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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Summary

Background

Alicaforsen is an antisense oligonucleotide inhibitor of intercellular adhesion molecule 1 protein expression with activity in subjects with ulcerative colitis and pouchitis.

Aim

To compare the effects of alicaforsen enema to standard of care mesalazine (mesalamine) enema in subjects with mild to moderate active left-sided ulcerative colitis.

Method

A randomized, double-blind, active-controlled multicentre clinical trial. Subjects received a nightly enema of 120 mg alicaforsen (n = 55), 240 mg alicaforsen (n = 50), or 4 g mesalazine (n = 54) for 6 weeks, followed by a 24-week monitoring period. The primary end point was Disease Activity Index at week 6. Clinical improvement, remission and relapse were secondary end points.

Results

No significant difference was observed between treatment arms in the primary end point. However, the median duration of response to alicaforsen enema treatment was two- to threefold longer (128 and 146 days) in comparison with mesalazine (54 days). Complete mucosal healing occurred in 24% of the 240 mg alicaforsen group, when compared with 17% in the mesalazine.

Conclusions

Alicaforsen enema demonstrated an acute response and safety profile similar to mesalazine enema, but was differentiated by a more durable response. The extended length of remission suggests that alicaforsen enema treatment may have a disease modifying effect.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Mesalazine, administered orally or as an enema, is the backbone of therapy for patients with mild to moderate left-sided ulcerative colitis.1 A meta-analysis of therapeutic trials involving subjects with active left-sided colitis reported that topical mesalazine treatment is superior to oral mesalazine, affects a higher remission rate than rectal corticosteroid administration, and is safe.2 The pooled advantage of the mesalazine enema in inducing clinical improvement and remission in comparison with placebo is 56% and 57% after 30 nightly enemas. A fraction of patients are completely resistant to mesalazine therapy however, and require treatment with corticosteroids or immunosuppressives, both of which are associated with significant toxicity.3 Therefore, there is a continuing need for new effective and non-toxic therapies for left-sided ulcerative colitis.

Intercellular adhesion molecule 1 (ICAM-1) is an inducible transmembrane glycoprotein of the immunoglobulin superfamily that is constitutively expressed at low levels on vascular endothelial cells and a subset of leucocytes. Induction of ICAM-1 expression occurs in many cell types, including colonic epithelial cells, in response to proinflammatory cytokines and mediators. ICAM-1 serves multiple functions in the propagation of inflammatory processes, including leucocyte recruitment and activation in the affected tissue.4, 5 The functional importance of ICAM-1 expression for recruitment of neutrophils has been observed in several experimental colitis models where administration of either antibody or antisense oligonucleotide inhibitors of ICAM-1 proved to be of therapeutic benefit.6

Alicaforsen (ISIS 2302; Isis Pharmaceuticals, Inc., Carlsbad, CA, USA) is a first-generation phosphorothioate-modified antisense oligodeoxynucleotide (PS-ODN) designed to specifically reduce ICAM-1 messenger RNA (mRNA) levels by an RNase H-based mechanism.7 Retention enema provides a means to apply alicaforsen directly to the involved colon of patients with ulcerative colitis, while minimizing systemic bioavailability.

Phase II studies have demonstrated that alicaforsen enema is safe and effective in the treatment of ulcerative colitis8 and chronic pouchitis.9 The aim of this study was to compare the efficacy of standard mesalazine enema treatment with two doses of alicaforsen enemas in subjects with mild to moderate active ulcerative colitis.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Subjects

Eligible subjects had active distal ulcerative colitis, or pancolitis, involving some or all of the colonic mucosa 5–50 cm from the anal verge. Subjects were at least 18 years of age with a Disease Activity Index (DAI) of 4–10, and were receiving, alone or in combination, stable doses of oral mesalazine [5-aminosalicylic acid (5-ASA): ≥30 days], azathioprine (aza-TP: ≥60 days), or mercaptopurine [6-mercaptopurine (MP): ≥60 days] prior to the study. Subjects were excluded if they were using steroids, 5-ASA enemas, other immunosuppressants [e.g. non-steroidal anti-inflammatory drugs (NSAIDs), anti-tumour necrosis factor (TNF) therapy] or if they had complications of ulcerative colitis such as bowel stricture, toxic megacolon, or colonic dysplasia, adenoma, or carcinoma. Other exclusions included a history of colonic resection, presence of enteric pathogens or Clostridium difficile toxin in the stool, other enteric infections or diseases with gastrointestinal involvement; active malignancy; uncontrolled haematological, metabolic, central nervous system (CNS), hepatic, renal, pulmonary, or cardiovascular disease; any active infection requiring treatment; major surgical procedure within 1 month prior to initial study visit; pregnant or lactating and significant laboratory abnormalities.

