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.[2]

Alicaforsen

Clinical data
Other names	DNA, 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
IUPAC name 2'-deoxy-P-thioguanylyl-(3'->5')-2'-deoxy-P-thiocytidylyl-(3'->5')-2'-deoxy-P- thiocytidylyl-(3'->5')-2'-deoxy-P-thiocytidylyl-(3'->5')-2'-deoxy-P-thioadenylyl-(3'->5')-2'-deoxy-P-thioadenylyl-(3'->5')-2'-deoxy-P-thioguanylyl-(3'->5')-2'-deoxy-P-thiocytidylyl-(3'->5')-P-thiothymidylyl-(3'->5')-2'-deoxy-P-thioguanylyl-(3'->5')-2'-deoxy-P-thioguanylyl-(3'->5')-2'-deoxy-P-thiocytidylyl-(3'->5')-2'-deoxy-P-thioadenylyl-(3'->5')-2'-P-thiothymidylyl-(3'->5')-2'-deoxy-P-thiocytidylyl-(3'->5')-2'-deoxy-P-thiocytidylyl-(3'->5')-2'-deoxy-P-thioguanylyl-(3'->5')-2'-P-thiothymidylyl-(3'->5')-2'-deoxy-P-thiocytidylyl (3'->5')-2'-deoxyadenosine
CAS Number	185229-68-9
PubChem CID	16197724
ChemSpider	17326145
UNII	J8435V445B
ChEMBL	ChEMBL2108326
Chemical and physical data
Formula	C192H244N75O98P19S19
Molar mass	6368.13 g·mol^−1
3D model (JSmol)	Interactive image
SMILES Cc1cn(c(=O)[nH]c1=O)[C@H]2C[C@@H]([C@H](O2)COP(=S)(O)O[C@H]3C[C@@H](O[C@@H]3COP(=S)(O)O[C@H]4C[C@@H](O[C@@H]4COP(=S)(O)O[C@H]5C[C@@H](O[C@@H]5COP(=S)(O)O[C@H]6C[C@@H](O[C@@H]6COP(=S)(O)O[C@H]7C[C@@H](O[C@@H]7COP(=S)(O)O[C@H]8C[C@@H](O[C@@H]8COP(=S)(O)O[C@H]9C[C@@H](O[C@@H]9COP(=S)(O)O[C@H]1C[C@@H](O[C@@H]1CO)n1cnc2c1nc([nH]c2=O)N)n1ccc(nc1=O)N)n1ccc(nc1=O)N)n1ccc(nc1=O)N)n1cnc2c1ncnc2N)n1cnc2c1ncnc2N)n1cnc2c1nc([nH]c2=O)N)n1ccc(nc1=O)N)OP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)n1cnc2c1nc([nH]c2=O)N)OP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)n1cnc2c1nc([nH]c2=O)N)OP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)n1ccc(nc1=O)N)OP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)n1cnc2c1ncnc2N)OP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)n1cc(c(=O)[nH]c1=O)C)OP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)n1ccc(nc1=O)N)OP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)n1ccc(nc1=O)N)OP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)n1cnc2c1nc([nH]c2=O)N)OP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)n1cc(c(=O)[nH]c1=O)C)OP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)n1ccc(nc1=O)N)OP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)n1cnc2c1ncnc2N)O
InChI InChI=InChI=1S/C192H244N75O98P19S19/c1-76-40-256(190(286)245-169(76)270)136-30-89(357-376(299,395)314-50-106-84(25-131(334-106)251-15-7-122(196)230-185(251)281)351-370(293,389)312-49-105-87(28-134(333-105)254-18-10-125(199)233-188(254)284)355-374(297,393)323-59-115-97(38-145(343-115)266-74-225-154-167(266)238-180(208)243-175(154)276)364-381(304,400)319-55-111-90(31-137(339-111)257-41-77(2)170(271)246-191(257)287)356-375(298,394)313-46-102-81(22-128(330-102)248-12-4-119(193)227-182(248)278)348-366(289,385)308-44-100-79(269)20-127(328-100)259-67-218-147-156(201)210-63-214-160(147)259)110(338-136)54-318-380(303,399)359-92-33-139(260-68-219-148-157(202)211-64-215-161(148)260)340-112(92)56-320-373(296,392)354-88-29-135(255-19-11-126(200)234-189(255)285)336-108(88)52-316-379(302,398)363-96-37-144(265-73-224-153-166(265)237-179(207)242-174(153)275)346-118(96)62-326-384(307,403)365-98-39-146(267-75-226-155-168(267)239-181(209)244-176(155)277)344-116(98)60-324-377(300,396)358-91-32-138(258-42-78(3)171(272)247-192(258)288)337-109(91)53-317-371(294,390)352-85-26-132(252-16-8-123(197)231-186(252)282)335-107(85)51-315-378(301,397)362-95-36-143(264-72-223-152-165(264)236-178(206)241-173(152)274)345-117(95)61-325-383(306,402)361-94-35-141(262-70-221-150-159(204)213-66-217-163(150)262)342-114(94)58-322-382(305,401)360-93-34-140(261-69-220-149-158(203)212-65-216-162(149)261)341-113(93)57-321-372(295,391)353-86-27-133(253-17-9-124(198)232-187(253)283)332-104(86)48-311-369(292,388)350-83-24-130(250-14-6-121(195)229-184(250)280)331-103(83)47-310-368(291,387)349-82-23-129(249-13-5-120(194)228-183(249)279)329-101(82)45-309-367(290,386)347-80-21-142(327-99(80)43-268)263-71-222-151-164(263)235-177(205)240-172(151)273/h4-19,40-42,63-75,79-118,127-146,268-269H,20-39,43-62H2,1-3H3,(H,289,385)(H,290,386)(H,291,387)(H,292,388)(H,293,389)(H,294,390)(H,295,391)(H,296,392)(H,297,393)(H,298,394)(H,299,395)(H,300,396)(H,301,397)(H,302,398)(H,303,399)(H,304,400)(H,305,401)(H,306,402)(H,307,403)(H2,193,227,278)(H2,194,228,279)(H2,195,229,280)(H2,196,230,281)(H2,197,231,282)(H2,198,232,283)(H2,199,233,284)(H2,200,234,285)(H2,201,210,214)(H2,202,211,215)(H2,203,212,216)(H2,204,213,217)(H,245,270,286)(H,246,271,287)(H,247,272,288)(H3,205,235,240,273)(H3,206,236,241,274)(H3,207,237,242,275)(H3,208,238,243,276)(H3,209,239,244,277)/t79-,80-,81-,82-,83-,84-,85-,86-,87-,88-,89-,90-,91-,92-,93-,94-,95-,96-,97-,98-,99+,100+,101+,102+,103+,104+,105+,106+,107+,108+,109+,110+,111+,112+,113+,114+,115+,116+,117+,118+,127+,128+,129+,130+,131+,132+,133+,134+,135+,136+,137+,138+,139+,140+,141+,142+,143+,144+,145+,146+,366?,367?,368?,369?,370?,371?,372?,373?,374?,375?,376?,377?,378?,379?,380?,381?,382?,383?,384?/m0/s1 Key:ZMJWRJKGPUDEOX-LMXUULCNSA-N

