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(N-Myristoyl-glycyl-L-threonyl-L-asparaginyl-L-leucyl-L-seryl-L-valyl-Lprolyl-L-asparaginyl-L-prolyl-L-leucyl-glycyl-L-phenylalanyl-L-phenylalanyl-L-prolyl-L-aspartyl-L-histidyl-Lglutaminyl-L-leucyl-L-aspartyl-L-prolyl-L-alanyl-L-phenylalanyl-glycyl-L-alanyl-L-asparaginyl-L-seryl-Lasparaginyl-L-asparaginyl-Lprolyl-L-aspartyl-L-tryptophanyl-L-aspartyl-L-phenylalanyl-L-asparaginyl-L-prolylL-asparaginyl-L-lysyl-L-aspartyl-L-histidyl-L-tryptophanyl-L-prolyl-L-glutamyl-L-alanyl-L-asparaginyl-L-lysylL-valylglycinamide, acetate salt.
molecular formula C248H355N65O72,
molecular mass is 5398.9 g/mol
APROVED 2020/7/31, EU, Hepcludex
Antiviral, Entry inhibitor
Hepatitis delta virus infection
Bulevirtide is a 47-amino acid peptide with a fatty acid, a myristoyl residue, at the N-terminus and an amidated C-terminus. The active substance is available as acetate salt. The counter ion acetate is bound in ionic form to basic groups of the peptide molecule and is present in a non-stoichiometric ratio. The chemical name of bulevirtide is (N-Myristoyl-glycyl-L-threonyl-L-asparaginyl-L-leucyl-L-seryl-L-valyl-Lprolyl-L-asparaginyl-L-prolyl-L-leucyl-glycyl-L-phenylalanyl-L-phenylalanyl-L-prolyl-L-aspartyl-L-histidyl-Lglutaminyl-L-leucyl-L-aspartyl-L-prolyl-L-alanyl-L-phenylalanyl-glycyl-L-alanyl-L-asparaginyl-L-seryl-Lasparaginyl-L-asparaginyl-Lprolyl-L-aspartyl-L-tryptophanyl-L-aspartyl-L-phenylalanyl-L-asparaginyl-L-prolylL-asparaginyl-L-lysyl-L-aspartyl-L-histidyl-L-tryptophanyl-L-prolyl-L-glutamyl-L-alanyl-L-asparaginyl-L-lysylL-valylglycinamide, acetate salt. It corresponds to the molecular formula C248H355N65O72, its relative molecular mass is 5398.9 g/mol
Bulevirtide appears as a white or off-white hygroscopic powder. It is practically insoluble in water and soluble at concentrations of 1 mg/ml in 50% acetic acid and about 7 mg/ml in carbonate buffer solution at pH 8.8, respectively. The structure of the active substance (AS) was elucidated by a combination of infrared spectroscopy (IR), mass spectrometry (MS), amino acid analysis and sequence analysis Other characteristics studied included ultraviolet (UV) spectrum, higher order structure (1D- and 2D- nuclear magnetic resonance spectroscopy (NMR)) and aggregation (Dynamic Light Scattering). Neither tertiary structure nor aggregation states of bulevirtide have been identified. With regard to enantiomeric purity, all amino acids are used in L-configuration except glycine, which is achiral by nature. Two batches of bulevirtide acetate were evaluated for enanatiomeric purity and no relevant change in configuration during synthesis was detected.
Bulevirtide is manufactured by a single manufacturer. It is a chemically synthesised linear peptide containing only naturally occurring amino acids. The manufacturing of this peptide is achieved using standard solidphase peptide synthesis (SPPS) on a 4-methylbenzhydrylamine resin (MBHA resin) derivatised with Rink amide linker in order to obtain a crude peptide mixture. This crude mixture is purified through a series of washing and preparative chromatography steps. Finally, the purified peptide is freeze-dried prior to final packaging and storage. The process involves further four main steps: synthesis of the protected peptide on the resin while side-chain functional groups are protected as applicable; cleavage of the peptide from the resin, together with the removal of the side chain protecting groups to obtain the crude peptide; purification; and lyophilisation. Two chromatographic systems are used for purification. No design space is claimed. Resin, Linker Fmoc protected amino acids and myristic acid are starting materials in line with ICH Q11. Sufficient information is provided on the source and the synthetic route of the starting materials. The active substance is obtained as a nonsterile, lyophilised powder. All critical steps and parameters were presented and clearly indicated in the description of the manufacturing process. The process description includes also sufficient information on the type of equipment for the SPPS, in-process controls (IPCs). The circumstances under which reprocessing might be performed were clearly presented. No holding times are proposed. Overall the process is sufficiently described.