Sample size

The target sample size of at least 171 evaluable subjects with 57 subjects in each treatment arm was estimated to provide 80% power to detect an 18% difference in percentage change in DAI from baseline for each arm against active control. This estimation assumed a reduction in mean DAI of 55% in mesalazine subjects, 73% in alicaforsen subjects, and a common standard deviation of 33%.

Study design and protocol

Study participation included screening, baseline, treatment and follow-up periods. The screening period began when the subject signed the informed consent form and underwent a comprehensive physical examination. Baseline endoscopic examination and mucosal biopsy were performed within 14 days of visit 1 to determine extent and severity of disease.

All subjects received nightly enema therapy for 6 weeks and were followed for safety and efficacy through week 30, unless relapse, new medical or surgical intervention, or discontinuation of study medication occurred. Those subjects not requiring additional or alternative medical or surgical intervention by week 30 continued to be followed for safety and efficacy through week 54.

This study was carried out in accordance with guidelines from the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH Guidelines) and approved by the investigators’ Research Ethics Committee and Institutional Review Board.

Study drug

Alicaforsen (ISIS 2302) is a 20 nucleotide PS-ODN manufactured by Isis Pharmaceuticals, Inc. Alicaforsen enema was provided as a hydroxypropyl-methylcellulose formulation in a volume of 60 mL at two different concentrations of 2.0 and 4.0 mg/mL (120 mg and 240 mg, respectively). Mesalazine enemas were obtained as ROWASA® enemas, with 4 g of mesalazine in a volume of 60 mL (Solvay Pharmaceuticals, Inc., Marrietta, GA, USA).

Study end points

The primary end point of this trial was the DAI at week 6 relative to baseline following either alicaforsen enema or mesalazine enema treatment (Table 1). Secondary end points included change from baseline in DAI at weeks 3, 10, 18, 30, 42 and 54; and the acute response, clinical improvement, clinical remission and clinical relapse rates.

Table 1.   Disease Activity Index11
Index numberActivities
  1. * Subject's record of symptoms over the 7-day interim period between visits.

  2. † Typical number of bowel movements per day during remission.

  3. ‡ Physician's assessment of disease is a summation of the subject's symptoms, the endoscopic appearance, physical examination, laboratory tests and subject's overall status.

Stool frequency (per day)*
 0Normal†
 11–2 stools > normal
 23–4 stools > normal
 34+ stools > normal
Rectal bleeding*
 0None
 1Blood in stool (no more than half of the time)
 2Blood in stool (most of the time)
 3Blood alone
Endoscopic appearance
 0Normal or inactive disease
 1Mild (erythema, decreased vascular pattern, mild friability)
 2Moderate (marked erythema, absent vascular pattern, friability, erosions)
 3Severe (spontaneous bleeding, ulcers)
Physician’s assessment of disease‡
 0Healthy/remission
 1Mild
 2Moderate
 3Severe

End point definitions and indices

Disease Activity Index was determined by summation of the index scores obtained from the subject's recollection of symptoms from the previous 7 days, the Physicians’ Assessment of Disease (PAD),10 and the endoscopic examination11 at time of visit, as described in Table 1.

Safety analyses

Safety was evaluated by monitoring subjects’ laboratory measures, vital signs and adverse events. Coagulation, haematology, serum chemistry and urinalysis tests were conducted from the screen up to week 30. Vital signs and adverse event monitoring were conducted at each visit from the screen to the exit visit, or for 30 days after the last study treatment, whichever occurred last.

