeltaub, who adds that primary care physicians too often follow outdated A gout drug has been approved by the FDA, the first in 40 years, guidelines on gout. “Even so, we need better with three more in the wings. What accounts for this sudden slew uric acid–lowering options. We have a population now of gout patients that constitute unmet of gout therapies? Jill U. Adams investigates. medical need—because a lot of these people are incapacitated with poor quality of life.” On February 16, the US Food and Drug by-product of purine metabolism. Red meat Some individuals with gout can’t take Administration (FDA) approved Deerfield, is a dietary source of purines, which is why allopurinol because of side effects, including Illinois–based Takeda Pharmaceuticals’ drug gout has been called a ‘rich man’s disease’. severe hypersensitivity reactions. Others simply Uloric (febuxostat), an oral inhibitor of xan- When its concentration rises above 6.8 mg/ don’t respond. “Allopurinol is typical of drugs thine oxidase, for the chronic management of dl, uric acid crystallizes out of solution and developed in the 1950s and 1960s: not very gout, and not far behind are three others (Table collects in joints—mostly peripheral ones like potent, not very specific and with a lot of side 1). Four new drugs after 40 years of drought may the toes and fingers. The main goal of gout effects,” says Paul Hamelin, president of Savient sound like an excess of riches or at least a tough therapy is to reverse this process. “I look at Pharmaceuticals of East Brunswick, New Jersey. battle for market share. And yet, the drugs bring treatment of gout as kind of an erosive pro- “A lot of patients don’t tolerate them well. In four different mechanisms of action to the clini- cess,” says John Sundy, a rheumatologist at those who do, other medical reasons can limit cian’s tool kit. They are poised to take up four Duke University Medical Center in Durham, dose and as a result they’re not getting good distinctive areas in the therapeutic urate-lowering activity.” space—although some overlap is Any kind of kidney trouble can likely—and they have very different pose problems as allopurinol is risk-benefit profiles. metabolized by the kidney. In these cases, physicians will use low doses No longer a Dickensian scourge of allopurinol, which then limits the Once thought to be a disease of drug’s effectiveness. Unfortunately, rich, old men, gout, which is charthe only other urate-lowering drug acterized by high concentrations of on the market, probenecid, must serum uric acid, is making a resuralso be managed carefully in those gence. Increased longevity and the who suffer from renal insufficiency. rise in diabetes and hypertension It must be taken two to three times a and resulting drug use is creating day and people are advised to drink a new population of gout sufferers, lots of water to prevent the formaincluding about 1 in 100 adult men tion of kidney stones. in industrialized countries (an estiLike allopurinol, Takeda’s Uloric is th mated million in the US according The once feared gout, depicted in this print by the 19 century a xanthine oxidase inhibitor. Uloric to the Centers for Disease Control). caricaturist James Gillray, may finally be under control as a set of new differs from allopurinol in two drugs reaches the market. important ways, however: it does Since 1964, the medicine cabinot have a purine backbone and it is net for gout has stayed virtually the same: colchicine, steroids and nonsteroidal North Carolina. “You’re trying to create a metabolized primarily in the liver. These differanti-inflammatory drugs (NSAIDs) for treat- concentration gradient that will cause these ences should allow Uloric to circumvent the two ing painful gout symptoms, and allopurinol insoluble deposits of uric to resolubilize and main problems with allopurinol—the develop(which inhibits the production of uric acid) move from the interstitial space back into ment of hypersensitivity reactions and dosing and probenicid (which increases the excretion the bloodstream, where it can be excreted by limitations dictated by renal insufficiency. In Europe, where the drug was approved last year, of uric acid) for lowering elevated serum uric the kidney.” Not only is the incidence of gout greater, Uloric is used in individuals who don’t tolerate acid. “Throughout the world, allopurinol is the drug that is most widely used,” says George but also the complexion of gout has changed allopurinol well. Charlie Baum, executive medical director Nuki, emeritus professor of rheumatology at the in the past 20 years, according to Robert University of Edinburgh. Across a whole host of Terkeltaub, chief of rheumatology at the San for internal medicine at Takeda, says the most surveys, as many as 90% of gout patients used Diego Veterans Administration Hospital. recent study demonstrated that doses of 40 mg Now, more people have tophi—lumps of and 80 mg Uloric were “significantly better” the drug, according to Nuki. After forty years of experience with crystallized urate that collect in joints caus- than the standard dose of allopurinol. (Earlier allopurinol, physicians may hesitate to take the ing inflammations and painful flare-ups— trials tested daily doses as high as 240 mg, but plunge with a new drug. And as with any drug and more gout sufferers have other chronic there was a higher rate of adverse events, such as for chronic diseases, long-term use can reveal medical conditions, like congestive heart diarrhea and dizziness, and more subjects withfailure, diabetes and chronic kidney disease. drew.) What’s more, in the subpopulation of unanticipated dangers. “We’re seeing a lot more patients and a lot of study subjects with impaired renal function (40 people are sicker, are older, have a lot more of the 1,072 enrolled in the pivotal clinical trial), An ailment fit for a king Gout is defined by arthritic joints, but the co-morbidities,” Terkeltaub says. “They’re an improved outcome was achieved with Uloric compared with allopurinol. “We reduced uric culprit is too much circulating uric acid, a tougher to manage.”

