Natalizumab

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Natalizumab
Mass / length primary structure 149  kDa
Identifier
External IDs
Drug information
ATC code L04 AA23
DrugBank DB00108
Drug class Monoclonal antibody , immunosuppressant

Natalizumab (trade name Tysabri ; manufacturer Biogen ) is a drug that is used to treat relapsing multiple sclerosis (MS), if z. B. Beta interferon or glatiramer acetate did not help. Natalizumab is a humanized monoclonal antibody ( ending -zumab ) and a selective inhibitor for adhesion molecules that are on the surface of white blood cells . It inhibits the migration of white blood cells to foci of inflammation.

Natalizumab is also called integrin α 4 - inhibitor referred to and belongs to the IgG 4 antibodies.

Clinical information

Approved areas of application (indications)

Natalizumab is indicated for the disease-modifying monotherapy of highly active, relapsing-remitting multiple sclerosis (MS) in the following patient groups:

  • Adult patients aged 18 years and over with high disease activity who have not responded to treatment with an interferon beta or glatiramer acetate . Patients should have had at least one relapse in the previous year during therapy and should have at least 9 T2 hyperintense lesions on cranial magnetic resonance imaging (MRI) or at least 1 gadolinium-enriching lesion.
  • Adult patients aged 18 years and over with rapidly progressive relapsing-remitting multiple sclerosis, defined by 2 or more relapses of disability progression in one year, and with 1 or more gadolinium-enriching lesions on brain MRI or with a significant increase in T2 lesions in the Compared to a recent MRI.

Natalizumab must not be used together with other medicines that could weaken the immune system.

The approval in the USA contains the note that natalizumab should only be used in patients who have not responded to previous treatment. However, since this restriction is only recommended in the USA, natalizumab can be prescribed in the USA as the first therapy even for normal relapsing MS.

Natalizumab is not effective in treating acute flare-ups .

Further possible areas of application

Natalizumab has also been studied as a treatment for Crohn's disease , a chronic inflammatory bowel disease. In January 2008, the US Food and Drug Administration approved natalizumab for the treatment of Crohn's disease. Before treatment with natalizumab, other treatment options must be exhausted.

Natalizumab has also been studied in rheumatoid arthritis . However, the results of a phase II study were disappointing.

Dosis, kind and Time of the Use

The drug is diluted every four weeks at a dose of 300 mg and infused intravenously over one hour . If the treatment is unsuccessful after 6 months of treatment, the continuation of the treatment should be reconsidered. There is no application data available beyond two years. Therefore, the risk-benefit assessment should be carried out again for continued treatment beyond two years.

Contraindications (contraindications)

Drug interactions

Natalizumab is an antibody and therefore has no classic interactions with chemical drugs. Concomitant treatment with other drugs that act on the immune system or are used to treat cancer can increase the risk of severe infections and should therefore be avoided , except for brief treatment of MS attacks with steroids .

Use during pregnancy and breastfeeding

Natalizumab should not be used during pregnancy unless clearly necessary. If a woman becomes pregnant while being treated with natalizumab, discontinuation of treatment should be considered. It is not known whether natalizumab is excreted in human milk, however this has been seen in studies in long-tailed macaques . Therefore, patients receiving natalizumab should not breast-feed.

Special patient groups

  • Elderly people
Use in patients over 65 years of age is not recommended as no data are available on this patient group.
  • Children and young people
Natalizumab is not approved for children and adolescents. In the absence of alternatives, however, it is sometimes used, which leads to good results, especially with young people.
  • Kidney and liver dysfunction
There are no studies in patients with kidney or liver damage. However, the available evidence suggests that dose adjustment is not necessary in patients with renal or hepatic impairment.

Adverse effects (side effects)

Natalizumab is generally well tolerated. In some cases, headaches, urinary tract infections, depression, mild respiratory infections , fatigue, pain in the limbs and joints, and sore throat can occur. Very rarely, natalizumab can cause severe liver damage.

Progressive multifocal leukoencephalopathy

The use of natalizumab has been associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML). PML is an opportunistic infection caused by the JC virus that can be fatal or cause severe disability. Because of this increased risk of developing PML, the benefits and risks of treatment with Tysabri should be weighed up after consulting your doctor.

The patient must be informed of the first signs of PML and its symptoms. The following risk factors are associated with an increased risk of developing PML:

  • Presence of anti-JCV antibodies.
  • Duration of treatment, especially for long-term treatment beyond 2 years. Experience in patients receiving Tysabri beyond 4 years is limited. Therefore, the risk of PML in these patients cannot currently be assessed.
  • Treatment with immunosuppressants before using Tysabri .

Anti-JCV antibody positive patients have an increased risk of developing PML compared to anti-JCV antibody negative patients. Serum anti-JCV antibody testing is recommended prior to initiating treatment with Tysabri or in patients receiving Tysabri if the antibody status is unknown. It is recommended that anti-JCV antibody negative patients be retested every 6 months. After 2 years of therapy, all patients must be re-informed about the increased risk of developing PML with Tysabri . In the event that PML is suspected, administration of Tysabri must be withheld until PML can be ruled out.

