BLOOD-BASED BIOMARKER CHANGES IN A PHASE 2B TRIAL ASSESSING LOMECEL-B IN OLDER ADULTS WITH FRAILTY

Aging frailty (AF) is a multidimensional geriatric syndrome that is characterized by physical and cognitive symptoms, increasing the vulnerability of affected older adults to adverse health outcomes. Mechanistically, a low-grade chronic inflammatory state (inflammaging), endothelial dysfunction, and decreased regenerative capacity are thought to be major contributors to AF pathophysiology. Lomecel-B is an allogenic medicinal signaling cell(MSC) formulation that can potentially ameliorate AF through pleiotropic mechanisms, including anti-inflammatory, pro-vascular, and pro-regenerative activities. We completed a Phase 2b randomized, double-blinded, placebo-controlled trial designed to assess Lomecel-B benefits for AF via change versus placebo in the six-minute walk test(6MWT), to assess the dose-response relationship, and to evaluate bioactivity via changes in blood-based biomarkers. Enrolled subjects were aged 70–85 years with mild-to-moderate AF, a reduced 6MWT of 200-400m, and Tumor Necrosis Factor-α of ≥ 2.5pg/mL indicative of inflammaging. In total, 143 subjects received a single intravenous infusion of Lomecel-B at doses of 2.5 x 107 cells (25M, N=35), 5.0 x 107 cells (50M, N=30), 1.0 x 108 cells (100M, N=33), or 2.0 x 108 cells (200M, N=16), or placebo (N=29). Safety and efficacy assessments were performed at 1, 3, 6, and 9 months post-infusion. Increases in 6MWT and decreases in serum levels of the blood-based biomarker Soluble-Tie-2 were observed at 9 months in the Lomecel-B groups versus placebo. Notably, both observations were seen in a dose dependent fashion with 200M showing the highest effect. Based on the findings, a next-phase trial is being developed to advance this clinical program and will be presented

Arsenic exposure and risk of nonalcoholic fatty liver disease (NAFLD) among U.S. adolescents and adults: an association modified by race/ethnicity, NHANES 2005–2014

Abstract Background While associated with obesity, the cause of the rapid rise in prevalence of nonalcoholic fatty liver disease (NAFLD) in children, which is highest among Hispanics, is not well understood. Animal experiments have demonstrated that arsenic exposure contributes to liver injury. Our objective was to examine the association between arsenic exposure and NAFLD in humans and to determine if race/ethnicity modifies the association. Methods Urinary inorganic arsenic concentrations among those ≥12 years in the National Health and Nutrition Examination Survey, 2005–2014 were used to assess the cross-sectional association with serum alanine aminotransferase (ALT) levels, a marker of liver dysfunction. We excluded high alcohol consumers (>4–5 drinks/day; n = 939), positive hepatitis B or C (n = 2330), those missing body mass index (n = 100) and pregnant women (n = 629) for a final sample of 8518. Arsenic was measured using liquid chromatography coupled with mass spectrometry and ALT was measured using standard methods. Sampling weights were used to obtain national estimates. Due to lack of normality, estimates were log transformed and are presented as geometric means. Logistic regression models controlling for age, sex, income, and weight category estimate adjusted odd ratios (aOR) of elevated ALT by quartile of arsenic and tested for effect modification by race/ethnicity and weight. Elevated ALT was defined as >25 IU/L and >22 IU/L for boys and girls ≤17 years, respectively and >30 IU/L and >19 IU/L for men and women, respectively. Results Among all, aOR of elevated ALT were higher among those in the highest vs. lowest arsenic quartile (referent), 1.4 (95% confidence interval [CI]: 1.1, 1.7) with a borderline significant interaction (p = 0.07) by race/ethnicity but not weight (p = 0.4). In analysis stratified by race/ethnicity, aOR of elevated ALT among those in the 4th quartile were higher among Mexican Americans, 2.0 (CI: 1.3, 3.1) and non-Hispanic whites only, aOR 1.4 (CI: 1.1, 1.8) despite the fact that obesity prevalence was highest among non-Hispanic blacks. Conclusions Our findings demonstrate a positive association between urinary arsenic exposure and risk of NAFLD among U.S. adolescents and adults that is highest among Mexican Americans and among those obese, regardless of race/ethnicity