Statistical analysis

Study end points were analysed on the intent-to-treat left-sided colitis population (n = 159). Analysis of the primary end point was performed using anova. Secondary end point results were tabulated and compared using either Pearson chi-square or Fisher's exact test. The median time to clinical relapse was estimated with a 95% confidence interval from a Kaplan–Meier curve. Comparisons between treatment groups were performed using the log-rank test. All analyses were conducted at the 0.05 significance level. Missing values were imputed by the last observation carried forward (LOCF) method for subjects terminated from the study due to progression or persistence of primary disease.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Subject enrolment and disposition

One-hundred and ninety subjects (104 males and 86 females; age: 17–81 years) were enrolled after 253 candidates were screened (Figure 1). Twenty percentage of the subjects (38 of 190) entered the trial with one or two exceptions to the specified eligibility criteria. Inclusion of subjects not on stable doses of oral medication (e.g. 5-ASA, aza-TP and/or MP) at time of baseline was the primary exception made to the enrolment criteria (10 of 190).

image

Figure 1.  Flow of participants through the study.

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Subjects were randomized to receive one of three nightly enema treatments for 6 weeks: alicaforsen 120 mg (n = 65), alicaforsen 240 mg (n = 62) or mesalazine 4 g (n = 63). Subjects were then stratified into two categories of colitis, left-sided (n = 159) and pancolitis (n = 31), for statistical analysis of the clinical data. In this report, we describe the results from the intent-to-treat analysis of the left-sided colitis population.

Demographics and baseline characteristics of enrolled subjects with left-sided colitis

Subjects categorized with mild to moderate left-sided colitis (Table 2) were predominantly Caucasian (137 of 159), with a near equivalent distribution of males (86 of 159) and females (73 of 159) ranging in age from 17 to 78 years. Six percent of the subjects with left-sided colitis were currently using tobacco (10 of 159), and 41% had used tobacco in the past (65 of 159). Approximately 90% of the subjects (146 of 159) were taking stable doses of oral mesalazine at baseline, and approximately 15% were taking MP or azathioprine (24 of 159). Baseline clinical characteristics were similar between treatment groups.

Table 2.   (a) Demographics and (b) clinical characteristics of acute left-sided subject population (n = 159)
 Mesalazine (4.0 g)Alicaforsen (120 mg)Alicaforsen (240 mg)
  1. 5-ASA, 5-aminosalicylic acid; MP, mercaptopurine; aza-TP, azathioprine.

(a)
Number of participants545550
Gender
 Male253229
 Female292321
Race
 Caucasian434945
 Other1165
Age (years)
 Mean464743
 Median454643
 Range25–7817–7619–66
Weight (kg)
 Mean788079
 Median778380
 Range48–12648–11548–115
(b)
Duration of disease (years)
 Mean9.49.49.0
 Median7.08.07.2
 Range0.4–430.3–320.3–31
Last disease flare (months)
 n = 54n = 52n = 49
 Mean6.67.38.0
 Median4.04.04.0
 Range1.0–251.0–600.0–84
Extent (cm from rectum)
 Mean333235
 Median323035
 Range 5.0–6015–6010–70
Disease Activity Index
 Mean7.27.57.3
 Median7.08.07.0
 Range4.0–113.0–113.0–10
Medications (n)
 Naive343
 Oral 5-ASA505046
 Rectal 5-ASA100
 MP or aza-TP9510

Dosing

With the exception of one subject in the 240 mg alicaforsen group, all subjects received at least one dose of study drug (158 of 159). The mean number of self-reported doses was 40, 38 and 36 doses for the mesalazine, 120 mg alicaforsen and 240 mg alicaforsen enema groups. A greater percentage of the mesalazine-treated subjects (87%) administered at least 39 of the 42 nightly enemas in comparison with the 120 and 240 mg alicaforsen-treated subjects (78% and 72% respectively). Conversely a smaller percentage of the mesalazine-treated subjects (4%) administered <22 of the 42 nightly enemas in comparison with the 120 and 240 mg alicaforsen-treated subjects (11% and 16% respectively).