nature biotechnology volume 27 number 4 april 2009

309

NEWS f e at u r e

Table 1 Gout drugs in development Drug

Mechanism

Company

Status

Uloric (febuxostat)

Small-molecule xanthine oxidase inhibitor

Takeda

Approved for gout in US February 2009, in Europe in 2008, sold as Adenuric (Ipsen, Paris)

Puricase (pegloticase)

Recombinant, pegylated urate oxidase

Savient

Biologic License Application for gout under FDA review

Arcalyst (rilonacept)

IL-1 trap

Regeneron

Phase 3 trial in gout initiated (drug approved for different indication)

RDEA594

Small-molecule URAT-1 inhibitor

Ardea

Phase 2 in gout set to commence

acid levels in patients with mild-to-moderate renal insufficiency without the need for a dose adjustment,” Baum says. “So we expect [Uloric] to be indicated for patients with renal insufficiency, which is a significant group that suffers with hyperuricemia and gout.” Although the drug’s makers feel that they have demonstrated Uloric to be superior to allopurinol, some rheumatologists note that the doses of allopurinol used in the published trial were too low to make that claim. The 300 mg dose of allopurinol used may well be standard, but current guidelines recommend upping the dose if urate-lowering is not achieved. In other words, higher doses of allopurinol—up to 800 mg—might have improved its performance in the trial. The UK’s National Health Service recommends Uloric as a second-line drug. “They were crazy to think that on the basis of some phase 3 studies, that it would be regarded as a first-line drug,” says Edinburgh’s Nuki, who has developed evidence-based guidelines for the treatment of gout in both Europe and the UK. “That’s not the way doctors operate really.” It takes time to trust a new drug, he says, especially given that most of the safety data come from the post-marketing phase, when the drug is used by a much wider population. In the pipeline On the eve of the new year, Savient Pharmaceuticals learned that its biologic drug Puricase (pegloticase), for those with gout who don’t respond to other treatments, was accepted for priority review by the FDA. Puricase is also a serum urate–lowering drug, but it works by directly metabolizing uric acid. The drug is based on the naturally occurring enzyme uricase, found in most animals. Humans don’t express the enzyme (thus are susceptible to the consequences of poor uric acid control) but do carry the gene. Savient licensed the gene sequence from Duke University and has tinkered with the expressed protein to come up with Puricase. Conjugating uricase with polyethylene glycol has reduced the immunogenicity of the protein, although immune reactions still occur.

310

Savient is seeking to market Puricase for use in gout patients for whom other therapies have failed and has worked to define them as an orphan population within the larger indication of gout. “So pegloticase is being developed as an orphan drug,” says Sundy, first author on the published phase 2 trial. Some 50,000 people are estimated to be treatment failures, he says, out of the nearly 3 million people with gout in the US. The published phase 2 trial was conducted in subjects who met the criteria for treatmentfailure gout—26 patients who had hyperuricemia and symptomatic gout, but who did not respond to treatment with current drugs or for whom approved drugs are contraindicated. Of those, 50–88% responded to Puricase with serum urate levels below 6 mg/dl at least 80% of the time. “We’re eliminating tophi from patients’ bodies,” says Savient president Paul Hamelin. “We’re reducing their pain, we’re improving their physical function—people are doing things that they haven’t been able to do in years. Patients with tophi in their hands, for example, who have gone years without being able to write or do the buttons on their shirts.” The Puricase data are compelling to rheumatologists trying to help patients with severe gouty arthritis. “We have the opportunity to rapidly debulk tophi in these people and I think that the performance of this compound has exceeded our expectations,” says Terkeltaub, who was not an investigator, but did refer some patients into the trials. “I’ve had people with massive tophi whose tophi melted away in six months. It’s really a dramatic effect. When it works, it works really well.” And yet it’s not a perfect drug. Terkeltaub tells of other individuals who had infusion reactions and severe gout flare-ups. “I think this is a drug that is going to have to be used by people who really know what they’re doing,” he says, meaning rheumatologists experienced with infusion drugs. In addition, many patients develop neutralizing antibodies to Puricase, Sundy says, which leads to early clearance of the drug and loss of efficacy. And the overall response rate has been about 40%. The good news is that 40% of people who were otherwise

