Dataset Information

Safety profile of anifrolumab in patients with active SLE: an integrated analysis of phase II and III trials.

ABSTRACT:

Objective

In phase II and III trials, anifrolumab, a human monoclonal antibody that binds type I interferon receptor subunit 1, has shown efficacy in adults with moderate to severe SLE. We evaluated the safety and tolerability of anifrolumab using data pooled from these trials to more precisely estimate the rate and severity of adverse events (AEs).

Methods

Data were pooled from patients receiving monthly intravenous anifrolumab 300?mg or placebo in MUSE, TULIP-1 and TULIP-2. Key safety endpoints included percentages and exposure-adjusted incidence rates (EAIRs) of patients who experienced AEs, serious AEs (SAEs), AEs leading to discontinuation and AEs of special interest.

Results

During treatment, 86.9% of patients receiving anifrolumab 300?mg (n=459) experienced AEs (?1) versus 79.4% receiving placebo (n=466), and 4.1% versus 5.2% experienced an AE leading to discontinuation of investigational product. SAEs (?1) were experienced by 11.8% and 16.7% of patients receiving anifrolumab and placebo, respectively (EAIR risk difference (95%?CI) -7.2 (-12.5 to -1.9)), including lupus exacerbations classified as SAEs (1.5% and 3%, respectively). Infections occurred in 69.7% and 55.4% of patients receiving anifrolumab and placebo, respectively; difference in reported rates was driven by herpes zoster (HZ) and mild and moderate respiratory (excluding pneumonia) infections. The risk of HZ was increased with anifrolumab versus placebo (6.1% vs 1.3%, respectively; EAIR risk difference (95% CI) 5.4 (2.8 to 8.4)); most HZ events were mild or moderate, cutaneous and resolved without treatment discontinuation. Serious infections occurred in 4.8% and 5.6% of patients receiving anifrolumab and placebo, respectively.

Conclusions

In this pooled analysis of 925 patients with moderate to severe SLE, monthly intravenous anifrolumab 300?mg was generally well tolerated over 52 weeks with an acceptable safety profile. Anifrolumab was associated with an increased incidence of HZ and respiratory tract infections and lower reported rate of SLE worsening as SAEs.

SUBMITTER: Tummala R

PROVIDER: S-EPMC7893670 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

Safety profile of anifrolumab in patients with active SLE: an integrated analysis of phase II and III trials.

Tummala Raj R Abreu Gabriel G Pineda Lilia L Michaels M Alex MA Kalyani Rubana N RN Furie Richard A RA Morand Eric F EF

Lupus science & medicine 20210201 1

<h4>Objective</h4>In phase II and III trials, anifrolumab, a human monoclonal antibody that binds type I interferon receptor subunit 1, has shown efficacy in adults with moderate to severe SLE. We evaluated the safety and tolerability of anifrolumab using data pooled from these trials to more precisely estimate the rate and severity of adverse events (AEs).<h4>Methods</h4>Data were pooled from patients receiving monthly intravenous anifrolumab 300 mg or placebo in MUSE, TULIP-1 and TULIP-2. Key ...[more]

PMID: 33597205

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Project description:ObjectivesTo evaluate the time course of clinical response following anifrolumab treatment in patients with SLE.MethodsA post hoc analysis was conducted using pooled data from phase III, randomised, 52-week, placebo-controlled, Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP)-1 and TULIP-2 trials of intravenous anifrolumab (every 4 weeks, 48 weeks) in patients with moderate-to-severe SLE receiving standard therapy. Anifrolumab 300 mg and placebo groups were compared for British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response over time, time to sustained BICLA response, SLE Responder Index ≥4 (SRI(4)) response over time, time to sustained Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity (CLASI-A) response and change in glucocorticoid dosage over time. All p values for comparisons were nominal.ResultsOf the 726 evaluated patients (anifrolumab 300 mg, n=360; placebo, n=366), a greater proportion attained a BICLA response in the anifrolumab versus the placebo group from Week 8 (p<0.001); treatment group differentiation was maintained at all subsequent visits to Week 52. Consistently, more patients achieved a BICLA response sustained to Week 52 in the anifrolumab versus placebo group (HR=1.73, 95% CI 1.37 to 2.20). More patients attained SRI(4) response with anifrolumab than placebo from Week 12 (p=0.005). As early as Week 8, more patients achieved CLASI-A skin response sustained to Week 52 with anifrolumab versus placebo (HR=1.72, 95% CI 1.17 to 2.55). Glucocorticoid dosage reductions from baseline were greater in anifrolumab-treated versus placebo-treated patients from Week 20 (p=0.010) through Week 52.ConclusionsAnifrolumab treatment was associated with sustained improvements in overall SLE disease activity and skin responses versus placebo from Week 8, which likely led to greater glucocorticoid reductions in the anifrolumab versus placebo groups from Week 20. These findings provide insights to physicians and patients on when to expect potential clinical responses following anifrolumab treatment.

