FDA Approval Summary: Olaparib in Combination With Abiraterone for Treatment of Patients With BRCA-Mutated Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: This article summarizes the US Food and Drug Administration (FDA) review of the data leading to approval of olaparib plus abiraterone for the treatment of patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC), as determined by an FDA-approved companion diagnostic test. PATIENTS AND METHODS: Approval was based on the results from PROpel, a double-blind trial that randomly assigned 796 patients with mCRPC to abiraterone plus prednisone or prednisolone with either olaparib or placebo. The primary end point was radiographic progression-free survival (rPFS) per investigator assessment. RESULTS: There was a statistically significant improvement in rPFS for olaparib plus abiraterone versus placebo plus abiraterone, with a median rPFS of 25 versus 17 months and a hazard ratio (HR) of 0.66 (95% CI, 0.54 to 0.81) in the intention-to-treat population. In an exploratory analysis of the subgroup of 85 patients with BRCAm mCRPC, the HR for rPFS was 0.24 (95% CI, 0.12 to 0.45) and the HR for overall survival (OS) was 0.30 (95% CI, 0.15 to 0.59). In an exploratory analysis of the subgroup of 711 patients without an identified BRCA mutation, the HR for rPFS was 0.77 (95% CI, 0.63 to 0.96) and the HR for OS was 0.92 (95% CI, 0.74 to 1.14). Adding olaparib to abiraterone resulted in increased toxicity, including anemia requiring transfusion in 18% of patients. CONCLUSION: In patients with mCRPC, efficacy of the combination of olaparib plus abiraterone was primarily attributed to the treatment effect in the BRCAm subgroup, the indicated population for the approval. For patients without BRCAm, the FDA determined that the modest rPFS improvement, combined with clinically significant toxicities, did not demonstrate a favorable risk/benefit assessment.

Astrovirology: how viruses enhance our understanding of life in the Universe.

Viruses are the most numerically abundant biological entities on Earth. As ubiquitous replicators of molecular information and agents of community change, viruses have potent effects on the life on Earth, and may play a critical role in human spaceflight, for life-detection missions to other planetary bodies and planetary protection. However, major knowledge gaps constrain our understanding of the Earth's virosphere: (1) the role viruses play in biogeochemical cycles, (2) the origin(s) of viruses and (3) the involvement of viruses in the evolution, distribution and persistence of life. As viruses are the only replicators that span all known types of nucleic acids, an expanded experimental and theoretical toolbox built for Earth's viruses will be pivotal for detecting and understanding life on Earth and beyond. Only by filling in these knowledge and technical gaps we will obtain an inclusive assessment of how to distinguish and detect life on other planetary surfaces. Meanwhile, space exploration requires life-support systems for the needs of humans, plants and their microbial inhabitants. Viral effects on microbes and plants are essential for Earth's biosphere and human health, but virus-host interactions in spaceflight are poorly understood. Viral relationships with their hosts respond to environmental changes in complex ways which are difficult to predict by extrapolating from Earth-based proxies. These relationships should be studied in space to fully understand how spaceflight will modulate viral impacts on human health and life-support systems, including microbiomes. In this review, we address key questions that must be examined to incorporate viruses into Earth system models, life-support systems and life detection. Tackling these questions will benefit our efforts to develop planetary protection protocols and further our understanding of viruses in astrobiology.

FDA Approval Summary: Lutetium Lu 177 Vipivotide Tetraxetan for Patients with Metastatic Castration-Resistant Prostate Cancer.

On March 23, 2022, the FDA approved Pluvicto (lutetium Lu 177 vipivotide tetraxetan, also known as 177Lu-PSMA-617) for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The recommended 177Lu-PSMA-617 dose is 7.4 gigabecquerels (GBq; 200 mCi) intravenously every 6 weeks for up to six doses, or until disease progression or unacceptable toxicity. The FDA granted traditional approval based on VISION (NCT03511664), which was a randomized (2:1), multicenter, open-label trial that assessed the efficacy and safety of 177Lu-PSMA-617 plus best standard of care (BSoC; n = 551) or BSoC alone (n = 280) in men with progressive, PSMA-positive mCRPC. Patients were required to have received ≥1 androgen receptor pathway inhibitor, and one or two prior taxane-based chemotherapy regimens. There was a statistically significant and clinically meaningful improvement in overall survival (OS), with a median OS of 15.3 months in the 177Lu-PSMA-617 plus BSoC arm and 11.3 months in the BSoC arm, respectively (HR: 0.62; 95% confidence interval: 0.52-0.74; P < 0.001). The most common adverse reactions (≥20%) occurring at a higher incidence in patients receiving 177Lu-PSMA-617 were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in ≥30% of patients receiving 177Lu-PSMA-617 were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium. This article summarizes the FDA review of data supporting traditional approval of 177Lu-PSMA-617 for this indication.

