An indirect comparison of long-term efficacy of every-2-week dosing vs. recommended dosing of ixekizumab in patients who had static Physician's Global Assessment > 1 at week 12.

BACKGROUND: Long-term efficacy and safety of ixekizumab [160 mg at week 0, then 80 mg every 2 weeks (Q2W) for 12 weeks, followed by every 4 weeks (Q4W) thereafter (i.e. Q2W/Q4W), which is the labelled psoriasis dosing where approved, except in Japan] have been established for the treatment of adults with moderate-to-severe plaque psoriasis. However, some patients may benefit from remaining on Q2W dosing beyond 12 weeks. METHODS: Among patients who had static Physician's Global Assessment (sPGA) > 1 at week 12, efficacy through week 52 of continuous Q2W dosing in the IXORA-P study was compared indirectly with Q2W/Q4W in the integrated data from the UNCOVER-1, UNCOVER-2 and UNCOVER-3 studies. The continuous Q4W dose group, which had comparable results across studies, was used as the common comparator. RESULTS: In the IXORA-P study, among patients with sPGA > 1 at week 12, 64% of patients in the continuous Q2W group achieved sPGA ≤ 1 at week 52, which was statistically significantly higher than the 36% of patients with sPGA > 1 in the Q2W/Q4W group based on the integrated data from the UNCOVER studies (P = 0·0007). There were no clinically meaningful differences in frequencies of safety events between patients with sPGA ≤ 1 and patients with sPGA > 1 at week 12 in the IXORA-P study. CONCLUSIONS: Among patients who did not have clear or almost clear skin at week 12, nearly 30% more patients who were treated continuously with ixekizumab Q2W in IXORA-P had clear or almost clear skin at week 52 when compared indirectly with those who were treated using the labelled psoriasis dosing in integrated UNCOVER studies. What's already known about this topic? Most patients with moderate-to-severe psoriasis who were given the labelled psoriasis dosing of ixekizumab [160-mg loading dose at week 0, 80 mg every 2 weeks (Q2W) through week 12, and 80 mg every 4 weeks (QW4) thereafter] respond quickly with a high percentage of skin clearance. Additionally, patients who achieve static Physician's Global Assessment (sPGA) ≤ 1 by week 12 tend to maintain this response, even after switching to Q4W. What does this study add? Here, we assessed whether patients with sPGA > 1 at week 12 benefited from receiving more frequent dosing beyond the first 12 weeks. The results showed that Q2W dosing beyond 12 weeks resulted in more patients achieving sPGA ≤ 1 by week 52 than the labelled psoriasis dosing among patients with sPGA > 1 at week 12.

Continued circulation in China of highly pathogenic avian influenza viruses encoding the hemagglutinin gene associated with the 1997 H5N1 outbreak in poultry and humans.

Since the outbreak in humans of an H5N1 avian influenza virus in Hong Kong in 1997, poultry entering the live-bird markets of Hong Kong have been closely monitored for infection with avian influenza. In March 1999, this monitoring system detected geese that were serologically positive for H5N1 avian influenza virus, but the birds were marketed before they could be sampled for virus. However, viral isolates were obtained by swabbing the cages that housed the geese. These samples, known collectively as A/Environment/Hong Kong/437/99 (A/Env/HK/437/99), contained four viral isolates, which were compared to the 1997 H5N1 Hong Kong isolates. Analysis of A/Env/HK/437/99 viruses revealed that the four isolates are nearly identical genetically and are most closely related to A/Goose/Guangdong/1/96. These isolates and the 1997 H5N1 Hong Kong viruses encode common hemagglutinin (H5) genes that have identical hemagglutinin cleavage sites. Thus, the pathogenicity of the A/Env/HK/437/99 viruses was compared in chickens and in mice to evaluate the potential for disease outbreaks in poultry and humans. The A/Env/HK/437/99 isolates were highly pathogenic in chickens but caused a longer mean death time and had altered cell tropism compared to A/Hong Kong/156/97 (A/HK/156/97). Like A/HK/156/97, the A/Env/HK/437/99 viruses replicated in mice and remained localized to the respiratory tract. However, the A/Env/HK/437/99 isolates caused only mild pathological lesions in these tissues and no clinical signs of disease or death. As a measure of the immune response to these viruses, transforming growth factor beta levels were determined in the serum of infected mice and showed elevated levels for the A/Env/HK/437/99 viruses compared to the A/HK/156/97 viruses. This study is the first to characterize the A/Env/HK/437/99 viruses in both avian and mammalian species, evaluating the H5 gene from the 1997 Hong Kong H5N1 isolates in a different genetic background. Our findings reveal that at least one of the avian influenza virus genes encoded by the 1997 H5N1 Hong Kong viruses continues to circulate in mainland China and that this gene is important for pathogenesis in chickens but is not the sole determinant of pathogenicity in mice. There is evidence that H9N2 viruses, which have internal genes in common with the 1997 H5N1 Hong Kong isolates, are still circulating in Hong Kong and China as well, providing a heterogeneous gene pool for viral reassortment. The implications of these findings for the potential for human disease are discussed.

