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Home , Abetimus, Atacicept

12 /CT Diseases R HEUMATOLOGY N EWS • March 2008 SLE Drug Pipeline: An Embarrassment of Riches

BY BRUCE JANCIN for longer than 12 months. That raises safety concerns. was found to have no effect on time to flare Denver Bureau And human antichimeric production has been or SLE Disease Activity Index in a randomized trial in- a problem. volving 449 patients with mild to moderate active SLE. In S NOWMASS, COLO. — The drug pipeline is sudden- ’s role in treating SLE should be clarified response, sponsor Human Genome Sciences Inc. created ly chock-full of biologic agents, good news for rheuma- within the year, upon completion of two ongoing phase a novel combined end point, applied it retroactively, and tologists, who have been waiting more than 3 decades III trials: Explorer in patients with active nonrenal lupus, declared the study a success. The new combined primary since the last approval of a new therapy for SLE. Some and Lunar in patients. end point is being used in two ongoing phase III trials of of these agents have completed promising phase II clin- is a second-generation anti-CD20 agent the anti-BlyS agent, each double the size of the earlier one. ical trials and are well along in phase III. in ongoing clinical trials. As a humanized monoclonal an- The new end point consists of at least a 4-point im- “For many years, I would give talks on the latest de- tibody, it is likely to have fewer safety issues. provement on the SLE Disease Activity Index, no new velopments in mouse models and speculate about what Another focus of research into 1A/2B British Isles Lupus Assess- might happen in patients. Today, I can talk about real clin- lupus therapy is : This ment Group domain scores, and ical data on a new generation of biologic therapies for lu- agent prevents costimulation of T ‘If atacicept is no worsening in Physician Global pus,” Dr. David Wofsy marvelled at a symposium spon- cells, and it appears to have syner- more effective, it Assessment. sored by the American College of Rheumatology. gistic efficacy when combined may also be more While Dr. Wofsy said the com- He offered up what he emphasized were personal and with a brief course of cyclophos- toxic. Only time pany’s persistence is laudable, he highly opinionated “shoot from the hip” predictions as to phamide. “In the mouse models of and more studies was highly critical of the new com- the first-generation biologic induction therapies for lupus lupus, nothing compares to this,” will tell.’ bined end point, as well as the fact most likely to emerge from the pack: the anti-CD20 agent said Dr. Wofsy, who did the origi- that the earlier negative trial has ocrelizumab, abatacept (Orencia), and—as a long shot— nal animal studies. DR. WOFSY never been published, although it an anti–tumor necrosis factor agent such as . Current or upcoming clinical was first presented in 2005. “I think the best chance for a new major step forward trials include Bristol-Myers Squibb Co.–sponsored stud- “This trial has been subjected to spin unlike any other in induction therapy lies in these three agents,” said Dr. ies of abatacept in SLE patients without nephritis and trial I’ve ever seen,” he said. “I think this novel end point Wofsy, the George A. Zimmermann Distinguished Pro- abatacept plus mycophenolate mofetil in lupus nephritis, is a disservice to the community. It doesn’t translate into fessor of Rheumatology and director of the clinical tri- as well as an NIH-sponsored study of abatacept plus anything meaningful to anybody who takes care of lupus als center at the University of California, San Francisco. short-course cyclophosphamide vs. cyclophosphamide patients.” He added that if the phase III trials prove pos- As for his predictions regarding likely first-generation alone for lupus nephritis to be conducted by Dr. Wofsy itive, “that may be a business triumph but it won’t be a biologic maintenance therapies, he named the anti–B-lym- and coworkers. scientific breakthrough.” phocyte stimulator (anti-BlyS) agent belimumab (Lym- “It will take a while longer to know about abatacept, “In the end, if you can’t make lupus nephritis better phoStat-B), atacicept, and abetimus sodium (Riquent), but I think the strong preclinical data and its effectiveness with these risky immunosuppressive drugs, you probably formerly known as LJP 394, as the top candidates. in rheumatoid arthritis gives us some hope,” he said. don’t have a drug,” Dr. Wofsy asserted. B cells make a compelling target for therapeutic re- Preliminary data on research with anti–tumor necrosis Like belimumab, atacicept blocks the BlyS pathway. But search because of the multiple mechanisms by which they factor–α therapy suggest TNF’s inflammatory effect in the atacicept also blocks the APRIL (a proliferation-inducing are believed to contribute to SLE: presentation of anti- kidney might be an important mediator in lupus renal ligand) pathway, thereby more effectively blocking signals gen, regulation of T-cell activation, differentiation into an- flares. A trial of as short-duration induction ther- to B cells. B-cell levels in treated patients fall by about 50%, tibody-producing plasma cells, and stimulation of proin- apy is underway in Europe. Dr. Wofsy and colleagues are as with belimumab, but atacicept-treated patients also flammatory . about to start a clinical trial with etanercept. show a 50% reduction in IgM and 20% decrease in IgG. Furthest along in development are the anti-CD20 mon- “Until those trials are in, I would discourage anybody “But if atacicept is more effective, it may also be more oclonal . And of these, the one surrounded by from doing it, but there are some anecdotes that have at toxic. Only time and more studies will tell. There’s an ar- the most buzz is rituximab (Rituxan), already approved least opened our eyes to the possibility,” the rheumatol- ray of B-cell therapies out there that are under investi- for rheumatoid arthritis. An audience show of hands in- ogist continued. gation, and no one can tell you which one is going to be dicated most have used rituximab in lupus patients—and Riquent was developed solely as a relatively safe thera- best,” Dr. Wofsy said. most believed it worked. py for the purpose of maintaining remission. This novel Both atacicept and belimumab are agents that are more “It’s a very widespread belief in our community that rit- agent binds specifically to B cells that make anti-DNA an- likely to sustain a remission than induce it, in his view. uximab is effective in lupus. I have to warn you to be care- tibodies, tolerizing them and causing selective B-cell anergy Other potential biologic therapies in lupus include anti- ful about that. We got the big surprise from the CellCept and death. The appeal of Riquent lies in its power to re- CD3, -4, or -22, anti-B7, anti-C5, anti-interleukin-10, and trial. The literature on anti-CD20 is pretty lean at this duce without global immune suppression. agents directed at the interleukin-6 receptor. Stem cell point,” said Dr. Wofsy, who is also a former ACR president. A 230-patient phase II trial proved negative. However, transplantation is also under investigation. “My hope mirrors yours, but I’m very cautious in this area La Jolla Pharmaceutical Co. saw positive signals in the Dr. Wofsy serves as a consultant to Serono and Zymo- because we continue to get disappointing surprises.” data and has completed enrollment in a phase III trial in- Genetics and is organizing the phase II-III clinical trials of Indeed, while 34 of 35 rituximab-treated lupus patients volving more than 700 lupus nephritis patients with atacicept for SLE. He is also a consultant to Bristol-Myers reported in the literature responded with peripheral B- high-affinity anti-DNA antibodies who were in remission Squibb regarding abatacept, and to Genentech/Biogen cell depletion, 4 of them experienced sustained depletion at baseline. The primary end point is time to renal flare. Idec/Roche regarding rituximab and ocrelizumab. „ Minipulse Cyclophosphamide Favored in Lupus Nephritis

