Early clinical development of artemether-lumefantrine dispersible tablet: palatability of three flavours and bioavailability in healthy subjects

BACKGROUND\ud \ud Efforts to ease administration and enhance acceptability of the oral anti-malarial artemether-lumefantrine (A-L) crushed tablet to infants and children triggered the development of a novel dispersible tablet of A-L. During early development of this new formulation, two studies were performed in healthy subjects, one to evaluate the palatability of three flavours of A-L, and a second one to compare the bioavailability of active principles between the dispersible tablet and the tablet (administered crushed and intact).\ud \ud METHODS\ud \ud Study 1 was performed in 48 healthy schoolchildren in Tanzania. Within 1 day, all subjects tasted a strawberry-, orange- and cherry-flavoured oral A-L suspension for 10 seconds (without swallowing) in a randomized, single-blind, crossover fashion. The palatability of each formulation was rated using a visual analogue scale (VAS). Study 2 was an open, randomized crossover trial in 48 healthy adults given single doses of A-L (80 mg artemether + 480 mg lumefantrine) with food. The objectives were to compare the bioavailability of artemether, dihydroartemisinin (DHA) and lumefantrine between the dispersible tablet and the tablet administered crushed (primary objective) and intact (secondary objective).\ud \ud RESULTS\ud \ud Study 1 showed no statistically significant difference in VAS scores between the three flavours but cherry had the highest score in several ratings (particularly for overall liking). Study 2 demonstrated that the dispersible and crushed tablets delivered bioequivalent artemether, DHA and lumefantrine systemic exposure (area under the curve [AUC]); mean ± SD AUC0-tlast were 208 ± 113 vs 195 ± 93 h.ng/ml for artemether, 206 ± 81 vs 199 ± 84 h.ng/ml for DHA and 262 ± 107 vs 291 ± 106 h x μg/ml for lumefantrine. Bioequivalence was also shown for peak plasma concentrations (Cmax) of DHA and lumefantrine. Compared with the intact tablet, the dispersible tablet resulted in bioequivalent lumefantrine exposure, but AUC and Cmax values of artemether and DHA were 20-35% lower.\ud \ud CONCLUSIONS\ud \ud Considering that cherry was the preferred flavour, and that the novel A-L dispersible tablet demonstrated similar pharmacokinetic performances to the tablet administered crushed, a cherry-flavoured A-L dispersible tablet formulation was selected for further development and testing in a large efficacy and safety study in African children with malaria

Safety/Acuity Outcomes 96-Weeks Post-Treatment with rAAV2/2-ND4; Gene Therapy for ND4 LHON: a Phase I/II Trial

rAAV2/2-ND4 is an investigational gene therapy enabling allotopic transgene expression. We report safety and visual acuity outcomes 96 weeks post-treatment in a Phase I/II open-label dose escalation trial

Safety and tolerability of high-dose formoterol (via Aerolizer®) and salbutamol in patients with chronic obstructive pulmonary disease

SummaryTo evaluate the safety and tolerability of high-dose formoterol and salbutamol in patients with chronic obstructive pulmonary disease (COPD).In this two-way crossover, double-blind, double-dummy study, 17 adults with mild-to-moderate COPD were randomized to receive either formoterol 24μg (2×12μg via Aerolizer®), or salbutamol 600μg (6×100μg via metered-dose inhaler), and the appropriate double-dummy q.i.d. at 4-h intervals for 3 consecutive days (total daily dose: 96 and 2400μg, respectively). After a 4–7-day washout period, patients were switched to the other treatment.Treatment with high-dose formoterol and salbutamol was equally well tolerated, with no reports of serious adverse events. Both agents were associated with decreased plasma potassium (mean minimum values: 3.4 and 3.3mmol/l for formoterol and salbutamol, respectively; P=0.914), increased serum glucose (mean maximum values: 9.0 and 8.7mmol/l, respectively; P=0.373), and small increases in mean QTc interval (mean maximum 439ms with both treatments; P=0.813). No clinically relevant between-treatment differences in adverse events or laboratory values occurred. Both drugs improved lung function (mean maximum forced expiratory volume in 1s [FEV1] 2.6l with both treatments; P=0.624), with the improvement being significantly greater with formoterol than with salbutamol on all 3 days of treatment (mean area under the curve [AUC](0–24h) of FEV1 formoterol vs. salbutamol on days 1–3, all P<0.05).High-dose formoterol via Aerolizer® (up to 96μg/day) has a comparable tolerability profile to that of salbutamol in patients with mild-to-moderate COPD

