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Background We previously discovered high expression of the disialoganglioside GD2 on H3K27M+ gliomas and demonstrated preclinical efficacy of intravenous (IV) GD2-targeted chimeric antigen receptor (CAR) T-cells in preclinical models of H3K27M-mutated diffuse intrinsic pontine glioma (DIPG) and diffuse midline gliomas (DMGs). We are now conducting a Phase I clinical trial (NCT04196413) of autologous GD2-targeting CAR T-cells for H3K27M+ DIPG and spinal cord DMG. Here we present the results of subjects treated at dose level 1 (DL1; 1 million GD2-CAR T-cells/kg IV). Methods Four patients (3 DIPG, 1 spinal DMG; ages 4–25; 1M/3F) were enrolled at DL1. Three subjects with H3K27M+ DIPG received 1e6 GD2-CAR T-cells/kg IV on study. One patient with spinal DMG enrolled but became ineligible after manufacturing and was treated on an eIND at DL1. An Ommaya reservoir was placed in all subjects for therapeutic monitoring of intracranial pressure. Subjects underwent lymphodepletion with fludarabine/cyclophosphamide and remained inpatient for at least two weeks post-infusion. Results All subjects developed cytokine release syndrome (Grade 1–3) manifested by fever, tachycardia and hypotension. Other toxicities included ICANS (Grade 1–2) and neurological symptoms/signs mediated by intratumoral inflammation which we have termed Tumor Inflammation-Associated Neurotoxicity (TIAN). No evidence of on-target, off-tumor toxicity was observed in any patients. No dose-limiting toxicities occurred. CAR T cells trafficked to the CNS and were detected in CSF and blood. 3/4 patients exhibited marked improvement or resolution of neurological deficits and radiographic improvement. The patient treated on an eIND exhibited >90% reduction in spinal DMG volume but progressed by month 3. Re-treatment of this subject via intracerebroventricular administration resulted in a second reduction in spinal DMG volume by ~80%. Conclusions GD2-CAR T-cells at DL1 demonstrate a tolerable safety profile in patients with H3K27M+ DIPG/DMG with clear signs of T-cell expansion and activity including clinical responses.

Purpose To evaluate the feasibility of implementing systematic patient symptom monitoring during treatment using a smartphone. Methods Endometrial [n = 50], ovarian [n = 70] and breast [n = 193] cancer patients participated in text-based symptom reporting for up to 12 months. In order to promote equity, patients without a smartphone were provided with a device, with the phone charges paid by program funds. Each month, patients completed the Patient Health Questionnaire (PHQ-9), and 4 single items assessing fatigue, sleep quality, pain, and global quality of life during the past 7 days rated on a 0 (low) –10 (high) scale. Patients’ responses were captured using REDCap, with oncologists receiving monthly feedback. Lay navigators provided assistance to patients with non-medical needs. Results Patients utilizing this voluntary program had an overall mean age of 60.5 (range 26–87), and 85% were non-Hispanic white. iPhones were provided to 42 patients, and navigation services were used by 69 patients. Average adherence with monthly surveys ranged between 75–77%, with breast patients having lower adherence after 5 months. The most commonly reported symptoms across cancer types were moderate levels (scores of 4–7) of fatigue and sleep disturbance. At 6 months, 71–77% of all patients believed the surveys were useful to them and their health care team. Conclusions We established the feasibility of initiating and managing patients in a monthly text-based symptom-monitoring program. The provision of smartphones and patient navigation were unique and vital components of this program.

