No abstract

Background Inability to tolerate statins because of muscle symptoms contributes to uncontrolled cholesterol levels and insufficient cardiovascular risk reduction. Bempedoic acid, a prodrug that is activated by a hepatic enzyme not present in skeletal muscle, inhibits ATP ‐citrate lyase, an enzyme upstream of β‐hydroxy β‐methylglutaryl‐coenzyme A reductase in the cholesterol biosynthesis pathway. Methods and Results The phase 3, double‐blind, placebo‐controlled CLEAR (Cholesterol Lowering via Bempedoic acid, an ACL‐Inhibiting Regimen) Serenity study randomized 345 patients with hypercholesterolemia and a history of intolerance to at least 2 statins (1 at the lowest available dose) 2:1 to bempedoic acid 180 mg or placebo once daily for 24 weeks. The primary end point was mean percent change from baseline to week 12 in low‐density lipoprotein cholesterol. The mean age was 65.2 years, mean baseline low‐density lipoprotein cholesterol was 157.6 mg/dL, and 93% of patients reported a history of statin‐associated muscle symptoms. Bempedoic acid treatment significantly reduced low‐density lipoprotein cholesterol from baseline to week 12 (placebo‐corrected difference, −21.4% [95% CI, −25.1% to −17.7%]; P <0.001). Significant reductions with bempedoic acid versus placebo were also observed in non–high‐density lipoprotein cholesterol (−17.9%), total cholesterol (−14.8%), apolipoprotein B (−15.0%), and high‐sensitivity C‐reactive protein (−24.3%; P <0.001 for all comparisons). Bempedoic acid was safe and well tolerated. The most common muscle‐related adverse event, myalgia, occurred in 4.7% and 7.2% of patients who received bempedoic acid or placebo, respectively. Conclusions Bempedoic acid offers a safe and effective oral therapeutic option for lipid lowering in patients who cannot tolerate statins. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 02988115.

Few therapeutic options are available for patients with Philadelphia chromosome-positive (Ph 1 ) B-precursor acute lymphoblastic leukemia (ALL) who progress after failure of tyrosine kinase inhibitor (TKI) 2based therapy. Here, we evaluated the efficacy and tolerability of blinatumomab in patients with relapsed or refractory Ph 1 ALL. Patients and MethodsThis open-label phase II study enrolled adults with Ph 1 ALL who had relapsed after or were refractory to at least one second-generation or later TKI or were intolerant to second-generation or later TKIs and intolerant or refractory to imatinib. Blinatumomab was administered in 28-day cycles by continuous intravenous infusion. The primary end point was complete remission (CR) or CR with partial hematologic recovery (CRh) during the first two cycles. Major secondary end points included minimal residual disease response, rate of allogeneic hematopoietic stem-cell transplantation, relapse-free survival, overall survival, and adverse events (AEs). ResultsOf 45 patients, 16 (36%; 95% CI, 22% to 51%) achieved CR/CRh during the first two cycles, including four of 10 patients with the T315I mutation; 88% of CR/CRh responders achieved a complete minimal residual disease response. Seven responders (44%) proceeded to allogeneic hematopoietic stem-cell transplantation, including 55% (six of 11) of transplantation-naïve responders. Median relapse-free survival and overall survival were 6.7 and 7.1 months, respectively. The most frequent AEs were pyrexia (58%), febrile neutropenia (40%), and headache (31%). Three patients had cytokine release syndrome (all grade 1 or 2), and three patients had grade 3 neurologic events, one of which (aphasia) required temporary treatment interruption. There were no grade 4 or 5 neurologic events. ConclusionSingle-agent blinatumomab showed antileukemia activity in high-risk patients with Ph 1 ALL who had relapsed or were refractory to TKIs. AEs were consistent with previous experience in Ph -ALL.