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In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 1396-1396

Abstract: GD is a genetic lysosomal disease characterized by deficiency in glucocerebrosidase (Glc) particularly affecting macrophage-like cells where glucocerebroside accumulates in the lysosomes. Alglucerase then imiglucerase (IMI, Genzyme-Sanofi Corporation), a recombinant human glucocerebrosidase, improved or reversed many type 1 GD symptoms; Two new biosimilar agents are now available: velaglucerase-alfa (Shire Human Genetic Therapies) and taliglucerase-alfa (Biotherapeutics, Pfizer). All three recombinant enzymes are administered with identical therapeutic regimens, i.e. one infusion (30-60 IU/kg) every two weeks. However, disease responses remain variable and there are no pharmacokinetic explanations justifying this dosage regimen since plasma half-life is estimated to be less than 10 min. in murine models and in humans We compared endogenous glucocerebrosidase (Glc) activity evaluated by flow cytometry in the blood monocyte (Mo) compartment of 20 patients with 71 healthy donors, and we then followed residual intra-Mo Glc activity in patients starting imiglucerase (n=8). By using the only technique able to identify blood leukocyte subsets, we confirmed the marked higher value in Mo (×43) as compared to lymphocytes and polymorphonuclear (PMN) cells. In the 20 type 1 GD patients, we confirmed that enzyme deficiency was clear in Mo (p = 10-11 compared to HD), residual Glc activity in Mo from type 1 GD representing only 10% of normal Glc activity. We then followed trough Glc activity in 8 patients starting imiglucerase treatment de novo (n=1) or restarting imiglucerase after shortage (n=7), at 40 (n=1) or 60 U (n=7) /Kg/2 weeks. We observed progressive uptake over 6 months and a significant cumulative persistence of enzyme activity in monocyte compartment even 14 days after infusion. The estimated increase of residual intra-monocyte enzyme activity at M6 was 1.4 of endogenous level (p=.04) leading to a steady state value. The estimated rate constant of increase corresponded to an initial half-life of 2.8 days. These results explain for the first time the clinical efficacy of the routine infusion regimen, since intra-cellular pharmacokinetics are longer than plasma pharmacokinetics. Furthermore, we can hypothesize that intra-cellular pharmacokinetics after infusion may vary between patients, as suggested by the different peaks of activity and variable residual levels of enzyme activity observed in this study. In this limited series, we observed several profiles: i) Four patients ( #1,2,3, 8) of whom one received 40 U/kg/2 weeks, showed progressive Glc uptake correlated with improvement of clinical and biological parameters; this corresponds to patients with hematological phenotype only (Figure S1 A). ii) Other patients showed variability of Glc uptake (Figure S1 B); these patients were more heterogenous, with bone disease (n=2), splenectomy (n=2), or BM disorders (myelodysplasia, n=1). Consequently intra-Mo imiglucerase uptake appears to be variable, suggesting for the first time a possible relation between Glc activity in cell compartments, phenotype and clinical efficacy. In summary, the persistence of imiglucerase in monocyte compartments explains the efficacy of 2-week infusion rates and variability may be a factor of ERT efficiency Disclosures Stirnemann: Genzyme/Sanofi: Consultancy. Belmatoug:Genzyme/Sanofi and Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rose:Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees. Berger:Genzyme/Sanofi and Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.1396.1396

