Roctavian (valoctocogene roxaparvovec) is a gene therapy indicated to treat severe hemophilia A in adult patients without a history of factor VIII (FVIII) inhibitors and without detectable antibodies to adeno-associated virus serotype 5 (AAV5).
Roctavian was developed by BioMarin Pharmaceutical.
The price of Roctavian is set at €1.5 million ($1.5 million).
By the end of September 2022, BioMarin planned to send the Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA).
One dose of betibeglogene autotemcel will permanently eliminate the dependence on regular blood transfusions.
What Is Hemophilia A
Hemophilia A is an X-linked recessive blood clotting disorder.
Hemophilia A is caused by an insufficient activity or dysfunction of coagulation factor VIII (FVIII) in the coagulation cascade (blood clotting process).
- FVIII, also called antihemophilic factor (AHF), is synthesized primarily in the liver, and its active form (FVIIIa) serves as a cofactor for activated factor IX (FIXa), accelerating the conversion of factor X (FX) to active factor X (FXa) in the clotting propagation phase. FXa promotes the conversion of prothrombin to thrombin. Thrombin in turn promotes the conversion of fibrinogen to fibrin, which leads to the formation of a thrombus (blood clot).
Hemophilia A can either be a hereditary disease due to a genetic aberrantity (chromosomal mutation) or an acquired immunological process.
Hereditary hemophilia A affects predominantly males, with a prevalence of 25 cases per 100,000 live births. Approximately 10% of female carriers have FVIII activity below 30%–35%, and they have mild symptoms of hemophilia A.
The clinical phenotype of hemophilia A patients usually correlates closely with the level of residual FVIII expression:
- Severe hemophilia A is characterized by FVIII activity below 1% of nonmutant FVIII activity (plasma FVIII levels below 1 IU/dL) and frequent spontaneous bleeding into joints or muscles.
- Moderate hemophilia A is characterized by FVIII activity from 1% to 5% (1-5 IU/dL), intermittent spontaneous bleeding, and prolonged bleeding during surgery or minor trauma.
- Mild hemophilia A is characterized by FVIII activity above 5%–40% (above 5–40 IU/dL) and severe bleeding after surgery or major trauma. Spontaneous bleeding is rare.
Clinical manifestations of severe hemophilia A are represented by frequent episodes of spontaneous bleeding, mostly in joints and soft tissues, with a significantly increased risk of death from hemorrhage involving the brain. Patients with the moderate form of the disease may have manifestations similar to those of patients with the severe form, resulting in a comparable bleeding phenotype.
Complications of hemophilia A include synovitis and arthropathy secondary to recurrent hemarthrosis (joint hemorrhage), delayed post-traumatic bleeding, and formation of inhibitors to FVIII.
Lethality in hemophilia A correlates with the economic development of the patient’s country of residence: In countries with resources for its therapy, mortality is comparable to the general population, while in poor countries life expectancy is dramatically reduced. The most common causes of death in hemophilia A are liver disease and hemorrhage, especially intracranial hemorrhage. The most common morbidity is associated with chronic joint disease.
Treatment of severe hemophilia A involves intravenous infusions of replacement concentrates of recombinant FVIII, both as prevention (usually two to three times a week) and directly at the time of bleeding, in order to respectively prevent or stop bleeding episodes.
Hemophilia A replacement therapy, which appeared in 1968, is now represented by a wide range of drugs, but they cannot be called successful. The half-life of FVIII replacement is 12–18 hours for most approved drugs, which is why frequent infusions (every two or three days) are required to prevent bleeding. Chemical modification (direct conjugation of FVIII to polyethylene glycol polymers) and bioengineering (fusion of FVIII to Fc protein) prolonged the half-life by approximately 50%, which allowed reduced dosing frequency of FVIII (every four to five days) while maintaining its activity level above 1% for most of the time between doses. Nevertheless, patients with severe hemophilia A still remain completely dependent on multiple infusions.
Despite significant progress in the treatment of hemophilia A, patients with severe hemophilia A still experience bleeding even with prophylactic therapy: the average annualized bleeding rate (ABR) is 1–4. The consequence of multiple bleeding is the development of debilitating joint arthropathy and a significantly increased risk of death.
