Bulevirtide acetate

(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

ブレビルチド酢酸塩;

APROVED 2020/7/31, EU, Hepcludex

MYR GmbH

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.

https://www.ema.europa.eu/en/documents/assessment-report/hepcludex-epar-public-assessment-report_en.pdf

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.

HDV infection is rare, and Hepcludex was designated an ‘orphan medicine’ (a medicine used in rare diseases) on 19 June 2015. For further information on the orphan designation, see EU/3/15/1500.

Hepcludex contains the active substance bulevirtide.

Bulevirtide, sold under the brand name Hepcludex, is an antiviral medication for the treatment of chronic hepatitis D (in the presence of hepatitis B).^[2]

The most common side effects include raised levels of bile salts in the blood and reactions at the site of injection.^[2]

Bulevirtide works by attaching to and blocking a receptor (target) through which the hepatitis delta and hepatitis B viruses enter liver cells.^[2] 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.^[2]

Bulevirtide was approved for medical use in the European Union in July 2020.^[2]

Bulevirtide is indicated for the treatment of chronic hepatitis delta virus (HDV) infection in plasma (or serum) HDV-RNA positive adult patients with compensated liver disease.^[2][3]

Pharmacology

Mechanism of action

Bulevirtide binds and inactivates the sodium/bile acid cotransporter, blocking both viruses from entering hepatocytes.^[4]

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^[5][6] that can also dock to NTCP, blocking the virus’s entry mechanism.^[7]

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.^[7]

References

External links

• “Bulevirtide”. Drug Information Portal. U.S. National Library of Medicine.

/////////Bulevirtide acetate, ブレビルチド酢酸塩 , orphan designation, MYR GmbH, PEPTIDE, EU 2020, 2020 APPROVALS