Potential Sjögren’s drugs may herald ‘paradigm shift’ to treating underlying processes
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Clinical trial results in Sjögren’s disease over the last decade have volleyed between encouraging successes and deflating failures, but with several new drugs advancing through the pipeline, hopes are high yet again.
“Patients understandably seek an improvement in their current universal Sjögren’s symptoms, including their dryness of the eyes and mouth,” David Isenberg, MD, ARC Diamond Jubilee professor and academic director of the University College London Center for Rheumatology and Bloomsbury Rheumatology Unit, told Healio. “They also seek reassurance that things will not get worse long term.”
That reassurance may be coming, according to Sara S. McCoy, MD, PhD, assistant professor in the department of medicine, division of rheumatology, at the University of Wisconsin, Madison.
“It is possible that in the next 1 to 2 years, we will witness a paradigm shift from supportive therapy to therapies that improve the underlying aberrant immune process of Sjögren’s disease,” she told Healio.
Various forms of B-cell depletion with medications like rituximab (Rituxan, Genentech) have undergone clinical trials, along with efforts to assess CD40 blockade in this population. Moreover, in the midst of all the attention chimeric antigen receptor (CAR) T-cell therapy has received in lupus and systemic sclerosis, Sjögren’s researchers have taken tentative steps investigating this approach, as well.
Results continue to be mixed, but McCoy does not necessarily view any failures as setbacks.
“Although we are hopeful that our new treatments will be effective for a broad swath of our patients suffering from Sjögren’s disease, it is possible they will apply to a subset of our patients with more active disease, evidence of B-cell activity, or similar,” she said.
Meanwhile, severity of disease can be another potential way of stratifying and managing patients, according to Isenberg.
“For those with internal organ concerns — including musculoskeletal and neurologic concerns — help will be appreciated,” he said. “These patients would like to know that a major effort is ongoing to try and alleviate these problems.”
Regardless of whether the clinical trial programs are successful or not, McCoy stressed that early intervention will continue to be an essential component of Sjögren’s management.
“It is imperative we ensure our ophthalmologists, oral experts, rheumatologists, primary care providers and advanced practitioners recognize Sjogren’s disease as early as possible,” she said.
Plan ‘B’
Despite B-cell depletion’s checkered past in Sjögren’s, Isenberg stated he remains hopeful.
“There are good reasons to be believe that B cells are critically involved in the development of Sjögren’s,” he said.
According to Dana DiRenzo, MD, MHS, assistant professor of clinical medicine in rheumatology at the University of Pennsylvania Perelman School of Medicine, blocking B cells may have significant benefit, especially for those with high immunological disease activity, based on the pathophysiology of Sjögren’s disease.
“Based on the half-life of the drug and the slow timeline it takes for B cells to repopulate, this can have a durable effect over months,” she said.
McCoy said she is encouraged specifically by anti-CD20 therapies that bind to and then deplete CD20+ B cells.
“The trajectory of clinical trial success has increased steeply in the last 5 years,” she said.
McCoy referenced two studies from 2014, including the TEARS trial, which was published by Devauchelle-Pensec and colleagues in the Annals of Internal Medicine, and the TRACTISS trial, which was published by Brown and colleagues in BMC Musculoskeletal Disorders.
TEARS studied individuals who were positive for anti-SSA antibodies , with evidence of B-cell activity, low complement, or one or more extra glandular manifestations or parotid gland enlargement. Meanwhile, the TRACTISS study evaluated participants who were anti-SSA-positive with some salivary gland function, fatigue and oral dryness with VAS>5/10.
According to McCoy, the results of these two trials are emblematic of the ambiguity Sjögren’s experts have reckoned with throughout the years.
“Though they did not achieve their primary endpoints, response rates trended higher in rituximab than the placebo groups,” she said. “It might be that the inclusion criteria or primary endpoints selected for these studies were not optimal to detect a significant difference between placebo and rituximab-treated groups. Alternatively, it might be that rituximab might not appropriately target pathologic mechanisms.”
McCoy noted that rituximab drives increased BAFF, which can drive autoreactive B cells.
“Furthermore, rituximab does not fully deplete CD20+ B cells in inflamed tissue, where BAFF is higher,” she said.
There may be another concern with B-cell depletion, according to DiRenzo.
“The risk of any approach such as this would be infection,” she said.
Regardless of the setbacks for rituximab, researchers continue to explore B cell targeting therapies.
