Safety, Tolerability, and Activity of ALXN1830 Targeting the Neonatal Fc Receptor in Chronic Pemphigus.

Pemphigus is a debilitating IgG-mediated autoimmune disease requiring better tolerated, more targeted, and rapid onset therapies. ALXN1830 is a humanized IgG4 antibody that blocks neonatal Fc receptor interactions with IgG. A multicenter, open-label safety and tolerability phase 1b/2 trial (NCT03075904) was conducted in North America from July 2017 to January 2019 and included patients aged ≥18 years with a confirmed diagnosis of pemphigus (vulgaris or foliaceus) and active disease. Dosing included five weekly intravenous doses of ALXN1830 (10 mg/kg) and follow-up through day 112 (study termination). Pharmacokinetics, pharmacodynamics, safety, and efficacy, as evaluated by determining the change in the median pemphigus disease area index, were determined. In this pilot study of eight patients, five weekly infusions of ALXN1830 produced a rapid improvement in the pemphigus disease area index score within 14 days of the first dose. Pemphigus disease area index improvement increased further together with reductions in IgG, circulating immune complexes of IgG, and anti-desmoglein antibodies without affecting albumin, IgM, IgA, or C-reactive protein levels. ALXN1830 was well-tolerated, with headache as the most common adverse event. This study reveals the importance of neonatal Fc receptor in the biology of pemphigus and the potential for use of ALXN1830 in pemphigus treatment.

Ethnogeographic prevalence and implications of the 677C>T and 1298A>C MTHFR polymorphisms in US primary care populations.

Aim: Variants of the MTHFR gene have been associated with a wide range of diseases. Materials & methods: The present study analyzed data from clinical genotyping of MTHFR 677C>T and 1298A>C in 1405 patients in urban primary care settings. Results: Striking differences in ethnogeographic frequencies of MTHFR polymorphisms were observed. African-Americans appear to be protected from MTHFR deficiency. Hispanics and Caucasians may be at elevated risk due to increased frequencies of 677C>T and 1298A>C, respectively. Conclusion: Individuals carrying mutations for both genes were rare and doubly homozygous mutants were absent, suggesting the TTcc is extremely rare in the greater population. The results suggest multilocus MTHFR genotyping may yield deeper insight into the ethnogeographic association between MTHFR variants and disease.

Practical interpretation of CYP2D6 haplotypes: Comparison and integration of automated and expert calling.

We describe a population genetic approach to compare samples interpreted with expert calling (EC) versus automated calling (AC) for CYP2D6 haplotyping. The analysis represents 4812 haplotype calls based on signal data generated by the Luminex xMap analyzers from 2406 patients referred to a high-complexity molecular diagnostics laboratory for CYP450 testing. DNA was extracted from buccal swabs. We compared the results of expert calls (EC) and automated calls (AC) with regard to haplotype number and frequency. The ratio of EC to AC was 1:3. Haplotype frequencies from EC and AC samples were convergent across haplotypes, and their distribution was not statistically different between the groups. Most duplications required EC, as only expansions with homozygous or hemizygous haplotypes could be automatedly called. High-complexity laboratories can offer equivalent interpretation to automated calling for non-expanded CYP2D6 loci, and superior interpretation for duplications. We have validated scientific expert calling specified by scoring rules as standard operating procedure integrated with an automated calling algorithm. The integration of EC with AC is a practical strategy for CYP2D6 clinical haplotyping.