Reslizumab, sold under the brand names Cinqair and Cinqaero, is a
humanized monoclonal antibody
Humanized antibodies are antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans. The process of "humanization" is usually applied to monoclonal ant ...
against human
interleukin-5
Interleukin 5 (IL-5) is an interleukin produced by type-2 T helper cells and mast cells.
Function
Through binding to the interleukin-5 receptor, interleukin 5 stimulates B cell growth and increases immunoglobulin secretion—primarily Ig ...
(IL-5). Reslizumab binds specifically to IL-5, a key
cytokine
Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling.
Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
responsible for the differentiation, maturation, recruitment and activation of human
eosinophil
Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along wi ...
s. By binding to human IL-5, it blocks its biological function; consequently survival and activity of eosinophils are reduced. The benefits with reslizumab are its ability to reduce the exacerbation rate and improve lung function and asthma-related quality of life in patients with severe
eosinophilic asthma
Asthma is a common long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheez ...
(with blood eosinophil count ≥ 400 cells/μL) and with at least one previous asthma exacerbation in the preceding year. The most common side effects are increased blood
creatine phosphokinase
Creatine kinase (CK), also known as creatine phosphokinase (CPK) or phosphocreatine kinase, is an enzyme () expressed by various tissues and cell types. CK catalyses the conversion of creatine and uses adenosine triphosphate (ATP) to create phos ...
,
myalgia
Myalgia or muscle pain is a painful sensation evolving from muscle tissue. It is a symptom of many diseases. The most common cause of acute myalgia is the overuse of a muscle or group of muscles; another likely cause is viral infection, espec ...
and
anaphylactic reactions.
In March 2016, the US
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA) approved reslizumab (Cinqair) for use with other asthma medicines for the maintenance treatment of severe asthma in people aged 18 years and older.
It is approved for people who have a history of severe asthma attacks (
exacerbation
In medicine, an exacerbation is the worsening of a disease or an increase in its symptom
Signs and symptoms are diagnostic indications of an illness, injury, or condition.
Signs are objective and externally observable; symptoms are a person' ...
s) despite receiving their current asthma medicines.
[ ]
In June 2016, the
European Medicines Agency
The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...
recommended the granting of a marketing authorisation for reslizumab (Cinqaero) intended as add-on treatment in adults with severe eosinophilic asthma.
Reslizumab is supplied as a refrigerated, sterile, single-use, preservative-free solution for intravenous infusion. The reslizumab solution is a slightly hazy/opalescent, slightly yellow liquid and is supplied as 100 mg in a 10 mL glass vial. Each single-use vial of reslizumab is formulated as 10 mg/mL reslizumab in an aqueous solution containing 2.45 mg/mL sodium acetate trihydrate, 0.12 mg/mL glacial acetic acid, and 70 mg/mL
sucrose
Sucrose, a disaccharide, is a sugar composed of glucose and fructose subunits. It is produced naturally in plants and is the main constituent of white sugar. It has the molecular formula .
For human consumption, sucrose is extracted and refined ...
, with a pH of 5.5.
Medical uses
Eosinophilic asthma
Reslizumab was first used for eosinophilic asthma in 2008. In a 106-patient, phase II
clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...
, the researchers showed reslizumab was effective in reducing
sputum
Sputum is mucus that is coughed up from the lower airways (the trachea and bronchi). In medicine, sputum samples are usually used for a naked-eye examination, microbiological investigation of respiratory infections, and Cytopathology, cytological ...
eosinophils. Furthermore, the patients receiving reslizumab showed improvements in airway function, and a general trend toward greater asthma control than those receiving
placebo
A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures.
Placebos are used in randomized clinical trials ...
was observed. A large, 981-patient, phase III clinical trial showed that reslizumab was effective at improving lung function, asthma control, and quality of life in comparison to placebo. These results led to the FDA approval for the maintenance treatment of severe asthma in patients aged 18 years and older, with an eosinophilic phenotype on March 23, 2016.
Adverse effects
Common adverse effects include:
*
oropharyngeal
The pharynx (: pharynges) is the part of the throat behind the mouth and nasal cavity, and above the esophagus and trachea (the tubes going down to the stomach and the lungs respectively). It is found in vertebrates and invertebrates, though its ...
pain
Less common adverse effects include:
* musculoskeletal pain
* neck pain
* muscle spasms
* extremity pain
* muscle fatigue
* anaphylaxis
*
malignancy
Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer.
A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not ...
