FROM ANNALS OF THE RHEUMATIC DISEASES
The injectable investigational biologic tabalumab met its primary endpoint only at higher doses, and failed to meet secondary endpoints in phase III clinical trials for moderate to severe systemic lupus erythematosus. A heterogeneous patient population, intensity of background therapy, and endpoints that set a relatively high bar for efficacy all contributed to the mixed results of the ILLUMINATE-1 and ILLUMINATE-2 trials, according one of the study’s lead authors.
“This is a complex set of data,” Dr. Joan T. Merrill, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, said in an interview. “Clinical trials are very hard to conduct,” she said, especially in an era where the standard of care already promotes aggressive treatment of patients with systemic lupus erythematosus (SLE). The fact that SLE is such a heterogeneous disease entity and the range of severity is so broad further complicates study design and data analysis, she said.
Tabalumab is a fully human monoclonal antibody that targets B-cell activating factor (BAFF), a ligand in the tumor necrosis factor (TNF) family that is necessary for B-cell development and survival. The elevated BAFF levels seen in SLE are associated with increased disease activity. Tabalumab binds to and neutralizes both soluble and membrane BAFF.
For ILLUMINATE-2 , a tabalumab phase III clinical trial, 1,124 patients with moderate-to-severe SLE who were maintained on standard of care therapy were randomized 1:1:1 to receive tabalumab 120 mg subcutaneously every 2 weeks, the same dose every 4 weeks, or to receive placebo. At the start of the trial, each group received either a 240-mg loading dose of the study drug or placebo. Patients were stratified according to anti-dsDNA status and according to African ancestry (Ann Rheum Dis. 2015 Aug 20. doi: 10.1136/annrheumdis-2015-207654 ).
Patient characteristics were balanced across study arms, and 872 patients completed the study period of 52 weeks.
The composite SLE Responder Index 5 (SRI-5) was used to identify the primary outcome measure, the proportion of patients who attained an SRI-5 response at week 52. This threshold was achieved by improvement of at least five points in the Safety of Estrogens in Lupus Erythematosus National Assessment–SLE Disease Activity Index (SELENA-SLEDAI) score; no scores of A and not more than one B score on the British Isles Lupus Assessment Group 2004 index (BILAG); no worsening on the Physician’s Global Assessment (PGA); no added or increased antimalarial or immunosuppressant treatment; adherence to corticosteroid-dosing requirements; and enrollment in the study through week 52.
The study identified multiple secondary endpoints, including the time to the first severe SLE flare, reduction of at least 25% in corticosteroid dosing (to an equivalent of 7.5 mg or less of prednisone per day) for at least 3 consecutive months during the second half of the study period, and the increase or decrease from baseline score on the Brief Fatigue Index (BFI) at week 52.
For the group of patients receiving tabalumab every 2 weeks, the primary endpoint was met by 38.4%, compared with 27.7% of the placebo group (P = .0002). Of the group on the 4-week injection schedule, 34.8% met SRI-5, but the difference from placebo was not significant (P = .051).
Although the tabalumab treatment arms did not meet secondary endpoints, “active treatment had better outcomes than placebo on some measures,” including the corticosteroid-sparing endpoint, Dr. Merrill and her colleagues wrote.
Depression and suicidal ideation, though rare, were reported more frequently in the treatment arms than in the placebo arm: A total of 32 of 745 patients receiving tabalumab reported depression, compared with 3 of 376 receiving placebo. Furthermore, 19 tabalumab patients reported suicidal thoughts, compared with 1 receiving placebo. Injection site reactions were more common among those on tabalumab. Other adverse events were similar between treatment arms, or more common with placebo.
In discussion, Dr. Merrill and her coauthors wrote that the effect of the background standard of care therapy on BAFF signals is not known, and the large corticosteroid-dosing adjustments that were permitted may also have had an impact on BAFF levels. “Whether forced steroid tapering or withdrawal of background treatments would increase tabalumab treatment effect remains unknown,” the investigators wrote.
In ILLUMINATE-1 , a similar phase III trial of tabalumab, investigators found that neither dosing regimen of the investigational drug yielded better SRI-5 response rates (31.8% for dosing every 2 weeks and 35.2% for every 4 weeks) than did placebo (29.3%). Depression and suicidal ideation also did not appear more frequently with tabalumab treatment than with placebo in ILLUMINATE-1 (Ann Rheum Dis. 2015 Sep 3. doi: 10.1136/annrheumdis-2015-207653 ).
However, Dr. Merrill and her coauthors noted that “ILLUMINATE-1 stipulated that new, increased or decreased standard of care medications would define a patient as nonresponsive, whereas only new or increased medications in [ILLUMINATE-2] determined nonresponse.” Analyses that did not consider patients who decreased antimalarials or immunosuppressants to be nonresponders found a significantly higher SRI-5 response rate for patients who took tabalumab every 4 weeks (37% vs. 29.8% with placebo), but not for biweekly dosing (34.1%).
In an interview, Dr. Merrill put forward the idea that rethinking study design for SLE drugs might make sense. Going forward, she said, investigators should consider breaking the population into two subgroups. For the sicker patients, background medication would have to be maintained, but the data would be more interpretable if this subgroup were analyzed separately. Patients who are less ill, she said, could be moved to homogeneous background drugs, easing data analysis and minimizing the effect of complicated and largely unknown biochemical interactions.
Regarding the rare events of depression and suicidal ideation seen in the treatment arms but not the control arm of the study, Dr. Merrill said, “You can never rule out a biochemical cause, even for a rare finding, and suicidal ideation and depression are serious events which were also numerically greater in the phase III trials of … belimumab, but also quite rare in those studies, too.” She said that she would be interested in tracking the clinical course of those patients who became depressed and learning more about immune signaling in those individuals. “There is a lot to be learned about these treatments,” she said.
Eli Lilly and Company, tabalumab’s manufacturer, elected not to proceed with the drug development and approval process. Noting that more therapies are needed for SLE, Dr. Merrill said, “I’m very sad that Lilly decided not to develop this drug further. I understand it, but as a doctor, I’m still very sad.”
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