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Therapeutic antisense oligonucleotide composition for the treatment of inflammatory bowel disease

An antisense oligonucleotide and oligonucleotide technology, applied in the field of therapeutic antisense oligonucleotide composition for treating inflammatory bowel disease

Inactive Publication Date: 2008-03-26
IONIS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The results showed promising acute and long-term effects However, the results still need to be confirmed by a large number of conclusive clinical trials
[0034] Although there are many possible therapeutic interventions for IBD, none of them are fully satisfactory due to limited efficacy, undesired side effects, or both

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] The bioavailability of ISIS 2302 was analyzed after intrajejunal and rectal administration of the formulations. The absolute bioavailability of ISIS 2302 was evaluated after intrajejunal instillation of several formulations. The percent bioavailability was calculated from the obtained data according to the following formula:

[0064] % Bioavailability = (AUC po / D o ) / (AUC iv / D o )×100%

[0065] where AUC po The area under the plasma concentration curve for the formulated oligonucleotide tablet when administered orally, AUC iv is the area under the plasma concentration curve when the oligonucleotide is administered i.v. solution (control), and D o For the respective doses of the two regimens.

[0066] Two different ways of administering the oligonucleotides were studied to determine the bioavailability of the drug formulation. Oligonucleotides were formulated in water-in-oil emulsions prepared as follows. First, two phases are prepared. The aqueous phase was...

Embodiment 2

[0072] Enema formulations were prepared for analysis of tissue uptake of oligonucleotides. To evaluate delivery of oligonucleotides following rectal administration and penetration of the mucosa into the colon, the following formulations were prepared (Table 1). Solution and emulsion formulations of ISIS 2302 were prepared. Additives used in the formulation included saline, hydroxypropylmethylcellulose (HPMC), carrageenan, vitamin E a-tocopheryl polyethylene glycol 1000 succinate (TPGS), Tween 80, and sorbitol.

[0073] Formulation la: A solution of ISIS 2302 was prepared at the desired concentration in sterile saline for in vivo evaluation.

[0074] Formulation 1b: A solution of ISIS 2302 and hydroxypropylmethylcellulose (HPMC) was prepared such that the final concentration of ISIS 2302 was the same as in Formulation 2a and the concentration of HPMC was 1.5%.

[0075] Formulation 1c: A solution of ISIS 2302 was prepared as in formulation 2a, containing 1.0% carrageenan, 2.5...

Embodiment 3

[0090] Analysis of Toxicity and Pharmacokinetics of Intravenously Administered ISIS 2302 in Humans in a Phase I Clinical Trial study.The first clinical trial of ISIS 2302 evaluated the safety and pharmacokinetics of intravenously administered anti-ICAM-1 antisense oligonucleotides in healthy individuals prior to initiation of an experimental therapeutic trial for the target disease state. This was a double-blind, placebo-controlled, randomized (3:1, drug:placebo) study. Each of the seven single-dose (0.06, 0.12, 0.24, 0.5, 1.0, 1.5, and 2.0 mg / kg) and multiple-dose groups (0.2, 0.5, 1.0, and 2.0 mg / kg given every other day, four doses) Four healthy male volunteers participated in the group. Groups were studied in a dose escalation fashion, with multiple doses initiated after completion of the initial five single dose groups. ISIS 2302 (or sterile saline as placebo) was administered by intravenous infusion in a volume of 80 ml over two hours. Subjects remained in a reclin...

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Abstract

Disclosed herein is a method for the sustained amelioration and / or treatment of ulcerative colitis comprising rectal administration of a compound comprising an antisense oligonucleotide having the sequence 5'-GCCCAAGCTGGCATCCGTCA-3', ISIS 2302. The method results in a decrease in the indications of ulcerative colitis for an extended period (greater than 90 days) after the conclusion of the administration of the composition. The composition is well tolerated and systemic exposure is minimal.

Description

[0001] related application [0002] This application is related to, and claims priority from, two US Provisional Patent Applications: 60 / 632,826, filed December 2, 2004, and 60 / 716,355, filed September 12, 2005. Both applications are hereby incorporated by reference in their entirety. [0003] sequence listing [0004] A Sequence Listing is filed with this application at 37 CFR 1.821, which is hereby incorporated by reference. field of invention [0005] The present invention relates to antisense oligonucleotide therapeutic compounds that modulate the expression of intracellular adhesion molecule 1 (ICAM-1) to improve and / or treat diseases including Crohn's disease, ulcerative colitis and storage Inflammatory bowel disease of pouchitis. Background of the invention [0006] ICAM-1, a member of the immunoglobulin (Ig) superfamily, is an inducible transmembrane glycoprotein constitutively expressed at low levels on vascular endothelial cells and leukocyte subtypes (Dustin et...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/70C07H21/02C07H21/04C12N5/00
Inventor 马克·K·韦德尔
Owner IONIS PHARMA INC
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