Browsing by Subject "Phase 1"

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    Evidence of trospium’s ability to mitigate cholinergic adverse events related to xanomeline: phase 1 study results
    (Springer, 2023) Breier, Alan; Brannan, Stephen K.; Paul, Steven M.; Miller, Andrew C.; Psychiatry, School of Medicine
    Rationale: The M1/M4 preferring muscarinic receptor agonist xanomeline demonstrated antipsychotic and procognitive effects in patients with Alzheimer's disease or schizophrenia in prior studies, but further clinical development was limited by cholinergic adverse events (AEs). KarXT combines xanomeline with the peripherally restricted muscarinic receptor antagonist trospium with the goal of improving tolerability and is in clinical development for schizophrenia and other neuropsychiatric disorders. Objective: Test the hypothesis that trospium can mitigate cholinergic AEs associated with xanomeline. Methods: Healthy volunteers enrolled in this phase 1 (NCT02831231), single-site, 9-day, double-blind comparison of xanomeline alone (n = 33) versus KarXT (n = 35). Rates of five prespecified cholinergic AEs (nausea, vomiting, diarrhea, excessive sweating, salivary hypersecretion) were compared between treatment arms. Vital signs, electrocardiograms (ECGs), safety laboratory values, and pharmacokinetic (PK) analyses were assessed. A self-administered visual analog scale (VAS) and clinician-administered scales were employed. Results: Compared with xanomeline alone, KarXT reduced composite incidences of the five a priori selected cholinergic AEs by 46% and each individual AE by ≥ 29%. There were no episodes of syncope in KarXT-treated subjects; two cases occurred in the xanomeline-alone arm. The rate of postural dizziness was 11.4% in the KarXT arm versus 27.2% with xanomeline alone. ECG, vital signs, and laboratory values were not meaningfully different between treatment arms. The VAS and clinician-administered scales tended to favor KarXT. PK analysis revealed that trospium did not affect xanomeline's PK profile. Conclusions: Trospium was effective in mitigating xanomeline-related cholinergic AEs. KarXT had an improved safety profile compared with xanomeline alone.
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    Phase 1 Study of THR-687, a Novel, Highly Potent Integrin Antagonist for the Treatment of Diabetic Macular Edema
    (Elsevier, 2021-07-14) Khanani, Arshad M.; Patel, Sunil S.; Gonzalez, Victor H.; Moon, Suk J.; Jaffe, Glenn J.; Wells, John A.; Kozma, Petra; Dugel, Pravin U.; Maturi, Raj K.; Ophthalmology, School of Medicine
    Purpose: To evaluate the safety and preliminary efficacy of THR-687 in patients with center-involved diabetic macular edema (DME). Design: Phase 1, open-label, multicenter, 3 + 3 dose-escalation study with 3-month follow-up. Participants: Patients 18 years of age or older with visual impairment resulting from DME. Methods: Single intravitreal injection of THR-687 (0.4 mg, 1.0 mg, or 2.5 mg). Main outcome measures: The primary outcome measure was the incidence of dose-limiting toxicities (DLTs). The secondary outcome measure was the incidence of adverse events (AEs), including the occurrence of laboratory abnormalities. Exploratory outcome measures included changes from baseline in best-corrected visual acuity (BCVA) and central subfield thickness (CST), assessments of ischemia and leakage on fluorescein angiography, and THR-687 levels in plasma. Results: Twelve patients were treated: 3 patients received 0.4 mg of THR-687, 3 patients received 1.0 mg of THR-687, and 6 patients received 2.5 mg of THR-687. Most patients were men (9/12 patients). Their mean age was 57.8 years. No DLTs or serious AEs were reported at any of the dose levels tested. Overall, 9 AEs in the study eye were reported for 5 of 12 patients. Of those, 4 AEs in 3 of 12 patients were deemed treatment related by the investigator, all of which were mild, started on the day of the injection, and had resolved within 28 days without treatment. Overall, mean gains from baseline in BCVA were observed at all study visits with a rapid onset (7.2 Early Treatment Diabetic Retinopathy Study [ETDRS] letters at day 7) and a durability up to the end of the study (8.3 ETDRS letters at month 3). A mean decrease in CST was observed up to month 1. Overall, the mean BCVA gains and CST decreases were highest at the highest THR-687 dose level tested. THR-687 was undetectable in plasma at 7 days after the injection. Conclusions: At all dose levels tested, a single intravitreal injection of THR-687 was safe and well tolerated. Preliminary efficacy was observed by a rapid gain in BCVA with 3 months' durability and a decrease in CST up to 1 month after the injection.