In vitro and in vivo characterization of a mouse adenovirus type 1 early region 3 null mutant.

Previous attempts to construct a mouse adenovirus type 1 early region 3 (E3) null mutant by initiator codon mutagenesis were unsuccessful because one of the E3 proteins, gp11K, is synthesized as a fusion protein from a late viral mRNA (A. N. Cauthen and K. R. Spindler, Virology 259:119-128, 1999). Therefore, a different mutagenesis strategy was employed that inserted termination codons into all three reading frames of the E3 proteins. This strategy produced a mutant, pmE314, that was null for the expression of E3 proteins as determined by immunoprecipitation with E3-specific antisera. This mutant grew as well as wild-type (wt) virus in both 3T6 mouse fibroblasts and mouse brain microvascular endothelial cells. However, the 50% lethal dose for pmE314 in adult NIH Swiss outbred mice was approximately 6 log units higher than that of wt virus, indicating that pmE314 was less virulent in mice. In situ hybridization experiments revealed that the absence of the E3 proteins did not alter the tropism of the mutant virus from that of wt virus. When the histopathology was evaluated, the characteristics of the pmE314 infection at both doses administered were strikingly different from those exhibited by wt virus. The central nervous system of wt-infected mice exhibited damage to the endothelium and recruitment of inflammatory cells, whereas the central nervous system of pmE314-infected mice showed no inflammatory response and only mild signs of endothelial damage.

Novel expression of mouse adenovirus type 1 early region 3 gp11K at late times after infection.

Mutations were introduced into mouse adenovirus type 1 (MAV-1) early region 3 (E3) initiator codons by homologous recombination between viral DNA and a plasmid containing a mutagenized E3 region. The resulting mutant virus, pmE312, contained ATG --> TTA mutations at codon positions 1 and 4 and was expected to be null for the expression of the E3 proteins. However, gp11K, an MAV-1 E3 glycoprotein of 14K molecular weight, was detected in mutant-infected cell lysates at levels about 10-12% of that of wild-type (wt) virus at late times in infection. The gp11K polypeptide produced by pmE312 at late times was immunoprecipitated with two E3-specific antisera prepared against different regions of the protein. Like gp11K produced by wt virus infections, it was sensitive to endoglycosidase H (endo H) and thus resident in the endoplasmic reticulum (ER). In pmE312-infected cells treated with cytosine arabinoside (araC), an inhibitor of DNA replication, the gp11K protein was not detected by immunoprecipitation. This indicates that gp11K expression in pmE312-infected cells at late times was dependent on DNA replication and that it was thus translated from a late transcript. In vitro translation of poly(A)+ RNA from mock-, wild-type-, and pmE312-infected cells showed that gp11K was translated from late mRNA as an approximately 28K fusion between a late protein and gp11K. Our data are consistent with a model in which gp11K is expressed at late times as a late protein-gp11K chimera in both wt- and mutant-infected cells. This chimera is then processed: removal of a large N-terminal sequence results in the observed 14K ER-localized gp11K.

Sequence of the mouse adenovirus type-1 DNA encoding the 100-kDa, 33-kDa and DNA-binding proteins.

The genomic nucleotide sequence for the region of 66 to 77 map units (m.u.) of mouse adenovirus type 1 (MAV-1) was determined and predicted to encode proteins homologous to the human adenovirus (Ad) 100-kDa, 33kDa and DNA-binding proteins (DBP). The putative MAV-1 100-kDa protein has 65-70% amino-acid similarity to 100-kDa proteins from five different human Ad serotypes. The mRNA for the putative 33-kDa protein is internally spliced within the coding sequence, as are its human Ad counterparts [Oosterom-Dragon and Anderson, J. Virol 45 (1983) 251-263]. The N-terminal region of the putative MAV-1 33-kDa protein has 41-44% similarity to two human Ad 33-kDa N-termini, and the C-terminal regions are more conserved, with 60-65% similarity. The MAV-1 DBP is predicted to be encoded in this region and was compared to six different human Ad DBP N-and C-termini. The N-termini of the MAV-1 and Ad DBP were 33-48% similar and the C-termini were 56-60% similar. The MAV-1 DBP contains conserved regions (CR) 1,2 and 3, and it retains important residues for a putative zinc finger (Zf) motif identified in Ad DBP [Eagle and Klessig, Virology 187 (1992) 777-787]. Additional sequence features of these proteins have also been identified.