Available Therapies for US Patients With R/R B-Cell Lymphoma – Targeted Oncology

Tycel Phillips, MD, associate professor, Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation, discusses treatment options for diffuse large B-cell lymphoma in the Unites States [US].

0:08 | At the current moment, if we look at patients with relapsed refractory diffuse large B cell lymphoma, which is the most common non-Hodgkin lymphoma in the US in that setting, we had several approved agents in the last several years. So, there was an oral medication lenalidomide [Revlimid] given together with an antibody called tafasitamab, and that is approved for patients [in] second-line or beyond, especially those in second-line who are unable to tolerate more traditional treatments. In that second-line space, we have historically had salvage chemotherapy, and the complications that we know come with that, followed by autologous stem cell transplantation. For a large number of patients, salvage chemo and autologous transplant was not a great option because these patients had intrinsic resistance to chemotherapy.

1:00 | More recently, we had the approval of 2 chimeric antigen receptor therapy treatments, or CAR T treatment. CAR T, as much as we advocate for it, is also available in the third-line is underutilized here in the US with only about a third of patients who are eligible for CAR T, or making it to CAR T. So, there's a large number of patients who cannot get to this treatment either because they do not live near a CAR T center or they don't want to travel to a CAR T center, or they can't keep their disease under control enough to get to CAR T.

1:29 | As of right now, CAR T is probably the only treatment that has durable responses in this patient population. So, with those other treatments that I didn't mention, there's probably a minority of those patients who will have a durable response. But the vast majority of those patients will likely relapse and die from the cancer, and if they can't get the CAR Tt that does leave a large number of patients who are at need, which prompts the need for more treatments in his patient population. Because even with CAR T, as much as I have advocated for have in this you know earlier in this conversation, about half of those patients, if not a little bit more, will fail to respond to CAR T or relapse after treatment with CAR T, and those patients have very poor outcomes as well.

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Available Therapies for US Patients With R/R B-Cell Lymphoma - Targeted Oncology

Immunology Center of Georgia recruits reflect expertise from … – Jagwire Augusta

Immune cells that can smell the metabolites of a high-fat Western diet and may produce inflammation and ultimately heart disease as a result, just what our longer RNAs are doing in our bodies and the role of immune cells called neutrophils in both cancer and heart disease are some areas of pursuit of the first five scientists recruited to the new Immunology Center of Georgia at the Medical College of Georgiaat Augusta University.

The new IMMCG, codirected by Georgia Research Alliance Eminent Scholars Catherine Lynn Hedrick, PhD, and Klaus Ley, MD, who joined the MCG at Augusta University faculty late last summer, focuses on better understanding the immune systems seemingly diametric roles in enabling good health and in contributing to major killers like cancer and heart disease.

The first recruits bring to MCG more immunological strength in major areas of research and clinical expertise of the medical school, says Hedrick.

Already onboard is Kunzhe Dong, PhD, a vascular immunologist with expertise in long noncoding RNA, literally long RNAs which regulate gene activity both up and down. He was first author on a 2022 study showing that a long noncoding RNA called CARMN is found in abundance in the healthy smooth muscle cells that give our blood vessels strength and flexibility and is significantly decreased in atherosclerosis. The finding provided more insight into how blood vessel disease happens as it pointed toward new ways to treat it. He also has studied autophagy, a fundamental the immune system uses to eliminate invading microorganisms and cell debris by ingesting them, and novel methods for protecting against destructive inflammation prompted by infection and by vascular disease.

Dong earned his PhD in animal genetics, breeding and reproduction from the Chinese Academy of Agricultural Sciences in Beijing, came to MCG in 2017 as a postdoctoral fellow studying with Vascular Biologist Jiliang Zhou, PhD, in the Department of Pharmacology and Toxicology, and was promoted to senior postdoctoral fellow in 2021. He received an American Heart Association Career Development Award in 2022, which runs through 2025, as well as an AHA Postdoctoral Fellowship during his training. Dong also received a 2022 travel grant for early career investigators from the AHA journal Arteriosclerosis, Thrombosis and Vascular Biology.

Marco Orecchioni, PhD, an immunologist and cellular biologist, who studied with Ley at the La Jolla Institute for Immunology in California, will be joining the IMMCG faculty May 1. The Italy native earned his PhD from the University of Sassari, before moving to La Jolla as a postdoctoral fellow in 2017. He was promoted to instructor in 2022.

