CRISPR-Cas9 In Vivo Gene Editing of KLKB1 for Hereditary Angioedema.

BACKGROUND: Hereditary angioedema is a rare genetic disease that leads to severe and unpredictable swelling attacks. NTLA-2002 is an in vivo gene-editing therapy based on clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9. NTLA-2002 targets the gene encoding kallikrein B1 (KLKB1), with the goal of lifelong control of angioedema attacks after a single dose. METHODS: In this phase 1 dose-escalation portion of a combined phase 1-2 trial of NTLA-2002 in adults with hereditary angioedema, we administered NTLA-2002 at a single dose of 25 mg, 50 mg, or 75 mg. The primary end points were the safety and side-effect profile of NTLA-2002 therapy. Secondary and exploratory end points included pharmacokinetics, pharmacodynamics, and clinical efficacy determined on the basis of investigator-confirmed angioedema attacks. RESULTS: Three patients received 25 mg of NTLA-2002, four received 50 mg, and three received 75 mg. At all dose levels, the most common adverse events were infusion-related reactions and fatigue. No dose-limiting toxic effects, serious adverse events, grade 3 or higher adverse events, or clinically important laboratory findings were observed after the administration of NTLA-2002. Dose-dependent reductions in the total plasma kallikrein protein level were observed between baseline and the latest assessment, with a mean percentage change of -67% in the 25-mg group, -84% in the 50-mg group, and -95% in the 75-mg group. The mean percentage change in the number of angioedema attacks per month between baseline and weeks 1 through 16 (primary observation period) was -91% in the 25-mg group, -97% in the 50-mg group, and -80% in the 75-mg group. Among all the patients, the mean percentage change in the number of angioedema attacks per month from baseline through the latest assessment was -95%. CONCLUSIONS: In this small study, a single dose of NTLA-2002 led to robust, dose-dependent, and durable reductions in total plasma kallikrein levels, and no severe adverse events were observed. In exploratory analyses, reductions in the number of angioedema attacks per month were observed at all dose levels. (Funded by Intellia Therapeutics; ClinicalTrials.gov number, NCT05120830.).

ARRY-382 in Combination with Pembrolizumab in Patients with Advanced Solid Tumors: Results from a Phase 1b/2 Study.

PURPOSE: ARRY-382 (PF-07265804) is a selective inhibitor of colony-stimulating factor-1 receptor. We evaluated the safety and preliminary efficacy of ARRY-382 plus pembrolizumab in patients with advanced solid tumors. PATIENTS AND METHODS: This was an open-label, multicenter, Phase 1b/2 study (NCT02880371) performed over September 1, 2016 to October 24, 2019. In the Phase 1b dose-escalation, patients with selected advanced solid tumors received ARRY-382 [starting dose 200 mg once daily (QD) orally] plus pembrolizumab [2 mg/kg intravenously (IV) every 3 weeks (Q3W)]. Phase 2 patients had: Pancreatic ductal adenocarcinoma (PDA); programmed cell death protein-1 (PD-1)/PD-ligand 1 (PD-L1) inhibitor-refractory (PD-1/PD-L1 IR) advanced solid tumors; or platinum-resistant ovarian cancer (prOVCA). Patients received ARRY-382 at the maximum tolerated dose (MTD) of 300 mg QD plus pembrolizumab 200 mg IV Q3W. RESULTS: Primary endpoints of dose-limiting toxicities (DLT; Phase 1b) and objective response rate (Phase 2) were met. In Phase 1b, 19 patients received ARRY-382 200-400 mg. Three patients reported DLTs. The MTD of ARRY-382 (plus pembrolizumab) was 300 mg QD. In Phase 1b, 2 patients (10.5%) had confirmed partial response (PR): 1 with PDA and 1 with ovarian cancer, lasting 29.2 and 3.1 months, respectively. In Phase 2, there were 27, 19, and 11 patients in the PDA, PD-1/PD-L1 IR, and prOVCA cohorts, respectively. One patient (3.7%) with PDA had a PR lasting 2.4 months. The most frequent ARRY-382-related adverse events were increased transaminases (10.5%-83.3%) and increased creatine phosphokinase (18.2%-50.0%). CONCLUSIONS: Although limited clinical benefit was observed, ARRY-382 plus pembrolizumab was well tolerated.

