Valoctocogene roxaparvovec, sold under the brand name Roctavian, is a

gene therapy Gene therapy is a medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying human DN ...

used for the treatment of

hemophilia A Haemophilia A (or hemophilia A) is a genetic deficiency in clotting factor VIII, which causes increased bleeding and usually affects males. In the majority of cases it is inherited as an X-linked recessive trait, though there are cases which arise ...

. It was developed by

BioMarin Pharmaceutical BioMarin Pharmaceutical Inc. is an American biotechnology company headquartered in San Rafael, California. It has offices and facilities in the United States, South America, Asia, and Europe. BioMarin's core business and research is in enzyme re ...

. Valoctocogene roxaparvovec is made of a virus (AAV5) that has been modified to contain the gene for factor VIII, which is lacking in people with hemophilia A. It is given by

intravenous infusion Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

. The most common side effects include increased levels of the liver enzymes

alanine aminotransferase Alanine transaminase (ALT) is a transaminase enzyme (). It is also called alanine aminotransferase (ALT or ALAT) and was formerly called serum glutamate-pyruvate transaminase or serum glutamic-pyruvic transaminase (SGPT) and was first character ...

and

aspartate aminotransferase Aspartate transaminase (AST) or aspartate aminotransferase, also known as AspAT/ASAT/AAT or (serum) glutamic oxaloacetic transaminase (GOT, SGOT), is a pyridoxal phosphate (PLP)-dependent transaminase enzyme () that was first described by Arthur ...

(signs of possible liver problems), increased levels of the enzyme

lactate dehydrogenase Lactate dehydrogenase (LDH or LD) is an enzyme found in nearly all living cells. LDH catalyzes the conversion of lactate to pyruvate and back, as it converts NAD+ to NADH and back. A dehydrogenase is an enzyme that transfers a hydride from on ...

(sign of possible tissue damage),

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

(feeling sick), and

headache Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Headaches can occur as a result ...

. Valoctocogene roxaparvovec was approved for medical use in the European Union in August 2022, and in the United States in June 2023.

Medical uses

Valoctocogene roxaparvovec is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

for the treatment of severe haemophilia A (congenital factor VIII deficiency) in adults without a history of factor VIII inhibitors and without detectable antibodies to adeno-associated virus serotype 5 (AAV5).

Mechanism of action

Valoctocogene roxaparvovec is a

that uses an adeno-associated virus 5 (AAV5) that codes for human Factor VIII, together with a human liver-specific promoter that encourages translation in hepatocytes, not liver endothelial and sinusoidal cells, where Factor VIII is ordinarily synthesised.

History

The US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) granted valoctocogene roxaparvovec

orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment of ...

status in 2016, and

breakthrough therapy Breakthrough therapy is a United States Food and Drug Administration designation that expedites drug development that was created by Congress under Section 902 of the 9 July 2012 Food and Drug Administration Safety and Innovation Act. The FDA's "br ...

designation in 2017. However, in August 2020, BioMarin received a

Complete Response Letter In United States pharmaceutical regulatory practice, a Complete Response Letter (CRL), or more rarely, a 314.110 letter, is a regulatory action by the Food and Drug Administration in response to a New Drug Application, New Drug Application, Amended ...

from the FDA, indicating that its

Biologics License Application A biologics license application (BLA) is defined by the U.S. Food and Drug Administration (FDA) as follows: The biologics license application is a request for permission to introduce, or deliver for introduction, a biologic product into inters ...

(which would have made valoctocogene roxaparvovec the first gene therapy to be approved for a

bleeding disorder Coagulopathy (also called a bleeding disorder) is a condition in which the blood's ability to coagulate (form clots) is impaired. This condition can cause a tendency toward prolonged or excessive bleeding (bleeding diathesis), which may occur spo ...

) would not be approved. The regulator was concerned that differences between results from the phase I/II trials (the 270-201 study) and the

phase III trial The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...

(the 270-301 study) were too dissimilar with regard to durability, the latter suggesting that the protective effect of valoctocogene roxaparvovec wore off after approx. 12-18 months. The safety and effectiveness of valoctocogene roxaparvovec were evaluated in a multinational study in adult men 18 to 70 years of age with severe hemophilia A who were previously treated with factor VIII replacement therapy. Effectiveness was established based on results from a cohort of 112 participants followed up for at least 3 years after valoctocogene roxaparvovec treatment. Following the infusion, the mean annualized bleeding rate decreased from 5.4 bleeds per year at baseline to 2.6 bleeds per year. The majority of participants who received valoctocogene roxaparvovec received

corticosteroid Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involv ...

s to suppress the immune system for the gene therapy to be effective and safe. The FDA granted the application for valoctocogene roxaparvovec orphan drug, breakthrough therapy, regenerative medicine advanced therapy, and

priority review Priority review is a program of the United States Food and Drug Administration (FDA) to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease. The priority review voucher program ...

designations. The FDA granted approval of Roctavian to BioMarin Pharmaceutical Inc.

Society and culture

Legal status

On 23 June 2022, the

Committee for Medicinal Products for Human Use The Committee for Medicinal Products for Human Use (CHMP), formerly known as Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regarding ...

(CHMP) of the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...

(EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Roctavian, intended for the treatment of severe haemophilia A. As Roctavian is an advanced therapy medicinal product, the CHMP positive opinion is based on an assessment by the Committee for Advanced Therapies. The applicant for this medicinal product is BioMarin International Limited. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Valoctocogene roxaparvovec was approved for medical use in the European Union in August 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. In June 2023, the US FDA approved valoctocogene roxaparvovec for the treatment of adults with severe hemophilia A without pre-existing antibodies to adeno-associated virus serotype 5 detected by an FDA-approved test.

References

Antihemorrhagics Breakthrough therapy Drugs that are a gene therapy Gene therapy Haemophilia Orphan drugs {{blood-drug-stub