Efficacy

The results of the primary aim demonstrated subjects responded in all treatment arms as reflected by a decrease in the DAI (Figure 2). The maximum DAI response was observed at the 6-week time point for each of the three treatment arms, where the mean percentage reduction from baseline was 50% for the mesalazine-treated group and 40% and 41% for the 120 and 240 mg alicaforsen groups (P = 0.27 and 0.32, respectively). Consistent with the composite DAI score, both alicaforsen and mesalazine enema improved individual components of the index by week 6 (Table 3).

image

Figure 2.  Mean percentage change of Disease Activity Index (DAI) from baseline vs. time.

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Table 3.   Disease Activity Index profiles at week 6 relative to baseline
 Stool frequencyRectal bleedingEndoscopic appearancePAD
  1. Values indicate the group mean with respective standard deviation in parentheses.

  2. PAD, Physicians’ Assessment of Disease.

4 g mesalazine
 Baseline (n = 54)1.9 (0.9)1.5 (0.8)2.0 (0.5)1.8 (0.5)
 Week 6 (n = 47)1.1 (1.0)0.5 (0.8)1.1 (0.8)1.0 (0.7)
 %Δ baseline−43 (47)−70 (48)−42 (38)−43 (44)
120 mg Alicaforsen
 Baseline (n = 55)2.0 (0.9)1.5 (0.9)2.1 (0.6)1.9 (0.5)
 Week 6 (n = 49)1.2 (1.0)0.7 (0.8)1.2 (0.9)1.1 (0.8)
 %Δ baseline−40 (55)−51 (57)−42 (42)−38 (47)
240 mg Alicaforsen
 Baseline (n = 50)1.9 (0.8)1.5 (0.8)2.0 (0.6)1.9 (0.4)
 Week 6 (n = 44)1.1 (1.0)0.8 (1.0)1.3 (1.0)1.2 (0.9)
 %Δ baseline−40 (55)−50 (66)−35 (53)−38 (50)

After 10 weeks the mean percentage change in DAI of all three groups coalesced within a range of 36–40% from baseline (Figure 2). By 18 weeks, or 3 months post-treatment, a dose-dependent response was observed with the alicaforsen enema, where the DAI of the 240 mg alicaforsen enema group displayed a twofold greater decrease relative to baseline in comparison with the 120 mg alicaforsen group, 34% vs. 17%.

Based upon a three-point reduction in DAI from baseline, a greater proportion of subjects demonstrated clinical improvement in the mesalazine cohort in comparison with either the 120 or 240 mg alicaforsen cohorts (50% vs. 36 and 30% by week 3). The proportion of improved subjects in each cohort; however, was similar by end of treatment (54% vs. 55 and 50% by week 6). And by week 18, the percentage of subjects that met the target improvement criteria was greater in the 120 and 240 mg alicaforsen enema groups (33% and 42%, respectively) in comparison with the mesalazine groups (24%).

The underlying efficacy and durability of alicaforsen enema in comparison with mesalazine enema was especially evident from the analysis of the rate of clinical remission (Figure 3) and clinical relapse (Figure 4). Analysis of the clinical remission rate by two different criteria showed a dose-dependent effect in the alicaforsen treatment groups that was superior to the mesalazine enema active control over time. In the first analysis (Figure 3a), the criteria for remission was a DAI score ≤2 with further limitations placed on each of the four indices – stool frequency (≤1), rectal bleeding (=0), endoscopy (=0) and PAD (≤1). By this definition, the maximum percentage clinical remission between the three groups was 20% in the 240 mg alicaforsen group (weeks 10 and 18), followed by 18% in the 120 mg alicaforsen group (week 10), and lastly 15% in the 4 g mesalazine group (week 6). The percentage of subjects who showed remission at the higher dose of alicaforsen enema was significantly greater than that of the mesalazine group at week 18, 20% vs. 6% (P = 0.03). Comparison of the area under the curves (AUC) up to week 54 also showed a significant difference between the 240 mg alicaforsen and 4 g mesalazine enema groups by the Pearson chi-square test (P = 0.03).

image

Figure 3.  Rate of clinical remission. (a) Percentage remission over time, where remission is defined as Disease Activity Index (DAI): ≤2, stool frequency: ≤1, rectal bleeding: 0, endoscopy: 0 and Physicians’ Assessment of Disease (PAD): ≤1. (b) Percentage remission over time, where remission is defined as an endoscopic score of zero (normal or inactive disease).

