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Background: Variants of the gene triggering receptor expressed on myeloid cells-2 (TREM2) increase the risk of Alzheimer's disease (AD) and other neurodegenerative disorders. Signaling by TREM2, an innate immune receptor expressed by microglia, is thought to enhance phagocytosis of amyloid beta (Aβ) and other damaged proteins, promote microglial proliferation, migration, and survival, and regulate inflammatory signaling. Thus, TREM2 activation has potential to alter the progression of AD. AL002 is an investigational, engineered, humanized monoclonal immunoglobulin G1 (IgG1) antibody designed to target TREM2. In AD mouse models, an AL002 murine variant has been previously shown to induce microglial proliferation and reduce filamentous Aβ plaques and neurite dystrophy. Methods: Preclinical studies assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of AL002 in cynomolgus monkeys. INVOKE-1 (NCT03635047) was a first-in-human phase 1, randomized, placebo-controlled, double-blind study assessing the safety, tolerability, PK, and PD of AL002 administered as single ascending doses (SAD) in healthy volunteers. Results: In cynomolgus monkeys, weekly intravenous injections of AL002 for 4 weeks were well tolerated, dose-dependently decreased soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF) and total TREM2 in hippocampus and frontal cortex, and increased biomarkers of TREM2 signaling in CSF and brain. In the phase 1 study of 64 healthy volunteers, a single intravenous infusion of AL002 demonstrated brain target engagement based on a dose-dependent reduction of sTREM2 in CSF and parallel increases in biomarkers of TREM2 signaling and microglia recruitment. Single-dose AL002 showed central nervous system penetrance and was well tolerated, with no treatment-related serious adverse events over 12 weeks. Conclusions: These findings support the continued clinical development of AL002 for AD and other neurodegenerative diseases in which TREM2 activation may be beneficial. AL002 is currently being tested in a phase 2, randomized, double-blind, placebo-controlled study in early AD. Trial registration: Clinicaltrials.gov, NCT03635047. Registered on August 15, 2018, https://www.clinicaltrials.gov/study/NCT03635047. [ABSTRACT FROM AUTHOR]

Summary: Combining a checkpoint inhibitor with an inhibitor of extracellular signal-regulated kinase (ERK) may result in synergistic antitumor activity. We evaluated MK-8353, an ERK1 and ERK2 inhibitor, plus pembrolizumab in a phase 1b study in patients with advanced solid tumors. This open-label, nonrandomized, dose-escalation study (NCT02972034) enrolled adults with advanced solid tumors previously treated with 1‒5 prior lines of therapy. MK-8353 was administered orally in combination with pembrolizumab 200 mg every 3 weeks as follows: twice daily (arm A; MK-8353 50‒350 mg), once daily (arm B; MK-8353 50‒600 mg), or once daily every other week (arm C; MK-8353 50‒300 mg). The primary objective was evaluation of safety via occurrence of dose-limiting toxicities (DLTs). A secondary objective was objective response by RECIST v1.1 per investigator assessment. Among 110 evaluable patients (arm A, n = 22; arm B, n = 50; arm C, n = 38), median age was 58.0 (range, 35‒79) years and 50% had received 1 or 2 prior lines of therapy. DLTs occurred in 19 patients (n = 6 [27%], n = 8 [16%], and n = 5 [13%], respectively); the most frequent was grade 3 maculopapular rash (n = 15). Grade 3/4 treatment-related AEs occurred in 35% of patients; the most common were maculopapular rash (13%) and increased lipase (5%); none were grade 5. Eight patients (7%) attained an objective response (arm B, n = 7 [complete response, n = 1; partial response, n = 6]; arm C, n = 1 [complete response]). In conclusion, MK-8353 once daily plus pembrolizumab could be administered with a manageable toxicity profile but had modest antitumor activity in patients with advanced solid tumors. [ABSTRACT FROM AUTHOR]

Abstract Background Variants of the gene triggering receptor expressed on myeloid cells-2 (TREM2) increase the risk of Alzheimer’s disease (AD) and other neurodegenerative disorders. Signaling by TREM2, an innate immune receptor expressed by microglia, is thought to enhance phagocytosis of amyloid beta (Aβ) and other damaged proteins, promote microglial proliferation, migration, and survival, and regulate inflammatory signaling. Thus, TREM2 activation has potential to alter the progression of AD. AL002 is an investigational, engineered, humanized monoclonal immunoglobulin G1 (IgG1) antibody designed to target TREM2. In AD mouse models, an AL002 murine variant has been previously shown to induce microglial proliferation and reduce filamentous Aβ plaques and neurite dystrophy. Methods Preclinical studies assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of AL002 in cynomolgus monkeys. INVOKE-1 (NCT03635047) was a first-in-human phase 1, randomized, placebo-controlled, double-blind study assessing the safety, tolerability, PK, and PD of AL002 administered as single ascending doses (SAD) in healthy volunteers. Results In cynomolgus monkeys, weekly intravenous injections of AL002 for 4 weeks were well tolerated, dose-dependently decreased soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF) and total TREM2 in hippocampus and frontal cortex, and increased biomarkers of TREM2 signaling in CSF and brain. In the phase 1 study of 64 healthy volunteers, a single intravenous infusion of AL002 demonstrated brain target engagement based on a dose-dependent reduction of sTREM2 in CSF and parallel increases in biomarkers of TREM2 signaling and microglia recruitment. Single-dose AL002 showed central nervous system penetrance and was well tolerated, with no treatment-related serious adverse events over 12 weeks. Conclusions These findings support the continued clinical development of AL002 for AD and other neurodegenerative diseases in which TREM2 activation may be beneficial. AL002 is currently being tested in a phase 2, randomized, double-blind, placebo-controlled study in early AD. Trial registration Clinicaltrials.gov, NCT03635047. Registered on August 15, 2018, https://www.clinicaltrials.gov/study/NCT03635047 .

Background: Noradrenergic signaling declines in Parkinson's disease (PD) following locus coeruleus neurodegeneration. Epidemiologic studies demonstrate that β-acting drugs slow PD progression. Objective: The primary objective was to compare the safety and effects of 3 β-adrenoceptor (β-AR) acting drugs on central nervous system (CNS) function after a single dose in healthy volunteers (HVs) and evaluate the effects of multiple doses of β-AR acting drugs in HVs and PD-patients. Methods: In Part A, HVs received single doses of 32 mg salbutamol, 160μg clenbuterol, 60 mg pindolol and placebo administered in a randomized, 4-way cross-over study. In Part B (randomized cross-over) and Part C (parallel, 2:1 randomized), placebo and/or clenbuterol (20μg on Day 1, 40μg on Day 2, 80μg on Days 3–7) were administered. CNS functions were assessed using the NeuroCart test battery, including pupillometry, adaptive tracking and recall tests. Results: Twenty-seven HVs and 12 PD-patients completed the study. Clenbuterol improved and pindolol reduced the adaptive tracking and immediate verbal recall performance. Clenbuterol and salbutamol increased and pindolol decreased pupil-to-iris ratios. Clenbuterol was selected for Parts B and C. In Part B, clenbuterol significantly increased performance in adaptive tracking with a tendency toward improved performance in immediate and delayed verbal recall. In Part C trends toward improved performance in immediate and delayed verbal recall were observed in PD-patients. Typical cardiovascular peripheral β2-AR effects were observed with clenbuterol. Conclusions: This study demonstrates the pro-cognitive effects of clenbuterol in HVs with similar trends in PD-patients. The mechanism of action is likely activation of β2-ARs in the CNS. Plain Language Summary: Aims and Purpose of the Research: This research aimed to explore how three different drugs affect brain function. These drugs are salbutamol, clenbuterol, and pindolol and work in the brain by stimulating specific brain cells that can improve aspects like memory and coordination. The main question was to see how safe these drugs were and how they impact the brain function after one dose in healthy people, and after multiple doses in both healthy people and those with Parkinson's disease. Background of the Research: Parkinson's disease is a condition where brain cells start to die, which affects different areas of the brain, including movement function, as well as memory and attention. This research matters because finding drugs that affect the brain function could improve the lives of people with Parkinson's disease. Methods and Research Design: The study was conducted in three parts. In the first part, healthy volunteers took one dose of each of the three drugs— salbutamol, clenbuterol, and pindolol— as well as a placebo (a harmless pill that has no effect). The researchers tested the participants' brain functions using various tasks including memory tests and eye response measurements. In the second and third part, healthy people and people with Parkinson's disease took the drug that performed best in healthy volunteers for seven days. Results and Importance: In the first part, a single dose of clenbuterol was safe and improved memory and attentions tasks in healthy people, and therefore was chosen for further testing in the second and third part. In these parts, multiple doses of clenbuterol were safe and helped improve memory and attention tasks in healthy people, with similar positive trends seen in people with Parkinson's disease. The study suggests that clenbuterol might help improve brain function by activating specific receptors in the brain. These results are important because they suggest that clenbuterol could be a potential treatment to help improve brain function in people with Parkinson's disease. However, more research is needed to fully understand its effects and to confirm these findings. [ABSTRACT FROM AUTHOR]

Currently, there is a lack of effective treatments or preventive strategies for bronchopulmonary dysplasia (BPD). Pre-clinical studies with mesenchymal stromal cells (MSCs) have yielded encouraging results. The safety of administering repeated intravenous doses of umbilical cord tissue-derived mesenchymal stromal cells (UC-MSCs) has not yet been tested in extremely-low-gestational-age newborns (ELGANs). to test the safety and feasibility of administering three sequential intravenous doses of UC-MSCs every 7 days to ELGANs at risk of developing BPD. Methods: In this phase 1 clinical trial, we recruited ELGANs (birth weight ≤1250 g and ≤28 weeks in gestational age [GA]) who were on invasive mechanical ventilation (IMV) with FiO2 ≥ 0.3 at postnatal days 7–14. Three doses of 5 × 106/kg of UC-MSCs were intravenously administered at weekly intervals. Adverse effects and prematurity-related morbidities were recorded. From April 2019 to July 2020, 10 patients were recruited with a mean GA of 25.2 ± 0.8 weeks and a mean birth weight of 659.8 ± 153.8 g. All patients received three intravenous UC-MSC doses. The first dose was administered at a mean of 16.6 ± 2.9 postnatal days. All patients were diagnosed with BPD. All patients were discharged from the hospital. No deaths or any serious adverse events related to the infusion of UC-MSCs were observed during administration, hospital stays or at 2-year follow-up. The administration of repeated intravenous infusion of UC-MSCs in ELGANs at a high risk of developing BPD was feasible and safe in the short- and mid-term follow-up. [ABSTRACT FROM AUTHOR]

Introduction: Nipocalimab is a high-affinity, fully human, aglycosylated, effectorless, immunoglobulin G (IgG) 1 monoclonal antibody that targets the neonatal Fc receptor (FcRn), decreases systemic IgG including autoantibodies, and is under development in several IgG autoantibody- and alloantibodymediated diseases, including generalized myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, maternal-fetal medicine, and multiple other therapeutic areas. An initial phase 1 study with single and multiple ascending doses of nipocalimab infused intravenously (IV) over 2 h demonstrated dose-dependent serum pharmacokinetics and IgG reductions, with an adverse event (AE) profile comparable to placebo. Methods: The current investigation evaluates the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of nipocalimab across various IV infusion rates in a randomized, double-blind, placebocontrolled, sequential-dose study. Forty participants were randomized to receive nipocalimab 30 mg/kg over 60, 30, 15 or 7.5 min (0.5, 1, 2, or 4 mg/kg/min); nipocalimab 60 mg/kg over 15 min (4 mg/kg/min); or matching placebo. Results: At doses up to 60 mg/kg and infusion rates up to 4 mg/kg/min (maximum clinically feasible rate), single doses of nipocalimab were tolerable, with 12 (40%) participants experiencing AEs across nipocalimab cohorts compared with 1 (10%) participant in the placebo cohort. AEs deemed treatment related occurred in 6 (20%) participants receiving nipocalimab and 1 (10%) participant receiving placebo. None of the AEs were severe, and no participants discontinued treatment due to AEs. Nipocalimab provided consistent, dose-dependent serum pharmacokinetics and IgG reductions, regardless of infusion rate. Discussion: This study supports the use of shortened durations of nipocalimab infusion for future studies. [ABSTRACT FROM AUTHOR]

