Hemophilia. New treatment options. Emicizumab.
Gene therapy. 3 [Part 1 and 2]

Hemophilia. New treatment options. Emicizumab.
Gene therapy. 3 [Part 1 and 2]
Hemophilia. New treatment options. Emicizumab.
Gene therapy. 3 [Part 1 and 2]

Hemophilia. New treatment options. Emicizumab.
Gene therapy. 3 [Part 1 and 2]

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Haemophilia A and Haemophilia B are important bleeding disorders. Classic therapy involves factor eight and factor nine replacement. This prevents bleeding, mostly into joints, into the muscles, which can be very debilitating to patients. But there are new Haemophilia medications that are being developed, for example, monoclonal antibodies. They don't provide coagulation factor replacement. What is the standard of treatment for hemophilia in the current time, in the precision medicine era? What are the new treatments for Haemophilia A and Haemophilia B?

Let us say that the mainstay, if not the gold standard of hemophilia treatment, is still replacing the deficient clotting factor eight or factor nine. Treatments have undergone continuous progress in terms of quality, purity, efficacy, and also safety. The half-life in the plasma of these protests, particularly of Haemophilia A factor eight, but also for Haemophilia B, factor nine, is relatively short. It is for hours. The half-life in the plasma of factor eight is 12 hours, the half-life of factor nine is 18 hours. And so to maintain a level of factor that prevents the bleeding in what we call prophylaxis. It is, of course, the mainstay of treatment; you need a very frequent intravenous infusion. This, of course, impairs the quality of life of patients with hemophilia. Because even though they learned to inject themselves in the vein, using ports. It is not an easy life to inject yourself every other day. Having said that, even until the miraculous progress that took place in the last ten years, the life expectancy of patients with hemophilia had become (they are males) has become similar to that of their sex, gender peers in general population. So they have a life expectancy similar to the other males. But of course, with a quality of life, that is not ideal.

To tackle this issue of the need for frequent infusion, there have been several approaches. They represent the progress in the last ten years, from Lego 2010 or 2012. And, of course, it is still ongoing research, with the prospects of gene therapy that we will deal afterward. But at the moment, gene therapy is not yet available. The first step toward new hemophilia therapy has been the manipulation of the molecule of factor eight and, more easily, of factor nine to prolong this short half-life. The result was that patients needed less frequent infusions. And so they have a better quality of life. Let us say that instead of being infused every day with a product currently available. Patients can instead be infused with medication every other day. For factor eight, patients can infuse themselves every three or four days. It is significant progress. And with factor nine, patients can be infused once a week because they manipulated the molecule of factor eight and nine. Of course, factor nine, starting from a better point because factor nine itself has a longer half-life. Scientists managed to prolong the half-life to reduce significantly the burden of intravenous infusion. And there is further progress that is ongoing. Because probably very soon, there will be further extended half-life of hemophilia treatments. They will be administered once a week, if not every ten days.

Of course, are they need an intravenous infusion. And that's where there was dramatic progress with the US at the moment. There is one medication, which is a monoclonal antibody that mimics the activity of factor eight without being factor eight. But from the point of view of securing hemostasis and avoiding bleeding, it is practically equivalent to factoring eight. The big advantage is that this medication can be given subcutaneously once a week. Sometimes it can also be given every fortnight and, in some lucky instances, even every 50 days. This is Emicizumab (Hemlibra) that already licensed and is available for a patient with all severity of Hemophilia A. It is not available yet for Hemophilia B. But as I told you before, patients with Hemophilia B are better off because they start from a better half-life. With the extended half-life of medication, they have reached satisfactory treatment. So, Emicizumab (Hemlibra) changed substantially the quality of life of these patients because now they can inject themselves subcutaneously. This is, of course, is much easier, for obvious reason, than the intravenous infusion.

They are the pipeline of other medication products, which we call non-factor therapy. They are not factor replacements. They are non-factor medications. As I told you, Emicizumab (Hemlibra) is not factor eight, even though Emicizumab behaves like factory eight. These products are in the pipeline. One of them is, I will tell you not the brand name but the generic name. It is fitusiran. There are also monoclonal antibodies against the tissue factor pathway inhibitor. But they are not yet licensed for clinical use. Their mechanism of action is different from Emicizumab. They rebalance hemostasis by the naturally occurring anticoagulant, antithrombin, protein C. I mentioned it at the beginning of the story of liver disease. So they rebalance hemostasis by quenching the activity of the naturally occurring inhibitor and thereby promoting the formation of thrombin. This occurs even in patients deficient in factor eight or factor nine. What are the advantages of these new non-factor hemophilia treatments? We don't know yet, because they are not yet licensed; they are not available. They are in an advanced phase of development. They may be licensed this year.