Project description:BackgroundThe risk and course of serum transaminase elevations (TEs) and clinical hepatic serious adverse event (SAE) development in ritonavir-boosted tipranavir (TPV/r) 500/200 mg BID recipients, who also received additional combination antiretroviral treatment agents in clinical trials (TPV/r-based cART), was determined.MethodsAggregated transaminase and hepatic SAE data through 96 weeks of TPV/r-based cART from five Phase IIb/III trials were analyzed. Patients were categorized by the presence or absence of underlying liver disease (+LD or -LD). Kaplan-Meier (K-M) probability estimates for time-to-first US National Institutes of Health, Division of AIDS (DAIDS) Grade 3/4 TE and clinical hepatic SAE were determined and clinical actions/outcomes evaluated. Risk factors for DAIDS Grade 3/4 TE were identified through multivariate Cox regression statistical modeling.ResultsGrade 3/4 TEs occurred in 144/1299 (11.1%) patients; 123/144 (85%) of these were asymptomatic; 84% of these patients only temporarily interrupted treatment or continued, with transaminase levels returning to Grade < or = 2. At 96 weeks of study treatment, the incidence of Grade 3/4 TEs was higher among the +LD (16.8%) than among the -LD (10.1%) patients. K-M analysis revealed an incremental risk for developing DAIDS Grade 3/4 TEs; risk was greatest through 24 weeks (6.1%), and decreasing thereafter (>24-48 weeks: 3.4%, >48 weeks-72 weeks: 2.0%, >72-96 weeks: 2.2%), and higher in +LD than -LD patients at each 24-week interval. Treatment with TPV/r, co-infection with hepatitis B and/or C, DAIDS grade >1 TE and CD4+ > 200 cells/mm3 at baseline were found to be independent risk factors for development of DAIDS Grade 3/4 TE; the hazard ratios (HR) were 2.8, 2.0, 2.1 and 1.5, respectively. Four of the 144 (2.7%) patients with Grade 3/4 TEs developed hepatic SAEs; overall, 14/1299 (1.1%) patients had hepatic SAEs including six with hepatic failure (0.5%). The K-M risk of developing hepatic SAEs through 96 weeks was 1.4%; highest risk was observed during the first 24 weeks and decreased thereafter; the risk was similar between +LD and -LD patients for the first 24 weeks (0.6% and 0.5%, respectively) and was higher for +LD patients, thereafter.ConclusionThrough 96 weeks of TPV/r-based cART, DAIDS Grade 3/4 TEs and hepatic SAEs occurred in approximately 11% and 1% of TPV/r patients, respectively; most (84%) had no significant clinical implications and were managed without permanent treatment discontinuation. Among the 14 patients with hepatic SAE, 6 experienced hepatic failure (0.5%); these patients had profound immunosuppression and the rate appears higher among hepatitis co-infected patients. The overall probability of experiencing a hepatic SAE in this patient cohort was 1.4% through 96 weeks of treatment. Independent risk factors for DAIDS Grade 3/4 TEs include TPV/r treatment, co-infection with hepatitis B and/or C, DAIDS grade >1 TE and CD4+ > 200 cells/mm3 at baseline.Trial registrationUS-NIH Trial registration number: NCT00144170.

Project description:BackgroundRolapitant, a long-acting neurokinin (NK)1 receptor antagonist (RA), has demonstrated efficacy in prevention of chemotherapy-induced nausea and vomiting in patients administered moderately or highly emetogenic chemotherapy. Unlike other NK1 RAs, rolapitant does not inhibit or induce cytochrome P450 (CYP) 3A4, but it does inhibit CYP2D6 and breast cancer resistance protein (BCRP). To analyze potential drug-drug interactions between rolapitant and concomitant medications, this integrated safety analysis of four double-blind, randomized phase II or III studies of rolapitant examined adverse events (AEs) by use versus non-use of drug substrates of CYP2D6 or BCRP.Patients and methodsPatients were randomized to receive either 180?mg oral rolapitant or placebo ?1-2?h before chemotherapy in combination with a 5-hydroxytryptamine type 3 RA and dexamethasone. Data for treatment-emergent AEs (TEAEs) and treatment-emergent serious AEs (TESAEs) during cycle 1 were pooled across the four studies and summarized in the overall population and by concomitant use/non-use of CYP2D6 or BCRP substrate drugs.ResultsIn the integrated safety population, 828 of 1294 patients (64%) in the rolapitant group and 840 of 1301 patients (65%) in the control group experienced at least one TEAE. Frequencies of common TEAEs were similar in the rolapitant and control populations. Overall, 53% of patients received CYP2D6 substrate drugs, none of which had a narrow therapeutic index (like thioridazine or pimozide), and 63% received BCRP substrate drugs. When grouped by concomitant use versus non-use of CYP2D6 or BCRP substrate drugs, TEAEs and TESAEs occurred with similar frequency in the rolapitant and control populations.ConclusionsThe results of this study support the safety of rolapitant as part of an antiemetic triple-drug regimen in patients receiving emetogenic chemotherapy, including those administered concomitant medications that are substrates of CYP2D6 or BCRP, such as ondansetron, docetaxel, or irinotecan.

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Dataset Information

Safety profile of anifrolumab in patients with active SLE: an integrated analysis of phase II and III trials.

Objective

Methods

Results

Conclusions

Publications

Safety profile of anifrolumab in patients with active SLE: an integrated analysis of phase II and III trials.

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