Alicaforsen

Alicaforsen is an antisense oligonucleotide therapeutic that targets the messenger RNA for the production of human ICAM-1 protein.[1] It was discovered by Ionis Pharmaceuticals (formerly Isis Pharmaceuticals) and as of 2017 was under development by Atlantic Healthcare for pouchitis in an enema formulation.

Alicaforsen
Clinical data
Other namesDNA, d[(R)-P-thio](G-C-C-C-A-A-G-C-T-G-G-C-A-T-C-C-G-T-C-A)
Identifiers
CAS Number
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
FormulaC192H244N75O98P19S19
Molar mass6368.171938 g/mol g·mol−1
3D model (JSmol)

Pharmacology

ICAM-1 promotes the extravasation and activation of leukocytes (white blood cells), which is part of the inflammation process.[2] Alicaforsen inhibits the activity of ICAM-1 protein by degrading mRNA coding for it via an RNase-H based mechanism.[2]

It appears to have better efficacy as a topical medication than via systemic administration which is typical of antisense drugs.[2]

Preclinical Studies of Alicaforsen

Alicaforsen was found to selectively inhibit cytokine-induced ICAM-1 expression in a variety of human cells in vitro (1). A murine analogue, ISIS 3082, has been shown to be active in multiple models of inflammation, demonstrating down-regulation of either ICAM-1 message or protein in involved tissue in the endotoxin pneumonitis (2) and the dextran-induced colitis (3) models. Control oligonucleotides failed to show pharmacological activity

In a phase 1 study, a single intravenous dose of alicaforsen from 0.06 to 2 mg/kg and four doses every other day ranging from 0.5 to 2 mg/kg was administered over 2 hours, were well tolerated in healthy volunteers. Drug-related adverse events observed were dose related, modest ~1.5-fold at the 2-mg/kg dose, and transient (2–4 hours after dosing) increases in the activated partial thromboplastin time (aPTT) and threshold effects on complement C3, but not C5, conversion at the highest doses. (4) Both of these dose-related effects (prolongation of the intrinsic coagulation pathway and alternative pathway complement activation) have been observed in monkeys given alicaforsen and a spectrum of other phosphorothioate oligodeoxynucleotides.(5) Alternative pathway complement activation seemed to be mediated by an interaction with the inhibitory protein factor H.(6) The prolongation of aPTT appears to be effected through inhibition of intrinsic tenase complex (factors IXa and VIIIa, phospholipid, and calcium) activity.

Clinical Studies of Alicaforsen (ISIS 2302) in Crohn’s Disease

The first clinical trial of a systemic antisense drug in humans and additionally, the first use of an anti-adhesion molecule therapy in human disease was performed using a single-center, double-blinded, placebo-controlled, randomized (3:1; alicaforsen to placebo), fixed-dose within patient, and dose-escalation trial(7). The study was designed to obtain pilot assessment of tolerability, pharmacology, and efficacy of alicaforsen in Crohn's disease. Twenty patients with active, steroid-treated Crohn's disease were randomized (3:1, alicaforsen to placebo) to received alicaforsen over 26 days 13 intravenous infusions of alicaforsen (0.5, 1, or 2 mg/kg) or placebo in a double-blinded study. The patients were followed up for 6 months. At the end of treatment, 47% (7 of 15) of alicaforsen–treated and 20% (1 of 5) of the placebo-treated patients were in remission (Crohn's Disease Activity Index [CDAI] < 150). At the end of month 6, 5 of these 7 alicaforsen–treated remitters were still in remission, and a 6th patient had a CDAI of 156. Corticosteroid usage was significantly lower (P = 0.0001) in the alicaforsen–treated patients. These findings were corroborated by significant increases in β7 and αd bearing CD3+ peripheral blood lymphocytes and by decreases in intestinal mucosal ICAM-1 expression during the treatment period.

A subsequent, pivotal, large study consisting of active (Crohn's disease activity index (CDAI) 200–350), steroid dependent (prednisone 10–40 mg) Crohn's patients randomized into three treatment groups: placebo versus Alicaforsen (2 mg/kg intravenously three times a week) for two or four weeks was performed (8). Patients were treated in months 1 and 3, with steroid withdrawal attempted by week 10. The primary end point (steroid free remission) was a CDAI <150 off steroids at the end of week 14. A total of 299 patients were enrolled, with a mean baseline CDAI of 276 and steroid dose of 23 mg/day. Rates of steroid free remission were equivalent for the two and four week ISIS 2302 groups (20.2% and 21.2%) and the placebo group (18.8%). At week 14, steroid withdrawal was successful in more alicaforsen patients compared with placebo treated patients (78% v 64%; p=0.032). Steroid free remission was highly correlated with exposure (p=0.0064). Other clinical responses were correlated with exposure, with significant results versus placebo being observed in the highest area under the curve subgroup. CDAI scores decreased by 136 (112) at week 14 versus 52 (107) for placebo (p=0.027) and inflammatory bowel disease score questionnaire improved by 43 (31) versus 15 (36) for placebo (p=0.027)

Although the primary outcomes failed to demonstrate efficacy, pharmacodynamic modelling identified a subset of patients with Crohn’s disease in whom the drug worked effectively, based upon CRP levels, CDAI scores and PK.

