The First FDA-Approved Gene Therapy for Hemophilia A: 5-Year Results and Market Withdrawal of Roctavian
In this article
Gene Therapy for Hemophilia A: Roctavian From Approval to Market Withdrawal, and Today's Treatment Options
Hemophilia A is an X-linked bleeding disorder caused by a deficiency of clotting factor VIII (FVIII). On June 29, 2023, the US Food and Drug Administration (FDA) approved valoctocogene roxaparvovec (Roctavian), the first gene therapy for adults with severe hemophilia A. Delivering a working FVIII gene to the liver with a single infusion, the therapy freed most patients from regular factor injections for years. However, because FVIII levels declined over time, and because of its $2.9 million price, reimbursement hurdles and the arrival of new drugs given infrequently under the skin, the manufacturer BioMarin announced in February 2026 that it would withdraw Roctavian from the market. In this updated guide, we explain what hemophilia A is, how gene therapy works, what the 5-year results showed, why the therapy was withdrawn and which options are available for hemophilia A as of 2026. We discussed how genetic changes lead to disease in our article on the Human Genome Project and a different approach to gene editing in our article on CRISPR and Casgevy.
- The article has been rewritten from scratch; diagrams, illustrations and charts have been added.
- BioMarin announced in October 2025 that it was seeking a buyer for Roctavian and in February 2026 that it would withdraw the product in the US, Germany and Italy; the therapy could be administered until the end of May 2026. Follow-up of patients who were previously treated continues.
- The 5-year results of the GENEr8-1 trial and the new hemophilia drugs approved or awaiting approval between 2024 and 2026 have been added.
- An error in the previous text has been corrected: the virus used in Roctavian is not an "adenovirus" but an adeno-associated virus (AAV); the two are different viruses.
- What is Roctavian? A one-time intravenous gene therapy for adults with severe hemophilia A that delivers the FVIII gene to the liver inside a harmless viral shell called AAV5. It received FDA approval on June 29, 2023.
- How effective was it? In the GENEr8-1 trial, the mean annualized bleeding rate fell from 5.4 to 2.6; after 5 years, 81% of patients were living without returning to regular factor therapy. However, the mean FVIII level declined from 42 IU/dL in year 1 to 14 IU/dL in year 5.
- Why was it withdrawn? BioMarin announced in February 2026 that it would withdraw the product because of uncertainty about how long the effect lasts, the $2.9 million price, reimbursement hurdles, eligibility requirements and competition from new subcutaneous drugs.
- What options are available today? Standard and extended half-life FVIII, emicizumab, anti-TFPI antibodies (marstacimab, concizumab) and fitusiran are in use; denecimig (Mim8) is awaiting an FDA decision. Gene therapy research continues.
Why does this matter?
If left untreated, a person with severe hemophilia A has spontaneous bleeding into the joints and muscles; over the years, joint damage, pain and limited mobility develop. Life-threatening bleeds, such as bleeding in the brain, can also occur. Standard treatment is to replace the missing FVIII intravenously several times a week; this is a lifelong, time-consuming and expensive treatment. Gene therapy, which enables the body to make its own FVIII after a single infusion, therefore generated great excitement.
The story of Roctavian shows both the power and the limits of gene therapy: a scientifically effective treatment can struggle to reach patients when the durability of its effect remains uncertain, its price is very high and more practical alternatives emerge. This experience also holds important lessons for expensive one-time therapies in many fields, including cancer (such as CAR T-cell therapy).
What is Roctavian?
Roctavian (valoctocogene roxaparvovec) is a one-time gene therapy developed for adults with severe hemophilia A that delivers the FVIII gene to liver cells inside a viral shell called AAV5. The liver begins to produce FVIII, and bleeding decreases. It received FDA approval in 2023; the manufacturer withdrew the product from the market in 2026.
What is hemophilia A?
Hemophilia A is a rare, inherited bleeding disorder caused by a change in the gene (F8) that encodes FVIII, a protein involved in blood clotting. It occurs in about 1 in every 5,000 male births. When FVIII is lacking, a blood clot cannot form quickly or firmly enough; bleeding lasts longer and sometimes starts for no reason at all.
