Reports of widespread thromboses and disseminated intravascular coagulation (DIC) in patients with coronavirus disease 19 (COVID-19) have been rapidly increasing in number. Key features of this ...disorder include a lack of bleeding risk, only mildly low platelet counts, elevated plasma fibrinogen levels, and detection of both severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and complement components in regions of thrombotic microangiopathy (TMA). This disorder is not typical DIC. Rather, it might be more similar to complement-mediated TMA syndromes, which are well known to rheumatologists who care for patients with severe systemic lupus erythematosus or catastrophic antiphospholipid syndrome. This perspective has critical implications for treatment. Anticoagulation and antiviral agents are standard treatments for DIC but are gravely insufficient for any of the TMA disorders that involve disorders of complement. Mediators of TMA syndromes overlap with those released in cytokine storm, suggesting close connections between ineffective immune responses to SARS-CoV-2, severe pneumonia and life-threatening microangiopathy.
What Did Not Work: The Drug or the Trial? Merrill, Joan T.
Arthritis & rheumatology (Hoboken, N.J.),
October 2021, 2021-10-00, 20211001, Letnik:
73, Številka:
10
Journal Article
Objective
To assess the efficacy and safety of anifrolumab, a type I interferon (IFN) receptor antagonist, in a phase IIb, randomized, double‐blind, placebo‐controlled study of adults with ...moderate‐to‐severe systemic lupus erythematosus (SLE).
Methods
Patients (n = 305) were randomized to receive intravenous anifrolumab (300 mg or 1,000 mg) or placebo, in addition to standard therapy, every 4 weeks for 48 weeks. Randomization was stratified by SLE Disease Activity Index 2000 score (<10 or ≥10), oral corticosteroid dosage (<10 or ≥10 mg/day), and type I IFN gene signature test status (high or low) based on a 4‐gene expression assay. The primary end point was the percentage of patients achieving an SLE Responder Index (SRI4) response at week 24 with sustained reduction of oral corticosteroids (<10 mg/day and less than or equal to the dose at week 1 from week 12 through 24). Other end points (including SRI4, British Isles Lupus Assessment Group BILAG–based Composite Lupus Assessment BICLA, modified SRI6, and major clinical response) were assessed at week 52. The primary end point was analyzed in the modified intent‐to‐treat (ITT) population and type I IFN–high subpopulation. The study result was considered positive if the primary end point was met in either of the 2 study populations. The Type I error rate was controlled at 0.10 (2‐sided), within each of the 2 study populations for the primary end point analysis.
Results
The primary end point was met by more patients treated with anifrolumab (34.3% of 99 for 300 mg and 28.8% of 104 for 1,000 mg) than placebo (17.6% of 102) (P = 0.014 for 300 mg and P = 0.063 for 1,000 mg, versus placebo), with greater effect size in patients with a high IFN signature at baseline (13.2% in placebo‐treated patients versus 36.0% P = 0.004 and 28.2% P = 0.029) in patients treated with anifrolumab 300 mg and 1,000 mg, respectively. At week 52, patients treated with anifrolumab achieved greater responses in SRI(4) (40.2% versus 62.6% P < 0.001 and 53.8% P = 0.043 with placebo, anifrolumab 300 mg, and anifrolumab 1,000 mg, respectively), BICLA (25.7% versus 53.5% P < 0.001 and 41.2% P = 0.018, respectively), modified SRI(6) (28.4% versus 49.5% P = 0.002 and 44.7% P = 0.015, respectively), major clinical response (BILAG 2004 C or better in all organ domains from week 24 through week 52) (6.9% versus 19.2% P = 0.012 and 17.3% P = 0.025, respectively), and several other global and organ‐specific end points. Herpes zoster was more frequent in the anifrolumab‐treated patients (2.0% with placebo treatment versus 5.1% and 9.5% with anifrolumab 300 mg and 1,000 mg, respectively), as were cases reported as influenza (2.0% versus 6.1% and 7.6%, respectively), in the anifrolumab treatment groups. Incidence of serious adverse events was similar between groups (18.8% versus 16.2% and 17.1%, respectively).
Conclusion
Anifrolumab substantially reduced disease activity compared with placebo across multiple clinical end points in the patients with moderate‐to‐severe SLE.
To evaluate the efficacy and safety of atacicept, an antagonist of B lymphocyte stimulator/APRIL-mediated B cell activation, in patients with systemic lupus erythematosus (SLE).
ADDRESS II is a ...24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-arm, phase IIb study evaluating the safety and efficacy of atacicept in patients with SLE (ClinicalTrials.gov identifier NCT01972568). Patients with active, autoantibody-positive SLE receiving standard therapy were randomized (1:1:1) to receive atacicept (75 mg or 150 mg) or placebo for 24 weeks. The primary end point was the SLE responder index 4 (SRI-4) at week 24.