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image

Figure 4.  Kaplan–Meier curve estimates of the probability of relapse through week 54. Relapse is defined as an endoscopic score ≥1. Subjects in remission at week 6 had a Mayo Score of zero [4 g mesalazine (n = 9), 120 mg alicaforsen (n = 11) and 240 mg alicaforsen (n = 10)].

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In the second analysis (Figure 3b), clinical remission was based solely on endoscopic appearance, where remission was defined by an endoscopic Mayo Score of zero. The rank order of maximum percentage of subjects who demonstrated clinical remission by complete mucosal healing was similar to that observed in the first analysis, where the 240 mg alicaforsen group showed the greatest percentage (24%, week 10), followed by the 120 mg alicaforsen group (20%, week 10), and lastly the mesalazine group (17%, weeks 3 and 6). The percentage of subjects who showed remission at the higher dose of alicaforsen enema (20%) was greater than that of the mesalazine group (7%) at week 18 (P = 0.06). The difference between the AUC up to week 54 of the 240 mg alicaforsen and 4 g mesalazine enema groups showed a similar trend, as indicated by the Pearson chi-square test (P = 0.06).

The long-term outcome of each enema treatment was determined by a Kaplan–Meier analysis of the rate of clinical relapse (Figure 4). This analysis showed that alicaforsen enema was two to three times more durable than mesalazine enema based on the endoscopic appearance of subjects over time. The estimated median time until relapse measured as 54 days for mesalazine, and 128 and 146 days for 120 and 240 mg alicaforsen respectively.

Safety

Consideration of all dosed subjects (n = 189) showed that fewer adverse events occurred in the 240 mg alicaforsen group (76 incidents in 35 subjects) in comparison with the mesalazine group (117 incidents in 40 subjects) or the 120 mg group (113 incidents in 40 subjects). The most frequently recorded adverse events, overall and in each of the three treatment groups, were categorized under gastrointestinal disorders. A smaller number of subjects were afflicted with gastrointestinal disorders over the course of the study in the 120 and 240 mg alicaforsen enema-treated groups in comparison with the mesalazine-treated group, 25% (16 of 65) and 21% (13 of 61) vs. 40% (25 of 63) respectively. Furthermore, the number of incidents that occurred in this category was lower in the 240 mg alicaforsen group (19 incidents) in comparison with the mesalazine group (36 incidents) or the 120 mg group (34 incidents). Adverse events for which the frequency favoured one treatment over the other included sinusitis, 7% alicaforsen vs. 2% of mesalazine-treated subjects; rash, 5% mesalazine vs. 0.8% of alicaforsen-treated subjects and vomiting, 5% mesalazine vs. 0% alicaforsen. Adverse events that occurred in three or more subjects of any treatment group are detailed in Table 4.

Table 4.   Adverse events occurring in three or more subjects in any given treatment group
System organ class (MedDRA Preferred Term)Mesalazine 4.0 g (N = 63)Alicaforsen 120 mg (N = 65)Alicaforsen 240 mg (N = 61)
  1. Values are expressed as n (%). NOS, not otherwise specified.

Overall40 (63.5)40 (61.5)35 (57.4)
Gastrointestinal disorders
 Abdominal pain NOS3 (4.8)4 (6.2)2 (3.3)
 Abdominal tenderness4 (6.3)4 (6.2)0 (0.0)
 Colitis ulcerative3 (4.8)0 (0.0)1 (1.6)
 Colitis ulcerative aggravated2 (3.2)3 (4.6)3 (4.9)
 Colon polyp3 (4.8)0 (0.0)0 (0.0)
 Dyspepsia0 (0.0)0 (0.0)3 (4.9)
 Nausea1 (1.6)3 (4.6)1 (1.6)
 Vomiting NOS3 (4.8)0 (0.0)0 (0.0)
General disorders
 Fatigue0 (0.0)0 (0.0)3 (4.9)
Infections and infestations
 Bronchitis NOS3 (4.8)0 (0.0)1 (1.6)
 Influenza3 (4.8)0 (0.0)2 (3.3)
 Nasopharyngitis2 (3.2)1 (1.5)3 (4.9)
 Sinusitis NOS1 (1.6)5 (7.7)4 (6.6)
 Upper respiratory tract infection2 (3.2)3 (4.6)4 (6.6)
Musculoskeletal
 Arthralgia1 (1.6)3 (4.6)2 (3.3)
Nervous system disorders
 Headache NOS0 (0.0)4 (6.2)1 (1.6)
Respiratory
 Sinus congestion2 (3.2)3 (4.6)0 (0.0)
Skin and subcutaneous skin disorders
 Rash NOS3 (4.8)0 (0.0)1 (1.6)