‘Still early days’
In 2022, Bowman and colleagues published a phase 2b study in which they investigated the BAFF receptor IgG1 monoclonal antibody ianalumab (Novartis) in patients with Sjögren's disease. Eligible participants had an ESSDAI score of at least 6 and a high symptom burden, as well as preserved salivary gland function. The primary outcome was change in ESSDAI from baseline to 24 weeks.
According to the researchers, who published their findings in The Lancet, the drug achieved its primary endpoint.
Isenberg expressed cautious optimism about this result.
“It is still early days for ianalumab,” he said.
Meanwhile, in light of the mixed results for individual B-cell depleting agents, Mariette and colleagues investigated a sequential therapy protocol with rituximab followed by belimumab (Benlysta, GlaxoSmithKline), a recombinant human monoclonal antibody binding soluble BAFF. The study, which was published in 2022 in the Journal of Clinical Investigation Insight, included four arms — rituximab followed by belimumab, rituximab alone, belimumab alone and placebo.
“They included subjects with high disease activity, symptoms of oral dryness, and preserved salivary gland function,” McCoy said. “The primary endpoint for this study was safety.”
According to the researchers, the combination of both rituximab and belimumab led to a greater and more sustained depletion of CD20+ B cells in tissue and of CD19+ B cells in peripheral blood vs. monotherapy.
“Though not significant, the combined therapy group had a trend toward improvement in ESSDAI and stimulated salivary flow,” McCoy said.
Again, Isenberg expressed encouragement but is awaiting further data.
“Belimumab and rituximab are now widely available drugs,” he said. “There are some data supporting their use, but it is not too compelling.”
Looking deeper into the pipeline, McCoy highlighted data for telitacicept (RC18, RemeGen), a TACI-Fc that targets BAFF and APRIL. She noted a phase 2 trial of this drug in 43 participants in China published by Xu and colleagues in Rheumatology (Oxford) in March.
“Telitacicept 240 mg resulted in significant improvement of the ESSDAI score compared to placebo,” McCoy said.
Broader analysis of these findings may reveal some trends in clinical trial processes overall, according to McCoy.
“Inclusion criteria and endpoints have evolved over time, and this evolution might have contributed to the apparent improvement of B-cell related therapies to achieve primary outcomes in Sjögren’s disease,” she said. “B-cell targeted therapies might be more likely to improve Sjögren’s disease patients with high disease activity or evidence of B-cell activity.”
As preserved salivary gland function was also a feature of inclusion, these participants might have demonstrated earlier disease before gland fibrosis, atrophy or end-stage loss of function occurred, according to McCoy.
Importantly, efficacy is not the only consideration in drug development programs. McCoy stressed that researchers and clinicians alike should additionally consider the reduced vaccine response associated with B-cell depletion.
“Thus, it is possible these promising therapies will work best in a subset of Sjögren’s disease patients where the risk is considered appropriate for the level of expected benefit,” she said.
The disease course of each individual patient is another crucial variable, according to Isenberg.
“Rituximab, belimumab, and ianalumab might have a role to play in treatment,” he said. “However, 80% of Sjogren’s patients suffer dry eyes, mouth or vagina with or without fatigue — but nothing more sinister — so there will always be a balance issue of benefit versus side effects.”
As researchers continue to find the balance in B-cell therapy, other mechanisms have gained attention in recent years.
‘Other facets of autoimmunity’
According to McCoy, several studies targeting CD40/CD40L interactions in Sjogren’s disease have met their primary endpoint. She explained that CD40 is expressed on B cells, but also on other hematopoietic and non-hematopoietic cells.
“CD40L is predominantly expressed on T cells, but also expressed on other cells including mast cells, basophils, B cells, NK cells, megakaryocytes and platelets,” she said.
The interactions between CD40-CD40L and B and T cells can drive germinal center response and isotype class switching, according to McCoy.
“Thus, this approach not only targets B- and T-cell interaction but might target other facets of autoimmunity,” she said.
Like McCoy, DiRenzo is encouraged by the potential of this mechanism.
“This can have considerable effect for dampening the pathways that lead to high immunologic disease activity for patients with Sjögren’s disease,” she said.
However, DiRenzo also noted a common disadvantage: “Infection is also a concern.”
The first drug targeting this pathway is iscalimab (Novartis), a fully human Fc-silenced IgG1 anti-CD40 antibody. In a paper published in The Lancet last August, Fisher and colleagues recruited two cohorts of patients with preserved salivary gland function and varying levels of ESSDAI score. The primary outcomes were change from baseline in ESSDAI for the first cohort, and change in ESSPRI for the second.
