The approval of efanesoctocog alfa by the European Commission is good news for patients with haemophilia A, offering them a treatment option with the potential for a considerable increase in quality of life. Here, Professor Robert Klamroth speaks to Helen Quinn about how the researchers overcame the limitations of von Willebrand factor to develop the therapy, how the clinical trials fared and what this approval means for clinical practice.
The granting of a marketing authorisation for efanesoctocog alfa (brand name Altuvoct) by the European Commission in June 2024 marked a turning point for the care of patients with haemophilia A, as the therapy has been shown to significantly improve protection from bleeds compared to existing treatments.
The new treatment, which is administered by injection into a vein over one to 10 minutes, means that patients with haemophilia A can have once-weekly prophylaxis and maintain non-haemophilia factor VIII activity levels above 40% for a significant part of the week.
Factor VIII is a protein crucial for blood clotting and is deficient in people with haemophilia. Efanesoctocog alfa extends the half-life of factor VIII so it stays in the blood longer, offering patients the potential for better management of the condition and substantial improvements in quality of life.
Trials have shown that weekly prophylaxis with efanesoctocog alfa also reduces annual bleeding rates compared to other factor VIII products, highlighting a clinically relevant benefit for both patients and clinicians.
Professor Robert Klamroth, a consultant in haematology, internal medicine and vascular medicine, and head of the department of angiology and hemostaseology at Vivantes Hospital Berlin-Friedrichshain in Germany, is one of the lead authors of the studies.
Working in this area of medicine was not part of Professor Klamroth’s original plan, but after taking a job in coagulation, he says he found it so fascinating that he ‘stayed forever’.
‘It’s so interesting, and it’s complicated, but if you understand the basics of coagulation, it’s a very broad field. It involves treating outpatients, very young children, very old patients – so the whole spectrum,’ he says.
Improving treatment for people with haemophilia A
Over the years, Professor Klamroth’s research interests have focused on improving treatment options for haemophilia patients. He has worked on several different drug trials, but this one for efanesoctocog alfa, he says, is likely to have the most significant impact on patients.
‘For the first time, we can convert patients with severe haemophilia A to normal haemostasis and offer them constant protection,’ he explains.
If prophylaxis is not undertaken, haemophilia patients will have spontaneous bleeds and early joint deterioration. Some 50 years ago, clinicians aimed to reduce the disease’s severity for patients with the most debilitating cases.
‘The first idea was regular infusions of factor VIII; you treat the disease and convert patients from severe to moderate,’ Professor Klamroth explains. ‘Before the recombinant era, patients had to inject quite often – at least every other day – to have a certain level of protection. With this, we were successful, so we could reduce spontaneous bleeding. But there was still joint disease and bleeding with this approach.’
But now, Professor Klamoth says things have changed: ‘The treatment goal shifted a little bit, and we wanted to be more ambitious.’
For treatment to be more effective, levels of factor VIII needed to be maintained within the bloodstream. The problem was, even with an extended half-life, factor VIII would bind to the von Willebrand factor glycoprotein.
‘The von Willebrand factor is a limitation for half-life factor VIII. Modifying the factor VIII molecule prolongs its half-life a little bit, but not beyond the half-life of von Willebrand factor,’ Professor Klamroth explains.
In response to this limiting factor, Professor Klamroth and his colleagues engineered the factor VIII molecules so that the binding site was covered and that, in turn, inhibits the binding of von Willebrand factor. ‘That’s why the half-life is now up to 50 hours and allows weekly injections,’ he says. ‘With this approach, we convert patients to normal haemostasis.’
Trialling efanesoctocog alfa
The granting of the marketing authorisation for efanesoctocog alfa (brand name Altuvoct) follows a positive opinion by the European Medicines Agency’s Committee for Medicinal Products for Human Use in May and is based on two trials, both of which Professor Klamroth was involved in.
