BY DAVID CLARK

As of May 2024

Many new families may not be aware of the large number of products available for treatment of hemophilia B.  Other patients and families also, may want an update on the many newer products available.  This is a brief survey of the products currently available in the U.S.

One of the most important principles in medicine is that every patient is different.  Although we all share many similarities, we also have unique genetic and medical backgrounds.  An advantage of the large number of products available is that a patient who does poorly on one product might have better results with another.  Patients are encouraged to work with their physician to find the best product for their needs.

Currently, most hemophilia B patients, except those with inhibitors, are treated with factor replacement products.  These products contain the normal factor IX protein to replace the defective factor IX molecules produced by their own bodies.  They all require periodic intravenous infusions to maintain the amount of factor IX in the patient’s blood at a level required for good hemostasis (adequate clotting).  There are improved factor IX products currently under development, as well as a number of non-factor products.

The current products fall into five general categories:  standard half-life (SHL) factor IX products, extended half-life (EHL) factor IX products, inhibitor treatment products, gene therapy and ancillary products.  Note that all of these products are only available by prescription.

Standard Half-Life (SHL) Products

The SHL factor IX products currently available in the U.S. are listed below in Table 1.

The four current SHL products all consist of normal human factor IX.  They are all descendants of the original plasma-derived concentrates that were developed in the 1960s.  The original products were called Factor IX Complex or Prothrombin Complex.  They were mixtures of several clotting factors including factors II, VII, IX, and X plus the anticoagulants protein C and protein S.  These proteins all have similar chemical structures, which makes them difficult to separate from each other.

The complexes were a huge leap forward in treatment of bleeds, but it was soon apparent that they could not be used in large amounts or for prolonged periods of time because they would cause thrombosis, dangerous unwanted clotting.  This prevented their use for prophylaxis or surgery.  Factor IX complex products are still on the market but should not be used for hemophilia B treatment because of their safety risks.  They are currently used mainly for treatment of liver disease.

AlphaNine, the sole remaining plasma-derived product, was one of the first products to contain highly-purified factor IX without the other factors.  It has proved to be safe from thrombotic complications and is still used by a number of patients.  The other big change in factor IX products was the introduction of methods for viral inactivation and removal, which happened in the mid-to-late 1980s.  Prior to the introduction of those methods, plasma-derived products often were contaminated with infectious agents like hepatitis B and C and HIV, the AIDS virus.  Plasma-derived products are now considered completely safe.  There have been no incidences of viral transmission from clotting factor products since the late 1980s, or from any other plasma-derived products since the early 1990s.

One of the main reasons for introduction of recombinant products was viral safety – to eliminate the dependence on human plasma for these products.  Another was the ability to produce unlimited amounts of a product without dependence on the limited supply of plasma.  Recombinant products are made in animal cells that have been genetically engineered to produce the desired protein.  All three recombinant SHL factor IX products are made in Chinese hamster ovary (CHO) cells that are grown in large tanks in a process called cell culture.

A little-appreciated fact is that all recombinant products are also treated for viral inactivation and removal.  Although the cells used for cell culture are thoroughly screened to make sure they are safe, it was discovered early on that some of these cells may contain hidden virus genes in their DNA.  These viral genes could under some production conditions be “turned on” and introduce infectious viruses into the products.  Now, in addition to having manufacturing steps to inactivate and remove any viruses, every batch of product, whether plasma-derived or recombinant, is also tested to make sure there are no known infectious agents present in the final product.

Most hemophilia B patients use recombinant products, but there are some patients who still use AlphaNine because it works better for them.  The reason for this is unknown, but there are two important possibilities.  One is that the recombinant products only contain a single version of factor IX, the most common variant, which is considered “normal” factor IX.  However, plasma, which is collected from thousands of donors, contains a whole range of factor IX variants.  Many people have small mutations in their genes and produce a factor IX that isn’t modified enough to produce hemophilia, but still has some changes that may make it work better or worse in hemophilia patients.

Another possibility is that the animal cells used in cell culture glycosylate the factor IX product differently than human cells do.  Many of the clotting factors, including factor IX, are glycosylated after the protein is made.  That means that they have carbohydrate chains attached to various parts of the molecule.  The carbohydrate chains are strings of sugar molecules linked together (glyco- comes from the Greek word for sweet or sugar).  There are many different types of sugars beyond what we think of as “table sugar.”  We don’t completely understand the reasons for these sugar chains, but we know that human cells add on different combinations of sugars than CHO cells do, for instance.  These differences may cause variations in how well the products work in some patients.

