Valoctocogene roxaparvovec

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Valoctocogene roxaparvovec
Gene therapy
Target gene Factor VIII
Vector Adeno-associated virus
Nucleic acid type DNA
Delivery method Intravenous
Clinical data
Trade names Roctavian
Other namesBMN-270, Valrox, valoctocogene roxaparvovec-rvox
License data
Routes of
administration 		Intravenous
Drug class Antihemorrhagics
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
UNII
KEGG

Valoctocogene roxaparvovec, sold under the brand name Roctavian, is a gene therapy used for the treatment of hemophilia A. [1] [3] It was developed by BioMarin Pharmaceutical. [4] [5] [6] 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. [3] It is an adeno-associated virus vector-based gene therapy. [1] It is given by intravenous infusion. [3]

Contents

The most common side effects include increased levels of the liver enzymes alanine aminotransferase and aspartate aminotransferase (signs of possible liver problems), increased levels of the enzyme lactate dehydrogenase (sign of possible tissue damage), nausea (feeling sick), and headache. [3]

Valoctocogene roxaparvovec was approved for medical use in the European Union in August 2022, [3] [4] and in the United States in June 2023. [7] [8]

Medical uses

In the European Union, valoctocogene roxaparvovec is indicated for the treatment of severe hemophilia 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). [3]

In the United States, valoctocogene roxaparvovec is indicated for the treatment of adults with severe hemophilia A (congenital factor VIII deficiency with factor VIII activity < 1 IU/dL) without pre-existing antibodies to adeno-associated virus serotype 5 detected by an FDA-approved test. [1] [7]

Mechanism of action

Valoctocogene roxaparvovec is a gene therapy 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. [9] [10]

History

The US Food and Drug Administration (FDA) granted valoctocogene roxaparvovec orphan drug status in 2016, [11] and breakthrough therapy designation in 2017. [12]

However, in August 2020, BioMarin received a Complete Response Letter from the FDA, indicating that its Biologics License Application (which would have made valoctocogene roxaparvovec the first gene therapy to be approved for a bleeding disorder) would not be approved. [13] The regulator was concerned that differences between results from the phase I/II trials (the 270-201 study) [14] and the phase III trial (the 270-301 study) [15] were too dissimilar with regard to durability, the latter suggesting that the protective effect of valoctocogene roxaparvovec wore off after approx. 12-18 months. [16]

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. [7] Effectiveness was established based on results from a cohort of 112 participants followed up for at least 3 years after valoctocogene roxaparvovec treatment. [7] Following the infusion, the mean annualized bleeding rate decreased from 5.4 bleeds per year at baseline to 2.6 bleeds per year. [7] The majority of participants who received valoctocogene roxaparvovec received corticosteroids to suppress the immune system for the gene therapy to be effective and safe. [7] The FDA granted the application for valoctocogene roxaparvovec orphan drug, breakthrough therapy, regenerative medicine advanced therapy, and priority review designations. [7] The FDA granted approval of Roctavian to BioMarin Pharmaceutical Inc. [7]

Society and culture

On 23 June 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (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. [17] [5] As Roctavian is an advanced therapy medicinal product, the CHMP positive opinion is based on an assessment by the Committee for Advanced Therapies. [5] The applicant for this medicinal product is BioMarin International Limited. [5] Valoctocogene roxaparvovec was approved for medical use in the European Union in August 2022. [3] [4]

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. [7]

Related Research Articles

<span class="mw-page-title-main">Gene therapy</span> Medical technology

Gene therapy is a medical technology that aims to produce a therapeutic effect through the manipulation of gene expression or through altering the biological properties of living cells.

<span class="mw-page-title-main">Haemophilia</span> Genetic disease involving blood clotting

Haemophilia, or hemophilia, is a mostly inherited genetic disorder that impairs the body's ability to make blood clots, a process needed to stop bleeding. This results in people bleeding for a longer time after an injury, easy bruising, and an increased risk of bleeding inside joints or the brain. Those with a mild case of the disease may have symptoms only after an accident or during surgery. Bleeding into a joint can result in permanent damage while bleeding in the brain can result in long term headaches, seizures, or an altered level of consciousness.

<span class="mw-page-title-main">Haemophilia A</span> Medical condition

Haemophilia A is a blood clotting disorder caused by a genetic deficiency in clotting factor VIII, thereby resulting in significant susceptibility to bleeding, both internally and externally. This condition occurs almost exclusively in males born to carrier mothers due to X-linked recessive inheritance. Nevertheless, rare isolated cases do emerge from de novo (spontaneous) mutations.

