In all cells examined, specific endoplasmic reticulum (ER) membrane arrays are induced in response to increased levels of the ER membrane protein 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase. In yeast, expression of Hmg1p, one of two yeast HMG-CoA reductase isozymes, induces assembly of nuclear-associated ER stacks called karmellae. Understanding the features of HMG-CoA reductase that signal karmellae biogenesis would provide useful insights into the regulation of membrane biogenesis. The HMG-CoA reductase protein consists of two domains, a multitopic membrane domain and a cytosolic catalytic domain. Previous studies had indicated that the HMG-CoA reductase membrane domain was exclusively responsible for generation of ER membrane proliferations. Surprisingly, we discovered that this conclusion was incorrect: sequences at the carboxyl terminus of HMG-CoA reductase can profoundly affect karmellae biogenesis. Specifically, truncations of Hmg1p that removed or shortened the carboxyl terminus were unable to induce karmellae assembly. This result indicated that the membrane domain of Hmg1p was not sufficient to signal for karmellae assembly. Using β-galactosidase fusions, we demonstrated that the carboxyl terminus was unlikely to simply serve as an oligomerization domain. Our working hypothesis is that a truncated or misfolded cytosolic domain prevents proper signaling for karmellae by interfering with the required tertiary structure of the membrane domain.

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Introduction: The 7 + 3 regimen, consisting of cytarabine treatment continuously for 7 days, and short infusions of an anthracycline on each of the first 3 days, has been the mainstay for adult acute myeloid leukemia (AML) therapy. However, in older adults and patients with secondary AML, 7+3 is associated with lower remission rates, shorter overall survival, and higher relapse rates than in younger adults and older patients with de novo AML (Kayser et al, Blood 117:2137-2145, 2011; Schoch et al, Leukemia 18: 120-125, 2004). CPX-351 (VYXEOS®) CPX-351 was approved by the FDA in the US in August 2017 and EU in August 2018 for the treatment of adults with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC). It is a fixed combination of daunorubicin and cytarabine at a synergistic 1:5 molar ratio, encapsulated in a liposome to provide optimal delivery of the two drugs. The Phase III pivotal trial demonstrated that CPX-351 significantly improved overall survival (OS; 9.56 vs 5.95 months; hazard ratio [HR] = 0.69; 1-sided P = 0.003) and complete remission rates versus 7+3, and was associated with shorter per patient year (PPY) hospital length of stay (LOS) without an increase in PPY non-drug costs (Chung, et al. AMCP HCRU Abstract JOV-62933; 2018). This study characterized the patients treated with CPX-351 and 7+3 and compared healthcare utilization and costs associated with the treatments using a large U.S.-based hospital administrative database. Methods: A retrospective, observational study was conducted using data from the Premier Healthcare Database. The study included patients aged 18+ years with any inpatient hospitalization or hospital-based outpatient visit with a diagnosis of AML, who received treatment of 7+3 or CPX-351 between 8/1/2017 and 2/28/2019. Variable-length follow-up was used. Patients were excluded if their length of follow-up was shorter than 30 days, or they had received treatment with gemtuzumab, midostaurin, sorafenib, venetoclax, quizartinib, or gilteritinib. Patients were assigned into two cohorts: 1) patients treated with CPX-351; 2) 7+3 treated patients with newly diagnosed t-AML or AML-MRC who were never treated with CPX-351 (CPX-351 eligible 7+3). Outcomes included total inpatient LOS, total costs, drug and non-drug costs. The outcomes were converted to per patient year (PPY) values, which was the original value divided by the length of follow-up and multiplied by 365. Unadjusted descriptive statistics were reported, and bivariate analysis was performed using Wilcoxon rank sum tests to examine the difference in outcomes between 7+3 treated patients and those treated with CPX-351. Results: The study included 195 qualifying patients treated with CPX-351, and 160 CPX-351 eligible 7+3 patients. The median age was 68 years (Q1-Q3: 61-71) in the CPX-351 patients and 61 years (Q1-Q3: 52.5-69) in CPX-351 eligible 7+3 patients. Male patients accounted for 62.6% of the CPX-351 patients and 55.0% of the CPX-351 eligible 7+3 patients. Among the CPX-351 patients, 72.3% were White, while the proportion of White is 75.0% in CPX-351 eligible patients. The median length of follow up was 136 days (Q1-Q3: 68-232) in the CPX-351 patients, and 126 days (Q1-Q3: 54.5-241.5) in the CPX-351 eligible 7+3 patients. The median total inpatient LOS per patient year (PPY) was shorter in CPX-351 patients compared to the CPX-351 eligible 7+3 patients (nominal p=0.068, Table). Although the median total hospital cost PPY of the CPX-351 patients was higher (nominal p<0.001), the non-drug medical cost PPY was not higher than the CPX-351 eligible 7+3 patients (nominal p=0.785, Table). Conclusions: In this inferential analysis, patients treated with CPX-351 appeared to be older than those treated with 7+3. CPX-351 treated patients spent fewer days as inpatients, and the non-drug medical cost incurred was not higher compared to the 7+3 patients eligible for CPX-351, although the drug costs for the CPX-351 treated patients were higher than the 7+3 treated patients. Further adjusted analysis is warranted to control for the differences in baseline characteristics such as age, clinical conditions, and other characteristics in this real-world data. Disclosures Price: Jazz Pharmaceuticals: Employment, Equity Ownership. Cao:Jazz Pharmaceuticals: Other: Zhun Cao is an employee of Premier Inc, which receives payments from Jazz Pharmaceuticals for this research project.; Premier Inc.: Employment, Other: Premier received funding from Jazz Parmaceuticals to perform the study and analysis. Lipkin:Jazz Pharmaceuticals: Other: Craig Lipkin is an employee of Premier Inc, which receives payments from Jazz Pharmaceuticals for this research project.; Premier Inc: Employment. Robinson:Premier Inc.: Employment, Other: Premier received funding from Jazz Pharmaceuticals to perform the study and analysis; Jazz Pharmaceuticals: Other: Scott Robinson is an employee of Premier Inc, which receives payments from Jazz Pharmaceuticals for this research project.. Profant:Jazz Pharmaceuticals: Employment, Equity Ownership.

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