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 4437-4437

Abstract: Background: Acute Myeloid Leukemia (AML) and high-risk Myelodysplastic Syndrome (MDS) patients frequently receive antibiotics (ABX) for febrile neutropenia (prophylaxis or empirical treatment) or for suspected or documented bacterial infections. ABX affect the composition of the human intestinal microbiome and the resulting dysbiosis can have important consequences for patients including Clostridioides difficile infections (CDI). The reported cumulative incidence of CDI in patients with AML varies from 9 to 24% in the first 120 days following the start of induction chemotherapy and from 8 to 31% after allogeneic Hematopoietic Stem Cell Transplant (allo-HSCT). In patients undergoing allo-HSCT, acute Graft-versus-Host Disease (GvHD) and GvHD-related mortality are other important complications associated with intestinal dysbiosis, as shown in experimental studies in mice and retrospective analyses in humans. DAV132 is a microbiome protective therapy that can be administered concomitantly with oral or intravenous ABX. It has been primarily developed for adsorbing antibiotic residues in the distal ileum and colon in order to preserve the integrity of the gut microbiome, without impacting antimicrobial pharmacokinetics. Randomized clinical trials conducted to date, both in heathy volunteers and in patients, showed that DAV132 adsorbed residues of ABX in the colon and protected the intestinal microbiome from the dysbiosis induced by ABX while preserving their bioavailability. In addition, DAV132 was safely used in hospitalized patients receiving (multiple) concomitant drugs. Study Design and Methods: MICROCARE is a multicenter, randomized, placebo-controlled, parallel-arm phase 3 clinical trial. A total of 900 patients (randomized 1:1 to either DAV132 or placebo) are planned to be enrolled in approximately 80 study sites worldwide. The primary objective of this study is to evaluate the efficacy of DAV132 in preventing CDI in patients with newly diagnosed AML or high-risk MDS treated with intensive chemotherapy. In addition, the study aims to determine whether the protection of the intestinal microbiome with DAV132 can reduce the incidence of colonization with multidrug-resistant bacteria, bacteremia, and acute GvHD, and improve the long-term outcomes of transplanted patients. Randomization will be stratified by (i) site, and (ii) use of ABX within 30 days before inclusion and/or history of CDI. During the cycle of induction chemotherapy, DAV132 will be administered to patients every day until neutrophil recovery, regardless of the administration of ABX treatment. After neutrophil recovery and up to day 120, DAV132 will be administered every time an ABX treatment is given, for the length of the ABX treatment plus 2 days. The primary analysis of this study is the comparison of the time to CDI between DAV132 patients versus placebo patients up to 120 days after randomization. This will be analyzed using the cause-specific Cox proportional hazards model, whereby time to CDI is the outcome of interest, and mortality will be considered as competing event. In the primary outcome, a cause-specific Cox model will be used assuming that the impact of DAV132 on mortality is negligible; this will be confirmed in a secondary analysis. Secondary and exploratory endpoints include the rate of patients with ABX-associated diarrhea, the rate of patients with a gut colonization by resistant bacteria or a bloodstream infection, the diversity of the gut microbiome, the incidence of acute GvHD and overall survival. Two interim analyses will be performed at approximately 35 and 50 CDI events. Study status: Recruitment of patients in the study is starting in multiple countries in Europe. A first patient has been randomized in July 2021. Topics: Microbiome; CDI; GvHD; Dysbiosis; Antibiotics Disclosure: This work is supported by the IMI Joint Undertaking (JU) (grant 115523), Combatting Bacterial Resistance in Europe, with resources including financial contribution from the EU's Seventh Framework Programme and in-kind contributions from Da Volterra, a company part of the European Federation of Pharmaceutical Industries and Associations (EFPIA). Disclosures Vehreschild: 3M: Research Funding; Astellas Pharma: Consultancy, Research Funding, Speakers Bureau; Biontech: Research Funding; Da Volterra: Consultancy, Research Funding, Speakers Bureau; Evonik: Research Funding; Gilead Sciences: Consultancy, Research Funding, Speakers Bureau; Glycom: Research Funding; Immunic AG: Consultancy, Research Funding, Speakers Bureau; MaaT Pharma: Consultancy, Research Funding; Merck/MSD: Consultancy, Research Funding, Speakers Bureau; Organobalance: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Seres Therapeutics: Research Funding; Takeda Pharmaceutical: Research Funding; Alb Fils Kliniken GmbH: Consultancy, Speakers Bureau; Arderypharm: Consultancy, Speakers Bureau; Basilea: Consultancy, Speakers Bureau; Bio-Mérieux: Consultancy, Speakers Bureau; Farmak International Holding GmbH: Consultancy, Honoraria, Speakers Bureau; Ferring: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; SocraTec R & D GmbH: Consultancy, Speakers Bureau. Dane: Da Volterra: Consultancy. Mentré: Da Volterra: Consultancy. Burdet: Da Volterra: Consultancy; Mylan: Consultancy. Sablier-Gallis: Da Volterra: Current Employment, Current holder of individual stocks in a privately-held company. Andremont: Da Volterra: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria. de Gunzburg: Da Volterra: Consultancy, Current holder of individual stocks in a privately-held company. Buffet: Da Volterra: Current Employment. Wilcox: Da Volterra: Consultancy, Research Funding. Cornely: Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, Scynexis: Other: Grants or Contracts. Bonten: Merck/MSD: Research Funding; Janssen Vaccines: Consultancy, Speakers Bureau; OM Pharma: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding. Vitry: Da Volterra: Current Employment.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-146501

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

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detail.hit.zdb_id: 80069-7