The F8 gene is located on the X chromosome. Because males have only one X chromosome, a faulty copy causes the disease. In females, the second X chromosome usually compensates for the deficiency; these women are "carriers," but some of them have low FVIII levels and may have mild bleeding symptoms. About one-third of cases arise from a new genetic change, with no previous history of hemophilia in the family.
Figure 1 · How hemophilia A is inherited
X-linked recessive inheritance
| Severity | FVIII level | Typical bleeding pattern |
|---|---|---|
| Severe | <1 IU/dL (less than 1% of normal) | Spontaneous bleeding into joints and muscles; roughly half to two-thirds of patients are in this group |
| Moderate | 1–5 IU/dL | Prolonged bleeding after minor trauma; occasional spontaneous bleeding |
| Mild | 5–40 IU/dL | Bleeding mostly after surgery, tooth extraction or serious injury |
Figure 2 · FVIII level and hemophilia severity
Which range did gene therapy move patients into?
Symptoms: easy bruising, prolonged bleeding from small cuts, pain, swelling and warmth in the joints (bleeding into a joint), bleeding into muscles, nose and gum bleeding, and blood in the urine or stool. These symptoms can also have other causes (nosebleeds, blood in the urine, blood in the stool); coagulation tests should be performed for prolonged or unexplained bleeding.
What does FVIII do, and where do treatments act?
Clotting is a chain of proteins that activate one another. FVIII is a key link in this chain: by forming a bridge between activated factor IX (IXa) and factor X, it enables large amounts of thrombin to be generated and a firm fibrin clot to form. When FVIII is lacking, this bridge cannot form; little thrombin is generated and the clot remains weak.
Figure 3 · The role of FVIII in clotting and where drugs act
Replacing the missing bridge, mimicking it or easing the brakes
How does gene therapy work?
Roctavian uses a viral shell that has been rendered harmless: adeno-associated virus serotype 5 (AAV5). Inside this shell is a shortened FVIII gene designed to work in the liver. The shell does not cause disease and cannot replicate in the body. After it is given as a one-time intravenous infusion, it enters liver cells; the gene it carries stays in the cell nucleus as a ring (episome) separate from the patient's own chromosomes and starts FVIII production. The FVIII produced enters the bloodstream and partially corrects clotting.
Figure 4 · The four steps of AAV gene therapy
Vector, infusion, liver cell, FVIII in the blood
This approach has two important limitations. First, if a person's immune system has previously encountered natural AAV5 infection and developed antibodies, the vector is neutralized before it reaches the liver. For this reason, before treatment, the blood is tested for AAV5 antibodies with an FDA-approved companion diagnostic (AAV5 DetectCDx); people with antibodies cannot receive the therapy. Second, a second dose cannot be given with the same vector, because the body produces strong antibodies after the first dose. In addition, because the added gene may be diluted as cells divide, the therapy is not suitable for children, whose livers are still growing.
Who was eligible for Roctavian?
Figure 5 · Eligibility criteria
Based on the US approval
The GENEr8-1 trial: what did it show?
Roctavian's approval is based on the multinational phase 3 GENEr8-1 trial, which enrolled men aged 18–70 years with severe hemophilia A who had previously received regular FVIII prophylaxis. A total of 134 participants were treated. In the group of 112 patients evaluated by the FDA and followed for at least 3 years, the mean annualized bleeding rate fell from 5.4 during regular FVIII therapy to 2.6 after gene therapy. In relative terms, this is a reduction of about 52%; the great majority of patients stopped regular factor injections.
Bleeding decreased markedly after gene therapy
GENEr8-1 phase 3 trial; men with severe hemophilia A who had previously received regular FVIII prophylaxis. Mean annualized bleeding rate.
The first rows show all bleeds from the FDA approval documents (at least 3 years of follow-up, 112 patients); the last rows show treated bleeds from the 5-year analysis. The comparison is between the same patients' periods before and after gene therapy; there is no control group.