Orecchionis work includes elucidating the role of olfactory (smell) receptors on macrophages, immune cells that can turn inflammation both up and down and can also consume cellular debris. He is working to better understand how these receptors, which seem to be more common in disease states like arteriosclerosis, affect immune cells, including driving inflammation, and whether they provide an unexplored connection between diet and the progression of heart disease and other metabolic problems. His research in collaboration with Ley and Hedrick has been published in top-tier journals including Science. A focus has been the simple chemical octanal which is detected by the olfactory receptors, and their connection prompts production of proinflammatory factors. The scientists have found levels of octanal in human and mouse blood sufficient to activate the respective receptors. When they boost octanal levels, they have found it increases characteristic plaque in blood vessels, and when they genetically delete the receptor it reduces disease, findings that point toward the smell receptor as both a sound prevention and treatment target. They also are exploring the possibility that octanal has effects in other diseases like cancer. Hedrick notes that despite the common ground of inflammation in the major killers of cancer and cardiovascular disease, they have two different environments with different inflammation types.

Orecchioni received an AHA Career Development Award in 2022 that continues today and received the Conrad Prebys Foundation Award in 2021. The foundation supports arts, medical research, health care and youth success in the San Diego community. He also received an AHA postdoctoral fellowship in 2018 and is associate editor of Frontiers in Immunology.

Also starting May 1 is Yanfang Peipei Zhu, PhD, a cancer immunologist coming to MCG and the IMMCG from the University of California San Diego. Zhu completed her postdoctoral fellowship at the La Jolla Institute for Immunology with Hedrick and was named an instructor at the institution before moving to the UCSD in 2020. Her research focus is neutrophils, short-lived immune cells that are early arrivers when we get a bacterial or viral infection. Their levels can shrink in response to problems like stress, as well as congenital or later problems that affect their production in the bone marrow. Zhus lab identified a progenitor cell called NeP that just makes neutrophils and a similar one called hNeP, in both mouse and human bone marrow. They also found that when cancer is present, these progenitor cells go right to the site of the tumor to support its growth. Now they are looking to better categorize which neutrophils and NePs support a healthy immune response versus cancer with the goal of identifying new biomarkers and treatment targets. Zhu also is exploring the cells potential role in atherosclerosis. Additionally, she is an expert in next-generation sequencing technologies that enable high throughput examination of the fine details of the genome.

Zhu earned her PhD from the University of Louisville School of Medicine in Kentucky before going to the Hedrick lab for her postdoc work, where she received a National Cancer Institute scholarship. She is academic editor for the Journal of Cellular Immunology and an editor for The Journal of Immunology and Microbiology.

Rafael S. Czepielewski, PhD, joins IMMCG July 1 from Washington University Medical School in Saint Louis, Missouri, one of the nations top immunology programs. The mucosal immunologists research focus is better understanding inflammatory bowel disease, or IBD, and changes to the lymphatic system during the course of the disease. The lymphatic system is part of the immune system defined as the tissues and organs that produce, store and carry white blood cells throughout the body where they patrol for infections and other invaders. IBD, which includes Crohns disease and ulcerative colitis, are both risk factors for colon cancer. Last year, Czepielewski received a Career Development Award from the Crohns & Colitis Foundation for his work on how crosstalk between the lymphatic vessels, microvessels throughout the body that carry lymph (fluid) away from tissues, and immune cells control IBD. His discoveries include little nests of immune cells along the lymphatic system in IBD, and now he and his new colleagues want to answer questions like how they got there and what they are doing.

Czepielewski received a Young Investigator Award from the 2021 Lymphatic Forum , a biennial event where researchers worldwide present and discuss studies of lymphatics in health and disease. Additionally, he is a fantastic microscopist, Hedrick says, in his case, that includes expertise in intravital microscopy, where you can look at more than one biological process at a time in living research animals, like transparent roundworms called C. elegans.

He earned his PhD from Brazils Pontificia Universidade Catlica do Rio Grande do Sul and joined the faculty as an instructor in 2021. During his PhD work he completed an international PhD fellowship at the Immunology Institute of the Icahn School of Medicine at Mount Sinai in New York City.

Adil Rasheed, PhD, a postdoctoral fellow completing his studies in vascular immunology at the University of Ottawa Heart Institute in Ontario, will start at IMMCG Sept. 11. At the Heart Institute, Rasheed has been honored for his leadership in postdoctoral studies and as the Ottawa Regions Cardiovascular Trainee of the Year. He is a member of the American Heart Association journal Arteriosclerosis, Thrombosis and Vascular Biology Early Career Editorial Board. He was a founding member of the online community Trainees in Metabolism, which hosted seminars and workshops on a range of relevant topics like effective mentorship and scientific communication.

Rasheed will bring with him studies of the protein MLKL, a protein known to play a key role in programmed cell death and which at high levels is associated with inflammatory bowel disease in children. He is finding MLKLs role in cell death appears to be a factor in accumulation of lipid and other substances inside blood vessels in atherosclerosis, and the protein has a significant role as an immune regulator in blood vessel and possibly other metabolic diseases. Rasheed also has an interest in the development of immune cells in the bone marrow, called hematopoiesis. He is the 2022 recipient of the Young Investigator Award from the journal STEM CELLS Translational Medicine for his pioneering research in heart disease while still working on his PhD at the University of Toronto.

