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Aim The purpose of this study is to evaluate the safety and pharmacokinetics of the novel morpholino oligomer NS‐089/NCNP‐02 which can induce exon 44 skipping, in patients with DMD. Additionally, we aimed to identify markers predictive of therapeutic efficacy and determine the optimal dosing for future studies. Methods This is an open‐label, dose‐escalation, two‐center phase I/II trial in ambulant patients with DMD, presence of an out‐of‐frame deletion, and a mutation amenable to exon 44 skipping. Part 1 is a stepwise dose‐finding stage (4 weeks) during which NS‐089/NCNP‐02 will be administered intravenously at four dose levels once weekly (1.62, 10, 40, and 80 mg/kg); Part 2 is a 24‐week evaluation period based on the dosages determined during Part 1. The primary (safety) endpoints are the results of physical examinations, vital signs, 12‐lead electrocardiogram and echocardiography tests, and adverse event reporting. Secondary endpoints include expression of dystrophin protein, motor function assessment, exon 44 skipping efficiency, plasma and urinary NS‐089/NCNP‐02 concentrations, and changes in blood creatine kinase levels. Discussion Exon‐skipping therapy using ASOs shows promise in selected patients, and this first‐in‐human study is expected to provide critical information for subsequent clinical development of NS‐089/NCNP‐02. The purpose of this study is to evaluate the safety and pharmacokinetics of the novel morpholino oligomer NS‐089/NCNP‐02 which can induce exon 44 skipping, in patients with DMD. Additionally, we aimed to identify markers predictive of therapeutic efficacy and determine the optimal dosing for future studies. Exon‐skipping therapy using ASOs shows promise in selected patients, and this first‐in‐human study is expected to provide critical information for subsequent clinical development of NS‐089/NCNP‐02.

ABBV‐47D11 is a neutralizing monoclonal antibody that targets a mutationally conserved hydrophobic pocket distal to the ACE2 binding site of SARS‐CoV‐2. This first‐in‐human safety, pharmacokinetics, and antiviral pharmacodynamic assessment in patients with COVID‐19 provide an initial evaluation of this antibody that may allow further development. This multicenter, randomized, double‐blind, and placebo‐controlled single ascending dose study of ABBV‐47D11 (180, 600, or 2400 mg) as an intravenous infusion, was in hospitalized and non‐hospitalized (confined) adults with mild to moderate COVID‐19. Primary outcomes were grade 3 or higher study drug‐related adverse events and infusion‐related reactions. Secondary outcomes were pharmacokinetic parameters and concentration‐time profiles to Day 29, immunogenicity (anti‐drug antibodies), and antiviral activity (change in RT‐PCR viral load) from baseline to Days 15 and 29. ABBV‐47D11 single doses up to 2400 mg were safe and tolerated and no safety signals were identified. The pharmacokinetics of ABBV‐47D11 were linear and showed dose‐proportional increases in serum concentrations with ascending doses. The exploratory anti‐SARS‐CoV‐2 activity revealed a reduction of viral load at and above the 600 mg dose of ABBV‐47D11 regardless of patient demographics and baseline characteristics, however; because of the high inter‐individual variability and small sample size a statistical significance was not reached. There is potential for anti‐SARS‐CoV‐2 activity with ABBV‐47D11 doses of 600 mg or higher, which could be evaluated in future clinical trials designed and powered to assess viral load reductions and clinical benefit. Left: CONSORT flow chart. Right: ABBV‐47D11 Dose–Response for SARS‐CoV‐2 Viral Load AUC of Change from Baseline to Day 15. AUC: area under the curve; Box plots represent 25th/75th percentiles, median (solid line), mean (dashed line), whiskers represent min‐max values, and dots represent individual patient data.

