Moving Targets in Lupus and Lupus Trials Save

Clinical Trial Data Quality is a Moving Target

In the 1990’s, treatment development for lupus became a serious endeavor, but for 20 years we failed. Belimumab was finally approved by acknowledging that optimal trial outcomes at that time could achieve only small differences between an effective treatment and placebo. It was the first trial to demonstrate statistical significance with modest findings required participation of 867 patients worldwide1  We could be confident about the efficacy of belimumab when the same outcome was reduplicated multiple times worldwide. However this model for lupus trials was short lived because it was unsustainable2. With many promising new treatments competing for limited resources, there were not enough patients or trained clinical trial sites, and insufficient economic incentive to sustain belimumab-sized trials when the results did not seem compelling to doctors or patients.

Smaller trials are only feasible if greater differences can be detected between treatment and placebo, but if a substantial treatment effect can be detected, the data are, of course, more marketable. For a long time it was argued that SLE placebo responses of 40-50% should not be a problem because a truly effective treatment ought to meet trial endpoints in 70-80% of patients. This might be true for a homogenous disease, but lupus is not that. There is likely no single targeted treatment that is truly effective for “all.” Even when occasional early phase trials seemed to show  efficacy well above the high placebo responses, these unusual treatment responses were not reduplicated in later phase studies. It became apparent that no given targeted treatment had proven effective for more than 40-60% of the population, so it would be necessary to design trials to ensure lower placebo responses. 

In 2018 an international ad hoc group of trialists and developers convened by the Lupus Foundation of America2 performed an extensive review of trial outcomes, and proposed three changes to how trials should be conducted: 
1. ensure patients have sufficient active disease when entering studies, 
2. employ experts to monitor data quality throughout the trial, and 
3. taper background medications (or at least steroids). 

It worked.

Since then, there have been a number of reasonably sized Phase 2 and 3 trials demonstrating efficacy for investigational treatments, associated with lower placebo responses. Will this advance also be short-lived? With a new explosion of clinical trials for lupus gobbling up most trained clinical investigators and almost all eligible patients, along with a massive invasion of cell therapy case-series studies promulgating assumptions that anecdotal perfection renders placebo control unnecessary, data quality is again in jeopardy.

Lupus is also a Moving Target

There is good news about the confusing heterogeneity of lupus pathophysiology. Recently, a phylogeny of gene expression patterns has been developed first in children and later in adults with SLE3,4.  The ordered co-expression subsets identified in adults with lupus were reduplicated in a nationwide trial of obexelimab, an inhibitor of B Cell activation, and two patient clusters that shared increased expression of B and T Cell pathway genes characterized most patients with clinical response to obexelimab5. In one Phase 2 trial of lupus, a simple signature of 4 interferon-related genes6 was associated with greater response to iberdomide, an inhibitor of transcription factors that impact that pathway. However, the same signature had earlier been related only to lower placebo responses in studies of anifrolumab7, which targets the major Type I interferon receptor on cells. These are only preliminary findings but what is evident is that one targeted treatment does not fit all, likely due to immunologic heterogeneity. We also know that the immune system, to protect our survival, is not static, Gene expression phenotypes change over time in healthy people and in lupus patients, adapting to each new molecular threat.

These considerations confirm what we already knew from clinical practice: lupus is a spectrum disorder, one targeted treatment will not fit all, and one treatment may not even help the same patient at all times. We have recently heard some dramatic anecdotal descriptions of response to cell therapy, but we should remember that even if you kill every B Cell in the body and reconstitute them with a tamer version for a few months or even a few years (which could be a wonderful thing), the body’s defenses are versatile. The causes of lupus are complex, and the immune system will find a way back. This will likely occur in some patients sooner than others.

Can we address the moving target of lupus pathology with the moving targets of quality clinical trials and scientific treatment selection? Sufficient technology is now available. However, if scientific discipline is not respected and controlled trials are considered unnecessary, we should be concerned.

References

1. Navarra SV, Guzmán RM, Gallacher AE, Hall S, Levy RA, Jimenez RE, Li EK, Thomas M, Kim HY, León MG, Tanasescu C, Nasonov E, Lan JL, Pineda L, Zhong ZJ, Freimuth W, Petri MA; BLISS-52 Study Group Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011 377:721-731
2. Merrill JT, Manzi S, Aranow C, Askanase A, Bruce I, Chakravarty E, Chong B, Costenbader K, Dall’Era M, Ginzler E, Hanrahan L, Kalunian K, Merola J, Raymond S, Rovin B, Saxena Am Werth VP. Lupus community panel proposals for optimising clinical trials: 2018 Lupus Sci Med 2018 23;5(1):e000258.
3. Banchereau R. Hong S, Cantarel B, Baldwin N, Baisch J et al  Personalized Immunomonitoring Uncovers Molecular Networks that Stratify Lupus Patients Cell 2016 21;165:551-565.
4. Guthridge JM, Lu R, Tran LT Adults with systemic lupus exhibit distinct molecular phenotypes in a cross-sectional study. EClinicalMedicine. 2020 20:100291
5. Merrill JTM, Guthridge J, Smith M et al Obexelimab in SLE With Exploration of Response Based on Gene Pathway Co-Expression Patterns: A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Trial Arthritis Rheumatol 2023 75:2185-2194.
6. Merrill JT, Werth VP, Furie R, et al Phase 2 Trial of Iberdomide in Systemic Lupus Erythematosus. N Engl J Med. 2022 386:1034-1045.

Vital EM, Merrill JT, Morand EF et al Anifrolumab efficacy and safety by type I interferon gene signature and clinical subgroups in patients with SLE: post hoc analysis of pooled data from two phase III trials. Ann Rheum Dis. 2022 81:951-961