BIOCHEMISTRY, BIOMEDICINE & PHARMACEUTICS

GIVLAARI (givosiran) injection, for subcutaneous use GIVLAARI is an aminolevulinate synthase 1-directed small interfering RNA (siRNA), covalently linked to a ligand containing three N-acetylgalactosamine (GalNAc) residues to enable the delivery of the siRNA to hepatocytes. CLINICAL PHARMACOLOGY Mechanism of Action  Givosiran is a double-stranded small interfering RNA that causes degradation of aminolevulinate synthase 1 (ALAS1) mRNA in hepatocytes through RNA interference, reducing the elevated levels of liver ALAS1 mRNA. This leads to reduced circulating levels of neurotoxic intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG), factors associated with attacks and other disease manifestations of AHP.  Pharmacodynamics The pharmacodynamic effects of GIVLAARI were evaluated in chronic high excreters treated with 0.035 to 2.5 mg/kg single dose and AHP patients treated with 2.5 to 5 mg/kg once monthly and 2.5 to 5 mg/kg once Reference ID: 4522564 quarterly dose...

MALS (Multi Angle Stable Light Scattering) 

Liquid Chromatography-Mass Sppectoromtery- It is a powerful analytical technique that combines the resolving power of liquid chromatography with the detection specificity of mass spectrometry. Liquid chromatography (LC) separates the sample components and then introduces them to the mass spectrometer (MS). The MS creates and detects charged ions. The LC/MS data may be used to provide information about the molecular weight, structure, identity, and quantity of specific sample components. Applications of LC-MS Proteomics Metabolomics Protein Identification, Characterization and Quntitation Protein Structural Analysis Triple quadrupole Mass Spectrometry Principle (Watch Video) 6470B Triple quadrupole LC/MS (Agilent) Technical Specification The Agilent 6470B triple quadrupole LC/MS system delivers robust performance and high versatility for commercial, life sciences research, and regulatory applications. It has best-in-class sensitivity, precision, and scan speed.  The 6470B LC/MS/MS t...

FDA Guidance for Biodistribution Studies in Gene Therapy The longer the GT product persists, the greater the duration and degree of risk of delayed adverse events. FDA recommends the clinical biodistribution studies using methods shown to be sensitive and quantitative to detect product sequences. These studies should be designed to determine the distribution of the product in non-target tissues and the persistence of the product in both non-target and target tissues following direct in vivo administration of the product. The studies should employ an animal species that permits vector transduction and/or vector replication and that the animal species be biologically responsive to the specific transgene of interest or to therapeutic components in the product (e.g., for products that may not contain transgenes and only genome editing components). Digital Droplet PCR (ddPCR) Platforms for Viral Biodistribution Studies QX200 AutoDG Droplet Digital PCR System Quantstudio 3D ...

 Zolgensma is the first gene therapy product approved for the treatment of children less than two years of age with Spinal Muscular Atrophy (SMA). Norvastis obtained the approval of the drug May 2019 & has been a blockbuster with a price tag of 2 million dollars. In the recent  FDA inspections, FDA observed that the standards were not meet in accordance to GMP guidance. Those include Failure to follow the standard procedures Failure to report complete data sets for the potency testing of the gene therapy product Failure to thoroughly review any unexplained discrepancy whether or not the batch has been already distributed. Laboratory records do not include completed records of any testing and standardization of laboratory standards. What action FDA is taking? FDA are carefully assessing the issue of the manipulation of the product testing data used in the production process and are conducting a thorough assessment of the information from a recently com...