The 5-year results, announced in June 2025, showed that the benefit persisted but that FVIII levels had declined. In year 5, 77.8% of patients had no treated bleeds at all; across the entire follow-up, the mean rate of treated bleeds was 0.8 per year. Of the 134 participants in total, 109 (81.3%) were living without returning to regular factor therapy at the end of year 5; 25 people (about 19%) resumed prophylaxis. No patient developed inhibitors against FVIII, blood clots (thrombosis) or treatment-related cancer.
FVIII levels declined over the years
GENEr8-1; mean FVIII activity, IU/dL (chromogenic assay). Normal level about 50–150; mild hemophilia range 5–40 IU/dL.
The decline was rapid in the first two years and slower thereafter; in year 5, most patients were still in the mild hemophilia or normal range, and about 19% had returned to regular treatment. Values measured in the same samples with the one-stage assay are higher (24.0 IU/dL in year 5).
The trend in the chart sums up the central question of gene therapy: how long does the effect last? FVIII levels fell rapidly in the first two years and slowly thereafter. The mean value in year 5 was still within the mild hemophilia range, but there were large differences between patients: in some, levels remained high, whereas in others they approached the severe hemophilia range within a few years. This individual unpredictability made decisions harder for both patients and payers.
Side effects and monitoring
The most common problem is elevated liver enzymes (ALT). In the pivotal trial, ALT rose in the great majority of patients (more than about 80%), and most patients needed corticosteroids for months, because the immune response to the vector can affect the FVIII-producing liver cells and lower FVIII levels (elevated liver enzymes). Long-term corticosteroid use (corticosteroids) also brought its own side effects, such as weight gain, sleep disturbance and high blood sugar. According to the year 5 data, no corticosteroid use for ALT elevation was needed after year 2.
Other side effects include headache, nausea, vomiting, fatigue, abdominal pain and reactions during or shortly after the infusion. Two theoretical risks were also closely monitored: an FVIII level above normal could increase the risk of blood clots, and rare insertion of vector DNA into the cell's genome could theoretically carry a risk of liver tumors. No events related to these risks were seen in 5 years of follow-up; however, long-term monitoring for many years is recommended for patients who have received gene therapy (liver cancer).
Figure 6 · Monitoring after gene therapy
From infusion to the long term
Why was Roctavian withdrawn from the market?
Roctavian received conditional approval in Europe in August 2022 and approval in the US in June 2023. Its US list price was $2.9 million. Sales fell far short of expectations: $26 million in 2024 and $36 million in 2025. BioMarin first limited its activities to the US, Germany and Italy, where reimbursement agreements were in place, and in October 2025 announced that it was seeking a buyer for the product. When no suitable buyer was found, it announced in February 2026 that it would withdraw Roctavian from the market and took a write-down of about $240 million. The therapy could be administered until the end of May 2026; the company stated that follow-up and support programs for previously treated patients would continue.
| Factor | What happened? |
|---|---|
| Durability of effect | FVIII levels declined over the years and varied greatly from person to person; the expectation of "one treatment for life" was not met. |
| Price and reimbursement | A one-time payment of $2.9 million; payers sought outcomes-based agreements (payment only if the effect lasts). |
| Eligibility | People with AAV5 antibodies, a history of inhibitors or liver disease could not receive the therapy; a substantial share of patients were not eligible. |
| Monitoring burden | Weekly blood tests for months and long-term corticosteroids could be required. |
| Competition | Drugs such as emicizumab, which can be given under the skin once a month, were already largely preventing bleeding in most patients. |
US list prices of one-time gene therapies
Single-dose price announced at approval, US$ millions.
Roctavian was priced to pay for itself within a few years compared with the annual cost of regular factor therapy; however, when the durability of the effect remained uncertain, payers were cautious.
Roctavian is not the only example: Pfizer stopped production of Beqvez, its approved gene therapy for hemophilia B, in February 2025. Hemgenix (November 2022), the first gene therapy for hemophilia B, remains in use. Research in gene therapy continues with the goals of longer-lasting effect, the ability to give a second dose, use in children and lower cost (an example of gene therapy in cancer).