1. Bennett, CF, Condon, T, Grimm, S, Chan, H, and Chiang, MY. Inhibition of endothelial cell–leukocyte adhesion molecule expression with antisense oligonucleotides. J Immunol. 1994; 152: 3530–3540

2. Kumasaka, T, Quinlan, WM, Doyle, NA, Condon, TP, Sligh, J, Takei, F, Beaudet, AL, Bennett, CF, and Doerschuk, CM. The role of ICAM-1 in endotoxin-induced pneumonia evaluated using ICAM-1 antisense oligonucleotides, anti–ICAM-1 monoclonal antibodies, and ICAM-1 mutant mice. J Clin Invest. 1996; 97: 2362–2369

3. Bennett, CF, Kornbrust, D, Henry, S, Stecker, K, Howard, R, Cooper, S, Dutson, S, Hall, W, and Jacoby, HI. An ICAM-1 antisense oligonucleotide prevents and reverses dextran sulfate sodium–induced colitis in mice. J Pharmacol Exp Ther. 1997; 280: 988–1000

4. Glover, JM, Leeds, JM, Mant, TGK, Amin, D, Kisner, DL, Zuckerman, JE, Geary, RS, Levin, AA, and Shanahan, WR. Phase 1 safety and pharmacokinetic profile of an intercellular adhesion molecule–1 antisense oligonucleotide (ISIS 2302). J Pharmacol Exp Ther. 1997; 282: 1173–1180

5. Henry, SP, Bolte, H, Auletta, C, and Kornbrust, DJ. Evaluation of the toxicity of ISIS 2302, a phosphorothioate oligonucleotide, in a 4-week study in cynomolgus monkeys. Toxicology. 1997; 120: 145–155

6. Henry, SP, Giclas, PC, Leeds, J, Pangburn, M, Auletta, C, Levin, AA, and Kornbrust, DJ. Activation of the alternative pathway of complement by a phosphorothioate oligonucleotide: potential mechanism of action. J Pharmacol Exp Ther. 1997; 281: 810–816

7. Yacyshyn BR, Bowen-Yacyshyn MB, Jewell L, Tami JA, Bennett CF, Kisner DL, Shanahan WR Jr. A placebo-controlled trial of ICAM-1 antisense oligonucleotide in the treatment of Crohn’s. Gastroenterology. 1998 Jun; 114(6):1133-42.

8. Yacyshyn BR, Chey WY, Goff J, Saltzberg B, Baerg R, Buchman AL, Tami J, Yu R, Gibiansky E, Shanahan WR.Double blind, placebo controlled trial of the remission inducing and steroid sparing properties of an ICAM-1 antisense oligodeoxynucleotide, alicaforsen (ISIS 2302), in active steroid dependent Crohn's disease. Gut. 2002 Jul; 51(1):30-6.

Chemistry

Alicaforsen is a 20 unit phosphorothioate modified antisense oligonucleotide.[3]

History

Alicaforsen was discovered and initially developed by Isis Pharmaceuticals,[4] which changed its name to Ionis Pharmaceuticals in 2015.

Isis partnered on development of alicaforsen with Boehringer Ingelheim starting in 1995; that deal ended in 1999, after each of IV and subcutaneously delivered alicaforsen failed in phase III trials for Crohn's disease and development of those formulations in that indication was terminated; development for rheumatoid arthritis was terminated the same year and development in kidney transplant apparently ceased as well at that time.[4]

The company reformulated alicaforsen as an enema and three small trials were published between 2004 and 2006, an open label trial in chronic pouchitis and two randomized trials in ulcerative colitis (UC); in the UC trials the drug missed its primary endpoint of improvements at 6 weeks, but showed a better effect in the longer term (between 18 and 30 weeks).[2]

Alicaforsen was licensed to Atlantic Healthcare in 2007.[5]

The use of the enema formulation of alicaforsen to treat pouchitis was granted orphan drug status in the US in 2008[6] and received the same in Europe in 2009.[7] As of April 2017 the enema formulation of alicaforsen for pouchitis had received FDA Fast Track designation and was in a Phase III trial.[8]

References

  1. "Alicaforsen". AdisInsight. Retrieved 28 April 2017.
  2. Marafini, I; Di Fusco, D; Calabrese, E; Sedda, S; Pallone, F; Monteleone, G (May 2015). "Antisense approach to inflammatory bowel disease: prospects and challenges". Drugs. 75 (7): 723–30. doi:10.1007/s40265-015-0391-0. PMID 25911184.
  3. "Recommended INN List 47" (PDF). WHO Drug Information. 16 (1). 2002.
  4. Gewirtz, AT; Sitaraman, S (October 2001). "Alicaforsen. Isis Pharmaceuticals". Current Opinion in Investigational Drugs. 2 (10): 1401–6. PMID 11890355.
  5. "Press Release: Atlantic Healthcare Completes Acquisition of ICAM-1 Portfolio of Late Stage Anti-inflammatory Drugs | Evaluate". Atlantic Healthcare via Evaluate. 2 April 2007.
  6. "Alicaforsen US Orphan designation". Orphanet. Retrieved 28 April 2017.
  7. "EU/3/09/641 Orphan drug designation". European Medicines Agency. 9 June 2009.
  8. "Alicaforsen (AP 1007) - Product Profile". BioCentury. Retrieved 28 April 2017.

Further reading

  • 2013 meta-analysis authored by scientists who work for or were funded by Atlantic: Vegter, S; Tolley, K; Wilson Waterworth, T; Jones, H; Jones, S; Jewell, D (August 2013). "Meta-analysis using individual patient data: efficacy and durability of topical alicaforsen for the treatment of active ulcerative colitis". Alimentary Pharmacology & Therapeutics. 38 (3): 284–93. doi:10.1111/apt.12369. PMID 23750909.
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