Expert Opinion on Investigational Drugs

ISSN: 1354-3784 (Print) 1744-7658 (Online) Journal homepage: http://www.tandfonline.com/loi/ieid20

Alicaforsen for the treatment of inflammatory

bowel disease

Vipul Jairath, Reena Khanna & Brian G. Feagan

To cite this article: Vipul Jairath, Reena Khanna & Brian G. Feagan (2017): Alicaforsen for
the treatment of inflammatory bowel disease, Expert Opinion on Investigational Drugs, DOI:
10.1080/13543784.2017.1349753

To link to this article: http://dx.doi.org/10.1080/13543784.2017.1349753

Accepted author version posted online: 03

Jul 2017.

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Download by: [Cornell University Library] Date: 04 July 2017, At: 14:48
Publisher: Taylor & Francis
Journal: Expert Opinion on Investigational Drugs
DOI: 10.1080/13543784.2017.1349753
Alicaforsen for the treatment of inflammatory bowel disease

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Vipul Jairath1,2,3, Reena Khanna1,2, Brian G. Feagan1,2,3

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1
Robarts Clinical Trials Inc., University of Western Ontario, London, Ontario, Canada

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2
Department of Medicine, Division of Gastroenterology, Western University, London, Canada
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3
Department of Epidemiology and Biostatistics, University of Western Ontario, London, Ontario,

Canada
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Corresponding author:
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Dr. Brian G. Feagan, MD; Robarts Clinical Trials Inc, 100 Dundas Street, Suite 200, London, ON,
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Canada; Email: brian.feagan@robartsinc.com; Tel: 226-270-7675; Fax: 519-931-5278

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Keywords: Inflammatory bowel disease, ulcerative colitis, anti-integrin, alicaforsen, safety,
adverse events

Abstract

Introduction

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Intracellular adhesion molecule-1 (ICAM-1), is a transmembrane glycoprotein of the immunoglobulin

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family, constitutively expressed on vascular endothelial cells and upregulated in inflamed colonic tissue.
Alicaforsen, a 20 base ICAM-1 anti-sense oligonucleotide and highly selective ICAM-1 inhibitor, down-

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regulates ICAM-1 mRNA.

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Areas covered
We review mechanism of action, pharmacokinetics, pre-clinical, clinical and safety data of alicaforsen
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for the treatment of ulcerative colitis (UC), pouchitis and Crohn’s disease (CD).

Expert opinion
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After 6 weeks of treatment, topical alicaforsen was significantly more effective than placebo in inducing
remission in patients with moderate-severe distal UC, with treatment effects lasting up to 30 weeks. No
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difference was observed in head-head comparison with mesalamine topical enema, although alicaforsen
appeared to have more durable treatment effect. Clinical trials of an intravenous formulation in Crohn’s
disease showed no significant treatment effect compared to placebo. An open-label trial in alicaforsen
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for pouchitis demonstrated encouraging results, now being assessed in a multi-national phase 3 trial. No
major safety signals have been observed in UC patients treated with alicaforsen enemas. The potential as
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a novel therapy for pouchitis has led to orphan designation for this indication by the FDA and European
Medicines Agency.
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Article highlights

• Alicaforsen is a 20 base intracellular adhesion molecule-1 (ICAM-1) anti-sense oligonucleotide

developed by ISIS pharmaceuticals Inc. (Carlsbad, CA, USA) and assigned the name ISIS 2302. It

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is a highly selective ICAM-1 inhibitor, leading to downregulation of ICAM-1 mRNA.

• In CD, it was not found to be any more effective than placebo in phase 2 and 3 trials, via parenteral

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administration.

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• For UC, administered as a topical enema, it was significantly more effective than placebo in the

treatment of distal colitis. There was no difference in comparison to mesalamine enemas, although
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alicaforsen appears to have a more durable treatment effect.

• An open label trial in patients with pouchitis showed encouraging results, now awaiting
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confirmation in a multi-national phase III trial which is currently recruiting

• No major safety signals have emerged to date

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• Currently alicaforsen is accessible as an unlicensed medicine in selected EU countries through a

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named patient program in accordance with international regulation.

• It has potential to establish a new therapeutic class for treatment of pouchitis and has been granted
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fast-track and orphan designation for this indication by the FDA accordingly.
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1. Background

Ulcerative colitis (UC) is a chronic, relapsing and remitting inflammatory disease of the colon and

rectum which typically manifests with diarrhea, rectal bleeding and urgency. The etiology is

incompletely understood but thought to arise from an interaction between genetic and environmental

factors, ultimately resulting in an excessive immune response against normal components of the gut

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microflora. Incidence of UC is rising worldwide, with a prevalence of up to 0.5% in Western

populations. Most therapies used in modern clinical practice focus upon treating an inappropriate

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immune response. Corticosteroids are effective for induction of remission, but are not maintenance

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agents. Aminosalicylates are effective for both induction and maintenance of mild-moderate UC, but are

not effective for more severe disease. Immunosuppressives such as azathioprine and mercaptopurine are
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indicated as maintenance agents in UC for patients who have failed 5-ASA, or are corticosteroid-

dependent or resistant. Tumor necrosis factor-α (TNF) antagonists for UC (e.g. infliximab, adalimumab,
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golimumab) are usually used after corticosteroids and/or immunosuppressives, but also used as first line

agents in patients with a more severe disease phenotype or acute severe colitis. Whilst anti TNF-agents
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are highly effective agents, approximately 40% of patients do not respond to induction therapy and a

similar number will ultimately lose response due to formation of anti-drug antibodies. Furthermore,
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adverse effects such as infections, infusion reactions and skin disease lead to discontinuation of
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treatment in many patients. Thus, there remains a need for new therapeutic agents with differing modes

of action both for induction and maintenance of remission.