Hemophilia A treatment in 2026: what options are available?
Even though Roctavian has been withdrawn, hemophilia A treatment has changed radically over the past decade. In many patients, factor given intravenously several times a week has been replaced by drugs given under the skin once a week, every two weeks, once a month or even every two months. The goal is no longer only to stop bleeding but to have no bleeds at all and to lead a normal life.
Figure 7 · Hemophilia A treatment options
As of October 2026
| Treatment | How does it work? | Administration | Status (US) |
|---|---|---|---|
| Standard and extended half-life FVIII | Replaces the missing FVIII | Intravenous; 2–3 times a week, once a week with efanesoctocog alfa | Standard for years; efanesoctocog alfa 2023 |
| Emicizumab | Bispecific antibody that mimics FVIII by bridging IXa and X | Subcutaneous; weekly, every 2 weeks or monthly | 2017–2018; in patients with and without inhibitors |
| Marstacimab | Antibody that releases the TFPI brake | Subcutaneous; weekly | October 2024; 12 years and older, without inhibitors |
| Concizumab | Antibody that releases the TFPI brake | Subcutaneous; daily | December 2024 in patients with inhibitors; later expanded |
| Fitusiran | siRNA that reduces antithrombin production | Subcutaneous; monthly to every two months | March 2025; with and without inhibitors, 12 years and older |
| Denecimig (Mim8) | Next-generation bispecific antibody similar to emicizumab | Subcutaneous; weekly to monthly | Application September 2025; FDA decision delayed because of a manufacturing facility, expected in 2027 |
| Gene therapy (Roctavian) | Adds an FVIII gene to the liver | One-time intravenous | Approved 2023; withdrawn from the market in 2026 |
In the fitusiran trials, the annualized bleeding rate fell by 71% in patients without inhibitors and by 73% in patients with inhibitors compared with factor therapy. However, because the risk of blood clots increases if antithrombin levels fall too low, the drug is dosed according to the antithrombin level in the blood and carries a boxed warning; monitoring for gallbladder problems and liver effects is also needed. Similarly, if bleeding occurs in patients taking rebalancing agents, additional factor or bypassing agents should be given cautiously and at low doses. Bispecific antibodies work on the same principle as the bispecific antibodies used in cancer (bispecific antibodies).
Hemophilia and cancer: why does it matter in oncology?
Thanks to advances in hemophilia treatment, the life expectancy of people with hemophilia has approached that of the general population; this means that age-related diseases such as cancer are being seen more often in this group. From an oncology perspective, three points stand out:
- Diagnostic and treatment procedures: Before a biopsy, endoscopy, surgery, port placement or radiation therapy, a plan to prevent bleeding with factor or other drugs should be made together with the hemophilia treatment center.
- Chemotherapy and low platelets: When chemotherapy lowers the platelet count, the risk of bleeding rises further; treatment should be managed through a joint decision of the hematology and oncology teams.
- Liver cancer risk: Patients with hemophilia who acquired hepatitis C and B from plasma-derived products before the 1990s have a high risk of cirrhosis and liver cancer (a new treatment for chronic hepatitis B); these patients benefit from regular liver cancer screening. This is also why the theoretical liver tumor risk of gene therapy is being monitored closely.
We explained how clinical trials and new treatments are evaluated in patients with cancer in our clinical trials guide and our article on phase 1 trials.
- Roctavian was not licensed in Türkiye; with its market withdrawal, the possibility of obtaining it from abroad has also disappeared.
- In Türkiye, standard and extended half-life FVIII products and emicizumab are available; reimbursement conditions depend on the regulations of the Social Security Institution (SGK, Türkiye's national health insurer) and on the report of the hemophilia treatment center (SGK reimbursement and the SUT).
- For newly approved drugs (marstacimab, concizumab, fitusiran), licensing status with the Turkish Medicines and Medical Devices Agency (TİTCK, the national drug regulator) varies by drug; drugs that are licensed but not reimbursed (examples) or unlicensed drugs may become an option through importation from abroad (importing drugs from abroad).
