Alemtuzumab

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Alemtuzumab
Alemtuzumab
Ribbon representation of the Fab fragment in complex with a synthetic peptide antigen (rods), according to PDB  1CE1
Mass / length primary structure 145.5  kDa
Identifier
External IDs
Drug information
ATC code L01 XC04
DrugBank BTD00109
Drug class Cytostatic , immunosuppressive

Alemtuzumab (trade name Lemtrada ; manufacturer Sanofi Genzyme ) is humanized monoclonal IgG 1κ - antibody and a drug that primarily in the treatment of multiple sclerosis (MS) is used.

Alemtuzumab was originally marketed in the EU and Switzerland by Genzyme , a company of the Sanofi Group, as an effective component of the finished drug MabCampath for the treatment of chronic lymphocytic leukemia (CLL). However, in August 2012 Genzyme withdrew MabCampath from the European market in order to bring the substance back onto the market under a new trade name (see above: Lemtrada ) and a different indication (see above: MS ). The Drugs Commission of the German Medical Association (AkdÄ) criticizes this decision of the voluntary withdrawal from the market and the planned “indication hopping” to the effect that the pharmaceutical company evades its responsibility in an unacceptable manner.

The European Medicines Agency (EMA) has been investigating several cases of serious, sometimes fatal side effects with alemtuzumab since April 2019. Until it has been clarified whether further monitoring requirements are necessary, only selected patients should be switched to alemtuzumab. The EMA Safety Committee (PRAC) again recommended restrictions on the use of Lemtrada® (alemtuzumab) at its meeting at the end of October 2019. In the meantime, the pharmaceutical company (Sanofi Genzyme) has also issued various Rote-Hand-Letters (RHB) for alemtuzumab, etc. a. published in April 2019 and January 2020. In RHBs, the manufacturers inform the specialist groups about newly identified drug risks.

properties

Alemtuzumab is produced by genetic engineering and binds specifically to the glycoprotein CD52 on the cell surface of normal and malignant B and T lymphocytes , thereby destroying them. The antibody is produced in a suspension culture from mammalian cells ( CHO cells ) in a nutrient medium.

Approved and possible areas of application

multiple sclerosis

The results of a double-blind phase II study (CAMMS223) that examined the effects of alemtuzumab against interferon- beta 1a sc in 334 MS patients over a period of three years suggested that the effects of alemtuzumab are superior to that of interferon.

Patients treated with alemtuzumab had a 74% reduced risk of relapse compared to those treated with interferon. The extent of the MS-related functional impairment decreased by 0.39 EDSS points in the three years of treatment , while it increased by 0.38 EDSS points in the interferon group. The brain volume increased with the administration of alemtuzumab, while it decreased in the interferon group.

Since September 2007, two phase III studies have been conducted to review the results of the CAMMS223 study. One study included around 600 patients who had not yet been treated with any anti-MS drug. The second study treated around 1,200 patients who did not respond well to drugs that were already available.

In September 2013, the drug was approved by the European Commission for the treatment of MS and was (re) launched on the market under the name Lemtrada . The costs of Lemtrada (2014: € 888 / mg) have increased 40 times compared to the previous product MabCampath (2012: € 22 / mg).

The US Food and Drug Administration (FDA), however, rejected the approval of alemtuzumab in the MS indication at the end of 2013. In April 2014, Genzyme / Sanofi submitted another application for approval to the FDA and finally received approval for the US market in November 2014.

Chronic lymphocytic leukemia

Treatment with alemtuzumab was cancer immunotherapy until 2012 . In contrast to chemotherapy drugs, this has a very specific effect on cancer cells. Alemtuzumab is approved as monotherapy for the treatment of patients with chronic lymphocytic leukemia (CLL). The safety and effectiveness of MabCampath were tested in a comparative study with chlorambucil . MabCampath was found to be superior in terms of progression-free survival ( PFS ). It also shows a good response rate in previously treated patients and is able to prevent the progression of the disease for a long time. However , it does not offer a curative therapeutic approach any more than conventional cancer therapies. The medical indication for the administration of alemtuzumab is now seen in a small subgroup of CLL patients, namely those who have alterations of the TP53 tumor suppressor gene on chromosome 17 (17p13). The rest of the CLL patients (if they are in need of treatment at all) are currently using other drugs in first-line therapy.

Withdrawal of MabCampath's approval for the treatment of chronic lymphocytic leukemia

By withdrawing or surrendering the approval of alemtuzumab in the indication of chronic lymphocytic leukemia, the manufacturer says it wants to prevent doctors from using MabCampath in off-label use for multiple sclerosis. After an approval for MS has meanwhile been granted in the EU - cave: not in the USA (!) - this argumentation is misleading. MabCampath could easily have expanded the indication. According to the manufacturer, adverse drug effects (“side effects”) of MabCampath were expressly not the reason for the withdrawal of the approval. Medical associations have therefore sharply criticized the fact that it is even possible for a pharmaceutical company to withdraw a recognized valuable and effective drug from the market for purely commercial reasons. (See also web links - "The sham package".)

