Tocilizumab

from Wikipedia, the free encyclopedia
Tocilizumab
Mass / length primary structure approx. 145 kDa
Identifier
External IDs
Drug information
ATC code L04 AC07
Drug class Immunosuppressants

Tocilizumab ( trade names RoActemra ® (EU), Actemra ® (CH); manufacturer Hoffmann-La Roche ) is a humanized, monoclonal antibody against the interleukin-6 (IL-6) receptor for the treatment of rheumatoid arthritis (RA) and the most severe Form of childhood rheumatism, systemic juvenile idiopathic arthritis (sJIA; Syn. Still's disease). Interleukin-6 is a cytokine that regulates inflammatory reactions in the human body and is increasingly produced in RA.

Clinical information

application areas

Rheumatoid arthritis

Tocilizumab, in combination with methotrexate (MTX), is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have inadequately responded to previous treatment with one or more disease-modifying anti-inflammatory drugs ( DMARDs , also basic therapeutics ) or tumor necrosis factor (TNF) - Addressed inhibitors or did not tolerate them. Tocilizumab can be administered as monotherapy in these patients if there is an intolerance to MTX or if continuation of therapy with MTX appears inappropriate. Tocilizumab is also approved in combination with MTX to reduce the progression of radiologically detectable structural joint damage and improve physical function.

Systemic juvenile idiopathic arthritis (sJIA)

Tocilizumab is approved for the treatment of systemic juvenile idiopathic arthritis (sJIA, Still's disease) in children aged two years and over. The approval by the American FDA was granted in April 2011. The European Commission granted approval in August 2011.

Tocilizumab can be administered as monotherapy if there is an intolerance to MTX or if therapy with MTX seems inappropriate. The approval in Europe is largely based on the results of the TENDER study.

Giant cell arteritis

Tocilizumab was also able to show a very good effect on giant cell arteritis , the most common systemic vasculitis in the USA , and was approved by the American FDA as the first specific drug in May 2017, two months before the phase III study was officially published Approved for the treatment of giant cell arteritis as a break-through therapy in a fast-track procedure with a shortened review . In the randomized placebo -controlled , double-blind - study were 251 patients at least 50 years old (75% female, 97% white) treated, of which a week, received 100 50 biweekly tocilizumab subcutaneously, while the prednisolone was reduced over 26 weeks. In the first placebo group with 50 patients, prednisolone was also reduced over 26 weeks, in the second placebo group (51 patients) over 52 weeks. After 52 weeks, 56% and 53% in the tocilizumab groups and 14% and 18% in the placebo groups were in sustained remission . The mean cumulative amount of prednisolone was 1862 mg in the two therapy groups and 3296 mg and 3818 mg in the placebo groups. Significant side effects were observed in 15% and 14% of the treatment groups and 22% and 25% in the placebo groups. An optic -Neuropathie it once came in the second treatment group.

Cytokine release syndrome

The CAR-T-cell therapy can cause serious side effects. One of the most common adverse "on-target" effects which is cytokine release syndrome (Engl. Cytokine release syndrome (CRS)) and its more progressive form, the " cytokine storm ". There are sometimes life-threatening side effects such as fever , chills , breathing difficulties and skin rashes . In August 2017, tocilizumab was approved by the FDA for the treatment of CRS in the United States. In June 2018, the Committee for Medicinal Products for Human Use (CHMP) of the European Marketing Authorization Authority (EMA) recommended an approval extension for tocilizumab also for the countries of the EU. As a rule, the European Commission complies with such a recommendation ( positive vote ).

Study and trials of effectiveness in severe COVID-19 pneumonia

On March 24, 2020, the US FDA approved a Phase III randomized , double-blind , placebo-controlled clinical trial submitted by Roche to evaluate the safety and efficacy of tocilizumab in adult inpatients with severe COVID-19 pneumonia. In Italy, among other places, tocilizumab was and is being tested on COVID-19 patients (→ compassionate use ). On July 29, 2020 Roche announced that the primary endpoint of the study, the improvement of the condition of seriously ill patients, had been missed and that tocilizumab also had no significant effect on the mortality rate.

effectiveness

The messenger substance interleukin-6 (IL-6) binds to soluble IL-6 receptors as well as to IL-6 receptors that are bound to the cell membrane. In this way, inflammatory signals are conducted into the cell interior, which are jointly responsible for RA and JIA . Tocilizumab binds to the IL-6 receptors, thus preventing the IL-6 from binding to its specific receptor. By inhibiting the IL-6 signaling pathway, the inflammatory response is interrupted and symptoms are reduced or eliminated. In various pretreated patients with RA , tocilizumab was effective in monotherapy or in combination with methotrexate (MTX) and other DMARDs: Around 30% of patients in the phase III studies achieved remission within 24 weeks , i.e. an almost complete relief of symptoms .

The efficacy of tocilizumab in sJIA was examined in the approval-relevant study TENDER. After 12 weeks, 85% of the patients achieved a 30% response to therapy according to the ACR-Pedi criteria with simultaneous freedom from fever.

Dosis, kind and Time of the Use

Treatment should only be started by a doctor experienced in the diagnosis and management of RA and JIA. Patients treated with tocilizumab should receive the patient passport. The recommended dosage in RA is 8 mg / kg body weight per infusion every four weeks. Dosages over 800 mg per infusion are not recommended for people weighing over 100 kg. Dosages greater than 1.2 g have not been studied in clinical trials. The infusion takes about an hour.