Sixteen percentage of the adverse events in subjects treated with alicaforsen (30 of 189) were considered possibly related to drug by the Investigator. However, the number of subjects and incidents were inversely related to dose, and the events were predominantly gastrointestinal in nature.

Seventeen serious adverse events occurred in this study, five of which were in the mesalazine-treated group, 10 in the 120 mg alicaforsen group, and two in the 240 mg alicaforsen-treated group. None of the serious adverse events was considered as drug-related. The inverse relationship observed between the alicaforsen enema dose and occurrence of adverse events may reflect the lack of efficacy and subsequent disease relapse at the lower dose.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Topical rectal therapy of left-sided ulcerative colitis provides the benefit of high-dose medication applied to the area of active colonic inflammation. Mesalazine enemas provide an effective dose regimen for treatment and set the standard for topical rectal therapy. Mesalazine enema is superior to oral mesalazine in induction of remission and has also shown effectiveness in maintenance of remission either alone or in combination with oral treatment.

Recent exploration of immune modification of inflammatory bowel disease (IBD) has focused on the development of biologically active drugs that target specific components of the inflammatory pathway. These have included the development of specific antibodies to cytokines and receptors involved in immune cell adhesion and signalling, such as the α4β7 integrin antibody MLN02.12

Antisense technology provides another approach to selectively block synthesis of proteins involved in the immunological response. The specificity and safety of the technology provides a unique opportunity for modification of the inflammatory pathways, which may permit new treatment approaches while elucidating the pathophysiology of IBD. Alicaforsen is a first generation antisense oligodeoxynucleotide designed to hybridize to the human ICAM-1 mRNA through Watson–Crick base pair interactions.13 Sequence-specific hybridization of alicaforsen to the complementary region of the target ICAM-1 mRNA generates a substrate for RNase H, a ubiquitous intracellular endoribonuclease that recognizes DNA:RNA heteroduplexes as substrate for selective hydrolysis of the RNA strand.7, 14 Alicaforsen-mediated RNase H activity results in reduction of ICAM-1 mRNA levels, and consequently ICAM-1 protein expression, as demonstrated in human endothelial cell culture models,13 human clinical trials15 and in mouse models of colitis with the respective mouse ICAM-1 antisense inhibitor.6

Mucosal immunology of ulcerative colitis is complex with infiltration, activation and proliferation of neutrophils into the colonic mucosal layers central to the pathophysiology of ulcerative colitis.16 ICAM-1 plays a pivotal role in transendothelial infiltration of leucocytes, e.g. neutrophils and eosinophils, and a secondary role in their activation and proliferation. Immunochemical analysis of colonic tissue derived from subjects with ulcerative colitis has shown increased ICAM-1 levels, relative to controls, which correlated directly with the level of disease activity.17 Furthermore, colonic biopsies from subjects displaying active disease, despite treatment with oral mesalazine, show a higher level of ICAM-1 expression on basal endothelial cells, macrophages and plasma cells within inflamed tissue in comparison with non-inflamed tissue.18

This study directly compares alicaforsen enemas with mesalazine enemas as an extension of the successful placebo-controlled dose escalation study of four alicaforsen enema doses.8 Mesalazine enemas improved the DAI in the active control group consistent with the beneficial effect of mesalazine in left-sided ulcerative colitis. Both alicaforsen doses improved the DAI at the end of treatment although there was no demonstrable difference between treatment groups, i.e. the primary end point. Secondary end point analysis however, showed that a higher percentage of alicaforsen-treated subjects remained in clinical remission compared with those in the mesalazine-treated group, and that alicaforsen enema provided a more durable treatment. The delayed and prolonged dose-dependent response time displayed by alicaforsen is likely a reflection of specific pharmacokinetic and pharmacodynamic attributes that often distinguish this class of compounds. Alicaforsen was safe and well-tolerated at the two doses studied, with a safety profile similar to the mesalazine enema.

