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Background and Aims: RNA interference (RNAi) therapy with JNJ-3989 silences HBV RNA transcripts from episomal cccDNA and integrated HBV DNA. In AROHBV1001 (phase 2a), JNJ-3989 (3 monthly doses 25-400 mg) + a nucleos(t)ide analogue (NA) demonstrated antiviral activity in patients (pts) with chronic hepatitis B (CHB) by reducing serum viral parameters (AASLD 2019). 9-month follow-up data for pts on >=100 mg are presented. Method(s): 8 CHB pts/cohort (NA experienced or naive; HBeAg +ve or -ve) received 3 subcutaneous JNJ-3989 doses (days 1, 27, 57) of 100, 200, 300 (n = 16) or 400 mg. Pts started/continued with an NA on day 1 and continued throughout the study. Safety and viral parameters (HBsAg, HBeAg, HBV DNA, HBV RNA, HBcrAg) were assessed. For all parameters, sustained suppression was defined as a >=1.0 log10 reduction from day 1 or a value >lower limit of quantification at day 336. Result(s): 40 pts were enrolled: 73% males; 85% Asian; median age 45 (26-66) yrs; HBeAg: 14 +ve, 26 -ve; 80% NA experienced. No deaths, treatment discontinuations or drug-related serious adverse events (AEs) were seen; 1 pt was lost to follow up. The most common drug-related AEs were mild injection site AEs (7 pts). One AE of elevated ALT (peak 136 U/L) was reported. HBsAg levels rapidly declined during treatment. At the HBsAg nadir, 39/40 pts had a >=1.0 log10 HBsAg reduction from day 1; range 1.11-3.77; for 1 pt the maximum decline was 0.77 log10. Mean nadir for HBsAg (SE) log10 reduction from day 1 was 1.72 (0.18; 100 mg), 1.79 (0.14; 200 mg), 2.04 (0.20; 300 mg; 11/16 HBeAg +ve) and 1.90 (0.18; 400 mg). 22/39 (56%) pts had sustained HBsAg reductions (>=1.0 log10 reduction at day 336, ~9 months after last JNJ-3989 dose, Fig); mean (SE; range) HBsAg reductions in pts with sustained suppression were: 1.74 (0.77; 1.00-3.38) vs 0.61 (0.06; 0.15-0.96) for non-sustained suppression. For pts with quantifiable parameters on day 1 and available data at day 336, a sustained suppression was obs

Background and Aims: RNA interference (RNAi) therapy with JNJ-3989 silences HBV RNA transcripts from episomal cccDNA and integrated HBV DNA. In AROHBV1001 (phase 2a), JNJ-3989 (3 monthly doses 25-400 mg) + a nucleos(t)ide analogue (NA) demonstrated antiviral activity in patients (pts) with chronic hepatitis B (CHB) by reducing serum viral parameters (AASLD 2019). 9-month follow-up data for pts on >=100 mg are presented. Method(s): 8 CHB pts/cohort (NA experienced or naive; HBeAg +ve or -ve) received 3 subcutaneous JNJ-3989 doses (days 1, 27, 57) of 100, 200, 300 (n = 16) or 400 mg. Pts started/continued with an NA on day 1 and continued throughout the study. Safety and viral parameters (HBsAg, HBeAg, HBV DNA, HBV RNA, HBcrAg) were assessed. For all parameters, sustained suppression was defined as a >=1.0 log10 reduction from day 1 or a value >lower limit of quantification at day 336. Result(s): 40 pts were enrolled: 73% males; 85% Asian; median age 45 (26-66) yrs; HBeAg: 14 +ve, 26 -ve; 80% NA experienced. No deaths, treatment discontinuations or drug-related serious adverse events (AEs) were seen; 1 pt was lost to follow up. The most common drug-related AEs were mild injection site AEs (7 pts). One AE of elevated ALT (peak 136 U/L) was reported. HBsAg levels rapidly declined during treatment. At the HBsAg nadir, 39/40 pts had a >=1.0 log10 HBsAg reduction from day 1; range 1.11-3.77; for 1 pt the maximum decline was 0.77 log10. Mean nadir for HBsAg (SE) log10 reduction from day 1 was 1.72 (0.18; 100 mg), 1.79 (0.14; 200 mg), 2.04 (0.20; 300 mg; 11/16 HBeAg +ve) and 1.90 (0.18; 400 mg). 22/39 (56%) pts had sustained HBsAg reductions (>=1.0 log10 reduction at day 336, ~9 months after last JNJ-3989 dose, Fig); mean (SE; range) HBsAg reductions in pts with sustained suppression were: 1.74 (0.77; 1.00-3.38) vs 0.61 (0.06; 0.15-0.96) for non-sustained suppression. For pts with quantifiable parameters on day 1 and available data at day 336, a sustained suppression was obs