Moreover, FVIII replacement therapy in some cases (up to 30% of patients) leads to the production of autoimmune antibodies that inhibit FVIII, which complicates therapy (FVIII elimination half-life is reduced to less than 7 hours). In order to remove the inhibitors and restore the normal clinical response to FVIII, immune tolerance is induced by adding immunosuppressive drugs (cyclophosphamide, corticosteroids, rituximab) to FVIII replacement therapy for several months or years.
The lives of patients with hemophilia A changed dramatically for the better when in mid-November 2017 Roche offered Hemlibra (emicizumab) indicated to prevent or reduce bleeding in hemophilia A. In a maintenance regimen, the drug is administered subcutaneously (by the patient himself) once a week, every two weeks, or even every month.
In any case, there is an unmet medical need for new drugs for the treatment and prevention of bleeding in hemophilia A.
Roctavian: Mechanism of Action of Valoctocogene Roxaparvovec
Valoctocogene roxaparvovec (AAV5-hFVIII-SQ, BMN 270), or valrox for short, is a gene therapy which, after a single administration, promises to get rid of hemophilia A once and for all. Well, or reduce it to a degree of severity that minimally affects the patient’s quality of life.
Valoctocogene roxaparvovec is an adenoviral vector serotype 5 (AAV5) lacking the ability to replicate and carrying a codon-optimized transgene of blood clotting factor VIII (FVIII), in which, due to the limited capacity of the AAV5 expressing cassette, the B-domain (SQ variant of FVIII) is eliminated. A small but efficient hybrid liver-specific transcriptional promoter was added.  
After a single intravenous infusion of Roctavian, the patient’s body starts to produce endogenous FVIII on its own (mainly by endothelial cells of the hepatic sinusoid), bringing its expression to an acceptable level to boldly claim the transformation of a severe form of hemophilia A into a mild or moderate one.
Roctavian: Efficacy and Safety of Hemophilia A Gene Therapy
The GENEr8-1 (NCT03370913) phase 3 (non-randomized, open-label, multicenter, international) clinical trial enrolled adult men (n=132) with hereditary hemophilia A.
Participants’ hemophilia A had to be characterized by a severe course, that is, coagulation factor VIII (FVIII) activity did not exceed 1% (FVIII level ≤ 1 IU/dL). Participants had to follow bleeding prophylaxis with FVIII concentrates for at least one year. They had to have no FVIII inhibitors or pre-existing antibodies to the AAV5 capsid.
Trial subjects received a single intravenous infusion of valoctocogene roxaparvovec at a dose of 6×1013 viral genomes/kg. After infusion, prophylactic administration of FVIII concentrates continued for 4 weeks.
The primary endpoint of treatment efficacy was established by a change in FVIII activity at 49–52 weeks after therapy.
After use of Roctavian, the mean and median FVIII activity levels were 43±46 IU/dL and 24 IU/dL (interquartile range [IQR] 12–62). In other words, gene therapy for hemophilia A completely transfomerized its course and severity.
Thus, median FVIII activity ≥ 40 IU/dL was observed in 38% of patients, that is, they were in a status without hemophilia A. FVIII activity within the range of 5−40 IU/dL was recorded in 50%; the disease acquired a mild form. FVIII activity < 5 or < 3 IU/dL was recorded for 12% and 9%; hemophilia A became characterized by a course with moderate severity.
Accordingly, there were positive changes related to the need for FVIII replacement therapy and the frequency of bleeding requiring treatment.
If initially patients required an average of 136 and a median of 129 FVIII concentrate infusion procedures per year with an average volume of 3961 IU/kg and a median volume of 3754 IU/kg, after gene therapy with Roctavian the number of such procedures decreased to 2.0 (99% reduction) and 0 with volumes decreased to 57 IU/kg (99% reduction) and 0 IU/kg.
While the initial annualized bleeding rate (ABR) was an average of 4.8 and a median of 2.8, the rate was reduced to 0.8 (84% reduction) and 0. The proportion of patients without any bleeding was 80% after single administration of valoctocogene roxaparvovec.
Patients (n=17) who received gene therapy at least 2 years ago had FVIII activity levels of average 24±29 IU/dL and median 15 IU/dL (IQR 6–29) after 104 weeks of follow-up. At the same time, 18% had fair status without hemophilia A, 59% had mild disease, and 24% had moderate hemophilia A.