- Hemophilia should be diagnosed and monitored at experienced hemophilia treatment centers; genetic counseling should be offered to carrier women (genetic counseling in inherited conditions).
Questions you can ask your doctor
- How severe is my hemophilia, and what are my FVIII level and inhibitor status?
- How many bleeds a year do I have on my current treatment? Would it be appropriate for me to switch to a drug given less often?
- Are emicizumab, anti-TFPI drugs or fitusiran suitable for me? What would the risk of blood clots and the monitoring look like?
- Can I take part in gene therapy research? Can I have my AAV antibody test done?
- If I need surgery, dental treatment or a biopsy, what plan should be made to prevent bleeding?
- Is carrier testing and genetic counseling recommended for the women in my family?
- "Gene therapy permanently cures hemophilia." With Roctavian, FVIII levels declined over the years, and about one in five patients returned to regular treatment within 5 years; because the faulty gene is not corrected, the disease does not go away.
- "The children of someone who received gene therapy will not have hemophilia." No. The added gene is present only in liver cells; inheritance does not change.
- "Roctavian is an adenovirus therapy." No. The vector used is an adeno-associated virus (AAV), a virus that is different from adenovirus and does not cause disease.
- "If it was withdrawn, the therapy did not work." No. The decision to withdraw it was made not because of a safety problem but for commercial and access reasons; the benefit continues in most treated patients.
- "Hemophilia occurs only in males." It occurs mostly in males, but some carrier women have low FVIII and may have bleeding symptoms.
Frequently Asked Questions
- What is Roctavian, and how is it given?
- Roctavian is a one-time gene therapy developed for adults with severe hemophilia A. It delivers the FVIII gene to the liver inside a harmless viral shell called AAV5 and enables the liver to produce FVIII. It is given once as an intravenous infusion; an AAV5 antibody test is required beforehand.
- Why was Roctavian withdrawn from the market?
- The manufacturer, BioMarin, announced in February 2026 that it would withdraw the product for commercial reasons. Contributing factors were the decline in FVIII levels over time, the $2.9 million price, reimbursement hurdles, strict eligibility requirements and competition from new subcutaneous drugs. The decision was not made because of a safety problem.
- What will happen to patients who received Roctavian?
- Follow-up and support programs for treated patients are continuing. FVIII levels, bleeding and liver health are checked regularly. If FVIII falls too low, the patient can switch back to factor or to a preventive therapy such as emicizumab.
- Which treatments are most commonly used for hemophilia A today?
- Intravenous standard or extended half-life FVIII and emicizumab, given under the skin anywhere from weekly to monthly, are the most common options. In recent years, marstacimab, concizumab and fitusiran have been approved; denecimig is awaiting an FDA decision. The choice is based on the person's bleeding history and preferences.
Glossary
- Hemophilia A
- An X-linked bleeding disorder caused by a deficiency of clotting factor VIII.
- Factor VIII (FVIII)
- The protein that forms a bridge between IXa and X in the clotting cascade.
- Prophylaxis
- Preventive treatment given at regular intervals, before any bleeding occurs.
- Inhibitor
- An antibody that develops in some patients against infused FVIII and neutralizes it.
- Gene therapy
- A treatment that adds a working copy of a gene to cells so that a missing protein can be produced.
- AAV (adeno-associated virus)
- A small virus that does not cause disease and is used as a carrier (vector) in gene therapy.
- Companion diagnostic
- A test approved together with a drug to determine who can receive it; for Roctavian, the AAV5 antibody test.
- Annualized bleeding rate (ABR)
- The number of bleeds a person has in a year; the main measure of effectiveness for hemophilia treatments.
- Emicizumab
- A bispecific antibody given under the skin that mimics the function of FVIII.
- Anti-TFPI
- A class of drugs that restores balance by blocking TFPI, one of the natural brakes on clotting.