“Cohort one met its primary endpoint with two treatment doses — 150 mg and 600 mg,” McCoy said. “Although cohort two did not meet its primary endpoint of improving total ESSPRI, the analysis of subscales showed that symptoms of dryness significantly improved, and fatigue trended toward improvement.”
A similar study was conducted for the CD40 ligand antagonist dazodalibep (Horizon Therapeutics) by St. Clair and colleagues, and published in Nature Medicine last June. The primary outcome for cohort one was ESSDAI change from baseline, while the researchers assessed cohort two for any ESSPRI changes from baseline. Both cohorts met their primary endpoint.
DiRenzo additionally noted findings from Gottenberg and colleagues, published in June in the Annals of the Rheumatic Diseases, investigating the FcRn receptor nipocalimab (Johnson & Johnson).
“Targeting the FcRn receptor leads to decreased levels of IgG, including pathogenic antibodies,” she said. “Phase 2 trials of nipocalimab have shown promising data in reducing clinESSDAI scores.”
However, in keeping with the apparent overall trend in Sjögren’s disease, there have been just as many failures with other agents.
According to McCoy, abatacept (Orencia, Bristol Myers Squibb) reached phase 2 trials but failed to meet primary endpoints there. The anti-ICOSL monoclonal antibody prezalumab (Amgen, AstraZeneca) met a similar fate.
“There are also clinical trials evaluating the inhibition of Bruton’s Tyrosine Kinase, such as remibrutinib (Novartis),” DiRenzo said. “BTK plays a role in B-cell receptor signaling. Phase 2 trials have noted improvements in ESSDAI scores, but not necessarily ESSPRI scores.”
Research into these approaches is likely to continue. However, the expectation among many experts is that they may be effective in certain subsets of Sjogren’s patients, and offer incremental therapeutic benefit, rather than a panacea.
Avoiding the ‘cure’ word
Although CAR-T cells have — so far — been a home run in lupus and systemic sclerosis, Sjögren’s researchers are more hesitant to talk about potentially curative therapies.
“There are ongoing clinical trials investigating the effects of CAR T cells for Sjogren’s disease,” DiRenzo said. “The CAR-T approach may induce a very durable and deep level of B cell depletion, but obviously the risk for infection would be of concern. After the CAR T infusion, a risk for cytokine storm also exists and thus infusions must be monitored very closely, and typically in a hospital setting.”
Isenberg suggested that this “very aggressive treatment” should only be performed in hematology/oncology units, and by physicians with significant experience in the procedure.
“The numbers of Sjögren’s patients for whom it might be considered must be very low,” he added.
That said, science marches on.
“Multiple studies are underway evaluating CAR T-cell therapy in Sjögren’s disease participants,” McCoy said. “Active studies include CD19/BCMA CART cells, CD19 CAR-T cells, and anti-CD19 CD3E CAR-T cells to treat Sjogren’s disease and other rheumatologic diseases. Though results have not been published specifically in a Sjogren’s disease cohort, it is likely that the robust effects on antibody and disease activity could be recapitulated in a Sjögren’s disease population.”
However, even with so many new strategies under investigation, coupled with the excitement sparked by the rush of recent CAR T-cell trials, the idea that a potential cure is currently on the horizon remains premature, according to Isenberg.
“I try very hard to avoid the ‘cure’ word,” he said. “It is loaded and carries a promise that we cannot truly say has been achieved for years afterwards. We are focused on short term remission with symptom improvement, then longer term remission. Only then, maybe, can we begin talking about a cure.”
References:
Bowman SJ, et al. Lancet. 2022;doi: 10.1016/S0140-6736(21)02251-0.
Brown S, et al. BMC Musculoskelet Disord. 2014; doi: 10.1186/1471-2474-15-21.
Devauchelle-Pensec V, et al. Ann Intern Med. 2014;doi: 10.7326/M13-1085.
Fisher BA, et al. Lancet. 2024;doi:10.1016/S0140-6736(24)01211-X.
Gottenberg JE, et al. Ann Rheum Dis. 2024;83:240.
Mariette X, et al. JCI Insight. 2022;doi:10.1172/jci.insight.163030
St. Clair EW, et al. Nat Med. 2024;doi:10.1038/s41591-024-03009-3.
Xu D, et al. Rheumatology (Oxford). 2024;doi:10.1093/rheumatology/kead265.
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