Ferric maltol therapy for iron deficiency anaemia in patients with inflammatory bowel disease: long-term extension data from a Phase 3 study

Background Ferric maltol was effective and well-tolerated in iron deficiency anaemia patients with inflammatory bowel disease during a 12-week placebo-controlled trial. Aim To perform a Phase 3 extension study evaluating long-term efficacy and safety with ferric maltol in inflammatory bowel disease patients in whom oral ferrous therapies had failed to correct iron deficiency anaemia. Methods After 12 weeks of randomised, double-blind treatment, patients with iron deficiency anaemia and mild-to-moderate ulcerative colitis or Crohn's disease received open-label ferric maltol 30 mg b.d. for 52 weeks. Results 111 patients completed randomised treatment and 97 entered the open-label ferric maltol extension. In patients randomised to ferric maltol ('continued'; n = 50), mean +/- s.d. haemoglobin increased by 3.07 +/- 1.46 g/dL between baseline and Week 64. In patients randomised to placebo ('switch'; n = 47), haemoglobin increased by 2.19 +/- 1.61 g/dL. Normal haemoglobin was achieved in high proportions of both continued and switch patients (89% and 83% at Week 64, respectively). Serum ferritin increased from 8.9 lg/L (baseline) to 26.0 lg/L (Week 12) in ferric maltol-treated patients, and to 57.4 lg/L amongst all patients at Week 64. In total, 80% of patients reported = 1 adverse event by Week 64. Adverse events considered related to ferric maltol were recorded in 27/111 (24%) patients: 8/18 discontinuations due to adverse events were treatment-related. One patient was withdrawn due to increased ulcerative colitis activity. Conclusions Normal haemoglobin was observed in = 80% of patients from weeks 20-64 of long-term ferric maltol treatment, with concomitant increases in iron storage parameters. Ferric maltol was well-tolerated throughout this 64-week study

Ferric maltol is effective in correcting iron deficiency anemia in patients with inflammatory bowel disease: results from a phase-3 clinical trial program

BACKGROUND: Iron deficiency anemia (IDA) is frequently seen in inflammatory bowel disease. Traditionally, oral iron supplementation is linked to extensive gastrointestinal side effects and possible disease exacerbation. This multicenter phase-3 study tested the efficacy and safety of ferric maltol, a complex of ferric (Fe) iron with maltol (3-hydroxy-2-methyl-4-pyrone), as a novel oral iron therapy for IDA. METHODS: Adult patients with quiescent or mild-to-moderate ulcerative colitis or Crohn's disease, mild-to-moderate IDA (9.5-12.0 g/dL and 9.5-13.0 g/dL in females and males, respectively), and documented failure on previous oral ferrous products received oral ferric maltol capsules (30 mg twice a day) or identical placebo for 12 weeks according to a randomized, double-blind, placebo-controlled study design. The primary efficacy endpoint was change in hemoglobin (Hb) from baseline to week 12. Safety and tolerability were assessed. RESULTS: Of 329 patients screened, 128 received randomized therapy (64 ferric maltol-treated and 64 placebo-treated patients) and comprised the intent-to-treat efficacy analysis: 55 ferric maltol patients (86%) and 53 placebo patients (83%) completed the trial. Significant improvements in Hb were observed with ferric maltol versus placebo at weeks 4, 8, and 12: mean (SE) 1.04 (0.11) g/dL, 1.76 (0.15) g/dL, and 2.25 (0.19) g/dL, respectively (P < 0.0001 at all time-points; analysis of covariance). Hb was normalized in two-thirds of patients by week 12. The safety profile of ferric maltol was comparable with placebo, with no impact on inflammatory bowel disease severity. CONCLUSIONS: Ferric maltol provided rapid clinically meaningful improvements in Hb and showed a favorable safety profile, suggesting its possible use as an alternative to intravenous iron in IDA inflammatory bowel disease

Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells

Common variable immunodeficiency disorder (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by B-cell abnormalities and inadequate antibody response. CVID patients have considerable autoimmune comorbidity and we therefore hypothesized that genetic susceptibility to CVID may overlap with autoimmune disorders. Here, in the largest genetic study performed in CVID to date, we compare 778 CVID cases with 10, 999 controls across 123, 127 single-nucleotide polymorphisms (SNPs) on the Immunochip. We identify the first non-HLA genome-wide significant risk locus at CLEC16A (rs17806056, P = 2.0 x 10(-9)) and confirm the previously reported human leukocyte antigen (HLA) associations on chromosome 6p21 (rs1049225, P = 4.8 x 10(-16)). Clec16a knockdown (KD) mice showed reduced number of B cells and elevated IgM levels compared with controls, suggesting that CLEC16A may be involved in immune regulatory pathways of relevance to CVID. In conclusion, the CLEC16A associations in CVID represent the first robust evidence of non-HLA associations in this immunodeficiency condition

Influence of genetic variants on development and course of inflammatory bowel diseases

