Efficacy and Safety of Ivarmacitinib Monotherapy in the Treatment of csDMARDs-IR Rheumatoid Arthritis

Efficacy and Safety of Ivarmacitinib Monotherapy in the Treatment of csDMARDs-IR Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting small joints, with a global prevalence of 0.5%-1.0% and 0.42% in China (around 5 million patients, mostly female and over 55). By 2050, RA patients worldwide are estimated to reach 31.7 million, an 80.2% increase from 2020. RA causes high disability rates, economic burdens, and can affect internal organs, leading to complications. Current treatments include csDMARDs (e.g., methotrexate, first-line but ineffective in half to two-thirds of patients), bDMARDs, tsDMARDs, NSAIDs, glucocorticoids, and traditional Chinese medicine.

Studies have explored bDMARDs' efficacy in csDMARDs-IR patients. Switching to or adding upadacitinib improves ACR20 response rates, with monotherapy showing higher safety. Filgotinib also showed superior efficacy over placebo in methotrexate-IR patients.

Ivarmacitinib, a novel JAK1 inhibitor, blocks cytokine signaling to reduce inflammation. A Phase II study (SHR0302-201) in moderate-to-severe RA patients showed ivarmacitinib 8 mg group had the highest ACR20 response rate (77.8%) after 12 weeks, with a dose-response relationship observed for ACR50/70 and DAS28-CRP improvements. TEAEs occurred in 73.9% of ivarmacitinib-treated patients, mostly infections, with upper respiratory tract infection being the most common.

A Phase III study (SHR0302-301) also in moderate-to-severe RA patients showed similar results after 24 weeks, with the ivarmacitinib 8 mg group again having the highest ACR20 response rate (75.1%). AEs were comparable between placebo and ivarmacitinib 4 mg groups but higher in the 8 mg group, with upper respiratory tract infection, anemia, and hyperlipidemia being common.

This project aims to investigate ivarmacitinib's therapeutic efficacy and safety in csDMARDs-IR RA patients, providing evidence for its use as a second-line treatment and exploring its effects at the single-cell sequencing and RNA-seq levels, offering new treatment options.

Rheumatoid arthritis (RA), a chronic, progressive, and disabling autoimmune disease primarily affecting small joints [1], has a worldwide prevalence rate of approximately 0.5% to 1.0%. According to estimates from the Chinese Rheumatism Data Center (CRDC), the prevalence rate in China is 0.42%, with around 5 million patients, of whom approximately 70% are female and 55% are over 55 years old [2]. The global age-standardized prevalence rate is 208.8 cases per 100,000 population, showing a significant increase of 14.1% since 1990. It is estimated that there will be 31.7 million RA patients worldwide by 2050, representing an 80.2% increase in case numbers compared to 2020 [3].

RA is a lifelong disease characterized by high disability rates, significant economic burdens, long disease duration, and a high proportion of moderate to severe cases. Due to chronic inflammation, RA can affect internal organs besides joints, leading to complications such as interstitial lung disease, fragility fractures, cardiovascular and cerebrovascular complications, and tumors. As the survival time of RA patients in China gradually increases, more patients will be classified as having "major diseases." Currently, commonly used treatment drugs include conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), biologic disease-modifying antirheumatic drugs (bDMARDs), targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs), nonsteroidal anti-inflammatory drugs, glucocorticoids, and traditional Chinese medicine. csDMARDs, represented by methotrexate, are the first-line drugs for RA patients [4]. However, one-half to two-thirds of patients do not achieve satisfactory disease control with methotrexate monotherapy [5]. The optimal sequencing of different drugs for these patients is a clinical focus.

Several studies have explored the efficacy and safety of bDMARDs in patients with inadequate response to csDMARDs (csDMARDs-IR). Research indicates that for patients with inadequate response to methotrexate, switching to or adding upadacitinib significantly improves ACR20 response rates, with monotherapy showing higher safety [6]. Filgotinib demonstrated superior efficacy over placebo in RA patients with inadequate response to methotrexate, with ACR20 response rates of 76.6% in the 200 mg group and 69.8% in the 100 mg group at 12 weeks, compared to only 49.9% in the placebo group (all p<0.001) [7].

