Custirsen, aliases including custirsen sodium, OGX-011, and CC-8490, is an investigational drug that was under clinical testing for the treatment of cancer. It is an antisense oligonucleotide (ASO) targeting

clusterin Clusterin (apolipoprotein J) is a 75-80 kDa disulfide-linked heterodimeric protein associated with the clearance of cellular debris and apoptosis. In humans, clusterin is encoded by the ''CLU'' gene on chromosome 8. CLU is a molecular chaperon ...

expression. In metastatic prostate cancer, custirsen showed no benefit in improving over all survival. Custirsen was developed through a collaboration of OncoGenex Pharmaceuticals Inc. and Isis. In 2009, OncoGenex Pharmaceuticals Inc. and

Teva Pharmaceutical Industries Teva Pharmaceutical Industries Ltd. (also known as Teva Pharmaceuticals) is an Israeli multinational pharmaceutical company with headquarters in Tel Aviv, Israel. It specializes primarily in generic drugs, but other business interests include ...

Ltd agreed to develop and commercialise Custirsen.

Mechanism of action

An antisense oligonucleotide (ASO) is a single-strand DNA sequence complementary to a desired messenger RNA (mRNA) sequence.

Antisense therapy Antisense therapy is a form of treatment that uses antisense oligonucleotides (ASOs) to target messenger RNA (mRNA). ASOs are capable of altering mRNA expression through a variety of mechanisms, including ribonuclease H mediated decay of the pre ...

targets gene sequences using antisense oligonucleotides by binding the ASO to the mRNA strand. This creates an inhibitory complex that reduces plasma protein levels by preventing

translation Translation is the communication of the Meaning (linguistic), meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The ...

. Custirsen is a second-generation phosphorothioate antisense oligonucleotide. Phosphorothioates are oligonucleotides with a sulfur ion replacing an oxygen molecule in the chain. They have high antisense activity due to their increased

chirality Chirality is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is distinguishable from i ...

, nuclease stability, and solubility. Second-generation oligonucleotides are highly specific to the target mRNA sequence, increasing the

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Part ...

of the compound. Custirsen acts as an anti-cancer drug by binding to the mRNA initiation site of the

gene, reducing

protein plasma concentrations. The synthetic addition of a 2’-methocyethyl on each nucleotide bookending the phosphorothioate backbone causes: * An increased affinity for the RNA54 targeted gene sequence * An increased resistance to digestive

nuclease A nuclease (also archaically known as nucleodepolymerase or polynucleotidase) is an enzyme capable of cleaving the phosphodiester bonds between nucleotides of nucleic acids. Nucleases variously effect single and double stranded breaks in their t ...

s * Decreased toxicity * Increased tissue

half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable at ...

by approximately seven days * Decrease adverse side effects, enabling more potent concentrations Clusterin is

upregulation In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary pr ...

in many tumours including prostate, breast, non-small cell lung, ovary and colorectal. It has been linked with the development of aggressive tumours by protecting the cells from apoptosis. It is also upregulated in response to standard cancer treatments including

chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...

androgen deprivation therapy Androgen deprivation therapy (ADT), also called androgen suppression therapy, is an antihormone therapy whose main use is in treating prostate cancer. Prostate cancer cells usually require androgen hormones, such as testosterone, to grow. ADT re ...

, and

radiation therapy Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a therapy using ionizing radiation, generally provided as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Rad ...

. This resistance is caused by the inhibition of the pro-apoptotic BLC2 gene, prevention of protein aggregation, and increased NF-KB. The anti-apoptotic activity of clusterin in aiding tumour growth is due to interactions with protein complexes. These include: * The binding of clusterin to a structurally altered Ku70–Bax complex * Regulation of Nuclear Factor (NF)-κB activity and signalling * Kinase ERK and AKT Kinase * Promoted epithelial-mesenchymal transition

Pharmacokinetics

A meta-analysis study evaluated 5588 Custirsen plasma concentrations from 631 subjects over seven clinical studies. Subjects with cancer received multiple doses between 40 mg and 640 mg

intravenously Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

over two hours, whilst healthy subjects received either a single or double dose at 320 mg-640 mg. Schematic-representation-of-a-three-compartment-model

