valoctocogene roxaparvovec-rvox

Action and Spectrum

Actions and Spectrum: 

Mechanism of Action:  

• valoctocogene roxaparvovec utilizes an adeno-associated virus serotype 5 (AAV5) vector to deliver a functional copy of the human factor VIII gene into the patient’s liver cells. The AAV5 vector is engineered to be non-replicative, meaning it cannot replicate or cause an ongoing infection in the body. Once administered, the vector targets and enters hepatocytes (liver cells). 
• Inside the hepatocytes, the AAV5 vector carries the human factor VIII gene, which is integrated into the cell’s DNA. The cell’s machinery then starts producing factor VIII protein based on the instructions provided by the gene. The newly produced factor VIII is released into the bloodstream, where it can fulfill its role in clotting and prevent excessive bleeding episodes. 

Spectrum of Activity:  

• valoctocogene roxaparvovec is explicitly designed for treating hemophilia A caused by a deficiency of clotting factor VIII. It is intended for use in patients with severe hemophilia A who have developed inhibitors to factor VIII, making common factor VIII replacement therapy less effective or ineffective. 
• This gene therapy product aims to provide a long-term solution by establishing sustained factor VIII production in the patient’s liver, potentially reducing the frequency of bleeding episodes and the need for common factor VIII replacement therapy. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

AST increases >ULN (69%) 

CPK increases >ULN (45%) 

Factor VIII activity levels >ULN (28%) 

Bilirubin increases >ULN (13%) 

ALT increases >ULN (81%) 

LDH increases >ULN (57%) 

Nausea (31%) 

GGT increases >ULN (18%) 

Fatigue (16%) 

1-10% 

Abdominal pain (6%) 

Diarrhea (4%) 

Gastroenteritis (1%) 

Headache (7%) 

Infusion-related reactions (7%) 

Vomiting (6%) 

Dizziness (2%) 

Rash (1%) 

Black Box Warning

Black box warning: 

None 

Contraindication / Caution

Contraindications/caution: 

Contraindications: 

• Active infections: The therapy is contraindicated in the presence of active infections, whether they are acute or uncontrolled chronic infections.  
• Significant hepatic fibrosis or cirrhosis: valoctocogene roxaparvovec is contraindicated in individuals with known significant hepatic fibrosis (stage 3 or 4) or cirrhosis.  
• Hypersensitivity to mannitol: mannitol is a sugar alcohol used as an excipient in some formulations of valoctocogene roxaparvovec. 

Caution: 

• Adverse Reactions: valoctocogene roxaparvovec may cause adverse reactions or side effects.  
• Immune Response: valoctocogene roxaparvovec utilizes an adeno-associated virus (AAV) vector to deliver the therapeutic gene. Sometimes, the body’s immune system may recognize the AAV vector as foreign and respond against it.  
• Pre-existing Immunity to AAV: Some individuals may already have pre-existing immunity to the AAV vector used in valoctocogene roxaparvovec.

Pregnancy / Lactation

Pregnancy consideration: Insufficient data available 

Lactation: Excretion of the drug in human breast milk is unknown 

Pregnancy category: 

Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 

Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    

Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    

Category N: There is no data available for the drug under this category 

Pharmacology

Pharmacology: 

The pharmacology of valoctocogene roxaparvovec involves using an adeno-associated virus (AAV) vector to deliver the therapeutic gene into the patient’s cells.  

• Gene Delivery: valoctocogene roxaparvovec uses an AAV serotype 5 (AAV5) vector as a delivery system. The AAV5 vector is engineered to be non-replicative.It is designed to target hepatocytes (liver cells) once administered specifically. 
• Factor VIII Gene Insertion: The AAV5 vector carries a functional copy of the human factor VIII gene, deficient in individuals with hemophilia A. The AAV5 vector enters the hepatocytes and delivers the factor VIII gene. Inside the hepatocytes, the gene is integrated into the cell’s DNA. 
• Factor VIII Production: Once integrated into the hepatocyte’s DNA, the cell’s machinery starts producing factor VIII protein based on the instructions provided by the gene. The newly produced factor VIII is then released into the bloodstream, contributing to the clotting process and preventing excessive bleeding. 
• Duration of Effect: valoctocogene roxaparvovec aims to provide long-term therapeutic benefit by establishing sustained production of factor VIII in the liver cells. The therapy is designed to provide a lasting effect, potentially reducing or eliminating the need for common factor VIII replacement therapy. 

Pharmacodynamics: 

The pharmacodynamics of valoctocogene roxaparvovec (valrox or ValRox) primarily revolves around restoring clotting factor VIII activity in individuals with hemophilia A.  

• Restoration of Factor VIII Activity: valoctocogene roxaparvovec aims to address the underlying cause of hemophilia A by introducing a functional copy of the factor VIII gene into liver cells. The therapeutic gene is delivered using an adeno-associated virus (AAV) vector.  
• Increased Factor VIII Levels: Functional factor VIII protein production within the liver cells increases factor VIII levels in the bloodstream. This increase helps restore the clotting process and improves the individual’s ability to form stable blood clots. 
• Reduction in Bleeding Episodes: The pharmacodynamic effect of valoctocogene roxaparvovec is to reduce or prevent bleeding episodes in individuals with hemophilia A. By maintaining adequate factor VIII levels, the therapy can improve clotting capacity, thus reducing the risk of spontaneous or excessive bleeding. 
• Long-Term Expression: valoctocogene roxaparvovec is designed to provide long-term expression of factor VIII. The therapy aims to establish sustained production of factor VIII within the liver cells, potentially reducing or eliminating the need for frequent factor VIII replacement therapy. 

Pharmacokinetics: 

Absorption 

valoctocogene roxaparvovec is typically administered via intravenous (IV) infusion. After administration, the AAV vector is expected to circulate in the bloodstream, allowing it to reach target cells, specifically hepatocytes in the liver. 

Distribution 

The AAV vector used in valoctocogene roxaparvovec, AAV5, is designed to target hepatocytes selectively. It may distribute to the liver and enter the cells to deliver the therapeutic gene (factor VIII) to the nucleus for integration into the cell’s DNA. 

Metabolism 

Once inside the hepatocytes, the AAV vector is not typically metabolized in the same way as small molecule drugs. Instead, the vector’s genetic material, containing the factor VIII gene, is integrated into the cellular DNA. The hepatocytes then utilize their cellular machinery to transcribe and translate the factor VIII gene into a functional protein. 

Elimination and Excretion 

The excretion pathway of valoctocogene roxaparvovec is not applicable in the traditional sense, as the AAV vector is not expected to be excreted from the body. Instead, the vector and the integrated genetic material persist within the hepatocytes, leading to sustained production of factor VIII protein. 

Adminstartion

Administration: 

• Intravenous Infusion: The therapy is delivered as an intravenous infusion, injected directly into a vein.  
• Dilution and Preparation: Before administration, the valoctocogene roxaparvovec product is typically diluted and prepared according to the instructions provided by the manufacturer.  
• Infusion Procedure: The diluted valoctocogene roxaparvovec solution is administered using a sterile infusion set and delivered through an intravenous line or catheter. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: valoctocogene roxaparvovec-rvox 

Why do we use valoctocogene roxaparvovec-rvox? 

• valoctocogene roxaparvovec (also known as valrox or ValRox) is a gene therapy product for treating hemophilia A, a genetic bleeding disorder caused by a deficiency of clotting factor VIII.  
• valoctocogene roxaparvovec primarily provides a functional copy of the factor VIII gene to individuals with hemophilia A, thereby restoring factor VIII activity and reducing the frequency and severity of bleeding episodes.