Phase 2 Trial Results for Sjögren’s Syndrome & SLE Presented in 2nd Plenary Session at ACR Convergence 2022

PHILADELPHIA—At the second Plenary Session of ACR Convergence on Sunday, Nov. 13, speakers shared compelling efficacy and safety results from two phase 2 trials: remibrutinib for Sjögren’s syndrome and deucravacitinib for moderate to severe systemic lupus erythematosus.

Remibrutinib in Phase 2 Sjögren’s Syndrome Trial

Thomas Dörner, MD

Thomas Dörner, MD, a professor of rheumatology and clinical immunology for innovative therapies at Charite University Hospital Berlin and DRFZ Berlin, presented promising but mixed phase 2 results of remibrutinib, an oral inhibitor of Bruton’s tyrosine kinase (BTK), in Sjögren’s syndrome.¹

Dr. Dörner explained that even though the predominant cells infiltrating the exocrine glands in Sjögren’s syndrome are CD4-positive T cells, the syndrome is considered a B cell driven autoimmune disease resulting from abnormal response to autoantigens. Currently, no systemic oral therapies for the treatment of Sjögren’s syndrome have been approved by the U.S. Food & Drug Administration (FDA) to reduce the mouth and eye dryness, fatigue and joint pain associated with the condition, and the disease is often difficult to adequately treat.²

BTK plays a critical role in B cell receptor signaling, influencing B cell proliferation and differentiation. It also affects proinflammatory signaling through immunoglobulin Fc receptors, such as those in mast cells and macrophages. Various BTK kinase inhibitors are used to treat B cell malignancies, but agents currently approved for malignancy have significant off-target effects on other kinases. These cause side effects that have limited their use in other disease settings; these adverse side effects include platelet activation, which can cause stroke, and other cardiovascular effects.^3,4

Remibrutinib (LOU064) is a novel BTK inhibitor with different binding characteristics and greater selectivity for BTK than previously developed drugs.³ Scientists have been exploring the drug in various autoimmune, allergic and inflammatory diseases, such as multiple sclerosis and chronic spontaneous urticaria, which recently completed a successful phase 2 trial.^5,6

LOUiSSe Trial Results

The LOUiSSe trial was a double-blind, randomized, placebo-controlled phase 2 trial to evaluate efficacy and safety in patients with moderate to severe Sjögren’s syndrome.¹ All patients met ACR classification criteria for Sjögren’s syndrome and had a score of 5 or higher on the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI), a clinician-reported outcome that includes 12 different domains of disease activity.^1,7

All participants also had an initial score of 5 or higher on the EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI). On this questionnaire, patients scale their dryness, fatigue and joint/muscle pain from 0–10 over the previous two weeks, and the mean of the three domains is the ESSPRI score.⁷

Patients were randomized into three groups receiving 100 mg of remibrutinib twice daily (n=24), 100 mg of remibrutinib once daily (n=25) or placebo (n=24). Due to similarity in responses across doses, data from both dose groups of remibrutinib were compiled in the study results.

“At week 24, the study was positive for its primary end point,” said Dr. Dörner. “The change in active treatment with remibrutinib led to a reduction of the ESSDAI of 2.86, compared to placebo” (P=0.003).

Disappointingly, patient-reported outcomes were similar in the remibrutinib and placebo groups; disease scores declined in both groups during the study. This included analysis via ESSPRI, which did not show a difference in any of its three domains. The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and EuroQol-5 Dimensions, two other patient-reported outcomes, were also similar between the two groups.

However, Dr. Dörner pointed out that unstimulated salivary flow showed a tendency for improvement with remibrutinib. CXCL13, an important chemokine to attract T and B cells into lymphoid follicles and autoimmune tissues, was decreased in the remibrutinib group compared to the placebo group. Anti-SSA and anti-SSB antibodies also declined in the remibrutinib group, as did serum IgM and IgG.