Background: Food allergy is a leading cause of anaphylaxis worldwide. Allergen‐specific immunotherapy is the only treatment shown to modify the natural history of allergic disease, but application to food allergy has been hindered by risk of severe allergic reactions and short‐lived efficacy. Allergen‐derived peptides could provide a solution. PVX108 comprises seven short peptides representing immunodominant T‐cell epitopes of major peanut allergens for treatment of peanut allergy. Methods: Pre‐clinical safety of PVX108 was assessed using ex vivo basophil activation tests (n = 185). Clinical safety and tolerability of single and repeat PVX108 doses were evaluated in a first‐in‐human, randomized, double‐blind, placebo‐controlled trial in peanut‐allergic adults (46 active, 21 placebo). The repeat‐dose cohort received six doses over 16 weeks with safety monitored to 21 weeks. Exploratory immunological analyses were performed at pre‐dose, Week 21 and Month 18 after treatment. Results: PVX108 induced negligible activation of peanut‐sensitised basophils. PVX108 was safe and well tolerated in peanut‐allergic adults. There were no treatment‐related hypersensitivity events or AEs of clinical concern. The only events occurring more frequently in active than placebo were mild injection site reactions. Exploratory immunological analyses revealed a decrease in the ratio of ST2+ Th2A:CCR6+ Th17‐like cells within the peanut‐reactive Th pool which strengthened following treatment. Conclusion: This study supports the concept that PVX108 could provide a safe alternative to whole peanut immunotherapies and provides evidence of durable peanut‐specific T‐cell modulation. Translation of these findings to clinical efficacy in ongoing Phase 2 trials would provide important proof‐of‐concept for using peptides to treat food allergy. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Heterozygous mutations in the GRN gene lead to reduced progranulin (PGRN) levels in plasma and cerebrospinal fluid (CSF) and are causative of frontotemporal dementia (FTD) with > 90% penetrance. Latozinemab is a human monoclonal immunoglobulin G1 antibody that is being developed to increase PGRN levels in individuals with FTD caused by heterozygous loss‐of‐function GRN mutations. METHODS: A first‐in‐human phase 1 study was conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of multiple‐dose intravenous administration of latozinemab in eight symptomatic participants with FTD caused by a heterozygous loss‐of‐function GRN mutation (FTD‐GRN). RESULTS: Latozinemab demonstrated favorable safety and PK/PD profiles. Multiple‐dose administration of latozinemab increased plasma and CSF PGRN levels in participants with FTD‐GRN to levels that approximated those seen in healthy volunteers. DISCUSSION: Data from the first‐in‐human phase 1 study support further development of latozinemab for the treatment of FTD‐GRN. Highlights: GRN mutations decrease progranulin (PGRN) and cause frontotemporal dementia (FTD).Latozinemab is being developed as a PGRN‐elevating therapy.Latozinemab demonstrated a favorable safety profile in a phase 1 clinical trial.Latozinemab increased PGRN levels in the CNS of symptomatic FTD‐GRN participants. [ABSTRACT FROM AUTHOR]

IntroductionNipocalimab is a high-affinity, fully human, aglycosylated, effectorless, immunoglobulin G (IgG) 1 monoclonal antibody that targets the neonatal Fc receptor (FcRn), decreases systemic IgG including autoantibodies, and is under development in several IgG autoantibody- and alloantibody-mediated diseases, including generalized myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, maternal-fetal medicine, and multiple other therapeutic areas. An initial phase 1 study with single and multiple ascending doses of nipocalimab infused intravenously (IV) over 2 h demonstrated dose-dependent serum pharmacokinetics and IgG reductions, with an adverse event (AE) profile comparable to placebo.MethodsThe current investigation evaluates the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of nipocalimab across various IV infusion rates in a randomized, double-blind, placebo-controlled, sequential-dose study. Forty participants were randomized to receive nipocalimab 30 mg/kg over 60, 30, 15 or 7.5 min (0.5, 1, 2, or 4 mg/kg/min); nipocalimab 60 mg/kg over 15 min (4 mg/kg/min); or matching placebo.ResultsAt doses up to 60 mg/kg and infusion rates up to 4 mg/kg/min (maximum clinically feasible rate), single doses of nipocalimab were tolerable, with 12 (40%) participants experiencing AEs across nipocalimab cohorts compared with 1 (10%) participant in the placebo cohort. AEs deemed treatment related occurred in 6 (20%) participants receiving nipocalimab and 1 (10%) participant receiving placebo. None of the AEs were severe, and no participants discontinued treatment due to AEs. Nipocalimab provided consistent, dose-dependent serum pharmacokinetics and IgG reductions, regardless of infusion rate.DiscussionThis study supports the use of shortened durations of nipocalimab infusion for future studies.

Abstract INTRODUCTION Heterozygous mutations in the GRN gene lead to reduced progranulin (PGRN) levels in plasma and cerebrospinal fluid (CSF) and are causative of frontotemporal dementia (FTD) with > 90% penetrance. Latozinemab is a human monoclonal immunoglobulin G1 antibody that is being developed to increase PGRN levels in individuals with FTD caused by heterozygous loss‐of‐function GRN mutations. METHODS A first‐in‐human phase 1 study was conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of multiple‐dose intravenous administration of latozinemab in eight symptomatic participants with FTD caused by a heterozygous loss‐of‐function GRN mutation (FTD‐GRN). RESULTS Latozinemab demonstrated favorable safety and PK/PD profiles. Multiple‐dose administration of latozinemab increased plasma and CSF PGRN levels in participants with FTD‐GRN to levels that approximated those seen in healthy volunteers. DISCUSSION Data from the first‐in‐human phase 1 study support further development of latozinemab for the treatment of FTD‐GRN. Highlights GRN mutations decrease progranulin (PGRN) and cause frontotemporal dementia (FTD). Latozinemab is being developed as a PGRN‐elevating therapy. Latozinemab demonstrated a favorable safety profile in a phase 1 clinical trial. Latozinemab increased PGRN levels in the CNS of symptomatic FTD‐GRN participants.

Human respiratory syncytial virus (RSV) causes a substantial proportion of respiratory tract infections worldwide. Although RSV reinfections occur throughout life, older adults, particularly those with underlying comorbidities, are at risk for severe complications from RSV. There is no RSV vaccine available to date, and treatment of RSV in adults is largely supportive. A correlate of protection for RSV has not yet been established, but antibodies targeting the pre-fusion conformation of the RSV F glycoprotein play an important role in RSV neutralization. We previously reported a Phase 1 study of an mRNA-based vaccine (V171) expressing a pre-fusion-stabilized RSV F protein (mDS-Cav1) in healthy adults. Here, we evaluated an mRNA-based vaccine (V172) expressing a further stabilized RSV pre-fusion F protein (mVRC1). mVRC1 is a single chain version of RSV F with interprotomer disulfides in addition to the stabilizing mutations present in the mDS-Cav1 antigen. The immunogenicity of the two mRNA-based vaccines encoding mVRC1 (V172) or a sequence-optimized version of mDS-Cav1 to improve transcriptional fidelity (V171.2) were compared in RSV-naïve and RSV-experienced African green monkeys (AGMs). V172 induced higher neutralizing antibody titers than V171.2 and demonstrated protection in the AGM challenge model. We conducted a Phase 1, randomized, placebo-controlled, clinical trial of 25 μg, 100 μg, 200 μg, or 300 μg of V172 in healthy older adults (60–79 years old; N = 112) and 100 μg, 200 μg, or 300 μg of V172 in healthy younger adults (18–49 years old; N = 48). The primary clinical objectives were to evaluate the safety and tolerability of V172, and the secondary objective was to evaluate RSV serum neutralization titers. The most commonly reported solicited adverse events were injection-site pain, injection-site swelling, headache, and tiredness. V172 was generally well tolerated in older and younger adults and increased serum neutralizing antibody titers, pre-fusion F-specific competing antibody titers, and RSV F-specific T-cell responses. [ABSTRACT FROM AUTHOR]

• Three doses of novel subtype C gp145 Env protein with alum in a Phase 1 HIV vaccine trial were safe and well-tolerated. • Participants demonstrated effector binding antibodies, Env-specific CD4 + T-cell, and tier 1 neutralizing antibodies. • However, the regimen failed to induce tier 2 or heterologous neutralizing antibody responses. An approach to a preventive HIV vaccine is induction of effective broadly neutralizing antibodies (bnAbs) and effector binding antibodies (bAbs). Preclinical studies suggest that trimeric envelope (Env) proteins may elicit nAbs, which led to the development of the recombinant gp145 subtype C Env protein (gp145 C.6980) immunogen. HVTN 122 was a Phase 1 trial that evaluated the safety, tolerability, and immunogenicity of gp145 C.6980 in adults. Healthy, HIV-1 seronegative adults received three intramuscular injections of gp145 C.6980 with aluminum hydroxide (alum) at months 0, 2, and 6 at either 300 mcg (high dose, n = 25) or 100 mcg (low dose, n = 15), or placebo/saline (placebo, n = 5). Participants were followed for 12 months. Forty-five participants were enrolled. High and low doses of the study protein were well-tolerated, with mild or moderate reactogenicity commonly reported. Only one adverse event (mild injection site pruritis) in one participant (low dose) was considered product-related; there were no dose-limiting toxicities. High and low dose recipients demonstrated robust bAb responses to vaccine-matched consensus gp140 Env and subtype-matched gp120 Env proteins two weeks post-last vaccination (response rates >90 %), while no responses were detected to a heterologous subtype-matched V1V2 antigen. No significant differences were seen between high and low dose groups. Participants in both experimental arms demonstrated nAb response rates of 76.5 % to a tier 1 virus (MW9635.26), but no responses to tier 2 isolates. Env-specific CD4 + T-cell responses were elicited in 36.4 % of vaccine recipients, without significant differences between groups; no participants demonstrated CD8 + T-cell responses. Three doses of novel subtype C gp145 Env protein with alum were safe and well-tolerated. Participants demonstrated bAb, Env-specific CD4 + T-cell, and tier 1 nAb responses, but the regimen failed to induce tier 2 or heterologous nAb responses. Clinical Trials Registration: NCT03382418 [ABSTRACT FROM AUTHOR]