The intent-to-treat (ITT) population included 306 patients. There was a trend toward an improved SRI-4 response rate with atacicept 75 mg (57.8%; adjusted odds ratio OR 1.78, P = 0.045) and 150 mg (53.8%; adjusted OR 1.56, P = 0.121) at week 24 as compared with placebo (44.0%) (primary analysis; using the screening visit as baseline). In a prespecified sensitivity analysis using study day 1 as baseline, a significantly larger proportion of patients receiving atacicept 75 mg and 150 mg achieved an SRI-4 response at week 24 compared with placebo. In predefined subpopulations with high levels of disease activity (HDA) at baseline, serologically active disease, or both, statistically significant improvements in the SRI-4 and SRI-6 response rates were seen with atacicept versus placebo. A severe risk of disease flare was reduced with atacicept therapy in both the ITT and the HDA populations. The risks of serious adverse events and serious or severe infection were not increased with atacicept as compared with placebo.
Atacicept treatment showed evidence of efficacy in SLE, particularly in HDA and serologically active patients. Reductions in disease activity and severe flare were observed with atacicept treatment, with an acceptable safety profile.
The efficacy and safety of sifalimumab were assessed in a phase IIb, randomised, double-blind, placebo-controlled study (NCT01283139) of adults with moderate to severe active systemic lupus ...erythematosus (SLE).
431 patients were randomised and received monthly intravenous sifalimumab (200 mg, 600 mg or 1200 mg) or placebo in addition to standard-of-care medications. Patients were stratified by disease activity, interferon gene-signature test (high vs low based on the expression of four genes) and geographical region. The primary efficacy end point was the percentage of patients achieving an SLE responder index response at week 52.
Compared with placebo, a greater percentage of patients who received sifalimumab (all dosages) met the primary end point (placebo: 45.4%; 200 mg: 58.3%; 600 mg: 56.5%; 1200 mg 59.8%). Other improvements were seen in Cutaneous Lupus Erythematosus Disease Area and Severity Index score (200 mg and 1200 mg monthly), Physician's Global Assessment (600 mg and 1200 mg monthly), British Isles Lupus Assessment Group-based Composite Lupus Assessment (1200 mg monthly), 4-point reductions in the SLE Disease Activity Index-2000 score and reductions in counts of swollen joints and tender joints. Serious adverse events occurred in 17.6% of patients on placebo and 18.3% of patients on sifalimumab. Herpes zoster infections were more frequent with sifalimumab treatment.
Sifalimumab is a promising treatment for adults with SLE. Improvement was consistent across various clinical end points, including global and organ-specific measures of disease activity.
NCT01283139; Results.
Objective
To compare the efficacy and safety of intravenous (IV) abatacept, a selective T cell costimulation modulator, versus placebo for the treatment of active class III or IV lupus nephritis, ...when used on a background of mycophenolate mofetil and glucocorticoids.
Methods
This was a 12‐month, randomized, phase II/III, multicenter, international, double‐blind study. A total of 298 patients were treated in 1 of 3 IV treatment arms: placebo, abatacept at the standard weight‐tiered dose (approximating 10 mg/kg), or abatacept at 30 mg/kg for 3 months, followed by the standard weight‐tiered dose (abatacept 30/10). The primary end point, time to confirmed complete response, was a composite measure that required maintenance of glomerular filtration rate, minimal proteinuria, and inactive urinary sediment over the 52‐week treatment period.
Results
There were no differences among treatment arms in the time to confirmed complete response or in the proportion of subjects with confirmed complete response following 52 weeks of treatment. Treatment with abatacept was associated with greater improvements from baseline in anti–double‐stranded DNA antibody, C3, and C4 levels. Among 122 patients with nephrotic‐range proteinuria, treatment with abatacept resulted in an ∼20–30% greater reduction in mean urinary protein‐to‐creatinine ratio compared with placebo. Abatacept was well tolerated; rates of deaths, serious adverse events, and serious infections were similar across treatment arms. Gastroenteritis and herpes zoster occurred more frequently with abatacept treatment.
Conclusion
Although the primary end point was not met, abatacept showed evidence of biologic activity and was well tolerated in patients with active class III or IV lupus nephritis.
Targeted inhibitors of B-cell activating factor (BAFF) have been evaluated in phase III trials in over 4000 patients with systemic lupus erythematosus (SLE). Post hoc analyses of these studies ...identify greater treatment effect in patients entering with higher disease activity, greater corticosteroid doses, anti double-stranded DNA (dsDNA) and low complement C3 or C4.
To evaluate the efficacy and safety of blisibimod, a BAFF inhibitor, in a population of patients with SLE enriched for high disease activity.