Background: Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal central nervous system tumors. We previously discovered that the disialoganglioside GD2 is highly and homogenously expressed on H3K27M+ gliomas and demonstrated that GD2 CAR T cells are effective in preclinical models (Mount/Majzner et al., Nat Med, 2018). Methods: Four subjects (3 DIPG, 1 spinal cord DMG; 4-25 yr; 1M/3F) were enrolled at DL1. Three subjects with H3K27M+ DIPG received 1e6 autologous GD2 CAR T cells/kg intravenously (IV) on study. One patient, a 25 y/o with spinal cord DMG, developed rapidly progressive disease after enrollment, resulting in complete paraparesis that led to removal from the study prior to cell infusion; she was treated on a single patient eIND with the same treatment regimen as DL1. We utilized a retroviral vector expressing a 14g2a.4-1BB.z CAR construct and an inducible iCasp9 safety switch. Manufacturing was performed in the Miltenyi Prodigy on CD4/CD8 enriched apheresis product. CAR T cells were cultured in the presence of dasatinib to improve T cell fitness (Weber et al., Science, 2021). An Ommaya reservoir was placed in all patients for monitoring of intracranial pressure (ICP). Results: We generated GD2 CAR T cell products meeting release criteria for all four patients. All subjects received lymphodepletion with cyclophosphamide and fludarabine and remained inpatient for 14+ days after infusion. All patients developed cytokine release syndrome (Grade 1-3) manifested by fever, tachycardia and hypotension, beginning 6-7 days after infusion. Due to concern for tumoral edema and increased ICP, patients were managed with conservative fluid resuscitation, and early intervention with tocilizumab and anakinra +/- corticosteroids. Other toxicities included ICANS (Grade 1-2) and neurotoxicity mediated by inflammation in sites of disease which we have termed Tumor Inflammation-Associated Neurotoxicity (TIAN). TIAN most often manifested as worsening of existing deficits, but one patient developed symptoms of increased ICP which quickly resolved upon removal of CSF via the Ommaya. No evidence of on-target, off-tumor toxicity was observed in any patients. No dose-limiting toxicities occurred.CAR T cells trafficked to the CNS and were detected in both the CSF and peripheral blood. Inflammatory cytokines including IL-6 were elevated in the CSF and blood. 3/4 patients exhibited marked improvement or resolution of neurological deficits and some radiographic improvement. The patient treated on a single patient eIND exhibited a >90% reduction in her spinal cord DMG tumor volume at two months post-infusion. Durability of the therapeutic benefit remains to be determined. Conclusions: This is the first report of GD2 CAR T cell therapy for DIPG and spinal cord DMG. Toxicities are similar to other CAR T cells with additional, manageable complications due to inflammation at CNS sites of tumor. Treatment at DL1 demonstrated a tolerable safety profile and clear signs of T cell expansion and activity including clinical responses. This approach has the potential to transform therapy for patients with H3K27M+ DIPG/DMG. Further correlative studies, including single-cell RNAseq, longer-term outcomes and results from patients on subsequent dose levels will also be presented. Citation Format: Robbie G. Majzner, Sneha Ramakrishna, Aaron Mochizuki, Shabnum Patel, Harshini Chinnasamy, Kristen Yeom, Liora Schultz, Rebecca Richards, Cynthia Campen, Agnes Reschke, Jasia Mahdi, Angus Martin Shaw Toland, Christina Baggott, Sharon Mavroukakis, Emily Egeler, Jennifer Moon, Kayla Landrum, Courtney Erickson, Lindsey Rasmussen, Valentin Barsan, John S. Tamaresis, Anne Cunniffe Marcy, Michael Kunicki, Michelle Fujimoto, Zach Ehlinger, Sreevidya Kurra, Timothy Cornell, Sonia Partap, Paul Fisher, Gerald Grant, Hannes Vogel, Bita Sahaf, Kara Davis, Steven Feldman, Crystal L. Mackall, Michelle Monje. GD2 CAR T cells mediate clinical activity and manageable toxicity in children and young adults with DIPG and H3K27M-mutated diffuse midline gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT031.

