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20 /CT DISEASES MAY 2010 • RHEUMATOLOGY NEWS RAVE Trial Portends New Era in Vasculitis Tx

BY BRUCE JANCIN ate, although , mycophenolate mofetil, longed cyclophosphamide exposure,” said Dr. Specks of , and intravenous immunoglobulin have the Mayo Clinic in Rochester, Minn. Key remaining S NOWMASS, COLO. — The future of therapeutics also been studied). questions—such as how best to reinfuse in at least one form of severe vasculitis appears to lie For non–life-threatening, early, systemic disease, the when B cells eventually return—are being addressed in in the biologic agents, in light of rituximab’s impressive NORAM (Non-Renal Vasculitis Alternative Treatment an ongoing follow-up study. showing in the RAVE trial, Dr. Leonard H. Calabrese With ) trial demonstrated that it was rea- Rituximab may not be the only biologic response observed at a symposium sponsored by the American sonable to do away with cyclophosphamide altogeth- modifier with a bright future in ANCA-associated vas- College of Rheumatology. er, and to use methotrexate for induction as an alter- culitis. RAVE (Rituximab for the Treatment of Wegener’s native (Arthritis Rheum. 2005;52:2461-9). Dr. Calabrese said that although he, like most rheuma- Granulomatosis and Microscopic Polyangiitis) was an However, in severe ANCA-associated vasculitis with tologists, has opted out of the use of anti–tumor necro- eagerly awaited, randomized trial presented last fall at impaired vital organ function, cyclophosphamide has sis factor–alpha therapies altogether in light of the neg- the annual meeting of the American College of remained the workhorse—that is, until RAVE. ative Wegener’s Granulomatosis Trial (N. Rheumatology. It demonstrated that rituximab (Ritux- RAVE was a National Institute of Allergy and Infec- Engl. J. Med. 2005;352:351-61), he wonders whether an) was as effective as—and safer than—standard-of-care tious Diseases–sponsored, 197-patient, randomized tri- etanercept (Enbrel) was the right drug. The anti-TNF cyclophosphamide at inducing remission in patients al involving assignment to B-cell depletion via four agents don’t all act in the same way, and most of the with severe antineutrophil cytoplasmic once-weekly infusions of rituximab (375 mg/m2) or anecdotal reports of treatment success have involved in- (ANCA)–associated vasculitis. oral cyclophosphamide (2 mg/kg per day). At 6 months, fliximab (Remicade), not etanercept, he noted. Moreover, in a prespecified subgroup analysis, pa- the remission rate was 64% in the rituximab arm and Dr. Peter A. Merkel, director of the vasculitis center tients who entered RAVE with a severe flare of their similar (53%) in the cyclophosphamide arm. However, at Boston University, conceded that it’s possible a dif- vasculitis rather than with new-onset disease had a sta- 19% of patients in the rituximab group experienced one ferent anti-TNF agent would have done better, but these tistically and clinically greater remission rate with rit- or more adverse events, compared with 32% of those large National Institutes of Health trials take years to uximab than with cyclophosphamide. “This is a very on cyclophosphamide. complete, and the research momentum has shifted important study that marks a major shift in thinking,” RAVE study chair Dr. Ulrich Specks, who was in the away from the older biologics. Now underway, for ex- said Dr. Calabreseof the Cleveland Clinic Foundation. audience for the ACR Snowmass symposium, rose to ample, is a clinical trial in Wegener’s granulomatosis of Indeed, in recent decades the emphasis has been on emphasize that in the 101 RAVE participants with (Orencia), a that inhibits co- developing strategies to fine-tune cyclophosphamide baseline severe flares, the 6-month remission rate was stimulation of T cells and is approved for the treatment therapy to minimize its serious toxicities. 67% with rituximab, which was statistically superior to of rheumatoid arthritis. ■ The most popular of these strategies is step-down the 42% rate in the cyclophosphamide arm. therapy—specifically, 3 months of cyclophosphamide “So for the treatment of severe flares of the disease, Disclosures: Dr. Calabrese disclosed that he serves as a as induction therapy, followed by maintenance treat- rituximab is probably going to be the standard of care consultant to Amgen Inc., Centocor Inc., Genentech Inc., ment with a nonalkylator (most commonly methotrex- as we move forward. It will spare patients from pro- Sanofi-Aventis, UCB, and Wyeth. Expert Outlines Drug-Development Obstacles in Lupus