Vaccine-induced thrombotic thrombocytopenia (VITT): first report from India.

BACKGROUND: Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare but devastating adverse event following adenoviral vector-based vaccinations for COVID-19, resulting in thrombosis, especially of the cerebral and splanchnic vasculature. Despite the progress in laboratory techniques for early diagnosis, VITT remains a clinical diagnosis supplemented by coagulation studies. We report on VITT for the first time from India. CASE: We describe cortical venous sinus thrombosis and intracerebral bleed associated with severe thrombocytopenia in two young men who had no other contributory cause besides a recent ChAdOx1 nCoV-19 vaccination. The diagnosis was supported with PF-4 antibodies in one patient. The second patient's test could not be processed to technical limitations. Both patients were treated with IVIG at 1 g/kg for 2 days and anticoagulation (Apixaban). One patient fully recovered with no residual deficits, and the other is under treatment and recovering. CONCLUSION: VITT can cause devastating fatality and morbidity in otherwise healthy patients via potential immune-mediated effects. Clinicians should have a high suspicion index and treat VITT in the appropriate setting even if the PF-4 antibody testing by ELISA is unavailable or delayed. Though counterintuitive, clinicians must not delay the administration of non-heparin anticoagulation, IVIG and restrict platelet transfusion even in the presence of intracerebral haemorrhage.

Advances in the application of Doppler ultrasonography in the newborn.

.

Sensory Neurons of the Dorsal Root Ganglia Become Hyperexcitable in a T-Cell-Mediated MOG-EAE Model of Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system. Patients with MS typically present with visual, motor, and sensory deficits. However, an additional complication of MS in large subset of patients is neuropathic pain. To study the underlying immune-mediated pathophysiology of pain in MS we employed the myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalitis (EAE) model in mice. Since sensory neurons are crucial for nociceptive transduction, we investigated the effect of this disease on sensory neurons of the lumbar dorsal root ganglia (DRG). Here, we report the disease was associated with activation of the complement system and the NLRP3 inflammasome in the DRG. We further observe a transient increase in the number of complement component 5a receptor 1-positive (C5aR1+) immune cells, CD4+ T-cells, and Iba1+ macrophages in the DRG. The absence of any significant change in the levels of mRNA for myelin proteins in the DRG and the sciatic nerve suggests that demyelination in the PNS is not a trigger for the immune response in the DRG. However, we did observe an induction of activating transcription factor 3 (ATF3) at disease onset and chronic disruption of cytoskeletal proteins in the DRG demonstrating neuronal injury in the PNS in response to the disease. Electrophysiological analysis revealed the emergence of hyperexcitability in medium-to-large (≥26 µm) diameter neurons, especially at the onset of MOG-EAE signs. These results provide conclusive evidence of immune activation, neuronal injury, and peripheral sensitization in MOG-EAE, a model classically considered to be centrally mediated.

FDA Approval Summary: Mylotarg for Treatment of Patients with Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia.

On September 2, 2017, the U.S. Food and Drug Administration approved gemtuzumab ozogamicin (GO; Mylotarg; Pfizer, New York City, NY) for treatment of relapsed or refractory (R/R) CD33-positive acute myeloid leukemia (AML) in patients 2 years of age and older. GO is a CD33-directed antibody drug conjugate linked to the cytotoxic antibiotic calicheamicin. It originally received accelerated approval for treatment of older patients with relapsed CD33-positive AML in 2000, but it was withdrawn from the market in 2010 when the confirmatory trial failed to demonstrate clinical benefit among safety concerns, such as a higher rate of induction fatalities on the GO combination arm compared with chemotherapy alone. In addition, GO was associated with hepatic veno-occlusive disease (VOD), which has substantial morbidity and mortality. Pharmacokinetic analyses suggested a lower maximum concentration of GO would result in less VOD without affecting target saturation or efficacy. A meta-analysis across dose schedules of GO in patients with R/R AML showed that a lower-dose "fractionated" schedule of 3 mg/m2 days 1, 4, and 7 was associated with less early mortality, hemorrhage, and VOD, without an apparent decrease in complete remission (CR) rate. MyloFrance 1 was a single-arm study evaluating response rates in patients with relapsed CD33-positive AML treated with the lower-dose fractionated GO regimen. The CR rate was 26% (95% confidence interval 16%-40%). Common adverse reactions were fever, infections, nausea, vomiting, constipation, bleeding, increased liver enzymes, and mucositis. There were no cases of VOD. These results supported the approval of GO as monotherapy for R/R CD33-positive AML using the lower-dose fractionated regimen. IMPLICATIONS FOR PRACTICE: Gemtuzumab ozogamicin (GO) 3 mg/m2 days 1, 4, and 7 is an active regimen for induction of remission when used to treat patients with relapsed or refractory CD33-positive acute myeloid leukemia without curative intent. The risks of hepatic veno-occlusive disease and early mortality with this regimen appear to be lower than reported previously for GO 9 mg/m2 days 1 and 15. The data were not sufficient to enable conclusions about the safety of GO in children younger than 2 years of age.