The initial pharmacokinetic analysis of alicaforsen enema in subjects with mild to moderate active ulcerative colitis showed a high, dose-dependent concentration of drug in mucosal biopsy samples of colon obtained after 28 daily treatments.8 In a more recent study, the systemic exposure to alicaforsen enema at 240 mg per dose was found to be <1% at the end of a 6-week nightly treatment period.19 The low systemic bioavailability of alicaforsen enema distinguishes the treatment from other rectal treatments, such as mesalazine or steroids, which have a significantly higher bioavailability and thus still pose the potential for systemic drug-related side-effects.

There are two primary limitations to this study. First, no difference between treatments was seen in the primary end point. This result implies that there is not an acute difference between the tested interventions. Secondly, the study was limited by the long-term subject drop out rate, which underpowered the assessment of durability.

Although no difference was observed in the primary end point between treatment groups, this study demonstrates alicaforsen enema effectively induces disease remission of symptoms in subjects with left-sided ulcerative colitis. As antisense technology permits highly selective blockade of specific protein synthesis, the beneficial effect of alicaforsen in ulcerative colitis supports a pivotal role for ICAM-1 in the pathophysiology of ulcerative colitis through the effect of ICAM-1 on cell trafficking and inflammatory cell activation. In addition, there appears to be a sustained period of remission that occurs presumptively in the absence of alicaforsen, as it is unlikely that active drug is present in the colonic mucosa longer than 2 weeks. The durable effect of alicaforsen suggests modification of the immunological factors that permit continuous colonic mucosal inflammation in ulcerative colitis.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This clinical study was supported by Isis Pharmaceuticals, Inc.

