Khoury, Julie

Importance Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis. Objective To evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy. Design, Setting, and Participants NEURO-TTRansform was an open-label, single-group, phase 3 trial conducted at 40 sites across 15 countries (December 2019-April 2023) in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with placebo from NEURO-TTR ( NCT01737398 ; March 2013–November 2017), an inotersen trial with similar eligibility criteria and end points, served as a historical placebo (“placebo”) group. Interventions Subcutaneous eplontersen (45 mg every 4 weeks; n = 144); a small reference group received subcutaneous inotersen (300 mg weekly; n = 24); subcutaneous placebo weekly (in NEURO-TTR; n = 60). Main Outcomes and Measures Primary efficacy end points at week 65/66 were changes from baseline in serum transthyretin concentration, modified Neuropathy Impairment Score +7 (mNIS+7) composite score (scoring range, –22.3 to 346.3; higher scores indicate poorer function), and Norfolk Quality of Life Questionnaire–Diabetic Neuropathy (Norfolk QoL-DN) total score (scoring range, –4 to 136; higher scores indicate poorer quality of life). Analyses of efficacy end points were based on a mixed-effects model with repeated measures adjusted by propensity score weights. Results Among 144 eplontersen-treated patients (mean age, 53.0 years; 69% male), 136 (94.4%) completed week-66 follow-up; among 60 placebo patients (mean age, 59.5 years; 68% male), 52 (86.7%) completed week-66 follow-up. At week 65, adjusted mean percentage reduction in serum transthyretin was −81.7% with eplontersen and −11.2% with placebo (difference, −70.4% [95% CI, −75.2% to −65.7%]; P < .001). Adjusted mean change from baseline to week 66 was lower (better) with eplontersen vs placebo for mNIS+7 composite score (0.3 vs 25.1; difference, −24.8 [95% CI, −31.0 to −18.6; P < .001) and for Norfolk QoL-DN (−5.5 vs 14.2; difference, −19.7 [95% CI, −25.6 to −13.8]; P < .001). Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group. Conclusions and Relevance In patients with ATTRv polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo. Trial Registration ClinicalTrials.gov Identifier: NCT04136184 ; EU Clinical Trials Register: EudraCT 2019-001698-10

Background:Patients with chronic myelomonocytic leukemia (CMML) have historically poor outcomes, with ∼6–7 month median overall survival (OS) in the relapsed/refractory (r/r) setting. Splenomegaly is a major cause of morbidity, is a poor prognostic factor and has emerged as a potential therapeutic target in CMML. Tagraxofusp (SL‐401) is a targeted therapy directed to CD123, a target expressed on CMML blasts, monocytes and neoplastic microenvironmental plasmacytoid dendritic cells (pDCs) that are part of the CMML malignant clone, as well as on a variety of additional malignancies. Tagraxofusp was approved by the US FDA for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) and is being investigated in other CD123‐expressing malignancies.Aims:Primary objectives include assessment of safety, determining the recommended Phase 2 dose (RP2D) and schedule, and evaluating efficacy in patients with CMML.Methods:This multicenter, open‐label, Phase 1/2 clinical trial is enrolling patients with CMML. In Stage 1 (dose escalation), tagraxofusp was administered as a daily IV infusion at 7, 9, and 12 mcg/kg on days 1–3 every 21 days (cycle 1–4), every 28 days (cycles 5–7), and every 42 days (cycles 8 and beyond). In Stage 2 (expansion), patients receive the RP2D (12 mcg/kg).Results:20 patients with CMML (CMML‐1 [n = 12]; CMML‐2 [n = 8]) were treated with tagraxofusp, including 18 in the relapsed/refractory setting, with hypomethylating agents (HMAs) being the most commonly administered prior therapy. Median age was 69 years (range 43–80) and 80% were male. 10 patients (50%) had baseline splenomegaly (defined as spleen palpable below the left costal margin [BCM]), of which 6 had baseline splenomegaly ≥ 5 cm BCM. Most common treatment‐related adverse events (TRAEs, incidence ≥ 20%) were hypoalbuminaemia, thrombocytopenia, nausea, vomiting and fatigue. Most common ≥ grade 3 TRAEs were thrombocytopenia (35%) and nausea (5%). Capillary leak syndrome was reported in 3 patients (grade 1–2). 100% (10/10) of patients with baseline splenomegaly had a spleen response by physical exam: 80% (8/10) had spleen size reduction of ≥ 50% and 67% (4/6) with baseline spleen size ≥ 5 cm had spleen size reduction of ≥ 50%. Three patients treated with tagraxofusp achieved bone marrow complete responses (BMCRs), including 1 patient who was bridged to stem cell transplant in remission on tagraxofusp.Summary/Conclusion:Tagraxofusp demonstrated single agent activity in patients with CMML and splenomegaly, an area of potential unmet medical need. Given the expression of CD123 in CMML, tagraxofusp represents a rational therapeutic approach in this disease. Updated data will be presented, and a registrational trial is planned. Trial information: NCT02268253.

Objective: To describe the spectrum of autonomic dysfunction in a uniformly evaluated cohort of patients with Sjögren syndrome. Methods: A series of 13 patients underwent a comprehensive evaluation for suspected autonomic impairment, including a neurological examination, autonomic testing, and laboratory studies. A diagnosis of Sjögren syndrome was established as the cause of autonomic dysfunction in all. Clinical features, findings on autonomic testing, and laboratory results are described. Results: All patients in this series reported postural lightheadedness and syncope or near-syncope. Autonomic testing confirmed the presence of orthostatic hypotension on tilt-table testing in 5 patients and an excessive postural tachycardia and/or hypertensive response in 8 patients. Only 2 of the patients with orthostatic hypotension had a significant sensory neuropathy. Symptoms suggestive of gastrointestinal and genitourinary impairment were seen in nearly all patients, with abnormal motility testing (most frequently esophageal dysmotility) in 5 of 6 patients who underwent formal testing. Patients in this series treated with immune-modulating therapy experienced significant improvement. Conclusions: A diagnosis of Sjögren syndrome should be aggressively pursued in patients with signs and symptoms suggestive of autonomic nervous system impairment. Although the spectrum of adrenergic failure is variable, ranging from orthostatic hypotension to an excessive postural tachycardia, most patients do have symptoms of more generalized autonomic failure. Patients who were treated with immune-modulating therapy did improve.