Alicaforsen (trade name Camligo) is an

antisense In molecular biology and genetics, the sense of a nucleic acid molecule, particularly of a strand of DNA or RNA, refers to the nature of the roles of the strand and its complement in specifying a sequence of amino acids. Depending on the context, ...

oligonucleotide therapeutic that targets the

messenger RNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...

for the production of human

ICAM-1 ICAM-1 (Intercellular adhesion molecule, Intercellular Adhesion Molecule 1) also known as CD54 (Cluster of Differentiation 54) is a protein that in humans is encoded by the ''ICAM1'' gene. This gene encodes a cell surface glycoprotein which is ty ...

receptor and is being developed for the treatment of acute disease flares in moderate to severe

Inflammatory Bowel Disease Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine, with Crohn's disease and ulcerative colitis (UC) being the principal types. Crohn's disease affects the small intestine and large intestine ...

(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 Pouchitis is an umbrella term for inflammation of the ileo-anal pouch, ileal pouch, an artificial rectum surgically created out of ileum (the last section of the small intestine) in patients who have undergone a proctocolectomy or total colectomy ...

and left-sided

ulcerative colitis Ulcerative colitis (UC) is one of the two types of inflammatory bowel disease (IBD), with the other type being Crohn's disease. It is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary sympto ...

. Given the positive results from an open-label trial and one case series in patients with chronic refractory pouchitis,

US FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

has agreed to a rolling submission for a license application for the treatment of pouchitis. It was discovered by

Ionis Pharmaceuticals Ionis Pharmaceuticals, Inc. is a biotechnology company based in Carlsbad, California, that specializes in discovering and developing RNA-targeted therapeutics. The company has three commercially approved medicines: Spinraza ( Nusinersen), Tegse ...

(formerly Isis Pharmaceuticals) and in 2017 Atlantic Healthcare plc took over the development for chronic antibiotic refractory

in an

enema An enema, also known as a clyster, is the rectal administration of a fluid by injection into the Large intestine, lower bowel via the anus.Cullingworth, ''A Manual of Nursing, Medical and Surgical'':155 The word ''enema'' can also refer to the ...

formulation.

Pharmacology

ICAM-1 promotes the

extravasation Extravasation is the leakage of a fluid out of its contained space into the surrounding area, especially blood or blood cells from vessels. In the case of inflammation, it refers to the movement of white blood cells through the capillary wall, ...

and activation of

leukocytes White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...

(white blood cells), which is part of the

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

process. Alicaforsen inhibits the activity of

protein by degrading

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...

coding for it via an RNase-H based mechanism. It appears to have better efficacy as a

topical medication A topical medication is a medication that is applied to a particular place on or in the body. Most often topical medication means application to body surface area, body surfaces such as the skin or mucous membranes to treat ailments via a large ...

than via

systemic administration Systemic administration is a route of administration of medication, nutrition or other substance into the circulatory system so that the entire body is affected. Administration can take place via enteral administration (absorption of the drug throu ...

which is typical of antisense drugs.

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. 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.

Chemistry

Alicaforsen is a 20 unit phosphorothioate modified antisense

oligonucleotide Oligonucleotides are short DNA or RNA molecules, oligomers, that have a wide range of applications in genetic testing, Recombinant DNA, research, and Forensic DNA, forensics. Commonly made in the laboratory by Oligonucleotide synthesis, solid-phase ...

History

Alicaforsen was discovered and initially developed by Isis Pharmaceuticals, which changed its name to

in 2015. Isis partnered on development of alicaforsen with

Boehringer Ingelheim C.H. Boehringer Sohn AG & Co. is the parent company of the Boehringer Ingelheim group, which was founded in 1885 by Albert Boehringer (1861–1939) in Ingelheim am Rhein, Germany. As of 2018, Boehringer Ingelheim is one of the world's List of la ...

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 Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea, fever, abdominal distension, and weight loss. Complications outside of the ...

and development of those formulations in that indication was terminated; development for

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...

was terminated the same year and development in kidney transplant apparently ceased as well at that time. The company reformulated alicaforsen as an

and three small trials were published between 2004 and 2006, an open label trial in chronic

and two randomized trials in

(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). 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. Alicaforsen was licensed to Atlantic Healthcare in 2007. The use of the enema formulation of alicaforsen to treat

was granted

orphan drug An orphan drug is a medication, pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by th ...

status in the US in 2008 and received the same in Europe in 2009. The enema formulation of alicaforsen for

received

FDA Fast Track Fast track is a designation by the United States Food and Drug Administration (FDA) of an investigational drug for expedited review to facilitate development of drugs that treat a serious or life-threatening condition and fill an unmet medical ne ...

designation. In a subsequent multicentre Phase 3 clinical trial in 138 subjects with Active, Chronic, Antibiotic Refractory Primary Idiopathic

Pouchitis Pouchitis is an umbrella term for inflammation of the ileo-anal pouch, ileal pouch, an artificial rectum surgically created out of ileum (the last section of the small intestine) in patients who have undergone a proctocolectomy or total colectomy ...

, 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. • 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

Pharmacology

Clinical trials

Chemistry

History

References

Further reading