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Immunology Center of Georgia recruits reflect expertise from ... - Jagwire Augusta

FDA Fast Tracks BCMA-Targeted CAR T-Cell Therapy for R/R … – AJMC.com Managed Markets Network

A version of this article was originally published on OncLive. This version has been lightly edited.

The FDA has granted a fast track designation to CB-011, a CRISPR-edited allogeneic chimeric antigen receptor (CAR) T-cell therapy developed by Caribou Biosciences, for the treatment of patients with relapsed/refractory multiple myeloma.1

CB-011 targets the B-cell maturation antigen (BCMA). This is the first allogeneic anti-BCMA CAR T-cell therapy engineered to improve duration of antitumor response through an immune cloaking, genome-editing approach that removes the B2M protein and inserts a B2MHLA-E fusion protein, according to the company.2

In November 2022, the FDA cleared an Investigational New Drug application for CB-011.2 Now, the product is under evaluation in the multicenter, open-label study CaMMouflage trial (NCT05722418).3,4

Fast Track designation for CB-011 allows us instrumental interactions with the FDA as we progress our clinical development and regulatory plans for CB-011, Syed Rizvi, MD, chief medical officer at Caribou Biosciences, stated in a press release.1 This designation could not be [timelier,] as we recently dosed our first patient in the phase 1 CaMMouflage trial.

The CaMMouflage trial will include patients who have received at least 3 prior lines of therapy. Eligible patients are also required to have an ECOG performance status of 0 or 1 and to have adequate hematologic, renal, hepatic, pulmonary, and cardiac function.3

Patients who have received a BCMA-targeted therapy within 3 months of enrollment and/or any prior CAR T-cell therapy are excluded. Those who received autologous stem cell transplant within 6 weeks of lymphodepletion or allogeneic stem cell transplant within 6 months of lymphodepletion, who have an active or prior history of central nervous system involvement, or who have received a live, attenuated vaccine with 4 weeks of lymphodepletion are not eligible.3

In the part A, the escalation stage of the trial, investigators will assess ascending doses of CB-011 in combination with cyclophosphamide and fludarabine to establish the recommended phase 2 dose (RP2D) of the regimen in a standard 3+3 dose-escalation design. For part B, the expansion stage, investigators will assess responses to the RP2D, or the maximum tolerated dose as measured by International Myeloma Working Group criteria.3

Recruitment for CaMMouflage is ongoing. Caribou shared plans to assign patients to a single administration of CB-011 at a dose of 50 x 106 CAR T cells this year.1

Cas12a CRISPR hybrid RNA-DNA (chRDNA) technology was utilized to make 4 gene edits in the creation of CB-011. In edits 1 and 2, investigators target cancer cells by site-specifically inserting a humanized anti-BCMA CAR into the TRAC gene. This mechanism knocks out T cell receptor expression, thereby reducing the risk for graft-vs-host disease (GVHD).2

In edits 3 and 4, investigators prevent recognition and rejection by patient T cells and blunt rejection by natural killer (NK) cells by site-specifically inserting a B2MHLA-E peptide fusion gene into the B2M gene of the CAR T cells. These edits disable endogenous B2M expression, which eliminates endogenous HLA class I presentation and reduces T cell-mediated rejection. At the same time, these changes facilitate expression of B2MHLA-E which reduces rejection caused by NK cells.2

Prior preclinical findings presented at the 2022 AACR Annual Meeting indicated that the CAR T cells expressing the B2M-HLA-E fusion induced a survival benefit compared with cells that do not express the fusion in the presence of NK cells in vitro.4 This result suggests that these cells may be able to fight off a recipients NK cells and circulate longer.

Furthermore, CB-011 induced long-term survival in mice carrying established orthotopically-engrafted multiple myeloma cells. Mice who received high doses of CB-011 also appeared to avoid GVHD.4

Our goal is to develop CB-011 as a readily available off-the-shelf treatment option for patients with relapsed or refractory multiple myeloma to overcome the need for apheresis or bridging therapy, variable quality and long manufacturing timelines, manufacturing failures, or the inability to bear the burden of treatments that require frequent dosing over several months, Rizvi added in the press release.1

CB-011 is Caribous second allogeneic CAR T-cell agent that is under exploration in hematologic malignancies.