Objective: Using global MSBase registry, this study establishes 6-month confirmed disability progression events as indicators of long-term disability worsening suitable for use in randomized clinical trials in multiple sclerosis (MS). Background(s): Randomized clinical trials evaluate short-term treatment effect on disability in the form of 3-6-month confirmed disability progression, but whether these translate into long-term disability outcomes is unknown. Design/Methods: A Cox proportional hazards model identified associations between patients' demographic and clinical characteristics and the probability of recovery from disability progression events. The coefficients from this model were used to calculate a sustained progression score, which was evaluated in a validation cohort and applied to a trial cohort. Result(s): 902 patients (development cohort), patient characteristics at the time of progression associated with lower probability of subsequent improvement were age (hazard ratio (HR)=0.98), primary progressive (HR=0.37) and progressive-relapsing (HR=0.36) MS, expanded disability status scale score >=6 (HR=0.71) and its change from baseline (HR=0.67), number of affected functional system scores (HR=0.92) and pyramidal (HR=0.79) functional system score (p<0.05). The strength of the association with pyramidal score decreased with time (HR=1.01). A relapse within previous month (HR=1.46) and worsening in sensory functional system score (HR=1.17) were associated with higher probability of improvement after progression. The sustained progression score (range 0.39-4.79) in the validation cohort with 1,271 progression events, estimated a 53% lower chance of improvement for each unit increase in the score (HR=0.47). The proportions of progression events sustained at 5 years stratified by the score were 1: 68%, 2: 79%, 3: 94%, 4: 100%. The progression scores were then applied to the CLARITY trial data. Conclusion(s): Estimate of the probability of disability progress

Objective: Using global MSBase registry, this study establishes 6-month confirmed disability progression events as indicators of long-term disability worsening suitable for use in randomized clinical trials in multiple sclerosis (MS). Background(s): Randomized clinical trials evaluate short-term treatment effect on disability in the form of 3-6-month confirmed disability progression, but whether these translate into long-term disability outcomes is unknown. Design/Methods: A Cox proportional hazards model identified associations between patients' demographic and clinical characteristics and the probability of recovery from disability progression events. The coefficients from this model were used to calculate a sustained progression score, which was evaluated in a validation cohort and applied to a trial cohort. Result(s): 902 patients (development cohort), patient characteristics at the time of progression associated with lower probability of subsequent improvement were age (hazard ratio (HR)=0.98), primary progressive (HR=0.37) and progressive-relapsing (HR=0.36) MS, expanded disability status scale score >=6 (HR=0.71) and its change from baseline (HR=0.67), number of affected functional system scores (HR=0.92) and pyramidal (HR=0.79) functional system score (p<0.05). The strength of the association with pyramidal score decreased with time (HR=1.01). A relapse within previous month (HR=1.46) and worsening in sensory functional system score (HR=1.17) were associated with higher probability of improvement after progression. The sustained progression score (range 0.39-4.79) in the validation cohort with 1,271 progression events, estimated a 53% lower chance of improvement for each unit increase in the score (HR=0.47). The proportions of progression events sustained at 5 years stratified by the score were 1: 68%, 2: 79%, 3: 94%, 4: 100%. The progression scores were then applied to the CLARITY trial data. Conclusion(s): Estimate of the probability of disability progress

We reviewed the medical records of all patients with confirmed mitochondrial diseases treated with any or all of thiamin, riboflavin, coenzyme Q, vitamin C (~10 mg/kg per day) and a high-fat diet (50-60% of caloric intake) between 1997 and 2003. There were 15 patients (9 male): 10 had enzymatic deficiency and 10 had a molecular diagnosis. Age at diagnosis was 11 months to 17 years 10 months. Treatment was commenced at time of clinical diagnosis in 12 patients. Follow-up period was 3 days to 7 years (median 22 months). Improvement was reported in 9 patients, of whom 4 attained further developmental skills, but this was only temporary in 6 patients. Five patients died during the follow-up period (3 days to 7 years). Patients with the 3243A > G mutation showed no significant change in the course of their disease, except for fewer migraine attacks. Of the six patients who had seizures, one has had a significant reduction in the severity of the seizures and one has had no further seizures. Plasma lactate levels were noncontributory. We conclude that high-dose vitamin and cofactor treatment and, where applicable, high-fat diet, are well tolerated and possibly effective in the short term, but ineffective in the longer term. © SSIEM and Kluwer Academic Publishers.

We reviewed the medical records of all patients with confirmed mitochondrial diseases treated with any or all of thiamin, riboflavin, coenzyme Q, vitamin C (~10 mg/kg per day) and a high-fat diet (50-60% of caloric intake) between 1997 and 2003. There were 15 patients (9 male): 10 had enzymatic deficiency and 10 had a molecular diagnosis. Age at diagnosis was 11 months to 17 years 10 months. Treatment was commenced at time of clinical diagnosis in 12 patients. Follow-up period was 3 days to 7 years (median 22 months). Improvement was reported in 9 patients, of whom 4 attained further developmental skills, but this was only temporary in 6 patients. Five patients died during the follow-up period (3 days to 7 years). Patients with the 3243A > G mutation showed no significant change in the course of their disease, except for fewer migraine attacks. Of the six patients who had seizures, one has had a significant reduction in the severity of the seizures and one has had no further seizures. Plasma lactate levels were noncontributory. We conclude that high-dose vitamin and cofactor treatment and, where applicable, high-fat diet, are well tolerated and possibly effective in the short term, but ineffective in the longer term. © SSIEM and Kluwer Academic Publishers.