Published: Lifelines for Health Spring 2018

By: Dr. Jonathan Bernstein, Md

Over the past several years, hemophilia care has been turned on its head as new opportunities and ideas for the treatment of hemophilia have emerged. During this time, we have seen the greatest change in hemophilia care since Judith Graham Poole first helped to develop cryoprecipitate and observed that Factor VIII could be made cheaply from this product. These new changes include new factors, new bypass products that can be used subcutaneously, and gene therapy. Finally, we now may have two new ways to treat bleeding diseases that have no treatment at this time.

With these new treatments come choices where we must weigh the risks versus the benefits of these drugs.

Sometimes it is hard to know what the risk might be when a drug is first being used to treat patients. We can look at the research that has been done to test the new drug in a well-defined protocol and see if any significant adverse events were reported.

However, research protocols are strict and can have no variance. When a drug is available for use in the medical community, the way it is used by doctors and patients often differ from the strict rules for use that were specified by the research protocol. How many of you have not used your medication in the way you were instructed by your doctor? I know I have – but, of course, doctors are the worst patients. When patients and doctors vary in how they use a drug, this leads to increased risk of something bad happening, and possibly death. Because of our concerns when we first introduce a drug to our patients, we tend to be more conservative in prescribing these drugs. Companies are now required to do what is called “phase 4 research” to try and capture the changes in use over time of a drug or treatment.

Hemlibra

The first of these newer drugs, Hemlibra, had problems early on with one death, and the development of both microangiopathic hemolytic anemia and blood clots. These adverse events occurred when Hemlibra was used with a high dose of FEIBA. This combination of a drug that activates Factor Xa (Hemlibra) and a drug containing both Factor Xa and prothrombin (FEIBA), at high doses seems to activate compliment and cause increased clotting and the development of microangiopathic hemolytic anemia (which always seems to involve compliment activation). With further studies, Genentech, the company that developed and tested this drug, was able to eliminate these serious complications, by decreasing the dose of FEIBA, or by avoiding its use completely. Many of you know that 5 patients have died who received this drug off study under compassionate use. While it is stated that these patients’ deaths were not caused by Hemlibra, it is curious that so many deaths occurred in the Factor VIII inhibitor group, when so few were exposed to the drug. Little information has been released on the causes of deaths in these patients. We also have no data on whether we can tolerize patients while on these drugs. Without tolerance, these patients may never be allowed onto gene therapy protocols, as they might have a greater risk of negative outcomes.

Hemlibra has also solved many of the problems that patients with Factor VIII inhibitors have. Patients on this drug are able to give themselves subcutaneous (SQ) shots once a week, with few if any breakthrough bleeds. Many patients who were bleeding once or twice a week are now going from a month to years without bleeding. This decreases the damage to and joints, improves quality improves compliance (much give a subcutaneous shot), and patients more independent. deciding whether to use this must make a choice weighing risks versus benefits. Patients who are doing well on current treatment with tolerance of their inhibitors, should probably avoid Hemlibra. However, for patients with higher titer inhibitors or frequent breakthrough bleeds, this drug’s benefits will most likely be greater than the risks as long as patients follow instructions for use.

Fitusiran

Another drug on the horizon is Alnylam’s/Sanofi’s Fitusiran. This drug increases the thrombin level in the blood by using small interfering RNA (siRNA) to silence the ability of the liver to produce Antithrombin III through RNA interference. It is similar to a process that the body uses to decrease production of certain proteins. This increases the thrombin level in the blood making up for the level lost when one is deficient in a factor. It can be used in patients with inhibitors of factors VIII and IX, as well as to treat patients with factor deficiencies and platelet disorders that can cause excessive bleeding. It is also given subcutaneously. It is currently being studied in a clinical trial protocol at this time. There has been one death in a patient with hemophilia A. This is thought to have occurred when the patient had a sinus venous thrombosis, which then hemorrhaged, resulting in the patient’s death. Protocols and education were put in place to decrease the chance that this would happen again. The decision to use this drug must be decided by both the patient and the physician after balancing risks against benefits to decide if the risks are greater than or less than the benefits. In patients with factor IX deficiency and an inhibitor, this would allow bypass and improve clotting greatly. In patients withwith no treatment other than antifibrinolytics, such as Factor V patients, as well as severe platelet disorders, such as Glanzmann’s Thrombasthenia and Bernard Soulier, Fitusiran may greatly improve quality of life and outcome.

Hemlibra and Fitusiran may also both make it hard to measure Factor VIII and inhibitors as they both bypass what we usually measure to determine levels. New methods must be discovered that will allow us to find the levels in patients on these drugs.

Gene Therapy

The next set of treatments on the horizon are gene therapies for Factor VIII and IX deficiency.
Both will soon be available. Studies are ongoing with increasing success. Gene therapy will only be offered to individuals above the age of 18 for the foreseeable future. This approach has been a long time coming. However, there are still substantial risks associated with gene therapy. In the past, patients (with disorders other than hemophilia) have developed cancers when treated with a retroviral vector (viral DNA that carries the gene into the cells). Genes carried by these vectors into the DNA often inserted themselves next to genes that allowed unrestrictive division, a hallmark of cancer. The improved treatments that were then developed avoid this problem by either not inserting into the genome or having more specific insertion. This is a vast improvement. One company estimated that only one in ten thousand would insert incorrectly. However, there may be millions of these vectors, that will have to be given. This might mean that several hundred could insert incorrectly. If this happens, it is possible that years later a patient could develop a malignancy – the most likely site of cancer would be the liver as these vectors insert the changes into liver cells. Next, although less worrisome, is that with time a patient who has undergone gene therapy may need to have boosts of the vector to maintain success. However, it is possible that patients might develop antibodies to the vector so that they are no longer candidates for repeat boosts of the vector.

Some patients may not be candidates for treatment with gene therapy. If one has an antibody to the vector the body may reject the treatment. Some companies are attempting to develop several vectors that would avoid this problem. If a hemophilia patient has an inhibitor it could either cause the inhibitor level to increase, or could allow the immune system to see a constant amount of factor and tolerize these patients. I believe that we will see both occur. Plasma-Derived Factor

Finally, a trial comparing plasma Factor VIII to Recombinant Factor VIII showed that plasma
Factor VIII was less likely to cause inhibitors than Recombinant Factor VIII. However, much has changed since the study was started. New factors, some of which had longer half-lives, became available. These factors were not compared to plasma. It is believed that humanized factor VIII or extended half-life Factor VIII may develop as few inhibitors as plasma does, and these may also be as good at tolerizing patients as plasma is. If studies prove this to be the case, we may find that more patients convert to these drugs.

Thus, we now have a wealth of new treatments available with many others on the horizon. There
will be risks and benefits, as is true of all drugs, even relatively benign drugs like acetaminophen or aspirin. When patients are given a chance to treat themselves with these drugs, they must weigh the risks against the benefits and decide whether to use the drug. They must also follow the instructions given to them by their doctors and the drug companies so that they can avoid side effects as much as possible.