BackgroundAcute myeloid leukemia (AML) is a heterogenous malignancy driven by genetic and epigenetic factors. Inhibition of bromodomain and extraterminal (BET) proteins, epigenetic readers that play pivotal roles in the regulation of genes relevant to cancer pathogenesis, constitutes a novel AML treatment approach.MethodsIn this first-in-human study of the pan-BET inhibitor mivebresib as monotherapy (MIV-mono) or in combination with venetoclax (MIV-Ven), the safety profile, efficacy, and pharmacodynamics of mivebresib were determined in patients with relapsed/refractory AML (ClinicalTrials.gov identifier NCT02391480). Mivebresib was administered at 3 monotherapy dose levels (1.5, 2.0, or 2.5 mg) or in combination with venetoclax (400 or 800 mg).ResultsForty-four patients started treatment: of 19 who started MIV-mono, 5 went on to receive MIV-Ven combination therapy after disease progression and a washout period. Twenty-five patients started MIV-Ven, resulting in a total of 30 patients treated with the combination. The most common mivebresib-related treatment-emergent adverse events were dysgeusia (74%), decreased appetite (42%), and diarrhea (42%) in the MIV-mono group and decreased appetite (44%), vomiting (44%), and nausea (40%) in the MIV-Ven group. Serious adverse events occurred in 14 patients (74%) who received MIV-mono and in 22 patients (88%) who received MIV-Ven. In the MIV-mono group, responses were complete remission with incomplete blood count recovery in 1 patient and resistant disease in 15 patients. In the MIV-Ven group, responses were complete remission in 2 patients, partial remission in 2 patients, morphologic leukemia-free state in 2 patients, resistant disease in 12 patients, and aplasia in 1 patient. The pharmacodynamic effects of mivebresib were proportional to dose and drug exposure.ConclusionsMivebresib was tolerated and showed antileukemic effects as monotherapy and in combination with venetoclax in patients with relapsed/refractory AML.Lay summaryMivebresib is a novel drug that influences the way cancer cells read genetic information. Mivebresib was tested together with venetoclax in patients with acute myeloid leukemia after standard medicines failed and the disease returned, or when standard medicine was unavailable. Adverse effects were described for different drug doses, and the dose that is tolerable was determined. In some patients, their leukemia improved for some time. More studies are necessary to determine whether mivebresib can be used to treat acute myeloid leukemia.

Abstract Background Heterozygous loss-of-function mutations in the progranulin (PGRN) gene (GRN) cause a reduction in PGRN and lead to the development of frontotemporal dementia (FTD-GRN). PGRN is a secreted lysosomal chaperone, immune regulator, and neuronal survival factor that is shuttled to the lysosome through multiple receptors, including sortilin. Here, we report the characterization of latozinemab, a human monoclonal antibody that decreases the levels of sortilin, which is expressed on myeloid and neuronal cells and shuttles PGRN to the lysosome for degradation, and blocks its interaction with PGRN. Methods In vitro characterization studies were first performed to assess the mechanism of action of latozinemab. After the in vitro studies, a series of in vivo studies were performed to assess the efficacy of a mouse-cross reactive anti-sortilin antibody and the pharmacokinetics, pharmacodynamics, and safety of latozinemab in nonhuman primates and humans. Results In a mouse model of FTD-GRN, the rodent cross-reactive anti-sortilin antibody, S15JG, decreased total sortilin levels in white blood cell (WBC) lysates, restored PGRN to normal levels in plasma, and rescued a behavioral deficit. In cynomolgus monkeys, latozinemab decreased sortilin levels in WBCs and concomitantly increased plasma and cerebrospinal fluid (CSF) PGRN by 2- to threefold. Finally, in a first-in-human phase 1 clinical trial, a single infusion of latozinemab caused a reduction in WBC sortilin, tripled plasma PGRN and doubled CSF PGRN in healthy volunteers, and restored PGRN to physiological levels in asymptomatic GRN mutation carriers. Conclusions These findings support the development of latozinemab for the treatment of FTD-GRN and other neurodegenerative diseases where elevation of PGRN may be beneficial. Trial registration ClinicalTrials.gov, NCT03636204. Registered on 17 August 2018, https://clinicaltrials.gov/ct2/show/NCT03636204 .

Abstract Background FIGHT‐102 was a phase 1, dose‐escalation, dose‐expansion study of pemigatinib in Japanese patients with advanced solid tumors. Here, we report safety, tolerability, and preliminary efficacy of pemigatinib from FIGHT‐102. Methods Patients (≥20 years old) self‐administered oral pemigatinib 9, 13.5, or 18 mg QD on intermittent dosing (Part 1) or 13.5 mg QD intermittent or continuous dosing (Part 2). A dosing cycle was 21 days (2 weeks on/1 week off or 21 continuous days). Primary endpoint was safety. Secondary endpoints were pharmacokinetics, pharmacodynamics, and preliminary efficacy. Results Forty‐four patients (Part 1, n = 14; Part 2, n = 30) were enrolled; most common tumors, cholangiocarcinoma, n = 8; esophageal, n = 6; 26 patients had confirmed FGF/FGFR alterations (Part 1, n = 3; Part 2, n = 23); 70.5% had ≥3 prior systemic therapies. Maximum tolerated dose was not identified. The recommended phase 2 dosage was determined to be 13.5 mg QD. Most common treatment‐emergent adverse events (TEAEs) were hyperphosphatemia (81.8%), dysgeusia (45.5%), stomatitis (43.2%), and alopecia (38.6%); most frequent Grade ≥3 TEAEs were anemia and decreased appetite (9.1% each). In Part 1, no patient achieved partial response (PR) or complete response, and 7 (50.0%) patients had stable disease (SD). In Part 2, 5 (16.7%) patients achieved PR (one each with cholangiocarcinoma, gall bladder cancer, breast cancer, urothelial tract/bladder cancer, and sweat gland carcinoma) and 6 (20%) had SD. Median duration of response was 9.56 months (95% CI: 4.17, 14.95). Conclusions Pemigatinib demonstrated manageable adverse events, consistent pharmacokinetics and pharmacodynamics profiles, and preliminary efficacy in Japanese patients with advanced solid tumors.

IntroductionAllopregnanolone is an endogenous neurosteroid with the potential to be a novel regenerative therapeutic for Alzheimer's disease (AD). Foundations of mechanistic understanding and well-established preclinical safety efficacy make it a viable candidate.MethodsA randomized, double-blinded, placebo-controlled, single and multiple ascending dose trial was conducted. Intravenous allopregnanolone or placebo was administered once-per-week for 12 weeks with a 1-month follow-up. Participants with early AD (mild cognitive impairment due to AD or mild AD), a Mini-Mental State Examination score of 20-26 inclusive, and age ≥55 years were randomized (6:2 to three allopregnanolone dosing cohorts or one placebo cohort). Primary endpoint was safety and tolerability. Secondary endpoints included pharmacokinetic (PK) parameters and maximally tolerated dose (MTD). Exploratory endpoints included cognitive and imaging biomarkers.ResultsA total of 24 participants completed the trial. Allopregnanolone was safe and well tolerated in all study participants. No differences were observed between treatment arms in the occurrence and severity of adverse events (AE). Most common AE were mild to moderate in severity and included rash (n = 4 [22%]) and fatigue (n = 3 [17%]). A single non-serious AE, dizziness, was attributable to treatment. There was one serious AE not related to treatment. Pharmacokinetics indicated a predictable linear dose-response in plasma concentration of allopregnanolone after intravenous administration over 30 minutes. The maximum plasma concentrations for the 2 mg, 4 mg, 6 mg, and 10 mg dosages were 14.53 ng/mL (+/-7.31), 42.05 ng/mL (+/-14.55), 60.07 ng/mL (+/-12.8), and 137.48 ng/mL (+/-38.69), respectively. The MTD was established based on evidence of allopregnanolone-induced mild sedation at the highest doses; a sex difference in the threshold for sedation was observed (males 10 mg; females 14 mg). No adverse outcomes on cognition or magnetic resonance imaging-based imaging outcomes were evident.ConclusionsAllopregnanolone was well tolerated and safe across all doses in persons with early AD. Safety, MTD, and PK profiles support advancement of allopregnanolone as a regenerative therapeutic for AD to a phase 2 efficacy trial.Trial registrationClinicalTrials.gov-NCT02221622.

Background: Heterozygous loss-of-function mutations in the progranulin (PGRN) gene (GRN) cause a reduction in PGRN and lead to the development of frontotemporal dementia (FTD-GRN). PGRN is a secreted lysosomal chaperone, immune regulator, and neuronal survival factor that is shuttled to the lysosome through multiple receptors, including sortilin. Here, we report the characterization of latozinemab, a human monoclonal antibody that decreases the levels of sortilin, which is expressed on myeloid and neuronal cells and shuttles PGRN to the lysosome for degradation, and blocks its interaction with PGRN. Methods: In vitro characterization studies were first performed to assess the mechanism of action of latozinemab. After the in vitro studies, a series of in vivo studies were performed to assess the efficacy of a mouse-cross reactive anti-sortilin antibody and the pharmacokinetics, pharmacodynamics, and safety of latozinemab in nonhuman primates and humans. Results: In a mouse model of FTD-GRN, the rodent cross-reactive anti-sortilin antibody, S15JG, decreased total sortilin levels in white blood cell (WBC) lysates, restored PGRN to normal levels in plasma, and rescued a behavioral deficit. In cynomolgus monkeys, latozinemab decreased sortilin levels in WBCs and concomitantly increased plasma and cerebrospinal fluid (CSF) PGRN by 2- to threefold. Finally, in a first-in-human phase 1 clinical trial, a single infusion of latozinemab caused a reduction in WBC sortilin, tripled plasma PGRN and doubled CSF PGRN in healthy volunteers, and restored PGRN to physiological levels in asymptomatic GRN mutation carriers. Conclusions: These findings support the development of latozinemab for the treatment of FTD-GRN and other neurodegenerative diseases where elevation of PGRN may be beneficial. Trial registration ClinicalTrials.gov, NCT03636204. Registered on 17 August 2018, https://clinicaltrials.gov/ct2/show/NCT03636204. [ABSTRACT FROM AUTHOR]

Background: FIGHT‐102 was a phase 1, dose‐escalation, dose‐expansion study of pemigatinib in Japanese patients with advanced solid tumors. Here, we report safety, tolerability, and preliminary efficacy of pemigatinib from FIGHT‐102. Methods: Patients (≥20 years old) self‐administered oral pemigatinib 9, 13.5, or 18 mg QD on intermittent dosing (Part 1) or 13.5 mg QD intermittent or continuous dosing (Part 2). A dosing cycle was 21 days (2 weeks on/1 week off or 21 continuous days). Primary endpoint was safety. Secondary endpoints were pharmacokinetics, pharmacodynamics, and preliminary efficacy. Results: Forty‐four patients (Part 1, n = 14; Part 2, n = 30) were enrolled; most common tumors, cholangiocarcinoma, n = 8; esophageal, n = 6; 26 patients had confirmed FGF/FGFR alterations (Part 1, n = 3; Part 2, n = 23); 70.5% had ≥3 prior systemic therapies. Maximum tolerated dose was not identified. The recommended phase 2 dosage was determined to be 13.5 mg QD. Most common treatment‐emergent adverse events (TEAEs) were hyperphosphatemia (81.8%), dysgeusia (45.5%), stomatitis (43.2%), and alopecia (38.6%); most frequent Grade ≥3 TEAEs were anemia and decreased appetite (9.1% each). In Part 1, no patient achieved partial response (PR) or complete response, and 7 (50.0%) patients had stable disease (SD). In Part 2, 5 (16.7%) patients achieved PR (one each with cholangiocarcinoma, gall bladder cancer, breast cancer, urothelial tract/bladder cancer, and sweat gland carcinoma) and 6 (20%) had SD. Median duration of response was 9.56 months (95% CI: 4.17, 14.95). Conclusions: Pemigatinib demonstrated manageable adverse events, consistent pharmacokinetics and pharmacodynamics profiles, and preliminary efficacy in Japanese patients with advanced solid tumors. [ABSTRACT FROM AUTHOR]

Botulism is caused by botulinum neurotoxin (BoNT), the most poisonous substance known. BoNTs are also classified as Tier 1 biothreat agents due to their high potency and lethality. The existence of seven BoNT serotypes (A-G), which differ between 35% to 68% in amino acid sequence, necessitates the development of serotype specific countermeasures. We present results of a Phase 1 clinical study of an anti-toxin to BoNT serotypes C and D, NTM-1634, which consists of an equimolar mixture of four fully human IgG1 monoclonal antibodies (mAbs), each binding to non-overlapping epitopes on BoNT serotypes C and D resulting in potent toxin neutralization in rodents. This first-in-human study evaluated the safety and pharmacokinetics of escalating doses of NTM-1634 administered intravenously to healthy adults (NCT03046550). Three cohorts of eight healthy subjects received a single intravenous dose of NTM-1634 or placebo at 0.33 mg/kg, 0.66 mg/kg or 1 mg/kg. Follow-up examinations and pharmacokinetic evaluations were continued up to 121 days post-infusion. Subjects were monitored using physical examinations, hematology and chemistry blood tests, and electrocardiograms. Pharmacokinetic parameters were estimated using noncompartmental methods. The results demonstrated that the materials were safe and well-tolerated with the expected half-lives for human mAbs and with minimal anti-drug antibodies detected over the dose ranges and duration of the study.