Schematic-representation-of-a-three-compartment-model

The

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...

of Custirsen was described by a three-compartment model with first-order elimination where: * Three-compartment model refers to the distribution of the drug. The body is divided into central, peripheral 1, and peripheral 2. Distribution rate of the drug is respectively highest to lowest. * First-order elimination describes the elimination rate of the drug. In first-order kinetics, elimination is proportional to concentration of drug present in the body. For a representative sixty-six year old with a body mass (kg) of eighty-two and a blood Custirsen level of 0.933 mg/dL, the estimated parameter values were: * Clearance (CL) = 2.36 * Central Volume of Distribution (V) = 6.08 * Peripheral Volume of Distribution (V ) = 1.13 * Volume of the Second Peripheral Compartment (V ) = 15.8

Side effects

A phase I study investigated the maximum tolerated dose of Custirsen in patients with recurrent or refractory high-grade gliomas. The recommended and safe dosing of Custirsen was determined in a Phase I same-dose escalation scheme involving forty patients with tumours known to upregulate clusterin with metastatic or locally recurrent disease (prostate, ovary, breast). Custirsen was infused intravenously on days 1, 3, and 5, with weekly dosing starting on day 8 for four weeks. The drug was increasingly administered in six dose cohorts of 40 mg, 80 mg, 160 mg, 320 mg, 480 mg, and 640 mg. The results found that the recommended dose of Custirsen was 640 mg, with maximum decrease of clusterin blood plasma occurring at this dose. Researchers found a statistically significant increase in the apoptotic index in

prostatectomy Prostatectomy (from the Greek , "prostate" and , "excision") as a medical term refers to the surgical removal of all or part of the prostate gland. This operation is done for benign conditions that cause urinary retention, as well as for prosta ...

specimens. This study provided the dosing framework for further studies into Custirsen, determining 640 mg as a tolerable and biologically active dose. In this study, no dose-limiting toxicities were reported in doses up to and including 480 mg. For patients who received the 640 mg dose, the following adverse reactions were present: *

Thrombocytopenia Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients a ...

Anaemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...

Leukopenia Leukopenia () is a decrease in the number of leukocytes (WBC). Found in the blood, they are the white blood cells, and are the body's primary defense against an infection. Thus the condition of leukopenia places individuals at increased risk of i ...

* Fever * Fatigue * Rigors *

Alopecia Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scarr ...

Anorexia Anorexia nervosa, often referred to simply as anorexia, is an eating disorder characterized by low weight, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. ''Anorexia'' is a term of Gre ...

In patients who received combined treatment with Docetaxel, four of sixteen patients experienced dose-limiting toxicities at 640 mg: *

Dyspnea Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing disc ...

Pleural effusion A pleural effusion is accumulation of excessive fluid in the pleural space, the potential space that surrounds each lung. Under normal conditions, pleural fluid is secreted by the parietal pleural capillaries at a rate of 0.6 millilitre per ...

Neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteri ...

* Fatigue *

Mucositis Mucositis is the painful inflammation and ulceration of the mucous membranes lining the digestive tract, usually as an adverse effect of chemotherapy and radiotherapy treatment for cancer. Mucositis can occur anywhere along the gastrointestinal ...

Phase III Studies

Phase III studies into the effectiveness of the combinational treatment of Custirsen and chemotherapy as a treatment of metastatic-castration-resistant prostate cancer and also Custirsen as a biomarker for clusterin are currently under evaluation. The Phase III SYNERGY trial looked into the addition of Custirsen to first-line Docetaxel and Prednisone chemotherapy, concluding that there was no marked increased survival rate compared to the Custirsen-independent treatment group. Researchers also found no difference in the progressive rates of the cancer. Contrasting previous research, subjects in the Custirsen group had more adverse reactions to the treatment than the Custirsen-independent group. The findings of this clinical study contradict the results found in previous studies. However, researchers suggested further studies into patients with metastatic-castration-resistant prostate cancer whom have poor prognostic features, believing there is a therapeutic effect of Custirsen in individuals with this feature of the disease.

References

{{reflist Antineoplastic and immunomodulating drugs Cancer treatments Antisense RNA Therapeutic gene modulation