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Clinical Trial
, 181 (2), 362-72

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

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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.

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.

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).

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