Habtemariam, Bahru

Abstract Introduction Elevated levels of fetal hemoglobin (HbF) ameliorate sickle cell disease (SCD) manifestations. BEAM-101 is an investigational cell therapy comprising ex vivo base-edited autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) that directly target the HBG1/2 promoters to disrupt BCL11A binding, switching production from sickle (HbS) to majority anti-sickling HbF. We present ongoing data from the BEACON study (NCT05456880), a Phase 1/2, single-arm, open-label study evaluating a single dose of BEAM-101 in individuals with SCD and severe vaso-occlusive crises (sVOCs). Methods Eligible patients were aged 12–35 years with SCD and ≥4 sVOCs in the 2-year period prior to informed consent. After mobilization with weight-based or tiered fixed-dose plerixafor, autologous CD34+ HSPCs were collected by leukapheresis and genetically modified with an adenine base editor. Following conditioning with pharmacokinetically adjusted myeloablative busulfan (target cumulative AUC 80 hr*mg/L), patients received a single dose of BEAM-101 (≥3.0×106 viable CD34+ cells/kg). Patients were then monitored for neutrophil and platelet engraftment, adverse events (AEs), total Hb, Hb fractions, % F-cells, hemolysis markers, sVOCs, and additional protocol endpoints for up to 24 months. Results As of June 16, 2025, enrollment has been completed and 46 patients have initiated mobilization. Of the 26 patients who have received BEAM-101, mean duration of follow-up was 6.2 (range 1.0–18.7) months. Baseline demographics were: age 18–34 years, 24 βS/βS genotype, 21 self-reported Black/African American, and 11 female. One patient, who successfully engrafted and obtained stable HbF levels >60%, withdrew consent 5 months post-infusion. For the 26 treated patients, the median number of stem cell collection cycles was 1 (range 1–4); 18 (69.2%) required a single cycle, 4 required 2 cycles, and 4 required >2 cycles. Target cell dose was achieved with a median of 3 (1–12) collection days. Patients received a mean BEAM-101 dose of 8.4 (range 3.2–23.4) ×106 viable CD34+ cells/kg. By the data cut, patients achieved neutrophil (n=26) and platelet (n=24) engraftment at a median of 18 (12–30) days and 19 (11–50) days, respectively, with a median duration of 7 (4–17) days of neutropenia. Of the 24 evaluable patients, 9 (37.5%) achieved platelet engraftment without requiring platelet transfusion through the transplant process. No patients had ≥Grade 3 AEs or serious AEs related to BEAM-101. One patient died due to respiratory failure, assessed as likely related to busulfan conditioning, 4 months post-infusion as previously reported. Mean total Hb increased to 12.1 (range 9.0–14.7) g/dL by Month (M) 1 (n=24), 15.6 (11.9–18.6) g/dL by M6 (n=11), and was sustained through follow-up. Four patients had total Hb levels above the normal range beyond M6 without any associated clinical manifestations or need for therapeutic intervention. Erythropoietin levels trended towards normal in all patients, including those with elevated total Hb. Mean endogenous HbF (HbF/[HbF+HbS]) was >60% and HbS was <40% by M1, which was sustained through last follow-up. At M6, mean % F-cells were 99.2% (97.0–99.9; n=10) and mean HbF/F-cell was 20.8 (18.0–23.9; n=9) pg, exceeding the protective threshold of 10 pg against sickling. Peripheral blood editing was at a mean of 68.5% by M3 (n=16), 69.6% by M6 (n=10), and 72.8% by M12 (n=5). Hemolysis markers and sickling parameters normalized or improved for all patients. No patients experienced any investigator-reported sVOCs post-engraftment. Conclusions The BEAM-101 treatment process is characterized by a low number of mobilization and collection cycles and high editing efficiency, resulting in rapid neutrophil and platelet engraftment and robust pancellular HbF expression, with durability observed up to 18 months. Additionally, there is a corresponding reduction in HbS levels to <40%, and improvements or resolution of hemolysis parameters and anemia, along with resolution of investigator-reported sVOCs post-engraftment. The safety profile of the BEAM-101 treatment regimen is consistent with busulfan conditioning, autologous HSCT, and underlying SCD. These results demonstrate the potential for base editing of the HBG1/2 promoters as a safe and effective therapeutic modality for the treatment of SCD that also has the potential to minimize hospitalization and treatment process burden for patients, families, and sites.

