Alicaforsen

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;

Last updated January 30, 2023

Alicaforsen (trade name Camligo) is an antisense oligonucleotide therapeutic that targets the messenger RNA for the production of human ICAM-1 receptor^[1] and is being developed for the treatment of acute disease flares in moderate to severe Inflammatory Bowel Disease (IBD).

Alicaforsen inhibits ICAM-1 production, which is an important adhesion molecule involved in leukocyte migration and trafficking to the site of inflammation. Hitherto, alicaforsen has been granted orphan drug designation and is prescribed as an unlicensed medicine in accordance with international regulation, for the treatment of pouchitis and left-sided ulcerative colitis. Given the positive results from an open-label trial and one case series in patients with chronic refractory pouchitis, US FDA has agreed to a rolling submission for a license application for the treatment of pouchitis.

It was discovered by Ionis Pharmaceuticals (formerly Isis Pharmaceuticals) and in 2017 Atlantic Healthcare plc took over the development for chronic antibiotic refractory pouchitis in an enema formulation.^[2]

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

In a Phase III randomised clinical trial with 299 patients with steroid dependent Crohn's disease, clinical response was correlated with drug exposure, with significant efficacy versus placebo being observed in the subgroup with greatest area under the curve, hence pharmacodynamic modelling suggests that alicaforsen (ISIS 2302) may be an effective therapy at adequate dose levels.^[4]

In another placebo-controlled study with 331 subjects with active Crohn's Disease, alicaforsen failed to demonstrate efficacy in any of its primary outcome measures. However there was a suggestion of a therapeutic response in a sub-population with elevated serum CRP (C-reactive Protein) levels >2mg/dl. The differential response highlights the confounding symptoms of a large subset of subjects whose needs are apparently not being met by the current clinical trial design. There is a need for more specific biomarkers that clearly can identify disease severity and subtypes of Crohn's disease and can be used to monitor disease response objectively.^[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]

A post hoc meta-analysis of individual data of 200 patients from four phase 2 studies evaluating nightly alicaforsen 240 mg enema for six weeks showed that alicaforsen is effective in patients with active, distal, moderate to severe UC. The efficacy of alicaforsen was durable in these sub-groups, with significantly improved duration of clinical response with no maintenance therapy, suggesting a disease-modifying effect. This analysis suggests that alicaforsen enema could offer an effective, potentially durable response in moderate/severe distal active UC.^[8]

Alicaforsen was licensed to Atlantic Healthcare in 2007.^[9]

The use of the enema formulation of alicaforsen to treat pouchitis was granted orphan drug status in the US in 2008^[10] and received the same in Europe in 2009.^[11] The enema formulation of alicaforsen for pouchitis received FDA Fast Track designation.^[12] In a subsequent multicentre Phase 3 clinical trial in 138 subjects with Active, Chronic, Antibiotic Refractory Primary Idiopathic Pouchitis, showed a clinically relevant 34% remission in stool frequency with 8% delta vs placebo. However the co-primary endpoints (an adaptation of the Mayo Score of improvement in endoscopic remission and bowel frequency) were not met, perhaps due to the high discontinuation rate of 35% that compromised the sample size available for statistical analysis. Disallowing background maintenance therapies contributed to this high dropout rate in this challenging, heterogenous patient group. Further the appropriateness of endoscopy as a primary end point is questionable.

Atlantic Healthcare has supplied over 350 courses of alicaforsen enema treatment on a named patient / compassionate use programme. Clinical outcomes published in case series have confirmed durable disease remission in patients with Ulcerative Colitis with no treatment related SAEs.^[13]

• UC case series publications confirming prolonged duration of action:

Ø Digestive Diseases Journal (Nov 2017); 10/12 patients with left-sided UC/proctitis responded to treatment, with a median durable response of 18 weeks

Ø Gastrodagarna Congress, Sweden (May 2016); all 7 distal UC patients that completed treatment responded, 57% remained in remission for 5-20 months

Ø Irish Society of Gastroenterology (Nov 2014); reported remission achieved in 57% of patients with UC with a durable response ¹

No drug-related SAEs have been reported in any usage of alicaforsen enema

Related Research Articles

Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and anemia may also occur. Often, symptoms come on slowly and can range from mild to severe. Symptoms typically occur intermittently with periods of no symptoms between flares. Complications may include abnormal dilation of the colon (megacolon), inflammation of the eye, joints, or liver, and colon cancer.