Abstract 17067: Long-Term Transplant-Free Survival is Improved in Hypoplastic Left Heart Syndrome With Cell-Based Therapy

Abstract only Hypoplastic left heart syndrome (HLHS) is a univentricular congenital heart defect that has high morbidity and mortality and requires three-stage surgical reconstruction so that the right ventricle (RV) delivers systemic circulation. Poor outcomes result from RV failure in the systemic position. Accordingly, we conducted a phase I clinical trial (called ELPIS) of Lomecel-B™, an allogeneic bone-marrow derived cell-based therapy designed to improve cardiovascular performance, delivered as a one-time treatment during the Stage II (Glenn) surgery at approximately 4 months after birth. This trial met its primary endpoint (safety through 1-year post-treatment). To assess whether Lomecel-B™ has survival benefits, all ELPIS patients ( n=10, 7 males, and 3 females) were enrolled in a multi-year follow-on study and compared to a retrospective control group which was identified by a relevant clinical HLHS database. Patients in both studies were assessed for up to 5 years (range 3.5 - 5.0 years post-treatment for ELPIS) for mortality, heart transplants, and stage III (Fontan) surgery. Outcomes were compared with long-term historical data from patients in the Single Ventricle Reconstruction (SVR) Trial receiving the same shunt type at Stage I (Norwood) operation. 5-year Kaplan-Meier survival was 100% in ELPIS patients with none requiring heart transplant. This compared to 81.6% (95% CI= [76.5, 87.0]) transplant-free survival in the SVR trial through 5 years post-Glenn surgery, and a 5.2% (95% CI= [2.0, 8.3]) heart transplantation rate (Figure 1). No stem cell related safety issues were reported. These findings support Lomecel-B™ as a potential adjunct to HLHS reconstruction surgery to improve clinical benefits and reduce the need for subsequent heart transplantation. Further long-term follow-up and controlled trials are both warranted and underway

Intramyocardial cell-based therapy with Lomecel-B during bidirectional cavopulmonary anastomosis for hypoplastic left heart syndrome: The ELPIS phase I trial

Abstract Background and Aims Hypoplastic left heart syndrome (HLHS) survival relies on surgical reconstruction for the right ventricle (RV) to provide systemic circulation. This substantially increases the RV load, wall stress, maladaptive remodeling, and dysfunction, which in turn increases the risk of death or transplantation. Methods We conducted a phase 1 open-label multicenter trial to assess the safety and feasibility of Lomecel-B as an adjunct to second stage HLHS surgical palliation. Lomecel-B, an investigational cell therapy consisting of allogeneic medicinal signaling cells (MSCs), was delivered via intramyocardial injections. The primary endpoint was safety, and measures of RV function for potential efficacy were obtained. Results Ten patients were treated. None experienced major adverse cardiac events (MACE). All were alive and transplant-free at 1-year post-treatment, and experienced growth comparable to healthy historical data. Cardiac magnetic resonance imaging (CMR) suggested improved tricuspid regurgitant fraction (TR RF) via qualitative rater assessment, and via significant quantitative improvements from baseline at 6 and 12 months post-treatment (p < 0.05). Global longitudinal strain (GLS) and RV ejection fraction (EF) showed no declines. To understand potential mechanisms of action, circulating exosomes from intramyocardially transplanted MSCs were examined. Computational modeling identified 54 MSC-specific exosome RNAs corresponding to changes in TR RF, including miR-215-3p, miR-374b-3p, and RNAs related to cell metabolism and MAPK signaling. Conclusions Intramyocardially-delivered Lomecel-B appears safe in HLHS patients and may favorably affect RV performance. Circulating exosomes of transplanted MSC-specific provide novel insight into bioactivity. Conduct of a controlled phase trial is warranted and is underway

