First‐in‐Human Studies of MW01‐6‐189WH, a Brain‐Penetrant, Antineuroinflammatory Small‐Molecule Drug Candidate: Phase 1 Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Studies in Healthy Adult Volunteers

Eldik, Linda J. Van; Sawaki, Lumy; Bowen, Karen; Laskowitz, Daniel T.; Noveck, Robert J.; Hauser, B.; Jordan, Lynn; Spears, Tracy; Wu, Huali; Watt, Kevin M.; Raja, Shruti; Roy, Saktimayee M.; Watterson, Daniel; Guptill, Jeffrey T.

doi:10.1002/cpdd.795

Cited by 8 publications

(7 citation statements)

References 26 publications

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“…As the search for effective treatment for ICH continues, some investigators are targeting post-ICH secondary brain injury in these patients. 20–25 However, clinical trials have thus far only applied baseline hematoma volume cutoffs as inclusion criteria for enrollment. 24 Given the emergence of automated ICH and PHE segmentation tools, 26 shape features beyond lesion volume (such as PHE sphericity) may also be incorporated in future acute ICH trial triage.…”

Section: Discussionmentioning

confidence: 99%

Peri-hematomal edema shape features related to 3-month outcome in acute supratentorial intracerebral hemorrhage

Dierksen,

Tran,

Zeevi

et al. 2024

European Stroke Journal

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Introduction: Perihematomal edema (PHE) represents secondary brain injury and a potential treatment target in intracerebral hemorrhage (ICH). However, studies differ on optimal PHE volume metrics as prognostic factor(s) after spontaneous, non-traumatic ICH. This study examines associations of baseline and 24-h PHE shape features with 3-month outcomes. Patients and methods: We included 796 patients from a multicentric trial dataset and manually segmented ICH and PHE on baseline and follow-up CTs, extracting 14 shape features. We explored the association of baseline, follow-up, difference (baseline/follow-up) and temporal rate (difference/time gap) of PHE shape changes with 3-month modified Rankin Score (mRS) – using Spearman correlation. Then, using multivariable analysis, we determined if PHE shape features independently predict outcome adjusting for patients’ age, sex, NIH stroke scale (NIHSS), Glasgow Coma Scale (GCS), and hematoma volume. Results: Baseline PHE maximum diameters across various planes, main axes, volume, surface, and sphericity correlated with 3-month mRS adjusting for multiple comparisons. The 24-h difference and temporal change rates of these features had significant association with outcome – but not the 24-h absolute values. In multivariable regression, baseline PHE shape sphericity (OR = 2.04, CI = 1.71–2.43) and volume (OR = 0.99, CI = 0. 98–1.0), alongside admission NIHSS (OR = 0.86, CI = 0.83–0.88), hematoma volume (OR = 0.99, CI = 0. 99–1.0), and age (OR = 0.96, CI = 0.95–0.97) were independent predictors of favorable outcomes. Conclusion: In acute ICH patients, PHE shape sphericity at baseline emerged as an independent prognostic factor, with a less spherical (more irregular) shape associated with worse outcome. The PHE shape features absolute values over the first 24 h provide no added prognostic value to baseline metrics.

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Section: Discussionmentioning

confidence: 99%

Peri-hematomal edema shape features related to 3-month outcome in acute supratentorial intracerebral hemorrhage

Dierksen,

Tran,

Zeevi

et al. 2024

European Stroke Journal

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“…Determination of participant eligibility can be accomplished remotely through EHR assessment, online surveys, or by leveraging technological advancements in algorithm development and machine learning to automate aspects of screening. The Biomarker and Edema Attenuation in IntraCerebral Hemorrhage (BEACH) trial [ 20 ] includes an AI algorithm deployed at each trial site that automatically reads every head computerized tomography (CT) scan taken, identifies and measures hemorrhages, and transmits this information to research staff in real time via a mobile application. This streamlines the identification of potential trial candidates and allows research staff at trial sites to conduct clinical screening and consenting more quickly.…”

Section: Decentralized Trials Processes and Tin Examplesmentioning

confidence: 99%

Decentralized clinical trials in the trial innovation network: Value, strategies, and lessons learned

Hanley¹,

Bernard²,

Wilkins³

et al. 2023

J. Clin. Trans. Sci.

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New technologies and disruptions related to Coronavirus disease-2019 have led to expansion of decentralized approaches to clinical trials. Remote tools and methods hold promise for increasing trial efficiency and reducing burdens and barriers by facilitating participation outside of traditional clinical settings and taking studies directly to participants. The Trial Innovation Network, established in 2016 by the National Center for Advancing Clinical and Translational Science to address critical roadblocks in clinical research and accelerate the translational research process, has consulted on over 400 research study proposals to date. Its recommendations for decentralized approaches have included eConsent, participant-informed study design, remote intervention, study task reminders, social media recruitment, and return of results for participants. Some clinical trial elements have worked well when decentralized, while others, including remote recruitment and patient monitoring, need further refinement and assessment to determine their value. Partially decentralized, or “hybrid” trials, offer a first step to optimizing remote methods. Decentralized processes demonstrate potential to improve urban-rural diversity, but their impact on inclusion of racially and ethnically marginalized populations requires further study. To optimize inclusive participation in decentralized clinical trials, efforts must be made to build trust among marginalized communities, and to ensure access to remote technology.

