Single Dose Gene Therapy Revolutionizes Hemophilia Treatment

Hemophilia, a rare genetic bleeding disorder, arises from mutations in genes encoding clotting factors that are synthesized in the liver. These mutations impede clot formation. Diagnosis usually occurs early in life. Hemophilia A is the most common type arising from clotting factor VIII deficiency and four times less prevalent is hemophilia B, which is linked to a factor IX deficiency.



The genes for hemophilia A and B reside on the X chromosome, making it an X-linked disorder. Men are primarily affected, while women are often carriers. However, it's important to note that women can also develop hemophilia, albeit rarely. Typically inherited through parental genes or DNA, hemophilia can also occur due to spontaneous mutations. The severity of hemophilia ranges from mild to moderate to severe and most often bleeding occurs in the muscle and joints. In life threatening cases bleeding could occur in the Gastrointestinal cavity, in neck/throat and in Intracranial regions.



Ground breaking non-Factor replacement therapy administered weekly via subcutaneous injection offers significant improvement in managing Hemophilia A.



The current standard treatment for hemophilia involves replacement therapy with CFCs (clotting factor concentrates). This therapy, delivered via frequent intravenous (IV) infusions, utilizes either recombinant (genetically engineered) or plasma-derived (from healthy blood donors) replacement factors. On the other hand non-factor replacement therapy offers an alternative approach where instead of directly replacing missing clotting factors, the therapy is focused on targets in the coagulation cascade. HYMPAVZITM (marstacimab-hncq) approved by FDA in 2024 for Pfizer, is anti-tissue factor pathway inhibitor (anti-TFPI), designed to be administered once-weekly via pre-filled, auto-injector pen for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and pediatric patients 12 years of age and older with Hemophilia A and B (without inhibitors) A significant limitation of current standard-of-care prophylaxis, encompassing both clotting factor concentrates (CFCs) and non-factor replacement therapies, is the requirement for recurrent infusions or subcutaneous administrations throughout a patient's lifetime. Additionally, a serious side effect of CFC treatment arises from the immune system's recognition of CFCs as foreign substances. This can lead to the production of inhibitory antibodies, which significantly complicates treatment.

For over half a century, scientists have been exploring gene therapy as a potential treatment for genetic diseases. The core principle of gene therapy is to introduce functional genes into cells to correct or compensate for genetic defects, with the aim of restoring normal function or inactivating harmful genes. Several pharmaceutical and therapeutic companies are racing to develop innovative gene therapies, offering a potential cure for hemophilia that aims to provide patients with a long-lasting, effective solution. This holds promise of freeing patients from the burden of frequent treatments and the fear of spontaneous bleeds.

Pfizer developed a one-time gene therapy called BEQVEZ™ (fidanacogene elaparvovec-dzkt) for adults with hemophilia B that is approved by the FDA. It is an adeno-associated virus (AAV) vector gene therapy to deliver a functional copy of the Factor IX gene, specifically designed to produce a high-activity variant of the protein. This one-time treatment aims to empower patients with hemophilia B by enabling their own bodies to produce Factor IX, eliminating the need for frequent infusions. BEQVEZ™ is indicated for the treatment of adults with moderate to severe hemophilia B who do not have neutralizing antibodies to adeno-associated virus serotype Rh74var (AAVRh74var) capsid. Antibodies against AAVRh74var can be detected by an invitro companion diagnostic test called nAbCyte Assay (nAbCyte™ Anti-AAVRh74var HB-FE Assay) to determine patient eligibility for treatment with BEQVEZ™.

Lipid nanoparticle-based gene delivery offers a non-viral alternative with potential for improved safety and efficacy. This approach may minimize off-target effects and immune responses, enabling sustained gene expression and long-term therapeutic benefits. As gene therapy continues to evolve, we are witnessing a new era of hope for patients with Hemophilia.

In recent decades, the landscape of RNA biology has been dramatically reshaped by the groundbreaking discovery of small noncoding RNAs and their pivotal role in gene regulation.

Among these, small interfering RNAs (siRNAs) stand out as powerful players. Synthetically produced, siRNAs are at the forefront of a new era in drug development. They operate by forming a complex called the RNA-induced silencing complex (RISC). This sophisticated machinery then precisely targets and degrades specific messenger RNA (mRNA) molecules. The result is a highly effective reduction in the production of unwanted proteins.

The FDA approval of Qfitlia (fitusiran) in 2025 for Sanofi is a testament to the power of cutting-edge small interfering RNA (siRNA) technology. This is the first therapy in the US to treat hemophilia A or B with or without inhibitors. This innovative approach targets and reduces antithrombin, a protein that naturally inhibits blood clotting. By precisely lowering AT levels, Qfitlia rebalances the body's clotting system, significantly increasing thrombin generation to restore crucial hemostasis in individuals with hemophilia.

The FDA's approval of Qfitlia represents not just a new drug, but a paradigm shift in hemophilia management, showcasing the immense potential of targeted RNA interference therapeutics to address critical unmet needs in complex diseases. This approval solidifies siRNA technology as a transformative force in modern medicine, offering hope for countless individuals living with hemophilia.