Effectiveness of mRNA Vaccines Against COVID-19 Hospitalization by Age and Chronic Medical Conditions Burden Among Immunocompetent US Adults, March-August 2021

Vaccine effectiveness (VE) against COVID-19 hospitalization was evaluated among immunocompetent adults (≥18 years) during March-August 2021 using a case-control design. Among 1669 hospitalized COVID-19 cases (11% fully vaccinated) and 1950 RT-PCR-negative controls (54% fully vaccinated), VE was 96% (95% confidence interval [CI], 93%-98%) among patients with no chronic medical conditions and 83% (95% CI, 76%-88%) among patients with ≥ 3 categories of conditions. VE was similar between those aged 18-64 years versus ≥65 years (P > .05). VE against severe COVID-19 was very high among adults without chronic conditions and lessened with increasing comorbidity burden

Sustained Effectiveness of Pfizer-BioNTech and Moderna Vaccines Against COVID-19 Associated Hospitalizations Among Adults - United States, March-July 2021

What is already known about this topic? COVID-19 mRNA vaccines provide strong protection against severe COVID-19; however, the duration of protection is uncertain. What is added by this report? Among 1,129 patients who received 2 doses of a mRNA vaccine, no decline in vaccine effectiveness against COVID-19 hospitalization was observed over 24 weeks. Vaccine effectiveness was 86% 2-12 weeks after vaccination and 84% at 13-24 weeks. Vaccine effectiveness was sustained among groups at risk for severe COVID-19. What are the implications for public health practice? mRNA vaccine effectiveness against COVID-19-associated hospitalizations was sustained over 24 weeks; ongoing monitoring is needed as new SARS- CoV-2 variants emerge. To reduce hospitalization, all eligible persons should be offered COVID-19 vaccination

Protection of Messenger RNA Vaccines Against Hospitalized Coronavirus Disease 2019 in Adults Over the First Year Following Authorization in the United States.

BackgroundCoronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccines were authorized in the United States in December 2020. Although vaccine effectiveness (VE) against mild infection declines markedly after several months, limited understanding exists on the long-term durability of protection against COVID-19-associated hospitalization.MethodsCase-control analysis of adults (≥18 years) hospitalized at 21 hospitals in 18 states 11 March-15 December 2021, including COVID-19 case patients and reverse transcriptase-polymerase chain reaction-negative controls. We included adults who were unvaccinated or vaccinated with 2 doses of a mRNA vaccine before the date of illness onset. VE over time was assessed using logistic regression comparing odds of vaccination in cases versus controls, adjusting for confounders. Models included dichotomous time (&lt;180 vs ≥180 days since dose 2) and continuous time modeled using restricted cubic splines.ResultsA total of 10 078 patients were included, 4906 cases (23% vaccinated) and 5172 controls (62% vaccinated). Median age was 60 years (interquartile range, 46-70), 56% were non-Hispanic White, and 81% had ≥1 medical condition. Among immunocompetent adults, VE &lt;180 days was 90% (95% confidence interval [CI], 88-91) versus 82% (95% CI, 79-85) at ≥180 days (P &lt; .001). VE declined for Pfizer-BioNTech (88% to 79%, P &lt; .001) and Moderna (93% to 87%, P &lt; .001) products, for younger adults (18-64 years) (91% to 87%, P = .005), and for adults ≥65 years of age (87% to 78%, P &lt; .001). In models using restricted cubic splines, similar changes were observed.ConclusionsIn a period largely predating Omicron variant circulation, effectiveness of 2 mRNA doses against COVID-19-associated hospitalization was largely sustained through 9 months