The finished product is a white to off white lyophilised powder for solution for injection supplied in single-use vials. Each vial contains bulevirtide acetate equivalent to 2 mg bulevirtide. The composition of the finished product was presented. The powder is intended to be dissolved in 1 ml of water for injection per vial. After reconstitution the concentration of bulevirtide net peptide solution in the vial is 2 mg/ml. The components of the formulation were selected by literature review and knowledge of compositions of similar products available on the market at that time, containing HCl, water, mannitol, sodium carbonate, sodium hydrogen carbonate and sodium hydroxide. All excipients are normally used in the manufacture of lyophilisates. The quality of the excipients complies with their respective Ph. Eur monographs. The intrinsic properties of the active substance and the compounding formulation do not support microbiological growth as demonstrated by the stability data. No additional preservatives are therefore needed.
Hepcludex is an antiviral medicine used to treat chronic (long-term) hepatitis delta virus (HDV) infection in adults with compensated liver disease (when the liver is damaged but is still able to work), when the presence of viral RNA (genetic material) has been confirmed by blood tests.
HDV is an ‘incomplete’ virus, because it cannot replicate in cells without the help of another virus, the hepatitis B virus. Because of this, patients infected with the virus always also have hepatitis B.
Hepcludex contains the active substance bulevirtide.
The most common side effects include raised levels of bile salts in the blood and reactions at the site of injection.
Bulevirtide works by attaching to and blocking a receptor (target) through which the hepatitis delta and hepatitis B viruses enter liver cells. By blocking the entry of the virus into the cells, it limits the ability of HDV to replicate and its effects in the body, reducing symptoms of the disease.
Bulevirtide was approved for medical use in the European Union in July 2020.
Mechanism of action
The hepatitis B virus uses its surface lipopeptide pre-S1 for docking to mature liver cells via their sodium/bile acid cotransporter (NTCP) and subsequently entering the cells. Myrcludex B is a synthetic N-acylated pre-S1 that can also dock to NTCP, blocking the virus’s entry mechanism.
The drug is also effective against hepatitis D because the hepatitis D virus is only infective in the presence of a hepatitis B virus infection.
- Deterding, K.; Wedemeyer, H. (2019). “Beyond Pegylated Interferon-Alpha: New Treatments for Hepatitis Delta”. Aids Reviews. 21 (3): 126–134. doi:10.24875/AIDSRev.19000080. PMID 31532397.
- “Hepcludex EPAR”. European Medicines Agency (EMA). 26 May 2020. Retrieved 12 August 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- “Summary of opinion: Hepcludex” (PDF). European Medicines Agency. 28 May 2020.
- Francisco, Estela Miranda (29 May 2020). “Hepcludex”. European Medicines Agency. Retrieved 6 August 2020.
- Volz T, Allweiss L, Ben MBarek M, Warlich M, Lohse AW, Pollok JM, et al. (May 2013). “The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus”. Journal of Hepatology. 58 (5): 861–7. doi:10.1016/j.jhep.2012.12.008. PMID 23246506.
- Abbas Z, Abbas M (August 2015). “Management of hepatitis delta: Need for novel therapeutic options”. World Journal of Gastroenterology. 21 (32): 9461–5. doi:10.3748/wjg.v21.i32.9461. PMC 4548107. PMID 26327754.
- Spreitzer H (14 September 2015). “Neue Wirkstoffe – Myrcludex B”. Österreichische Apothekerzeitung (in German) (19/2015): 12.
- “Bulevirtide”. Drug Information Portal. U.S. National Library of Medicine.
|Other names||MyrB, Myrcludex-B|
/////////Bulevirtide acetate, ブレビルチド酢酸塩 , orphan designation, MYR GmbH, PEPTIDE, EU 2020, 2020 APPROVALS
MDSFSANQEI RYSEVTPYHV TSVWTKGVTP PANFTQGEDV FHAPYVANQG WYDITKTFNG
KDDLLCGAAT AGNMLHWWFD QNKDQIKRYL EEHPEKQKIN FNGEQMFDVK EAIDTKNHQL
DSKLFEYFKE KAFPYLSTKH LGVFPDHVID MFINGYRLSL TNHGPTPVKE GSKDPRGGIF
DAVFTRGDQS KLLTSRHDFK EKNLKEISDL IKKELTEGKA LGLSHTYANV RINHVINLWG
ADFDSNGNLK AIYVTDSDSN ASIGMKKYFV GVNSAGKVAI SAKEIKEDNI GAQVLGLFTL
EMA APPROVED, 2020/8/25, Idefirix
Pre-transplant treatment to make patients with donor specific IgG eligible for kidney transplantation
Immunosuppressant, Immunoglobulin modulator (enzyme)
Imlifidase is under investigation in clinical trial NCT02854059 (IdeS in Asymptomatic Asymptomatic Antibody-Mediated Thrombotic Thrombocytopenic Purpura (TTP) Patients).