untreatable respond. The bad news is that some people don’t respond to any treatment. The third urate-lowering drug in the pipeline is RDEA594, which was discovered when scientists at Ardea Biosciences of San Diego noticed urate-lowering properties in its nonnucleoside reverse transcriptase inhibitor RDEA806, which they are developing for the treatment of HIV infection. RDEA594 is the major metabolite of RDEA806 but does not have antiviral activity. The mechanism of serum urate–lowering action of RDEA594 differs from the other drugs on the market and underdevelopment. Rather than blocking the production of uric acid (allopurinol, Uloric) or directly breaking it down (Puricase), RDEA594 enhances the elimination of uric acid by the kidney, akin to the generic drug probenecid. It appears to inhibit the recently discovered uric acid transporter URAT1, which mediates the reuptake of uric acid in the kidney. Ardea is finishing up a phase 1 clinical trial, but as the drug is a metabolite of a drug already in trials, the company already has safety data for over 250 people. Barry Quart, Ardea’s president and CEO, told an audience at the BIO CEO conference in New York in February that RDEA594 might work well in combination with a xanthine oxidase inhibitor—taking a two-pronged attack: reducing production and increasing clearance of uric acid from the blood, a tactic often used with allopurinol and probenecid. “The question is will it work once it goes through clinical development? Will it work in people who have more pronounced renal dysfunction?” asks Terkeltaub. If so, RDEA594 could gain traction in the US, where one drug that increases excretion of uric acid, probenicid, doesn’t work well in people with kidney disease and another, benzbromarone, is not available because of hepatotoxicity (although it is available in Europe, South Africa and Japan). Treating gout symptoms Although hyperuricemia is responsible for gout, what patients deal with is pain, inflammation and loss of function. And the pain experienced by patients during a gout flare— which can last for a week—is excruciating. “When you ask a patient to rate the pain of that flare on a 10-point scale—with 10 being the most excruciating pain you’ve ever experienced in your life—they will almost always rate it an 8, 9 or 10,” says Hamelin. “It’s a disabling type of pain.” Gout flare-ups can be spontaneous, and are often the first indication of the disease. Doctors use frequency of gout flare-ups as a guideline for recommending chronic uratelowering therapy to patients—typically when

volume 27 number 4 april 2009 nature biotechnology

n e w s f e at u r e patients experience one or two flare-ups a year. Flare-ups are also induced when patients begin chronic urate-lowering therapy. As the serum levels of uric acid decrease, crystal deposits begin to solubilize, and something about that shift in homeostasis causes flare-ups and pain. Currently, painful flare-ups are managed with anti-inflammatory drugs and colchicine. The biologic drug Arcalyst (rilonacept), which may be the next choice for the treatment of gouty pain and inflammation, traps the cytokine interleukin 1 (IL-1), preventing its proinflammatory effects. Arcalyst is a dimeric fusion protein consisting of the ligand-binding domains of the extracellular portions of the human IL-1 receptor component (IL-1RI) and IL-1 receptor accessory protein (IL-1RAcP) linked to the Fc portion of human immunoglobulin G1. It has proven useful in rare disorders involving the cryopyrin inflammasome, which research suggests may also mediate gout flare pain. The drug received orphan drug approval from FDA in February last year for use in familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Now Regeneron Pharmaceuticals, of Tarrytown, New York, is positioning Arcalyst to be indicated for gout flare-ups, both spontaneous ones and those induced by urate-lowering therapy. In a phase 2 study, completed last September, of 83 gout patients taking chronic allopurinol treatment with or without Arcalyst, 15% of those on Arcalyst experienced flares (6 flares total) compared with 45% of those receiving placebo (33 flares total), according to company data. The data are currently being written up for publication. Robert Terifay, a senior vice president at Regeneron, describes the need for better pain management of gout flare-ups. “Although rheumatologists are well aware of the induction of flares for the first few months of therapy, they’re not the primary treaters of gout—internal medicine physicians and primary care physicians are,” he says. Citing audited prescription data, Terifay says only 12.4% of people initiating allopurinol therapy are given concomitant anti-inflammatory therapy—either colchicine or nonsteroidal anti-inflammatory drugs (NSAIDs). “So there’s a large number of patients who are not getting anything with their allopurinol.” Terkeltaub says colchicine could certainly be used better, but given problems with NSAIDs and steroids, “We clearly need more choices of anti-inflammatories.” What’s next “It’s an exciting time in the gout field,” Nuki says of the drugs in development. “It’s like the proverbial buses—you wait for a long time

