Aim\nMethods\nResults\nDiscussion\nSystematic Review Registration\nTraditionally, early phase clinical trials in oncology have been performed in patients based on safety risk-benefit assessment.... Show moreAim\nMethods\nResults\nDiscussion\nSystematic Review Registration\nTraditionally, early phase clinical trials in oncology have been performed in patients based on safety risk-benefit assessment. Therapeutic transition to immuno-oncology may open new opportunities for studies in healthy volunteers, which are conducted faster and are less susceptible to confounders. Aim of this study was to investigate to what extent this approach is utilized and whether pharmacodynamic endpoints are evaluated in these early phase trials. We conducted a comprehensive review of clinical trials with healthy volunteers using immunotherapies potentially relevant for oncology.\nLiterature searches according to PRISMA guidelines and after registration in PROSPERO were conducted in PubMed, Embase, Web of Science and Cochrane databases with the cut-off date 20 October 2020, using search terms of relevant targets in immuno-oncology. Articles describing clinical trials with immunotherapeutics in healthy volunteers with a mechanism relevant for oncology were included. "Immunotherapeutic" was defined as compounds exhibiting effects through immunological targets. Data including study design and endpoints were extracted, with specific attention to pharmacodynamic endpoints and safety.\nIn total, we found 38 relevant immunotherapeutic compounds tested in HVs, with 86% of studies investigating safety, 82% investigating the pharmacokinetics (PK) and 57% including at least one pharmacodynamic (PD) endpoint. Most of the observed adverse events (AEs) were Grade 1 and 2, consisting mostly of gastrointestinal, cutaneous and flu-like symptoms. Severe AEs were leukopenia, asthenia, syncope, headache, flu-like reaction and liver enzymes increase. PD endpoints investigated comprised of cytokines, immune and inflammatory biomarkers, cell counts, phenotyping circulating immune cells and ex vivo challenge assays.\nHealthy volunteer studies with immuno-oncology compounds have been performed, although not to a large extent. The integration of healthy volunteers in well-designed proof-of-mechanism oriented drug development programs has advantages and could be pursued more in the future, since integrative clinical trial protocols may facilitate early dose selection and prevent cancer patients to be exposed to non-therapeutic dosing regimens.\nhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=210861, identifier CRD42020210861. Show less
Aim: Traditionally, early phase clinical trials in oncology have been performed in patients based on safety risk-benefit assessment. Therapeutic transition to immuno-oncology may open new... Show moreAim: Traditionally, early phase clinical trials in oncology have been performed in patients based on safety risk-benefit assessment. Therapeutic transition to immuno-oncology may open new opportunities for studies in healthy volunteers, which are conducted faster and are less susceptible to confounders. Aim of this study was to investigate to what extent this approach is utilized and whether pharmacodynamic endpoints are evaluated in these early phase trials. We conducted a comprehensive review of clinical trials with healthy volunteers using immunotherapies potentially relevant for oncology. Methods: Literature searches according to PRISMA guidelines and after registration in PROSPERO were conducted in PubMed, Embase, Web of Science and Cochrane databases with the cut-off date 20 October 2020, using search terms of relevant targets in immuno-oncology. Articles describing clinical trials with immunotherapeutics in healthy volunteers with a mechanism relevant for oncology were included. "Immunotherapeutic " was defined as compounds exhibiting effects through immunological targets. Data including study design and endpoints were extracted, with specific attention to pharmacodynamic endpoints and safety. Results: In total, we found 38 relevant immunotherapeutic compounds tested in HVs, with 86% of studies investigating safety, 82% investigating the pharmacokinetics (PK) and 57% including at least one pharmacodynamic (PD) endpoint. Most of the observed adverse events (AEs) were Grade 1 and 2, consisting mostly of gastrointestinal, cutaneous and flu-like symptoms. Severe AEs were leukopenia, asthenia, syncope, headache, flu-like reaction and liver enzymes increase. PD endpoints investigated comprised of cytokines, immune and inflammatory biomarkers, cell counts, phenotyping circulating immune cells and ex vivo challenge assays. Discussion: Healthy volunteer studies with immuno-oncology compounds have been performed, although not to a large extent. The integration of healthy volunteers in well-designed proof-of-mechanism oriented drug development programs has advantages and could be pursued more in the future, since integrative clinical trial protocols may facilitate early dose selection and prevent cancer patients to be exposed to non-therapeutic dosing regimens. Show less
