An HPA-1a-positive platelet-depleting agent for prevention of fetal and neonatal alloimmune thrombocytopenia: a randomized, single-blind, placebo-controlled, single-center, phase 1/2 proof-of-concept study.

BACKGROUND: Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a rare and potentially life-threatening bleeding disorder of the fetus/newborn. Antibodies against human platelet antigen 1a (HPA-1a) are associated with the most frequent FNAIT cases. There are no approved therapies for FNAIT prevention or treatment. RLYB211 is a polyclonal HPA-1a hyperimmune IgG being developed to prevent FNAIT. OBJECTIVES: To investigate whether a single dose of anti-HPA-1a (1000 IU) could markedly accelerate the elimination of HPA-1ab platelets transfused into healthy, HPA-1a-negative participants as compared with placebo. METHODS: This randomized, single-blind, placebo-controlled, single-center, phase 1/2 proof-of-concept study (EudraCT: 2019-003459-12) included HPA-1a- and HLA-A2-negative healthy men. Cohort 1 received intravenous RLYB211 or placebo 1 hour after transfusion of HPA-1ab platelets. Cohort 1B received RLYB211 or placebo, followed by platelet transfusion 1 week later. Primary endpoint was the half-life of transfused platelets in circulation after administration of RLYB211 or placebo, determined by flow cytometry. Proof of concept was ≥90% reduction of half-life relative to placebo. RESULTS: Twelve participants were allocated to cohort 1 or 1B and randomized to receive RLYB211 (n = 9) or placebo (n = 3). RLYB211 markedly accelerated the elimination of HPA-1ab platelets in all participants vs placebo. In cohort 1B, this effect was observed 7 days after RLYB211 administration. Two treatment-emergent adverse events were possibly related to treatment, both in RLYB211-treated participants. No participants developed HPA-1a antibodies at 12 or 24 weeks. CONCLUSION: These data support the hypothesis that anti-HPA-1a could be used as prophylaxis in women at risk of having an FNAIT-affected pregnancy.

Eculizumab monotherapy for NMOSD: Data from PREVENT and its open-label extension.

During PREVENT (a phase 3, randomized, double-blind, placebo-controlled, time-to-event study) and its open-label extension (interim analysis), 33 adults with aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG + NMOSD) received eculizumab monotherapy for a median of 2.8 years (range, 14 weeks-5.2 years). At 192 weeks (~4 years), 96% of these patients were free from adjudicated relapses (Kaplan-Meier analysis; 95% confidence interval, 75.7-99.4). During PREVENT, 95% (20/21) of patients receiving eculizumab monotherapy had no disability worsening. Eculizumab monotherapy provides effective long-term relapse prevention, relieving the chronic immunosuppression burden in patients with AQP4-IgG + NMOSD. ClinicalTrials.gov; PREVENT: NCT01892345; open-label extension: NCT02003144.

Benefits of eculizumab in AQP4+ neuromyelitis optica spectrum disorder: Subgroup analyses of the randomized controlled phase 3 PREVENT trial.

BACKGROUND: Antibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in astrocyte damage and subsequent neuronal injury. The PREVENT study demonstrated that the terminal complement inhibitor eculizumab reduces adjudicated relapse risk in patients with anti-AQP4 immunoglobulin G-positive (AQP4+) NMOSD. The objective of this analysis was to evaluate the efficacy of eculizumab in reducing relapse risk and its safety in AQP4+ NMOSD across clinically relevant subgroups in PREVENT. METHODS: In the randomized, double-blind, time-to-event, phase 3 PREVENT trial, 143 adults received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo (2:1), with stable-dose concomitant immunosuppressive therapy (IST) permitted (except rituximab and mitoxantrone). Post hoc analyses of relapses and adverse events were performed for prespecified and post hoc subgroups based on concomitant IST and prior rituximab use, demographic and disease characteristics, and autoimmune comorbidity. RESULTS: The significant reduction in relapse risk observed for eculizumab versus placebo in the overall PREVENT population was consistently maintained across subgroups based on concomitant IST and previous rituximab use, age, sex, region, race, time since clinical onset of NMOSD, historical annualized relapse rate, baseline Expanded Disability Status Scale score, and history of another autoimmune disorder. The serious infection rate was lower with eculizumab than placebo regardless of rituximab use in the previous year, concomitant IST use, or history of another autoimmune disorder. CONCLUSION: Across a wide range of clinically relevant AQP4+ NMOSD patient subgroups in PREVENT, eculizumab therapy was consistently effective versus placebo in reducing relapse risk, with no apparent increase in serious infection rate. TRIAL REGISTRATION: NCT01892345 (ClinicalTrials.gov).