We are grateful to the ISIS 2302 CS22 Principal Investigators for their participation in this study: Rajih Alkhafaji, M.D.; Charles Barish, M.D., F.A.C.P, F.A.C.G.; Jason Bodzin, M.D., F.A.C.S.; Roger Carlisle, M.D.; Tawfik Chami, M.D.; William Y. Chey, M.D., M.Sc., D.Sc.; Russell Cohen, M.D.; Florian Cortese, M.D., F.A.C.G.; Ramin Farsad, M.D.; C. Allen Goetsch, M.D.; John Goff, M.D.; John Hanson, M.D.; Debra Helper, M.D.; James Hogin, D.O., F.A.C.G.; David James, D.O.; Bruce Johnson, M.D.; Robert Kaplan, M.D.; Jeffry Katz, M.D.; Seymour Katz, M.D., F.A.C.P.; George Koval, M.D.; Kenneth Maxwell, M.D.; Trent Nichols, M.D.; Daniel Pambianco, M.D.; William Pandak, M.D.; Lenin Peters, M.D., M.R.C.P.; W. Michael Priebe, M.D.; Ron Pruitt, M.D., F.A.C.P., F.A.C.G.; Charles Randall, M.D.; Prakash Rau, M.D.; Dean Rider, M.D., F.A.C.P.; Vance Rodgers, M.D.; Michael Safdi, M.D.; Julio Salcedo, M.D.; Howard Schwartz, M.D.; Arunkumar Shah, M.D.; David Stanton, M.D.; Mark Stern, M.D.; Williamson Strum, M.D.; Abdul S. Thannoun, M.D.; Jeff Willis, M.D.; Douglas Wolf, M.D.; Lawrence Wruble, M.D.; Bruce Yacyshyn, M.D., F.R.C.P.C.; Richard Zander, M.D.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  • 1
    Hanauer SB. Medical therapy for ulcerative colitis 2004. Gastroenterology 2004; 126: 158292.
  • 2
    Cohen RD, Woseth DM, Thisted RA, Hanauer SB. A meta-analysis and overview of the literature on treatment options for left-sided ulcerative colitis and ulcerative proctitis. Am J Gastroenterol 2000; 95: 126376.
    Direct Link:
  • 3
    Nielsen OH, Vainer B, Rask-Madsen J. Review article: The treatment of inflammatory bowel disease with 6-mercaptopurine or azathioprine. Aliment Pharmacol Ther 2001; 15: 1699708.
  • 4
    Van Seventer GA, Shimizu Y, Horgan KJ, Shaw S. The LFA-1 ligand ICAM-1 provides an important costimulatory signal for T cell receptor-mediated activation of resting T cells. J Immunol 1990; 144: 457986.
  • 5
    Oppenheimer-Marks N, Davis LS, Bogue DT, Ramberg J, Lipsky PE. Differential utilization of ICAM-1 and VCAM-1 during the adhesion and transendothelial migration of human T lymphocytes. J Immunol 1991; 147: 291321.
  • 6
    Bennett CF, Kornbrust D, Henry S, et al. An ICAM-1 antisense oligonucleotide prevents and reverses dextran sulfate sodium-induced colitis in mice. J Pharmacol Exp Ther 1997; 280: 9881000.
  • 7
    Crooke ST. Progress in antisense technology. Annu Rev Med 2004; 55: 6195.
  • 8
    Van Deventer SJ, Tami JA, Wedel MK. A randomised, controlled, double blind, escalating dose study of alicaforsen enema in active ulcerative colitis. Gut 2004; 53: 164651.
  • 9
    Miner P, Wedel M, Bane B, Bradley J. An enema formulation of alicaforsen, an antisense inhibitor of intercellular adhesion molecule-1, in the treatment of chronic, unremitting pouchitis. Aliment Pharmacol Ther 2004; 19: 2816.
  • 10
    Hanauer S, Schwartz J, Robinson M, et al. Mesalamine capsules for treatment of active ulcerative colitis: results of a controlled trial. Pentasa Study Group. Am J Gastroenterol 1993; 88: 118897.
  • 11
    Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med 1987; 317: 16259.
  • 12
    Feagan BG, Greenberg GR, Wild G, et al. Treatment of ulcerative colitis with a humanized antibody to the alpha-4 beta-7 integrin. N Engl J Med 2005; 352: 2499507.
  • 13
    Bennett CF, Condon TC, Grimm S, Chan H, Chiang MY. Inhibition of endothelial cell-leukocyte adhesion molecule expression with antisense oligonucleotides. J Immunol 1994; 152: 353040.
  • 14
    Wu H, Lima WF, Zhang H, Fan A, Sun H, Crooke ST. Determination of the role of the human RNase H1 in the pharmacology of DNA-like antisense drugs. J Biol Chem 2004; 279: 171819.
  • 15
    Yacyshyn BR, Bowen-Yacyshyn MB, Jewell L, et al. A placebo-controlled trial of ICAM-1 antisense oligonucleotide in the treatment of Crohn's disease. Gasteroenterology 1998; 114: 113342.
  • 16
    Van Assche G, Rutgeerts P. Physiological basis for novel drug therapies used to treat the inflammatory bowel diseases. I. Immunology and therapeutic potential of antiadhesion molecule therapy in inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 2005; 288: G16974.
  • 17
    Vainer B, Nielsen OH. Changed colonic profile of P-selectin, platelet-endothelial cell adhesion molecule-1 (PECAM-1), intercellular adhesion molecule-1 (ICAM-1), ICAM-2, and ICAM-3 in inflammatory bowel disease. Clin Exp Immunol 2000; 121: 2427.
  • 18
    Vainer B, Sorensen S, Nielsen OH, Horn T. Subcellular localization of intercellular adhesion molecule-1 in colonic mucosa in ulcerative colitis. Ultrastruct Pathol 2002; 26: 11321.
  • 19
    Miner PB Jr, Geary RS, Matson J, et al. Bioavailability and therapeutic activity of alicaforsen (ISIS 2302) administered as a rectal retention enema to subjects with active ulcerative colitis. Aliment Pharm Ther 2006; 23: 142734.