Infliximab, a chimeric monoclonal antibody, sold under the brand name Remicade among others, is a medication used to treat a number of autoimmune diseases. This includes Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, and Behçet's disease. It is given by slow injection into a vein, typically at six- to eight-week intervals.

Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine, Crohn's disease and ulcerative colitis being the principal types. Crohn's disease affects the small intestine and large intestine, as well as the mouth, esophagus, stomach and the anus, whereas ulcerative colitis primarily affects the colon and the rectum.

Colitis is swelling or inflammation of the large intestine (colon). Colitis may be acute and self-limited or long-term. It broadly fits into the category of digestive diseases.

In medicine, the ileal pouch–anal anastomosis (IPAA), also known as restorative proctocolectomy (RPC), ileal-anal reservoir (IAR), an ileo-anal pouch, ileal-anal pullthrough, or sometimes referred to as a J-pouch, S-pouch, W-pouch, or a pelvic pouch, is an anastomosis of a reservoir pouch made from ileum to the anus, bypassing the former site of the colon in cases where the colon and rectum have been removed. The pouch retains and restores functionality of the anus, with stools passed under voluntary control of the person, preventing fecal incontinence and serving as an alternative to a total proctocolectomy with ileostomy.

Pouchitis is an umbrella term for inflammation of the ileal pouch, an artificial rectum surgically created out of ileum in patients who have undergone a proctocolectomy or total colectomy. The ileal pouch-anal anastomosis is created in the management of patients with ulcerative colitis, indeterminate colitis, familial adenomatous polyposis, cancer, or rarely, other colitides.

Management of Crohn's disease involves first treating the acute symptoms of the disease, then maintaining remission. Since Crohn's disease is an immune system condition, it cannot be cured by medication or surgery. Treatment initially involves the use of medications to eliminate infections and reduce inflammation. Surgery may be required for complications such as obstructions or abscesses, or if the disease does not respond to drugs within a reasonable time. However, surgery cannot cure Crohn's disease. It involves removing the diseased part of the intestine and rejoining the healthy ends, but the disease tends to recur after surgery.

Management of ulcerative colitis involves first treating the acute symptoms of the disease, then maintaining remission. Ulcerative colitis is a form of colitis, a disease of the intestine, specifically the large intestine or colon, that includes characteristic ulcers, or open sores, in the colon. The main symptom of active disease is usually diarrhea mixed with blood, of gradual onset which often leads to anaemia. Ulcerative colitis is, however, a systemic disease that affects many parts of the body outside the intestine.

Biological therapy, the use of medications called biopharmaceuticals or biologics that are tailored to specifically target an immune or genetic mediator of disease, plays a major role in the treatment of inflammatory bowel disease. Even for diseases of unknown cause, molecules that are involved in the disease process have been identified, and can be targeted for biological therapy. Many of these molecules, which are mainly cytokines, are directly involved in the immune system. Biological therapy has found a niche in the management of cancer, autoimmune diseases, and diseases of unknown cause that result in symptoms due to immune related mechanisms.

Ustekinumab, sold under the brand name Stelara is a monoclonal antibody medication developed by Janssen Pharmaceuticals, for the treatment of Crohn's disease, ulcerative colitis, plaque psoriasis and psoriatic arthritis, targeting both IL-12 and IL-23.

Vedolizumab, sold under the brand name Entyvio, is a monoclonal antibody medication developed by Millennium Pharmaceuticals, Inc. for the treatment of ulcerative colitis and Crohn's disease. It binds to integrin α₄β₇. Blocking the α₄β₇ integrin results in gut-selective anti-inflammatory activity.

Budesonide, sold under the brand name Pulmicort among others, is a medication of the corticosteroid type. It is available as an inhaler, nebulization solution, pill, nasal spray, and rectal forms. The inhaled form is used in the long-term management of asthma and chronic obstructive pulmonary disease (COPD). The nasal spray is used for allergic rhinitis and nasal polyps. The pills in a delayed release form and rectal forms may be used for inflammatory bowel disease including Crohn's disease, ulcerative colitis, and microscopic colitis.

Guselkumab, sold under the brand name Tremfya, is a monoclonal antibody against interleukin-23 used for the treatment of plaque psoriasis.