In terms of safety concerns, remibrutinib was well tolerated. The incidence of adverse events was similar across the treatment groups, including one serious adverse event in each arm leading to study discontinuation. Adverse events of special interest, such as bleeding, infections and cytopenia, were equally distributed across the groups. Dr. Dörner also shared that the study highlighted no cardiovascular concerns, which can sometimes be a problem for other members of the BTK inhibitor drug class (e.g., no increased blood pressure, atrial fibrillation or prolongation of the QT interval on electrocardiogram.)⁴

Both ESSDAI and ESSPRI are validated measures commonly used as clinical trial end points, and it is difficult to know what to make of the discrepancy between the two outcomes. It is possible that treatment past 24 weeks may lead to eventual ESSPRI improvements. Some other Sjögren’s syndrome trials have shown a poor association between ESSDAI and ESSPRI, and ESSDAI may have greater responsiveness to disease changes than ESSPRI.^8,9

Dr. Dörner concluded that, in sum, the evidence suggests that remibrutinib may prove to be an effective oral disease-modifying treatment for Sjögren’s syndrome, although this will need to be demonstrated through further studies.

Deucravacitinb in Lupus

Marilyn Pike, MD, PhD

In another presentation, Marilyn Pike, MD, PhD, a rheumatologist in Raleigh, N.C., and president of MedPharm Consulting Inc., discussed encouraging efficacy and safety results from a phase 2 trial of the oral tyrosine kinase 2 (TYK2) inhibitor decravacitinib in moderate to severe systemic lupus erythematosus.¹⁰

A member of the Janus kinase (JAK) family of enzymes, TYK2 mediates the signaling of multiple key cytokines involved in lupus pathogenesis, including type I interferons, interleukin (IL) 10, IL-12 and IL-23. However, it does not participate in some of the pathways triggered by other members of the JAK family. For example, JAK 1, 2 and 3 respond to different immune cytokines, as well as extra-immune pathways related to hematopoiesis and lipid metabolism.¹¹

Tofacitinib and other existing JAK inhibitor drugs may cause changes in laboratory parameters such as hemoglobin, leukocytes and kidney and liver blood tests, partly due to the activation of these other pathways. In contrast, TYK2’s signaling profile may increase the safety of TYK2 inhibition relative to current JAK inhibitors.¹²

Deucravacitinib, an oral, selective inhibitor of TYK2, binds to a unique domain on the enzyme, locking it in its inactive state. A recent phase 2 study of deucravacitinib in psoriatic arthritis demonstrated promising safety and efficacy signals, and in September the FDA approved deucravacitinib for the treatment of moderate-to-severe psoriasis, making it the only TYK2 inhibitor approved for any indication.¹¹

PAISLEY Trial Results

Through the 48-week randomized, double-blind, placebo-controlled PAISLEY trial, Dr. Pike and colleagues sought to test the efficacy of the drug in active systemic lupus erythematosus.¹⁰ All participants had moderate to severe disease, measured by a score of at least six on the SLE Disease Activity Index 2000 (SLEDAI-2K), which assesses overall disease activity. All participants also had to have at least one severe or two moderate disease manifestations as assessed by the British Isles Lupus Assessment Group (BILAG), another lupus disease activity score.

The 363 participants were randomized into four groups—placebo or one of three different dose regimens of deucravacitinib: 3 mg twice a day, 6 mg twice a day or 12 mg once a day. Patients were required to be on background therapy with at least one antimalarial or immunosuppressant drug. Patients could receive up to 30 mg prednisolone or equivalent daily, but tapering to 7.5 mg day was required between weeks 8–20; another optional steroid taper took place between weeks 32 and 40.

