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New Lupus Treatments: Many Ideas, Few Successes

Discussion in 'Immunology and Rheumatology' started by Mahmoud Abudeif, Apr 7, 2019.

  1. Mahmoud Abudeif

    Mahmoud Abudeif Golden Member

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    If development of new therapies for systemic lupus erythematosus appears to be lagging, it's not for want of interest or ideas for treatment targets, a researchers suggested here.

    In a 45-minute talk at the American College of Rheumatology State of the Art Clinical Symposium, Richard Furie, MD, of Northwell Health in Great Neck, New York, reviewed efforts to bring new drug therapies to market since the 2011 approval of belimumab (Benlysta) -- most of them unsuccessful.

    In fact, even before belimumab came along, finding effective treatments has been marked by many more fits than starts. Furie noted that belimumab is unique among lupus treatments in having earned FDA approval by demonstrating efficacy in randomized, placebo-controlled phase III trials.

    The condition's complexity is part of the reason for the difficulty, yet it also provides a tantalizing array of possible treatment targets for drug developers to try to exploit.

    lupus involves virtually the entire spectrum of immune systems, cells, and signaling factors, Furie explained. Both innate and adaptive immune mechanisms play roles; B cells, T cells, plasma cells, and dendritic cells all have significant involvement; and so do multiple members of the interleukin, interferon, and chemokine families. And researchers must consider not only how to attack individual components of lupus's pathophysiology, but also the feasibility of hitting multiple components without sacrificing too much healthy immune function.

    Furie said the experience of the past couple decades has taught the field three lessons: "to be humble, logical, and perseverant."

    Several drugs that initially appeared to be sure winners ended up as disappointments. For example, the pivotal involvement of B cells led many to expect that rituximab (Rituxan), which quickly kills off B cells, would be highly effective. Yet placebo-controlled trials failed to demonstrate a clear benefit, despite evidence from other types of studies that the drug can help.

    In part, that may stem from issues with designing randomized trials in lupus, Furie said. One issue is that the "placebo" arms are never just placebo, but also include conventional drugs such as hydroxychloroquine that are standard of care, which "blunts discrimination" of the novel drug's effects, he said. Investigators must also walk a fine line in deciding trial endpoints between making them strict enough that a positive result really does mean the drug is effective, but not so strict that they become impossible to achieve.

    Another disappointment hit Furie more personally. One of the more intriguing targets in recent years has been the interferon family. These signalling molecules, especially the so-called type I group, appear elevated in lupus, with clinical activity associated with the degree of interferon gene expression.

    AstraZeneca has been developing a monoclonal antibody targeting the receptor for type I interferons, called anifrolumab. Furie led a phase II trial with the drug that indicated it was dramatically effective. In his talk here, he repeated what he said when presenting those results in 2016: "These are the best lupus data we've ever seen." The drug moved on to phase III trials and there was no reason to think that they wouldn't be positive.

    So he was as surprised as anyone when, last summer, AstraZeneca released topline results for the first of these pivotal studies indicating the primary efficacy endpoint -- reduced disease activity as indicated by the SRI4 responder index -- was not met (Findings from the second phase III trial are expected to be announced this year). Other anti-interferon drugs remain in development, Furie pointed out.

    Another area of optimism is agents targeting plasmacytoid dendritic cells. These cells are important for normal immunity so it would be desirable not to kill them, but rather to modulate their function. Furie mentioned an agent called BIIB059 -- now in phase II testing, with Furie among the investigators -- that causes these dendritic cells to stop displaying a certain surface molecule that acts as a trigger for release of a wide array of interferons, cytokines, and chemokines.

    And despite rituximab's failures, the field has not given up on B cells as a lupus target, he said. Other B cell-targeting agents are under study, including obinutuzumab (Gazyva), and some groups have sought to combine rituximab with belimumab in a sequential therapy. Initial results with rituximab followed by belimumab weren't encouraging, Furie acknowledged, but researchers think the concept has merit and now the reverse sequence is being tested.

    Still other groups are studying drugs targeting plasma cells (one of the cell types into which B cells eventually evolve) and T cells. Also, because interleukin-2 appears to be suppressed in lupus patients, there is the possibility of simply infusing it into patients. An early single-arm study suggested it could be effective, Furie said.

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