Investigators are assessing CB-010, a CAR T-cell therapy with a PD-1 knockout, in patients with relapsed or refractory B cell non-Hodgkin lymphoma as part of the ongoing phase 1 ANTLER trial NCT04637763).2 One patient in that trial who received 8 prior lines of systemic therapy had an ongoing complete response through month 15.5

References

1. Caribou Biosciences announces FDA granted fast track designation to CB-011, an allogeneic CAR-T cell therapy for relapsed or refractory multiple myeloma. News release. Caribou Biosciences. April 4, 2023. Accessed April 6, 2023. https://investor.cariboubio.com/

2. Caribou Biosciences announces FDA clearance of IND application for CB-011, an allogeneic anti-BCMA CAR-T Cell therapy for the treatment of relapsed or refractory multiple myeloma. News release. Caribou Biosciences. November 21, 2022. Accessed April 6, 2023. https://investor.cariboubio.com/news-releases/

3. CRISPR-edited allogeneic anti-BCMA CAR-T cell therapy in patients with relapsed/refractory multiple myeloma (CaMMouflage). Updated March 2, 10, 2023. Accessed April 6, 2023. https://www.clinicaltrials.gov/ct2/show/NCT05722418

4. Garner E, Degagne E, Roy S, et al. A BCMA-specific allogeneic CAR-T cell therapy (CB-011) genome-engineered to express an HLA-E fusion transgene to prevent immune cell rejection. Cancer Res. 2022;82(suppl 12):LB009. doi:10.1158/1538-7445.AM2022-LB009

5. CRISPR-edited allogeneic anti-CD19 CAR-t cell therapy with PD-1 knockout induces prolonged complete response in relapsed/refractory follicular lymphoma patient: case report from CB-010 ANTLER trial. Presented at: the Lymphoma, Leukemia, & Myeloma Congress; New York, NY; October 18-22, 2022.

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Bazedoxifene and cholecalciferol | DDDT – Dove Medical Press

Introduction

Osteoporosis is a skeletal disorder characterized by low bone mass and an increased risk of bone fracture. Bone mass reaches its peak in young adulthood, and increased bone resorption relative to bone formation leads to the lowering of bone mass. According to the World Health Organization, osteoporosis is defined as hip or lumbar spine bone marrow density of more than 2.5 standard deviations below the mean found in the young-adult population.1 Osteoporosis is a significant public health concern among the elderly due to the increased morbidity and mortality associated with bone fractures. It affects both sexes and all races, and its prevalence is expected to rise as the global population continues to age.1

The pharmacologic agents for the prevention and treatment of osteoporosis include calcium, vitamin D, bisphosphonates, calcitonin, estrogen, selective estrogen receptor modulator (SERM), parathyroid hormone, and anti-receptor activator of nuclear factor-kappa B ligandantibody (denosumab).2 The therapeutic potential of new treatment approaches, such as exosomes derived from endothelial cells or mesenchymal stem cells, has been investigated recently in animal models.3,4

Bazedoxifene, a third-generation SERM, exhibits tissue-selective action, functioning as an agonist in skeletal tissue but as an antagonist in breast and uterine tissues.5,6 Bazedoxifene has been approved for the treatment of postmenopausal osteoporosis by the European Medicines Agency, and conjugated estrogens/bazedoxifene have been approved for the prevention of postmenopausal osteoporosis by the United States Food and Drug Administration.7,8 Cholecalciferol, commonly known as vitamin D3, plays an important role in bone metabolism. Cholecalciferol is converted to calcifediol (25-hydroxycholecalciferol) in the liver and then to calcitriol (1,25-dihydroxycholecalciferol), the active form of vitamin D, in the kidney. Although vitamin D can be obtained from dietary intake and synthesized in the skin after exposure to sunlight, its deficiency is common. The National Osteoporosis Foundation recommends 8001000 IU of vitamin D intake per day for individuals aged 50 and older.1

A fixed-dose combination formulation of bazedoxifene and cholecalciferol is a potentially promising therapeutic option for postmenopausal osteoporosis patients as it can improve treatment efficacy and medication compliance. Before developing a fixed-dose combination formulation, the pharmacokinetic (PK) interactions between bazedoxifene and cholecalciferol need to be assessed. This study aimed to examine the PK interactions between these drugs as well as their safety and tolerability when co-administered in healthy male subjects.

The study was designed as an open-label, randomized, three-period, three-treatment, six-sequence, crossover clinical trial. Healthy male volunteers aged between 19 and 40 years with body mass index (BMI) between 19 and 28 kg/m2 were eligible for inclusion. Subjects were screened based on past medical history, physical examination including vital signs (blood pressure, heart rate, and body temperature), urine drug screening, clinical laboratory tests, serology tests, and 12-lead electrocardiogram (ECG). Subjects with a history of venous thromboembolism, hypercalciuria, renal stone, hepatobiliary disease, galactose intolerance, drug abuse, or clinically significant hypersensitivity reaction were excluded.