Extended Half-Life (EHL) Factor IX Products

The EHL factor IX products currently available in the U.S. are shown below in Table 2.  All of the EHL products are recombinant.

The body is constantly removing existing copies of proteins from the bloodstream and replacing them with new copies.  This is part of the process for keeping the body in good working order.  The factor IX proteins introduced by the various products are subject to the same removal process.  The half-life is the amount of time it takes for half of the protein to be removed.

The typical half-life of normal factor IX is 23 – 25 hours, although that can vary significantly from person to person.  The SHL products all have half-lives similar to that of normal factor IX derived from plasma.  That means that a patient using an SHL product has to infuse new factor IX every three days or so.  (Note that some of the SHL products, like BeneFix, have developed alternate dosing schemes using higher doses to keep factor IX levels in the needed range for a week or more.)

The EHL products use various methods to keep their factor IX in circulation for longer periods of time.  These products can be dosed at intervals of one to two weeks, again depending on the patient’s individual response.

Alprolix contains factor IX molecules attached to the Fc region of an antibody molecule.  The body has a special mechanism to keep antibodies in circulation longer than most other proteins.  Antibody molecules are shaped like a Y.  The two arms of the Y are the Fab regions of the molecule that bind to viruses, bacteria and foreign proteins to remove them from circulation.  The base of the Y is the Fc region that attracts immune cells to destroy anything that the arms bind to.  The Fc region is also the part of the molecule that interacts with the system that keeps antibodies in circulation longer.  It turns out that linking factor IX to an Fc molecule also keeps the factor IX in circulation longer.

Idelvion uses a similar method.  Its factor IX is linked to an albumin molecule.  Albumin is the most prevalent protein in plasma.  It thickens the plasma and also carries many other molecules around in the circulation.  There is also a special mechanism in the body to keep albumin in circulation longer.  Linking factor IX to albumin also improves its half-life.

Rebinyn uses a different method to keep its factor IX in circulation longer.  Polyethylene glycol (PEG) is a long water-soluble polymer that has found many uses in medicine including improving the half-lives of drugs.  Rebinyn uses factor IX with PEG chains attached to the ends of the carbohydrate chains described above in the SHL section.  These long PEG chains wave around and coil up randomly around the factor IX molecule.  They form a loose shell that tends to hide the factor IX molecules from the liver cells that normally remove factor IX from circulation.

Another aspect of Alprolix is that it is made in cell culture in human embryonic kidney (HEK) cells.  Using human cells to produce the product potentially produces a factor IX that is glycosylated (has carbohydrate chains attached) more similarly to the factor IX molecules made naturally in the human body.  Whether that actually improves the performance of Alprolix is unknown.

Although the SHL products are very similar to each other, the EHL products are each quite different and may perform differently from person to person.  This has been seen in a number of clinical studies of patients switching from SHL to EHL products.  Therefore, if one product doesn’t work, don’t assume that the others would also not perform well.

Inhibitor Treatment Products

The products used for treatment of patients with inhibitors are listed below in Table 3.

Inhibitors are antibodies that the immune system produces because it thinks that an infused factor IX product is a foreign protein that could be dangerous.  Some of these, known as non-neutralizing antibodies, bind to factor IX but don’t interfere with its function.  Inhibitors are neutralizing antibodies that bind to factor IX in locations on the molecule that prevent it from working.  Inhibitors also occur against factor VIII in hemophilia A where they are a major problem.  Inhibitors occur much less frequently in hemophilia B.  Only about 3 - 5% (the numbers are hard to pin down) of hemophilia B patients develop inhibitors, but when they do, it can be a very serious problem.

Factor VIII inhibitors can often be eliminated by a process called immune tolerance induction (ITI).  However, ITI works poorly in many hemophilia B patients with inhibitors.  In addition, many hemophilia B inhibitor patients also develop allergic reactions to factor IX including anaphylaxis, a severe reaction that can be life-threatening.  Hemophilia B inhibitor patients are also prone to a kidney disorder called nephrotic syndrome.  Most hemophilia B inhibitor patients end up just living with their inhibitor and using bypassing agents to treat bleeds.