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Furthermore, surgical treatment is required in up to 30 % of patients with UC after a decade of disease,

either as a consequence of medically refractory disease or the development of dysplasia. In this situation

restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is usually the operation of

choice. However, post-surgical pouchitis occurs in up to half of patients within 5 years and is associated
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with impaired quality of life (HRQL) due to symptoms of diarrhea, urgency and rectal bleeding. Some

patients with pouchitis develop chronic inflammation and either become dependent on antibiotics for

symptom relief or develop symptoms refractory to conventional treatments. With no approved

treatments for this condition, a large unmet medical need exists.

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A final common pathway in the inflammatory cascade is the migration of white blood cells from the

systemic circulation into the gastrointestinal tract. Therapies which interfere with this process are

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referred to as anti-adhesion molecules. The majority of anti-adhesion molecules are targeted at the

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integrin family. Most notably, vedolizumab (Entyvio®, Takeda Pharmaceutical Company Ltd, Japan;

previous versions known as LDP02, MLN02, and MLN0002) a humanized monoclonal antibody
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approved for both moderate-to-severe UC selectively targets the α4 β7-integrin. Other agents include

etrolizumab (a mAb against the β7 subunit), AJM300 (antagonist against α4 subunit), CCX282-B which
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selectively block CCR9) and alicaforsen which reduces the expression of intracellular adhesion

molecule-1 (ICAM-1). This paper reviews the mechanism of action, pharmacokinetics, pre-clinical,
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clinical and safety of alicaforsen for the treatment of IBD, with a focus on UC.
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2. Rationale and mode of action of Alicaforsen for UC

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Colonic epithelial damage occurs in areas with large infiltration of leucocytes and their resultant release

of cytokines. This process is partly regulated by continuous recruitment of cells from the bloodstream to
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intestine, which is mediated by soluble molecules (e.g. chemokines) and cell-associated molecules (e.g.

integrins and adhesion molecules)1. Adhesion molecules include members of the selectin family which

mediate rolling of leucocytes on vascular endothelium and members of the immunoglobulin family

which interact with integrins expressed on leucocytes, leading to adhesion and transmigration1. One of

the key intracellular adhesion molecules is ICAM-1, a transmembrane glycoprotein of the

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immunoglobulin family, constitutively expressed on vascular endothelial cells and a subset of

leucocytes, as well as being upregulated in inflamed colonic tissue in inflammatory bowel disease2.

Accordingly, a key function of ICAM-1 is regulation of leucocyte migration from blood to sites of

inflammation within tissue. In UC, neutrophil infiltration into colonic tissue is a key event in its

pathophysiology, with a number of observations supporting a critical role for ICAM-1 in this process. First,

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colonic tissue from UC patients contains higher concentrations of ICAM-1 relative to controls3. Second, ICAM-1

significantly increases during active disease compared with remission such that an increasing ICAM-1 concentration is

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observed with increasing disease activity.3 Third, ultrastructural studies of colonic biopsies from UC patients

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demonstrate ICAM labeling on basal endothelial cell membranes, on macrophages, and on plasma cells in

active disease, suggesting that ICAM-1 is involved in the entire leucocyte infiltration process and not simply in
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the early extravasation phase4. Blockade of ICAM-1 with neutralizing antibodies or antisense oligonucleotides

is associated with reduced leucocyte trafficking to the intestine and reduction in colitis in mouse models,
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forming the basis for testing inhibitors of endothelial-leucocyte interactions as therapeutic agents for IBD.
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Accordingly, alicaforsen - a 20 base ICAM-1 anti-sense oligonucleotide- was developed by ISIS

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pharmaceuticals Inc. (Carlsbad, CA, USA) and assigned the name ISIS 2302. It is a highly selective

ICAM-1 inhibitor, leading to downregulation of ICAM-1 mRNA, the messenger RNA which is
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responsible for cell surface expression of ICAM-1.5 Alicaforsen is known as an anti-sense

oligonucleotide, since its base sequence is complementary to the ICAM messenger RNA 6. It binds the
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ICAM-1 mRNA, leading to formation of a DNA:RNA heteroduplex which leaves the ICAM-1mRNA
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ineffective and vulnerable to cleavage by ribonucleases , which results in reduced translation of

ICAM-1 mRNA and ICAM-1 expansion 8. In patients treated with intravenous alicaforsen, a reduction

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in ICAM-1 expression was observed in the colon, although not on peripheral lymphocytes or for serum

ICAM-1 concentrations.

3. Introduction to Alicaforsen

Pharmacokinetics

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The pharmacokinetic (PK) profile of alicaforsen has been evaluated both for the intravenous and topical

formulations. Intravenous alicaforsen has a plasma half-life of approximately 1 hour and clearance is

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correlated with lean body mass9. The maximal concentration after standard intravenous treatment was

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found to range from 17.7 to 32.9 ug/ml.9
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For topical (rectal) therapy, systemic absorption is minimal. In an open-label study in patients with UC,

15 patients were administered an alicaforsen enema to assess local and systemic absorption10.
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Participants received a daily 240 mg enema for 6 weeks with drug concentrations measured in plasma

and colonic tissue. Plasma concentrations of parent alicaforsen represented < 0.6% mean bioavailability
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when compared with historical intravenous area under the plasma concentration-time curves.

