Problems remain in lupus clinical trial design
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When it comes to studying treatments for systemic lupus erythematosus, issues such as clinical trial design and patient selection still loom large, according to a speaker at the 2020 Congress of Clinical Rheumatology-East.
For proof of that, one need only to review the history of belimumab (Benlysta, GlaxoSmithKline) and BLyS inhibition in SLE, said Joan T. Merrill, MD, of the Oklahoma Medical Research Foundation.
“Where we are in 2020 in SLE treatment is that there have been about 40 failed clinical trials for lupus,” Merrill told attendees on the live stream, as she demonstrated a collage of fruitless graphs and data. “This isn’t the end of the story, but we have had a very rough start in trying to develop a targeted treatment for lupus, and a very steep learning curve. Here I am just showing you the sad data from many, many of the trials where you really couldn’t detect a difference between treatment and placebo.”
“This was a disheartening set of affairs until, finally, in 2011, there was a breakthrough,” she added. “Belimumab was able to show efficacy in two very large, international phase 3 trials.”
Since then, belimumab has met its primary endpoint in four large, phase 3 non-nephritis trials, according to Merrill. And although the differences between the treatment and placebo were “not all that great,” they were nonetheless consistent, she said.
However, although these trials demonstrated efficacy for belimumab, participants who received the standard of care — which included hydroxychloroquine and steroids — also did well.
“Is it really pretty good that 40% of our patients get better no matter what we do?” Merrill said. “Maybe it isn’t. And maybe if we were looking at the right biological subsets of patients, we could get much higher response rates to treatment, and then we would be able to do smaller trials and be able to interpret them a little better.”
Moreover, the success of BLyS inhibition has not been universal, even as patients continue to do well on placebo and standard of care.
In stark contrast to the BELIMUMAB BLyS 52 trial — the pathway’s best-performing study — the Atacicept ADDRESS II trial, Blisibimod phase 3 and the TABALUMAB phase 3 studies 1 and 2 all failed to meet their endpoints, Merrill said.
Although the reasons for this discrepancy are complicated, one of the principal explanations, according to Merrill, is that as more drugs entered development internationally, the quality of the data suffered due to an increase in trial sites that were not well-trained.
In addition, even among the successful trials, Merrill said the results seemed to differ, in part, based on how each allowed its patients to taper steroids.
“In the BLISS 76 study, there were more patients on immunosuppressants, and in BLyS 52 there were fewer on immunosuppressants but more receiving steroids,” she said. “So, the design of this trial encouraged the tapering of steroids. You were actually allowed to increase your immunosuppressants in order to make sure your patients were well enough to continue the study, and if you did increase immunosuppressants, you were allowed to stay on that higher dose for the rest of the trial, so there was kind of a handicap on the BLISS 76 study, that wasn’t there in BLyS 52, and you can see you got a better result in BLyS 52.
“The data from BLyS 52 shows that steroids were being tapered significantly more in the treatment groups than in the placebo groups, and that enabled the placebo group response rate to go down a bit,” she added. “It’s an interesting way of looking at it, but it certainly generated the hypothesis that maybe clinical trials suffer from too much polypharmacy.”
In addition, a study by van Vollenhoven and colleagues, published in Annals of the Rheumatic Diseases in 2013, included the “sicker subset” of patients from the BLISS 76 trial, which resulted in a wider difference in response between the treatment and placebo groups.
“So, when you do a study and you make sure patients are sick enough, you are going to lower your placebo rates enough to be able to see whether the treatment is having an effect with a little bit more clarity,” Merrill said. “Also, if you can somehow moderate the background medication in a way that is safe, you may also get more clarity in your trial. All of this was taught to us by belimumab, but over time, it’s been confirmed by many other studies.”
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Merrill JT. Update in Targeted Treatments for SLE. Presented at: Congress of Clinical Rheumatology-East annual symposium; September 10-13, 2020 (virtual meeting).
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