A systematic review was performed to evaluate how the maximum recommended starting dose (MRSD) was determined in first-in-human (FIH) studies with monoclonal antibodies (mAbs). Factors associated with the choice of each MRSD determination method were also identified. PubMed was searched for FIH studies with mAbs published in English between January 1, 1990 and December 31, 2013, and the following information was extracted: MRSD determination method, publication year, therapeutic area, antibody type, safety factor, safety assessment results after the first dose, and number of dose escalation steps. Seventy-nine FIH studies with mAbs were identified, 49 of which clearly reported the MRSD determination method. The no observed adverse effects level (NOAEL)-based approach was the most frequently used method, whereas the model-based approach was the least commonly used method (34.7% vs 16.3%). The minimal anticipated biological effect level (MABEL)- or minimum effective dose (MED)-based approach was used more frequently in 2011-2013 than in 1990-2007 (31.6% vs 6.3%, =0.036), reflecting a slow, but steady acceptance of the European Medicines Agency's guidance on mitigating risks for FIH clinical trials (2007). The median safety factor was much lower for the MABEL- or MED-based approach than for the other MRSD determination methods (10 vs 32.2-53). The number of dose escalation steps was not significantly different among the different MRSD determination methods. The MABEL-based approach appears to be safer and as efficient as the other MRSD determination methods for achieving the objectives of FIH studies with mAbs faster.

SummaryPurposes Vactosertib is a new investigational inhibitor of activin receptor-like kinase 5. The objective of this study was to characterize vactosertib pharmacokinetics that are to be applied for subsequent clinical studies. Methods Vactosertib plasma concentration-time data were obtained from a multicenter, dose-escalation, first-in-human phase 1 study conducted in patients with advanced solid tumors. Each patient orally received a fixed dose of vactosertib with the range of 30 mg to 340 mg once daily under fasted condition. Pharmacokinetic analysis was performed using a non-compartmental method. Results Pharmacokinetic data were evaluable in 29 patients. Vactosertib was rapidly absorbed after the first dose with a median time to maximum concentration (tmax) of 1.2 h (interquartile range, 0.8–1.8 h) and quickly eliminated with a median terminal half-life (t1/2) of 3.2 h (2.2–4.2 h) over the dose range studied. Such trend was also observed after repeated doses for five days (median tmax, 1.5 h; median t1/2, 3.0 h). The area under the concentration-time curve within a dosing interval increased in proportion to dose. The median values of apparent clearance and volume of distribution were 29 L/h (21–44 L/h) and 133 L (77–222 L), respectively. The median accumulation ratio after repeated once-daily doses for five days was 0.87 (0.69–1.07). Conclusions Vactosertib pharmacokinetics were dose-proportional within tested dose range with negligible accumulation when administered once daily for five days. Considering the short half-life, it seems necessary to administer vactosertib twice- or thrice-daily to maintain its concentrations above minimum effective level over a dosing interval.

PurposeAT04A and AT06A are two AFFITOPE® peptide vaccine candidates being developed for the treatment of hypercholesterolemia by inducing proprotein convertase subtilisin/kexin type 9 (PCSK9)-specific antibodies. This study aimed to investigate safety, tolerability, antibody development, and reduction of low-density lipoprotein cholesterol (LDLc) following four subcutaneous immunizations.MethodsThis phase I, single-blind, randomized, placebo-controlled study was conducted in a total of 72 healthy subjects with a mean fasting LDLc level at baseline of 117.1 mg/dL (range 77–196 mg/dL). Each cohort enrolled 24 subjects to receive three priming immunizations at weeks 0, 4, and 8 and to receive a single booster immunization at week 60 of either AT04A, AT06A, or placebo. In addition to safety (primary objective), the antigenic peptide- and PCSK9-specific antibody response and the impact on LDLc were evaluated over a period of 90 weeks.ResultsThe most common systemic treatment-related adverse events (AEs) reported were fatigue, headache, and myalgia in 75% of subjects in the AT06A group and 58% and 46% of subjects in the placebo and AT04A groups, respectively. Injection site reactions (ISR) representing 63% of all treatment-emergent adverse events (TEAEs), were transient and mostly of mild or moderate intensity and rarely severe (3%). Both active treatments triggered a robust, long-lasting antibody response towards the antigenic peptides used for immunization that optimally cross-reacted with the target epitope on PCSK9. In the AT04A group, a reduction in serum LDLc was observed with a mean peak reduction of 11.2% and 13.3% from baseline compared to placebo at week 20 and 70 respectively, and over the whole study period, the mean LDLc reduction for the AT04A group vs. placebo was −7.2% (95% CI [−10.4 to −3.9], P < 0.0001). In this group, PCSK9 target epitope titers above 50 were associated with clinically relevant LDLc reductions with an individual maximal decrease of 39%.ConclusionsAlthough both AT04A and AT06 were safe and immunogenic, only AT04A demonstrated significant LDLc-lowering activity, justifying further development.Trial registrationEudraCT: 2015-001719-11. ClinicalTrials.gov Identifier: NCT02508896.

