Intrathecal Gene Therapy for Giant Axonal Neuropathy.

BACKGROUND: Giant axonal neuropathy is a rare, autosomal recessive, pediatric, polysymptomatic, neurodegenerative disorder caused by biallelic loss-of-function variants in GAN, the gene encoding gigaxonin. METHODS: We conducted an intrathecal dose-escalation study of scAAV9/JeT-GAN (a self-complementary adeno-associated virus-based gene therapy containing the GAN transgene) in children with giant axonal neuropathy. Safety was the primary end point. The key secondary clinical end point was at least a 95% posterior probability of slowing the rate of change (i.e., slope) in the 32-item Motor Function Measure total percent score at 1 year after treatment, as compared with the pretreatment slope. RESULTS: One of four intrathecal doses of scAAV9/JeT-GAN was administered to 14 participants - 3.5×1013 total vector genomes (vg) (in 2 participants), 1.2×1014 vg (in 4), 1.8×1014 vg (in 5), and 3.5×1014 vg (in 3). During a median observation period of 68.7 months (range, 8.6 to 90.5), of 48 serious adverse events that had occurred, 1 (fever) was possibly related to treatment; 129 of 682 adverse events were possibly related to treatment. The mean pretreatment slope in the total cohort was -7.17 percentage points per year (95% credible interval, -8.36 to -5.97). At 1 year after treatment, posterior mean changes in slope were -0.54 percentage points (95% credible interval, -7.48 to 6.28) with the 3.5×1013-vg dose, 3.23 percentage points (95% credible interval, -1.27 to 7.65) with the 1.2×1014-vg dose, 5.32 percentage points (95% credible interval, 1.07 to 9.57) with the 1.8×1014-vg dose, and 3.43 percentage points (95% credible interval, -1.89 to 8.82) with the 3.5×1014-vg dose. The corresponding posterior probabilities for slowing the slope were 44% (95% credible interval, 43 to 44); 92% (95% credible interval, 92 to 93); 99% (95% credible interval, 99 to 99), which was above the efficacy threshold; and 90% (95% credible interval, 89 to 90). Between 6 and 24 months after gene transfer, sensory-nerve action potential amplitudes increased, stopped declining, or became recordable after being absent in 6 participants but remained absent in 8. CONCLUSIONS: Intrathecal gene transfer with scAAV9/JeT-GAN for giant axonal neuropathy was associated with adverse events and resulted in a possible benefit in motor function scores and other measures at some vector doses over a year. Further studies are warranted to determine the safety and efficacy of intrathecal AAV-mediated gene therapy in this disorder. (Funded by the National Institute of Neurological Disorders and Stroke and others; ClinicalTrials.gov number, NCT02362438.).

Effect of Sotagliflozin on Total Hospitalizations in Patients With Type 2 Diabetes and Worsening Heart Failure : A Randomized Trial.

BACKGROUND: In the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure) trial, sotagliflozin, a sodium-glucose cotransporter-1 and sodium-glucose cotransporter-2 inhibitor, reduced total occurrences of cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure relative to placebo by 33%. OBJECTIVE: To determine whether sotagliflozin increased the prespecified efficacy outcome of days alive and out of the hospital (DAOH) in the SOLOIST-WHF trial. DESIGN: Randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT03521934). SETTING: 306 sites in 32 countries. PARTICIPANTS: 1222 patients with type 2 diabetes and reduced or preserved ejection fraction who were recently hospitalized for worsening heart failure. INTERVENTION: 200 mg of sotagliflozin once daily (with a possible dose increase to 400 mg) or matching placebo. MEASUREMENTS: The primary analysis included hospitalizations for any reason on the basis of investigator-reported incidence and duration of admissions after randomization. Days alive and out of the hospital and its converse (days dead and days in the hospital) were analyzed using prespecified Poisson regression models. RESULTS: Although similar proportions of patients in the sotagliflozin and placebo groups were hospitalized at least once (38.5% vs. 41.4%), fewer patients in the sotagliflozin group were hospitalized more than once (16.3% vs. 22.1%). There were 64 and 76 deaths in the sotagliflozin and placebo groups, respectively. The DAOH rate in the sotagliflozin group was 3% higher than in the placebo group (rate ratio [RR], 1.03 [95% CI, 1.00 to 1.06]; P = 0.027). This difference was primarily driven by a reduction in the rate of days dead (RR, 0.71 [CI, 0.52 to 0.99]; P = 0.041) rather than by a reduction in the rate of days hospitalized for any cause. For every 100 days of follow-up, patients in the sotagliflozin group were alive and out of the hospital for 3% or 2.9 more days than those in the placebo group (91.8 vs. 88.9 days); this difference reflected a 2.6-day difference in days dead (6.3 vs. 8.9 days) and a 0.3-day difference in days in the hospital (1.9 vs. 2.2 days). LIMITATION: Other than heart failure, the primary reason for each hospitalization was unspecified. CONCLUSION: Sotagliflozin increased DAOH, a metric that may provide an additional patient-centered outcome to capture the totality of disease burden. Future studies are needed to quantify the consequences of increasing DAOH in terms of health economics and patient quality of life. PRIMARY FUNDING SOURCE: Sanofi at initiation and Lexicon Pharmaceuticals at completion.

The effect of hepatic or renal impairment on the pharmacokinetics of edivoxetine, a selective norepinephrine transporter reuptake inhibitor.

PURPOSE: To assess the impact of hepatic or renal impairment on the pharmacokinetics (PK) of edivoxetine. METHODS: Two separate multi-center, open-label studies with males and females were conducted. Subjects were categorized according to their hepatic function, determined by the Child-Pugh classification, or renal function, determined by creatinine clearance using the Cockcroft-Gault equation. Subjects received a single dose of 18 mg in the hepatic impairment study or 6 mg in the renal impairment study. Noncompartmental PK parameters were computed from the edivoxetine plasma concentration-time data. RESULTS: In the hepatic study, the geometric least squares mean (GLSM) and 90 % confidence interval (CI) of the ratio [impaired : normal] of area under the concentration versus time curve from time zero to infinity (AUC0-∞; h × ng/mL) was 1.24 (0.93, 1.64) in the mild, 1.60 (1.21, 2.12) in the moderate, and 1.70 (1.28, 2.24) in the severe group. In the renal impairment study, the GLSM (90 % CI) of the ratio [impaired : normal] of AUC0-∞ was 1.13 (0.73, 1.73) in mild, 1.90 (1.28, 2.82) in moderate, 1.55 (0.94, 2.55) in severe, and 1.03 (0.66, 1.59) in ESRD groups. Overall, the GLSM of the ratio [impaired : normal] of Cmax was slightly less than or approximately 1 across the hepatic and renal impairment groups. Across both studies, there were no clinically significant changes in vital signs and laboratory values, the adverse events were mild in severity and mostly related to nervous system and gastrointestinal disorder-related events. CONCLUSIONS: PK changes in subjects with hepatic or renal impairment were of small magnitude and did not appear to impact overall subject tolerability. Daily dosing of edivoxetine in a larger population of impaired subjects, including those with dual impairment, would aid in establishing edivoxetine tolerability and PK in a clinical practice scenario.