Vasopressor magnitude predicts poor outcome in adults with congenital heart disease after cardiac surgery.

BACKGROUND: High levels of vasoactive inotrope support (VIS) after congenital heart surgery are predictive of morbidity in pediatric patients. We sought to discern if this relationship applies to adults with congenital heart disease (ACHD). METHODS: We retrospectively studied adult patients (≥18 years old) admitted to the intensive care unit after cardiac surgery for congenital heart disease from 2002 to 2013 at Mayo Clinic. Vasoactive medication dose values within 96 hours of admission were examined to determine the relationship between VIS score and poor outcome of early mortality, early morbidity, or complication related morbidity. RESULTS: Overall, 1040 ACHD patients had cardiac surgery during the study time frame; 243 (23.4%) met study inclusion criteria. Sixty-two patients (25%), experienced composite poor outcome [including eight deaths within 90 days of hospital discharge (3%)]. Thirty-eight patients (15%) endured complication related early morbidity. The maximum VIS (maxVIS) score area under the curve was 0.92 (95% CI: 0.86-0.98) for in-hospital mortality; and 0.82 (95% CI: 0.76-0.89) for combined poor clinical outcome. On univariate analysis, maxVIS score ≥3 was predictive of composite adverse outcome (OR: 14.2, 95% CI: 7.2-28.2; P < 0.001), prolonged ICU LOS ICU LOS (OR: 19.2; 95% CI: 8.7-42.1; P < 0.0001), prolonged mechanical ventilation (OR: 13.6; 95% CI: 4.4-41.8; P < 0.0001) and complication related morbidity (OR: 7.3; 95% CI: 3.4-15.5; P < 0.0001). CONCLUSIONS: MaxVIS score strongly predicted adverse outcomes and can be used as a risk prediction tool to facilitate early intervention that may improve outcome and assist with clinical decision making for ACHD patients after cardiac surgery.

Duration and magnitude of vasopressor support predicts poor outcome after infant cardiac operations.

BACKGROUND: The vasoactive inotrope score (VIS) is a sum of the total vasopressor dose at a single point in time. Incorporating duration and magnitude of vasopressor requirements during the postcardiac surgical period could improve VIS sensitivity for predicting poor outcome. METHODS: This is a retrospective review of 244 infants (aged ≤365 days) who underwent cardiopulmonary bypass during congenital cardiac operations from 2002 to 2011. The VIS was calculated hourly for the first 72 hours. Poor outcome was defined as prolonged mechanical ventilation (≥6 days) or intensive care length of stay (≥12 days). First, the association between the maximum VIS (maxVIS) in the first 48 postoperative hours and poor outcome was confirmed for our study population. Next, postoperative intervals and VIS values that were significantly associated with poor outcome were identified and incorporated into a formula, termed the VISindex, which was compared with the traditional maxVIS. RESULTS: The VISindex demonstrated improved sensitivity for predicting prolonged mechanical ventilation (VISindex: area under the curve [AUC], 0.85; 95% confidence interval [CI], 0.79 to 0.90; maxVIS: AUC, 0.80; 95% CI, 0.75 to 0.86) and intensive care unit length of stay (VISindex: AUC, 0.84; 95% CI, 0.79 to 0.89; maxVIS: AUC, 0.77; 95% CI, 0.71 to 0.83) after cardiac operations in infants. CONCLUSIONS: Incorporating magnitude and duration of postoperative vasopressor support into the VIS improves its sensitivity for predicting poor outcome.