ACR Convergence 2024: Spondyloarthritis Including Psoriatic Arthritis – Treatment II

 

Bimekizumab Treatment Resulted in Improvements in MRI Inflammatory and Structural Lesions in the Sacroiliac Joints of Patients with Axial Spondyloarthritis: 52-Week Results and Post Hoc Analyses from Two Phase 3 Studies

Speaker: Dr. Walter P. Maksymowych – University of Alberta

Key Highlights:

Dr. Maksymowych discussed bimekizumab, a bispecific antibody targeting both IL-17A and IL-17F, as well as their homodimers and heterodimers. He highlighted its demonstrated consistent and sustained efficacy over two years in treating non-radiographic and radiographic axial spondyloarthritis, as observed in the BE MOBILE 1 and BE MOBILE 2 studies.

Study Design:

1. BE MOBILE 1
   1. Population: Patients with non-radiographic axial spondyloarthritis (nr-axSpA).
   2. Number of patients: 254
   3. Randomization: Patients were randomized 1:1 to receive either:
      1. Bimekizumab 160 mg monthly, or
      2. Placebo.
   4. Primary Endpoint: Assessed at week 16.
   5. Crossover Design: After week 16, patients on placebo crossed over to active therapy with bimekizumab.
2. BE MOBILE 2
   1. Population: Patients with radiographic axial spondyloarthritis (r-axSpA).
   2. Number of patients: 332
   3. Randomization: Patients were randomized 2:1 in favor of: Bimekizumab 160 mg monthly, with a smaller group receiving placebo.
   4. Primary Endpoint: Similar to BE MOBILE 1, assessed at week 16.
   5. Open-Label Extension: After week 52, patients had the option to participate in an open-label extension study.
3. MRI Assessments:
   1. Sacroiliac joint inflammation was scored on 6 consecutive slices, assessed by quadrants of the joint.
   2. Scores incorporated weighting based on the depth and intensity of inflammation.
   3. Scoring ranged from 0 to 72.
   4. Conducted at baseline, week 16, and week 52.
4. Structural Lesions: Analyzed as a post-hoc component.

Results:

1. Reduction in MRI Inflammation:
   1. Bimekizumab treatment showed a marked decrease in SPARCC (Sacroiliac Joint Inflammation Score) inflammation scores.
   2. Patients in BE MOBILE 1 exhibited a decrease of 7.0 points by week 16, whereas those in BE MOBILE 2 showed a reduction of 4.8 points due to baseline ankylosis in the radiographic axSpA group.
   3. Inflammation scores in the placebo group showed minimal changes until patients switched to active treatment, after which reductions aligned with the bimekizumab group.
2. Clinical Remission:
   52. By week 16, 60-70% of patients achieved remission (SPARCC score <2), increasing to 70-80% by week 52.
   53. Patients initially on placebo reached comparable remission levels after crossing over to bimekizumab.
3. Structural Lesion Improvements:
   1. Erosion Scores: Patients in BE MOBILE 1 and BE MOBILE 2 showed reductions of -0.9 points by week 16 and -1.8 by week 52.
   2. Post-Inflammatory Lesions: Backfill and fat metaplasia increased in treated patients, indicative of healing responses. Scores for backfill rose by 0.3–0.4 points and for fat lesions by 0.6 points.
   3. Ankylosis: Minimal changes were noted, reflecting the limited progression of this condition during the study duration.

Dr. Maksymowych concluded that bimekizumab provides rapid and sustained reduction in inflammation, significant structural improvements, and high remission rates in axSpA patients. These effects suggest a potent anti-inflammatory response, with implications for long-term tissue healing and disease management.

 

Minimal Spinal Radiographic Progression in Patients with Radiographic Axial Spondyloarthritis over 2 Years of Bimekizumab Treatment: Results from a Phase 3 Open-Label Extension Study

Speaker: Dr. Xenofon Baraliakos – Ruhr University, Bochum, Rheumazentrum Ruhrgebiet Herne

Key Highlights:

Dr. Xenofon Baraliakos presented two-year data from the BE MOBILE 2 open-label extension study evaluating spinal radiographic progression in patients with radiographic axial spondyloarthritis (axSpA) treated with bimekizumab.

• 332 patients initially were randomised to bimekizumab or placebo (2:1 ratio) transitioned to the active drug after 16 weeks. 267 patients completed the week 104.
• Out of the 267 patients, 190 had an mSASSS available at baseline, forming the X-ray population.
• X-rays were obtained at baseline and at two years and analysed centrally using mSASSS. Readers were blinded to timepoints and clinical data to ensure unbiased assessments.

Radiographic Progression:

The mean mSASSS score increased minimally from 0.3 at baseline to 0.6 at two years, reflecting negligible radiographic progression. Less than 20% of patients exhibited any progression, and 80%+ remained stable, indicating effective disease control.

