Skip to main page content
U.S. flag

An official website of the United States government

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2015 Aug;181(2):362-72.
doi: 10.1111/cei.12640.

Oral administration of non-absorbable delayed release 6-mercaptopurine is locally active in the gut, exerts a systemic immune effect and alleviates Crohn's disease with low rate of side effects: results of double blind Phase II clinical trial

E Israeli  1 , E Goldin  2 , S Fishman  3 , F Konikoff  4 , A Lavy  5 , Y Chowers  6 , E Melzer  7 , A Lahat  8 , M Mahamid  9 , H Shirin  10 , E Nussinson  11 , O Segol  12 , A Ben Ya'acov  1 , Y Shabbat  1 , Y Ilan  1
Affiliations
Clinical Trial

Oral administration of non-absorbable delayed release 6-mercaptopurine is locally active in the gut, exerts a systemic immune effect and alleviates Crohn's disease with low rate of side effects: results of double blind Phase II clinical trial

E Israeli et al. Clin Exp Immunol. 2015 Aug.

Abstract

Therapy for Crohn's disease (CD) with thiopurines is limited by systemic side effects. A novel formulation of fixed-dose, delayed-release 6-mercaptopurine (DR-6MP) was developed, with local effect on the gut immune system and minimal absorption. The aim of this study was to evaluate the safety and efficacy of DR-6MP in patients with moderately severe CD compared to systemically delivered 6-mercaptopurine (Purinethol). Seventy CD patients were enrolled into a 12-week, double-blind controlled trial. The primary end-point was the percentage of subjects with clinical remission [Crohn's Disease Activity Index (CDAI) < 150] or clinical response (100-point CDAI reduction). Twenty-six (56·5%) and 13 (54·2%) subjects from the DR-6MP and Purinethol cohorts, respectively, completed the study. DR-6MP had similar efficacy to Purinethol following 12 weeks of treatment. However, the time to maximal clinical response was 8 weeks for DR-6MP versus 12 weeks for Purinethol. A higher proportion of patients on DR-6MP showed clinical remission at week 8. A greater improvement in Inflammatory Bowel Disease Questionnaire (IBDQ) score was noted in the DR-6MP group. DR-6MP led to a decrease of CD62(+) expression on T cells, implying a reduction of lymphocyte adhesion to site of inflammation. DR-6MP was safer than Purinethol, with significantly fewer adverse events (AEs). There was no evidence of drug-induced leucopenia in the DR-6MP group; the proportion of subjects who developed hepatotoxicity was lower for the DR-6MP. Non-absorbable DR-6MP is safe and biologically active in the gut. It is clinically effective, exerting a systemic immune response with low systemic bioavailability and a low incidence of side effects.

Keywords: 6-mercaptopurine; Crohn's disease; gut immune system; oral therapy.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Plasma levels of delayed-release 6-mercaptopurine (DR-6MP) 40 mg in the pharmacokinetic (PK) trial.
Figure 2
Figure 2
Disposition of subjects the Phase IIa trial.
Figure 3
Figure 3
Proportion of responders at week 12 [intent-to treat Crohn’s Disease Activity Index (ITT CDAI) completers population] in the Phase IIa trial. Clinical response = CDAI decrease of at least 100 points or CDAI < 150. Response = CDAI drcrease of at least 100 points. Clinical remission – CDAI < 150. The population analysed included all subjects who provided CDAI data.
Figure 4
Figure 4
Crohn’s Disease Activity Index (CDAI) score by week [intent-to treat (ITT) population] in the Phase IIa trial.
Figure 5
Figure 5
Proportion of responders at week 8 [intent-to treat Crohn’s Disease Activity Index (ITT CDAI) completers population] completers population), Phase IIa trial. Clinical response = CDAI decrease of at least 100 points or CDAI < 150. Response = CDAI drcrease of at least 100 points. Clinical remission – CDAI < 150. The population analysed included all subjects who provided CDAI data.
Figure 6
Figure 6
Change in FACS immunology parameters from baseline to week 12 by treatment, Phase IIa trial [intent-to treat (ITT) population].
Figure 7
Figure 7
Change in interferon (IFN)-gamma enzyme-linked immunospot (ELISPOT) assay from baseline to week 12 by treatment, Phase IIa trial. Analysis included a subgroup of patients with available ELISPOT assays [for delayed-release 6-mercaptopurine (DR-6MP), n = 6; for Purinethol, n = 1]. Subset of patients = only patients who had undergone a colonoscopy and provided biopsy samples at both baseline and week 12 could be analysed.
Figure 8
Figure 8
Patients (%) with white blood cell (WBC) result within normal range at baseline and week 12, Phase IIa trial [intent-to treat (ITT)] completers population] population).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Waters OR, Lawrance IC. Understanding the use of immunosuppressive agents in the clinical management of IBD. Curr Drug Targets. 2011;12:1364–71. - PubMed
    1. Bokkerink JP, Stet EH, De Abreu RA. 6-Mercaptopurine: cytotoxicity and biochemical pharmacology in human malignant T-lymphoblasts. Biochem Pharmacol. 1993;45:1455–63. - PubMed
    1. Ebbesen MS, Nersting J, Jacobsen JH, et al. Incorporation of 6-thioguanine nucleotides into DNA during maintenance therapy of childhood acute lymphoblastic leukemia-the influence of thiopurine methyltransferase genotypes. J Clin Pharmacol. 2013;53:670–4. - PubMed
    1. Ben-Horin S, Goldstein I, Fudim E, et al. Early preservation of effector functions followed by eventual T cell memory depletion: a model for the delayed onset of the effect of thiopurines. Gut. 2009;58:396–403. - PubMed
    1. Tiede I, Fritz G, Strand S, et al. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest. 2003;111:1133–45. - PMC - PubMed

Publication types

MeSH terms