Summary: Background: Impaired wound healing is a growing medical problem and very few approved drugs with documented clinical efficacy are available. CXCL12-expressing lactic acid bacteria, Limosilactobacillus reuteri (ILP100-Topical), has been demonstrated to accelerate wound healing in controlled preclinical models. In this first-in-human study, the primary objective was to determine safety and tolerability of the drug candidate ILP100-Topical, while secondary objectives included assessments of clinical and biologic effects on wound healing by traditionally accepted methods and explorative and traceable assessments. Methods: SITU-SAFE is an adaptive, randomised, double-blind, placebo-controlled, first-in-human phase 1 trial (EudraCT 2019-000680-24) consisting of a single (SAD) and a multiple ascending dose (MAD) part of three dose cohorts each. The study was performed at the Phase 1 Unit, Uppsala University Hospital, Uppsala, Sweden. Data in this article were collected between Sep 20th, 2019 and Oct 20th 2021. In total 240 wounds were induced on the upper arms in 36 healthy volunteers. SAD: 12 participants, 4 wounds (2/arm), MAD: 24 participants, 8 wounds (4/arm). Wounds in each participant were randomised to treatment with placebo/saline or ILP100-Topical. Findings: In all individuals and doses, ILP100-Topical was safe and well-tolerated with no systemic exposure. A combined cohort analysis showed a significantly larger proportion of healed wounds (p = 0.020) on Day 32 by multi-dosing of ILP100-Topical when compared to saline/placebo (76% (73/96) and 59% (57/96) healed wounds, respectively). In addition, time to first registered healing was shortened by 6 days on average, and by 10 days at highest dose. ILP100-Topical increased the density of CXCL12+ cells in the wounds and local wound blood perfusion. Interpretation: The favourable safety profile and observed effects on wound healing support continued clinical development of ILP100-Topical for the treatment of complicated wounds in patients. Funding: Ilya Pharma AB (Sponsor), H2020 SME Instrument Phase II (#804438), Knut and Alice Wallenberg foundation.

Purpose: Belinostat is an intravenous histone deacetylase inhibitor with approval for T-cell lymphomas. Adavosertib is a first in class oral Wee1 inhibitor. Preclinical studies of the combination demonstrated synergy in various human acute myeloid leukemia (AML) lines as well as AML xenograft mouse models. Experimental design: This was a phase 1 dose-escalation study of belinostat and adavosertib in patients with relapsed/refractory AML and myelodysplastic syndrome (MDS). Patients received both drugs on days 1–5 and 8–12 of a 21-day cycle. Safety and toxicity were monitored throughout the study. Plasma levels of both drugs were measured for pharmacokinetic analysis. Response was determined by standard criteria including bone marrow biopsy. Results: Twenty patients were enrolled and treated at 4 dose levels. A grade 4 cytokine release syndrome at dose level 4 (adavosertib 225 mg/day; belinostat 1000 mg/m2) qualified as a dose-limiting toxicity event. The most common non-hematologic treatment-related adverse events were nausea, vomiting, diarrhea, dysgeusia, and fatigue. No responses were seen. The study was terminated prior to maximum tolerated dose/recommended phase 2 dose determination. Conclusions: The combination of belinostat and adavosertib at the tested dose levels was feasible but without efficacy signals in the relapsed/refractory MDS/AML population. [ABSTRACT FROM AUTHOR]

• Japanese adults aged 20–55 years or ≥ 65 years received Ad26.COV2.S or placebo. • A homologous booster dose was given 2 months (56 days) after the first dose. • Reactogenicity was increased with the higher dose (1 × 1011 vp) in both age groups. • Post-booster immunogenicity was higher in younger versus older adults. • Neutralizing and binding antibody levels peaked at/around Day 71 in both age groups. This study evaluated safety, reactogenicity, and immunogenicity of a 2-month homologous booster regimen of Ad26.COV2.S in Japanese adults. In this multicenter, placebo-controlled, Phase 1 trial, adults (Cohort 1, aged 20–55 years, N = 125; Cohort 2, aged ≥ 65 years, N = 125) were randomized 2:2:1 to receive Ad26.COV2.S 5 × 1010 viral particles (vp), Ad26.COV2.S 1 × 1011 vp, or placebo, followed by a homologous booster 56 days later. Safety, reactogenicity, and immunogenicity were assessed. Two hundred participants received Ad26.COV2.S and 50 received placebo. The most frequent solicited local adverse event (AE) was vaccination-site pain, and the most frequent solicited systemic AEs were fatigue, myalgia, and headache. After primary vaccination, neutralizing and binding antibody levels increased through Day 57 (post-prime) in both cohorts. Fourteen days after boosting (Day 71), neutralizing antibody geometric mean titers (GMTs) had almost reached their peak value in Cohort 1 (5 × 1010 vp: GMT = 1049; 1 × 1011 vp: GMT = 1470) and peaked in Cohort 2 (504; 651); at Day 85, GMTs had declined minimally in Cohort 2. For both cohorts, binding antibody levels peaked at Day 71 with minimal decline at Day 85. A single dose and homologous Ad26.COV2.S booster increased antibody responses with an acceptable safety profile in Japanese adults (ClinicalTrials.gov Identifier: NCT04509947). [ABSTRACT FROM AUTHOR]

Background: Improving clinical trial design is important for optimizing approval of safe and effective drugs. Phase 1 clinical trials seek to determine phase 2 doses by investigating predefined dose‐limiting toxicities. Traditional definitions of dose‐limiting toxicity may not be applicable to intravesical therapies for bladder cancer. This study compared the frequency of dose‐limiting toxicities and serious adverse events in bladder cancer trials for intravesical therapies to other routes of administration. Methods: Studies were abstracted from ClinicalTrials.gov and reconciled with a PubMed search. Primary and secondary end points were predefined before data abstraction, and the primary end point was subject–level dose‐limiting toxicity rate. Fisher exact tests were performed with p <.05 designated as significant. Results: Eighteen intravesical studies and 24 studies with other routes of administration (the per os/intravenous/intramuscular [PO/IV/IM] group) were identified. Dose‐limiting toxicities were reported in 38.9% of intravesical studies, affecting 3.29% of subjects, compared with 30.0% of PO/IV/IM studies representing 4.19% of subjects (p =.52 for study‐level and p =.60 for subject‐level comparisons). Serious adverse events occurred in 53.9% of intravesical studies in 10.3% of subjects versus 91.0% of studies reporting serious adverse events affecting 41.4% of subjects in the PO/IV/IM group (p =.03 for subject‐level and p <.0001 for study‐level comparisons). Conclusions: There was no difference in subject–level dose‐limiting toxicity rate between intravesical and PO/IV/IM bladder cancer trials. The serious adverse event rate was lower in the intravesical group. Heterogeneity of dose‐limiting toxicity definition may affect interpretation of toxicity in phase 1 bladder cancer clinical trials studying different routes of administration. Lay summary: Bladder cancer is a common cancer type that may be treated with therapies that are instilled into the bladder and act locally, called intravesical therapies.This study used publicly available regulatory data from early phase clinical trials to determine whether measures of tolerability used in clinical trials are applicable to intravesical therapies for bladder cancer. In phase 1 studies, dose‐limiting toxicity may not adequately represent the tolerability of intravesical therapies for bladder cancer. Measures other than dose‐limiting toxicities demonstrate increased tolerability of these therapies compared to therapies with other routes of administration. [ABSTRACT FROM AUTHOR]