A total of 30 subjects were randomly assigned to six sequences comprised of three treatments: one tablet of 20 mg bazedoxifene (Viviant; Pfizer Ltd., Seoul, Korea), two tablets of 800 IU cholecalciferol (HGP1501; Hanmi Pharmaceutical Co. Ltd., Seoul, Korea), or one tablet of 20 mg bazedoxifene along with two tablets of 800 IU cholecalciferol (Table 1). Outpatient visits were scheduled on day 10 of period 1 and day 9 of periods 2 and 3. At that time, subjects were provided with sunscreens (sun protection factor 50) and diaries to record their diet and activity. Subjects were asked to limit their exposure to sunlight by applying sunscreen and covering themselves with clothes and hats for outdoor activities. Subjects were required to refrain from taking dietary supplements and foods high in vitamin D content. Between two consecutive periods, there was a washout period of at least 14 days. These subjects were admitted to the Clinical Trial Center at Asan Medical Center (Seoul, Korea) the day before drug administration. The test drugs were administered orally under fasting conditions with 150 mL of water. After receiving the investigational drug(s), subjects were required to fast for four hours. Depending on the treatment, subjects were discharged on either day 2 (bazedoxifene monotherapy) or day 6 (cholecalciferol monotherapy or combined therapy). A follow-up visit was scheduled two weeks after the last dose.

Table 1 Overall Study Design

To determine the plasma bazedoxifene concentration, serial blood samples were collected at 0 (pre-dose), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, 24, 48, 72, 96, and 120 hours after the dosing. To measure the baseline cholecalciferol level, blood samples were collected at 16, 12, 8, and 0 hours before the cholecalciferol dosing, and the average concentration for each individual was used as the baseline cholecalciferol concentration. Baseline-adjusted cholecalciferol concentrations were obtained by subtracting the baseline from the post-dose plasma cholecalciferol concentrations measured at 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 24, 48, 72, 96 and 120 hours after the treatment. If the baseline-adjusted cholecalciferol concentration had a negative value, zero was assigned.

Blood samples used for the drug concentration measurements were drawn into ethylenediaminetetraacetic acid K2 tubes. Plasma was separated by centrifugation at 1800 g for 8 minutes at 4 C and stored in Eppendorf tubes at 70 C until analysis. At the analytical laboratory (BioCore Co. Ltd., Seoul, Korea), samples were thawed at room temperature. The plasma concentrations of bazedoxifene and cholecalciferol were assayed using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS). Bazedoxifene samples were prepared by liquid-liquid extraction, and cholecalciferol samples by protein precipitation and solid-phase extraction. Liquid chromatography was conducted using a Shimadzu UFLC system (Shimadzu Corp., Kyoto, Japan). For tandem mass spectrometry, a SCIEX TQ5500 mass spectrometer (AB Sciex LLC, MA, USA) was used. The calibration curves covered the ranges of 0.120 ng/mL for bazedoxifene and 0.110 ng/mL for cholecalciferol. For bazedoxifene, the accuracy of LC-MS/MS was 91.8113.0%, and the precision was 0.15.5%. For cholecalciferol, the accuracy of LC-MS/MS was 92.7105.6%, and the precision was 0.24.5%. The lower limit of quantification was 0.1 ng/mL for both compounds.

The study protocol was approved by the Institutional Review Board (IRB) of Asan Medical Center (IRB number: 20170227) and by the Korean Ministry of Food and Drug Safety. The study was registered at ClinicalTrials.gov (NCT03089112). All subjects provided written informed consent before receiving screening tests. All study procedures were conducted in accordance with the ethical principles stated in the Declaration of Helsinki and by the Good Clinical Practice Guidelines of the International Council for Harmonisation.9,10 The study was conducted from March 31, 2017 to June 16, 2017.

The PK parameters of bazedoxifene and cholecalciferol in each subject were analyzed by the non-compartmental method using Phoenix WinNonlin version 6.4 (Certara, NJ, USA). This analysis was based on the actual sampling time. The maximum plasma concentration (Cmax) and the time to reach Cmax (Tmax) were determined from the observed values. The terminal elimination rate constant (z) was estimated by linear regression analysis of the terminal portion of the semilogarithmic concentration-time curve. The terminal elimination half-life (t1/2) was calculated as the natural log of two divided by z. Demographic data and PK parameters were summarized using descriptive statistics. The Cmax and the values for the area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUClast) were log-transformed to compare the drug exposure between the combined therapy and monotherapy. The point estimate and 90% confidence interval (CI) for the geometric mean ratio (GMR) of the combined therapy to monotherapy were obtained for Cmax and AUClast.

Safety and tolerability were assessed throughout the study by physical examinations, laboratory tests (complete blood count, blood chemistry, and urinalysis), 12-lead ECG, and monitoring of adverse events (AEs). AEs were coded according to the Medical Dictionary for Regulatory Activities (MedDRA version 19.1) and recorded in terms of symptom/sign, onset, duration, severity, relationship to the investigational drug(s), action taken, and outcome.

Of the 30 study participants who received the investigational drug(s) at least once, 27 subjects completed the study (Figure 1). Two subjects withdrew their consent to participate, and one subject was excluded at the investigators discretion due to a medical need for concomitant medication that could potentially affect the PK data. Participant demographics, including age, weight, height, and BMI, are summarized in Table 2. The mean standard deviation (SD) values were 28.63 4.18 years for age, 71.53 6.99 kg for weight, 173.55 4.80 cm for height, and 23.75 2.09 kg/m2 for BMI. All subjects who received the investigational drug(s) at least once were included in the safety and tolerability assessment.