BY BRUCE JANCIN fessor of medicine at the University of Cal- regimen can achieve the same efficacy These [ELNT] data support that strong- Denver Bureau ifornia, San Francisco, and a former ACR with fewer adverse effects (Arthritis ly,” he continued. president. Rheum. 2004;50:3934-40). Patients and physicians alike look long- S NOWMASS, COLO. — Most Ameri- For many years, the standard therapy for The European minipulse regimen con- ingly at the bursting-full SLE drug devel- can physicians who treat systemic lupus lupus nephritis has been the high-dose sists of six pulses of 500 mg given at 2- opment pipeline, eager for the day when erythematosus have been overly slow to pulse intravenous cyclophosphamide (Cy- week intervals, followed by . they can finally discard cyclophosphamide adopt the low-dose, less toxic minipulse in- toxan) regimen that has shown to be ef- Patients tend to be deeply grateful to be in favor of agents that are less toxic and/or travenous cyclophosphamide regimen pi- fective in an NIH trial. This regimen typ- done with cyclophosphamide after just 12 more effective. But there is reason to be- oneered in the landmark Euro-Lupus ically involves dosing monthly for 6 weeks. lieve that cyclophosphamide may contin- Nephritis Trial, Dr. David Wofsy said at a months at 0.5-1.0 g/m2, followed by two Some American physicians have criti- ue to play an important role in the com- symposium sponsored by the American pulses at 3-month intervals, then mainte- cized the ELNT because its Northern ing biologic therapy era. College of Rheumatology. nance therapy with azathioprine. It’s a European patient population isn’t repre- Preliminary evidence suggests at least “I think we should move away from tra- highly toxic regimen associated with in- sentative of the lupus patients they see. two of the investigational biologics—rit- ditional, [National Institutes of Health] creased infections, leukopenia, cancer, in- But, according to Dr. Wofsy, the ELNT is uximab (Rituxan) and atacicept—may –style cyclophosphamide. If you’re going fertility, alopecia, and cystitis. actually a much better trial methodolog- have unique synergistic benefit when used to use cyclophosphamide, I would favor In the ELNT, investigators led by Dr. ically than the NIH study upon which with cyclophosphamide. This synergistic using [the Euro-Lupus Nephritis Trial cy- Frederic A. Houssiau of Catholic Univer- high-dose pulse therapy is based. “My effect isn’t present when either biologic is clophosphamide regimen] at this point sity of Louvain, Brussels, demonstrated own feeling is that it’s time to begin us- combined with mycophenolate mofetil without hesitation,” said Dr. Wofsy, pro- that a more modest cyclophosphamide ing cyclophosphamide in a gentler way. (CellCept), Dr. Wofsy said. „