Despite the increased number of novel immunotherapy (IO) agents under current development, their toxicity profile remains to be fully elucidated. An IO risk stratification model was developed based on 5 different variables: treatment-related deaths; rate of grade ≥3 treatment-related adverse events or treatment-emergent adverse events; grade ≥2 encephalopathy or central nervous system toxicity; grade ≥2 cytokine release syndrome; and the number and type of dose-limiting toxicity. Phase 1 IO trials published from January 2014 to December 2020 were reviewed and categorised based on our risk stratification model into three categories: low-, intermediate- and high-risk. Clinical trial variables were associated with the high-risk category. To review the quality of reporting across phase 1 IO trials, a subset of studies was further examined by the use of the ASCO/SITC Trial Reporting in Immuno-Oncology (TRIO) standards. Different IO compounds demonstrated diverse risk profiles. In multivariable analysis, combination versus IO single agent treatment, and testing IO agents different from anti-programmed death-1/programmed death ligand-1 (anti-PD1/L1), anti-cytotoxic t-lymphocyte antigen-4 (anti-CTLA4) antibodies and anti-cancer vaccines were associated with a higher toxicity risk. None of the studies examined in our dataset reported all the items included in the TRIO standards. Our results have important implications for future clinical trial design. Additionally, standards for reporting are urgently needed. • The toxicity of novel immunotherapy (IO) agents remains to be fully elucidated. • A risk stratification model for phase 1 IO clinical trials was developed. • Published phase 1 trials were classified into low-, intermediate- or high-risk. • IO regimen and IO class were associated with different risks of toxicity. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) and its progression are thought to be caused and driven by misfolding of α‐synuclein (ASYN). UCB0599 is an oral, small‐molecule inhibitor of ASYN misfolding, aimed at slowing disease progression. Objective: The aim was to investigate safety/tolerability and pharmacokinetics (PK) of single and multiple doses of UCB0599. Methods: Safety/tolerability and PK of single and multiple doses of UCB0599 and its metabolites were investigated in two phase 1 studies in healthy participants (HPs), where food effect and possible interaction with itraconazole (ITZ) were assessed (UP0030 [randomized, placebo‐controlled, dose‐escalation, crossover study, N = 65] and UP0078 [open‐label study, N = 22]). Safety/tolerability and multi‐dose PK of UCB0599 were subsequently investigated in a phase 1b randomized, double‐blind, placebo‐controlled study of participants with PD (UP0077 [NCT04875962], N = 31). Results: Across all studies, UCB0599 displayed rapid absorption with linear, time‐independent PK properties; PK of multiple doses of UCB0599 were predictable from single‐dose exposures. No notable food‐effect was observed; co‐administration with ITZ affected UCB0599 disposition (maximum plasma concentration and area under the curve increased ~1.3‐ and ~2 to 3‐fold, respectively) however, this did not impact the safety profile. Hypersensitivity reactions were reported in UP0030 (n = 2) and UP0077 (n = 2). Treatment‐related adverse events occurred in 43% (UCB0599), and 30% (placebo) of participants with PD were predominantly mild‐to‐moderate in intensity and were not dose related. Conclusions: Seventy‐three HPs and 21 participants with PD received UCB0599 doses; an acceptable safety/tolerability profile and predictable PK support continued development of UCB0599 for the slowing of PD progression. A phase 2 study in early‐stage PD is underway (NCT04658186). © 2022 UCB Pharma. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Selective internal radiation therapy (SIRT) has a potential role in patients with renal cell carcinoma (RCC) who are unsuitable for conventional treatment. RESIRT is the first prospective trial investigating SIRT for RCC. Intended doses were delivered without any dose-limiting toxicity. SIRT may be a treatment option for RCC unsuitable for conventional therapy and warrants further clinical study. Introduction: Selective internal radiation therapy (SIRT) is a potential treatment of primary renal cell carcinoma (RCC) deemed unsuitable for conventional therapy. RESIRT is the first-in-human study to evaluate safety and feasibility of SIRT for primary RCC. Patients and Methods: Patients with RCC, unsuitable for, or who declined conventional therapy, were eligible. A single transfemoral micro-catheter administration of yttrium-90 (Y-90) resin microspheres (SIR-Spheres) was delivered super selectively via the renal artery to the tumour at intended radiation doses of 75, 100, 150, 200, 300 Gy and a final cohort with a procedural endpoint of "imminent stasis," in a dose-escalation design. Post-SIRT follow-up was 12 months. Study endpoints included safety and toxicity 30-days and 12-months post-SIRT and tumour response (RECIST v1.1). Results: In total, 21 patients were enrolled, mean (SD) age was 75 (9.3) years, WHO performance status was 0 in 81%, 12 (57%) had stage 3 chronic kidney disease, and 7 (33%) had prior contralateral nephrectomy. Overall, 71% of patients completed 12 months of follow-up. Intended doses were delivered without any dose-limiting toxicity. Seventeen out of 21 (81%) patients experienced an adverse event (AE) from any cause within 30 days post-SIRT; all SIRT-related AEs were grade 1 to 2. Best overall tumour responses were partial response 1/21 (4.8%), stable disease 19/21 (90.5%) and progressive disease 1/21 (4.8%). Conclusion: This study demonstrated good tolerability of SIRT at all dose levels including "imminent stasis" in treating primary tumours in RCC patients otherwise unsuitable for conventional therapy. SIRT with Y-90 resin microspheres may be a feasible treatment option for RCC. [ABSTRACT FROM AUTHOR]

Background: Methoxyethyl etomidate hydrochloride (ET-26) is a novel etomidate analogue. This is the first-in-human study of a bolus i.v. formulation of ET-26 to assess its safety, tolerability, hypnotic effects, and pharmacokinetics., Methods: We enrolled 58 subjects in a dose-escalating study (stage 1a, 10 cohorts, ET-26 0.05-2.8 mg kg -1 ) and 40 subjects in a head-to-head study (stage 1b, four cohorts). Safety estimates included vital signs, adverse events, physical examination, and laboratory tests. Hypnotic effects were evaluated using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale, bispectral index, loss of eyelash reflex, and response to pain. Adrenocortical function was assessed using plasma total cortisol (PTC), and area above the PTC baseline (AUC PTC ) after adrenocorticotropic hormone stimulation. Pharmacokinetics of plasma ET-26 concentrations were investigated., Results: No severe adverse events occurred; the most common adverse events were myoclonus (53.8%) and injection pain (47.4%), which were transient and resolved spontaneously. Vital signs remained stable. ET-26 produced rapid-onset, short-duration unconsciousness. At the 95% effective dose (ED 95 , 0.8 mg kg -1 ), ET-26 produced unconsciousness with a similar onset time (1.9 [0.6] min vs 2.1 [1.3] min) and slightly shorter duration (2.9 [0.9] vs 4.8 [1.8]) compared with etomidate 0.3 mg kg -1 , and resulted in higher AUC PTC (614 [454] vs -932 [555] nmol h -1 ). ET-26 showed linear pharmacokinetics, and a two-compartment model best described the pharmacokinetics., Conclusions: ET-26 was tolerated in healthy volunteers up to 2.8 mg kg -1 . It produced rapid-onset, short-acting unconsciousness with stable cardiovascular and respiratory properties. Adrenocortical function was better preserved compared with etomidate 0.3 mg kg -1 ., Clinical Trial Registration: ChiCTR2100047525 (https://www.chictr.org.cn/index.aspx, ChiCTR2100047525)., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

A dose-escalation, randomized, double-blind, placebo-controlled phase 1 clinical trial enrolled 145 eligible participants aged 18–55 years in March 2015 in Liuzhou, China. Stratified by age and sex, the participants were randomly assigned to receive either 30, 60, or 90 μg of the HPV-6/11 vaccine (n = 41/40/40) or the parallel placebo vaccine (n = 8/8/8) with a 0/1/6-month dose-escalation schedule. Participants were actively followed-up to record local and systemic AEs occurring within 30 days after each vaccination, and SAEs occurred in 7 months. Blood and urine samples of each participant were collected before and 2 days after the first and third vaccination to determine changes in routine blood, serum biochemical, and urine indexes. Serum HPV-6/11-specific IgG and neutralizing antibody levels at month 7 were analyzed. A total of 79 adverse events were reported, and no SAEs occurred. The incidences of total adverse reactions in the 30 μg, 60 μg, and 90 μg HPV vaccine groups and the control group were 31.7%, 50.0%, 42.5%, and 62.5%, respectively. All but one of the adverse reactions was mild or moderate with grade 1 or 2. No vaccine-related changes with clinical significance were found in paired blood and urine indexes before and after vaccinations. All the participants in the per-protocol set seroconverted at month 7 for both IgG and neutralizing antibodies. The candidate novel Escherichia-coli-produced bivalent HPV-6/11 vaccine has been preliminarily proven to be well tolerated and with robust immunogenicity in a phase 1 clinical study, supporting further trials with larger sample size. The study has been registered at ClinicalTrials.gov (NCT02405520)

Phase 1 immuno-oncology (IO) trials frequently involve pharmacodynamic (PD) biomarker assessments involving tumour biopsies and/or blood collection, with increasing use of molecular imaging. PD biomarkers are set to play a fundamental role in early drug development of immuno-oncology (IO) agents. In the IO era, the impact of PD biomarkers for confirmation of biologic activity and their role in subsequent drug development have not been investigated. Phase 1 studies published between January 2014 and December 2020 were reviewed. Studies that reported on-treatment PD biomarkers [tissue-derived (tissue-PD), blood-based (blood-PD) and imaging-based (imaging-PD)] were analysed. PD biomarker results and their correlation with clinical activity endpoints were evaluated. Authors' statements on the influence of PD biomarkers on further drug development decisions, and subsequent citations of PD biomarker study results were recorded. Among 386 trials, the most frequent IO agent classes evaluated were vaccines (32%) and PD-(L)1 inhibitors (25%). No PD biomarker assessments were reported in 100 trials (26%). Of the remaining 286, blood-PD, tissue-PD, and imaging-PD data were reported in 270 (94%), 94 (33%), and 12 (4%) trials, respectively. Assessments of more than one PD biomarker type were reported in 82 studies (29%). Similar proportions of blood-PD (9%), tissue-PD (7%), and imaging-PD studies (8%) had positive results that correlated with clinical activity. Results of 22 PD biomarker studies (8%) were referenced in subsequent clinical trials. Most phase 1 IO studies performed PD biomarker assessments. Overall, positive PD biomarker results were infrequently correlated with clinical activity or cited in subsequent trials, suggesting a limited impact on subsequent drug development. With emerging health regulatory emphasis on optimal dose selection based on PD activity, more informative and integrative multiplexed assays that capture the complexity of tumour-host immunity interactions are warranted to improve phase 1 IO trial methodology. • 386 Phase 1 IO trials reviewed and 74% reported PD biomarkers (PD). • 94% of PD biomarkers were blood-based; 33% were tissue-based; 4% were imaging- based. • Evaluation of immune cell subsets in the circulation and/or tissue were most common. • Under 10% of PD correlated with clinical activity, or were subsequently referenced. • With greater emphasis on dose optimization, more informative PD assays are warranted. [ABSTRACT FROM AUTHOR]

Background: New strategies to increase measles and rubella vaccine coverage, particularly in low- and middle-income countries, are needed if elimination goals are to be achieved. With this regard, measles and rubella vaccine microneedle patches (MRV-MNP), in which the vaccine is embedded in dissolving microneedles, offer several potential advantages over subcutaneous delivery. These include ease of administration, increased thermostability, an absence of sharps waste, reduced overall costs and pain-free administration. This trial will provide the first clinical trial data on MRV-MNP use and the first clinical vaccine trial of MNP technology in children and infants.Methods: This is a phase 1/2, randomized, active-controlled, double-blind, double-dummy, age de-escalation trial. Based on the defined eligibility criteria for the trial, including screening laboratory investigations, 45 adults [18-40 years] followed by 120 toddlers [15-18 months] and 120 infants [9-10 months] will be enrolled in series. To allow double-blinding, participants will receive either the MRV-MNP and a placebo (0.9% sodium chloride) subcutaneous (SC) injection or a placebo MNP and the MRV by SC injection (MRV-SC). Local and systemic adverse event data will be collected for 14 days following study product administration. Safety laboratories will be repeated on day 7 and, in the adult cohort alone, on day 14. Unsolicited adverse events including serious adverse events will be collected until the final study visit for each participant on day 180. Measles and rubella serum neutralizing antibodies will be measured at baseline, on day 42 and on day 180. Cohort progression will be dependent on review of the unblinded safety data by an independent data monitoring committee.Discussion: This trial will provide the first clinical data on the use of a MNP to deliver the MRV and the first data on the use of MNPs in a paediatric population. It will guide future product development decisions for what may be a key technology for future measles and rubella elimination.Trial Registration: Pan-African Clinical Trials Registry 202008836432905 .Clinicaltrials: gov NCT04394689. [ABSTRACT FROM AUTHOR]

Objective: This article identifies the core values that play a role in patients' decision-making process about participation in early-phase clinical cancer trials.Methods: Face-to-face, semi-structured serial interviews (n = 22) were performed with thirteen patients with advanced cancer recruited in two Dutch specialized cancer centers. In a cyclic qualitative analysis process, open and axial coding of the interviews finally led to an overview of the values that are woven into patients' common language about cancer and clinical trials.Results: Six core values were described, namely, acceptance creates room for reconsideration of values, reconciliation with one's fate, hope, autonomy, body preservation, and altruism. Previously found values in advanced cancer, such as acceptance, hope, autonomy, and altruism, were further qualified. Reconciliation with one's fate and body preservation were highlighted as new insights for early-phase clinical cancer trial literature.Conclusions: This article furthers the understanding of core values that play a role in the lives and decision-making of patients with advanced cancer who explore participation in early-phase clinical cancer trials. These values do not necessarily have to be compatible with one another, making tragic choices necessary. Understanding the role of core values can contribute to professional sensitivity regarding what motivates patients' emotions, thoughts, and decisions and help patients reflect on and give words to their values and preferences. It supports mutual understanding and dialog from which patients can make decisions according to their perspectives on a good life for themselves and their fellows in the context of participation in an early-phase clinical cancer trial. [ABSTRACT FROM AUTHOR]