The advantage is that probably non-factor hemophilia medication can be given subcutaneously, like Emicizumab. But even a longer space interval, say, once a month is another advantage. Also, they can also be given in patients with Hemophilia B because they are in a situation in which there is a defect in the formation of the final coagulation step that is a thrombus. So they can be used in Haemophilia B. Emicizumab is specific for Factor Eight. It does not work in Haemophilia B. Emicizumab can also be used in other rare coagulation defects because their action is by quenching the naturally occurring anticoagulant. So rebalancing of hemostasis occurs, similar to what I told you at the beginning of the discussion, for liver disease. So it is a novelty; it is not yet available, Emicizumab is not as yet available.

Having said that, unless you have a specific question, I can go to the latter final point, to the issue of a new therapy. Patients with hemophilia have already enjoyed, even before, over the last decade, excellent quality of life. The life expectancy is similar to man in the general population. But of course, there's some problem in the quality of life, because of the different needs of patients or frequency intervals of injections. And okay, subcutaneous injections are easier, but still, it is bothersome. And so, patients with hemophilia want to be cured. I speak to my patients about this miraculous progress in the last ten years. Patients say, okay, okay, that's true, that's better, and they benefit from this progress. Even though the progress in the past years has been fantastic since the beginning of my long career. As you can see, I have a bright future behind my shoulders. So I've seen and treated Haemophilia at a time when all these therapies were not available.

But patients with hemophilia want to be cured. And for them, the cure is gene therapy. And gene therapy is the transfer, the correction of the gene defect, the transfer with vectors that bring into the body corrected gene. Regarding the vectors, there are at the moment only virus vectors. The gene-producing Factor Eight or Factor Nine, which is now the main target in gene therapy of hemophilia. They go into the liver, and in the liver, they stimulate the production of Factor Eight or Factor Nine. And indeed, we are at an advanced stage with both Factor nine and Factor eight gene therapy. Factor nine was the first to be attempted in gene therapy trials. Why? Because the gene is smaller. So it was easier to find a gene therapy vector containing this relatively small gene. Factor Eight took longer because it's a bigger gene. But eventually, this problem was solved. So now, that is no longer a problem.

We have now evidence that in both instances, there is an endogenous production by the transgene, by the new gene of Factor of Nine and Factor Eight. We have evidence of this endogenous production. The patients with hemophilia were not able to make themselves previously. Now transgene can normalize the coagulation and avoid the need for replacement therapy. And many of these hemophilia patients stopped prophylactic treatment, early treatment. But there are still some open problems, which are worthy of being mentioned. We don't know several answers. The first, and probably for me, the most important unknown issue is that gene therapy cannot be given to children; gene therapy can only be given to adults. Why? Because transgenes go to the liver. And, of course, they don't integrate into the gene. Gene therapy vectors go to perisomes. And also, of course, if the liver is regenerating. And the children's liver is regenerating, their own cells take over, of course, and the transgene disappears. So now the studies are already done in adults. And of course, when I speak with the mother or the patient, they usually mother or children. They want to be cured more than the adults. Even the adults, of course, but children want a cure from hemophilia much more. So that is the main problem so far. And for the reason that I mentioned, at the moment, I don't see a solution. These studies were done in adults above the age of 20 or so, which, of course, is very important. And I'm sure that the hemophilia gene therapy problem will eventually be tackled. But at the moment, I want to emphasize a variance in the hemophilia gene therapy product that I mentioned. No gene therapy product for hemophilia is licensed. So it's still experimental, it is experimental, it is in an advanced stage.