Patient Subgroup Analysis:

• Without Baseline Syndesmophytes: Among 133/190 patients, only 1.5% developed new syndesmophytes.
• With Baseline Syndesmophytes: Among 57/190 patients, 21% experienced progression, reflecting a higher baseline risk.

Predictive Factors for Progression:

Multivariable analysis identified predictors of progression, including baseline syndesmophytes, elevated CRP, male sex, and smoking. B27-negative patients were less likely to progress, but the sample size of this subgroup was small, warranting further research.

Clinical Implications and Recommendations:

Dr. Baraliakos underscored the importance of early and aggressive treatment to minimise radiographic progression. Patients with risk factors (e.g., high CRP or smoking) may require closer monitoring and potentially adjunctive therapies.

Concluding Remarks:

Dual IL-17A/F inhibition with bimekizumab demonstrated a strong signal for halting radiographic progression, particularly in high-risk patients. This outcome highlights bimekizumab's potential as a cornerstone therapy in axSpA management.

 

Predictors of Radiographic Spinal Progression in Patients with Axial Spondyloarthritis Receiving IL-17A Inhibitor or TNF Inhibitor Therapy over 2 Years: A Post Hoc Analysis of a Phase IIIb Study

Speaker: Dr. Denis Poddubnyy – University Health Network, Toronto

Key Highlights:

The SURPASS study compared the IL-17A inhibitor secukinumab and adalimumab biosimilar, a TNF inhibitor, in patients with r-axSpA to explore predictors of radiographic spinal progression. Patients were stratified into moderate-to-fast progressors (mSASSS ≥ 2 units) and non-progressors over two years. This open-label study assessed structural damage progression in patients with radiographic axial spondyloarthritis (r-axSpA) over two years.

Study Design:

1. Population: 859 patients with r-axSpA who:
   1. Were unresponsive to NSAIDs and biologics.
   2. Were biologic-naïve.
   3. Had elevated CRP level of > 5 mg/L or presence of > 1 syndesmophytes
2. Randomization and Treatment Groups: Participants were randomized into three treatment arms:
   1. Secukinumab 150 mg.
   2. Secukinumab 300 mg.
   3. Adalimumab biosimilar.
3. Duration and Primary Endpoint:
   1. Patients were treated for two years.
   2. The primary endpoint was radiographic spinal progression assessed via the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS).
4. Imaging and Lesion Evaluation:
   1. Serial MRIs were performed to evaluate structural lesions, including:
      1. Syndesmophytes.
      2. Spinal inflammation.
   2. Fat lesions: Presence of syndesmophytes was defined as an mSASSS of ≥2 at a given vertebral corner, confirmed by at least 2 out of 3 independent readers.
   3. Progression Categories: Patients were categorized based on mSASSS change over 2 years:
      1. Moderate to Fast Progressors: mSASSS change ≥2 points.
      2. Low Progressors / Non-Progressors: mSASSS change <2 points.
   4. Outcomes:
      1. Proportion of patients developing new syndesmophytes was recorded.
      2. Statistical analyses evaluated factors associated with syndesmophyte formation at week 104.

Baseline Characteristics:

• 3% of patients had syndesmophytes at baseline, while 77.1% had elevated CRP, indicating a high-risk cohort.
• The mean MSAS score was 14, reflective of substantial baseline structural damage.

Findings and Predictive Factors:

1. Baseline Syndesmophytes:
   1. Strongly associated with new syndesmophyte formation (OR: significant).
   2. Patients with pre-existing damage were more likely to progress, emphasizing the need for early treatment.
2. Inflammatory Markers:
   1. Elevated CRP and MRI BME scores at baseline correlated with higher odds of progression.
   2. Persistent inflammation, despite therapy, was observed in progressors, highlighting a need for more aggressive control in high-risk patients.
3. Fat Lesions: Progressors showed a higher fat lesion burden at all-time points, suggesting fat metaplasia as a marker of prior inflammation and future progression risk.
4. Treatment Comparison:
   1. Both secukinumab and adalimumab demonstrated similar efficacy in preventing radiographic progression.
   2. No significant differences in outcomes between the two groups were observed, though baseline variation in fat lesion burden was noted.
5. Subgroup and Longitudinal Analyses:
   1. Moderate-to-fast progressors consistently had higher MRI inflammation scores compared to non-progressors, regardless of treatment.
   2. Trends suggested that prior inflammation and fat metaplasia predispose patients to ongoing damage despite effective anti-inflammatory therapy.

Conclusion:

Baseline syndesmophytes, elevated CRP, and MRI-detected inflammation are key drivers of radiographic progression in r-axSpA. Early and aggressive intervention is critical, particularly for patients with high inflammatory activity or pre-existing structural damage. While IL-17A and TNF inhibitors are effective, achieving deeper inflammation control in high-risk populations remains a challenge.