Introduction: Apomorphine is used to treat OFF periods in Parkinson's disease (PD) patients. AZ-009 is a novel apomorphine formulation that delivers a thermally-generated aerosol to the deep lung... Show moreIntroduction: Apomorphine is used to treat OFF periods in Parkinson's disease (PD) patients. AZ-009 is a novel apomorphine formulation that delivers a thermally-generated aerosol to the deep lung via inhalation with a single breath.Methods: Part A was a randomized, placebo-controlled, double-blind study investigating the safety and pharmacokinetics of multiple ascending doses of AZ-009. PD patients (n = 24) received placebo or 2, 3 or 4 mg AZ-009 once daily for 5 days, followed by three times daily for 2 days with 2 h between doses. Part B was a double-blind crossover study in 8 PD patients who experience OFF periods. During an OFF state, patients received 4 mg AZ-009 and placebo on two consecutive days in a randomized order. MDS-UPDRS III and ON/OFF state were assessed pre- and post-dose.Results: Three times daily dosing with 2, 3 and 4 mg AZ-009 was relatively well tolerated with no apparent accumulation or changes in safety profile. Mild and transient throat irritation and cough were reported most often. AZ-009 was rapidly absorbed with median T-max between 1 and 2 min. When corrected for placebo response, the maximum effect of 4 mg AZ-009 based on MDS-UPDRS III scores was observed at 10 and 30 min post-dose with mean (SD) reductions of 6.8 (9.4) and 6.1 (9.1) points respectively. Whereas 0% of patients turned ON after placebo, 50% turned ON 10 min after 4 mg AZ-009 treatment.Conclusion: AZ-009 is rapidly systemically absorbed and safe to dose three times daily. AZ-009 could provide a faster-acting and easier to use formulation than currently available therapies. Show less
Selective inhibition of certain voltage-gated sodium channels (Na(v)s), such as Na(v)1.8, is of primary interest for pharmacological pain research and widely studied as a pharmacological target due... Show moreSelective inhibition of certain voltage-gated sodium channels (Na(v)s), such as Na(v)1.8, is of primary interest for pharmacological pain research and widely studied as a pharmacological target due to its contribution to repetitive firing, neuronal excitability, and pain chronification. VX-128 is a highly potent and selective Na(v)1.8 inhibitor that was being developed as a treatment for pain. We evaluated the safety, tolerability, and pharmacokinetics of VX-128 in healthy subjects in a single-and multiple-ascending dose (MAD) first-in-human study. Pharmacodynamics were evaluated in the MAD part using a battery of evoked pain tests. Overall, single doses of VX-128 up to 300 mg were well-tolerated, although adverse effect (AE) incidence was higher in subjects receiving VX-128 (41.7%) compared with placebo (25.0%). After multiple dosing of up to 10 days, skin rash events were observed at all dose levels (up to 100 mg once daily [q.d.]), in five of 26 (19.2%) subjects, including one subject receiving VX-128 (100 mg q.d.) who had a serious AE of angioedema. A trend in pain tolerance were observed for cold pressor-and pressure pain, which was dose-dependent for the latter. VX-128 was rapidly absorbed (median time to maximum plasma concentration between 1 and 2 h) with a half-life of similar to 80 h at 10 mg q.d., and approximately two-fold accumulation ratio after 10 and 30 mg q.d. Although VX-128, when given in a multiple dose fashion, resulted in early study termination due to tolerability issues, effects were observed on multiple pain tests that may support further investigation of Na(v)1.8 inhibitors as pain treatments. Show less