The main issue with gene therapy treatment of severe hemophilia A in patients who have had single-dose Roctavian (valoctocogene roxaparvovec) is the level of coagulation factor VIII (FVIII) activity, which, after reaching levels in people without hemophilia A, gradually decreases.
Thus, during the 5-year follow-up of participants in the NCT02576795 phase 1/2 clinical trial who were administered valoctocogene roxaparvovec at a dose of 6×1013 viral genomes/kg, FVIII activity fell each year: to respective mean of 64%, 36%, 33%, 24%, and 12% and median 60%, 26%, 20%, 16%, and 8%. In other words, if immediately after treatment we could talk about a complete cure of hemophilia A, then it returned, by the results stopping at the stage of mild severity.   
Looking at the annualized bleeding rate (ABR), all is well here: Over the 5-year period, it dropped 95% from baseline to a cumulative mean of 0.8 and median of 0.0 ([interquartile range, IQR] 0.0–5.0), with 86% of patients having no bleeding at all.
Here’s how the ABR, which before treatment was a mean 16.3 and median 16.5 (IRQ 0.0–40.0), changed over 5 years after use of Roctavian: mean 1.3, 0.2, 0.7, 1.3, and 0.7 and median 0.0 (IRQ 0.0–7.6), 0.0 (IRQ 0.0–1.0), 0.0 (IRQ 0.0–4.0), 0.0 (IRQ 0.0–7.9), and 0.0 (IRQ 0.0–4.0).
Overall, it is still unclear how long the healing effect of hemophilia A gene therapy will last in terms of maintaining FVIII activity levels at acceptable and clinically meaningful levels. It should be understood that Roctavian can only be administered once due to the production of autoantibodies to the viral vector. Repeated exposure to the same vector is accompanied by the risk of a powerful immune response, which will not only impede the successful delivery of genetic material into the body, but may be reflected by life-threatening adverse reactions.
Patients who might want to get rid of the burden of hemophilia A for good will be in no particular hurry, looking very closely at Roctavian and hoping in passing for some other treatment that is more reliable.
It is precisely because of the lack of clarity about the duration of the therapeutic effect of Roctavian that its market launch has been accompanied by a number of obstacles. In early November 2020, BioMarin withdrew Marketing Authorisation Application (MAA) for Roctavian in Europe due to its inability to satisfy the European Medicines Agency (EMA), which questioned the safety of the gene therapy for hemophilia A and the duration of its effect due to a relatively short clinical trial. In mid-August 2020, the U.S. Food and Drug Administration (FDA) refused to approve Roctavian as a whole for the same reason.
BioMarin estimates that there are approximately 8,000 patients with severe hemophilia A in Europe, of whom somewhere around 3,200 are eligible for gene therapy with Roctavian.
BioMarin is continuing negotiations with health systems in selected European countries, including Germany, France, Italy, and Spain. Agreements will be made to return part of the payment if the treatment stops working within 5 years afterwards, meaning that the patient has had to go back to standard replacement therapy for hemophilia A. So, for example, if the effect of Roctavian disappears after 4 years, BioMarin will return 20% of the €1.5 million paid. There are not many risks here, as only 4.5% of patients (n=6/134) who have undergone clinical trials have experienced failure of gene therapy.
The price of Roctavian in the U.S., if approved, will be traditionally higher than in Europe. In January 2020, even before the FDA rejected its Biologics License Application (BLA), BioMarin was expecting between $2 million and $3 million. Such an astronomical cost seemed to satisfy health insurance providers, because lifelong replacement therapy for an American patient with severe hemophilia A costs incomparably more, up to $25 million.
According to calculations by the U.S. Institute for Clinical and Economic Review (ICER) in the fall of 2020, the estimated U.S. price of $2.5 million for Roctavian is reasonable, but solely because of the high cost of hemophilia A replacement therapy with recombinant FVIII. By the end of 2022, ICER will complete an assessment of the fair price of valoctocogene roxaparvovec based on accumulated evidence of its long-term benefit.
According to industry forecasts, sales of Roctavian will reach $695 million in 2026.