Concentrations of the intact oligonucleotide in mucosal colonic tissue biopsies were orders of magnitude
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higher than those observed in plasma. The systemic PK data were compared with data from a
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previously completed PK study in Crohn’s disease in which subjects h a d received

intravenous alicaforsen9. Using a topical 240g enema, the mean maximum plasma concentration was
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0.03 ug/ml at 1 – 2 h post administration. P l a s m a levels in the enema-treated patients e q u a t e d

t o 0.4% of the levels found following a single intravenous dose of alicaforsen. Drug clearance from

plasma occurred by 24 h indicating that alicaforsen was active locally as an enema with minimal

systemic absorption. Systemic drug absorption from enemas was found not to correlate to the level of

inflammation.

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4. Preclinical studies

Proof of concept for inflammatory bowel disease was demonstrated in animal models, where targeting

of ICAM-1 was shown to reduce inflammation in both a murine model for colitis11 and ileitis12. After
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intracolonic administration of anti-adhesion molecule antibodies in mice with DSS colitis ,

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immunohistochemical staining demonstrated increased expression of ICAM-1 on endothelial cells of

vessels in the lamina propria and submucosa at inflamed sites. Intracolonic administration of anti- anti-

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ICAM-1 antibody decreased bloody stools, anemia, and histological disease activity. In an SAMP-1/Yit

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adoptive transfer-induced murine ileitis model, however, ICAM-1 antibodies were only effective when

administered in combination with anti-VCAM-1 or anti-4-integrin-blocking antibodies, indicating

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possible redundancy in adhesion molecule based pathways during acute inflammation. Furthermore,

only the acute component of the ileitis was affected, and the anti-adhesion molecule therapy did not
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influence signs of chronic inflammation, such as architectural changes in the mucosa12. Pre-clinical

studies evaluating toxicity were reassuring. At levels far exceeding the pharmacological dose, only
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minimal toxicity was noted in mice. Evaluation of the genotoxicity of the compound has been performed

in pregnant rats and rabbits13. At doses far in excess of the pharmacologic dose, no important
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toxicological concerns were identified.

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5. Clinical studies
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5.1 Phase 1

A double-blind, placebo-controlled study phase 1 study of intravenous infusions of ISIS 2302 was

conducted in 44 male volunteers to assess safety and PK14. Four subjects were recruited to each of

seven single-dose groups (dose levels 0.06, 0.12, 0.24, 0.5, 1.0, 1.5 and 2.0 mg/kg ISIS 2302) and each

of four multiple-dose groups (dose levels 0.2, 0.5, 1.0 and 2.0 mg/kg ISIS 2302). No adverse events

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were considered related to treatment with the drug. The plasma half-life was similar at the two doses

(0.5 and 2.0 mg/kg) and the Cmax was linearly related to dose. Non-linear changes in area under the

plasma concentration/time curve and steady-state volume of distribution with increasing dose suggesting

a saturable component. The predictable clinical profile and pharmacokinetics resulting from repeated

infusions of ISIS 2302 in this study provided confidence for pilot therapeutic trials in multiple

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indications including inflammatory bowel disease, renal transplantation, rheumatoid arthritis and

psoriasis.

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5.2 Phase 2 and 3 clinical development
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Initial clinical development of the compound was for Crohn’s disease (CD), with subsequent evaluation

for the treatment of UC and ultimately pouchitis. Results in Crohn’s Disease are briefly covered since
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the results are relevant to the context of the subsequent development program in UC and pouchitis.
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5.2.1 Crohn’s Disease

In a double-blind, placebo-controlled, proof of concept study, twenty patients were randomized (3:1,
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ISIS 2302 to placebo) to receive over 26 days 13 intravenous infusions of ISIS 2302 (0.5, 1, or 2 mg/kg)
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or placebo15. Rates of clinical remission (defined as a Crohn's Disease Activity Index < 150) were higher

in the ISIS 2302-treated patients (7/15, 47% vs. 1/5, 20%). At the end of month 6, 5 of these 7 ISIS
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2302-treated remitters were still in remission. Corticosteroid usage was also significantly lower in the

ISIS 2302-treated patients. These findings were corroborated by significant increases in beta7 bearing

CD3+ peripheral blood lymphocytes and decreases in intestinal mucosal ICAM-1 expression.

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Subsequently, three larger clinical trials were conducted, all with negative results. In the first trial which

tested the intravenous formulation, 299 steroid-dependent patient with active (CDAI 200-350 were

randomized into three treatment groups: ISIS 2302 (2 mg/kg iv three times a week) for two, four weeks

or placebo infusions16. Participants were treated in months 1 and 3, with steroid withdrawal attempted

by week 10. The primary end point was a CDAI <150 and discontinuation of corticosteroids at week 14.

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No important difference was observed between any of the three groups (ISIS 2302 groups (20.2% and

21.2%) and the placebo group (18.8%). In post-hoc analysis, patients with the highest AUC

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demonstrated improvement in clinical end points, especially corticosteroid- free remission. Adverse

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events were limited to hypersensitivity reactions and transient abnormalities of in vitro coagulation tests

that had no clinical consequences.