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“…In a first-in-human phase 1a single ascending dose study, MW189 was administered as a single intravenous (IV) dose at 0.025, 0.05, 0.1, or 0.25 mg/kg (15- to 20-min infusion) to 24 healthy adult participants (female and male) and was well tolerated [ 18 ]. No serious adverse events (AEs) or discontinuations due to AEs occurred.…”

Section: Introductionmentioning

confidence: 99%

“…MW189’s pharmacokinetic profile was consistent across doses, with linear kinetics and no significant accumulation. In a pilot phase 1a study of endotoxin-induced changes in plasma cytokine levels in healthy male volunteers, a single IV dose (0.25 mg/kg) of MW189 resulted in lower levels of the proinflammatory cytokine tumor necrosis factor-α and increased levels of the antiinflammatory cytokine interleukin-10 compared with placebo treatment [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

“…A phase 1b multiple ascending dose study [ 18 ] of eight healthy participants (male/female) per dose cohort randomized to MW189 (0.075, 0.15, 0.25, or 0.30 mg/kg IV twice a day [or matched saline placebo control]) for 5 days consecutively, given 12 h apart, reported that MW189 was safe and well tolerated. The MW189 group showed milder to moderate infusion-related AEs (e.g., extremity pain, infusion site pain), with minimal laboratory test result, vital signs, and electrocardiogram changes.…”

Section: Introductionmentioning

confidence: 99%

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Clinical Trial Protocol for BEACH: A Phase 2a Study of MW189 in Patients with Acute Nontraumatic Intracerebral Hemorrhage

Avadhani,

Ziai,

Thompson

et al. 2023

Neurocrit Care

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Patients with acute spontaneous intracerebral hemorrhage (ICH) develop secondary neuroinflammation and cerebral edema that can further damage the brain and lead to increased risk of neurologic complications. Preclinical studies in animal models of acute brain injury have shown that a novel small-molecule drug candidate, MW01-6-189WH (MW189), decreases neuroinflammation and cerebral edema and improves functional outcomes. MW189 was also safe and well tolerated in phase 1 studies in healthy adults. The proof-of-concept phase 2a Biomarker and Edema Attenuation in IntraCerebral Hemorrhage (BEACH) clinical trial is a first-in-patient, multicenter, randomized, double-blind, placebo-controlled trial. It is designed to determine the safety and tolerability of MW189 in patients with acute ICH, identify trends in potential mitigation of neuroinflammation and cerebral edema, and assess effects on functional outcomes. A total of 120 participants with nontraumatic ICH will be randomly assigned 1:1 to receive intravenous MW189 (0.25 mg/kg) or placebo (saline) within 24 h of symptom onset and every 12 h for up to 5 days or until hospital discharge. The 120-participant sample size (60 per group) will allow testing of the null hypothesis of noninferiority with a tolerance limit of 12% and assuming a “worst-case” safety assumption of 10% rate of death in each arm with 10% significance and 80% power. The primary outcome is all-cause mortality at 7 days post randomization between treatment arms. Secondary end points include all-cause mortality at 30 days, perihematomal edema volume after symptom onset, adverse events, vital signs, pharmacokinetics of MW189, and inflammatory cytokine concentrations in plasma (and cerebrospinal fluid if available). Other exploratory end points are functional outcomes collected on days 30, 90, and 180. BEACH will provide important information about the utility of targeting neuroinflammation in ICH and will inform the design of future larger trials of acute central nervous system injury.

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First‐in‐Human Studies of MW01‐6‐189WH, a Brain‐Penetrant, Antineuroinflammatory Small‐Molecule Drug Candidate: Phase 1 Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Studies in Healthy Adult Volunteers

Cited by 8 publications

References 26 publications

Peri-hematomal edema shape features related to 3-month outcome in acute supratentorial intracerebral hemorrhage

Peri-hematomal edema shape features related to 3-month outcome in acute supratentorial intracerebral hemorrhage

Decentralized clinical trials in the trial innovation network: Value, strategies, and lessons learned

Clinical Trial Protocol for BEACH: A Phase 2a Study of MW189 in Patients with Acute Nontraumatic Intracerebral Hemorrhage

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