Parkinson's disease (PD) is a progressive neurodegenerative disease that affects almost 2% of the population above the age of 65. To better quantify the effects of new medications, fast and... Show moreParkinson's disease (PD) is a progressive neurodegenerative disease that affects almost 2% of the population above the age of 65. To better quantify the effects of new medications, fast and objective methods are needed. Touchscreen-based tapping tasks are simple yet effective tools for quantifying drug effects on PD-related motor symptoms, especially bradykinesia. However, there is no consensus on the optimal task set-up. The present study compares four tapping tasks in 14 healthy participants. In alternate finger tapping (AFT), tapping occurred with the index and middle finger with 2.5 cm between targets, whereas in alternate side tapping (AST) the index finger with 20 cm between targets was used. Both configurations were tested with or without the presence of a visual cue. Moreover, for each tapping task, within- and between-day repeatability and (potential) sensitivity of the calculated parameters were assessed. Visual cueing reduced tapping speed and rhythm, and improved accuracy. This effect was most pronounced for AST. On average, AST had a lower tapping speed with impaired accuracy and improved rhythm compared to AFT. Of all parameters, the total number of taps and mean spatial error had the highest repeatability and sensitivity. The findings suggest against the use of visual cueing because it is crucial that parameters can vary freely to accurately capture medication effects. The choice for AFT or AST depends on the research question, as these tasks assess different aspects of movement. These results encourage further validation of non-cued AFT and AST in PD patients. Show less
Aim Dual enkephalinase inhibitors (DENKIs) are involved in the regulation of nociception via opioid receptors. The novel compound STR-324 belongs to the DENKI pharmacological class. This first-in... Show moreAim Dual enkephalinase inhibitors (DENKIs) are involved in the regulation of nociception via opioid receptors. The novel compound STR-324 belongs to the DENKI pharmacological class. This first-in-human study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of STR-324 in healthy male participants. Methods This was a randomised, double-blind, placebo-controlled ascending dosing study in two parts: in part 1, 30 participants received 0.004-11.475 mg h(-1) of STR-324 or placebo (ratio 4:1) by 4 h intravenous infusion in a two-group, partial crossover design with four treatment periods separated by 1 month wash-out, and in part 2, 48 participants divided into three groups received either the active drug (1.25-11.25 mg h(-1)) or placebo (ratio 3:1) by 48 h intravenous infusion. Safety and tolerability parameters, pharmacokinetics and pharmacodynamic effects on neurocognitive and neurophysiological tasks and on a nociceptive test battery were evaluated. Results No clinically relevant changes in safety parameters were observed. All treatment-emergent adverse events were mild and transient. The pharmacokinetics of STR-324 could not be determined due to most concentrations being below quantifiable limits. STR-324 metabolite concentrations were measurable, showing dose proportionality of C-max and AUC(inf) with an estimated t(1/2) of 0.2-0.5 h. Significant changes in pharmacodynamic parameters were observed, but these were not consistent or dose-dependent. Conclusion STR-324 displayed favourable safety and tolerability profiles at all doses up to 11.475 mg h(-1). Although pharmacokinetic characterisation of STR-324 was limited, dose proportionality could be assumed based on major metabolite data assayed as proxy. No clear effects on nociceptive thresholds or other pharmacodynamic measures were observed. Trial registry: EudraCT (2014-002402-21) and toetsingonline.nl (63085). Show less
Aims: Evaluate safety, tolerability, pharmacokinetics (PK) and target engagement (TE) of losmapimod in blood and muscle in facioscapulohumeral dystrophy (FSHD).Methods: This study included Part A:... Show moreAims: Evaluate safety, tolerability, pharmacokinetics (PK) and target engagement (TE) of losmapimod in blood and muscle in facioscapulohumeral dystrophy (FSHD).Methods: This study included Part A: 10 healthy volunteers randomized to single oral doses of losmapimod (7.5 mg then 15 mg; n = 8) or placebo (both periods; n = 2); Part B: 15 FSHD subjects randomized to placebo (n = 3), or losmapimod 7.5 mg (n = 6) or 15 mg (n = 6); and Part C: FSHD subjects received open-label losmapimod 15 mg (n = 5) twice daily for 14 days. Biopsies were performed in FSHD subjects at baseline and Day 14 in magnetic resonance imaging-normal appearing (Part B) and affected muscle identified by abnormal short-tau inversion recovery