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In the second trial 75 patients with steroid refractory CD (CDAI 200-400) were treated with ISIS-2302
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or placebo via the subcutaneous route17. Just 2/60 ISIS-2302 patients reached the primary endpoint of

corticosteroid-free remission and no placebo treated patients, resulting in early termination of the study.
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Overall the treatment appeared to be safe, although injection site reactions were observed in 23% of
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ISIS-2302 treated patients, compared to none in the placebo group.

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Thereafter, two identical phase placebo-controlled phase III trials were conducted in which 331 patients

with moderately to severely active CD (n=221 alicaforsen; n=110 placebo) were randomized to receive
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300 mg of alicaforsen or placebo infusions 3 times per week for 4 weeks, with a primary end point of

week 12 clinical remission18. There was no statistically significant difference between the alicaforsen

and placebo groups for the primary outcome (alicaforsen 33.9% vs placebo 34.5%; P = 0.89). A post-

hoc PK analysis in patients with a baseline elevated serum CRP concentration and adequate serum

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concentration of alicaforsen (2nd – 4th quartile) suggested a possible benefit in clinical remission rate

between the alicaforsen and placebo groups (40 versus 16.2%, p = 0.02). Possible explanation of failure

of the drug in the phase III trials was insufficient dosing to provide adequate tissue penetration and

enrolment of patients without sufficient disease activity (over 2/3 patients had a normal CRP on

enrolment). Alternatively, recruitment of leucocytes to inflamed tissue in patients with CD is mediated

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by other molecules aside from ICAM-1 and thus failure in CD may be a reflection of a non-dominant

role of ICAM-1in the inflammatory response in this condition19.

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5.2.2 Pouchitis

Surgical treatment is required in up to 30 % of patients with UC after a decade of disease, either as a

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consequence of medically refractory disease or the development of dysplasia. In this situation restorative

proctocolectomy with ileal pouch-anal anastomosis (IPAA) is usually the operation of choice. However,
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post-surgical pouchitis occurs in up to half of patients within 5 years and is associated with impaired

quality of life (HRQL) due to symptoms of diarrhea, urgency and rectal bleeding20. Some patients with
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pouchitis develop chronic inflammation and either become dependent on antibiotics for symptom relief
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or develop symptoms refractory to conventional treatments. With no approved treatments for this

condition, a large unmet medical need exists.

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Failure of the pivotal phase III trials if alicaforsen in CD, and the association of parenteral
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administration with infusion and local injection site reactions, lead to reformulation of the drug as a

topical enema and subsequent testing in patients with distal UC and then pouchitis. In 2004 an open-

label, uncontrolled study assessing the effect of rectal administration of alicaforsen in 12 patients

with chronic pouchitis was published21. Patients were treated with 240 mg alicaforsen daily for 6 weeks

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with clinical evaluation and pouchoscopy at baseline then weeks 3, 6 and 10. Pouchoscopy with biopsy

was carried out at baseline and at weeks 6 and 10. After 6 weeks of treatment, there was a statistically

significant (P = 0.001) reduction in the pouchitis disease activity index (PDAI) from baseline (11.42) to

week 6 (6.83). In addition, there were statistically significant reductions in the endoscopy sub-score

from baseline (5.25) to week 3 (3.08) and week 6 (2.58) (P = 0.0039 and P = 0.0005, respectively). Ten

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of the 12 patients achieved a mucosal appearance score of 0 or 1 at endoscopy. Five of the 12 patients

(42%) had a decrease in the histology component of their PDAI from baseline to week 6. No serious

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side-effects were noted.

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Currently, a phase III, multicenter, double-blind randomized controlled trial in subjects with chronic
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antibiotic refractory pouchitis sponsored by Atlantic Pharmaceuticals Ltd (Alicaforsen was licensed to

Atlantic Pharmaceuticals in 2007) is underway, aiming to recruiting 138 subjects across the United
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States, Canada, Europe and Israel22. Eligible participants are being randomized on a 1:1 basis to either a

240 mg alicaforsen enema or matching placebo, administered once daily, at night for 6 weeks. Safety
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and efficacy assessments are being scheduled at weeks 3, 6, 10, 18 and 26. The primary outcome
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measures are indicated as a combination of endoscopic remission and relative reduction in stool

frequency. This program, which has potential to establish a new therapeutic class for treatment of
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pouchitis, has been granted fast-track designation by the FDA.

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5.2.3 Ulcerative Colitis

The first clinical evaluation of topical alicaforsen for distal UC was published in 200423. Forty patients

with mild t o m o d e r a t e distal ulcerative colitis were assigned to four dosing cohorts with each

patient receiving 60 ml of alicaforsen enema (0.1, 0.5, 2, or 4 mg/ml or placebo), daily for 28

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days. A dose- dependent dose improvement in the disease activity index (DAI) was observed. At

day 29, a 70% improvement in the DAI was observed for the 4 mg/ml dose compared with the

placebo response rate of 28% (p = 0.004). At month 3, 2 and 4 mg/ml of alicaforsen improved the

DAI by 72% and 68% respectively, compared with a placebo response of 11.5% (p = 0.016 and

0.021, respectively). All four dosing regimens resulted in dose-dependent tissue concentrations in

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mucosal biopsy samples of colon obtained on day 29. Median tissue concentrations ranged from 0.48

to 5.49 mg/g. Patient compliance with the retention enemas was excellent and no major safety signals

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were observed, nor were any derangements in coagulation tests noted.