Organ transplant

Outside of the approval, alemtuzumab is used in kidney transplantation for induction therapy.

Side effects

In the Red Hand letter from Sanofi from April 2019 (see also the introduction to the third paragraph) it says a .: The EMA is reviewing the benefit-risk balance of Lemtrada (alemtuzumab) for the treatment of multiple sclerosis after reports of serious cardiovascular events, newly identified autoimmune hepatitis and hemophagocytic lymphohistiocytosis. The following measures have been agreed until the review is completed:

  • New treatment should only be initiated in adult patients with highly active relapsing-remitting multiple sclerosis (RRMS) if complete and adequate treatment with at least two other disease-modifying treatments (DMTs) has been performed or in patients with highly active RRMS for which all other DMTs are contraindicated or otherwise unsuitable.
  • ... s. Red hand letters

Side effects with alemtuzumab occur in almost all patients. It is not uncommon for a cytokine release syndrome to occur. Rarely, severe infections due to immune deficiency and pancytopenia can also occur. The side effects can be reduced if alemtuzumab is administered subcutaneously rather than intravenously .

In 2008, six cases of idiopathic thrombocytopenic purpura (ITP) were observed in the CAMMS223 study ; one patient died as a result. In order to be able to recognize and treat this side effect as early as possible, the blood count is closely monitored. In 2017, the Medicines Commission of the German Medical Association also pointed out this possibility of a serious side effect in adult patients who suffer from active relapsing-remitting multiple sclerosis.

About a quarter of the treated MS patients developed an autoimmune reaction against the thyroid gland , which may a. led to an overactive gland ( Graves disease ).

history

Alemtuzumab is the first humanized monoclonal antibody. Its origins date back to the human proteins from lymphocytes directed rat antibody Campath-1 back, by a working group of Pathology Department of the University of Cambridge by Herman Waldmann was developed. The name Campath derives from Cam bridge and Path ology from.

Since the original rat antibody was not suitable for the treatment of humans due to the high proportion of foreign protein, the Cambridge working group developed a technique to reduce rat protein in the late 1980s. This technique later became known as the humanization of antibodies. The modified antibody was now called Campath-1H . The name alemtuzumab was later introduced as an international non-proprietary name .

Alemtuzumab took a long time to develop into a commercial drug. It was first investigated in rheumatoid arthritis by Burroughs Wellcome, which later became part of Glaxo , and passed on to a forerunner of Millennium in 1997 due to disappointing results . Millennium - now part of Takeda  - later sold the project to Ilex Oncology (now part of Genzyme ). The marketing rights were transferred to Schering AG in 1999 (now: Bayer). The approval of alemtuzumab for CLL was carried out in 2001 almost simultaneously in the EU and in the USA .

Scientists at the University of Cambridge have been working on the use of alemtuzumab in MS since the mid-1990s. Today, Genzyme and Bayer are jointly developing the antibody for use in MS.