Introduction: Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC), and provides a target for a dendritic cell (DC) vaccine. CD137 ligand (CD137L) expressed on antigen presenting cells, costimulates CD137-expressing T cells, and reverse CD137L signaling differentiates monocytes to CD137L-DC, a type of DC, which is more potent than classical DC in stimulating T cells. Methods: In this phase I study, patients with locally recurrent or metastatic NPC were administered CD137L-DC pulsed with EBV antigens (CD137L-DC-EBV-VAX). Results: Of the 12 patients treated, 9 received full 7 vaccine doses with a mean administered cell count of 23.9 × 106 per dose. Treatment was well tolerated with only 4 cases of grade 1 related adverse events. A partial response was obtained in 1 patient, and 4 patients are still benefitting from a progression free survival (PFS) of currently 2–3 years. The mean pre-treatment neutrophil: lymphocyte ratio was 3.4 and a value of less than 3 was associated with prolonged median PFS. Progressors were characterized by a high frequency of naïve T cells but a low frequency of CD8+ effector T cells while patients with a clinical benefit (CB) had a high frequency of memory T cells. Patients with CB had lower plasma EBV DNA levels, and a reduction after vaccination. Conclusion: CD137L-DC-EBV-VAX was well tolerated. The use of CD137L-DC-EBV-VAX is demonstrated to be safe. Consistent results were obtained from all 12 patients, indicating that CD137L-DC-EBV-VAX induces an anti-EBV and anti-NPC immune response, and warranting further studies in patients post effective chemotherapy. Precis. The first clinical testing of CD137L-DC, a new type of monocyte-derived DC, finds that CD137L-DC are safe, and that they can induce an immune response against Epstein-Barr virus-associated nasopharyngeal carcinoma that leads to tumor regression or prevents tumor progression. [ABSTRACT FROM AUTHOR]

Abstract Background Classical phase 1 dose-finding designs based on a single toxicity endpoint to assess the maximum tolerated dose were initially developed in the context of cytotoxic drugs. With the emergence of molecular targeted agents and immunotherapies, the concept of optimal biological dose (OBD) was subsequently introduced to account for efficacy in addition to toxicity. The objective was therefore to provide an overview of published phase 1 cancer clinical trials relying on the concept of OBD. Methods We performed a systematic review through a computerized search of the MEDLINE database to identify early phase cancer clinical trials that relied on OBD. Relevant publications were selected based on a two-step process by two independent readers. Relevant information (phase, type of therapeutic agents, objectives, endpoints and dose-finding design) were collected. Results We retrieved 37 articles. OBD was clearly mentioned as a trial objective (primary or secondary) for 22 articles and was traditionally defined as the smallest dose maximizing an efficacy criterion such as biological target: biological response, immune cells count for immunotherapies, or biological cell count for targeted therapies. Most trials considered a binary toxicity endpoint defined in terms of the proportion of patients who experienced a dose-limiting toxicity. Only two articles relied on an adaptive dose escalation design. Conclusions In practice, OBD should be a primary objective for the assessment of the recommended phase 2 dose (RP2D) for a targeted therapy or immunotherapy phase I cancer trial. Dose escalation designs have to be adapted accordingly to account for both efficacy and toxicity.

MW33 is a fully humanized IgG1κ monoclonal neutralizing antibody, and may be used for the prevention and treatment of coronavirus disease 2019 (COVID-19). We conducted a randomized, double-blind, placebo-controlled, single-dose, dose-escalation Phase 1 study to evaluate the safety, tolerability, pharmacokinetics (PK), and immunogenicity of MW33. Healthy adults aged 18–45 years were sequentially enrolled into the 4, 10, 20, 40, and 60 mg/kg dose groups and infused with MW33 over 60 ± 15 min and followed for 85 days. All 42 enrolled participants completed the MW33 infusion, and 40 participants completed the 85-day follow-up period. 34 participants received a single infusion of 4 (n = 2), 10 (n = 8), 20 (n = 8), 40 (n = 8), and 60 mg/kg (n = 8) of MW33. 27 subjects in the test groups experienced 78 adverse events (AEs) post-dose, with an incidence of 79.4% (27/34). The most common AEs included abnormal laboratory test results, vascular and lymphatic disorders, and infectious diseases. The severity of AEs was mainly Grade 1 (92 AEs), and three Grade 2 and one Grade 4. The main PK parameters, maximum concentration (Cmax), and area under the concentration-time curve (AUC0–t, and AUC0–∞) in 34 subjects showed a linear kinetic relationship in the range of 10–60 mg/kg. The plasma half-life was approximately 25 days. The positive rates of serum ADAs and antibody titres were low with no evidence of an impact on safety or PK. In conclusion, MW33 was well-tolerated, demonstrated linear PK, with a lower positive rate of serum ADAs and antibody titres in healthy subjects.Trial registration: ClinicalTrials.gov identifier: NCT04427501.Trial registration: ClinicalTrials.gov identifier: NCT04533048.Trial registration: ClinicalTrials.gov identifier: NCT04627584.

Background: Advances in therapeutic drugs have increased life-expectancies for HIV-infected individuals, but the need for an effective vaccine remains. We assessed safety and immunogenicity of HIV-1 vaccine, Trimer 4571 (BG505 DS-SOSIP.664) adjuvanted with aluminum hydroxide (alum), in HIV-negative adults. Methods: We conducted a phase I, randomized, open-label, dose-escalation trial at the National Institutes of Health Clinical Center in Bethesda, MD, USA. Eligible participants were HIV-negative, healthy adults between 18-50 years. Participants were randomized 1:1 to receive Trimer 4571 adjuvanted with 500 mcg alum by either the subcutaneous (SC) or intramuscular (IM) route at weeks 0, 8, and 20 in escalating doses of 100 mcg or 500 mcg. The primary objectives were to evaluate the safety and tolerability of Trimer 4571 with a secondary objective of evaluating vaccine-induced antibody responses. The primary and safety endpoints were evaluated in all participants who received at least one dose of Trimer 4571. Trial results were summarized using descriptive statistics. This trial is registered at ClinicalTrials.gov, NCT03783130. Findings: Between March 7 and September 11, 2019, 16 HIV-negative participants were enrolled, including six (38%) males and ten (62%) females. All participants received three doses of Trimer 4571. Solicited reactogenicity was mild to moderate in severity, with one isolated instance of severe injection site redness (6%) following a third 500 mcg SC administration. The most commonly reported solicited symptoms included mild injection site tenderness in 14 (88%) and mild myalgia in six (38%) participants. The most frequent unsolicited adverse event attributed to vaccination was mild injection site pruritus in six (38%) participants. Vaccine-induced seropositivity occurred in seven (44%) participants and resolved in all but one (6%). No serious adverse events occurred. Trimer 4571-specific binding antibodies were detected in all groups two weeks after regimen completion, primarily focused on the glycan-free trimer base. Neutralizing antibody activity was limited to the 500 mcg dose groups. Interpretation: Trimer 4571 was safe, well tolerated, and immunogenic in this first-in-human trial. While this phase 1 trial is limited in size, our results inform and support further evaluation of prefusion-stabilized HIV-1 envelope trimers as a component of vaccine design strategies to generate broadly neutralizing antibodies against HIV-1. Funding: Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Purpose: New immuno-oncology therapies targeting programmed cell death receptor 1 (PD-1) have improved patient outcomes in a broad range of cancers. The objective of this analysis was to evaluate the PK, pharmacodynamics (PDy), and safety of dostarlimab monotherapy in adult patients with previously-treated advanced solid tumors who participated in parts 1 and 2A of the phase 1 GARNET study. Methods: Part 1 featured a 3 + 3 weight-based dose–escalation study, in which 21 patients received dostarlimab 1, 3, or 10 mg/kg intravenously every 2 weeks. The 2 fixed-dose nonweight-based dosing regimens of dostarlimab 500 mg every 3 weeks (Q3W) and 1000 mg every 6 weeks (Q6W) were evaluated using a modified 6 + 6 design in part 2A (n = 13). In parts 1 and 2A, treatment with dostarlimab could continue for up to 2 years or until progression, unacceptable toxicity, patient withdrawal, investigator's decision, or death. Results: The dostarlimab PK profile was dose proportional, and maximal achievable receptor occupancy (RO) was observed at all dose levels in the weight-based and fixed-dose cohorts. Trough dostarlimab concentration after administration of dostarlimab 500 mg Q3W was similar to that after dostarlimab 1000 mg Q6W, the values of which (≈40 µg/mL) projected well above the lowest dostarlimab concentration required for full peripheral RO. No dose-limiting toxicities were observed. Conclusions: Dostarlimab demonstrated consistent and predictable PK and associated PDy. The observed safety profile was acceptable and characteristic of the anti-PD-1 drug class. Trial registration: ClinicalTrials.gov, NCT02715284. Registration date: March 9, 2016. [ABSTRACT FROM AUTHOR]

Abstract Background The main objective of phase I cancer clinical trials is to identify the maximum tolerated dose, usually defined as the highest dose associated with an acceptable level of severe toxicity during the first cycle of treatment. Several dose-escalation designs based on mathematical modeling of the dose-toxicity relationship have been developed. The main ones are: the continual reassessment method (CRM), the escalation with overdose control (EWOC) method and, for late-onset and cumulative toxicities, the time-to-event continual reassessment method (TITE-CRM) and the time-to-event escalation with overdose control (TITE-EWOC) methods. The objective of this work was to perform a user-friendly R package that combines the latter model-guided adaptive designs. Results GUIP1 is an R Graphical User Interface for dose escalation strategies in Phase 1 cancer clinical trials. It implements the CRM (based on Bayesian or maximum likelihood estimation), EWOC and TITE-CRM methods using the dfcrm and bcrm R packages, while the TITE-EWOC method has been specifically developed. The program is built using the TCL/TK programming language, which can be compiled via R software libraries (tcltk, tkrplot, tcltk2). GUIP1 offers the possibility of simulating and/or conducting and managing phase I clinical trials in real-time using file management options with automatic backup of study and/or simulation results. Conclusions GUIP1 is implemented using the software R, which is widely used by statisticians in oncology. This package simplifies the use of the main model-based dose escalation methods and is designed to be fairly simple for beginners in R. Furthermore, it offers multiple possibilities such as a full traceability of the study. By including multiple innovative adaptive methods in a free and user-friendly program, we hope that GUIP1 will promote and facilitate their use in designing future phase I cancer clinical trials.