BY DIANA MAHONEY “The irony, of course, is that the standard that background have on pa- the BLISS-52 ( in Subjects of care in lupus is off-label therapy, be- tient response and adverse events, and if With Systemic Lupus Erythematosus–52) D ESTIN, FLA. — “The problem with cause there hasn’t been a new drug ap- more specific responder indices were and BLISS-76 phase III trials, said Dr. drug development in lupus is lupus,” Dr. proved for the disease in more than 50 available to assess treatment effect, ac- Merrill. Joan T. Merrill said at the Congress of years,” she said. cording to Dr. Merrill. In both BLISS trials, belimumab met Clinical Rheumatology. Because the standard treatments are In fact, it is the attention paid to some the efficacy end point, which was defined “Lupus is an incredibly heterogeneous off label, their therapeutic effect has not of these factors that likely contributed to as a reduction from baseline of at least 4 disease. We know from the results of been established in clinical trials. “Many the recent success of two separate phase points on the SLEDAI disease activity clinical trials that no one drug can be ex- clinical trials in lupus have to be carried III trials of belimumab (Benlysta), the scale, no worsening of disease as mea- pected to work for more than 60% of pa- out for a whole year, and they can’t re- that targets B-lym- sured by the PGA, no new BILAG grade tients with lupus. But we can’t yet pick out ally be performed unless patients are on phocyte stimulator (BLyS), she said. A organ domain score, and no more in advance the subgroup of patients who these background medications, but we In the initial phase II, double-blind, than one new BILAG grade B organ do- will respond to a given drug,” she said. placebo-controlled trial of belimumab main score, Dr. Merrill noted. The heterogeneity of the disease In lupus, in patients with active lupus, the drug The differences between the treat- across patients and the absence of sci- ‘targeted failed to improve disease activity as ment and control groups that were ob- entific evidence to explain the biological therapies can measured by the SLEDAI (Systemic Lu- served in both trials were small but sta- mechanisms underlying the variations only work if you pus Erythematosus Disease Activity In- tistically significant, and they were have been impediments to fruitful clini- know what you’re dex), and did not decrease time to first historically meaningful because they put cal experimentation, and have led to a se- targeting, in SLE flare (Arthritis Rheum. the drug on the pathway for FDA ap- ries of disappointing clinical trial out- whom, and why.’ 2009;61:1168-78). proval, she said. comes, said Dr. Merrill, of the University In a post hoc exploratory analysis of “This is a major development, not be- of Oklahoma in Oklahoma City. DR. MERRILL the data, however, the investigators “no- cause [belimumab] is expected to be a “Targeted therapies can only work if ticed that if they looked just at the sub- cure-all or the best treatment for every you know what you’re targeting, in don’t know what these background med- set of patients who had been either ANA lupus patient, because it is not,” said Dr. whom, and why,” she noted. “We have ications are doing biologically to pa- [antinuclear antibody] positive or Merrill. Rather, FDA approval of beli- the technology to be able to identify tients, or how they are interfering with [anti–double-stranded DNA] positive at mumab, if it happens, will break ground those subsets of patients that we ought our assessment of a study agent,” Dr. study entry, they actually could see more for other studies to follow and, after 50 to be targeting with each treatment, but Merrill said. patients with a 4-point reduction in the years, “there will finally be an approved we don’t have the will. Arguably, the potentially promising SLEDAI over time at each visit” than in therapy that we can hold other [experi- Additional complications include the agents that have failed to achieve in- the placebo group, said Dr. Merrill. mental] therapies up against.” ■ inconsistent clinical course of the dis- tended levels of improvement in patient Based on this observation, the investi- ease, which is characterized by flares outcomes in lupus trials—including my- gators used the phase II trial data to de- Disclosures: Dr. Merrill has served as a and remissions that make it difficult to cophenolate mofetil (CellCept), abata- velop a new SLE Responder Index (SRI) consultant and clinical trialist for assess the impact of investigational ther- cept (Orencia), prasterone (Prestara), that incorporated components of the Genentech/Roche, Bristol-Myers Squibb apies and also complicate the selection of abetimus sodium (Riquent), and ritux- SLEDAI, the BILAG (British Isles Lupus Co., MedImmune Inc., and Human meaningful clinical end points, and the imab (Rituxan)—might have demon- Assessment Group) disease activity in- Genome Sciences; she has been a need (according to the Food and Drug strated treatment effects if patient selec- strument, and the PGA (Physician Glob- consultant for Amgen Inc., UCB Pharma Administration) to show clinical superi- tion had been optimized based on al Assessment). Inc., and Serono Inc.; and she has received ority of the investigational agents over patient-specific biology, if investigators They used the new instrument as the grants from Aspreva/Vifor and standard treatment, said Dr. Merrill. had a better understanding of the impact primary efficacy end point at week 52 in Wyeth/Pfizer for investigator-initiated