The JAK kinase family plays a crucial role in intracellular immune and inflammatory signaling pathways [8]. Ivarmacitinib is a novel small-molecule targeted drug that precisely inhibits JAK1, thereby blocking the signaling of various cytokines (such as interleukins) and regulating immune responses to reduce inflammatory mediator production [9].

A multicenter, randomized, double-blind, placebo-controlled Phase II study (SHR0302-201) evaluating the efficacy and safety of ivarmacitinib tablets in patients with moderate to severe active RA has completed enrollment of all subjects and core period data analysis, with extended period data under analysis. In the first 12 weeks (core treatment period), 194 subjects were enrolled, and 174 completed treatment. SHR0302-201 core treatment period analysis revealed that after 12 weeks of dosing, the proportion of subjects achieving a 20% improvement in the American College of Rheumatology core criteria for RA disease activity assessment (ACR20) was highest in the ivarmacitinib 8 mg group (77.8%), followed by the 4 mg group (67.5%), with significant statistical differences compared to the placebo group (27.0%) (P<0.01). The proportions of subjects achieving 50% (ACR50) and 70% (ACR70) improvements were also highest in the ivarmacitinib 8 mg group, showing a dose-response relationship. After 12 weeks of dosing, the improvement in the 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) from baseline was highest in the ivarmacitinib 8 mg group, followed by the 4 mg group, with significant differences compared to the placebo group (P<0.05), indicating a clear dose-response relationship. During the core treatment period, at least one treatment-emergent adverse event (TEAE) occurred in 23 subjects (62.2%) in the placebo group and 116 subjects (73.9%) in the ivarmacitinib group overall. According to the MedDRA system organ classification, the highest incidence of TEAEs was infections and infestations, with 6 cases (16.2%) in the placebo group and 48 cases (30.6%) in the ivarmacitinib group overall. The highest incidence was in the ivarmacitinib 8 mg group (22 cases, 48.9%), followed by the 4 mg group (9 cases, 22.5%). According to the MedDRA preferred terms, the most common adverse event with an incidence ≥5% was upper respiratory tract infection, with 3 cases (8.1%) in the placebo group and 33 cases (21.0%) in the ivarmacitinib group overall. Upper respiratory tract infection was most common in the ivarmacitinib 8 mg group (18 cases, 40.0%), followed by the 4 mg group (6 cases, 15.0%).

A multicenter, randomized, double-blind, placebo-controlled Phase III study (SHR0302-301) evaluating the efficacy and safety of ivarmacitinib tablets in patients with moderate to severe active RA has completed enrollment of all subjects and core period data analysis, with extended period data under analysis. In the first 24 weeks (core treatment period), 566 subjects were enrolled, and 496 completed treatment [9]. SHR0302-301 core treatment period analysis revealed that after 24 weeks of dosing, the proportion of subjects achieving ACR20 was highest in the ivarmacitinib 8 mg group (75.1%), followed by the 4 mg group (70.4%), with significant statistical differences compared to the placebo group (40.4%) (P<0.01). The proportions of subjects achieving ACR50 and ACR70 were also highest in the ivarmacitinib 8 mg group, showing a dose-response relationship. After 24 weeks of dosing, the improvement in DAS28-CRP from baseline was highest in the ivarmacitinib 8 mg group, followed by the 4 mg group, with significant differences compared to the placebo group (P<0.05), indicating a clear dose-response relationship. During the core treatment period, the incidence of adverse events (AEs) (79.3% vs 81.5%) and drug-related AEs (48.9% vs 56.6%) was comparable between the placebo group and the ivarmacitinib 4 mg group, while the incidence was slightly higher in the ivarmacitinib 8 mg group (90.5% for AEs and 64.0% for drug-related AEs). During the core treatment period, the most common (≥10%) AEs in the placebo group were upper respiratory tract infection (13.8%) and anemia (11.7%); in the ivarmacitinib 4 mg group, they were upper respiratory tract infection (21.7%) and hyperlipidemia (15.3%); and in the ivarmacitinib 8 mg group, they were upper respiratory tract infection (22.8%), hyperlipidemia (12.2%), and hypercholesterolemia (10.1%).