Pharmacology

ICAM-1 promotes the extravasation and activation of leukocytes (white blood cells), which is part of the inflammation process.[3] Alicaforsen inhibits the activity of ICAM-1 protein by degrading mRNA coding for it via an RNase-H based mechanism.[3]

It appears to have better efficacy as a topical medication than via systemic administration which is typical of antisense drugs.[3]

Clinical trials

The results of testing alicaforsen in Crohn's disease have largely been negative.[4][5]

Chemistry

Alicaforsen is a 20 unit phosphorothioate modified antisense oligonucleotide.[6]

History

Alicaforsen was discovered and initially developed by Isis Pharmaceuticals,[7] 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.[7]

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).[3]

Alicaforsen was licensed to Atlantic Healthcare in 2007.[8]

The use of the enema formulation of alicaforsen to treat pouchitis was granted orphan drug status in the US in 2008[9] and received the same in Europe in 2009.[10] The enema formulation of alicaforsen for pouchitis received FDA Fast Track designation [11]. However, in a subsequent Phase 3 clinical trial, the co-primary endpoints in the primary analysis (an adaptation of the Mayo Score of improvement in endoscopic remission and bowel frequency) were not met[12].

References

1. "Alicaforsen". AdisInsight. Retrieved 28 April 2017.
2. Greuter T, Rogler G (November 2017). "Alicaforsen in the treatment of pouchitis" (PDF). Immunotherapy. 9 (14): 1143–1152. doi:10.2217/imt-2017-0085. PMID 29067882.
3. 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. S2CID 19072006.
4. Jairath V, Khanna R, Feagan BG (August 2017). "Alicaforsen for the treatment of inflammatory bowel disease". Expert Opinion on Investigational Drugs. 26 (8): 991–997. doi:10.1080/13543784.2017.1349753. PMID 28670932. S2CID 26604386.
5. Reinisch W, Hung K, Hassan-Zahraee M, Cataldi F (August 2018). "Targeting Endothelial Ligands: ICAM-1/alicaforsen, MAdCAM-1". Journal of Crohn's & Colitis. 12 (suppl_2): S669–S677. doi:10.1093/ecco-jcc/jjy059. PMID 29757363.
6. "Recommended INN List 47" (PDF). WHO Drug Information. 16 (1). 2002.
7. Gewirtz AT, Sitaraman S (October 2001). "Alicaforsen. Isis Pharmaceuticals". Current Opinion in Investigational Drugs. 2 (10): 1401–6. PMID 11890355.
8. "Press Release: Atlantic Healthcare Completes Acquisition of ICAM-1 Portfolio of Late Stage Anti-inflammatory Drugs | Evaluate". Atlantic Healthcare via Evaluate. 2 April 2007.
9. "Alicaforsen US Orphan designation". Orphanet. Retrieved 28 April 2017.
10. "EU/3/09/641 Orphan drug designation". European Medicines Agency. 9 June 2009.
11. "Alicaforsen (AP 1007) - Product Profile". BioCentury. Retrieved 28 April 2017.
12. "Atlantic Healthcare Announces Results from Phase 3 Trial of Alicaforsen Enema for Orphan-Designated Pouchitis". Biospace. 31 July 2019. Retrieved 17 January 2020.

Further reading

• 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.