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In 2006, Van Deventer and colleagues published a phase II trial to determine the optimal dosing
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regimen of alicaforsen enemas in patients with mild-moderately active distal UC and to further

investigate safety and tolerability24. In a randomized, double blind, placebo-controlled, two-dose

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ranging study, 112 subjects were randomized to receive one of four alicaforsen enema regimens

or placebo daily for 6 weeks. The primary endpoint was week 6 disease Activity Index and
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secondary endpoints included relapse rates and durability of response. The study failed to reach
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the primary endpoint. However a prolonged reduction in the mean DAI relative to baseline was

observed in the 240 mg alicaforsen enema arm, compared with placebo, from week 18 to week 30
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leading the authors to propose a durability of drug response and possible disease modification based

upon ICAM-1 inhibition24.

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Similar results were observed in a s e c o n d study in which an alicaforsen enema was compared with

mesalamine enema in 190 patients with mild to moderate distal colitis25. In this randomized,

double-blind, active-controlled multicenter clinical trial participants received a nightly

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enema of 120 mg alicaforsen, 240 mg alicaforsen, or 4 g mesalamine 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.

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

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threefold longer (128 and 146 days) in comparison with mesalamine (54 days), suggesting

that alicaforsen had a more durable effect than mesalamine 1 . Complete mucosal healing

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occurred in 24% of the 240 mg alicaforsen group, compared with 17% in those who

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received mesalamine.
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Subsequently, Vetger and colleagues conducted a meta-analysis of individual participant data (IPD)

from four phase II clinical trials conducted in patients with UC24, 26- 29. The purpose of this analysis was
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to investigate efficacy in specific patient subgroups, defined by disease severity and extent and severity.

Three separate analyses were conducted. The first, which compared the efficacy of alicaforsen with
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placebo in patients with distal disease only, showed a statistically significant reduction in the mean DAI
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at weeks 6 (51.4% vs. 27.1%) and 10 (51.0% vs 24.7%) in favor of alicaforsen, but not at week 30.

There was no difference observed in the efficacy of alicaforsen and mesalamine at weeks 6 and 10, and
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a trend towards improved efficacy with alicaforsen at week 30 (40.1% vs 20.6%, P=0.05). T h e s econd

analysis compared the e f f i c a c y of alicaforsen with placebo in patients with moderate-severe disease
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in patients with active UC; alicaforsen was significantly more efficacious than placebo at week 6, but

not at weeks 10 or 30. In comparison to mesalamine enemas, no difference was seen at weeks 6, 10 or

30. The third analysis, which examined patients with limited distal disease and moderate-severe

disease, essentially showed similar results to the first and second meta-analyses, with borderline

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improved efficacy at week 30 between the alicaforsen and mesalamine enema groups (39.6% vs 18.6%,

P=0.049).

Taken together, the results from the pooled IPD analyses indicate that alicaforsen enemas are superior to

placebo in patients with limited disease (<40cm) and also in-patients with moderate-severe disease. The

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lack of efficacy in mild distal colitis is postulated due to more limited over-expression of ICAM-1 in this

anatomical subgroup. The efficacy of alicaforsen was similar to that of a standard of care comparator,

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mesalamine enema up to 6 weeks of treatment. However the effect of mesalamine diminished over the

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longer term period (30 weeks), whilst persisting for alicaforsen. Since treatment of alicaforsen was only

6 weeks, and the drug has a 24 hour half-life, these results indicate a possible disease modifying effect
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of alicaforsen. A similar durability of treatment effect was observed the open-label trial for pouchitis21.

The observation that alicaforsen appears effective in UC but not in CD may be dependent on the route
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of administration of the drug or could reflect the different contributions of ICAM in the pathogenesis

of these two IBDs1.

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6. Safety and Tolerability

Rapid infusion of alicaforsen in non-human primates has resulted in cardiovascular collapse, considered
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to be related to complement activation, although monkeys are substantially more sensitive to

complement activation than humans. With 2 hour infusions of alicaforsen at a dose of 2mg/kg no
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increases in complement split products was observed in more than 300 patients with inflammatory

bowel disease treated with alicaforsen. All phosphorothioate oligodeoxynucleotides administered by the

intravenous route lead to brief but dose related increases in the activated partial thromboplastin time

(APTT) at Cmax. The effects appear to be most prominent after the first dose, although in no instances

has this lead to a bleeding diathesis.13 In a dose ranging PK trial of IV alicaforsen for CD, the transient
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post infusion aPTT were 18, 21 and 23 secs for doses of 250mg, 300mg, and 350mg respectively,

although this was transient and had no clinical consequences. The mechanism of action of this transient

anticoagulant effect is unclear, but is postulated to be related to binding to thrombin.30

Following intravenous administration, commonly described side effects reported from earlier clinical

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trials were fever, nausea or arthralgias, most often reported within 2-4 hours of dosing, although

premedication with corticosteroids in later trials was able to reduce the incidence of these such that no

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withdrawals subsequently occurred due to these events . Injection site reactions were reported in 23% of

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patients with CD were injection site reactions and infusion reactions (23% and 2% respectively).
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For topical alicaforsen, safety data from IPD were pooled across four phase II RCTs in UC26. Compared

to placebo, there was no increased rate of adverse events or intolerance with alicaforsen. In the clinical
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trial comparing alicaforsen and mesalamine, gastrointestinal effects were reported more frequently in

mesalamine-treated patients (40%) compared with alicaforsen-treated patients (21%). In most of these
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cases (89% for both alicaforsen and mesalamine), the event severity was either mild or moderate. In all
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four UC trials, alicaforsen enemas were safe and well tolerated, with no differences reported compared

to placebo and no drug-related SAEs were reported. Treatment compliance was excellent in all studies
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and discontinuation due to noncompliance was low.