The XTEND-1 trial evaluated the efficacy and safety of the new factor VIII prophylaxis in adults and adolescents, and the XTEND-Kids trial concentrated on children.
A total of 159 patients from 48 centres in 19 countries were enrolled in the XTEND-1 trial. All patients were 12 years of age or older with severe haemophilia A and were divided into two cohorts. The first cohort (n= 133) received once-weekly prophylaxis with efanesoctocog alfa at 50 IU per kilogram of body weight for one year. The second (n=26) received on-demand treatment with efanesoctocog alfa for 26 weeks, followed by once-weekly prophylaxis with efanesoctocog alfa for 26 weeks.
The aim was to assess whether the number of annual bleeds could be reduced in a year with the new therapy compared to any previous treatments the patients had undertaken. The researchers also looked at how well the new therapy treats bleeding episodes and the impact of the treatment on a patient’s joint health.
In the XTEND-Kids trial, 73 previously treated children up to the age of 12 with severe haemophilia A received a weekly dose of efanesoctocog alfa at 50 IU per kilogram of body weight for one year. Bleeds were treated with a single dose of efanesoctocog alfa (50 IU per kilogram). The researchers recorded the number and location of bleeds, as well as the dose and number of efanesoctocog alfa injections required to resolve the bleeds.
Both patients and clinicians favoured the new treatment. ‘A weekly treatment offers patients a much lower treatment burden with better protection and is more convenient for them,’ Professor Klamroth says.
Efanesoctocog alfa will result in very little extra training for patients and clinicians, according to Professor Klamroth. Since most haemophilia patients are already on prophylactic treatment, the introduction of the new therapy will simply reduce their treatment burden.
‘This new drug offers constant protection, and then the constant protection monitoring is much less important because if you normalise haemostasis, it doesn’t matter if factor VIII is 40, 50, or 60 [IU per decilitre], it makes no difference,’ he says.
Efanesoctocog alfa and the MDT
One of the hallmarks of haemophilia care is the close surveillance of patients by a range of healthcare professionals, and with efanesoctocog alfa, Professor Klamroth thinks there will be little change. Nurses who are in close contact with the patients and physiotherapists who examine joints will continue to be important and form an essential part of the multidisciplinary team (MDT).
‘It will still be necessary to cover all the aspects [of MDT care], but I hope that we will need less [input from] orthopaedic surgeons because we will protect the joints better,’ Professor Klamroth explains. ‘If you look at my older patients [with haemophilia] here in my centre, they have all had a knee replaced or a hip replaced, or there is no older patient who has not had at least one joint replacement. That’s what we hope to prevent in the future.’
Indeed, efanesoctocog alfa is novel in preventing joint deterioration, which is not seen in standard prophylaxis. ‘If you have structural changes in the joints, you cannot change it because if the structure is broken, there is nothing [that can be done]. I think it’s quite unique in this trial that there was an improvement in the haemophilia joint health score mainly reducing chronic synovitis,’ says Professor Klamroth. ‘With this new drug, I think at least we can successfully treat this residual inflammation in the joint.’
Treatment choices for the future
Despite its strong efficacy and safety profiles, factor VIII treatment is not always suitable for every patient, especially not for patients who have haemophilia A and inhibitors against factor VIII. As such, Professor Klamroth also anticipates addition of emicizumab – a bispecific antibody that mimics factor VIIIa activity – to clinicians’ treatment arsenals. He also expects to see new subcutaneous treatments emerge for haemophilia, alongside treatment with gene therapy, which is also becoming increasingly important. ‘There are always different possibilities, and it’s always a discussion of the shared decision-making with a patient,’ he says.
For now, the approval of efanesoctocog alfa gives patients another therapy option and one that can offer a clinically relevant advantage and significant improvements to their quality of life. Professor Klamroth concludes: ‘For intravenous treatment, replacing the missing clotting factor is a great step forward because [the patients] have higher levels, better protection and once-weekly injections. From my point of view, it is great progress.’