The most common adverse effect of reslizumab was oropharyngeal (mouth and throat) pain. According to the phase III clinical trials data, oropharyngeal pain occurred in ≥2% of individuals along with elevated baseline creatine phosphokinase (CPK), which was more common in patients treated with reslizumab versus placebo. Myalgia was also reported more in patients in the reslizumab 3 mg/kg group versus the placebo group as well as some musculoskeletal adverse reactions. Lastly, some serious adverse reactions that occurred in subjects treated with reslizumab but not in those treated with placebo included anaphylaxis and malignancy.
Pharmacology
Mechanism of action
Reslizumab is an interleukin IL-5 antagonist monoclonal antibody. IL-5 is the major cytokine responsible for the growth and differentiation, recruitment, activation, and survival of eosinophils. Eosinophils play a role in the mediation of inflammation in the airways. Eosinophilic asthma is a phenotype of asthma that is characterized by the higher than normal presence of eosinophils in the lung and sputum. It has been shown that the numbers of eosinophils in the blood and bronchial fluid can correlate with asthma severity. Reslizumab binds to IL-5 with a dissociation constant of 81
pM and inhibiting IL-5 signaling, which reduces the production and survival of eosinophils. However, the mechanism of reslizumab action in asthma has not been definitively established.
Pharmacodynamics
Reductions in blood eosinophil counts were observed following the first dose of reslizumab and maintained through 52 weeks of treatment. In phase III clinical trials, mean eosinophil counts were 696 cells/
μL
The litre ( Commonwealth spelling) or liter (American spelling) (SI symbols L and l, other symbol used: ℓ) is a metric unit of volume. It is equal to 1 cubic decimetre (dm3), 1000 cubic centimetres (cm3) or 0.001 cubic metres (m3). A cubic ...
(n=245) and 624 cells/μL (n=244) at baseline. Following 52 weeks of reslizumab treatment, eosinophil cells were counted and were reported to be 55 cells/μL (92% reduction, n=212) and 496 cells/μL (21% reduction, n=212) for the reslizumab and placebo treatment groups, respectively. Furthermore, eosinophil count returned towards baseline in those reslizumab-treated patients who completed a follow-up assessment (n=35, 480 cells/μL), approximately 120 days after the last dose of reslizumab. Therefore, reductions of blood eosinophils were related to reslizumab serum levels.
Pharmacokinetics
The
pharmacokinetic
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 describing how the body affects a specific subs ...
characteristics of reslizumab are similar across the children and adults. Peak serum concentrations are observed at the end of infusion and declines in a biphasic manner. The mean observed accumulation ratio of reslizumab following multiple doses of administration ranged from 1.5 to 1.9-fold. Reslizumab has a
volume of distribution
In pharmacology, the volume of distribution (VD, also known as apparent volume of distribution, literally, ''volume of dilution'') is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same c ...
of approximately 5 L, clearance of approximately 7 mL/hour, and a half-life of about 24 days. Reslizumab is degraded by enzymatic
proteolysis
Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Protein degradation is a major regulatory mechanism of gene expression and contributes substantially to shaping mammalian proteomes. Uncatalysed, the hydrolysis o ...
into small
peptide
Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...
s and
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s, as are other monoclonal antibodies.
History
Reslizumab was initially developed by Chuan-Chu Chou at
Schering-Plough
Schering-Plough Corporation was an American pharmaceutical company. It was originally the U.S. subsidiary of the German company Schering AG, which was founded in 1851 by Ernst Christian Friedrich Schering. As a result of nationalization, it becam ...
and was previously known as SCH-55700. In 1993, Chou and his group at Schering-Plough were granted the patent for the design, cloning and expression of the reslizumab drug.
Ception Therapeutics acquired the drug and continued its development under the name CTx55700. In 2010, Ception Therapeutics was acquired by
Cephalon
Cephalon, Inc. was an American biopharmaceutical company co-founded in 1987 by pharmacologist Frank Baldino Jr., Frank Baldino, Jr., neuroscientist Michael Lewis, and organic chemist James C. Kauer—all three former scientists with the DuPont ...
for $250 million and the drug continued under development under the codename CEP-38072. In 2011,
Teva Pharmaceuticals
Teva Pharmaceutical Industries Ltd. (also known as Teva Pharmaceuticals) is an Israeli multinational Pharmaceutical industry, pharmaceutical company. Teva specializes primarily in generic drugs, but other business interests include branded-drug ...
acquired Cephalon for $6.8 billion and continued the development of reslizumab.
References
{{Portal bar , Medicine
Anti-interleukin monoclonal antibodies
Antiasthmatic drugs