Table 2 Demographic Characteristics of the Participants (n=30)

Figure 1 Subject disposition.

The 27 subjects who completed the study were included in the PK analysis set, and the PK parameters are presented in Table 3. For bazedoxifene, the Cmax values (mean SD) for monotherapy and combined therapy were 3.30 0.92 ng/mL and 3.62 1.39 ng/mL, respectively. The AUClast values (mean SD) for monotherapy and combined therapy were 44.32 22.24 hng/mL and 50.78 24.98 hng/mL, respectively. The mean plasma concentration-time profiles of bazedoxifene for monotherapy and combined therapy nearly overlapped (Figure 2A). For bazedoxifene, the GMR (90% CI) of the combined therapy to monotherapy was 1.044 (0.92631.1765) for Cmax and 1.1329 (1.02321.2544) for AUClast (Table 4).

Table 3 Pharmacokinetic Parameters of Bazedoxifene and Baseline-Adjusted Cholecalciferol in Healthy Male Subjects (n=27)

Table 4 Geometric Mean Ratios of Combined Therapy to Monotherapy for AUClast and Cmax

Figure 2 Mean plasma concentration-time curves: (A) bazedoxifene (B) baseline-adjusted cholecalciferol. The error bars denote standard deviations.

For baseline-adjusted cholecalciferol, the Cmax values (mean SD) for monotherapy and combined therapy were 2.25 0.47 ng/mL and 1.95 0.54 ng/mL, respectively. The AUClast values (mean SD) for monotherapy and combined therapy were 59.43 22.95 hng/mL and 49.18 24.40 hng/mL, respectively. The mean plasma concentration-time profiles of baseline-adjusted cholecalciferol for monotherapy and combined therapy are shown in Figure 2B. For baseline-adjusted cholecalciferol, the GMR (90% CI) of combined therapy to monotherapy was 0.8543 (0.80050.9117) for Cmax and 0.8056 (0.74450.8717) for AUClast (Table 4).

Seventeen subjects showed a total of 26 AEs after drug administration (Table 5). No serious AE occurred throughout the entire study. All AEs were mild in severity and resolved without any sequelae. The most common AE was nasopharyngitis (five events in five subjects). Clinically significant findings from the physical examination were phlebitis of the arm and venipuncture site bruise. Clinically significant laboratory abnormalities included increased blood levels of creatine phosphokinase and triglyceride and decreased blood levels of neutrophil count. No clinically significant abnormalities were found with respect to vital signs and 12-lead ECG. Twenty-five AEs were considered to have no or unlikely relationship with the investigational drugs. One AE, fatigue observed after combined therapy, was considered to have a possible relationship with the administered drugs.

Table 5 Adverse Events in the Study Population After Drug Administration

This study investigated the PK characteristics of bazedoxifene and cholecalciferol, their PK interactions, and the safety and tolerability of combined therapy with these drugs in healthy male subjects.

The terminal elimination half-life of bazedoxifene was approximately 27 hours, and that of cholecalciferol was 13 hours in our study. The washout period of 14 days should therefore have been sufficient for both investigational drugs to be fully eliminated by the next period. The blood samples obtained up to 120 hours after dosing provided sufficient information for characterizing the exposures to bazedoxifene and cholecalciferol.

Previous studies on bazedoxifene pharmacokinetics have indicated a Tmax of 12 hours and a half-life of approximately 28 hours.11 As shown in Figure 2 and Table 3, bazedoxifene was rapidly absorbed when administered alone or in combination with cholecalciferol, showing median Tmax values of 2.00 h and 1.53 h, respectively. The Tmax of cholecalciferol is known to be approximately 15 hours. In our study, the median Tmax of cholecalciferol was 11.98 h when administered alone, similar to the 12.00 h value found for its co-administration with bazedoxifene.

In a recent study on bazedoxifene, the mean Cmax and AUClast in healthy male subjects after a single 20 mg oral dose were 3.191 ng/mL and 44.697 hng/mL, respectively.12 These numbers are consistent with the results of the current study (3.30 ng/mL and 44.32 hng/mL). The PK parameters Cmax and AUClast were used in our analyses to compare the combined therapy and monotherapy exposures. With bazedoxifene, the 90% CI for the GMR of the combined therapy to bazedoxifene monotherapy for Cmax fell within the 0.801.25 range, and for AUClast it was nearly within the above-mentioned range.