Introduction We are conducting a Phase I clinical trial utilizing chimeric antigen receptor (CAR) T-cells targeting GD2 (NCT04196413) for H3K27M-mutant diffuse intrinsic pontine glioma (DIPG) and spinal cord diffuse midline glioma (DMG). Cerebrospinal fluid (CSF) is collected for correlative studies at the time of routine intracranial pressure monitoring via Ommaya catheter. Here we present single cell RNA-sequencing results from the first 3 subjects. Methods Single cell RNA-sequencing was performed utilizing 10X Genomics on cells isolated from CSF at various time points before and after CAR T-cell administration and on the CAR T-cell product. Output was aligned with Cell Ranger and analyzed in R. Results As detailed in the Majzner et al. abstract presented at this meeting, three of four subjects treated at dose-level one exhibited clear radiographic and/or clinical benefit. We have to date completed single cell RNA-sequencing for three of these four subjects (two with benefit, one without). After filtering out low-quality signals and doublets, 89,604 cells across 3 subjects were analyzed. Of these, 4,122 cells represent cells isolated from CSF and 85,482 cells represent CAR T-cell product. Two subjects who demonstrated clear clinical and radiographic improvement exhibited fewer S100A8+S100A9+ myeloid suppressor-cells and CD25+FOXP3+ regulatory T-cells in the CSF pre-infusion compared to the subject who did not derive a therapeutic response. In one subject with DIPG who demonstrated improvement, polyclonal CAR T-cells detectable in CSF at Day +14 demonstrated enrichment of CD8A, GZMA, GNLY and PDCD1 compared to the pre-infusion CAR T-cells by trajectory analysis, suggesting differentiation toward a cytotoxic phenotype; the same subject exhibited increasing numbers of S100A8+S100A9+ myeloid cells and CX3CR1+P2RY12+ microglia over time. Further analyses will be presented as data become available. Conclusions The presence of immunosuppressive myeloid populations, detectable in CSF, may correlate to clinical response in CAR T cell therapy for DIPG/DMG.

255 Background: With advances in technology, smartphones are being used for multiple research and clinical care functions. However, not all patients have these devices, leading to disparities in participation. We report on a quality improvement program that provided smartphones to patients without these devices. Methods: Gynecologic (n = 120) and breast (n = 193) cancer patients under active treatment were enrolled in a 12-month text-based symptom monitoring program to facilitate communication and optimize patient management. Patients without a smartphone were provided with an iPhone through a partnership with a U.S. wireless company. The company provided smartphone devices at zero cost, and program funds paid for 12 months of phone service. Program staff helped patients set up the iPhones, and provided basic education and ongoing phone support. After 12 months, patients were able to keep their iPhones, but had to secure their own phone plan for calling and texting functions. Results: iPhones were provided to 42 (13.4%) patients across all cancer types. Patients who received iPhones, compared with those who had a smartphone, had incomes below $50,000/year (p = 0.03) and an educational level of < high school (p < 0.0001). Program staff had few difficulties training patients to operate the phones or in patients’ adherence to symptom monitoring after receiving the iPhones. Phone service charges averaged $40 per month or $500 per person for 12 months. Greater than 90% of patients believed the phones enabled them to better communicate with their health care team and family/support networks, and 95% believed the phones had a positive impact on their life. However, only 70% planned on getting a phone service plan at the end of the 12 months, due to cost or believing a smartphone was not a necessity. Conclusions: Providing smartphones to patients enabled them to better communicate with their health care team and families, and participate in remote symptom monitoring during active treatment. Programs such as these are needed to reduce disparities in patient care, and support quality improvement efforts using electronic devices.