Toshihiro Kita,1 Yoshikazu Kaji,2 Kazuo Kitamura1 1Division of Circulatory and Body Fluid Regulation, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; 2Souseikai Hakata Clinic, Fukuoka, JapanCorrespondence: Toshihiro KitaDivision of Circulatory and Body Fluid Regulation, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Miyazaki 889-1692, JapanTel +81-985-85-0872Fax +81-985-85-6596Email toshihiro_kita@med.miyazaki-u.ac.jpBackground: Adrenomedullin (AM), an endogenous vasodilative peptide, has immunomodulative effects and acts as an accelerator of mucosal regeneration in the digestive tract. AM has shown beneficial effects in rodent models of inflammatory bowel disease and patients with ulcerative colitis. The present study aimed to evaluate the pharmacodynamic properties and safety of AM in healthy male adults in a phase 1 clinical trial.Methods: This phase 1, randomized, double-blind, single-center study was conducted on healthy males aged 20–65 years. Subjects received either a placebo, 3 ng/kg/min AM, 9 ng/kg/min AM, or 15 ng/kg/min AM via continuous 12-h intravenous infusion. Other subjects received either placebo or 15 ng/kg/min AM for 8 h per day for 7 days. Adverse events (AEs), vital signs, physical examinations, laboratory tests, electrocardiograms (ECG), and pharmacokinetics were assessed.Findings: All 24 subjects in the single-dose test completed the study. Of the 12 subjects in multiple dosing test, one from the AM group withdrew owing to a headache. No serious AEs were reported. Hemodynamic parameters were well maintained in all subjects. Slight ECG abnormalities were observed in the single-dose test. The plasma concentration of AM progressively increased in a dose-dependent manner and reached Cmax at the end of administration. Plasma AM rapidly returned to baseline concentrations after termination, with a T1/2 of under 60 min.Interpretation: This is the first phase 1 trial in healthy men evaluating the safety of AM. Our results demonstrate the safety and tolerability of AM for subsequent Phase 2 trials.Keywords: adrenomedullin, Phase 1 clinical trial, clinical pharmacology, inflammatory bowel disease

Purpose: Assess the safety, tolerability, and feasibility of subcutaneous administration of the mitochondrial-targeted drug elamipretide in patients with dry age-related macular degeneration (AMD) and noncentral geographic atrophy (NCGA) and to perform exploratory analyses of change in visual function. Design: Phase 1, single-center, open-label, 24-week clinical trial with preplanned NCGA cohort. Participants: Adults ≥ 55 years of age with dry AMD and NCGA. Methods: Participants received subcutaneous elamipretide 40-mg daily; safety and tolerability assessed throughout. Ocular assessments included normal-luminance best-corrected visual acuity (BCVA), low-luminance BCVA (LLBCVA), normal-luminance binocular reading acuity (NLBRA), low-luminance binocular reading acuity (LLBRA), spectral-domain OCT, fundus autofluorescence (FAF), and patient self-reported function by low-luminance questionnaire (LLQ). Main Outcome Measures: Primary end point was safety and tolerability. Prespecified exploratory end-points included changes in BCVA, LLBCVA, NLBRA, LLBRA, geographic atrophy (GA) area, and LLQ. Results: Subcutaneous elamipretide was highly feasible. All participants (n = 19) experienced 1 or more nonocular adverse events (AEs), but all AEs were either mild (73.7%) or moderate (26.3%); no serious AEs were noted. Two participants exited the study because of AEs (conversion to neovascular AMD, n = 1; intolerable injection site reaction, n = 1), 1 participant discontinued because of self-perceived lack of efficacy, and 1 participant chose not to continue with study visits. Among participants completing the study (n = 15), mean ± standard deviation (SD) change in BCVA from baseline to week 24 was +4.6 (5.1) letters (P = 0.0032), while mean change (SD) in LLBCVA was +5.4 ± 7.9 letters (P = 0.0245). Although minimal change in NLBRA occurred, mean ± SD change in LLBCVA was –0.52 ± 0.75 logarithm of the minimum angle of resolution units (P = 0.005). Mean ± SD change in GA area (square root transformation) from baseline to week 24 was 0.14 ± 0.08 mm by FAF and 0.13 ± 0.14 mm by OCT. Improvement was observed in LLQ for dim light reading and general dim light vision. Conclusions: Elamipretide seems to be well tolerated without serious AEs in patients with dry AMD and NCGA. Exploratory analyses demonstrated possible positive effect on visual function, particularly under low luminance. A Phase 2b trial is underway to evaluate elamipretide further in dry AMD and NCGA.

Purpose: To assess safety, tolerability, and feasibility of subcutaneous administration of the mitochondrial-targeted drug elamipretide in patients with intermediate age-related macular degeneration (AMD) and high-risk drusen (HRD) and to perform exploratory analyses of change in visual function. Design: Phase 1, single-center, open-label, 24-week clinical trial with preplanned HRD cohort. Participants: Adult patients ≥55 years of age with intermediate AMD and HRD. Methods: Participants received subcutaneous elamipretide 40 mg daily, with safety and tolerability assessed throughout the study. Ocular assessments included normal-luminance best-corrected visual acuity (BCVA), low-luminance best-corrected visual acuity (LLVA), normal-luminance binocular reading acuity (NLRA), low-luminance binocular reading acuity (LLRA), spectral-domain OCT, fundus autofluorescence (FAF), mesopic microperimetry, dark adaptation, and low-luminance questionnaire (LLQ). Main Outcome Measures: The primary end point was safety and tolerability. Prespecified exploratory end points included changes from baseline in BCVA, LLVA, NLRA, LLRA, retinal pigment epithelium (RPE)-drusen complex (DC) volume by OCT, FAF, mesopic microperimetry, dark adaptation, and LLQ results. Results: Subcutaneous administration of elamipretide was highly feasible. All participants with HRD (n = 21) experienced 1 or more adverse events (AEs), but all were mild (57%) or moderate (43%), with the most common events related to injection site reactions. No serious systemic AEs occurred. One participant discontinued because of injection site reaction, 1 participant withdrew because they did not wish to continue study visits, and 1 participant withdrew after experiencing transient visual impairment. Among the 18 participants who completed the study, mean change in BCVA from baseline to 24 weeks was +3.6 letters (P = 0.014) and LLVA was +5.6 letters (P = 0.004). Compared with baseline, mean NLRA improved by –0.11 logarithm of the minimum angle of resolution (logMAR) units (P = 0.001), and LLRA by −0.28 logMAR units (P < 0.0001). Significant improvements were found in 6 of 7 subscales of the LLQ (P

LNA-i-miR-221 is a novel microRNA(miRNA)-221 inhibitor designed for the treatment of human malignancies. It has recently undergone phase 1 clinical trial (P1CT) and early pharmacokinetics (PKs) data in cancer patients are now available. We previously used multiple allometric interspecies scaling methods to draw inferences about LNA-i-miR-221 PKs in humans and estimated the patient dose based on the safe and pharmacodynamic (PD) active dose observed in mice, therefore providing a framework for the definition of safe starting and escalation doses for the P1CT. The preliminary data collected during the P1CT showed that the LNA-i-miR-221 anticipated doses, according to our human PK estimation approach, were indeed well tolerated and effective. PD data demonstrated concentration-dependent downregulation of miR-221 and upregulation of its CDKN1B/p27 and PTEN canonical targets as well as stable disease in 8 (50.0%) patients and partial response in 1 (6.3%) colorectal cancer case. Here, we detail the experimentally evaluated PK parameters of LNA-i-miR-221 in human, using both a non-compartmental and a population PKs approach. The population approach was adequately described by a three-compartments model with first-order elimination. The recorded age, sex and body weight of patients were evaluated as potential covariates. The estimated typical population parameter values were clearance (CL = 200 mL/h/kg), central volume of distribution (V1 = 45 mL/kg), peripheral volume of distribution (V2 = 200 mL/kg, volume of the second peripheral compartment V3 = 930 mL/h/kg) and inter-compartmental clearance (Q2 = 480 mL/h/kg and Q3 = 68 mL/h/kg). Age was found to be a predictor of Q3, with a statistically significant correlation. This work aimed also at retrospectively comparing the measured plasmatic clearance values with those predicted by different allometric scaling approaches. Our comparative analysis showed that the most accurate prediction was achieved by applying the single species allometric scaling approach and that the use of more than one species in allometric scaling to predict therapeutic oligonucleotides PKs would not necessarily generate the best prediction. Finally, our predictive approach was found accurate not only in predicting the main PK parameters in human but suggesting the range of effective and safe dose to be applied in the next clinic phase 2., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Aims: Dysregulation of histone methylation epigenetic marks may result in intellectual and developmental disability, as seen in Kabuki syndrome. Animal data suggest that increasing histone methylation by inhibiting lysine‐specific demethylase 1A (LSD1) may improve cognitive outcomes in a model of Kabuki syndrome. TAK‐418 is a novel LSD1 inhibitor, developed as a potential therapeutic agent for central nervous system disorders such as Kabuki syndrome. Here, we report safety, tolerability, pharmacokinetic and pharmacodynamic profiles of single and multiple doses of TAK‐418 (ClinicalTrials.gov: NCT03228433, NCT03501069). Methods: Two randomized, double‐blind, placebo‐controlled, phase 1 studies of oral TAK‐418 were performed, a first‐in‐human single‐rising‐dose (SRD) study (5–60 mg) in healthy adult male and female volunteers (placebo, n = 10; TAK‐418, n = 30), and an SRD (120–160 mg) and multiple‐rising‐dose (MRD) study (20–160 mg once daily for 10 days) in healthy female volunteers (placebo, n = 2 [SRD] and n = 6 [MRD]; TAK‐418, n = 6 [SRD] and n = 18 [MRD]). Results: TAK‐418 was well tolerated. No clinically significant changes in laboratory test results or vital signs were observed and no serious adverse events were reported. TAK‐418 had a nearly linear pharmacokinetic profile, with rapid absorption and short terminal half‐life across the evaluated dose range. No obvious accumulation was observed after daily administration for 10 days. Administration with food delayed peak plasma concentrations but overall exposure was unaffected. TAK‐418 rapidly crossed the blood–brain barrier and generally showed a dose‐dependent response in the peripheral pharmacodynamic biomarker formyl‐flavin adenine dinucleotide. Conclusion: The brain‐penetrant LSD1 inhibitor TAK‐418 was well tolerated, with pharmacokinetic and pharmacodynamic effects that support further investigation. [ABSTRACT FROM AUTHOR]

• COReNAPCIN is a mRNA-based vaccine candidate, encoding the complete sequence of the pre-fusion stabilized Spike protein of SARS-CoV-2. • COReNAPCIN as a booster dose was safe and well tolerated in all vaccinated individuals. • The COReNAPCIN vaccinated groups exhibited potent neutralizing capacity as well as significant rise in anti-Spike and anti-RBD IgG antibody levels. The recurrent COVID-19 infection, despite global vaccination, highlights the need for booster doses. A heterologous booster has been suggested to enhance immunity and protection against emerging variants of concern of the SARS-CoV-2 virus. In this report, we aimed to assess the safety, and immunogenicity of COReNAPCIN, as a fourth booster dose after three doses of inactivated vaccines. The study was conducted as a double-blind, randomized, placebo-controlled phase 1 clinical trial of the mRNA-based vaccine candidate, COReNAPCIN. The vaccine was injected as a heterologous booster in healthy Iranian adults aged 18–50 who had previously received three doses of inactivated SARS-CoV-2 vaccines. In the study, 30 participants were randomly assigned to receive either COReNAPCIN in two different doses (25 µg and 50 µg) or placebo. The vaccine candidate contained mRNA encoding the complete sequence of the pre-fusion stabilized Spike protein of SARS-CoV-2, formulated within lipid nanoparticles. The primary endpoint was safety and the secondary objective was humoral immunogenicity until 6 months post-vaccination. The cellular immunogenicity was pursued as an exploratory outcome. COReNAPCIN was well tolerated in vaccinated individuals in both doses with no life-threatening or other serious adverse events. The most noticeable solicited adverse events were pain at the site of injection, fatigue and myalgia. Regarding the immunogenicity, despite the seroprevalence of SARS-CoV-2 antibodies due to the vaccination history for all and previous SARS-CoV-2 infection for some participants, the recipients of 25 and 50 µg COReNAPCIN, two weeks post-vaccination, showed 6·6 and 8·1 fold increase in the level of anti-RBD, and 11·5 and 21·7 fold increase in the level of anti-spike antibody, respectively. The geometric mean virus neutralizing titers reached 10.2 fold in the 25 µg group and 8.4 fold in 50 µg group of pre-boost levels. After 6 months, the measured anti-spike antibody concentration still maintains a geometric mean fold rise of 2.8 and 6.3, comparing the baseline levels in 25 and 50 µg groups, respectively. Additionally, the significant increase in the spike-specific IFN-ϒ T-cell response upon vaccination underscores the activation of cellular immunity. COReNAPCIN booster showed favorable safety, tolerability, and immunogenicity profile, supporting its further clinical development (Trial registration : IRCT20230131057293N1). [ABSTRACT FROM AUTHOR]