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7. Regulatory approval

Alicaforsen is licensed to Atlantic pharmaceuticals. Currently it is accessible as an unlicensed medicine

in selected EU countries through a named patient program in accordance with international regulation.

The most widely employed method for the use of alicaforsen has been via retention enema. The

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recommended dosage is 240mg (60 ml), once daily by enema, with a total of 42 sessions corresponding

to a full treatment course.

Given its potential to establish a new class of therapy for pouchitis it has accordingly been granted FDA

fast track designation, and FDA orphan drug designation for this indication. Similarly in 2009, orphan

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designation (EU/3/09/641) has been granted by the European Medicines Agency for the treatment of

pouchitis. Orphan drug designation will render the product at least ten years of market exclusivity. More

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recently, the US Food and Drug Administration (FDA) has agreed to begin a rolling submission of

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Atlantic Healthcare’s approval application for the drug alicaforsen. Rolling submission means that the

FDA will accept some sections of Atlantic’s application for drug approval before receiving the final
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results from Phase III trials. This means the company does not have to complete the application before

submitting it, which may lead to a faster overall application process. Results for the phase III trial for
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pouchitis are anticipated within the next 12 months.

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8. Conclusions

Alicaforsen was no more effective than placebo treatment in clinical trials for the treatment of Crohn’s
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disease. As a topical enema formulation, it was more effective than placebo for the treatment of patients
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with distal UC and no difference was observed in a head to head trial with mesalamine enema. Notably,

treatment effects for UC appear to be more durable than topical mesalamine, suggesting a possible
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disease modifying effect. In addition, in an open-label, uncontrolled trial for pouchitis, alicaforsen

appeared highly effective and is now recruiting to a phase 3 trial and has orphan designation for this

indication by the FDA and European Medicines Agency.

9. Expert Opinion
17
Ulcerative colitis and Crohn’s disease are chronic inflammatory bowel diseases of uncertain etiology

and with no known cure. Treatment goals are rapid induction of response and remission to achieve

symptomatic control, and then maintenance of clinical response/remission as well as steroid free

remission. Several classes of therapeutic agents are currently marketed or are entering late stage clinical

trials. Whilst this expanding armamentarium holds promise to improve quality of life and disease burden

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in patients, it poses considerable challenges to treating physicians in terms of positioning and sequence

of therapies in the clinic. Multiple patient and disease related factors require assessment in order to

cr
select the right treatment, for the right patient at the right time. With this in mind, alicaforsen belongs to

us
a class of drugs known as anti-adhesion molecules. Specifically it is a 20 base ICAM-1 anti-sense

oligonucleotide, which selective inhibits ICAM-1, and downregulates ICAM-1 mRNA, the messenger
an
RNA which is responsible for cell surface expression of ICAM-1. Summary of the research to date

presented in this review demonstrates that it is effective and durable as a treatment in patients who have
M

moderate to severe distal ulcerative colitis and has an excellent safety profile to date. Its treatment effect

for distal UC appears similar to mesalamine enema, although it has a more durable treatment effect and
ed

is available on a named patient basis for use. The enema is well tolerated and no drug-related SAEs have

been reported in clinical trials to date for UC. Whilst it is unlikely to replace the use of topical
pt

mesalamine enemas in patients with distal UC, it could be positioned as an alternative in patients
ce

intolerant to mesalamine. It could also be trialed as an adjunctive therapy in patients with resistant distal

colitis, despite other topical and systemic therapies, as in such patients panproctocolectomy may be the
Ac

only option

The greatest potential for alicaforsen as a market leading therapeutic agent undoubtedly lies in the

treatment of patients with chronic antibiotic dependent pouchitis. Pouchitis occurs in almost 50% of

18
patients who have had restorative ileo-anal pouch surgery, following proctocolectomy for UC and leads

to impaired quality of life, bleeding and diarrhea. There are currently no approved therapies for

pouchitis and many patients require long-term antibiotics. Accordingly, alicaforsen has achieved orphan

designation for this indication and results of the ongoing phase III trial are eagerly awaited. If effective

for pouchitis, it highly likely that alicaforsen would be positioned as a first line therapy in patients with

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recurrent flares despite treatment with antibiotics and the therapy would establish a niche indication in

the growing treatment armamentarium for IBD.