<span class="mw-page-title-main">Haemophilia B</span> Genetic X-linked recessive bleeding disorder

Haemophilia B, also spelled hemophilia B, is a blood clotting disorder causing easy bruising and bleeding due to an inherited mutation of the gene for factor IX, and resulting in a deficiency of factor IX. It is less common than factor VIII deficiency.

von Willebrand disease Medical condition

Von Willebrand disease (VWD) is the most common hereditary blood-clotting disorder in humans. An acquired form can sometimes result from other medical conditions. It arises from a deficiency in the quality or quantity of von Willebrand factor (VWF), a multimeric protein that is required for platelet adhesion. It is known to affect several breeds of dogs as well as humans. The three forms of VWD are hereditary, acquired, and pseudo or platelet type. The three types of hereditary VWD are VWD type 1, VWD type 2, and VWD type 3. Type 2 contains various subtypes. Platelet type VWD is also an inherited condition.

<span class="mw-page-title-main">Adeno-associated virus</span> Species of virus

Adeno-associated viruses (AAV) are small viruses that infect humans and some other primate species. They belong to the genus Dependoparvovirus, which in turn belongs to the family Parvoviridae. They are small replication-defective, nonenveloped viruses and have linear single-stranded DNA (ssDNA) genome of approximately 4.8 kilobases (kb).

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 replacement therapies (ERTs). BioMarin was the first company to provide therapeutics for mucopolysaccharidosis type I, by manufacturing laronidase. BioMarin was also the first company to provide therapeutics for phenylketonuria (PKU).

<span class="mw-page-title-main">Factor VIII (medication)</span> Pharmaceutical drug

Factor VIII is a medication used to treat and prevent bleeding in people with hemophilia A and other causes of low factor VIII. Certain preparations may also be used in those with von Willebrand's disease. It is given by slow injection into a vein.

Recombinant factor VIIa (rfVIIa) is a form of blood factor VII that has been manufactured via recombinant technology. It is administered via an injection into a vein. It is used to treat bleeding episodes in people who have acquired haemophilia, among other indications. There are several disimilar forms, and biosimilars for each. All forms are activated.

Vosoritide, sold under the brand name Voxzogo, is a medication used for the treatment of achondroplasia, a genetic condition that causes severely short stature and disproportionate growth.

<span class="mw-page-title-main">Emicizumab</span> Monoclonal antibody

Emicizumab, sold under the brand name Hemlibra, is a humanized bispecific monoclonal antibody for the treatment of haemophilia A, developed by Genentech and Chugai. A Phase I clinical trial found that it was well tolerated by healthy subjects.

<span class="mw-page-title-main">Spark Therapeutics</span> American pharmaceutical company

Spark Therapeutics, Inc. is a developer of gene therapy treatments, which treat debilitating genetic diseases. It is a subsidiary of Hoffmann-La Roche.

Acquired haemophilia A (AHA) is a rare but potentially life-threatening bleeding disorder characterized by autoantibodies directed against coagulation factor VIII. These autoantibodies constitute the most common spontaneous inhibitor to any coagulation factor and may induce spontaneous bleeding in patients with no previous history of a bleeding disorder.

Damoctocog alfa pegol, sold under the brand name Jivi is a recombinant DNA-derived, Factor VIII concentrate used to treat hemophilia A.

<span class="mw-page-title-main">Ultragenyx</span> American biopharmaceutical company

Ultragenyx Pharmaceutical Inc. is an American biopharmaceutical company involved in the research and development of novel products for treatment of rare and ultra-rare genetic diseases for which there are typically no approved treatments and high unmet medical need. The company works with multiple drug modalities including biologics, small molecule, gene therapies, and ASO and mRNAs in the disease categories of bone, endocrine, metabolic, muscle and CNS diseases.

<span class="mw-page-title-main">Viral vector vaccine</span> Type of vaccine

A viral vector vaccine is a vaccine that uses a viral vector to deliver genetic material (DNA) that can be transcribed by the recipient's host cells as mRNA coding for a desired protein, or antigen, to elicit an immune response. As of April 2021, six viral vector vaccines, four COVID-19 vaccines and two Ebola vaccines, have been authorized for use in humans.

Elivaldogene autotemcel, sold under the brand name Skysona, is a gene therapy used to treat cerebral adrenoleukodystrophy (CALD). It was developed by Bluebird bio and was given breakthrough therapy designation by the U.S. Food and Drug Administration in May 2018.

Etranacogene dezaparvovec, sold under the brand name Hemgenix is a gene therapy used for the treatment of hemophilia B. Etranacogene dezaparvovec is an adeno-associated virus vector-based gene therapy which consists of a viral vector carrying a gene for clotting Factor IX. The gene is expressed in the liver to produce Factor IX protein, to increase blood levels of Factor IX and thereby limit bleeding episodes. Hemophilia B is a genetic bleeding disorder resulting from missing or insufficient levels of blood clotting Factor IX, a protein needed to produce blood clots to stop bleeding.