The trial’s primary end point was the proportion of patients who achieved SRI-4 (SLE Responder Index 4) at week 32. This is defined as an improvement of SLEDAI of 4 points or more, along with a physician’s global assessment score that has not worsened by 10% or more, with no new severe symptoms and no more than one new moderate symptom as assessed by BILAG.¹³

Many lupus trials have higher rates of placebo response compared to trials in other disease states, such as rheumatoid arthritis, and the same was true here.¹⁴ For the SRI-4 end point, the response rate was 34% in patients on placebo. However, the trial still met its primary end point, with 58%, 50% and 45% of patients taking deucravacitinib (i.e., 3 mg daily, 6 mg twice daily and 12 mg daily, respectively) achieving SRI-4 at week 32, although this just missed statistical significance in the 12 mg daily group.

“There was no added effect in efficacy by increasing the dose,” Dr. Pike said. She speculated this may be because of additional effects on other parts of the immune system stimulated at higher doses; ongoing studies of cytokine response may help elucidate that.

This trend of better efficacy in those patients receiving the lowest dose of deucravacitinib was repeated across all secondary end points. For example, the BICLA (BILAG-based composite assessment), is another overall response end point comparable to the SRI-4. Dr. Pike pointed out that at week 48, “The BICLA and SRI-4 both showed very similar response rates and dose effects as the primary end point.” These responses were statistically significant in the 3 mg twice daily group, with clinically meaningful differences not reaching statistical significance in the other groups.

Dr. Pike noted that this trend continued for the Lupus Low Activity Disease State (LLDAS), the Cutaneous Lupus Erythematosus Disease Area and Severity Index-50 (CLASI-50) and active joint count assessments. “You saw rather robust treatment effects at the 3 mg BID doses,” added Dr. Pike.

Importantly, safety data showed no increase in adverse events or serious adverse events in the treatment group, with no cardiac or thromboembolic events and no increased risk of COVID-19 or herpes zoster. Rates of skin-related events such as rash and acne were higher in the deucravacitinib groups, most pronounced at higher doses. Blood testing showed that liver and renal function were not affected, nor were red or white blood cells. “The safety was very similar with what has been seen in psoriasis and psoriatic arthritis trials,” said Dr. Pike.

Serology studies also showed that all doses of deucravacitinib decreased levels of anti-double stranded DNA, bringing them closer to baseline. Complement numbers also returned toward normal in patients who had abnormally low levels at treatment initiation. Additionally, treatment with deucravacitinib at all doses suppressed production of interferon and cytokines and chemokines downstream of interferon activity, while also suppressing markers associated with B cell activation and differentiation.^10,15

Dr. Pike concluded, “We feel that deucravacitinib shows promise as a novel therapy for SLE and warrants further investigation in phase 3 trials.”

Ruth Jessen Hickman, MD, is a graduate of the Indiana University School of Medicine. She is a freelance medical and science writer living in Bloomington, Ind.

References

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2. Negrini S, Emmi G, Greco M, et al. Sjögren’s syndrome: A systemic autoimmune disease. Clin Exp Med. 2022 Feb;22(1):9–25.
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11. Mease PJ, Deodhar AA, van der Heijde D, et al. Efficacy and safety of selective TYK2 inhibitor, deucravacitinib, in a phase II trial in psoriatic arthritis. Ann Rheum Dis. 2022 Jun;81(6):815–822.
12. Chimalakonda A, Burke J, Cheng L, et al. Selectivity profile of the tyrosine kinase 2 inhibitor deucravacitinib compared with Janus kinase 1/2/3 inhibitors. Dermatol Ther (Heidelb). 2021 Oct;11(5):1763–1776.
13. Ohmura K. Which is the best SLE activity index for clinical trials? Mod Rheumatol. 2021 Jan;31(1):20–28.
14. Mucke J, Alarcon-Riquelme M, Andersen J, et al. What are the topics you care about making trials in lupus more effective? Results of an Open Space meeting of international lupus experts. Lupus Sci Med. 2021 May;8(1):e000506.
15. Kahlenber JM, Sanz I, Wu C, et al. Deucravacitinib reduces interferons, B cell pathways, and serological biomarkers of systemic lupus disease activity: Pharmacodynamic analysis from the phase 2 PAISLEY study. Arthritis Rheumatol. 2022;74(suppl 9).