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us
Funding

This paper was not funded.

an
Declaration of Interest
M

V. Jairuth has received scientific advisory board fees from Abbvie, Sandoz, Ferring and Janssen;

speaker's fees from Takeda and Ferring. B. Feagan has received grant/research support from Millennium
ed

Pharmaceuticals, Merck, Tillotts Pharma AG, AbbVie, Novartis Pharmaceuticals, Centocor Inc.,

Elan/Biogen, UCB Pharma, Bristol-Myers Squibb, Genentech, ActoGenix, and Wyeth Pharmaceuticals
pt

Inc.; consulting fees from Millennium Pharmaceuticals, Merck, Centocor Inc., Elan/Biogen, Janssen-
ce

Ortho, Teva Pharmaceuticals, Bristol-Myers Squibb, Celgene, UCB Pharma, AbbVie, Astra Zeneca,

Serono, Genentech, Tillotts Pharma AG, Unity Pharmaceuticals, Albireo Pharma, Given Imaging Inc.,
Ac

Salix Pharmaceuticals, Novonordisk, GSK, Actogenix, Prometheus Therapeutics and Diagnostics,

Athersys, Axcan, Gilead, Pfizer, Shire, Wyeth, Zealand Pharma, Zyngenia, GiCare Pharma Inc., and

Sigmoid Pharma; and speakers bureaux fees from UCB, AbbVie, and J&J/Janssen. R. Khanna has

received honoraria from AbbVie, Janssen, and Takeda PharmaThe authors have no other relevant

affiliations or financial involvement with any organization or entity with a financial interest in or

19
financial conflict with the subject matter or materials discussed in the manuscript apart from those

disclosed.

Bibliography

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Papers of special note have been highlighted as either of interest (•) or of considerable interest (••)

ip
to readers.

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1. Marafini I, Di Fusco D, Calabrese E, et al. Antisense approach to inflammatory bowel disease:
prospects and challenges. Drugs 2015;75:723-30.
2. Dustin ML, Rothlein R, Bhan AK, et al. Induction by IL-1 and interferon-gamma: Tissue

us
distribution, biochemistry, and function of a natural adherence molecule (ICAM-1). J Immunol
1986;137:245-254.
3. 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
an
inflammatory bowel disease. Clin Exp Immunol 2000;121:242-7.
4. Vainer B, Sorensen S, Nielsen OH, et al. Subcellular localization of intercellular adhesion
molecule-1 in colonic mucosa in ulcerative colitis. Ultrastruct Pathol 2002;26:113-21.
5. Philpott JR, Miner PB, Jr. Antisense inhibition of ICAM-1 expression as therapy provides insight
M
into basic inflammatory pathways through early experiences in IBD. Expert Opin Biol Ther
2008;8:1627-32.
6. Morcos PA. Achieving targeted and quantifiable alteration of mRNA splicing with Morpholino
ed

oligos. Biochem Biophys Res Commun 2007;358:521-7.

7. Hosten TA, Zhao K, Han HQ, et al. Alicaforsen: An Emerging Therapeutic Agent for Ulcerative
Colitis and Refractory Pouchitis. Gastroenterology Res 2014;7:51-55.
8. Miner P, Wedel M, Bane B, et al. An enema formulation of alicaforsen, an antisense inhibitor of
pt

intercellular adhesion molecule-1, in the treatment of chronic, unremitting pouchitis. Alimentary

Pharmacology & Therapeutics 2004;19:281-286.
9. Yacyshyn BR, Barish C, Goff J, et al. Dose ranging pharmacokinetic trial of high-dose
ce

alicaforsen (intercellular adhesion molecule-1 antisense oligodeoxynucleotide) (ISIS 2302) in

active Crohn's disease. Aliment Pharmacol Ther 2002;16:1761-70.
•• Pivotal dose ranging trial in CD.
10. Miner PB, Jr., Geary RS, Matson J, et al. Bioavailability and therapeutic activity of alicaforsen
Ac

(ISIS 2302) administered as a rectal retention enema to subjects with active ulcerative colitis.
Alimentary Pharmacology & Therapeutics 2006;23:1427-34.
11. Hamamoto N, Maemura K, Hirata I, et al. Inhibition of dextran sulphate sodium (DSS)-induced
colitis in mice by intracolonically administered antibodies against adhesion molecules
(endothelial leucocyte adhesion molecule-1 (ELAM-1) or intercellular adhesion molecule-1
(ICAM-1)). Clin.Exp.Immunol. 1999;117:462-468.
12. Burns RC, Rivera-Nieves J, Moskaluk CA, et al. Antibody blockade of ICAM-1 and VCAM-1
ameliorates inflammation in the SAMP-1/Yit adoptive transfer model of Crohn's disease in mice.
Gastroenterology 2001;121:1428-1436.

20
13. Crooke ST. Progress in antisense technology. Annu.Rev.Med. 2004;55:61-95.:61-95.
14. Glover JM, Leeds JM, Mant TG, et al. Phase I safety and pharmacokinetic profile of an
intercellular adhesion molecule-1 antisense oligodeoxynucleotide (ISIS 2302). J Pharmacol Exp
Ther 1997;282:1173-80.
•• Pivotal Phase 1 trial of alicaforsen
15. Yacyshyn B, Chey W, Goff J, et al. A randomized, placebo-controlled trial of antisense ICAM-1
inhibitor (ISIS 2302) in steroid-dependent Crohn's disease showed clinical improvement at high
serum levels. Gastroenterology 2001;120:A279-A280.
16. Yacyshyn BR, Chey WY, Goff J, et al. Double blind, placebo controlled trial of the remission

t
inducing and steroid sparing properties of an ICAM-1 antisense oligodeoxynucleotide,

ip
alicaforsen (ISIS 2302), in active steroid dependent Crohn's disease. Gut 2002;51:30-6.
17. Schreiber S, Nikolaus S, Malchow H, et al. Absence of efficacy of subcutaneous antisense
ICAM-1 treatment of chronic active Crohn's disease. Gastroenterology 2001;120:1339-46.

