Hemophilia: A Therapeutic Revolution Underway to 'Dethrone' the Disease of Kings

A wedding, held in London on February 10, 1840, removed hemophilia from the precarious medical practices of the time and placed it at the center of high politics and international relations.

Queen Victoria of England married Prince Albert of Saxe-Coburg-Gotha on that date and, unknowingly, she introduced into the DNA of her offspring the defective gene that causes the disease by preventing blood clotting.

The nine children of the couple spread hemophilia through the monarchies of almost the entire continent, including Spain.

Despite all their power, these sagas were forced from then on to live with disabling hemorrhages and premature deaths.

Almost two centuries later, in a town near A Coruña, a security system operator has become one of the first citizens in the world to have experienced something for which many monarchs would have given half a crown: complete remission of symptoms. of hemophilia for more than three years thanks to gene therapy.

“It has been an amazing process”, exclaims Iván Torcal.

This 38-year-old man remembers his childhood as almost constant scaring.

“I have severe hemophilia.

Not only do I bleed from a small blow or the slightest cut, but they occur spontaneously in the joints: elbows, knees, ankles... They swell, they hurt, you lose mobility... You need to lead a very planned life, have a lot of Be careful, go to the hospital several times a week to get your clotting factor... If it's hard to live like this when you're older, imagine being a child.

You have parents all day on top of you, ”he ironically.

One day in August 2019, Iván went to the Complejo Hospitalario Universitario de La Coruña (CHUAC, of ​​public health) to enroll in a clinical trial.

They laid him on a stretcher and gave him an intravenous injection.

In reality, they were putting a virus modified in the laboratory that had become a kind of shuttle to deliver the healthy gene to the liver that makes it possible to correctly synthesize the coagulation factors that hemophiliacs do not have.

“It was all quite slow and calm.

They kept me under surveillance for a few hours, but since everything was going well, I was able to go home to sleep, ”she recalls.

Waking up the next day, Ivan was

.

The analyzes immediately showed very high levels of factor: the liver had begun to produce them as in any other person.

“After a lifetime of constant care, everything suddenly changes.

Nothing happens to you if you get hit, you can ride a bike in peace, your joints stop aching... At first it's all very strange, ”he says.

Ivan suffers from hemophilia A, caused by a congenital deficiency in coagulation factor VIII.

Almost half of the patients suffering from this type of hemophilia develop the severe or severe form.

The rest, depending on the levels of the factor in the blood, will develop the moderate form —bleeding is caused by small blows and injuries— or mild —only with major trauma or surgery.

According to reports from the Ministry of Health, the prevalence of hemophilia A in the European Union is about six cases per 100,000 inhabitants and in Spain there are just over 2,600 affected.

Hemophilia B, caused by a deficiency in factor IX, is rarer although the disorders it causes are similar.

In Spain, according to Health, there are "about 77 people genotyped with severe hemophilia B and 50 with the moderate form, although the total number of those affected could be around 300."

There is a third type of hemophilia, C, even less common and generally much milder.

The laws of genetics are what cause it to be almost always men who suffer from the disease, explains Victor Jiménez Yuste, vice president of the Spanish Society of Hematology and Hemotherapy (SEHH) and head of the specialty service at the Hospital de La Peace (Madrid).

“The gene responsible for hemophilia A and B is on the X chromosome. Since women have two X chromosomes, they can be carriers but not develop the disease, since they still have a healthy gene.

But a female carrier has a 50% chance of passing the affected chromosome to her offspring.

In the case of men, since they only have one X chromosome [the other is Y], if they receive it, it is certain that they will be hemophiliacs, ”he explains.

Victoria Eugenia de Battenberg, granddaughter of Queen Victoria of England and wife of Alfonso XIII, introduced hemophilia into the Spanish Royal HouseHulton Archive (Getty)

This specialist describes the experience experienced by the available treatments as an "authentic revolution".

“We have advanced in a few years the same as in the previous three or four decades.

Before we only had replacement treatments of factor 8 or 9 with derivatives of donor blood.

Then recombinant drugs emerged ”, he details.

This type of drug, synthesized in the laboratory, gave patients much greater security after decades in which infections by viruses arriving through blood products were frequent.