SummaryBackground This was a phase I/IIa study to investigate the tolerability, efficacy and pharmacokinetics (PK)/ pharmacodynamics (PD) of CRLX301, CDP-based nanoparticle formulation of docetaxel. Methods The study was conducted in two parts. In part 1, dose-escalation using a standard 3 + 3 design was performed in two dosing schedules (every week (QW) and every 3 weeks (Q3W)). Part 2 was comprised of a dose expansion at 75 mg/m2 Q3W. PK studies were performed on both dosing schedules. Results Forty-two patients were recruited onto the study with a median age of 64(range 38–76); median number of prior systemic therapies was 5(range 0–10). Grade 3/4 treatment-related toxicities included: neutropenia (21.4 %), infusion related reaction (11.9 %), anemia (7.1 %), fatigue (4.8 %), diarrhea (4.8 %), and peripheral neuropathy (4.8 %). The maximum tolerated dose was 75 mg/m2 given on the Q3W schedule and was not determined on the QW schedule. In this heavily pre-treated population, four patients (12.9 %) achieved stable disease (SD) ≥ 4 months and 2 patients (6.5 %) achieved partial response (PR) for a clinical benefit rate (CBR) of 19.4 % (6/31 patients). The PRs were seen in prostate and breast adenocarcinoma (one each). CRLX301 exhibited some PK advantages over docetaxel including higher retention of drug in plasma, slower clearance and controlled slow release of docetaxel from the carrier. Conclusions In this heavily pretreated patient population, the safety profile was acceptable for CRLX301 therapy. There was some evidence of preliminary tumor efficacy, but further work is necessary to find the optimal dose and schedule of this formulation.Clinicaltrials.gov trial registration number: NCT02380677 (Date of registration: March 2, 2015).

Lymphomas are a heterogeneous group of lymphoproliferative disorders, with unique clinical and biological characteristics that exhibit variable response to therapy. Advances in chemo-immunotherapy have improved outcomes in a number of lymphoma subtypes; however, the prognosis for many patients with relapsed and refractory disease remains poor. Novel therapies including several small molecule inhibitors and chimeric antigen receptor T cells have been approved for the treatment of different lymphoma subtypes at relapse, changing the therapy landscape and further improving survival in many of these diseases. This has led to a focus on the development of new cellular therapy, antibody-based therapy, and small molecule inhibitors for relapsed and refractory disease that offer an alternative approach to cytotoxic chemotherapy. We will review these promising novel therapies and discuss their safety and efficacy in first in human studies.