For the treatment of sJIA, tocilizumab should be used at a dose of 8 mg / kg body weight every two weeks in children ≥ 30 kg or at a dose of 12 mg / kg body weight in children under 30 kg.

Side effects

The following adverse drug reactions (ADRs) can occur during treatment with tocilizumab :

There is currently a signal of a possible connection between the administration of tocilizumab and the occurrence of psoriasis or the worsening of existing psoriasis.

By blocking IL-6 activity, the synthesis of acute phase proteins (e.g. CRP ) by the liver is inhibited. This eliminates the diagnostically important CRP increase in the early phase of infections, which can cause diagnostic problems.

pregnancy and breast feeding period

There are insufficient data on the use of tocilizumab in pregnant women. Accordingly, the potential risk to humans is not known. An animal study has shown an increased risk of spontaneous abortion / embryonic-fetal death at high doses. Women of childbearing potential must use effective contraception during treatment and for six months afterwards. Tocilizumab should not be used during pregnancy unless specifically advised by a specialist. It is not known whether tocilizumab is excreted in breast milk . Corresponding animal studies have not been carried out. The decision for or against breastfeeding or tocilizumab should be weighed with the doctor with regard to the benefits and risks.

History

The Japanese scientist Tadamitsu Kishimoto researched the properties of interleukin-6 as early as the 1980s . In 1997, the clinical development of the IL-6 receptor blocker tocilizumab for the treatment of rheumatoid arthritis , Castleman's disease (2001), systemic juvenile idiopathic arthritis (2002) and other chronic inflammatory diseases began in Japan . Tocilizumab is manufactured by the Japanese pharmaceutical company Chugai , the license holder worldwide (except in Japan, China, Taiwan) is Roche. The product is marketed jointly in Germany (as well as in France and Great Britain) by Chugai and Roche. In 2020, patients in Italy who suffered from severe pneumonia due to the SARS-CoV-2 coronavirus were treated with tocilizumab.

Individual evidence

  1. ↑ a b c d e RoActemra: Summary of the drug on the website of the European Medicines Agency (PDF, 514 kB), accessed on August 4, 2011.
  2. ↑ Fleischmann RM et al., ACR 2009: Poster FRI0205: LITHE: Tocilizumab Inhibits Radiographic Progression and Improves Physical Function in Rheumatoid Arthritis (RA) Patients (Pts) at 2 Yrs with Increasing Clinical Efficacy Over Time.
  3. ↑ Benedetti F et al., In: Ann Rheum Dis 2010; 69 (Suppl 3): 146: Tocilizumab in Patients With Systemic Juvenile Idiopathic Arthritis: Efficacy Data From the Placebo-Controlled 12-Week Part of the Phase 3 TENDER Trial.
  4. ↑ FDA: FDA News Release - FDA approves first drug to specifically treat giant cell arteritis , May 22, 2017, [1]
  5. ↑ John H. Stone, Katie Tuckwell, Sophie Dimonaco, Micki Klearman, Martin Aringer, Daniel Blockmans, Elisabeth Brouwer, Maria C. Cid, Bhaskar Dasgupta, Juergen Rech, Carlo Salvarani, Georg Schett, Hendrik Schulze-Koops, Robert Spiera, Sebastian H. Unizony, Neil Collinson: Trial of Tocilizumab in Giant-Cell Arteritis . New England Journal of Medicine 2017, Volume 377, Issue 4, July 27, 2017, pages 317-328, [DOI: 10.1056 / NEJMoa1613849]
  6. ^ CAR T Cells: Engineering Patients' Immune Cells to Treat Their Cancers , Cancer.gov, accessed September 9, 2017.
  7. ↑ FDA approves Roche's Actemra / RoActemra (tocilizumab) for the treatment of CAR T cell-induced cytokine release syndrome , Roche PM, August 30, 2017, accessed September 9, 2017.
  8. ↑ RoActemra tocilizumab , Summary of opinion (post authorization) of the EMA, accessed on July 17, 2018.
  9. ↑ arznei-news.de
  10. ↑ FAZ.net April 2, 2020: "Not being able to breathe is terrible"
  11. ↑ Christina Müller: COVID-19: Tocilizumab fails in phase III. July 29, 2020, accessed July 31, 2020 .
  12. ↑ Emery P et al., Ann Rheum Dis 2008; 67: 1516-23: IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to antitumour necrosis factor biologicals: results from a 24-week multicentre randomized placebo- controlled trial.
  13. ↑ Genovese MC et al., Arthritis Rheum 2008; 58 (10): 2968-80: Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in patients with rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study.
  14. ↑ Jones G et al., Ann Rheum Dis 2009: Online 17 March 2009. doi : 10.1136 / ard.2008.105197 : Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study.
  15. ↑ Tocilizumab (RoActemra®) and the occurrence of psoriasis (UAW-News International) ( Memento of the original from March 16, 2017 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. , Report from the Drugs Commission of the German Medical Association (AkdÄ) published in Deutsches Ärzteblatt , vol. 111, issue 14, April 4, 2014. @1@ 2Template: Webachiv / IABot / www.akdae.de
  16. ↑ Information from the Drugs Commission of the German Medical Association (AkdÄ) about RoActemra® (tocilizumab)
  17. ↑ Dr. med. Markus Harwart: The development of tocilizumab - medical progress based on a successful cooperation between Chugai and Roche.
  18. ↑ https://www.deutschlandfunkkultur.de/coronatherapie-ein-rheumamittel-als-hoffnungsschimmer.2165.de.html?dram:article_id=473095

Web links