Safety/Acuity Outcomes 96-Weeks Post-Treatment with rAAV2/2-ND4; Gene Therapy for ND4 LHON: a Phase I/II Trial

rAAV2/2-ND4 is an investigational gene therapy enabling allotopic transgene expression. We report safety and visual acuity outcomes 96 weeks post-treatment in a Phase I/II open-label dose escalation trial

Phase I/IIa Visual Acuity Outcomes 1.5-Years Post-Treatment with rAAV2/2-ND4,; Investigational Gene Therapy for ND4 LHON (video)

rAAV2/2-ND4 is an experimental gene therapy enabling allotopic transgene expression. We report visual acuity (VA) outcomes 1.5- years post-treatment in a Phase I/IIa (NCT02064569) open-label, dose-escalation safety study

Phase I/IIa Visual Acuity Outcomes 1.5-Years Post-Treatment with rAAV2/2-ND4, Investigational Gene Therapy for ND4 LHON (abstract)

rAAV2/2-ND4 is an experimental gene therapy enabling allotopic transgene expression. We report visual acuity (VA) outcomes 1.5- years post-treatment in a Phase I/IIa (NCT02064569) open-label, dose-escalation safety study

Preliminary Safety and Tolerability Results Of A Recombinant Adeno-Associated Viral Vector Serotype 2

Introduction: Our goal is to report the results of a first-in-man safety trial of gene therapy in patients with Leber Hereditary Optic Neuropathy (LHON)

Preliminary Safety and Tolerability Results Of A Recombinant Adeno-Associated Viral Vector Serotype 2 (Raav2/2) Containing the Human Wild-Type Mitochondrial NADH Dehydrogenase 4 (ND4) Gene, in Patients with Leber Hereditary Optic Neuropathy Due to the G11778A Mitochondrial DNA Mutation

Our goal is to report the results of a first-in-man safety trial of gene therapy in patients with Leber Hereditary Optic Neuropathy (LHON)

Immune Response and Intraocular Inflammation in Patients With Leber Hereditary Optic Neuropathy Treated With Intravitreal Injection of Recombinant Adeno-Associated Virus 2 Carrying the ND4 Gene

International audienceImportance: Intravitreal gene therapy is regarded as generally safe with limited mild adverse events, but its systemic effects remain to be investigated.Objective: To examine the association between immune response and intraocular inflammation after ocular gene therapy with recombinant adeno-associated virus 2 carrying the ND4 gene (rAAV2/2-ND4).Design, Setting, and Participants:This secondary analysis of an open-label, dose-escalation phase 1/2 randomized clinical trial of rAAV2/2-ND4 included data from February 13, 2014 (first patient visit), to March 30, 2017 (last patient visit at week 96), the first 2 years after injection. Patients older than 15 years with diagnosed ND4 Leber hereditary optic neuropathy (LHON) and visual acuity of at least counting fingers were enrolled in 1 of 5 cohorts. Four dose cohorts of 3 patients each were treated sequentially. An extension cohort of 3 patients received the dose of 9 × 1010 viral genomes per eye.Interventions: Patients received increasing doses of rAAV2/2-ND4 (9 × 109, 3 × 1010, 9 × 1010, and 1.8 × 1011 viral genomes per eye) as a single unilateral intravitreal injection. Patients were monitored for 96 weeks after injection; ocular examinations were performed regularly, and blood samples were collected for immunologic testing.Main Outcomes and Measures: A composite ocular inflammation score (OIS) was calculated based on grades of anterior chamber cells and flare, vitreous cells, and haze according to the Standardization of Uveitis Nomenclature. The systemic immune response was quantified by enzyme-linked immunospot (cellular immune response), enzyme-linked immunosorbent assay (IgG titers), and luciferase assay (neutralizing antibody [NAb] titers).Results: The present analysis included 15 patients (mean [SD] age, 47.9 [17.2] years; 13 men and 2 women) enrolled in the 5 cohorts of the clinical trial. Thirteen patients experienced intraocular inflammation after rAAV2/2-ND4 administration. Mild anterior chamber inflammation and vitritis were reported at all doses, and all cases were responsive to treatment. A maximum OIS of 9.5 was observed in a patient with history of idiopathic uveitis. Overall, OIS was not associated with the viral dose administered. No NAbs against AAV2 were detected in aqueous humor before treatment. Two patients tested positive for cellular immune response against AAV2 at baseline and after treatment. Humoral immune response was not apparently associated with the dose administered or with the immune status of patients at baseline. No association was found between OISs and serum NAb titers.Conclusions and Relevance: In this study, intravitreal administration of rAAV2/2-ND4 in patients with LHON was safe and well tolerated. Further investigations may shed light into the local immune response to rAAV2/2-ND4 as a potential explanation for the observed intraocular inflammation