See also

Web links

Individual evidence

  1. ↑ Withdrawal of MabCampath ® (PDF; 114 kB) Information letter from Genzyme, a company of the Sanofi Group, dated August 10, 2012
  2. ↑ From leukemia drug to MS drug . Pharmaceutical Newspaper Online
  3. ↑ Information and statement from AkdÄ on the withdrawal from the market of MabCampath ® (alemtuzumab) ( Memento from September 1, 2012 in the Internet Archive ) AkdÄ newsletter of August 24, 2012
  4. ↑ How to drastically increase the price of a drug . In: Süddeutsche Zeitung , August 18, 2012, accessed August 21, 2012.
  5. ↑ Leukemia drug: market withdrawal outraged doctors . Spiegel Online , August 27, 2012, accessed August 27, 2012.
  6. ↑ Lemtrada®: Measures to minimize the risk of serious side effects , report from October 31, 2019 on www.multiple-sklerose.com , accessed on November 1, 2019
  7. ↑ Lemtrada (alemtuzumab) - PRAC recommends measures to minimize serious side effects ( memento of November 2, 2019 in the Internet Archive ), message Paul Ehrlich Institute of November 1, 2019, accessed on November 2, 2019
  8. ↑ Use of multiple sclerosis medicine Lemtrada restricted while EMA review is ongoing , PM EMA of April 12, 2019, accessed on April 14, 2019
  9. ↑ Alemtuzumab - only for severe cases , Pharmazeutische Zeitung of April 12, 2019, accessed on April 14, 2019
  10. ↑ a b Alemtuzumab (LEMTRADA): Restriction of use in multiple sclerosis due to safety concerns , Red Hand Brief Sanofi April 2019, accessed on April 24, 2019
  11. ↑ a b LEMTRADA (alemtuzumab): restriction of the indication, additional contraindications and risk-minimizing measures , Red Hand Brief Sanofi January 2020, accessed on February 11, 2020
  12. ↑ a b c CAMMS223 Trial Investigators. Alemtuzumab vs. Interferon beta-1a in early multiple sclerosis. In: N Engl J Med. , 2008, 359 , pp. 1786-1801, PMID 18946064 .
  13. ↑ Phase III development program started with alemtuzumab in patients with multiple sclerosis. Bayer AG, September 26, 2007; Retrieved October 29, 2008.
  14. ↑ Multiple sclerosis: EMA approves further drugs for MS therapy . , (PDF; 149 kB). Retrieved September 19, 2013.
  15. ↑ European Commission Approves Genzyme's Multiple Sclerosis Treatment Lemtrada ™ (alemtuzumab) . Retrieved September 19, 2013.
  16. ↑ Alemtuzumab (LEMTRADA) against multiple sclerosis 29,000 times more expensive than gold . In: Medicinal Telegram . tape 44 , October 7, 2013 ( arznei-telegramm.de [accessed February 13, 2017]).
  17. ↑ Genzyme Receives Complete Response Letter from FDA on Lemtrada ™ (alemtuzumab) Application . ( Memento of April 21, 2014 in the Internet Archive ) Genzyme, press release, December 30, 2013, accessed April 20, 2014.
  18. ↑ Genzyme to Resubmit LemtradaTM Application for FDA review . ( Memento of April 8, 2014 in the Internet Archive ) (PDF) Sanofi, press release, April 7, 2014, accessed on April 8, 2014.
  19. ↑ US approval for Lemtrada . In: DAZ.online . November 17, 2014 ( deutsche-apotheker-zeitung.de [accessed June 24, 2018]).
  20. ↑ Alemtuzumab: Former cancer drug approved for the treatment of MS . In: Ärzteblatt of September 18, 2013.
  21. ^ Specialist information from the Swiss Medicines Compendium, as of December 2008.
  22. ↑ Hillmen et al .: Alemtuzumab compared with Chlorambucil as first-line Therapy for chronic lymphocytic leukemia . In: JCO, 2007, Vol25, No35, pp. 5616–5622, doi: 10.1200 / JCO.2007.12.9098 .
  23. ↑ Keating et al .: Therapeutic role of alemtuzumab (Campath -1H) in patients who failed fludarabine: results of a large international study . In: Blood , 2002, Vol99, No10, pp. 3554-3561, doi: 10.1182 / blood.V99.10.3554 .
  24. ↑ Onkopedia guidelines for chronic lymphocytic leukemia. January 2017, accessed on February 13, 2017 (guidelines of the German Society for Hematology and Oncology (DGHO), the Austrian Society for Hematology and Oncology (ÖGHO) and the Swiss Society for Hematology (SGH)).
  25. ↑ MabCampath's withdrawal from the market for commercial reasons - a precedent . In: Der Arzneimittelbrief , 46, September 2012, pp. 67/68.
  26. ↑ Profit before patient welfare Coordination against Bayer dangers , press release from September 24, 2013.
  27. ↑ Michael J Hanaway, E Steve Woodle, Shamkant Mulgaonkar, V Ram Peddi, Dixon B Kaufman, M Roy First, Richard Croy, John Holman: Alemtuzumab induction in renal transplantation . In: The New England Journal of Medicine . 364, No. 20, May 19, 2011, pp. 1909-1919. doi : 10.1056 / NEJMoa1009546 . PMID 21591943 .
  28. ↑ Therapy-refractory autoimmune thrombocytopenia after alemtuzumab for the treatment of multiple sclerosis ("From the UAW database") , Drug Commission of the German Medical Association, from Deutsches Ärzteblatt, vol. 114, issue 46, November 17, 2017 on akdae.de
  29. ↑ AJ Coles, M Wing, S Smith et al .: Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. In: Lancet , 1999, 354, pp. 1691-1695, PMID 10568572
  30. ↑ G Hale, S Bright, G Chumbley et al .: Removal of T cells from bone marrow for transplantation: a monoclonal antilymphocyte antibody that fixes human complement. In: Blood , 1983, 62, pp. 873-882, PMID 6349718
  31. ^ L Riechmann, M Clark, H Waldmann, G. Winter: Reshaping human antibodies for therapy. In: Nature , 1988, 332, pp. 323-327, PMID 3127726
  32. ↑ FJ. Dumont: Alemtuzumab (Millennium / ILEX). In: Curr Opin Investig Drugs , 2001, 2, pp. 139-160, PMID 11527007
  33. ^ T Moreau, A Coles, M Wing et al .: Campath-1H in multiple sclerosis. In: Mult Scler. , 1996, 1, pp. 357-365, PMID 9345418