DROZDOGAN Academy Commentary
Roctavian is an important example of the gap in medicine between "scientific success" and "success that reaches patients." Living for years without bleeds after a single infusion became possible; but this benefit could not be offered to everyone, at all times and at a sustainable cost.
⚡ Why it matters
Hemophilia A was one of the first major tests of gene therapy. The results showed that very expensive one-time therapies can become widely used only when their effect is durable and predictable. This lesson also applies to CAR T-cell therapy and other cell and gene therapies.
✅ Strengths
Over 5 years of follow-up, 81% of patients lived without returning to regular factor therapy, bleeding decreased markedly and no serious safety problems such as inhibitors, blood clots or cancer were seen. It was proven that gene therapy can make the liver produce a protein for years.
⚠️ Limitations
FVIII levels declined and varied unpredictably from person to person. The comparison was made without a control group, against the same patients' earlier period. Long-term corticosteroid use, strict eligibility requirements and the high price limited access.
🩺 In practice
For our patients with hemophilia, we plan cancer diagnosis and treatment together with the hemophilia treatment center, and we set the bleeding prevention strategy in advance for biopsy, surgery and chemotherapy. In patients with a history of hepatitis, we give priority to liver cancer screening.
❓ Open questions
Will next-generation vectors be able to provide more durable and predictable FVIII levels? Will a second dose or use in children become possible? With bleeding prevented so well by drugs given infrequently under the skin, what will the place of gene therapy be?
Bottom line: Roctavian showed that one-time gene therapy is possible in severe hemophilia A, but it was withdrawn from the market in 2026 because of declining FVIII levels, its high price and strong alternatives. Today, most patients with hemophilia A can live without bleeds, or with very few, on drugs given infrequently under the skin.
- This article was prepared in October 2026; it is a comprehensive update of the article "First Gene Therapy for Adults With Severe Hemophilia A Receives FDA Approval: Roctavian," published in June 2023.
- Efficacy data are based on the FDA approval documents and the 5-year results of the GENEr8-1 trial presented by BioMarin; the year 1 and year 2 FVIII values are taken from published trial reports. The trial had no control group.
- Information on the market withdrawal is based on the National Bleeding Disorders Foundation (NBDF) and industry news. The approval status of new drugs refers to the US; licensing and reimbursement conditions in Türkiye may change.
- The illustrations are simplified and not to scale. The Academy commentary is our own.
- This article is for general information; make your treatment decisions together with your hemophilia treatment center.
References
- U.S. Food and Drug Administration. FDA approves first gene therapy for adults with severe hemophilia A. June 29, 2023. fda.gov
- Ozelo MC, Mahlangu J, Pasi KJ, et al. Valoctocogene roxaparvovec gene therapy for hemophilia A. N Engl J Med 2022;386:1013-1025. doi:10.1056/NEJMoa2113708
- Mahlangu J, Kaczmarek R, von Drygalski A, et al. Two-year outcomes of valoctocogene roxaparvovec therapy for hemophilia A. N Engl J Med 2023;388:694-705. doi:10.1056/NEJMoa2211075
- BioMarin. Five-year phase 3 results reinforcing long-term efficacy and safety of ROCTAVIAN presented at ISTH 2025. June 24, 2025. biospace.com
- BioMarin. GENEr8-1 5-year poster, ISTH 2025. medical.biomarin.com
- National Bleeding Disorders Foundation. BioMarin pulls Roctavian hemophilia A gene therapy from US market. February 26, 2026. bleeding.org
- Fierce Pharma. BioMarin pulls hemophilia gene therapy Roctavian, taking $240M hit after divestiture efforts flounder. February 2026. fiercepharma.com
- AJMC. FDA approves fitusiran for reducing bleeds in patients with hemophilia A, B. March 28, 2025. ajmc.com
- National Bleeding Disorders Foundation. Pfizer discontinues Beqvez hemophilia B gene therapy. February 2025. bleeding.org
- Drugs.com. Novo provides update on the denecimig Biologics License Application in the US. October 2, 2026. drugs.com
Sources
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