442 patients with SLE with antinuclear antibodies or anti-dsDNA and Safety of Estrogen in Lupus Erythematosus National Assessment - Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score ≥10 on standard-of-care medications were randomised to receive weekly subcutaneous blisibimod (200 mg) or placebo. Corticosteroid taper was encouraged from week 8. The primary end point was the week 52 SLE Responder Index-6 (SRI-6).
The SRI-6 primary end point was not met. There was a statistically significant steroid-sparing effect, and significantly more blisibimod-treated subjects achieved corticosteroid taper. Increased blisibimod treatment effect on SRI-6 was observed in subjects who achieved a concomitant decrease in corticosteroid dose from baseline. In subjects with baseline urinary protein:creatinine ratio (UPCR) ≥56.5 mg/mmol, significantly higher proportions of blisibimod subjects achieved >50% reduction in UPCR and/or UPCR <56.5 mg/mmol. Reductions in SLE autoantibodies and B cells, and increases in complement C3 and C4 were observed with blisibimod.Blisibimod was well-tolerated. The most common adverse events were upper respiratory tract infection, urinary tract infection, injection site erythema/reaction and diarrhoea.
Although the SRI-6 end point was not met, blisibimod was associated with successful steroid reduction, decreased proteinuria and biomarker responses.
NCT01395745.
To examine the safety and efficacy of rontalizumab, a humanised IgG1 anti-interferon α (anti-IFN-α) monoclonal antibody, in patients with moderate-to-severe systemic lupus erythematosus (SLE).
...Patients with active SLE were randomised (2:1) to 750 mg intravenous rontalizumab every 4 weeks or placebo (Part 1), and 300 mg subcutaneous rontalizumab every 2 weeks or placebo (Part 2).
Hydroxychloroquine and corticosteroids were allowed. Patients taking immunosuppressants at baseline were required per protocol to discontinue. Efficacy end points included reduction in disease activity by British Isles Lupus Disease Activity Group (BILAG)-2004 (primary), and SLE response index (SRI, secondary) at Week 24. Efficacy was also examined by an exploratory measure of IFN-regulated gene expression (interferon signature metric, ISM).
Patients (n=238) received rontalizumab (n=159) or placebo (n=79). At baseline, the mean Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index (SELENA-SLEDAI) score in all cohorts was ~10, and 75.6% of patients had a high ISM (ISM-High). Efficacy response rates by BILAG and SRI were similar between rontalizumab and placebo groups. However, in the exploratory subgroup of ISM-Low patients, SRI response was higher and steroid use was lower in the rontalizumab-treated patients. There was also a reduction in SELENA-SLEDAI flare index rates (HR 0.61, 0.46 to 0.81, p=0.004) in this subgroup. Adverse events were similar between placebo and rontalizumab groups.
The primary and secondary end points of this trial were not met in all patients or in patients with high ISM scores. In an exploratory analysis, rontalizumab treatment was associated with improvements in disease activity, reduced flares and decreased steroid use in patients with SLE with low ISM scores.
NCT00962832.
Objective
To assess the efficacy and safety of deucravacitinib, an oral, selective, allosteric inhibitor of TYK2, in a phase II trial in adult patients with active systemic lupus erythematosus (SLE).
...Methods
Adults with active SLE were enrolled from 162 sites in 17 countries. Patients (n = 363) were randomized 1:1:1:1 to receive deucravacitinib 3 mg twice daily, 6 mg twice daily, 12 mg once daily, or placebo. The primary end point was SLE Responder Index 4 (SRI‐4) response at week 32. Secondary outcomes assessed at week 48 included SRI‐4, British Isles Lupus Assessment Group–based Composite Lupus Assessment (BICLA) response, Cutaneous Lupus Erythematosus Disease Area and Severity Index 50 (CLASI‐50), Lupus Low Disease Activity State (LLDAS), and improvements in active (swollen plus tender), swollen, and tender joint counts.
Results
At week 32, the percentage of patients achieving SRI‐4 response was 34% with placebo compared to 58% with deucravacitinib 3 mg twice daily (odds ratio OR 2.8 95% confidence interval (95% CI) 1.5, 5.1; P < 0.001 versus placebo), 50% with 6 mg twice daily (OR 1.9 95% CI 1.0, 3.4; P = 0.02 versus placebo), and 45% with 12 mg once daily (OR 1.6 95% CI 0.8, 2.9; nominal P = 0.08 versus placebo). Response rates were higher with deucravacitinib treatment for BICLA, CLASI‐50, LLDAS, and joint counts compared to placebo. Rates of adverse events were similar across groups, except higher rates of infections and cutaneous events, including rash and acne, with deucravacitinib treatment. Rates of serious adverse events were comparable, with no deaths, opportunistic infections, tuberculosis infections, major adverse cardiovascular events, or thrombotic events reported.
Conclusion
Deucravacitinib treatment elicited higher response rates for SRI‐4 and other end points compared with placebo, with an acceptable safety profile, in adult patients with active SLE.
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