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General Description:

Valoctocogene roxaparvovec, identified by CAS number 1819334-78-5, is a notable compound with significant therapeutic applications. Valoctocogene roxaparvovec is an adeno-associated virus serotype 5 (AAV5) based gene therapy vector that expresses the B-domain deleted SQ form of human coagulation factor VIII (hFVIII-SQ). The expression of hFVIII-SQ is driven by a liver-specific promoter, which enables hepatocytes to produce factor VIII protein and increase the levels of active factor VIII in blood. Valoctocogene roxaparvovec was approved by EMA in September 2022 and is indicated for the treatment of severe hemophilia A. It is not approved for use in the United States. Hemophilia A treatments such as prophylactic regimens of exogenous factor VIII or improve the clinical outcomes of patients but do not eliminate breakthrough bleeding. As opposed to these therapies, valoctocogene roxaparvovec offers the advantage of continuous and measurable steady-state levels of coagulation factor VIII.

Indications:

This drug is primarily indicated for: Valoctocogene roxaparvovec is indicated for the treatment of severe hemophilia A (congenital factor VIII deficiency) in adult patients without a history of factor VIII inhibitors and without detectable antibodies to adeno-associated virus serotype 5 (AAV5). Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Valoctocogene roxaparvovec undergoes metabolic processing primarily in: As a gene therapy medicinal product, valoctocogene roxaparvovec is expected to be metabolized by nucleases throughout the body. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Valoctocogene roxaparvovec are crucial for its therapeutic efficacy: The total amount of vector DNA in tissues, blood, and shedding matrices was evaluated in patients treated with valoctocogene roxaparvovec. A quantitative polymerase chain reaction (qPCR) assay was used in order to measure transgene DNA and fragments of degraded DNA. Vector DNA was detected in blood and shedding matrices, with peak concentrations between 1 and 9 days after valoctocogene roxaparvovec administration. Blood, saliva, semen, stool, and urine showed the highest vector DNA concentrations. The highest concentration detected in blood was 2×10¹¹ vg/mL, and the highest concentration detected in any shedding matrix was 1×10¹⁰ vg/mL. Levels declined steadily after reaching the highest transgene DNA concentration. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Route of Elimination:

The elimination of Valoctocogene roxaparvovec from the body primarily occurs through: Clinical studies have shown that valoctocogene roxaparvovec is eliminated through urine (all patients), saliva (99% of patients) and feces (84% of patients). Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Clearance:

The clearance rate of Valoctocogene roxaparvovec is a critical factor in determining its safe and effective dosage: The maximum time to clearance of valoctocogene roxaparvovec was 8 weeks for urine, 26 weeks for saliva, and 88 weeks for stool. The maximum time to clearance of vector DNA in semen is 36 weeks. The maximum time to clearance of encapsidated and potentially infectious vector DNA in semen was 12 weeks. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Valoctocogene roxaparvovec exerts its therapeutic effects through: The pharmacodynamic effects of valoctocogene roxaparvovec were evaluated by measuring the activity of circulating factor VIII. Adult males with severe hemophilia A were given a single intravenous infusion of 6×10¹³ vg/kg valoctocogene roxaparvovec, and their factor VIII activity levels were tracked at least for 6 months. Within 5 months post-infusion, 95% of patients had factor VIII activity levels equal to or higher than 5 IU/dL. Long-term data (5 years follow-up) are available from 7 patients treated with valoctocogene roxaparvovec, and they all continued to show a clinically meaningful response to treatment. The presence of pre-existing anti-adeno-associated virus serotype 5 (AAV5) antibodies has a significant effect on valoctocogene roxaparvovec efficiency; therefore, it should not be used in patients with detectable anti-AAV5 antibodies. Shortly after valoctocogene roxaparvovec infusion, patients may experience infusion-related side effects. Also, due to the increased production of active factor VIII, patients may have an increased possibility of unwanted blood clot formation. Since there is a possibility that valoctocogene roxaparvovec inserts into body cells other than liver cells, its use may contribute to a higher risk of malignancy. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Valoctocogene roxaparvovec functions by: Valoctocogene roxaparvovec is an adeno-associated virus serotype 5 (AAV5) based gene therapy vector containing a coagulation factor VIII complementary DNA driven by a liver-specific promoter; and is used to treat hemophilia A, a condition characterized by the deficient activity of coagulation factor VIII. After valoctocogene roxaparvovec is infused into patients, the AAV5 vector delivers a B-domain deleted SQ form of a recombinant human factor VIII (hFVIII-SQ) to cells. This working copy of coagulation factor VIII is then expressed in the liver, producing an active form of factor VIII that is then released into the bloodstream. This leads to bleeding normalization and a lower risk of bleeding episodes. The long-term production of hFVIII-SQ is supported following valoctocogene roxaparvovec infusion. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Valoctocogene roxaparvovec is categorized under the following therapeutic classes: Adeno-associated Viral Vector Therapies, Blood Coagulation Factors, Cellular and Gene Therapy, Genetic Therapy, Recombinant Proteins. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.