8 research outputs found
Photoaffinity Labeling the Agonist Binding Sites of Torpedo and α4ÎČ2 Nicotinic Acetylcholine Receptors and Acetylcholine Binding Proteins (AChBPs) with [3H]Cytisine
Fitxes dels barri
SHP656, a polysialylated recombinant factor VIII (PSA-rFVIII): First-in-human study evaluating safety, tolerability and pharmacokinetics in patients with severe haemophilia A
Introduction
SHP656 is the first factor VIII (FVIII) product developed using polysialylation (PSA) technology, in which fullâlength recombinant (r) FVIII (antiâhaemophilic factor [recombinant]) is conjugated with a 20 kDa PSA polymer.
Aim
To compare the safety, immunogenicity and pharmacokinetics of SHP656 vs the parent rFVIII (octocog alfa) after single infusions of 25â75 IU/kg in patients with severe haemophilia A (FVIII activity <1%).
Methods
Multinational, phase 1, prospective, openâlabel, twoâperiod, fixedâsequence, doseâescalation trial (clinicaltrials.gov NCT02716194). Patients received single doses of rFVIII and then SHP656 sequentially at the same dose: 25 ± 3 IU/kg (Cohort 1), 50 ± 5 IU/kg (Cohort 2) and 75 ± 5 IU/kg (Cohort 3).
Results
Forty patients received rFVIII: 11 in Cohort 1, 16 in Cohort 2 and 13 in Cohort 3. Two patients withdrew before receiving SHP656, leaving 38 patients who completed the study and received both treatments. No treatmentârelated adverse events (AEs), serious AEs, deaths, study withdrawals, thrombotic events or allergic reactions were reported; and no significant treatmentârelated changes in laboratory parameters or vital signs. No patients developed FVIII inhibitors or antibodies to PSA. FVIII activity was significantly prolonged following SHP656 administration vs rFVIII with an approximately 1.5âfold extension in mean residence time (P < .05). Exposure increased proportional to the SHP656 dose over the 25â75 IU/kg dose range
Photoaffinity Labeling the Agonist Binding Sites of Torpedo and α4ÎČ2 Nicotinic Acetylcholine Receptors and Acetylcholine Binding Proteins (AChBPs) with [3H]Cytisine
Interim Analysis from the OPTIC Trial - A Dose-Ranging Study of 3 Starting Doses of Ponatinib
Retrospective analysis of arterial occlusive events in the PACE trial by an independent adjudication committee
Background:
The phase 2 PACE (Ponatinib Ph+ ALL and CML Evaluation) trial of ponatinib showed robust long-term benefit in relapsed Philadelphia chromosome-positive (Ph+) leukemia; arterial occlusive events (AOEs) occurred inââ„â25% of patients based on investigator reporting. However, AOE rates vary depending on the definitions and reporting approach used.
Methods:
To better understand clinically relevant AOEs with ponatinib, an independent cardiovascular adjudication committee reviewed 5-year AOE data from the PACE trial according to a charter-defined process and standardized event definitions.
Results:
A total of 449 patients with chronic myeloid leukemia (CML) or Ph+ acute lymphoblastic leukemia (ALL) received ponatinib (median age 59 y; 47% female; 93%ââ„â2 prior tyrosine kinase inhibitors (TKIs); median follow-up, 37.3 months). The adjudicated AOE rate (17%) was lower than the non-adjudicated rate (i.e., rate before adjudication; 25%). The only adjudicated AOE inâ>â2% of patients was peripheral arterial occlusive disease (4%). Exposure-adjusted incidence of newly occurring adjudicated AOEs decreased over time. Patients with multiple baseline cardiovascular risk factors had higher adjudicated AOE rates than those without risk factors.
Conclusions:
This independent adjudication study identified lower AOE rates than previously reported, suggesting earlier overestimation that may inaccurately reflect AOE risk with ponatinib. This trial was registered under ClinicalTrials.gov identifier NCT01207440 on September 23, 2010 (https://clinicaltrials.gov/ct2/show/NCT01207440)
Photoaffinity labeling the agonist binding domain of α4ÎČ4 and α4ÎČ2 neuronal nicotinic acetylcholine receptors with [125I]epibatidine and 5[125I]A-85380
Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia: a randomized, open-label phase 2 clinical trial
International audienceIn PACE (Ponatinib Ph+ ALL and CML Evaluation), a phase 2 trial of ponatinib that included patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to multiple prior tyrosine kinase inhibitors (TKIs), ponatinib showed deep and durable responses, but arterial occlusive events (AOEs) emerged as notable adverse events. Post hoc analyses indicated that AOEs are dose dependent. We assessed the benefit/risk ratio across 3 ponatinib starting doses in the first prospective study to evaluate a novel, response-based, dose-reduction strategy for TKI treatment. Adults with CP-CML resistant to or intolerant of at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1 T315I mutation were randomly assigned 1:1:1 to 3 cohorts receiving ponatinib 45, 30, or 15 mg once daily. In patients who received 45 or 30 mg daily the dose was reduced to 15 mg upon response (BCR-ABL1IS transcript levels â€1%). The primary end point was response at 12 months. From August 2015 through May 2019, 283 patients were randomly assigned to the cohorts: 282 (94 per dose group) received treatment (data cutoff, 31 May 2020). The primary end point (98.3% confidence interval) was achieved in 44.1% (31.7-57.0) in the 45-mg cohort, 29.0% (18.4-41.6) in the 30-mg cohort, and 23.1% (13.4-35.3) in the 15-mg cohort. Independently confirmed grade 3 or above treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 45-, 30-, and 15-mg cohorts, respectively. All cohorts showed benefit in this highly resistant CP-CML population. Optimal benefit/risk outcomes occurred with the 45-mg starting dose, which was decreased to 15 mg upon achievement of a response. This trial is registered on www.clinicaltrials.gov as NCT02467270