It is essential to identify intermediate marker endpoints of carcinogenesis for the evaluation of the effectiveness of cancer-chemopreventive agents. We have observed that levels of proteolytic activities (as detected by 4 different substrates) are increased 2-3-fold (P < 0.003) in oral buccal mucosa cells of smokers and patients with oral leukoplakia or erythroplakia as compared to a nonsmoking comparison group. In addition, proteolytic activity levels in the buccal cells were increased nearly 3-fold in patients with oral trauma (P < 0.01) or diabetes (P < 0.02), as well as pregnant women (P < 0.04). Excluding these subgroups of patients in epidemiological studies increase the differences in levels of proteolytic activities between both the nonsmoking comparison group and smokers and between the comparison group and patients with oral leukoplakia or erythroplakia. Evaluation of prerandomization levels of proteolytic activities of patients in cancer chemoprevention trials will increase the statistical power by allowing stratified randomization based on levels of proteolytic activities. The observed increases in levels of proteolytic activities in tissues at higher than normal risk of cancer development suggest that levels of proteolytic activities should be used as immediate marker endpoints in human cancer prevention trials using protease inhibitors as potential anticarcinogenic agents.

Objectives: To report the 3‐year follow‐up of a Phase I study of magnetic resonance imaging (MRI)‐guided transurethral ultrasound ablation (TULSA) in 30 men with localised prostate cancer. Favourable 12‐month safety and ablation precision were previously described. Patients and Methods: As a mandated safety criterion, TULSA was delivered as near whole‐gland ablation, applying 3‐mm margins sparing 10% of peripheral prostate tissue in 30 men. After 12‐month biopsy and MRI, biannual follow‐up included prostate‐specific antigen (PSA), adverse events (AEs), and functional quality‐of‐life assessment, with repeat systematic biopsy at 3 years. Results: A 3‐year follow‐up was completed by 22 patients. Between 1 and 3 years, there were no new serious or severe AEs. Urinary and bowel function remained stable. Erectile function recovered by 1 year and was stable at 3 years. The PSA level decreased 95% to a median (interquartile range) nadir of 0.33 (0.1–0.4) ng/mL, stable to 0.8 (0.4–1.6) ng/mL at 3 years. Serial biopsies identified clinically significant disease in 10/29 men (34%) and any cancer in 17/29 (59%). By 3 years, seven men had recurrence (four histological, three biochemical) and had undergone salvage therapy without complications (including six prostatectomies). At 3 years, three of 22 men refused biopsy, and two of the 22 (9%) had clinically significant disease (one new, one persistent). Predictors of salvage therapy requirement included less extensive ablation coverage and higher PSA nadir. Conclusion: With 3‐year Phase I follow‐up, TULSA demonstrates safe and precise ablation for men with localised prostate cancer, providing predictable PSA and biopsy outcomes, without affecting functional abilities or precluding salvage therapy. [ABSTRACT FROM AUTHOR]

We report the results of a phase 1 dose-escalation study of belinostat and bortezomib in adult patients with acute leukemia or MDS or CML with blast crisis. Thirty-eight patients received IV belinostat days 1-5 and 8-12 with IV bortezomib days 1, 4, 8, and 11 every 21 days. QTc prolongation was the only identified DLT. The RP2Ds were 1.3 mg/m2 bortezomib and 1000 mg/m2 belinostat. One patient with highly refractory MLL-ENL rearranged biphenotypic AML with multiple karyotypic aberrations had a complete pathologic and karyotypic response. One patient with post-MPN AML remained on study with stable disease (SD) for 32 cycles. Whole-exome sequencing revealed no aberrations in the first patient and a hyper-mutator genotype in the second. Eighteen patients had a best response of SD. We conclude that this treatment strategy is feasible but has limited activity in this population. Nevertheless, the factors that predict exceptional responses to this strategy warrant further investigation. [ABSTRACT FROM AUTHOR]

Background: Classical phase 1 dose-finding designs based on a single toxicity endpoint to assess the maximum tolerated dose were initially developed in the context of cytotoxic drugs. With the emergence of molecular targeted agents and immunotherapies, the concept of optimal biological dose (OBD) was subsequently introduced to account for efficacy in addition to toxicity. The objective was therefore to provide an overview of published phase 1 cancer clinical trials relying on the concept of OBD.Methods: We performed a systematic review through a computerized search of the MEDLINE database to identify early phase cancer clinical trials that relied on OBD. Relevant publications were selected based on a two-step process by two independent readers. Relevant information (phase, type of therapeutic agents, objectives, endpoints and dose-finding design) were collected.Results: We retrieved 37 articles. OBD was clearly mentioned as a trial objective (primary or secondary) for 22 articles and was traditionally defined as the smallest dose maximizing an efficacy criterion such as biological target: biological response, immune cells count for immunotherapies, or biological cell count for targeted therapies. Most trials considered a binary toxicity endpoint defined in terms of the proportion of patients who experienced a dose-limiting toxicity. Only two articles relied on an adaptive dose escalation design.Conclusions: In practice, OBD should be a primary objective for the assessment of the recommended phase 2 dose (RP2D) for a targeted therapy or immunotherapy phase I cancer trial. Dose escalation designs have to be adapted accordingly to account for both efficacy and toxicity. [ABSTRACT FROM AUTHOR]

Subsets of non-acute promyelocytic leukemia (APL) acute myelogenous leukemia (AML) exhibit aberrant retinoid signaling and demonstrate sensitivity to retinoids in vitro. We present the results of a phase 1 dose-escalation study that evaluated the safety, pharmacodynamics, and efficacy of IRX195183, a novel retinoic acid receptor α agonist, in patients with relapsed or refractory myelodysplastic syndrome (MDS) or AML. In this single center, single arm study, eleven patients with relapsed or refractory MDS/AML were enrolled and treated. Oral IRX195183 was administered at two dose levels: 50 mg daily or 75 mg daily for a total of two 28-day cycles. Patients with stable disease or better were allowed to continue on the drug for four additional 28-day cycles. Common adverse events included hypertriglyceridemia, fatigue, dyspnea, and edema. Three patients at the first dose level developed asymptomatic Grade 3 hypertriglyceridemia. The maximally tolerated dose was not reached. Four of the eleven patients had (36%) stable disease or better. One had a morphological complete remission with incomplete hematologic recovery while on the study drug. Two patients had evidence of in vivo leukemic blast maturation, as reflected by increased CD38 expression. In a pharmacodynamics study, plasma samples from four patients treated at the lowest dose level demonstrated the capacity to differentiate leukemic cells from the NB4 cell line in vitro. These results suggest that IRX195183 is safe, achieves biologically meaningful plasma concentrations and may be efficacious in a subset of patients with MDS/AML. Clinical Trial Registration:clinicaltrials.gov, identifier NCT02749708.

Background: Relapsed/refractory small cell lung cancer (SCLC) has a poor prognosis, with no good options. We evaluated a novel combination of topotecan and doxorubicin, providing sequential topoisomerase I and II inhibition, in this setting. Materials and methods: Adult patients (>19 years) with relapsed/refractory SCLC, who had received at least one prior chemotherapy regimen were eligible. Patients received escalating doses of oral topotecan on days 1–5 of each three week cycle (maximum - 5 cycles). The dosing cohorts were: 0.85 mg/m2, 1.05 mg/m2, 1.35 mg/m2, 1.65 mg/m2 and 2.30 mg/m2. All patients received weekly doxorubicin 20 mg/m2 intravenously starting day 6 of the first cycle and continued weekly for a maximum of 15 weeks. In the absence of pre-specified dose limiting toxicities (DLT), patients were enrolled serially to escalated dose level cohorts. Results: Twenty-two patients were enrolled, of which 20 were evaluable. Median age was 61 years; 74% were male and 95% were Caucasian. Hematologic side effects were the most common adverse events. There were no therapy-related Grade 5 toxicities. Incidence of DLT based on cohorts were: DL2: 1/6 (Grade 4 thrombocytopenia), DL3: 1/6 (AST elevation) and DL4: 2/4 (Grade 4 thrombocytopenia). Response rate was 20% (4/20) and disease control rate (SD + PR) was 36%. The median progression free and overall survival were 3.6 months and 6 months, respectively. Conclusions: The combination of topotecan and doxorubicin was safe and effective in relapsed/refractory SCLC. The maximum tolerated dose of oral topotecan was 1.35 mg/m2 when given concurrently with weekly doxorubicin.

Abstract Introduction Allopregnanolone is an endogenous neurosteroid with the potential to be a novel regenerative therapeutic for Alzheimer's disease (AD). Foundations of mechanistic understanding and well‐established preclinical safety efficacy make it a viable candidate. Methods A randomized, double‐blinded, placebo‐controlled, single and multiple ascending dose trial was conducted. Intravenous allopregnanolone or placebo was administered once‐per‐week for 12 weeks with a 1‐month follow‐up. Participants with early AD (mild cognitive impairment due to AD or mild AD), a Mini‐Mental State Examination score of 20–26 inclusive, and age ≥55 years were randomized (6:2 to three allopregnanolone dosing cohorts or one placebo cohort). Primary endpoint was safety and tolerability. Secondary endpoints included pharmacokinetic (PK) parameters and maximally tolerated dose (MTD). Exploratory endpoints included cognitive and imaging biomarkers. Results A total of 24 participants completed the trial. Allopregnanolone was safe and well tolerated in all study participants. No differences were observed between treatment arms in the occurrence and severity of adverse events (AE). Most common AE were mild to moderate in severity and included rash (n = 4 [22%]) and fatigue (n = 3 [17%]). A single non‐serious AE, dizziness, was attributable to treatment. There was one serious AE not related to treatment. Pharmacokinetics indicated a predictable linear dose‐response in plasma concentration of allopregnanolone after intravenous administration over 30 minutes. The maximum plasma concentrations for the 2 mg, 4 mg, 6 mg, and 10 mg dosages were 14.53 ng/mL (+/−7.31), 42.05 ng/mL (+/−14.55), 60.07 ng/mL (+/−12.8), and 137.48 ng/mL (+/−38.69), respectively. The MTD was established based on evidence of allopregnanolone‐induced mild sedation at the highest doses; a sex difference in the threshold for sedation was observed (males 10 mg; females 14 mg). No adverse outcomes on cognition or magnetic resonance imaging–based imaging outcomes were evident. Conclusions Allopregnanolone was well tolerated and safe across all doses in persons with early AD. Safety, MTD, and PK profiles support advancement of allopregnanolone as a regenerative therapeutic for AD to a phase 2 efficacy trial. Trial registration ClinicalTrials.gov‐NCT02221622