Abstract BACKGROUND AND AIMS Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder characterised by hepatic oxalate overproduction that leads to progressive kidney disease. As kidney function declines, oxalate elimination is compromised and plasma oxalate (POx) increases, leading to systemic oxalosis. In chronic kidney disease (CKD) stages 3b–5, elevated POx is directly related to the pathophysiology of oxalosis, and reduction of POx is a relevant clinical trial endpoint. Lumasiran, an RNA interference therapeutic designed to reduce hepatic oxalate production, is indicated for the treatment of PH1 in all age groups. Data from the ILLUMINATE-C trial (EudraCT: 2019–0 013 346-17) demonstrated substantial reductions in POx and acceptable safety in patients with PH1 with impaired kidney function, including patients on haemodialysis (HD), who received lumasiran for 6 months. In Cohorts A (no HD) and B (on HD), respectively, lumasiran led to 33.33% [95% confidence interval (95% CI): −15.16 to 81.82] and 42.43% (95% CI: 34.15–50.71) least-squares (LS) mean reductions in POx from baseline to Month 6 (the primary endpoint). Here, we present METHOD ILLUMINATE-C is an ongoing Phase 3, single-arm study with two cohorts, Cohort A (N = 6; no HD at study start) and Cohort B (N = 15; on HD). The 6-month primary analysis period is followed by an extension period (EP) of up to 54 months. Key inclusion criteria include genetically confirmed PH1, eGFR ≤ 45 mL/min/1.73 m2 and POx ≥ 20 μmol/L. Patients received weight-based dosing of subcutaneous lumasiran. Outcomes of interest for the current analysis included assessments of cardiac oxalosis using echocardiography, medullary nephrocalcinosis by kidney ultrasound, kidney stone events and burdensome symptoms of PH1. RESULTS All 21 patients [43% female; 76% white; median age 8 (range 0–59) years] completed the 6-month primary analysis period. Among patients with abnormal left ventricular ejection fraction (LVEF; abnormal defined as LVEF < 55%) at baseline, 1/1 patient in Cohort A and 2/4 patients in Cohort B showed ≥ 5% improvement at Month 6. Among patients with abnormal global longitudinal strain (GLS, a measure of LV contractility more sensitive than LVEF for predicting outcomes; abnormal defined as |GLS| <15%) at baseline, 1/1 patient in Cohort A and 3/3 patients in Cohort B showed ≥ 2% improvement at Month 6. In Cohort A, 5/6 patients had nephrocalcinosis at baseline, 2 remained stable, none worsened, and 3 improved (2 unilateral and 1 bilateral improvement) at Month 6. In Cohort A, 1 patient did not have nephrocalcinosis at baseline and had bilateral worsening at Month 6. In Cohort B, 2/11 patients had nephrocalcinosis at baseline; both improved (1 unilateral and 1 bilateral improvement). In Cohort A, the rate of kidney stone events per person-year was 3.20 (95% CI: 1.96–5.22) in the 12 months prior to consent and 1.48 (95% CI: 0.55–3.92) during the first 6 months of lumasiran treatment. For patients in both cohorts, the most burdensome symptoms at baseline, including fatigue, nausea/decreased appetite, bone pain and decreased mobility, improved or remained stable at Month 6; none of the symptoms worsened. CONCLUSION Lumasiran treatment resulted in substantial reductions in POx in patients of all ages with PH1 and advanced kidney disease. The observations regarding cardiac measures that reflect systemic oxalosis, together with the kidney stone event and nephrocalcinosis results, are consistent with mobilisation of oxalate from systemic stores. Data on these long-term outcomes will continue to be collected and further evaluated in the EP. These results, along with previous reports from ILLUMINATE-A and ILLUMINATE-B, provide evidence supporting the effectiveness of lumasiran across the full spectrum of patients affected by PH1.

Background and objectives In the rare disease primary hyperoxaluria type 1, overproduction of oxalate by the liver causes kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an RNA interference therapeutic, suppresses glycolate oxidase, reducing hepatic oxalate production. The objective of this first-in-human, randomized, placebo-controlled trial was to evaluate the safety, pharmacokinetic, and pharmacodynamic profiles of lumasiran in healthy participants and patients with primary hyperoxaluria type 1. Design, setting, participants, & measurements This phase 1/2 study was conducted in two parts. In part A, healthy adults randomized 3:1 received a single subcutaneous dose of lumasiran or placebo in ascending dose groups (0.3–6 mg/kg). In part B, patients with primary hyperoxaluria type 1 randomized 3:1 received up to three doses of lumasiran or placebo in cohorts of 1 or 3 mg/kg monthly or 3 mg/kg quarterly. Patients initially assigned to placebo crossed over to lumasiran on day 85. The primary outcome was incidence of adverse events. Secondary outcomes included pharmacokinetic and pharmacodynamic parameters, including measures of oxalate in patients with primary hyperoxaluria type 1. Data were analyzed using descriptive statistics. Results Thirty-two healthy participants and 20 adult and pediatric patients with primary hyperoxaluria type 1 were enrolled. Lumasiran had an acceptable safety profile, with no serious adverse events or study discontinuations attributed to treatment. In part A, increases in mean plasma glycolate concentration, a measure of target engagement, were observed in healthy participants. In part B, patients with primary hyperoxaluria type 1 had a mean maximal reduction from baseline of 75% across dosing cohorts in 24-hour urinary oxalate excretion. All patients achieved urinary oxalate levels ≤1.5 times the upper limit of normal. Conclusions Lumasiran had an acceptable safety profile and reduced urinary oxalate excretion in all patients with primary hyperoxaluria type 1 to near-normal levels. Clinical Trial registry name and registration number: Study of Lumasiran in Healthy Adults and Patients with Primary Hyperoxaluria Type 1, NCT02706886