Fidanacogene elaparvovec, sold under the brand name Beqvez among others, is a gene therapy delivered via adeno-associated virus used for the treatment of hemophilia B.

References

  1. 1 2 3 4 "Roctavian- valoctocogene roxaparvovec-rvox injection, solution". DailyMed. 20 December 2019. Retrieved 28 August 2023.
  2. ↑ "Roctavian". U.S. Food and Drug Administration (FDA). 30 June 2023. Archived from the original on 5 July 2023. Retrieved 4 July 2023.
  3. 1 2 3 4 5 6 7 8 "Roctavian EPAR". European Medicines Agency (EMA). 20 June 2022. Archived from the original on 4 March 2023. Retrieved 4 March 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  4. 1 2 3 4 "Roctavian Product information". Union Register of medicinal products. 25 August 2022. Archived from the original on 22 May 2023. Retrieved 6 September 2022.
  5. 1 2 3 4 "Roctavian: Pending EC decision". European Medicines Agency (EMA). 23 June 2022. Archived from the original on 26 June 2022. Retrieved 26 June 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. ↑ "Roctavian (formerly Valrox/BMN 270)". BioNews Services, LLC. Archived from the original on 9 July 2021. Retrieved 1 July 2021.
  7. 1 2 3 4 5 6 7 8 9 "FDA Approves First Gene Therapy for Adults with Severe Hemophilia A". U.S. Food and Drug Administration (FDA) (Press release). 30 June 2023. Retrieved 4 July 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  8. ↑ "U.S. Food and Drug Administration Approves BioMarin's Roctavian (valoctocogene roxaparvovec-rvox), the First and Only Gene Therapy for Adults with Severe Hemophilia A" (Press release). BioMarin Pharmaceutical. 29 June 2023. Retrieved 4 July 2023– via PR Newswire.
  9. ↑ Bunting S, Zhang L, Xie L, Bullens S, Mahimkar R, Fong S, et al. (February 2018). "Gene Therapy with BMN 270 Results in Therapeutic Levels of FVIII in Mice and Primates and Normalization of Bleeding in Hemophilic Mice". Molecular Therapy. 26 (2): 496–509. doi:10.1016/j.ymthe.2017.12.009. PMC   5835117 . PMID   29292164.
  10. ↑ Rosen S, Tiefenbacher S, Robinson M, Huang M, Srimani J, Mackenzie D, et al. (November 2020). "Activity of transgene-produced B-domain-deleted factor VIII in human plasma following AAV5 gene therapy". Blood. 136 (22): 2524–2534. doi:10.1182/blood.2020005683. PMC   7714098 . PMID   32915950.
  11. ↑ "BioMarin Receives Orphan Drug Designation From FDA for First AAV-Factor VIII Gene Therapy, BMN 270, for Patients With Hemophilia A" (Press release). BioMarin Pharmaceutical Inc. 1 March 2016. Archived from the original on 9 July 2021. Retrieved 1 July 2021– via GlobeNewswire.
  12. ↑ "FDA Grants Breakthrough Therapy Designation for BioMarin's Valoctocogene Roxaparvovec (formerly BMN 270), an Investigational Gene Therapy for Hemophilia A". BioMarin Investors (Press release). Archived from the original on 23 June 2021. Retrieved 1 July 2021.
  13. ↑ "BioMarin Receives Complete Response Letter (CRL) from FDA for Valoctocogene Roxaparvovec Gene Therapy for Severe Hemophilia A". BioSpace. Archived from the original on 9 July 2021. Retrieved 1 July 2021.
  14. ↑ "Gene Therapy Study in Severe Haemophilia A Patients (270-201)". ClinicalTrials.gov. January 2021. Archived from the original on 9 July 2021. Retrieved 1 July 2021.
  15. ↑ "A Phase 3 Open-Label, Single-Arm Study To Evaluate The Efficacy and Safety of BMN 270, an Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Hemophilia A Patients With Residual FVIII Levels ≤ 1 IU/dL Receiving Prophylactic FVIII Infusions". ClinicalTrials.gov. January 2021. Archived from the original on 9 July 2021. Retrieved 1 July 2021.
  16. ↑ Adams B (19 August 2020). "FDA gets out its red pen again, rejecting BioMarin's gene therapy valrox amid durability worries". FierceBiotech. Archived from the original on 9 July 2021. Retrieved 1 July 2021.
  17. ↑ "First gene therapy to treat severe haemophilia A". European Medicines Agency (EMA) (Press release). 24 June 2022. Archived from the original on 26 June 2022. Retrieved 26 June 2022.


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