Imlifidase is a cysteine protease derived from the immunoglobulin G (IgG)‑degrading enzyme of Streptococcus pyogenes. It cleaves the heavy chains of all human IgG subclasses (but no other immunoglobulins), eliminating Fc-dependent effector functions, including CDC and antibody-dependent cell-mediated cytotoxicity (ADCC). Thus, imlifidase reduces the level of donor specific antibodies, enabling transplantation.
The benefits with imlifidase are its ability to convert a positive crossmatch to a negative one in highly sensitized people to allow renal transplantation. The most common side effects are infections and infusion related reactions.
Per the CHMP recommendation, imlifidase will be indicated for desensitization treatment of highly sensitized adult kidney transplant people with positive crossmatch against an available deceased donor. The use of imlifidase should be reserved for people unlikely to be transplanted under the available kidney allocation system including prioritization programmes for highly sensitized people.
Imlifidase was granted orphan drug designations by the European Commission in January 2017, and November 2018, and by the U.S. Food and Drug Administration (FDA) in both February and July 2018.
In February 2019, Hansa Medical AB changed its name to Hansa Biopharma AB.
|2||Recruiting||Treatment||Anti-Glomerular Basement Membrane Disease||1|
|2||Recruiting||Treatment||Guillain-Barré Syndrome (GBS)||1|
|2||Recruiting||Treatment||Kidney Transplant Rejection||1|
|2||Terminated||Treatment||Thrombotic Thrombocytopenic Purpura (TTP)||1|
|Not Available||Recruiting||Not Available||Kidney Transplant Failure and Rejection||1|
- “Imlifidase: Pending EC decision”. European Medicines Agency (EMA). 25 June 2020. Retrieved 26 June 2020. This article incorporates text from this source, which is in the public domain.
- “New treatment to enable kidney transplant in highly sensitised patients”. European Medicines Agency (Press release). 26 June 2020. Retrieved 26 June 2020. This article incorporates text from this source, which is in the public domain.
- “EU/3/16/1826”. European Medicines Agency (EMA). 12 January 2017. Retrieved 27 June 2020. This article incorporates text from this source, which is in the public domain.
- “EU/3/18/2096”. European Medicines Agency (EMA). 13 February 2019. Retrieved 27 June 2020. This article incorporates text from this source, which is in the public domain.
- “Imlifidase Orphan Drug Designation and Approval”. U.S. Food and Drug Administration (FDA). 3 July 2018. Retrieved 27 June 2020.
- “Imlifidase Orphan Drug Designation and Approval”. U.S. Food and Drug Administration (FDA). 14 February 2018. Retrieved 27 June 2020.
- Ge S, Chu M, Choi J, Louie S, Vo A, Jordan SC, et al. (October 2019). “Imlifidase Inhibits HLA Antibody-Mediated NK Cell Activation and Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) In Vitro”. Transplantation. doi:10.1097/TP.0000000000003023. PMID 31644495.
- Lin J, Boon L, Bockermann R, Robertson AK, Kjellman C, Anderson CC (March 2020). “Desensitization using imlifidase and EndoS enables chimerism induction in allosensitized recipient mice”. Am. J. Transplant. doi:10.1111/ajt.15851. PMID 32185855.
- Lonze BE, Tatapudi VS, Weldon EP, Min ES, Ali NM, Deterville CL, et al. (September 2018). “IdeS (Imlifidase): A Novel Agent That Cleaves Human IgG and Permits Successful Kidney Transplantation Across High-strength Donor-specific Antibody”. Ann. Surg. 268 (3): 488–496. doi:10.1097/SLA.0000000000002924. PMID 30004918.
- Lorant T, Bengtsson M, Eich T, Eriksson BM, Winstedt L, Järnum S, et al. (November 2018). “Safety, immunogenicity, pharmacokinetics, and efficacy of degradation of anti-HLA antibodies by IdeS (imlifidase) in chronic kidney disease patients”. Am. J. Transplant. 18 (11): 2752–2762. doi:10.1111/ajt.14733. PMC 6221156. PMID 29561066.
- “Imlifidase”. Drug Information Portal. U.S. National Library of Medicine.
|Pronunciation||im lif’ i dase|
|Chemical and physical data|
|Molar mass||35071.36 g·mol−1|
//////////Imlifidase, Idefirix, PEPTIDE, イムリフィダーゼ , 2020 APPROVALS, EMA 2020, EU 2020