Inhibitor treatment products are called bypassing agents because they trigger other parts of the clotting system, bypassing the factor VIII/factor IX step.  They work for both hemophilia A and B inhibitor patients, but they don’t work as well as a regular factor product would work in a hemophilia patient without inhibitors.  They have fairly short half-lives, requiring frequent infusions to treat bleeds, and are expensive.  They can be used prophylactically, but most patients just use them for on-demand treatment of bleeds.  They are the best option available at present, but fortunately, there are a number of new inhibitor treatments under development.

FEIBA is a plasma-derived version of factor IX complex in which the clotting factors have been activated using a proprietary method.  It is used by some hemophilia B inhibitor patients, but because it contains factor IX, it carries a risk of allergic/anaphylactic reactions.  The way FEIBA works is not fully understood, but it contains activated factor VII like the other two bypassing agents.  The other activated factors in FEIBA probably also trigger other parts of the clotting system.

NovoSeven is a recombinant activated factor VII product.  The overall clotting system consists of two pathways, one that depends on factors VIII and IX, and the other that depends on factor VII.  Adding activated factor VII triggers that alternative pathway to eventually form a clot.  Note that NovoSeven is produced in cell culture using a different microorganism, baby hamster kidney (BHK) cells.  The choice of cell type is usually determined by which type works best to produce a particular product.

Sevenfact is a new recombinant activated factor VII product.  It is similar to NovoSeven but made by a completely different process.  For Sevenfact, rabbits have been genetically engineered to produce factor VII in their milk.  The rabbits are milked and the milk purified to capture the factor VII, which is then activated to produce the final product.  Producing a protein in a genetically-engineered animal is called transgenic production. It has also been used for other pharmaceutical products approved by FDA.  Its advantage is that very large amounts of protein can be produced at relatively low cost.  It was originally seen as a way to produce high-quality but lower-cost products for developing countries, but that aspect has yet to be realized.

Gene Therapy

Gene therapy is the process of inserting new, functional factor IX genes into the body to allow it to produce its own normal factor IX.  The single gene therapy product currently available in the U.S. for treatment of hemophilia B is listed below in Table 4.

Hemgenix and Beqvez both use an adeno-associated virus, serotype 5 (AAV5) for Hemgenix and serotype Rh74var (AAVRh74var) for Beqvez to deliver the high-activity Padua factor IX gene to cells in the liver.  The AAV viral genes are replaced with the factor IX gene, so there is no risk of infection.  AAV targets the liver to introduce the new factor IX gene into liver cells, where factor IX is normally made.  The results are somewhat variable.  Most patients will obtain factor IX levels in the mild hemophilia range (5 – 50% of normal), but a few will see higher levels in the normal range (50 – 150%).  The products may also be ineffective in a few patients   The duration of the effect, the length of time that factor IX production will last, is currently unknown, but similar, earlier experimental versions have lasted up to 15 years so far.

There are a number of limitations to these treatments.  Beqvez requires patients to be negative for pre-existing antibodies to the AAVRh74var viral vector.  Hemgenix does not have a limitation against pre-existing antibodies to AAV5, but their clinical studies show that it was not effective in a patient with an extremely high level.

Neither product is indicated for patients under 18 years of age or for women with hemophilia.  There is also a risk of liver inflammation after receiving the infusions, and patients with pre-existing liver damage should only be treated under the supervision of a hepatologist (liver doctor).  If liver inflammation occurs, patients are treated with corticosteroids.  Untreated inflammation can result in decreased factor IX production, as well as other health effects.

Ancillary Treatments

The ancillary products currently available in the U.S. for treatment of patients with hemophilia B are listed below in Table 5.

These three products can be used to treat minor bleeds in patients with mild (factor level 5 - 50% of normal) or moderate (1 - 5%) hemophilia.  All three are fibrinolytics, which inhibit the breakdown of clots.  As soon as the clotting system is activated, the fibrinolytic system, which is part of the healing process, is also activated to start breaking down the clot.  In a patient without hemophilia, the clotting process is very rapid compared to the fibrinolytic process, so a good clot is produced that only gradually breaks down over time.  In a patient with hemophilia, however, the clotting process is much slower, so inhibiting the fibrinolytic process can make a difference in whether or not a stable clot is formed.

The large number of products available for treatment of hemophilia B increases the chances that every patient can find a product that works well for them.  Selecting the best product may be a process of trial and error, but working with an experienced hemophilia treater can shortcut the process.  If you think you could be getting better results, don’t hesitate to ask your physician.