Currently, there are no reports on the use of ivarmacitinib in csDMARDs-IR RA. This project aims to investigate the therapeutic efficacy and safety of ivarmacitinib in csDMARDs-IR RA. Other JAK1 inhibitors have explored the feasibility of such research, and this study can provide evidence on the efficacy and safety of ivarmacitinib as a second-line treatment for csDMARDs-IR patients. It will explore the therapeutic efficacy of ivarmacitinib at the single-cell sequencing and RNA-seq levels, offering new treatment options for RA patients.

Inclusion Criteria:

1. Aged between 18 and 75 years (inclusive) at the time of signing the informed consent form, regardless of gender;
2. Meeting the diagnostic criteria for rheumatoid arthritis (RA) as defined in the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria for RA;
3. Having moderate to severe active RA, defined as having a tender joint count (TJC) ≥ 6 or a swollen joint count (SJC) ≥ 6 based on a 68/66-joint count at screening, or a Disease Activity Score in 28 joints with erythrocyte sedimentation rate (DAS28 ESR)/C-reactive protein (CRP) ≥ 3.2, and having an ESR > 28 mm/h or CRP/high-sensitivity CRP (hsCRP) > 5 mg/L at screening;
4. Having an inadequate response to or intolerance of at least one or more conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Subjects must have received regular csDMARD therapy for at least 3 months and have been on a stable dose for at least 4 weeks prior to initiating study drug treatment. Allowable csDMARDs include methotrexate (MTX), sulfasalazine, hydroxychloroquine, chloroquine, and leflunomide, among others.

Exclusion Criteria:

1. Requiring continued combination therapy with methotrexate (MTX), hydroxychloroquine, and sulfasalazine, or any combination of three csDMARDs;
2. Subjects who have previously received a standard course of JAK inhibitors (e.g., tofacitinib, upadacitinib, baricitinib, filgotinib, deucravacitinib, etc., including topical formulations) and have primary failure to biologic DMARDs (bDMARDs) treatment;
3. Subjects judged by the investigator to have active symptoms of primary fibromyalgia or other conditions that may interfere with the assessment of RA symptoms;
4. Lactating or pregnant women, or fertile subjects unwilling to take effective contraceptive measures throughout the trial period and for 1 month after the last administration of emmacitinib tablets;
5. Subjects with uncontrolled infections, such as hepatitis B carriers with liver dysfunction (aspartate aminotransferase or alanine aminotransferase ≥ 3 times the upper limit of the laboratory normal range, or bilirubin ≥ 1.5 times the upper limit of the laboratory normal range); subjects with a history of latent or active tuberculosis who have not completed an adequate course of anti-tuberculosis treatment; subjects with symptomatic herpes zoster infection;
6. Subjects with an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m² calculated by the Modified Diet in Renal Disease (MDRD) formula or other methods;
7. Subjects with moderate to severe congestive heart failure (New York Heart Association Class III or IV), or those who have experienced a cardiovascular or cerebrovascular event requiring hospitalization within 6 months prior to enrollment, including but not limited to percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, cerebral hemorrhage, or subarachnoid hemorrhage;
8. Subjects with a current or history of malignancy (except for adequately treated or excised non-metastatic basal cell carcinoma or squamous cell carcinoma of the skin, or cervical carcinoma in situ);
9. Subjects who have received a live/attenuated vaccine within the previous 3 months or are expected to receive a live/attenuated vaccine during the study period or within 28 days after the end of the study;
10. Subjects who have participated in another clinical trial within 30 days prior to the screening period;
11. Subjects who refuse to sign the informed consent form or are unwilling or unable to cooperate with the collection of medical history and clinical photographs;
12. Subjects considered by the investigator to have any other conditions that make them unsuitable for participation in this study.