Eculizumab in Aquaporin-4-Positive Neuromyelitis Optica Spectrum Disorder.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing, autoimmune, inflammatory disorder that typically affects the optic nerves and spinal cord. At least two thirds of cases are associated with aquaporin-4 antibodies (AQP4-IgG) and complement-mediated damage to the central nervous system. In a previous small, open-label study involving patients with AQP4-IgG-positive disease, eculizumab, a terminal complement inhibitor, was shown to reduce the frequency of relapse. METHODS: In this randomized, double-blind, time-to-event trial, 143 adults were randomly assigned in a 2:1 ratio to receive either intravenous eculizumab (at a dose of 900 mg weekly for the first four doses starting on day 1, followed by 1200 mg every 2 weeks starting at week 4) or matched placebo. The continued use of stable-dose immunosuppressive therapy was permitted. The primary end point was the first adjudicated relapse. Secondary outcomes included the adjudicated annualized relapse rate, quality-of-life measures, and the score on the Expanded Disability Status Scale (EDSS), which ranges from 0 (no disability) to 10 (death). RESULTS: The trial was stopped after 23 of the 24 prespecified adjudicated relapses, given the uncertainty in estimating when the final event would occur. The mean (±SD) annualized relapse rate in the 24 months before enrollment was 1.99±0.94; 76% of the patients continued to receive their previous immunosuppressive therapy during the trial. Adjudicated relapses occurred in 3 of 96 patients (3%) in the eculizumab group and 20 of 47 (43%) in the placebo group (hazard ratio, 0.06; 95% confidence interval [CI], 0.02 to 0.20; P<0.001). The adjudicated annualized relapse rate was 0.02 in the eculizumab group and 0.35 in the placebo group (rate ratio, 0.04; 95% CI, 0.01 to 0.15; P<0.001). The mean change in the EDSS score was -0.18 in the eculizumab group and 0.12 in the placebo group (least-squares mean difference, -0.29; 95% CI, -0.59 to 0.01). Upper respiratory tract infections and headaches were more common in the eculizumab group. There was one death from pulmonary empyema in the eculizumab group. CONCLUSIONS: Among patients with AQP4-IgG-positive NMOSD, those who received eculizumab had a significantly lower risk of relapse than those who received placebo. There was no significant between-group difference in measures of disability progression. (Funded by Alexion Pharmaceuticals; PREVENT ClinicalTrials.gov number, NCT01892345; EudraCT number, 2013-001150-10.).

Breast cancer incidence in the randomized PEARL trial of lasofoxifene in postmenopausal osteoporotic women.

BACKGROUND: Currently available selective estrogen receptor modulators reduce the risk of breast cancer, but they are not widely used. In the Postmenopausal Evaluation and Risk-Reduction with Lasofoxifene (PEARL) trial, lasofoxifene was shown to reduce the risk of estrogen receptor-positive (ER+) breast cancer, nonvertebral and vertebral fractures, coronary artery disease, and stroke, but the effects on total breast cancer (invasive and ductal carcinoma in situ, ER+ and estrogen receptor-negative [ER-]) and ER+ invasive breast cancer are unknown. METHODS: Postmenopausal women (n = 8556) aged 59-80 years with low bone density and normal mammograms were randomly assigned to two doses of lasofoxifene (0.25 and 0.5 mg) or placebo. The primary endpoints of the PEARL trial were incidence of ER+ breast cancer and nonvertebral fractures at 5 years. A nested case-control study of 49 incident breast cancer case patients and 156 unaffected control subjects from the PEARL trial was performed to evaluate treatment effects on risk of total and ER+ invasive breast cancer by baseline serum estradiol and sex hormone-binding globulin levels using logistic regression models. Cox proportional hazards models were used to evaluate risk of total breast cancer and ER+ invasive breast cancer using intention-to-treat analysis. All statistical tests were two-sided. RESULTS: Breast cancer was confirmed in 49 women. Compared with placebo, 0.5 mg of lasofoxifene statistically significantly reduced the risk of total breast cancer by 79% (hazard ratio = 0.21; 95% confidence interval [CI] = 0.08 to 0.55) and ER+ invasive breast cancer by 83% (hazard ratio = 0.17; 95% CI = 0.05 to 0.57). The effects of 0.5 mg of lasofoxifene on total breast cancer were similar regardless of Gail score, whereas the effects were markedly stronger for women with baseline estradiol levels greater than the median (odds ratio = 0.11; 95% CI = 0.02 to 0.51) vs those with levels less than the median (odds ratio = 0.78; 95% CI = 0.16 to 3.79; P(interaction) = .04). CONCLUSION: A 0.5-mg dose of lasofoxifene appears to reduce the risks of both total and ER+ invasive breast cancer in postmenopausal women with osteoporosis.

Lasofoxifene and cardiovascular events in postmenopausal women with osteoporosis: Five-year results from the Postmenopausal Evaluation and Risk Reduction with Lasofoxifene (PEARL) trial.