In the case of cholecalciferol, the AUClast was lower when this drug was co-administered with bazedoxifene, as indicated by the GMR of 0.8056 and associated 90% CI of 0.74450.8717. Bazedoxifene and cholecalciferol are drugs that exhibit wide therapeutic ranges.1315 Cholecalciferol is known to reach a sigmoidal dose-response curve plateau at a dose of 600 IU.15 Hence, based on the GMRs observed in our exploratory study, the difference in the AUClast for cholecalciferol is unlikely to have clinical significance in treatment efficacy at the dose level used in our protocol.

All of the AEs observed in our study population were mild, and the frequency of AEs in subjects who received combined therapy was not significantly different from that in subjects who received monotherapy. The most common AE observed in our present trial cohort was nasopharyngitis, which we considered unrelated to the investigational drugs.

One limitation of the present study was that the participants were all healthy men. The study was exploratory in nature, and male subjects were included to facilitate enrollment and minimize health risks to subjects. Drug-drug interaction studies are often conducted with male subjects, and the results are applied to women as well as men because gender does not seem to affect the pattern of drug-drug interaction for many drugs. Assuming that the PK interactions would follow the same pattern in men and women, this study was conducted in men instead of women. Additional studies in postmenopausal women with osteoporosis and patients with different pathophysiological conditions will help further characterize the PK interactions between bazedoxifene and cholecalciferol.

The combined therapy of 20 mg bazedoxifene (one tablet) and 1600 IU cholecalciferol (two tablets of 800 IU) was safe and well tolerated in healthy male subjects. In this present study, the oral co-administration of bazedoxifene with cholecalciferol tended to decrease the cholecalciferol exposure slightly. Considering that both drugs have wide therapeutic ranges, dose adjustment of cholecalciferol may not be necessary for its co-administration with bazedoxifene.

AE, adverse event; AUClast, area under the concentration-time curve from time zero to the last quantifiable concentration; BMI, body mass index; CI, confidence interval; Cmax, maximum plasma concentration; ECG, electrocardiogram; GMR, geometric mean ratio; IRB, Institutional Review Board; LC-MS/MS, liquid chromatography with tandem mass spectrometry; z, terminal elimination rate constant; PK, pharmacokinetic; SD, standard deviation; SERM, selective estrogen receptor modulator; Tmax, time to reach Cmax; t1/2, terminal elimination half-life.

The authors do not intend to share individual de-identified participant data of this study due to confidentiality.

This study was sponsored by Hanmi Pharmaceutical Co. Ltd.

Hyeong-Seok Lim has received grants from Hanmi Pharmaceutical Co. Ltd. for a range of research projects, including the study reported in this article. Jina Jung and Sung Hee Hong are employees of Hanmi Pharmaceutical Co. Ltd. The remaining authors declare no competing interests in relation to this article.

1. Cosman F, de Beur SJ, LeBoff MS, et al. National Osteoporosis Foundation. Clinicians guide to prevention and treatment of osteoporosis. Osteoporos Int. 2014;25(10):23592381. doi:10.1007/s00198-014-2794-2

2. Rejnmark L, Mosekilde L. New and emerging antiresorptive treatments in osteoporosis. Curr Drug Saf. 2011;6(2):7588. doi:10.2174/157488611795684686

3. Song H, Li X, Zhao Z, et al. Reversal of osteoporotic activity by endothelial cell-secreted bone targeting and biocompatible exosomes. Nano Lett. 2019;19(5):30403048. doi:10.1021/acs.nanolett.9b00287

4. Zeng ZL, Xie H. Mesenchymal stem cell-derived extracellular vesicles: a possible therapeutic strategy for orthopaedic diseases: a narrative review. Biomater Transl. 2022;3(3):175187. doi:10.12336/biomatertransl.2022.03.002

5. Komm BS, Kharode YP, Bodine PV, Harris HA, Miller CP, Lyttle CR. Bazedoxifene acetate: a selective estrogen receptor modulator with improved selectivity. Endocrinology. 2005;146(9):39994008. doi:10.1210/en.2005-0030

6. Stump AL, Kelley KW, Wensel TM. Bazedoxifene: a third-generation selective estrogen receptor modulator for treatment of postmenopausal osteoporosis. Ann Pharmacother. 2007;41(5):833839. doi:10.1345/aph.1H428

7. Conbriza. European medicines agency; 2009. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/conbriza. Accessed October 21, 2022.

8. DUAVEE. Drug Label (NDA 022247). Silver Spring, MD: US Food and Drug Administration; 2013.

9. World Medical Association. World medical association declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):21912194. doi:10.1001/jama.2013.281053

10. Guideline for Good Clinical Practice E6(R2). International council for harmonisation of technical requirements for pharmaceuticals for human use; 2016. Available from: https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf. Accessed October 21, 2022.