cr
18. Yacyshyn B, Chey WY, Wedel MK, et al. A randomized, double-masked, placebo-controlled
study of alicaforsen, an antisense inhibitor of intercellular adhesion molecule 1, for the treatment

us
of subjects with active Crohn's disease. Clinical Gastroenterology & Hepatology 2007;5:215-
220.
19. Lobaton T, Vermeire S, Van Assche G, et al. Review article: anti-adhesion therapies for
inflammatory bowel disease. Aliment Pharmacol Ther 2014;39:579-94.
an
• Thorough review article on anti-adhesion therapies.
20. Tiainen J, Matikainen M. Health-related quality of life after ileal J-pouch-anal anastomosis for
ulcerative colitis: long-term results. Scand J Gastroenterol 1999;34:601-5.
21. Miner P, Wedel M, Bane B, et al. An enema formulation of alicaforsen, an antisense inhibitor of
M
intercellular adhesion molecule-1, in the treatment of chronic, unremitting pouchitis.
Aliment.Pharmacol.Ther. 2004;19:281-286.
•• First trial of topical therapy for pouchitis.
22. Randomized Study of Topical Alicaforsen Enema in Antibiotic Refractory Pouchitis.
ed

https://clinicaltrials.gov/ct2/show/record/NCT02525523?term=alicaforsen&rank=1.
23. van Deventer SJ, Tami JA, Wedel MK. A randomised, controlled, double blind, escalating dose
study of alicaforsen enema in active ulcerative colitis. Gut 2004;53:1646-1651.
24. van Deventer SJ, Wedel MK, Baker BF, et al. A phase II dose ranging, double-blind, placebo-
pt

controlled study of alicaforsen enema in subjects with acute exacerbation of mild to moderate
left-sided ulcerative colitis. Aliment.Pharmacol.Ther. 2006;23:1415-1425.
ce

25. Miner PB, Jr., Wedel MK, Xia S, et al. Safety and efficacy of two dose formulations of
alicaforsen enema compared with mesalamine enema for treatment of mild to moderate left-sided
ulcerative colitis: a randomized, double-blind, active-controlled trial. Aliment Pharmacol Ther
2006;23:1403-13.
Ac

26. Vegter S, Tolley K, Wilson Waterworth T, et al. Meta-analysis using individual patient data:
efficacy and durability of topical alicaforsen for the treatment of active ulcerative colitis.
Aliment Pharmacol Ther 2013;38:284-93.
• Individual patient data meta-analysis of alicaforsen for UC.
27. van Deventer SJ, Tami JA, Wedel MK. A randomised, controlled, double blind, escalating dose
study of alicaforsen enema in active ulcerative colitis. Gut 2004;53:1646-51.
•• First controlled trial for UC.
28. Miner PB, Wedel MK, Xia S, et al. Safety and efficacy of two dose formulations of alicaforsen
enema compared with mesalamine enema for treatment of mild to moderate left-sided ulcerative

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 colitis: a randomized, double-blind, active-controlled trial. Alimentary Pharmacology &
Therapeutics 2006;23:1403–1413.
29. van Deventer SJ, Wedel MK, Baker BF, et al. A phase II dose ranging, double-blind, placebo-
controlled study of alicaforsen enema in subjects with acute exacerbation of mild to moderate
left-sided ulcerative colitis. Aliment Pharmacol Ther 2006;23:1415-25.
30. Henry SP, Novotny W, Leeds J, et al. Inhibition of coagulation by a phosphorothioate
oligonucleotide. Antisense Nucleic Acid Drug Dev 1997;7:503-10.

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Box 1. Drug summary.

Drug name Alicaforsen

Phase (for indication under discussion) Available on a named patient basis for UC.

Orphan designation for treatment of pouchitis

by FDA and European Commission

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Indication (specific to discussion) Treatment of distal UC. In Phase III trial for

pouchitis

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Pharmacology description/mechanism of ICAM-1 anti-sense oligonucledotide, leading to

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action downregulation of ICAM-1 mRNA, the

messenger RNA which is responsible for cell

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surface expression of ICAM.

Route of administration Topical enema

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Chemical structure 20 base ICAM-1 anti-sense oligonucledotide.

Binds ICAM-1 mRNA, leading to formation of a

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DNA:RNA heteroduplex which leaves the ICAM-

1mRNA ineffective and vulnerable to cleavage

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by ribonucleases

Pivotal trials Miner PB, Jr., Geary RS, Matson J, et al.

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Bioavailability and therapeutic activity of

alicaforsen (ISIS 2302) administered as a
rectal retention enema to subjects with active
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ulcerative colitis. Alimentary Pharmacology

& Therapeutics 2006;23:1427-3410

van Deventer SJ, Tami JA, Wedel MK. A

randomised, controlled, double blind,
escalating dose study of alicaforsen enema in
active ulcerative colitis. Gut 2004;53:1646-
1651.23

van Deventer SJ, Wedel MK, Baker BF, et al.

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 A phase II dose ranging, double-blind,
placebo-controlled study of alicaforsen enema
in subjects with acute exacerbation of mild to
moderate left-sided ulcerative colitis.
Aliment.Pharmacol.Ther. 2006;23:1415-
1425.24

Miner PB, Jr., Wedel MK, Xia S, et al. Safety

and efficacy of two dose formulations of

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alicaforsen enema compared with mesalamine

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enema for treatment of mild to moderate left-
sided ulcerative colitis: a randomized, double-

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blind, active-controlled trial. Aliment
Pharmacol Ther 2006;23:1403-13.28

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