BACKGROUND: In the Postmenopausal Evaluation and Risk Reduction With Lasofoxifene (PEARL) trial, women assigned to lasofoxifene 0.5 mg/d had a lower risk of major coronary heart disease (CHD) events and stroke, whereas women assigned to lasofoxifene 0.25 mg/d had a lower risk of stroke. Both doses of lasofoxifene increased the risk of venous thromboembolic events. In this report, we provide comprehensive cardiovascular end-point data, including component events comprising the composite end point of major CHD events, and evaluate whether the effect of lasofoxifene 0.5 mg/d is consistent across different categories of CHD risk. METHODS AND RESULTS: In this study, 8556 women 59 to 80 years of age with osteoporosis received lasofoxifene 0.25 mg/d, lasofoxifene 0.5 mg/d, or placebo for 5 years. Cardiovascular events, including major CHD events, were prespecified secondary end points. Compared with placebo, lasofoxifene 0.5 mg/d reduced the risk of major CHD events 32% (hazard ratio, 0.68; 95% confidence interval, 0.50 to 0.93), including the risk of coronary revascularization (hazard ratio, 0.56, 95% confidence interval, 0.32 to 0.98). Reductions in risk of hospitalization for unstable angina (hazard ratio, 0.55; 95% confidence interval, 0.29 to 1.04) and diagnosis of new ischemic heart disease (hazard ratio, 0.52; 95% confidence interval, 0.26 to 1.04) nearly reached significance (P=0.06 for both comparisons). Although both hazard ratios were <1.0, no significant effect of lasofoxifene at 0.5 mg/d was demonstrated for coronary death or nonfatal myocardial infarction. The reduction in CHD events with lasofoxifene 0.25 mg/d was not significant (hazard ratio, 0.76; 95% confidence interval, 0.56 to 1.03; P=0.08). The effectiveness of lasofoxifene 0.5 mg/d in reducing CHD events was similar across strata of major cardiovascular risk factors. CONCLUSIONS: In postmenopausal women with osteoporosis, lasofoxifene 0.5 mg/d for 5 years reduced the risk of CHD events, regardless of the presence or absence of risk factors for cardiovascular disease. The significant reduction in risk of CHD events with lasofoxifene 0.5 mg/d was due primarily to lower risks of coronary revascularization procedures, hospitalization for unstable angina, and diagnosis of new ischemic heart disease. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00141323.

Lasofoxifene in postmenopausal women with osteoporosis.

BACKGROUND: The effects of lasofoxifene on the risk of fractures, breast cancer, and cardiovascular disease are uncertain. METHODS: In this randomized trial, we assigned 8556 women who were between the ages of 59 and 80 years and had a bone mineral density T score of -2.5 or less at the femoral neck or spine to receive once-daily lasofoxifene (at a dose of either 0.25 mg or 0.5 mg) or placebo for 5 years. Primary end points were vertebral fractures, estrogen receptor (ER)-positive breast cancer, and nonvertebral fractures; secondary end points included major coronary heart disease events and stroke. RESULTS: Lasofoxifene at a dose of 0.5 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (13.1 cases vs. 22.4 cases per 1000 person-years; hazard ratio, 0.58; 95% confidence interval [CI], 0.47 to 0.70), nonvertebral fracture (18.7 vs. 24.5 cases per 1000 person-years; hazard ratio, 0.76; 95% CI, 0.64 to 0.91), ER-positive breast cancer (0.3 vs. 1.7 cases per 1000 person-years; hazard ratio, 0.19; 95% CI, 0.07 to 0.56), coronary heart disease events (5.1 vs. 7.5 cases per 1000 person-years; hazard ratio, 0.68; 95% CI, 0.50 to 0.93), and stroke (2.5 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.64; 95% CI, 0.41 to 0.99). Lasofoxifene at a dose of 0.25 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (16.0 vs. 22.4 cases per 1000 person-years; hazard ratio, 0.69; 95% CI, 0.57 to 0.83) and stroke (2.4 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.61; 95% CI, 0.39 to 0.96) Both the lower and higher doses, as compared with placebo, were associated with an increase in venous thromboembolic events (3.8 and 2.9 cases vs. 1.4 cases per 1000 person-years; hazard ratios, 2.67 [95% CI, 1.55 to 4.58] and 2.06 [95% CI, 1.17 to 3.60], respectively). Endometrial cancer occurred in three women in the placebo group, two women in the lower-dose lasofoxifene group, and two women in the higher-dose lasofoxifene group. Rates of death per 1000 person-years were 5.1 in the placebo group, 7.0 in the lower-dose lasofoxifene group, and 5.7 in the higher-dose lasofoxifene group. CONCLUSIONS: In postmenopausal women with osteoporosis, lasofoxifene at a dose of 0.5 mg per day was associated with reduced risks of nonvertebral and vertebral fractures, ER-positive breast cancer, coronary heart disease, and stroke but an increased risk of venous thromboembolic events. (ClinicalTrials.gov number, NCT00141323.)