Kein wissenschaftliches Forschungsgebiet hat in den letzten Jahren einen solchen Zugewinn an Informationen zu der Entstehung diverser Krankheiten beigetragen wie die Molekulargenetik. Glücklicherweise trifft dies insbesondere auf die chronisch entzündlichen Darmerkrankungen zu, wo im Vergleich zu anderen Erkrankungen wie arterielle Hypertonie, Diabetes mellitus Typ II sowie die rheumatoide Arthritis deutlich mehr Suszeptibilitätsgene vermutet werden (241). Die Identifikation relevanter pathophysiologischer Konzepte – Bakterienerkennung über das angeborene Immunsystem, Autophagie sowie die Subpopulation der TH17-Lymphozyten – stellen einen wichtigen Beitrag dar, hierauf aufbauende neue therapeutische Ansätze werden jedoch weiterhin erwartet. Die individuelle Genotypisierung eines Patienten könnte jedoch zu folgenden Zwecken verwendet werden: einerseits eine bessere Vorhersagbarkeit des Krankheitsverlaufs mit hieran adaptierter Therapie sowie zudem Ansprechen und Nebenwirkungen des ausgewählten Medikaments. Die gegenwärtige Diskussion einer frühen und aggressiven Therapie beim M. Crohn ist auch dadurch limitiert, dass wir keine relevanten Marker haben, die solche Patienten eindeutig als aggressive Verlaufsform identifizieren. Bei der Vielzahl der bislang bekannten genetischen Varianten der chronisch entzündlichen Darmerkrankungen steht weiterhin die NOD2-Mutation im Vordergrund. Patienten mit Mutationen im NOD2-Gen zeigen einen aggressiven Krankheitsverlauf. Es kommt unabhängig vom Befall des terminalen Ileums im Verlauf häufig zu einer Operation im Ileozökalbereich. Zudem weisen Merkmalsträger ein hohes postoperatives Rezidivrisiko auf. Klinische Studien sollten somit eine Genotypisierung für NOD2-Mutationen zur Subklassifizierung durchführen, um zu klären, ob eine aggressivere Therapie – welcher Form auch immer – gerechtfertigt ist. Einen solchen Zusammenhang zu einem bestimmten Phänotyp ist bislang für keine andere Variante beschreiben worden. Dies gilt insbesondere für die p.Arg381Gln-Variante im IL23R-Gen sowie p.Thr300Ala- Variante innerhalb des ATG16L1-Gens. Möglicherweise müssen hier erst weitere Varianten in TH17-Genen (JAK2, STAT3) sowie in Autophagie-Genen (IRGM) untersucht werden, bevor ein definitiver Phänotyp identifiziert werden kann. Zudem sind erste Varianten identifiziert worden, die einen Einfluss auf die intestinale Barrierestörung beim M. Crohn haben könnten: erneut das NOD2-Gen sowie das Myosin-IXb-Gen. Hier zeigen sich Assoziationen zu einer erhöhten intestinalen Permeabilität in vivo. Ausgehend von der Hypothese, dass die intestinale Barrierestörung entweder ein früher Entwicklungsprozess ist oder nach Ausbrechen der Erkrankung das Rezidivrisiko erhöht, könnte die Beeinflussung dieser beiden Signalwege ein therapeutischer Ansatz zur Rezidivprophylaxe sein. Weitere CED-Gene – IL23R, ATG16L1, DLG5, CD14, TLR4, CARD8 – scheinen jedoch keinen Einfluss auf die Barrierestörung haben. Von besonderem Interesse sind die genauen Mechanismen, mit denen NOD2 und MYO9B die intestinale Permeabilität erhöhen, diese sind jedoch weiterhin unbekannt. Trotz dieser Fortschritte führt die unerwartet hohe Anzahl an genetischen Varianten für chronisch entzündliche Darmerkrankungen an einen Scheideweg, der über Sinn und Zweck der Genotypisierung entscheiden wird. Der gegenwärtige Kenntnisstand reicht nicht aus, um eine Genotypisierung in Diagnostik oder Therapie der chronisch entzündlichen Darmerkrankungen einzubeziehen. Dies wird bislang nur zu wissenschaftlichen Zwecken durchgeführt. Hier sind zwingend prospektive Studien notwendig, sonst wird der klinische Nutzen für Patienten gering sein.Recent moleculargenetic studies have increased the number of putative genetic variants to be involved in the pathophysiology of inflammatory bowel diseases (IBD). This has highlighted new and unexpected pathways, such aus autophagy and IL23-signalling for IBD development. One unsolved phenomenen in IBD is a disturbed epithelial barrier function that is suggested to increase e.g. bacterial antigen uptake and thus support chronic inflammation. From a clinicians point of view, genotyping for specific variants should help to improve diagnosis, predict disease behaviour and foresee response to medical treatment. This would help to identify patients with severe disease behaviour and improve therapy. Although numerous variants have been found so far, we could show in different populations that mutations in the NOD2 gene are assocaietd with an aggressive disease behaviour: early onset, ileocecal resections early within the disease, and frequent surgical recurrence. Future studies should therefore estimate whether aggressive treatment in patients positive for NOD2 mutations would benefit from a more aggressive therapy. Such a significant genotype phenotype correlation was not observed for any other of the variants analysed in our studies, such as p.Arg381Gln within IL23R and p.Thr300Ala within ATG16L1. In addition, we have showen that a frameshift mutation within NOD2, p.Leu1007fs, is associated with an increased intestinal permeability in Crohn’s disease. Furthermore, variants in the Myosin IXb gene also increase the risk for an increased intestinal permeability. With respect to many other variants in genes like IL23R, ATG16L1, DLG5, CD14, TLR4, CARD8, no such association was observed. Despite these new and important findings, a lot of work needs to be done to clearly define the phenotype relationship of IBD genetics. Furthermore the molecular mechanism of how NOD2 and Myosin IXb variants contribute to barrier dysfunction need to be identified