e19173 Background: Unreported symptoms during cancer treatment can lead to poorer patient care and quality of life. eHealth technologies enable effective means to track patients’ health in real time to provide assistance in meeting patients’ needs and facilitating symptom management. Methods: Gynecologic (endometrial and ovarian) and breast oncology patients were enrolled in a quality improvement program post-surgically to respond to 12-monthly, text-based symptom surveys assessing fatigue, sleep quality, pain, and depression (PHQ-9). At baseline, 6 and 12 months, patients also completed the PROMIS-10 to assess their physical and mental health functioning. All patient responses were captured in REDCap and monitored by program staff, with patients’ oncologists receiving monthly feedback for patient follow-up. Patient navigators were also engaged for patients needing assistance with non-medical concerns. We provide the interim results of this program on PROMIS-10 scores from baseline to 6 months. Results: 198 breast and 120 gynecologic oncology patients (ovarian [n = 70] and endometrial [n = 50]) were enrolled. Multiple regression examined the impact of demographic (age, race, education), clinical (stage, chemotherapy, radiation), and monitoring program variables (# of monthly surveys completed, navigation services [yes/no]) on PROMIS-10 physical and mental health subscale scores at 6 months, adjusting for baseline PROMIS scores. For the breast patients, the only significant predictor of worse PROMIS physical health scores was a cancer stage of 4 vs 1 (p = 0.049), whereas a higher number of symptom surveys completed was associated with worse mental health functioning (p = 0.033). For the gynecologic oncology patients, worse PROMIS physical health scores were only associated with higher age (p = 0.037), but higher PROMIS mental health was also associated with higher age (p = 0.029) and borderline significantly associated with not using navigation services (p = 0.07). Conclusions: These results indicate that greater adherence in completing monthly symptom surveys and using navigation services were more likely to be associated with patients reporting lower mental health. PROMIS physical health scores, however, were not significantly associated with adherence to monthly surveys or navigation services. These interim results suggest that monitoring programs, such as this, may assist in identifying and treating patients with lower mental health functioning during treatment.

OBJECTIVES Current osteoarthritis therapies aim to alleviate pain and maintain joint function. Non-prescription oral non-steroidal anti-inflammatory drugs are frequently used alone for pain relief in osteoarthritis. This post-hoc pooled analysis evaluated the analgesic efficacy and safety of two non-prescription doses of naproxen sodium for short-term use in patients with osteoarthritis of the knee or hip. A separate sub-group analysis of older patients who were administered a lower dose of naproxen sodium was performed. METHODS In four multi-center, multi-dose, randomized, parallel, double-blind, placebo-controlled studies, oral naproxen sodium (age-based dosing regimen

More than 25 years of clinical trial data have established statins as first-line therapy for the prevention and treatment of atherosclerotic cardiovascular disease. With regard to low-density lipoprotein cholesterol, a wealth of evidence indicates that ‘lower is better,’ although recent guidelines from the American College of Cardiology and the American Heart Association take a different approach. A variety of approved and experimental lipid-lowering agents may be used as supplements or alternatives to statin therapy in patient subgroups, including those with familial hypercholesterolemia, mixed dyslipidemia or statin intolerance. Strategies to achieve further reductions in low-density lipoprotein cholesterol, target high-density lipoprotein cholesterol and triglycerides or reduce inflammation may help address residual cardiovascular risk, although early lifestyle interventions are crucial to prevention strategies.

Increasing student body diversity is a priority for national health education and professional organizations and for many medical schools. However, national rankings of medical schools, such as those published by U.S. NewsWorld Report, place a heavy emphasis on grade point average (GPA) and Medical College Admissions Test (MCAT) scores, without considering student body diversity. These rankings affect organizational reputation and admissions outcomes, even though there is considerable controversy surrounding the predictive value of GPA and MCAT scores.Our aim in this article was to explore the relationship between standard admissions practices, which typically aim to attract students with the highest academic scores, and student body diversity. We examined how changes in GPA and MCAT scores over 5 years correlated with the percentage of enrolled students who are underrepresented in medicine. In a majority of medical schools in the United States from 2005 to 2009, average GPA and MCAT scores of applicants increased, whereas the percentage of enrolled students who are underrepresented in medicine decreased.Our findings suggest that efforts to increase the diversity of medical school student bodies may be complicated by a desire to maintain high average GPA and MCAT scores. We propose that U.S. News revise its ranking methodology by incorporating a new diversity score into its student selectivity score and by reducing the weight placed on GPA and MCAT scores.

Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor that has previously been shown to reduce low-density lipoprotein cholesterol (LDL-C) and raise high-density lipoprotein cholesterol (HDL-C) in patients with or at high risk of coronary heart disease in the 76-week, placebo-controlled, Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib (DEFINE) trial. Here, we report the results of the 2-year extension to the DEFINE study where patients (n = 803) continued on the same assigned treatment as in the original 76-week study. Treatment with anacetrapib during the 2-year extension was well tolerated with a safety profile similar to patients on placebo. No clinically important abnormalities in liver enzymes, blood pressure, electrolytes, or adverse experiences were observed during the extension. At the end of the extension study, relative to the original baseline value, anacetrapib reduced Friedewald-calculated LDL-C by 39.9% and increased HDL-C by 153.3%, compared to placebo. The apparent steady state mean plasma trough concentration of anacetrapib was ∼640 nmol/L. Geometric mean plasma concentrations of anacetrapib did not appear to increase beyond week 40 of the 2-year extension of the 76-week DEFINE base study. In conclusion, an additional 2 years of treatment with anacetrapib were well tolerated with durable lipid-modifying effects on LDL-C and HDL-C.

e18299 Background: Unreported symptoms during cancer treatment can lead to poorer patient care and quality of life. Newer technology enables effective means to track patients’ health in real time. We evaluated the feasibility of implementing systematic patient symptom monitoring during the first 12 months after diagnosis. Methods: Newly diagnosed endometrial and ovarian cancer patients were enrolled post-surgically to respond to monthly text message symptom surveys. Patients’ fatigue, sleep quality, pain, and quality of life during the past 7 days were rated on a 0 (worst) -10 (best) scale, and depressive symptoms were assessed using the Patient Health Questionnaire (PHQ-9). Patients’ responses were captured in REDCap and monitored by program staff, with patients’ oncologists receiving monthly feedback. Patient navigators were also engaged for patients needing assistance during treatment. We provide the results of the first 6 months of this program. Results: 134 patients were approached, and 120 patients (ovarian [n = 70] and endometrial [n = 50]) were enrolled among 5 physicians. The mean participant age was 63 (range: 35-87), 85% were non-Hispanic White, and 66% had education beyond high school. The most commonly reported monthly symptoms for both cancer types were moderate levels (scores of ≥ 4-7) of fatigue and sleep disturbance. 35 patients with PHQ-9 scores ≥ 10 and/or with suicidal ideation were reported to their oncologists for appropriate follow-up. At the 6 month survey, patients were asked to evaluate the text messaging program: 97% found the symptom surveys easy to complete on their smart phone or computer; 77% believed reporting their symptoms monthly was useful all or most of the time; 78% liked being monitored for symptoms all or most of the time; and 89% liked being asked if they needed any assistance prior to their next clinic visit. Patient navigators were used by 13 patients, and 17 patients dropped from the program over the 6 months due to death (n = 9) or lack of need/interest (n = 8). Average monthly compliance was 81%. Conclusions: We established the feasibility of enrolling patients in a monthly text-based monitoring program to facilitate symptom management during treatment. Patient follow-up is continuing.

Results from multiple clinical trials, primarily with the class of lipid-lowering agents known as statins, have shown that reductions in low-density lipoprotein (LDL) cholesterol are associated with reduced risk of coronary artery disease. Although LDL cholesterol is the primary target of cholesterol management strategies, increasing attention has focused on the role of inflammation, high-density lipoprotein cholesterol, and triglycerides in atherosclerosis and cardiovascular disease. We review major trials with lipid-modifying therapies published since the 2004 update of the Adult Treatment Panel (ATP) III guidelines. A pivotal trial was the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), which demonstrated significant reductions in cardiovascular morbidity and mortality in healthy individuals without elevated LDL cholesterol but with high levels of the inflammatory marker high-sensitivity C-reactive protein. Additional trials demonstrated the efficacy of intensive statin therapy in secondary prevention, whereas other agents, including fibrates, omega-3 fatty acids, niacin, ezetimibe, and experimental cholesteryl ester transfer protein inhibitors, have been evaluated for their ability to reduce residual cardiovascular risk.