Malignant mesothelioma (MM) is an aggressive and currently incurable cancer with limited therapeutic options. Due to the high expression of mesothelin in this cancer, anti‐PD‐1 nanobody‐armored mesothelin‐targeting CAR‐T (NAC‐T) cells are developed. Based on the enhanced anti‐tumor activity observed in preclinical in vitro and in vivo studies, a first‐in‐human clinical trial is initiated. Eleven patients with malignant mesothelioma who have progressed after standard therapies receive intravenous infusions of 5–20 × 10 6 per kg NAC‐T cells following lymphodepletion. The treatment is well tolerated, with no dose‐limiting toxicity observed. The overall response rate is 63.6%, including one complete response, and the disease control rate is 100%. The median progression‐free survival is 5.0 months, and the median overall survival is 25.6 months. Moreover, T cell receptor and single‐cell sequencing analyses in patients with varying responses revealed specific clonal expansion of T cell subtypes and enhanced reactivity to tumor‐associated antigens. These findings suggest that NAC‐T cell therapy represents a promising therapeutic strategy for patients with malignant mesothelioma.

Calcium-dependent, neuronal adenylyl cyclase subtype 1 (AC1) is critical for cortical potentiation and chronic pain. NB001 is a first-in-class drug acting as a selective inhibitor against AC1. The present study delineated the pharmacokinetic (PK) properties of human-used NB001 (hNB001) formulated as immediate-release tablet. This first-in-human (FIH) study was designed as randomized, double-blind, placebo-controlled trial. hNB001 showed placebo-like safety and good tolerability in healthy volunteers. A linear dose-exposure relationship was demonstrated at doses between 20 mg and 400 mg. The relatively small systemic exposure of hNB001 in human showed low bioavailability of this compound through oral administration, which can be improved through future dosage research. Food intake had minimal impact on the absorption of hNB001 tablet. Animal experiments further confirmed that hNB001 had strong analgesic effect in animal models of neuropathic pain. In brain slice prepared from the anterior cingulate cortex (ACC), bath application of hNB001 blocked the induction of long-term potentiation (LTP). These results from both rodents and human strongly suggest that hNB001 can be safely used for the future treatment of different types of chronic pain in human patients.

BT-11 is a new oral, gut-restricted, first-in-class investigational drug for Crohn disease (CD) and ulcerative colitis (UC) that targets the lanthionine synthetase C-like 2 (LANCL2) pathway and immunometabolic mechanisms. Oral BT-11 was assessed for safety, tolerability, and pharmacokinetics (PK) in normal healthy volunteers (n = 70) in a randomized, double-blind, placebo-controlled trial. Subjects (n = 70) were randomly assigned to one of five single ascending dose cohorts (up to 100 mg/kg, p.o.) and three multiple ascending dose cohorts [up to 100 mg/kg daily (QD) for seven days, orally]. Safety and tolerability were assessed by adverse event (AE) reporting, vital signs, electrocardiogram, hematology, and clinical chemistry. BT-11 did not increase total or gastrointestinal AE rates, as compared with placebo, and no serious adverse events were observed. Oral BT-11 dosing does not result in any clinically significant findings by biochemistry, coagulation, electrocardiogram, hematology, or urinalysis as compared with placebo. Mean fecal concentrations of BT-11 increased linearly with increasing oral doses, with 2.39 mg/g at 7.7 mg/kg on day 7 of the multiple ascending dose (MAD). Analysis of plasma pharmacokinetics indicates that maximum systemic concentrations are approximately 1/6000th of observed concentrations in feces and the distal gastrointestinal tract. Fecal calprotectin levels were lower in BT-11 treated groups as compared to placebo. BT-11 significantly decreases interferon gamma positive (IFNγ+) and tumor necrosis factor alpha positive (TNFα+) cluster of differentiation 4 positive (CD4+) T cells and increases forkhead box P3 positive (FOXP3+) CD4+ T cells in colonic lamina propria mononuclear cells from patients with CD and patients with UC at concentrations of 0.01 µM when treated ex vivo. BT-11 treatment is well-tolerated with no dose-limiting toxicities up to daily oral doses of 100 mg/kg (16 tablets); whereas the efficacious dose is a single tablet (8 mg/kg). Phase II studies in CD and UC patients are ongoing.BT-11 treatment is well-tolerated with no dose-limiting toxicities or systemic immunosuppression up to daily oral doses of 100 mg/kg in the first-in-human single ascending dose and 7-day multiple ascending dose studies.