Gene therapies show promising results

The goals of hemophilia therapy are becoming increasingly ambitious. The aim is now to normalize coagulation as far as possible. For adult patients, gene therapy is now one of many effective treatment options, although in Switzerland, unlike in the EU, a gene therapy drug has only been approved for patients with haemophilia B. In addition to criteria-based patient selection prior to gene therapy, several months of monitoring are required after the therapy has been carried out.

Hemophilia is a congenital x-linked hereditary bleeding disorder caused by a lack of or reduced activity of factor VIII (hemophilia A) or factor IX (hemophilia B) is marked. As both factors are components of the coagulation cascade, a deficiency can lead to greatly slowed blood clotting [1,4]. The symptoms depend on the severity of the disease**. More severe cases suffer from prolonged and more severe bleeding after injuries, and spontaneous bleeding can also occur in these patients (e.g. hematomas, joint bleeding and other internal bleeding). The milder forms of hemophilia only manifest clinically after major trauma or surgery. The classic therapy to reduce the frequency of spontaneous and traumatic bleeding is prophylaxis with exogenously supplied clotting factor [1]. “This is relatively time-consuming for the patients,” reported PD Dr. med. Robert Klamroth, Chief Physician, Clinic for Internal Medicine Angiology and Hemostaseology, Vivantes Klinikum im Friedrichshain, Berlin [2]. Up to three weekly injections are required. As an alternative to prophylactic factor replacement, the bispecific monoclonal antibody emicizumab, which mimics the function of activated FVIII and is applied subcutaneously at intervals of 1, 2 or 4 weeks, is available for patients with haemophilia A [3]. Emicizumab (Hemlibra®) has been approved in Switzerland since 2018 [6].

** The severity of hemophilia is divided into severe (<1 IU/dl or <1% of the norm), moderate (1-5 IU/dl or 1-5%) and mild (5-40 IU/dl or 5-40%) based on residual factor activity [1].

As a monogenetic disease, hemophilia is also suitable for gene therapy. The latter represents an innovative treatment option by introducing intact genes for the production of deficient coagulation factors into body cells [4]. By transferring a functioning gene into the liver cell, long-term, sometimes even normal production of the blood coagulation factor can be achieved, so that a single infusion can lead to a permanent reduction in bleeding events [5].

The first representatives of this new form of therapy are Valoctocogen-Roxaparvovec for hemophilia A and Etranacogene-Dezaparvovec for hemophilia B [6].

Gene therapy uses AAV as a vector

The basic principle of gene therapy for the treatment of hemophilia is that a specific gene for a coagulation factor is transported together with a vector. An adeno-associated virus (AAV) is used as a vector for this purpose. To ensure that the gene functions correctly in the target organ, the liver, the vector contains additional elements such as promoters and enhancers. These control elements help to bring the gene into the liver cells and regulate its activity there [5]. “The special thing about AAV viruses is that the genetic information is not integrated into the cell’s own DNA, but remains episomal,” explained the speaker [2]. The gene transfer is therefore an additive, not a corrective gene therapy [1]. Due to its predominantly episomal location, it was initially assumed that the transgene is lost when the hepatocytes divide. This does not appear to be relevant in adults with healthy livers; in clinical studies on hemophilia B, stable factor levels were observed for up to 8 years [1,7].

The AAV serotype (variable characteristics of the surface structure) plays a decisive role in the efficiency of hepatocellular transduction and the probability of the presence of preformed neutralizing antibodies against AAV in the recipient, which can reduce the effectiveness of the therapy [1,8].

GENEr8-1 study for hemophilia A: Valoctocogene roxaparvovec

The GENEr8-1 study included HIV-negative patients with severe hemophilia A [9]. Inclusion criteria included the absence of inhibitors and the absence of antibodies against AAV5. The study participants received a single infusion of Valoctocogene roxaparvovec at a dose of ^6×103 vector genomes per kilogram of body weight (vg/kg).132 study participants had analyzable data available at week 104 [12]. The mean annualized bleeding rate decreased by 84.5% since baseline (p<0.001). From week 76 onwards, the course of transgenic factor VIII activity showed first-order elimination kinetics; the estimated half-life was 123 weeks (95% confidence interval: 84-232). The risk of joint bleeding was also estimated using models. This showed a similar relationship between factor VIII activity and bleeding episodes in mild to moderate hemophilia A. Two years after the infusion, no new safety signals had emerged and there were no new serious adverse events related to the treatment. Across the entire study population, 82.9% fewer bleeding episodes requiring treatment occurred over the three-year period compared to baseline (p<0.0001) [10].
The speaker pointed out that there is considerable inter-individual variability in the response to therapy with regard to factor VIII activity. “We have no parameter to predict which patient will benefit,” says Dr. Klamroth [2].

HOPE-B study for hemophilia B

A total of 54 patients received a single dose of etranacogene-dezaparvovec in the pivotal study, with 53 patients completing at least 18 months of follow-up [11]. The primary endpoint in the HOPE-B study was the annualized bleeding rate 52 weeks after reaching a stable Factor IX expression level (months 7 to 18) compared to the six-month lead-in phase. For this endpoint, the annualized bleeding rate was measured from month 7 to month 18 post-infusion to ensure that the observation period represented stable Factor IX transgene expression. Secondary endpoints included the assessment of factor IX activity. The efficacy results 18 months after treatment with Etranacogene-Dezaparvovec showed superiority over previous continuous routine Factor IX prophylaxis. The total annual bleeding rate fell significantly by 64% and 96% of all patients no longer required routine Factor IX prophylaxis. No serious adverse drug reactions were reported and no inhibitors against factor IX were detected. In Switzerland, Etranacogene-Dezaparvovec (Hemgenix®) is approved for adult patients with haemophilia B [6,11]. According to current knowledge, AAV gene therapy can only be used once.

Follow-up checks are necessary

In addition to usually only mild intolerance reactions, there may be an increase in transaminases (ALT), which usually occurs a few weeks to months after the vector infusion. The ALT elevation is asymptomatic; the need for treatment arises from the observation that, if left untreated, it can be accompanied by a loss of factor expression [1]. “It is important to recognize and treat this in good time,” explained Dr. Klamroth [2]. The treatment consists of immunosuppression with prednisolone. It is recommended that patients with haemophilia B should be monitored weekly for three months and those with haemophilia A for six months in order to detect whether liver values are rising and whether cortisone therapy is indicated. As transaminases are subject to a circadian rhythm, the determination should be carried out at a similar time of day if possible. According to the speaker, 1 in 5 patients with hemophilia B require immunosuppression with prednisolone, and 4 in 5 with hemophilia A [2]. It is suggested that prednisolone 60 mg per day per os be given initially for a period of at least 14 days and then gradually phased out depending on the course [1].

Literature:

Miesbach W, et al: Gene therapy der Hämophilie: Empfehlung der Gesellschaft für Thrombose- und Hämostaseforschung (GTH) [Gene therapy of Hemophilia: Recommendations from the German, Austrian, and Swiss Society for Thrombosis and Haemostasis Research (GTH)]. Hemostaseology 2023; 43(3): 196-207.
“Hemophilia and new gene therapies”, PD Dr. Robert Klamroth, 130. Congress of the German Society of Internal Medicine (DGIM), 15.04.2024.
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