OPINION S E P T E M B E R 2 0 1 0 • W W W. R H E U M AT O L O G Y N E W S . C O M 19 COMMENTARY Is Bias Behind the Lack of New Obesity Drugs? n July, a Food and Drug Administra- the epidemic nature of adiposity and its tion advisory committee voted 10-6 devastating consequences, only two against approval of the phentermine- drugs have been approved in the United topiramate controlled-release combina- States for long-term treatment of obesition agent for weight loss. The panel ty: orlistat and sibutramine (the latter’s members and the agency agreed that the fate is uncertain). Past antiobesity drug expecombination was effective. riences often have been disasAmong the main safety controus regarding appropriatecerns reported by the panel ness of use and safety. were an increase in heart rate However, these experiences (an average of about one excannot fully account for the tra beat per minute), potenvirtual absence of currently tial adverse psychological efapproved weight-loss drug fects, impaired memory and therapies. One might reasonconcentration, metabolic aciably question whether biases dosis, and that both phenterexist, which may include that: mine and topiramate are BY HAROLD pregnancy category C drugs. 씰 Medical science has a hisB AY S , M . D . Obesity is an epidemic. Aditorical bias against obese paposity often causes pathogentients (Vesalius 2009;15:59-70). ic endocrine and immune responses that 씰 Many chosen for FDA advisory panels lead to the most common metabolic dis- have limited to no clinical experience orders in endocrine patients: diabetes, hy- with anti-obesity drug development, at pertension, and dyslipidemia (Expert Rev. least compared with the many clinical reCardiovasc. Ther. 2008;6:343-68). searchers who conduct the trials. This seWeight-loss drug therapies that im- lective process is presumably done to prove metabolic disease (such as phen- avoid bias. But without impugning the termine-topiramate CR) are, therefore, objectivity of the FDA panel, it is reaof keen interest to practicing endocri- sonable to speculate that this selection nologists and their patients. Yet, despite process actually has the potential to in- I troduce bias through the unbalanced 씰 Many “experts” have concerns that the collection of individuals with certain high demand for a newly approved antipredispositions. obesity drug would mean not only use, but misuse, by clin씰 Many view obesity as a See related icians and patients. Thus, to lifestyle disorder. Thus, unless story on page protect clinicians and patients a weight-loss drug has almost 38. from themselves through offno associated adverse experilabel use, the FDA is encourences, many feel the drug is unsuitable for FDA approval. This aged against approval of anti-obesity unique standard does not apply to other agents, irrespective of the potential bendiseases. For example, the same dose of efits to endocrine patients when used aptopiramate in the full dose of phenter- propriately. This protectionism bias does mine-topiramate CR is the commonly not apply to drug treatment of other disused and approved dose for preventing eases. migraine headaches. To say that the riskContinued on following page to-benefit ratio of topiramate to prevent a migraine headache is acceptable, while that of the same topiramate dose LETTERS to treat obesity is unacceptable, suggests Letters in response to articles in disease bias. RHEUMATOLOGY NEWS and its supplements should include your name and address, 씰 Some of the FDA advisory panel affiliation, and conflicts of interest in members expressed concern that, should regard to the topic discussed. Letters new weight-loss drugs be approved, givmay be edited for space and clarity. en the profound need and relative lack of Mail: Letters, RHEUMATOLOGY NEWS, available alternatives (other than 5635 Fishers Lane, Suite 6000, surgery), they might result in a largeRockville, MD 20852 Fax: 240-221-2541 scale use of the drug. Obese patients and E-mail: [email protected] their treating clinicians might find this Comment Voice Mail: 877-524-9335 “fear” to represent a blatant, if not bizarre bias. ACTEMRA® (tocilizumab) ACTEMRA® (tocilizumab) In the all-exposure population, the rate of malignancies remained consistent (1.10 events per 100 patient-years) with the rate observed in the 6-month controlled period [see Warnings and Precautions]. Other Adverse Reactions Adverse reactions occurring in 2% or more of patients on 4 mg/kg or 8 mg/kg ACTEMRA plus DMARD, and at least 1% greater than that observed in patients on placebo plus DMARD, are summarized in Table 2. abortion/embryo-fetal death at 10 mg/kg and 50 mg/kg doses (1.25 and 6.25 times the human dose of 8 mg/kg every 4 weeks based on a mg/kg comparison). Nonteratogenic Effects. Testing of a murine analogue of tocilizumab in mice did not yield any evidence of harm to offspring during the pre- and postnatal development phase when dosed at 50 mg/kg intravenously with treatment every three days from implantation until day 21 after delivery (weaning). There was no evidence for any functional impairment of the development and behavior, learning ability, immune competence and fertility of the offspring. Pregnancy Registry: To monitor the outcomes of pregnant women exposed to ACTEMRA, a pregnancy registry has been established. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972. Nursing Mothers It is not known whether tocilizumab is excreted in human milk or absorbed systemically after ingestion. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ACTEMRA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of ACTEMRA in pediatric patients have not been established. Geriatric Use Of the 2644 patients who received ACTEMRA in Studies I to V, a total of 435 rheumatoid arthritis patients were 65 years of age and older, including 50 patients 75 years and older. The frequency of serious infection among subjects treated with ACTEMRA 65 years of age and older was higher than those under the age of 65. As there is a higher incidence in infections in the elderly population in general, caution should be used when treating the elderly. Hepatic Impairment The safety and efficacy of ACTEMRA have not been studied in patients with hepatic impairment, including patients with positive HBV and HCV serology [see Warnings and Precautions]. Renal Impairment No dose adjustment is required in patients with mild renal impairment. ACTEMRA has not been studied in patients with moderate to severe renal impairment. OVERDOSAGE There are limited data available on overdoses with ACTEMRA. One case of accidental overdose was reported in which a patient with multiple myeloma received a dose of 40 mg/kg. No adverse drug reactions were observed. No serious adverse drug reactions were observed in healthy volunteers who received single doses of up to 28 mg/kg, although all 5 patients at the highest dose of 28 mg/kg developed dose-limiting neutropenia. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate symptomatic treatment. PATIENT COUNSELING INFORMATION Patient Counseling Patients should be advised of the potential benefits and risks of ACTEMRA. Physicians should instruct their patients to read the Medication Guide before starting ACTEMRA therapy. • Infections: Inform patients that ACTEMRA may lower their resistance to infections. Instruct the patient of the importance of contacting their doctor immediately when symptoms suggesting infection appear in order to assure rapid evaluation and appropriate treatment. • Gastrointestinal Perforation: Inform patients that some patients who have been treated with ACTEMRA have had serious side effects in the stomach and intestines. Instruct the patient of the importance of contacting their doctor immediately when symptoms of severe, persistent abdominal pain appear to assure rapid evaluation and appropriate treatment. Table 2 Adverse Reactions Occurring in at Least 2% or More of Patients on 4 mg/kg or 8 mg/kg ACTEMRA plus DMARD and at Least 1% Greater Than That Observed in Patients on Placebo plus DMARD 6-Month Phase III Controlled Study Population ACTEMRA 8 mg/kg Methotrexate ACTEMRA 4 mg/kg + DMARDs ACTEMRA 8 mg/kg + DMARDs Placebo + DMARDs N = 288 (%) 7 7 7 6 6 3 3 2 2 2 1 1 N = 284 (%) 5 6 2 2 4 1 2 1 2 2 2 5 N = 774 (%) 6 4 6 4 3 2 4 4 1 3 1 2 N = 1582 (%) 8 6 5 4 3 3 3 3 2 3 2 2 N = 1170 (%) 6 4 3 3 1 2 3 1 1 2 1 1 Monotherapy Preferred Term Upper Respiratory Tract Infection Nasopharyngitis Headache Hypertension ALT increased Dizziness Bronchitis Rash Mouth Ulceration Abdominal Pain Upper Gastritis Transaminase increased DRUG INTERACTIONS Other Drugs for Treatment of Rheumatoid Arthritis Population pharmacokinetic analyses did not detect any effect of methotrexate, nonsteroidal anti-inflammatory drugs or corticosteroids on tocilizumab clearance. Concomitant administration of a single dose of 10 mg/kg ACTEMRA with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure. ACTEMRA has not been studied in combination with biological DMARDs such as TNF antagonists [see Dosage and Administration]. Interactions with CYP450 Substrates In vivo studies with omeprazole, metabolized by CYP2C19 and CYP3A4, and simvastatin, metabolized by CYP3A4, showed up to a 28 % and 57% decrease in exposure one week following a single dose of ACTEMRA, respectively. The effect of tocilizumab on CYP enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of ACTEMRA, in patients being treated with these types of medicinal products, therapeutic monitoring of effect (eg, warfarin) or drug concentration (eg, cyclosporine or theophylline) should be performed and the individual dose of the medicinal product adjusted as needed. Prescribers should exercise caution when ACTEMRA is coadministered with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, eg, oral contraceptives, lovastatin, atorvastatin, etc. