麻豆传媒

WASHINGTON -- Patients with IgG4-related disease appeared to benefit from inebilizumab (Uplizna), currently approved for neuromyelitis optica (NMO), in a pivotal clinical trial.

Just 10% of patients treated with the drug in the 135-person developed disease flares during 1 year of follow-up, compared with 60% of a placebo group (P<0.001), reported John H. Stone, MD, MPH, of Massachusetts General Hospital in Boston, and colleagues.

Complete flare-free remission with no use of steroids or other medications was achieved for 57% of those assigned to inebilizumab, versus 22% of the placebo group, the researchers . While serious adverse events were twice as common among patients receiving the active drug, Stone and colleagues concluded that the trial supports "inebilizumab as a treatment option for patients with IgG4-related disease."

Results from the study were also slated to be presented at the American College of Rheumatology's annual meeting, opening here Friday.

IgG4-related disease is very uncommon, seen in approximately five people per 100,000 in the U.S., Stone and colleagues observed. It currently has no specific approved therapy: corticosteroids form the backbone of treatment and are at least somewhat effective, but of course long-term use comes with a host of increasingly serious side effects. Immunosuppressants have been tried as alternatives, but, Stone's group noted, "their usefulness has yet to be shown in randomized, placebo-controlled trials."

Abnormal B-cell activity is thought to be at the disease's roots. The prototypical anti-B-cell drug rituximab (Rituxan) has been tried, too, but again, no hard data support it. Inebilizumab also depletes B cells, though by binding to the CD19 antigen versus rituximab's CD20 target, and Stone's group (backed by the drug's manufacturer, Amgen) thought that this mechanism might make it more effective. The product is currently indicated only for NMO, with that approval coming in 2020, but is also under study for myasthenia gravis, anti-N-methyl-D-aspartate receptor encephalitis, and systemic sclerosis.

For the current study, 135 patients with confirmed IgG4-related disease, and at least two organ systems affected, were enrolled and randomized 1:1 to the active drug or placebo. Mean age was 58 and about two-thirds were men. Just under half were newly diagnosed; the rest had recurrent illness lasting a median of 3.6 years. A large majority had not had treatments other than steroids.

Infusions of inebilizumab or placebo were given on study days 1 and 15, with another at week 26. Steroids were withdrawn gradually over the first 8 weeks, but could be resumed if flares occurred. Patients were followed out to week 52.

Annualized flare rates during the study were 0.71 with placebo versus 0.10 with inebilizumab (P<0.001). Odds ratios for achievement of complete flare-free and steroid-free remission, versus remission without use of any other medications, were almost identical at 4.96 and 4.68 (both P<0.001) -- no surprise since hardly any participants received other kinds of treatment.

Profound effects on B-cell counts from inebilizumab were observed, with CD20-positive cells disappearing entirely by week 2 and remaining at zero through the full 52 weeks. In parallel, serum IgG4 levels did not change much in the placebo group, whereas the median change from baseline was around -50% throughout the study for those receiving inebilizumab.

Safety results, however, did not favor inebilizumab. Twelve patients receiving the drug had serious adverse events, compared with six in the placebo group. The types ranged widely and no single type was seen in more than one patient (except for COVID-19, occurring in two). Among them were gout, anal cancer, pulmonary embolism, appendicitis, and hyponatremia -- such that most would not ordinarily be expected from B-cell depletion or any other single drug effect.

Overall adverse events were also more common with inebilizumab, but because the trial sample was relatively small, it wasn't clear whether this was true for particular categories. But numerically more cases of lymphopenia, COVID-19, urinary tract infection, and serious/opportunistic infections occurred with the active drug. One patient receiving the antibody had an anaphylactic reaction. But oddly, infusion-related reactions overall were more common with placebo (five vs three).

Limitations to the study included the lack of follow-up beyond 1 year, and fewer participants than expected had received previous treatments other than steroids. "Longer-term data are needed to establish the safety profile of inebilizumab in the treatment of IgG4-related disease and to characterize the patterns of B-cell and immunoglobulin changes; for these reasons, a 3-year open-label period is ongoing," Stone and colleagues wrote.

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