The Spanish Federation of Hemophilia (Fedhemo) estimates that a thousand hemophiliacs died in Spain from HIV and hepatitis C in the last two decades of the 20th century.

Little by little, the advancement of medicine allowed the life expectancy of hemophiliacs to approach that of the normal population.

But the quality of life was still not the same: “Patients need to go to the hospital several times a week to receive these drugs intravenously as prophylaxis.

Only mild cases can lead a more or less normal life and receive the factor only when the injury has occurred”, says Jiménez Yuste.

Some patients also develop antibodies against the factor they receive, which the body identifies as foreign, which worsens the prognosis and complicates treatment.

The release of Hemlibra (Roche), introduced in Spanish public health in 2019, represented a qualitative leap for patients with hemophilia A. This treatment can be administered with a simple prick under the skin weekly, biweekly or monthly, depending on the case.

"Gene therapies are the last great leap that we needed to take," defends Jiménez Yuste.

Iván Torcal received, still in the clinical trials phase, the first gene therapy approved by the European Medicines Agency (EMA), Roctavian, whose commercialization was authorized by the European Commission for hemophilia A in August 2022. Just one month ago, on February 20, the Commission authorized Hemgenix (CSL Behring) for hemophilia B.

“These are treatments with a very high initial efficacy, which greatly increase the factor 8 or 9, depending on the case, in a first phase.

But after six months, the levels start to drop and we don't know how long they will be effective.

For this reason, the EMA has approved them conditionally, until the companies provide more data," explains Vicente Arocas, a member of the GENESIS Group for drug evaluation of the Spanish Society of Hospital Pharmacy (SEFH).

The other big issue pending to be resolved is that of security.

“Trials and real-world data include very few patients, so we don't yet know the rarer side effects.

We do know that they have liver toxicity and also that the DNA used can be introduced into other cells in the body, which carries the risk that they may contribute to the development of some types of cancer”, continues Arocas.

Iván Torcal explains that, despite the good results obtained, he had "high transaminases", which forced him to take corticosteroids for about a year and a half.

"I gained about 10 or 12 kilos of weight, in that part the treatment is quite annoying," he recalls.

The worst thing, however, is that his coagulation factor levels have dropped a lot and, three and a half years after receiving Roctavian, he is already on the verge of having to go back to taking the treatments he took before receiving gene therapy. .

Fernanda López is the head of the hematology service at the A Coruña hospital that has treated Iván.

“The coagulation factor levels of the four patients we have have dropped a lot since the first year, but all remain in mild hemophilia, which allows them to lead an almost normal life, although in the case of Iván they are almost moderate hemophilia,” he says.

Despite the "giant advance" that the first gene therapies have brought about, this specialist believes that there is still potential for improvement.

"Currently, they cannot be used in children, nor in liver patients or people who have antibodies against the virus used as a vector," she adds.

There are currently a dozen other gene therapies in development against the two types of hemophilia, which raises a horizon in which the cure or almost total remission of symptoms for much longer periods of time "is not far off," López confides. .

The available data suggest a duration of the symptom remission stage of up to 10 years in hemophilia A and 20 in hemophilia B, although these trial results tend to be diminished with the arrival of treatments in the real world.

In Spain, there remains an important obstacle to overcome: the incorporation of Roctavian and Hemgenix into public health, something that the Ministry of Health negotiates with pharmaceutical companies, which ask for very high prices.

Although these data are confidential, the information available in other countries indicates that the starting price requested by BioMarin for the Roctavian is close to 1.5 million euros, while the official price set by CSL Behring for the Hemgenix is ​​3.3 million. euros, which makes it the most expensive medicine in the world today.

“They are very innovative treatments and, therefore, they also require innovative financing systems.

One formula that we believe should be explored, and that has already been applied with other innovative medicines, is that of payment for results, which could include an annual payment while the treatment is effective and that the public health system stops paying when it is no longer effective.

It must be taken into account that the current average cost of treating a patient with hemophilia is close to 200,000 euros A wonderful product is of no use to us if such a high price is imposed on it that the health systems cannot afford”, concludes Daniel- Aníbal García Diego, president of Fedhemo.

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