<span class="mw-page-title-main">Filgotinib</span>

Filgotinib, sold under the brand name Jyseleca, is a medication used for the treatment of rheumatoid arthritis (RA). It was developed by the Belgian-Dutch biotech company Galapagos NV.

<span class="mw-page-title-main">Ozanimod</span> Medication

Ozanimod, sold under the brand name Zeposia, is an immunomodulatory medication for the treatment of relapsing multiple sclerosis and ulcerative colitis. It acts as a sphingosine-1-phosphate (S1P) receptor agonist, sequestering lymphocytes to peripheral lymphoid organs and away from their sites of chronic inflammation.

<span class="mw-page-title-main">Upadacitinib</span> Chemical compound (medication)

Upadacitinib, sold under the brand name Rinvoq, is a Janus kinase (JAK) inhibitor medication for the treatment of moderately to severely active rheumatoid arthritis and psoriatic arthritis in adults where methotrexate did not work well or could not be tolerated. It was approved for medical use in the United States and in the European Union in 2019, and was developed by the biotech company AbbVie. On January 14, 2022 Rinvoq received FDA approval for treating treatment refractory atopic dermatitis.

Abivax SA is a French clinical-stage, publicly traded biotechnology company harnessing the immune system to develop novel treatments against inflammatory diseases, viral diseases and cancer. The company is headquartered in Paris, France and closely cooperates with the CNRS Collaborative Laboratory in Montpellier, France.

Darvadstrocel, sold under the brand name Alofisel, is a medication to treat complex perianal fistulas in adults with non-active/mildly active luminal Crohn's disease, when fistulas have shown an inadequate response to at least one conventional or biologic therapy. It contains mesenchymal stem cells from fat tissue of adult donors.

Shomron Ben-Horin is an Israeli physician, a co-founder & Chief Medical Officer of Evinature, and professor of medicine at the Tel-Aviv University.

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References

↑ "Alicaforsen". AdisInsight. Retrieved 28 April 2017.
↑ 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. S2CID 31681751.
1 2 3 4 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.
↑ Yacyshyn, B. R.; Chey, W. Y.; Goff, J.; Salzberg, B.; Baerg, R.; Buchman, A. L.; Tami, J.; Yu, R.; Gibiansky, E.; Shanahan, W. R.; ISIS 2302-CS9 Investigators (2002). "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. 51 (1): 30–36. doi:10.1136/gut.51.1.30. PMC 1773277 . PMID 12077088.
↑ Yacyshyn, Bruce; Chey, William Y.; Wedel, Mark K.; Yu, Rosie Z.; Paul, David; Chuang, Emil (2007). "A Randomized, Double-Masked, Placebo-Controlled Study of Alicaforsen, an Antisense Inhibitor of Intercellular Adhesion Molecule 1, for the Treatment of Subjects with Active Crohn's Disease". Clinical Gastroenterology and Hepatology. 5 (2): 215–220. doi: 10.1016/j.cgh.2006.11.001 . PMID 17296530.
↑ "Recommended INN List 47" (PDF). WHO Drug Information. 16 (1). 2002.
1 2 Gewirtz AT, Sitaraman S (October 2001). "Alicaforsen. Isis Pharmaceuticals". Current Opinion in Investigational Drugs. 2 (10): 1401–6. PMID 11890355.
↑ Vegter, S.; Tolley, K.; Wilson Waterworth, T.; Jones, H.; Jones, S.; Jewell, D. (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): 284–293. doi: 10.1111/apt.12369 . PMID 23750909.
↑ "Press Release: Atlantic Healthcare Completes Acquisition of ICAM-1 Portfolio of Late Stage Anti-inflammatory Drugs | Evaluate". Atlantic Healthcare via Evaluate. 2 April 2007.
↑ "Alicaforsen US Orphan designation". Orphanet. Retrieved 28 April 2017.
↑ "EU/3/09/641 Orphan drug designation". European Medicines Agency. 9 June 2009.
↑ "Alicaforsen (AP 1007) - Product Profile". BioCentury. Retrieved 28 April 2017.
↑ "Heetun Z, Gibson D, Keegan D, Byrne K, Mulcahy HE, Cullen G, Doherty G. Alicaforsen retention enema induces long-term remission in patients with ulcerative colitis". Irish Soc Gastroenterol. November 2014.