The regulatory elements that determine the expression pattern of a number of eukaryotic genes expressed specifically in certain tissues have been defined and studied in detail. In general, however, the expression conferred by these elements on genes reintroduced into the genomes of cell lines and transgenic animals has turned out to be at a low level relative to that of endogenous genes, and influenced by the chromosomal site of insertion of the exogenous construct. We have previously shown that if regions flanking the human beta-globin locus are introduced into the mouse genome along with the human beta-globin gene, a level of expression comparable to that of endogenous genes can be achieved that is also independent of integration site. We have now defined a dominant control region with these properties consisting of 6.5 kilobases of DNA encompassing erythroid cell-specific DNase I hypersensitive sites. The identification of such dominant control regions could have important applications in somatic gene therapy.

Treatment of acute seasonal influenza in hospitalized adults with either peramivir or oseltamivir resulted in generally similar clinical outcomes. Treatment with peramivir was generally safe and well tolerated and could be of benefit in this population.

BackgroundEffective inhibition of plasma kallikrein may have significant benefits for patients with hereditary angioedema due to deficiency of C1 inhibitor (C1‐INH‐HAE) by reducing the frequency of angioedema attacks. Avoralstat is a small molecule inhibitor of plasma kallikrein. This study (OPuS‐2) evaluated the efficacy and safety of prophylactic avoralstat 300 or 500 mg compared with placebo.Methods OPuS‐2 was a Phase 3, multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group study. Subjects were administered avoralstat 300 mg, avoralstat 500 mg, or placebo orally 3 times per day for 12 weeks. The primary efficacy endpoint was the angioedema attack rate based on adjudicator‐confirmed attacks.ResultsA total of 110 subjects were randomized and dosed. The least squares (LS) mean attack rates per week were 0.589, 0.675, and 0.593 for subjects receiving avoralstat 500 mg, avoralstat 300 mg, and placebo, respectively. Overall, 1 subject in each of the avoralstat groups and no subjects in the placebo group were attack‐free during the 84‐day treatment period. The LS mean duration of all confirmed attacks was 25.4, 29.4, and 31.4 hours for the avoralstat 500 mg, avoralstat 300 mg, and placebo groups, respectively. Using the Angioedema Quality of Life Questionnaire (AE‐QoL), improved QoL was observed for the avoralstat 500 mg group compared with placebo. Avoralstat was generally safe and well tolerated.ConclusionsAlthough this study did not demonstrate efficacy of avoralstat in preventing angioedema attacks in C1‐INH‐HAE, it provided evidence of shortened angioedema episodes and improved QoL in the avoralstat 500 mg treatment group compared with placebo.

Avoralstat was well tolerated, and drug exposure was sufficient to meet target levels for inhibition of plasma kallikrein. Based on these results, the 400 mg q8 h dose was selected for further evaluation in patients with HAE.

APeX-2, a randomized double-blind, placebo-controlled study, evaluated efficacy and safety of berotralstat, an oral kallikrein inhibitor, as once-daily prophylaxis in HAE Type 1/2 (NCT03485911). METHODS: Subjects (n5121) were randomized into 3 arms (berotralstat 110mg, 150mg or placebo). All AEs were recorded over 24 weeks. AE incidence was analyzed overall and by onset month, defined as 4 weeks. RESULTS: AE incidence was similar in all 3 arms over the 24-week period, occurring in 82.9%, 85.0% and 76.9% of subjects receiving 110mg, 150mg, and placebo respectively. The greatest incidence of AEs was reported in the first month of study (51.2%, 42.5% and 59.0%) and afterwards declined. Gastrointestinal abdominal-associated AEs occurred primarily in the first month: 34.1%, 30% and 33.3% of 110mg, 150mg, and placebo subjects, respectively. In the 2 nd and 3 rd month, GI AEs were more common in subjects receiving 110mg (9.8% and 4.9%) and 150mg (17.5% and 8.1%) compared to placebo (2.6% and 2.6%). By the 4 th month, GI AEs had a similarly low incidence in all 3 arms (2.4%, 2.7% and 2.7%), which was sustained. GI events were generally mild except for 2 subjects on 110mg experiencing brief, severe abdominal pain. One subject on 110mg discontinued due to moderate dyspepsia, nausea, and vomiting. 87.8%, 90.0% and 92.3% of GI AEs resolved without medication on 110mg, 150mg, and placebo. CONCLUSIONS: GI AEs were predominantly mild, self-limited, and most frequent in the first 3 months of treatment. The rate of GI events with berotralstat was similar to placebo in months 4 through 6.