And there are also some questions besides the ones that I mentioned. It does not apply to children. That is the true target of cure from hemophilia. If you think about the problem is that the transgenes are directed to the liver. So gene therapy transgenes cause some liver problems, some increase in transaminases. Some of my colleagues call this transaminitis. But calling it 'transaminitis' is to trivialize the phenomenon. An increase in transaminases means that some liver cells become dead. So this is necrosis. So I am a little bit worried. And so, it is a problem. It is also a problem, particularly with Factor Eight gene therapy. There is some decline in the production of Factor Eight from the transgene after some years. With this being said, the ideal hemophilia gene therapy treatment situation is a single intravenous infusion given once for life. It is not going to happen. And you will need a repeat infusion. And here are problems, because, at the moment, the vectors are viruses. And the viruses engender the development of an antibody against the viruses. There are possibilities to tackle this problem. But he's not something very pleasant. Of course, I'm sure the problem will be solved. And I want to emphasize that the development of hemophilia gene therapy, the studies are in the advanced phase. But none reached the regulatory agency approvals. Neither the EMEA in Europe nor the FDA in the United States has already licensed this gene therapy for hemophilia, which is not available except in an experimental setting.

Yeah, are there any other technologies that might be coming maybe in the research phase for Haemophilia gene therapy that is completely different, that don't require the targeting to the liver?

There are attempts, for instance, to break the transgenes through microvesicles. But at the moment, there are only two studies. All the studies that are ongoing at the moment are based on the adeno-associated viral vectors. There is an attempt to use lentivirus. This is the virus, of course, that causes HIV and AIDS. But lentiviral vectors will be naked, of course. They would have advantages or disadvantages. The advantage would be that lentiviruses will integrate into the DNA. So they could also be used in children. But the disadvantage is that integration in the genome may cause no problem but may cause some problems. So, the formation of oncogene as it happened many years ago. The case of that boy, I don't remember, in Pennsylvania, I think he has been solved. That happened, if I remember well, in the first decade of the third millennium. And that problem has been solved. So far, the side effects that I mentioned have been liver disease, mainly liver disease. Also, the fact that they develop antibodies against the virus. So that, I think, so far, so good, let us say, in the last ten years. Of course, we need a long-term evaluation [of patients with hemophilia after gene therapy]. So it is still premature to [draw conclusions]. I will say that I'm very pleased with that. The regulatory agency differs in assessment with the producers of these gene therapy products. They are very slow in the approval process. And they continue to ask for a longer follow-up. I'm sure that Biomarin Pharmaceutical is expecting the hemophilia gene therapy product to be licensed within a year. It is Biomarin, a producer of the Factor Eight gene therapy product. They also predict that hemophilia gene therapy will cost 2 million. And again, a small comment. It is a huge sum. But if it is done once in life, the cost of Haemophilia cure is still substantial. And so I think that will probably be worth it, but only if it is given only once in life. And so far, we have seen progressive data. Also, there is a lot of variability between patients among more than 100 patients with hemophilia treated in phase three clinical study for Factor Eight gene therapy with Biomarin. There has been at least one patient that simply did not respond at all. Other patients responded with a huge level of Factor Eight production, which then stabilized. But in general, the average level of Factory Eight production after gene therapy was about 20% to 30%. This is more than enough to avoid spontaneous bleeding. They may need additional Factor Eight treatment for surgery. But the problem is that there is a slow disappearance of the treatment effect. And also the low ability to predict variability of responses: my response vs. your response vs. her response. So that is still an open issue. And if it were me, I would wait another good year, if not more, to license this gene therapy for hemophilia. I don't know. They are might be some problems, incidentally.

Well, it may be another five to 10 years before the gene therapy for hemophilia might be licensed?

No, maybe I am being too pessimistic; 5 to 10 years is too pessimistic, probably. But I mean, I haven't got a glass sphere to predict. And certainly, I hope that despite the pressure coming from the manufacturer of hemophilia gene therapy, but also some of the patients, but I would rather be very cautious. So again, also because we have to consider that, as I mentioned before, what happened in the last 30 years was sort of miraculous. And these hemophilia treatments and others are available. But also with what is available, the extended half-life Factor Eight and factor Nine, Emicizumab (Hemlibra). There has been tremendous progress in hemophilia treatment. So that is also the fact that I'm sure the regulatory agencies take into account. We are not dealing with the disease that is desperate, for which there is no treatment like for many neurological diseases. It is worthy of taking a risk there because there is no other treatment, like in muscular dystrophy, for the sake of an example. The situation is less dramatic for cystic fibrosis, or hemophilia, or thalassemia. Those diseases are the most frequent monogenic diseases. For those diseases, there is no life expectancy that is similar to that of people in the general population. So again, this has to be taken into account, particularly by those like me, who are rather senior. As I said, I have a bright future behind their shoulders. So that is my personal view. So my colleagues and some of the patients might have a bold attitude.

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