The German drug authority (then BfArm / PEI) assumed a risk of 1: 263 within three years after the start of therapy in 2010. A retrospective post-marketing study by the manufacturing company with data up to February 29, 2012 found 212 cases worldwide among 99,551 patients treated for a maximum of four years (2.1 per 1000 = 1 per 476), of which 46 (22%) had died on the reference date. Blood samples were only available from 54 patients; all of them had detectable JC virus antibodies before the start of therapy. In addition, the risk of illness was significantly increased if immunosuppressive therapy had already been carried out and if treatment with natalizumab was continued for two years. If all three risk factors were present, the risk of the disease was 11.1 per 1000 patients (1 per 91). There were four cases of PML (0.04 per 1000) in the first year of treatment and 37 cases (0.56 per 1000) in the second year.

Other opportunistic infections

Individual cases of other opportunistic infections have also occurred with the use of natalizumab. An increased risk of other opportunistic infections cannot be ruled out when using natalizumab.

Hypersensitivity

Hypersensitivity reactions, including severe systemic reactions, may occur with the infusion of natalizumab . These reactions usually occurred during the infusion or up to an hour after the end of the infusion. The risk of hypersensitivity was greatest with the first infusions.

Neutralizing Antibodies

Neutralizing antibodies to natalizumab were seen in nine percent of treated patients. In a third of these patients, however, the antibodies disappear again. The presence of the antibodies can be detected after just a few infusions and significantly reduces the effectiveness of natalizumab. Affected patients may also experience more side effects.

Pharmacological properties

Mechanism of action (pharmacodynamics)

Natalizumab binds to α 4 - integrin , thereby blocking its function. Integrins are found on the surface of white blood cells ( leukocytes ) and all other animal cells except red blood cells. They enable the white blood cells to “dock” to binding sites on the vessel wall. Inflammation in the tissue leads to an immigration of white blood cells. In immune diseases like MS, the otherwise very useful cells often have a destructive effect. Natalizumab inhibits the migration of white blood cells through the vessel wall into the inflamed tissue and thus protects the nerve cells from attacks by misdirected, destructive white blood cells. This mode of action can also be linked to the occurrence of PML, as natalizumab prevents the movement of white blood cells even if they are infected by a pathogen such as B. the JC virus to fight.

Absorption and distribution in the body (pharmacokinetics)

After administration of 300 mg natalizumab, maximum blood concentrations of around 110 µg / ml are observed. The average concentrations of natalizumab in long-term treatment fluctuated between 23 µg / ml and 29 µg / ml. The mean plasma half-life is 16 days. The presence of neutralizing antibodies increased the excretion of natalizumab approximately three-fold.

toxicology

No cases of overdoses were reported. There is no specific antidote .

Other Information

origin

Natalizumab was from a myeloma - cell line derived from mice and using recombinant technology humanized .

history

Natalizumab was first obtained in the 1990s. During clinical development, it was temporarily known as Antegren . It was approved by the US FDA in November 2004 for the treatment of patients with relapsing MS on the basis of several small studies and the 1-year data from the Phase III studies AFFIRM and SENTINEL. Until then, MS drugs were usually only approved after a two-year review.

Natalizumab was then withdrawn from the market in February 2005 after only three months, after initially two and later three cases of PML became known. Two of the patients died; the third has suffered severe disabilities. The first two known cases occurred in patients treated concomitantly with natalizumab and interferon beta-1a. Approval in Europe had not yet been granted at this point in time. More than 3,000 patients were followed up following the recall. No further PML cases were discovered. Then, in March 2006, an advisory committee recommended the reauthorisation of natalizumab to the FDA. Natalizumab came back on the US market in mid-2006 and was also approved in Europe. The re-approval of a drug after such a withdrawal for safety reasons is rare.

Cost and cost effectiveness

The cost of treatment with natalizumab is significantly higher than with comparable drugs. According to an HTA report by DIMDI in 2008, natalizumab was 1.6 times more expensive than the drug used for comparison ( beta interferon ). The authors of the report see an outstanding need for research to assess the cost-benefit ratio.

Studies

The phase III AFFIRM study, which led to the approval of natalizumab as monotherapy, showed the following improvements:

  • The frequency of clinical relapses decreased by 67%.
  • The time to progression to permanent clinical disability could be delayed by 42%.
  • The sum of new or enlarging, T2-weighted lesions was reduced by 83%.
  • The number of new T1 hypointense lesions - so-called black holes, which are regarded as markers for permanent brain damage - was reduced by 44%.
  • The number of gadolinium- enriching lesions decreased by 92%.