Strategies to reduce cardiovascular risk in primary and secondary prevention focus on optimization of low-density lipoprotein (LDL) cholesterol levels. Since the 2004 update of the Adult Treatment Panel (ATP) III guidelines, developments in the field of preventive cardiology have included new guidelines for women and for familial hypercholesterolemia; a risk assessment algorithm incorporating the inflammatory marker high-sensitivity C-reactive protein (hsCRP); and clinical trial data confirming the efficacy of aggressive lipid management. Within secondary prevention in particular, there is a need for more widespread use of intensive statin therapy to achieve low LDL cholesterol levels to reduce cardiovascular morbidity and mortality in patients at high risk for recurrent events. Within primary prevention, individuals with diabetes mellitus, mixed dyslipidemia, or elevated hsCRP also are at increased risk and may warrant treatment with aggressive lipid-modifying therapy. In this article, we provide an update on recent guidelines, risk algorithms, and trials related to the prevention and treatment of coronary artery disease.

Pitavastatin is a new, synthetic member of the statin class of lipid-lowering drugs. Compared with other available statins, it has a unique cyclopropyl group on its base structure that is believed to increase 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition by a factor of five and to significantly increase the transcription and activity of LDL receptors. Pitavastatin is primarily metabolized via glucuronidation and is not a substrate for the cytochrome P450 3A4 enzyme, thus avoiding the potential for cytochrome P450-mediated drug-drug interactions. Clinical trials have shown that pitavastatin is comparable to atorvastatin and simvastatin in improving lipid measures, and more potent than pravastatin. Pitavastatin is effective in reducing triglycerides and increasing HDL-cholesterol, so it will be particularly beneficial in treating patients with mixed dyslipidemia. Its safety and adverse event profile is similar to that of other available statins, and it has an established history of use in Asia indicating tolerability and safety for treatment lasting up to 7 years.

e12523Background: Despite the proven clinical efficacy of adjuvant hormone therapy (AHT) for breast cancer survivors, evidence suggests that up to 50% of patients do not complete treatment as recom...

Statins are the mainstay of therapy for the management of dyslipidemia, and particularly elevations in low-density lipoprotein cholesterol (LDL-C). Currently available statins include atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. The advent of statin therapy has contributed to a substantial decrease in cardiovascular mortality over the past several decades. Results from multiple clinical trials have shown conclusively that lowering LDL-C levels leads to clinical event reduction in primary and secondary prevention, for both men and women, and across various other patient subgroups. Extensive clinical experience indicates that statin therapy may be initiated and maintained over the long term with a high degree of safety, and adverse effects associated with statin use are outweighed by their proven benefits in clinical event reduction.

Aim We aim to evaluate the efficacy and safety of determining the presence of true biventricular pacing by administration of intravenous adenosine. This aims to determine whether non-response to biventricular pacing therapy is partially explained by over-counting of the percentage of pacing therapy by the presence of fusion beats. We compared the proportion of patients with fusion beats in non-responders compared to responders Methods This will be a single centre, prospective, cohort study. 71 consecutive patients with implanted cardiac resynchronisation devices between July 2006 and November 2015 were identified. Patients underwent the adenosine trial at least 12 months post CRT device implantation to detect the presence of potentially ineffective biventricular pacing. This was compared with the recorded percentage of biventricular pacing reported during device interrogation. Correlation was made between response to CRT therapy and presence of effective biventricular pacing. Results Preliminary results from 24 patients demonstrate that symptomatic adenosine administration was successful in identifying true effective biventricular paced beats. This has allowed us to identify patients with fusion beats. 8 patients were non-responders to CRT, whereas 16 patients were responders. 50% (n=4) of non-responders and 12.5% (n=2) of responders had definite electrocardiography (ECG) changes through the symptomatic adenosine administration, showing that a percentage of the paced beats counted by the CRT device may in fact be fusion beats. Figure 1 shows the clear change in the morphology of the QRS complex in one of the non-responders. Figure 1 Electrocardiogram of a non-responder during symptomatic adenosine administration Conclusion Preliminary results suggest that symptomatic adenosine administration is successful in identifying true effective biventricular paced beats which may be overestimated by CRT device interrogation. Correlation with response to CRT is yet to be established, but in 50% of the non-responders we identified a definite change in the morphology of the paced rhythm during the symptomatic response to adenosine. This raises a question of whether the poor response to CRT for these patients is actually due to the insufficient percentage of effective biventricular pacing (