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy. Live Vaccines Live vaccines should not be given concurrently with ACTEMRA [see Warnings and Precautions]. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects. Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. ACTEMRA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. An embryo-fetal developmental toxicity study was performed in which pregnant cynomolgus monkeys were treated intravenously with tocilizumab (daily doses of 2, 10, or 50 mg/kg from gestation day 20-50) during organogenesis. Although there was no evidence for a teratogenic/dysmorphogenic effect at any dose, tocilizumab produced an increase in the incidence of Genentech USA, Inc., A Member of the Roche Group South San Francisco, California 94080-4990 Copyright © 2010 Genentech USA, Inc. All rights reserved. 10081800 OPINION 20 S E P T E M B E R 2 0 1 0 • R H E U M AT O L O G Y N E W S COMMENTARY A Look Down the Gout Treatment Pipeline llopurinol should, at least for now, remain the standard hyperuricemia treatment for gout, despite febuxostat’s approval and the ongoing development of other gout pharmaceuticals. The reason is that allopurinol—if adequately dosed—works for most patients. And after decades on the market, its safety profile is well known; it’s also the least expensive option. But even with BY ROBERT L. adequate dosing, W O R T M A N N , M . D . allopurinol does not work for everyone. For some, renal problems or previous hypersensitivity reactions make its use problematic. That’s where the newer options come in. For rheumatologists and patients alike, they mean that allopurinol is not the end of the line anymore. Soon, there will likely be enough options to treat every gout patient. We recently reviewed febuxostat, as well as pegloticase and other drugs in the gout pipeline (Lancet 2010 Aug. 17 [doi: 10.1016/S0140-6736(10)60665-4]). Our conclusion: Recent developments signal a new era in the treatment of gout. Febuxostat (Uloric), approved by the Food and Drug Administration in Feb- A Continued from previous page 씰 Many believe that obesity is not a real “disease.” As detailed at the recent Physiology and Pathophysiology of Adipose Tissue State of the Science Conference, sponsored by the American Association of Clinical Endocrinologists, increased adiposity has pathogenic potential (“adiposopathy” or “sick fat”), which directly contributes to metabolic disease (http://atp.aace. com). Unfortunately, many clinicians, patients, and even “opinion leaders” lack the basic science knowledge of adipose physiology and pathophysiology and how it applies to adverse clini- ruary 2009, is already making a difference in clinical practice. It has been the experience of rheumatologists that patients who have had trouble with allopurinol often respond to febuxostat. The first dose can quickly drop the serum urate level down to 5 mg/dL or so, without side effects or rash. It’s a great drug that is here to stay. Like allopurinol, febuxostat is a xanthine oxidase inhibitor, but a more selecAND tive one that does CHRISTOPHER M. not inhibit other B U R N S, M . D. enzymes in the purine and pyrimidine metabolic pathways. Febuxostat dosing is easier, too. There are two options in the United States: 40 mg and 80 mg/day. The allopurinol dosing range is 100-800 mg/day, depending on patient renal history and response. Even with those advantages, febuxostat should be seen as a second-line agent, considered mainly for patients who are intolerant to allopurinol. Febuxostat just has too many unknowns that are awaiting further information. For instance, it is not known if it is more effective than allopurinol. Febuxostat was better at dropping uric acid levels in trials, but it was compared with a suboptical outcomes. This is a bias of ignorance. Overall, the lack of approval of antiobesity drugs suggests that, for the first time in history, medical science is on the cusp of proclaiming a major metabolic epidemic as being untreatable with pharmaceuticals. This is more than bias. It is a tragic failing of those of us entrusted to patient care. ■ DR. BAYS is chairman of the AACE Pathogenic Adipose Tissue Task Force. He has received research grants and has served as an adviser or consultant for Vivus (which is developing obesity therapies) and other drug companies. E DITORIAL A DVISORY B OARD ROY D. ALTMAN, M.D., University of California, Los Angeles DIMITRIOS BOUMPAS, M.D., University of Crete, Heraklion, Greece CHRISTOPHER M. BURNS, M.D., Dartmouth University, Lebanon, N.H. DANIEL E. FURST, M.D., University of California, Los Angeles ERIC P. GALL, M.D., University of Arizona, Tucson NORMAN B. GAYLIS, M.D., Private Practice, Aventura, Fla. KAREN S. KOLBA, M.D., Private Practice, Santa Maria, Calif. TORE K. KVIEN, M.D., University of Oslo THOMAS J.A. LEHMAN, M.D., The Hospital for Special Surgery, New York ROBERT F. SPIERA, M.D., The Hospital for Special Surgery, New York VIRGINIA