Phase-0/microdosing studies using PET, AMS, and LC-MS/MS: a range of study methodologies and conduct considerations. Accelerating development of novel pharmaceuticals through safe testing in humans - a practical guide.

INTRODUCTION: Phase-0 studies, including microdosing, also called Exploratory Investigational New Drug (eIND) or exploratory clinical trials, are a regulatory framework for first-in-human (FIH) trials. Common to these approaches is the use and implied safety of limited exposures to test articles. Use of sub-pharmacological doses in phase-0/microdose studies requires sensitive analytic tools such as accelerator mass spectrometer (AMS), Positron Emission Tomography (PET), and Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) to determine drug disposition. Areas covered: Here we present a practical guide to the range of methodologies, design options, and conduct strategies that can be used to increase the efficiency of drug development. We provide detailed examples of relevant developmental scenarios. Expert opinion: Validation studies over the past decade demonstrated the reliability of extrapolation of sub-pharmacological to therapeutic-level exposures in more than 80% of cases, an improvement over traditional allometric approaches. Applications of phase-0/microdosing approaches include study of pharmacokinetic and pharmacodynamic properties, target tissue localization, drug-drug interactions, effects in vulnerable populations (e.g. pediatric), and intra-target microdosing (ITM). Study design should take into account the advantages and disadvantages of each analytic tool. Utilization of combinations of these analytic techniques increases the versatility of study designs and the power of data obtained.

Genetic and epigenetic biomarkers in cancer : improving diagnosis, risk assessment, and disease stratification.

Gene expression patterns change during the initiation, progression, and development of cancer, as a result of both genetic and epigenetic mechanisms. Genetic changes arise due to irreversible changes in the nucleotide sequence, whereas epigenetic changes occur due to changes in chromatin conformation, histone acetylation, and methylation of the CpG islands located primarily in the promoter region of a gene. Both genetic and epigenetic markers can potentially be utilized to identify different stages of tumor development. Several such markers exhibit high sensitivity and specificity for different tumor types and can be assayed in biofluids and other specimens collected by noninvasive technologies. In spite of the availability of large numbers of diagnostic markers, only a few have been clinically validated so far. The current status and the challenges in the field of genetic and epigenetic markers in cancer diagnosis, risk assessment, and disease stratification are discussed.

Sigma receptor scintigraphy with N-[2-(1'-piperidinyl)ethyl]-3-(123)I-iodo-4-methoxybenzamide of patients with suspected primary breast cancer: first clinical results.

UNLABELLED: The aim of this study was to investigate the potential of a new iodobenzamide, N-[2-(1'-piperidinyl)ethyl]-3-(123)I-iodo-4-methoxybenzamide (P-(123)I-MBA), to visualize primary breast tumor in humans in vivo. Tumor accumulation of benzamides is based on a preferential binding to sigma receptors that are overexpressed on breast cancer cells. METHODS: P-(123)I-MBA (148-185 MBq) was administered to 12 patients with a mammographically suspicious breast mass. Two hours after administration, whole-body and spot images of the healthy and the diseased breast were obtained. RESULTS: A focal increased tracer accumulation was observed in 8 of 10 patients with histologically confirmed breast cancer (mean tumor-to-background ratio, 2.04). No uptake was seen in a case of lymphatic adenitis. CONCLUSION: This preliminary patient study shows that P-(123)I-MBA accumulates in most breast tumors in vivo. Future work should focus on the relationship between P-(123)I-MBA uptake and the proliferative activity of cells to anticipate use of this technique as a tool to noninvasively assess the degree of tumor proliferation.