Two further studies examined the safety and effectiveness of Tysabri in long-term therapy:

  • STRATA (6 year observation period): significant reduction in relapse rates and stable or improved EDSS values
  • TYSABRI 24 PLUS (prospective, previous> 24 months therapy): consistent safety profile with stable degree of disability (EDSS of approx. 3.5) and low relapse rate (mean annual relapse rate at 0.18 relapses)

Web links

Individual evidence

  1. ↑ a b c Summary of the product characteristics (information for healthcare professionals), website of the European Health Authority (EMA), accessed on February 24, 2014 (PDF; 221 kB)
  2. ^ O'Connor PW, Goodman A, Willmer-Hulme AJ et al. Randomized multicenter trial of natalizumab in acute MS relapses: clinical and MRI effects . Neurology 2004; 62 : 2038-43, PMID 15184611 .
  3. ↑ MacDonald JK, McDonald JW. Natalizumab for induction of remission in Crohn's disease . Cochrane Database Syst Rev 2007 (1): CD006097, PMID 17253580 .
  4. ↑ FDA approves TYSABRI (R) for the treatment of moderate-to-severe CROHN'S DISEASE ( Memento from February 27, 2014 in the Internet Archive ) Press release from Biogen Idec of January 14, 2008, accessed on February 24, 2014
  5. ↑ a b Natalizumab in the Treatment of Rheumatoid Arthritis in Subjects Receiving Methotrexate ClinicalTrials.gov NCT00083759, accessed February 24, 2014
  6. ↑ Cohen S, Birbara C, Pazdur J et al. A phase 2 study of natalizumab in subjects with moderate to severe rheumatoid arthritis . ACR Annual Meeting; 10-15 November 2006; Washington. Poster 497.
  7. ↑ Kornek B, Aboul-Enein F, Rostasy K, Milos R, Steiner I, Penzien J, Hellwig K, Pitarokoili K, Storm van's Gravesande K, Karenfort M, Blaschek A, Meyer A, Seidl R, Debelic D, Vass K, Prayer D, Kristoferitsch W, Bayas A. Natalizumab Therapy for Highly Active Pediatric Multiple Sclerosis. JAMA Neurol. 2013; (): 1-7. doi : 10.1001 / jamaneurol.2013.923
  8. ^ Food and Drug Administration. Natalizumab (marketed as Tysabri): Serious liver injury. Drug Safety Newsletter 2008; 1 : 33-35. Accessed March 25, 2010.
  9. ↑ Yousry TA, Major EO, ​​Ryschkewitsch C et al .: Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy , New England Journal of Medicine 2006; 354 : 924-33, PMID 16510746 .
  10. ↑ K. Weisser, D. Mentzer, P. Volkers, B. Keller-Stanislawski: PML after treatment with natalizumab (Tysabri ® ) in patients with multiple sclerosis. ( Memento of March 1, 2014 in the Internet Archive ) Pharmaceutical Safety Bulletin, Issue 1, March 29, 2010, pp. 8-11, accessed on February 25, 2014
  11. ↑ G. Bloomgren, S. Richman, C. Hotermans, M. Subramanyam, S. Goelz, A. Natarajan, S. Lee, T. Plavina, JV Scanlon, A. Sandrock, C. Bozic: Risk of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy , New England Journal of Medicine 2012, 366 : 1870-1880, PMID 22591293 .
  12. ↑ a b c Polman CH, O'Connor PW, Havrdova E et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis . N Engl J Med 2006, 354 : 899-910, PMID 16510744 .
  13. ↑ a b Rudick RA, Stuart WH, Calabresi PA et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis . N Engl J Med 2006, 354 : 911-23, PMID 16510745 .
  14. ↑ Calabresi PA, Giovannoni G, Confavreux C et al. The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL. Neurology. 2007; 69 : 1391-403, PMID 17761550 .
  15. ↑ Leger OJ, Yednock TA, Tanner L et al. Humanization of a mouse antibody against human alpha-4 integrin: a potential therapeutic for the treatment of multiple sclerosis . Hum Antibodies 1997; 8 : 3-16, PMID 9265500 .
  16. ^ Yousry TA, Major EO, ​​Ryschkewitsch C et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy . N Engl J Med 2006; 354 : 924-33, PMID 16510746 .
  17. ↑ Interferons and Natalizumab in the Treatment of Multiple Sclerosis (MS) Health Technology Assessment (HTA) in the Federal Republic of Germany (PDF; 1 MB)
  18. ↑ Richard Rudick: Six-year natalizumab safety and efficacy data from the STRATA study Poster P593 from the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, Copenhagen, 2013
  19. ↑ M. Mäurer, H. Wiendl , C. Heesen, A. Gass, C. Wernsdörfer, C. Wettmarshausen, V. Zingler, BC Kieseier: Long-term therapy with natalizumab in routine clinical practice: final results of the prospective observational study Tysabri 24 plus poster P250 from the 86th Congress of the German Society for Neurology (DGN), Dresden, 2013