and then they all come along together. What’s interesting is that they’re not just me-toos… that they all act differently.” Still, chances are good that some overlap will occur in the market for gout drugs. The drugs furthest along—Uloric and Puricase—are both poised for use in people who don’t tolerate or don’t respond to allopurinol. Uloric has the advantage of being a once-a-day oral drug. Puricase has shown its might by resolving tophi in the toughest of patients. Allopurinol itself may enjoy a resurgence as a result of the new information on the management of gout that will accompany the new drugs. With new drugs will come new education. Rheumatologists have revisited and revised guidelines over the past four decades, and yet, 300 mg allopurinol still is the most commonly given dose. Of the gap between disease and treatment, Duke’s Sundy says, “It’s not a medical gap, but a physician gap. Too often, allopurinol doesn’t get dosed at appropriate levels to achieve a therapeutic response.” So is there room for all these drugs should the new ones pass muster with the FDA? Takeda’s Baum says, “It’s a little hard to say at this point. But I do think there are nuances within the management and treatment of gout that suggest that different mechanisms of treatment may have benefit.” Once they hit the market, both Uloric and Puricase may have additional uses. Takeda wants to push forward with research on nongout effects of hyperuricemia, Baum says, such as what role uric acid may play in metabolic disease. Epidemiological data have linked elevated uric acid levels to cardiovascular disease and stroke, and recent evidence shows that uric acid transporters are expressed not only in the kidney, but also in tissues such as vascular endothelium. Rheumatologists await real-world experience with Puricase to better understand its safety profile for a disease that requires chronic therapy. And yet, no one denies that the biologic drug has done what no drug has done before—reversed years’ worth of crystal deposits. “Because of its extreme effectiveness in getting rid of the huge amounts of accumulated urate that you get in these treatment-resistant patients, there may a role for [Puricase] in initiating treatment to debulk the patients,” Nuki says. After that, another urate-lowering drug might be used to maintain a patient’s lowered uric acid level if long-term Puricase should prove troublesome. Nuki speaks for many doctors who treat patients with gout when he says, “I’m enthusiastic about these things, but on the other hand I’m sufficiently skeptical.” Jill U Adams, Albany, New York Corrected after print 8 July 2009.

nature biotechnology volume 27 number 4 april 2009

311

c o r r i g e n d a & e r r ata

Corrigendum: Transfection of small RNAs globally perturbs gene regulation by endogenous microRNAs Aly A Khan, Doron Betel, Martin L Miller, Chris Sander, Christina S Leslie & Debora S Marks Nat. Biotechnol. 6, 549–555 (2009); published online 24 May 2009; corrected after print 8 July 2009 In the version of this article initially published, Figure 2f is not referenced in the figure legend and is referenced as Figure 2e in the main text. Also, on p.5, right col., para. 1, line 8, miR-21 should be miR-122. The errors have been corrected in the HTML and PDF versions of the article.

Erratum: Venture capital shifts strategies, startups suffer Peter Mitchell Nat. Biotechnol. 27, 103–104 (2009); published online 9 February 2009; corrected after print 8 July 2009

© 2009 Nature America, Inc. All rights reserved.

In the version of this article initially published, “GSK Ventures” should have read “GlaxoSmithKline’s SR One.” The error has been corrected in the HTML and PDF versions of the article.

Erratum: New relief for gout Jill U Adams Nat. Biotechnol. 27, 309–311 (2009); published online 7 April 2009; corrected after print 8 July 2009 In the version of this article initially published, the incidence of gout was incorrectly stated to be in the hundreds of millions worldwide and 300 million in the US (p. 309, para. 2). The incidence is known for industrialized countries, not worldwide. In the US, the number is 3 million. The last five lines of the paragraph should have read, “including about 1 in 100 adult men in industrialized countries (an estimated 3 million in the US according to the Centers for Disease Control).” The errors have been corrected in the HTML and PDF versions of the article.

Erratum: Biotech hirings and firings Michael Francisco Nat. Biotechnol. 27, 395, 2009; published online 7 April 2009; corrected after print 8 July 2009 In the version of this article initially published, a company name was omitted from Table 2. GlaxoSmithKline should be listed in third place. The error has been corrected in the HTML and PDF versions of the article.

Erratum: Wyeth preemption case ruling sparks labeling confusion Malorye Allison Nat. Biotechnol. 27, 399–400 (2009); published online 8 May 2009; corrected after print 8 July 2009 In the version of this article initially published, Phenergan is incorrectly mentioned in paragraph 2 as Merck’s antinausea drug. Phenergan is made by Wyeth. The original version also states in paragraph 3 that Wyeth is located in Whitehouse Station, New Jersey. The company’s correct location is Madison. The errors have been corrected in the HTML and PDF versions of the article.

Erratum: Academia and the company coin Jim Kling Nat. Biotechnol. 27, 411–414 (2009); published online 8 May 2009; corrected after print 8 July 2009 In the version of this article initially published, on p. 411, left column, last paragraph, one of the researchers’ names was incorrectly given as “Martin Feller.” It should have read Martin Keller. The error has been corrected in the HTML and PDF versions of the article.

nature biotechnology volume 27 number 7 july 2009

671