D. STEEN, M.D., Georgetown University, Washington. JOHN S. SUNDY, M.D., Duke University, Durham, N.C. KENNETH R. WILSKE, M.D., University of Washington, Seattle mal allopurinol dose (300 mg), and about 50% of gout patients need a higher dose to control hyperuricemia. Also, febuxostat’s cardiac safety is a concern. Cardiac events were more common in febuxostat patients during trials, although the implications of that are not yet clear. Takeda Pharmaceutical Co., the drug’s maker, is investigating the matter further. Finally, although no hypersensitivity reactions were attributed to febuxostat during trials, the FDA had received reports of 11 as of last May, including 2 anaphylactic reactions, 1 case of angioedema, and 2 of Stevens-Johnson syndrome (RHEUMATOLOGY NEWS, June 2010, p. 4). At this time, clinicians need to use their judgment whether to push allopurinol to therapeutic levels rather than use febuxostat. Patients with mild or moderate renal insufficiency might be an exception, however. Febuxostat dosage adjustments are not needed as long as patients’ creatinine clearance is higher than 30 mL/min, according to the review article. Allopurinol is typically adjusted downward for diminished renal function. Most people with renal insufficiency do fine even on allopurinol, as long as they are started on a low dose that is titrated upward to therapeutic effect, and are monitored for kidney function. Febuxostat is making inroads in the United States: Some 139,565 prescriptions were written for it during its first 6 months on the market, according to health care market analytics firm SDI Health LLC. One should expect a more modest reception for the next gout treatment— pegloticase (Krystexxa)—that’s likely to be approved by the FDA. The FDA’s arthritis advisory committee recommended approval of the pegylated uricase in June 2009; the agency and pegloticase’s manufacturer, Savient Pharmaceuticals Inc., appear to be working out the final manufacturing and prescribing details. Pegloticase’s strength is rapid reduction of uric acid levels, to about 1 mg/dL within 24 hours in most cases. Its market will be among patients who need that kind of power: those with severe tophaceous gout whose urate loads are so high that there is an urgent clinical need to lower it. Having a “big gun” for those situations would be a major advance, especially when allopurinol and febuxostat don’t work or can’t be used. But pegloticase is destined to remain in the hands of subspecialists because it’s tricky to use. The drug is a biologic that is administered intravenously a few times a month. In trials, at least 25% of patients developed antibodies to it, with subsequent infusion reactions, diminished effects, and treatment withdrawals, according to our review article. Anaphylaxis developed in 7.3% of those who were infused every other week. The rapid uric acid reduction also led to frequent and sometimes severe gout flares. Safe use is possible if rising concentrations of serum urate—a sign of antibody development and impending infusion reaction—are caught in time. But the use issues mean that pegloticase will have a limited audience. If approved, it is unlikely to be something that is used freely. Other drugs intended for the management of gout are in early development. But, like febuxostat and pegloticase, they may help plug gaps in current therapy if they’re approved for gout. Already approved for cryopyrin-associated periodic syndromes, the anti-inflammatory interleukin-1 inhibitors rilonacept (Arcalyst) and canakinumab (Ilaris) are being studied both for acute gout and for prophylaxis. Conceivably, they could find a home among gout patients who have relative contraindications to steroids or can’t use colchicine or NSAIDs because they have heart failure, kidney disease, peptic ulcers, or some other problem. The gout pipeline also contains the uricosuric RDEA594. It is thought to be more selective than probenecid and benzbromarone, leading to the possibility that it would be a candidate for concomitant use with other urate-lowering treatments. However, findings from a small phase II trial show that RDEA594 was less effective than 300 mg allopurinol in lowering serum urate. And combination therapy is already an option with allopurinol and probenecid. It is too early in development to predict whether RDEA594 itself will make it through the FDA approval gauntlet, but a more selective uricosuric would be a useful addition to the expanding gout armamentarium. ■ DR. WORTMANN is professor of medicine in the division of rheumatology at the Dartmouth-Hitchcock Medical Center, Lebanon, N.H. and reports that he is a paid consultant for Takeda Pharmaceutical Co. and Savient Pharmaceuticals Inc. DR. BURNS is assistant professor of medicine in the rheumatology division of Dartmouth-Hitchcock, and reports that he has no conflicts of interest. 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