sequence + (Part C). PK and TE, based on pHSP27:total HSP27, were assessed in muscle and sorbitol-stimulated blood.Results: PK profiles were similar between healthy volunteers and FSHD subjects, with mean C-max and AUC(0-12) for 15 mg in FSHD subjects (Part B) of 85.0 +/- 16.7 ng*h/mL and 410 +/- 50.3 ng*h/mL, respectively. Part B and Part C PK results were similar, and 7.5 mg results were approximately dose proportional to 15 mg results. Dose-dependent concentrations in muscle (42.1 +/- 10.5 ng/g [7.5 mg] to 97.2 +/- 22.4 ng/g [15 mg]) were observed, with plasma-to-muscle ratio from similar to 0.67 to similar to 1 at estimated t(max) of 3.5 hours postdose. TE was observed in blood and muscle. Adverse events (AEs) were mild and self-limited.Conclusion: Losmapimod was well tolerated, with no serious AEs. Dose-dependent PK and TE were observed. This study supports advancing losmapimod into Phase 2 trials in FSHD. Show less
Background: Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in early infancy and in elderly. A pediatric vaccine against RSV would not only prevent... Show moreBackground: Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in early infancy and in elderly. A pediatric vaccine against RSV would not only prevent morbidity and mortality amongst infants and young children but could also reduce transmission to elderly. The RSVDG vaccine consists of a live-attenuated RSV that lacks the G attachment protein. RSVDG is severely impaired in binding to host cells and exhibits reduced infectivity in preclinical studies. Intranasal immunization of cotton rats with RSVDG vaccine protected against replication of wildtype RSV, without inducing enhanced disease.Methods: We performed a first-in-human trial with primary objective to evaluate safety and shedding of RSV Delta G (6.5 log(10) CCID50) after intranasal administration. Healthy adults aged between 18 and 50, with RSV neutralizing serum titers below 9.6 log(2), received a single dose of either vaccine or placebo (n = 48, ratio 3:1). In addition to safety and tolerability, nasal viral load, and systemic and humoral immune responses were assessed at selected time points until 4 weeks after immunization.Results: Intranasal administration of RSV Delta G was well tolerated with no findings of clinical concern. No infectious virus was detected in nasal wash samples. Similar to other live-attenuated RSV vaccines, neutralizing antibody response following inoculation was limited in seropositive adults.Conclusions: A single dose of 6.5 log(10) CCID50 of RSV Delta G was safe and well-tolerated in seropositive healthy adults. RSV Delta G was sufficiently attenuated but there were no signs of induction of antibodies. Safety and immunogenicity can now be explored in children and eventually in seronegative infants. (C) 2020 The Author(s). Published by Elsevier Ltd. Show less
Plas, J.L. van der; Verdijk, P.; Brummelen, E.M.J. van; Jeeninga, R.E.; Roestenberg, M.; Burggraaf, J.; Kamerling, I.M.C. 2019
One of the main challenges in early clinical research with respiratory syncytial virus (RSV) live-attenuated vaccines (LAVs) is to assess immunogenicity in healthy adults. Healthy adults will have... Show moreOne of the main challenges in early clinical research with respiratory syncytial virus (RSV) live-attenuated vaccines (LAVs) is to assess immunogenicity in healthy adults. Healthy adults will have preexisting levels of serum neutralizing antibodies that could prematurely neutralize the LAV and underestimate the potential effect of the vaccine on the immune system. Data on prevalence and distribution of virus neutralizing titers (VNTs) in healthy adults is limited and there is no absolute threshold for protection against RSV-infection that can serve as an eligibility criterion in early phase trials. We assessed the RSV-specific serum VNT in healthy adults outside the Dutch RSV-Season in two clinical studies performed in 2017 (exploratory study, n = 100) and 2018 (first-in-human LAV-study, n = 190) using the same neutralizing assay. Our findings show that the prevalence and distribution of serum VNT was overall consistent in the two clinical studies. Log(2) VNTs were normally distributed, distributions of VNTs were similar and there was no statistical difference in mean log(2) VNT for both studies (p = .3). Serum VNTs were comparable during the 6 months of screening in the FIH LAV-study. Our findings will help to determine a cutoff serum VNT to be used as an eligibility criterion in future early phase clinical trials. Show less