11. Gatti D, Rossini M, Sblendorio I, Lello S. Pharmacokinetic evaluation of bazedoxifene for the treatment of osteoporosis. Expert Opin Drug Metab Toxicol. 2013;9(7):883892. doi:10.1517/17425255.2013.794221

12. Yeun JS, Kan HS, Lee M, et al. Pharmacokinetic comparison of two bazedoxifene acetate 20 mg tablet formulations in healthy Korean male volunteers. Transl Clin Pharmacol. 2020;28(2):102108. doi:10.12793/tcp.2020.28.e7

13. Archer DF, Pinkerton JV, Utian WH, et al. Bazedoxifene, a selective estrogen receptor modulator: effects on the endometrium, ovaries, and breast from a randomized controlled trial in osteoporotic postmenopausal women. Menopause. 2009;16(6):11091115. doi:10.1097/gme.0b013e3181a818db

14. Kawate H, Takayanagi R. Efficacy and safety of bazedoxifene for postmenopausal osteoporosis. Clin Interv Aging. 2011;6:151160. doi:10.2147/CIA.S15711

15. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press; 2011.

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Bazedoxifene and cholecalciferol | DDDT - Dove Medical Press

Paterson Teacher Dies After Battling Brain Infection, Cancer – Daily Voice

EmilySetteducato has died after battling cancer and a subsequent brain infection on Saturday, April 8, her obituary reads. She was 28 years old.

After battling leukemia, braving multiple rounds of chemotherapy, and receiving a life-saving stem cell transplant from an anonymous donor at just 27 years old, Emily thought her medical woes were over.

The Paterson elementary school teacher had left the hospital, returned to the classroom, celebrated a birthday, and was back to planning a future with her long-time boyfriend, Will.

The future was looking bright for Emily, until she contracted an infection known as the JC Virus, wreaking havoc on her brain.

Emily sister,Jackie Griffin launched a GoFundMe campaignlast January. While Emily was able to undergo treatment atCincinnati Children's Hospital, "recent test results show that the minor improvements were only temporary," Griffin said.

"Based on medical advice, our focus is now on making Emily as comfortable as possible through in-home care, which will require around the clock care for an unknown amount of time, possibly months."

Emily slipped away surrounded by her loved ones.

Emily's final weeks were spent showering her friends and family with love, her obituary reads, "lighting up whenever her life partner and 'her rock', Will, was nearby, making her family laugh with jokes and eyerolls, planning celebrations for her friends, and bragging about her new nephew to her many visitors," it reads.

Emily graduated Fair Lawn High School and William Paterson University, before beginning her career as a preschool teacher. She was a cherished member of the BJ Wilkerson Memorial Child Development Center and DA Quarles Early Childhood Center.

Services will be held at theVander Plaat Colonial Home. Click here for funeral details and here to donate to the GoFundMe page for Emily.

Click here to follow Daily Voice South Passaic and receive free news updates.

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Paterson Teacher Dies After Battling Brain Infection, Cancer - Daily Voice

Berlusconi says he believes he’ll recover ‘once again’ – The Associated Press

ROME (AP) Former Italian Premier Silvio Berlusconi said he believes he will overcome the lung infection caused by a chronic leukemia that has hospitalized him in intensive care, Italian daily Il Giornale reported on Friday.

Its hard, but Ill make it once again, the 86-year-old media mogul said in a phone call with Il Giornales editor in chief, Augusto Minzolini.

I managed, also in delicate and difficult situations, to pull myself up, Berlusconi added, according to the report.

The media tycoon and three-time premier spent a second consecutive night in intensive care at Milans San Raffaele Hospital, where his doctors on Thursday signed off on a medical bulletin saying that he has had leukemia for some time, but that the cancer of the blood cells is in a persistent chronic phase.

The statement was the first official word from doctors since Berlusconi was admitted to San Raffaele on Wednesday.

The current treatment strategy envisions treatment of the pulmonary infection as well as specialized treatment aimed at limiting the negative effects of the chronic leukemia, the bulletin stated.

On Friday morning, Foreign Minister Antonio Tajani, quoting Berlusconis personal doctor Alberto Zangrillo, reported that Berlusconi was alert and was responding to the treatments. Tajani is the coordinator of Forza Italia, the political party that Berlusconi created some 30 years ago.

Berlusconi was admitted to an intensive care unit at San Raffaele Hospital on Wednesday for treatment of what aides indicated was a respiratory problem stemming from a previous infection.

The former premier and now senator had left the same hospital a week earlier after several days of tests.

Doctors said the kind of leukemia afflicting Berlusconi usually appears in people of advanced age and is characterized by an increase in white blood cells known as monocytes.

Treatment for older patients can involve a stem cell transplant. But that could be difficult, according to an Italian nonprofit association dedicated to combating leukemia. Another treatment would involve controlling the white blood cell count.

The last years have seen Berlusconi suffer numerous health problems, including heart ailments and COVID-19 in 2020, which saw him hospitalized then in critical condition with pneumonia.

He has had a pacemaker for years, underwent heart surgery to replace an aortic valve in 2016 and overcame prostate cancer decades ago.

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Berlusconi says he believes he'll recover 'once again' - The Associated Press