Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial.

Nonalcoholic steatohepatitis (NASH), a chronic liver disease without an approved therapy, is associated with lipotoxicity and insulin resistance and is a major cause of cirrhosis and hepatocellular carcinoma. Aramchol, a partial inhibitor of hepatic stearoyl-CoA desaturase (SCD1) improved steatohepatitis and fibrosis in rodents and reduced steatosis in an early clinical trial. ARREST, a 52-week, double-blind, placebo-controlled, phase 2b trial randomized 247 patients with NASH (n = 101, n = 98 and n = 48 in the Aramchol 400 mg, 600 mg and placebo arms, respectively; NCT02279524 ). The primary end point was a decrease in hepatic triglycerides by magnetic resonance spectroscopy at 52 weeks with a dose of 600 mg of Aramchol. Key secondary end points included liver histology and alanine aminotransferase (ALT). Aramchol 600 mg produced a placebo-corrected decrease in liver triglycerides without meeting the prespecified significance (-3.1, 95% confidence interval (CI) -6.4 to 0.2, P = 0.066), precluding further formal statistical analysis. NASH resolution without worsening fibrosis was achieved in 16.7% (13 out of 78) of Aramchol 600 mg versus 5% (2 out of 40) of the placebo arm (odds ratio (OR) = 4.74, 95% CI = 0.99 to 22.7) and fibrosis improvement by ≥1 stage without worsening NASH in 29.5% versus 17.5% (OR = 1.88, 95% CI = 0.7 to 5.0), respectively. The placebo-corrected decrease in ALT for 600 mg was -29.1 IU l-1 (95% CI = -41.6 to -16.5). Early termination due to adverse events (AEs) was <5%, and Aramchol 600 and 400 mg were safe, well tolerated and without imbalance in serious or severe AEs between arms. Although the primary end point of a reduction in liver fat did not meet the prespecified significance level with Aramchol 600 mg, the observed safety and changes in liver histology and enzymes provide a rationale for SCD1 modulation as a promising therapy for NASH and fibrosis and are being evaluated in an ongoing phase 3 program.

Copaxone's effect on MRI-monitored disease in relapsing MS is reproducible and sustained.

All but 6% of the subjects with relapsing remitting MS who were randomly assigned to receive glatiramer acetate or placebo for the 9-month controlled phase of the European/Canadian MRI trial entered an open-label extension with quarterly clinical and MRI evaluations for another 9 months. There was a 54% reduction in the mean number of enhanced lesions for those converted from placebo to glatiramer acetate and an additional 24.6% reduction for those always on glatiramer acetate. Over the entire study the accumulated T2 disease burden was 34.2% less for those always on glatiramer acetate.

Impaired T-lymphocyte function in B-chronic lymphocytic leukaemia as measured by the local xenogeneic graft-versus-host reaction.

The immunological dysfunction observed in B-chronic lymphocytic leukaemia (B-CLL) is often related to T-lymphocyte incompetence. The local xenogeneic graft-vs.-host reaction (XGVHR), an assay to evaluate T-lymphocyte function, was performed in 112 untreated B-CLL patients. The XGVHR results significantly correlated with clinical parameters: 37.1% of the patients in the stable phase (Rai stage 0-1-2) and only 13.3% of the patients in the progressive phase (Rai stage 3-4) had positive XGVHR results. Patients with negative results had a higher number and percentage of lymphocytes (25,247 vs. 17,071/microliter and 75.9% vs. 65.6%, respectively), much lower T/B lymphocyte ratio (0.37 vs. 0.93), higher WBC count (30,977 vs. 23,458/microliter), lower platelet count (158,068 vs. 181,684/microliter) and lower levels of IgA and IgM (115.6 vs. 200.5 mg/dl and 80.4 vs. 124.3 mg/dl, respectively) compared to those with positive results. Among those with negative XGVHR results, a higher mortality rate was found in those who had infections compared with those who did not (73.7% vs. 9.1%). In conclusion, the XGVHR assay significantly correlates with important characteristics of B-CLL and may be useful in the clinical evaluation of B-CLL patients.

Alfacalcidol (alpha D3) and calcium in osteoporosis.

In a prospective, randomized study, 66 osteoporotic postmenopausal women (mean age, 67 years) were scheduled to receive either alfacalcidol 0.25 microgram twice daily together with calcium 500 mg twice daily (treatment group, n = 24) or placebo twice daily with calcium 500 mg twice daily (control group, n = 42) for three years. In the treatment group, bone mineral content at the distal radius may have increased by 2% compared to a significant decrease of 7.8% in the control group. The difference between the two groups was also significant. Since the dose of alfacalcidol and calcium remained unadjusted, frequent hypercalciuria, as well as occasional mild, transient elevations of serum calcium, were observed in the treatment group. No changes in serum creatinine levels or creatinine clearance throughout the study were observed. The two groups did not differ with respect to the frequency of clinical side effects, which were mainly gastrointestinal and probably related to the calcium supplementation. Alfacalcidol and calcium may prevent further bone loss in women suffering from postmenopausal osteoporosis.