Safety and tolerability of KAN-101, a liver-targeted immune tolerance therapy, in patients with coeliac disease (ACeD): a phase 1 trial.

BACKGROUND: Coeliac disease management is limited to strict adherence to a gluten-free diet with no approved therapies. This first-in-human phase 1 study evaluated the safety and tolerability of KAN-101, a liver-targeting glycosylation signature conjugated to a deaminated gliadin peptide designed to induce immune tolerance to gliadin. METHODS: Adults (aged 18-70 years) with biopsy-confirmed, HLA-DQ2.5 genotype coeliac disease were enrolled from clinical research units and hospitals in the USA. Part A of the trial was an open-label, single ascending dose study of intravenous KAN-101 using sentinel dosing in evaluation of the following cohorts: 0·15 mg/kg, 0·3 mg/kg, 0·6 mg/kg, 1·2 mg/kg, and 1·5 mg/kg. Following safety monitoring committee review of the 0·3 mg/kg dose level in part A, part B was initiated as a randomised, placebo-controlled, multiple ascending dose study. In part B, interactive response technology was used to randomly assign (5:1) patients to receive intravenous KAN-101 (0·15 mg/kg, 0·3 mg/kg, or 0·6 mg/kg) or placebo following a 1:1 assignment of the first two eligible patients in each cohort for sentinel dosing. Patients in part B received three administrations of KAN-101 or placebo followed by a 3-day oral gluten challenge (9 g per day) 1 week after completing dosing. Study personnel and patients were masked to treatment assignments in part B, and not in part A. The primary endpoint was the incidence and severity of adverse events with escalating doses of KAN-101, assessed in all patients who received any amount of study drug based on dose level received. The secondary endpoint was assessment of plasma concentrations and pharmacokinetic parameters of KAN-101 following single and multiple doses, assessed in all patients who received at least one dose and had one or more values for drug concentration. This study is registered with ClinicalTrials.gov, NCT04248855, and is completed. FINDINGS: Between Feb 7, 2020, and Oct 8, 2021, 41 patients were enrolled at ten US sites. 14 patients were assigned to part A (four 0·15 mg/kg, three 0·3 mg/kg, three 0·6 mg/kg, three 1·2 mg/kg, one 1·5 mg/kg) and 27 patients to part B (six 0·15 mg/kg with two placebo, seven 0·3 mg/kg with two placebo, and eight 0·6 mg/kg with two placebo). Treatment-related adverse events were reported in 11 (79%) of 14 patients in part A and 18 (67%) of 27 in part B (placebo two [33%] of six patients; KAN-101 16 [76%] of 21 patients), were grade 2 or lower, and were mild to moderate in severity. The most commonly observed adverse events were nausea, diarrhoea, abdominal pain, and vomiting, consistent with symptoms had by patients with coeliac disease on gluten ingestion. No grade 3-4 adverse events, serious adverse events, dose-limiting toxicities, or deaths occurred. Pharmacokinetic analyses showed KAN-101 was cleared from systemic circulation within roughly 6 h with a geometric mean half-life of 3·72 min (CV% 6·5%) to 31·72 min (83·7%), and no accumulation with repeated dosing. INTERPRETATION: KAN-101 has an acceptable safety profile in patients with coeliac disease with no dose-limiting toxicities and no maximum tolerated dose was observed. Rapid systemic clearance of KAN-101 was observed and no accumulation on repeated dosing. A future study will evaluate the safety and efficacy, including biomarker responses with a gluten challenge, of KAN-101 at doses 0·6 mg/kg and greater in patients with coeliac disease. FUNDING: Kanyos Bio.

Studies into radiolytic decomposition of fluorine-18 labeled radiopharmaceuticals for positron emission tomography.

Radiolytic decomposition of high specific concentration radiopharmaceuticals is an undesired side-effect that can hamper development of novel PET tracers. This was particularly evident in a series of carbon-11 and fluorine-18 labeled mono- and dimethyl-substituted aryl amines, where rapid decomposition was observed in isolation and formulation steps. We tested a number of additives that inhibit radiolysis and can be safely added to the synthesis procedures (purification and isolation) and reformulation steps to provide suitable clinical formulations. Ethanol and sodium ascorbate are established anti-oxidant stabilizers that completely inhibit radiolytic decomposition and are amenable to human use. Herein, we also demonstrate for the first time that nitrones are non-toxic radical scavengers that are capable of inhibiting radiolysis.

Preclinical evaluation of technetium 99m-labeled P1827DS for infection imaging and comparison with technetium 99m IL-8.

BACKGROUND: The technetium 99 m (99mTc)-radiolabeled, leukocyte-avid peptide-glycoseaminoglycan complex, [99mTc]P1827DS, has been synthesized as an improved infection/inflammation imaging agent to [99mTc]P483H (LeukoTect, Diatide). In a phase I/II clinical trail, [99mTc]P483H images were equivalent to those obtained with 111In ex vivo labeled leukocytes. However, there was physiologic accumulation of radioactivity in the body that could hamper interpretation of the images. In this study, the potential of [99mTc]P1827DS for infection imaging was assessed in comparison with [99mTc]P483H and the well-described imaging agent [99mTc] hydrazinonicotinamide (HYNIC)-interleukin 8 (IL-8). METHODS: The binding of [99mTc]P1827DS to human blood cell was studied in vitro. A rabbit Escherichia coli infection model was used to perform the biodistribution and imaging studies with [99mTc]P1827DS, [99mTc]P483H and [99mTc]HYNIC-IL-8. RESULTS: [99mTc]P1827DS binds to leukocytes but not to erythrocytes. The leukocyte binding was not saturable up to an investigated concentration of 10 microM. The accumulation of [99mTc]P1827/DS at the infection site strongly depends on the P1827/DS ratio and was optimal at a molar ratio of 10:1. [99mTc]P1827DS shows improved biodistribution over [99mTc]P483H with similar uptake at the infection site. Abscess uptake of [99mTc]HYNIC-IL-8 was approximately three times higher than that of [99mTc]P1827DS. [99mTc]HYNIC-IL-8 showed high accumulation in the kidneys, whereas [99mTc]P1827DS showed high lung uptake and slightly higher accumulation in the liver and spleen. CONCLUSION: [99mTc]P1827DS is a potential new inflammation imaging agent, which clearly visualized the abscess in the rabbit E. coli infection model and showed improved biodistribution compared to [99mTc]P483H. However, the infection uptake and biodistribution of [99mTc]P1827DS is not superior to that of [99mTc]HYNIC-IL-8 in this animal model.