The widespread clinical use of statins has contributed to significant reductions in the rate of cardiovascular morbidity and mortality over the past 3 decades, and statins are considered first-line therapy for the prevention and treatment of atherosclerotic vascular disease. Nevertheless, various other lipid-lowering agents can provide clinical benefit by supplementing or augmenting statin therapy in patients with severe hypercholesterolaemia or mixed dyslipidaemia, or by providing an alternative for patients who are intolerant to statins. Bile acid resins and niacin were prescribed for lipid modification for years before the introduction of the statins, and new data continue to emerge regarding their use in different patient groups and for specific conditions. Ezetimibe can be appropriate for patients whose primary lipid abnormality is an elevated LDL-cholesterol level, whereas the fibrates seem to be most beneficial in patients with low levels of HDL cholesterol and elevated triglycerides. At the end of 2012 and the beginning of 2013, the first microsomal triglyceride transfer protein inhibitor, lomitapide, and the first antisense therapy to target apolipoprotein B, mipomersen, were approved for the treatment of individuals with extremely elevated LDL-cholesterol levels caused by homozygous familial hypercholesterolaemia. Although two agents in the experimental class of cholesteryl ester transfer protein inhibitors have failed to show a benefit in clinical trials, newer drugs in this class could provide an additional strategy to address residual cardiovascular risk in patients treated with statins.

The aim of this study was to assess the effects on lipids and safety during a 12-week reversal period after 18 months of treatment with anacetrapib. The cholesteryl ester transfer protein inhibitor anacetrapib was previously shown to reduce low-density lipoprotein cholesterol by 39.8% (estimated using the Friedewald equation) and increase high-density lipoprotein (HDL) cholesterol by 138.1%, with an acceptable side-effect profile, in patients with or at high risk for coronary heart disease in the Determining the Efficacy and Tolerability of CETP Inhibition With Anacetrapib (DEFINE) trial. A total of 1,398 patients entered the 12-week reversal-phase study, either after completion of the active-treatment phase or after early discontinuation of the study medication. In patients allocated to anacetrapib, placebo-adjusted mean percentage decreases from baseline were observed at 12 weeks off the study drug for Friedewald-calculated low-density lipoprotein cholesterol (18.6%), non-HDL cholesterol (17.6%), and apolipoprotein B (10.2%); placebo-adjusted mean percentage increases were observed for HDL cholesterol (73.0%) and apolipoprotein A-I (24.5%). Residual plasma anacetrapib levels (about 40% of on-treatment apparent steady-state trough levels) were also detected 12 weeks after cessation of anacetrapib. No clinically important elevations in liver enzymes, blood pressure, electrolytes, or adverse experiences were observed during the reversal phase. Preliminary data from a small cohort (n = 30) revealed the presence of low concentrations of anacetrapib in plasma 2.5 to 4 years after the last anacetrapib dose. In conclusion, after the cessation of active treatment, anacetrapib plasma lipid changes and drug levels decreased to approximately 40% of on-treatment trough levels at 12 weeks after dosing, but modest HDL cholesterol elevations and low drug concentrations were still detectable 2 to 4 years after the last dosing.

Anacetrapib is a cholesteryl ester transfer protein inhibitor that has previously been shown to be well tolerated, reduce low-density lipoprotein cholesterol (LDL-C) and raise high-density lipoprotein cholesterol (HDL-C) in patients with or at high risk for coronary heart disease in the DEFINE base