 

A Phase 2 Multicenter, Randomized, Double-Blinded, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy and Safety of a Mitogen-activated Protein Kinase-activated Protein Kinase 2 (MK2) Inhibitor in Active Ankylosing Spondylitis

Speaker: Dr. Walter P. Maksymowych – University of Alberta

Key Highlights:

Dr. Maksymowych talked about the current treatments for axial spondyloarthritis that achieved major clinical responses (ASAS 40) in approximately 40–50% of patients using TNF, IL-17, or targeted synthetic therapies. However, significant gaps remain, especially for patients with long disease durations and therapeutic failures, as retention rates over five years are only 60–70%.

Efforts to explore the p38a MAP kinase pathway as a target were unsuccessful due to toxicity, tachyphylaxis, and unintended reduction of anti-inflammatory cytokines. Attention has now shifted to downstream pathways, particularly MK2, which plays a pivotal role in stabilizing pro-inflammatory cytokine mRNA by phosphorylating regulatory proteins like TTP (Tristetraproline). This regulatory mechanism underscores the potential for MK2 inhibitors to address unmet needs in managing inflammation in axial spondyloarthritis.

Rationale for MK2 Inhibition in Arthritis:

1. MK2 knockout mice showed a reduced incidence of collagen-induced arthritis, exhibited lower levels of pro-inflammatory cytokines, and appeared normal, suggesting no major adverse effects.
2. ATP-competitive inhibitors demonstrated efficacy in other models, such as streptococcal cell wall-induced arthritis.
3. MK2 inhibition (ATI-450) in phase I placebo-controlled single or multiple ascending dose RCT over 7 days was well-tolerated and demonstrated dose-dependent inhibition of TNFα, IL-6, IL-8 and IL-1β3.

Study Design:

The study was a phase 2, randomized, placebo-controlled trial in patients with ankylosing spondylitis (AS). Participants met the modified New York criteria for AS and had active symptomatology despite treatment with at least two non-steroidal anti-inflammatory drugs (NSAIDs).

The study had two patient groups:

• Bio DMARD-naïve group: Patients with no prior exposure to biological disease-modifying anti-rheumatic drugs (bDMARDs).
• Bio DMARD-inadequate responder group: Patients with an insufficient response to prior bDMARDs, with at least 50% recruited based on lack of efficacy to their previous bDMARD.

Key features:

1. Patients were assessed for ASAS20 response at week 12 as the primary endpoint.
2. 123 patients completed the trial.
3. Non-responders at week 16 were withdrawn from the trial.
4. Responders could enter an extension phase up to week 54.
5. The study was powered based on a 59% response rate for the treatment group versus 34% for placebo, ensuring adequate statistical rigor.
6. Endpoints:
   12. Primary Endpoint: Achievement of ASAS20 (Assessment of Spondyloarthritis International Society 20) response at week 12.
   13. Secondary Endpoints:
       1. ASAS 40
       2. Changes in ASDAS, BASDAI, BASFI, CRP

• SPARCC MRI SIJ and spine

1. Exploratory Endpoint:
   1. Spinal Mobility
   2. Swollen Joints

• QoL, PK-PD

1. Gene expression profiles

Results:

1. Efficacy Outcomes:
   1. The ASAS20 response at 12 weeks showed no meaningful difference between treatment and placebo groups.
   2. More stringent metrics, such as ASAS40, similarly failed to demonstrate separation between treatment arms.
   3. MRI assessments of sacroiliac and spinal inflammation revealed minimal, clinically insignificant changes.
2. Safety Data: The treatment was well-tolerated, with no significant adverse events or safety signals.
3. Pharmacodynamic Observations
   1. Phase 1 studies showed robust cytokine suppression, yet the phase 2 study revealed no significant reduction in TNF-alpha or other pro-inflammatory markers.
   2. Surprisingly, IL-17 levels increased in a dose-dependent manner, indicating potential compensatory feedback mechanisms.

Mechanistic Challenges and Interpretation: The failure of the MK2 inhibitor may stem from:

• MK2 inhibition may not suppress all the key inflammatory cytokines e.g. IL-17A
• Role of MK2 in feedback pathways e.g. synthesis of non-phosphorylated TTP¹
• MX
• MK2 may stabilize mRNA of anti-inflammatory cytokines and pathways e.g. IL- 102, Suppressor of Cytokine Signalling-3 (SOCS3)³
• Target engagement of MK2 in relevant tissues (e.g., entheses) may be insufficient to lead to adequate clinical benefits

Conclusion:

The study underscores the importance of conducting robust phase 2 trials even for agents with compelling preclinical profiles. While the MK2 inhibitor showed an attractive mechanism of action, its failure to impact key efficacy endpoints suggests that targeting MK2 may not be viable for AS treatment. Future investigations might focus on refining tissue engagement or exploring combination strategies.

American College of Rheumatology Convergence 2024, November 14–19, Washington, D.C.