Reslizumab

Reslizumab is a humanized monoclonal antibody against human interleukin-5 (IL-5).[1] Reslizumab binds specifically to IL-5, a key cytokine responsible for the differentiation, maturation, recruitment and activation of human eosinophils. 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 (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, myalgia and anaphylactic reactions.[2]

Reslizumab
Monoclonal antibody
TypeWhole antibody
SourceHumanized (from rat)
TargetIL-5
Clinical data
Trade namesCinqair (US), Cinqaero (EU)
AHFS/Drugs.comMonograph
License data
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • US: ℞-only
  • EU: Rx-only
Pharmacokinetic data
MetabolismProteolysis
Elimination half-life~24 days
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
 NY (what is this?)  (verify)

The FDA approved reslizumab (US trade name Cinqair) for use with other asthma medicines for the maintenance treatment of severe asthma in patients aged 18 years and older on 23 March 2016. Cinqair is approved for patients who have a history of severe asthma attacks (exacerbations) despite receiving their current asthma medicines.[3]

The European Medicines Agency recommended the granting of a marketing authorisation for reslizumab (EU trade name Cinqaero) intended as add-on treatment in adult patients with severe eosinophilic asthma on 23 June 2016.[2]

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, with a pH of 5.5.[4]

Medical uses

Eosinophilic asthma

Reslizumab was first used for eosinophilic asthma in 2008. In a 106-patient, phase II clinical trial, the researchers showed reslizumab was effective in reducing sputum eosinophils. Furthermore, the patients receiving reslizumab showed improvements in airway function, and a general trend toward greater asthma control than those receiving placebo was observed.[5] 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.[6]

Adverse effects

Common adverse effects include:

Less common adverse effects include:

  • musculoskeletal pain
  • neck pain
  • muscle spasms
  • extremity pain
  • muscle fatigue
  • anaphylaxis
  • malignancy

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.[7]

Pharmacology

Mechanism of action

Reslizumab is an interleukin-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.[8] 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.[6]

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 (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.[9]

Pharmacokinetics

The pharmacokinetic 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 of approximately 5 L, clearance of approximately 7 mL/hour, and a half-life of about 24 days. Reslizumab is degraded by enzymatic proteolysis into small peptides and amino acids, as are other monoclonal antibodies.[10]

History

Reslizumab was initially developed by Chuan-Chu Chou at Schering-Plough 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.[11] Ception Therapeutics acquired the drug and continued its development under the name CTx55700. In 2010, Ception Therapeutics was acquired by Cephalon for $250 million and the drug continued under development under the codename CEP-38072.[12] In 2011, Teva Pharmaceuticals acquired Cephalon for $6.8 billion and continued the development of reslizumab.[13]

References
  1. Walsh GM (June 2009). "Reslizumab, a humanized anti-IL-5 mAb for the treatment of eosinophil-mediated inflammatory conditions". Current Opinion in Molecular Therapeutics. 11 (3): 329–36. PMID 19479666.
  2. "Cinqaero : reslizumab" (PDF). Ema.europa.eu. Retrieved 2016-11-22.
  3. "Press Announcements - FDA approves Cinqair to treat severe asthma". Food and Drug Administration. 2019-09-10.
  4. "PULMONARY-ALLERGY DRUGS ADVISORY COMMITTEE (PADAC) MEETING" (PDF). Fda.gov. Retrieved 2016-11-22.
  5. Castro M, Mathur S, Hargreave F, Boulet LP, Xie F, Young J, et al. (November 2011). "Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study". American Journal of Respiratory and Critical Care Medicine. 184 (10): 1125–32. doi:10.1164/rccm.201103-0396OC. PMID 21852542.
  6. "CENTER FOR DRUG EVALUATION AND RESEARCH : APPLICATION NUMBER : 761033Orig1s000" (PDF). Accessdata.fda.gov. Retrieved 2016-11-22.
  7. "CENTER FOR DRUG EVALUATION AND RESEARCH : APPLICATION NUMBER : 761033Orig1s000" (PDF). Accessdata.fda.gov. Retrieved 2016-11-22.
  8. Bousquet J, Chanez P, Lacoste JY, Barneon G, Ghavanian N, Enander I, Venge P, Ahlstedt S, Simony-Lafontaine J, Godard P, et al.. Eosinophilic inflammation in asthma. N Engl J Med 1990;323:1033–1039.DOI: 10.1056/NEJM199010113231505
  9. "HIGHLIGHTS OF PRESCRIBING INFORMATION : CINQAIR" (PDF). Accessdata.fda.gov. Retrieved 2016-11-22.
  10. Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, Murphy K, Maspero JF, O'Brien C, Korn S (May 2015). "Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials". The Lancet. Respiratory Medicine. 3 (5): 355–66. doi:10.1016/S2213-2600(15)00042-9. PMID 25736990.
  11. WO 1993016184, "Design, cloning and expression of humanized monoclonal antibodies against human interleukin-5", published 19 August 1993, assigned to Schering Corporation
  12. "Cephalon pays $250M to snare Ception Therapeutics". FierceBiotech.com. 2010-02-23. Retrieved 2016-11-22.
  13. "Teva to Acquire Cephalon in $6.8 Billion Transaction". Tevapharm.com. Retrieved 2016-11-22.
  • "Reslizumab". Drug Information Portal. U.S. National Library of Medicine.
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