During Symposium 2022, we hosted our annual On the Horizon sessions. Several attendees asked great questions, so we assembled the questions and answers for you here.聽For more information on these topics, please visit the Current, New, and Emerging Therapies courses in HFA鈥檚 Learning Central鈥檚 University section. Enjoy!

Question Answer
Isn鈥檛 NovoSeven used for acquired hemophilia? Yes, NovoSeven (eptacog alfa) can be used to treat acute bleeding in acquired hemophilia in addition to persons with hemophilia A or B and inhibitors.
How would a patient potentially switch from HEMLIBRAto another non-factor product? How long does [HEMLIBRA] take to clear the system? The clinical trials to date have all mandated that a patient should be off HEMLIBRA for 6 months prior to starting a new drug given that is the expected time for the drug to fully clear the system. It is likely that once drugs are commercially available, we will be able to shorten that time by a few months, but the exact timing is not clear yet. There will likely be studies investigating this, and I anticipate a shortened period of maybe 3 months, but this is purely my hypothesis.
If an individual receives gene therapy, will that eliminate the possibility of their offspring having hemophilia? It will not. Current gene therapies approaching market are gene transfer or gene editing. While 鈥済ene editing鈥 sounds like it could change heredity, the editing occurs only to add the clotting factor gene to the DNA strand. It does not change reproductive genes or inheritance.
What gene research is being done to correct defects so no longer passed to offspring? Or, is any zygote modification or in-utero correction in research? I am not familiar with any current research that would affect offspring or modify prior to birth.


IVF can provide genetic assessment prior to implantation, which is currently the only option I am aware of that would allow avoidance of hemophilia in offspring.

Is gene therapy one time or ongoing? Gene therapy is a one-time infusion. The therapy itself does not require multiple treatments, and at this time, we do not have any firm data on the efficacy of a second infusion. Whether a second infusion with a different adeno-associated virus (AAV) would be possible is still unknown. It is currently not feasible as the patient develops antibodies to AAV following infusion preventing a second infusion. It will likely take some technologic advancement before we sort this out or the use of modified viral vectors. Also, how many years it will last is still under investigation.
As a hemophilia B patient, which gene therapy should I be most looking forward to? UniQure / CSL Behring and Pfizer have both completed their phase III clinical trials. The Uniqure study is exciting as pre-existing antibodies for the most part do not seem to affect expression of FIX in the patient opening it up to more patients as a possible long-term increase of their FIX. Compared to hemophilia A gene therapy, expression seems more stable meaning likely a longer period of time before the FIX returns back to <1%.
Are HTCs prepared for gene therapies? Will patients need to travel to HTCs that can administer gene therapies? It鈥檚 hard to know what the exact model will be. However, it鈥檚 likely that some larger HTCs will be able to offer gene therapy at first, so patients may have to travel to have access. It鈥檚 possible that follow-up could be done at the patient鈥檚 regular HTC. There is a proposed 鈥渉ub and spoke鈥 model that is being investigated that would allow some of the smaller centers to send their patients to more specialized centers.
Have you heard anything about a companion diagnostic for hemophilia B gene therapy? Or anything to help determine eligibility? I would anticipate that as companies apply to the FDA for commercial approval, they will develop a companion as described. Currently, the closest thing would be going to and looking at the inclusion/exclusion criteria for the trials. Note: CSL identifier NCT03569891 and Pfizer identifier NCT03861273.
It was mentioned that during gene therapy some other small changes or modification to DNA can happen. What other changes happen, and what are the effects of those small changes? Small changes in DNA can occur resulting in insertional mutagenesis. For most of our DNA, this will be inconsequential (e.g., insertion into an inactive part of the DNA, insertion into the DNA for a protein in that one cell alone, resulting in minimal-to-no change). The concern is if the insertion happens in a cancer gene and results in cancer. We anticipate this to be very rare, but also very hard to study because cancer will take time to develop. ATHN has a registry trial that will monitor this occurrence, as well as any other complications of gene therapy that present. At this time, there is no evidence of insertion leading to cancer but long-term follow-up is ongoing. We highly recommend participation.
What happened to adding factor to milk (about 15 years ago)? There are a number of clotting factor products that are made in transgenic animals with it being produced in its milk. For example, eptacog beta (SEVENFACT) is produced in transgenic rabbits. This is in contrast to many other products produced in large bioreactors in animal cell lines.
In gene therapy, what if some other illness happens in replacing o adding to the gene? (see above)
1.聽聽聽聽 驴Cu谩ntos tipos de factor hay? [How many types of factor are there?]

2.聽聽聽聽 驴La terapia gen茅tica es solo para los que no teinen factor IX o tambien para los que les factor VIII? [Is there only gene therapy for those with factor IX deficiency, or also for those with factor VIII deficiency?]

There are 13 clotting factors:

1.聽聽聽聽 Factor I (fibrinogen)

2.聽聽聽聽 Factor II (prothrombin)

3.聽聽聽聽 Factor III (tissue thromboplastin or tissue factor)

4.聽聽聽聽 Factor IV (ionized calcium)

5.聽聽聽聽 Factor V (labile factor or proaccelerin)

6.聽聽聽聽 Von Willebrand factor (VWF)

7.聽聽聽聽 Factor VII (stable factor or proconvertin)

8.聽聽聽聽 Factor VIII (antihemophilic factor)

9.聽聽聽聽 Factor IX (plasma thromboplastin component or the Christmas factor)

10.聽 Factor X (Stuart-Prower factor)

11.聽 Factor XI (plasma thromboplastin antecedent)

12.聽 Factor XII (Hageman factor)

13.聽 Factor XIII (fibrin-stabilizing factor).

There are gene therapy trials in progress for both factor VIII and factor IX.

The benefits of the peaks were mentioned, and it was not elaborated on. Can we elaborate on the benefits of the peaks?


Also, when on HEMLIBRA, are we missing out on these peaks? Are HEMLIBRApatients pretreating with factor to peaks before sports and such?

Evolving research suggests that as factor products evolve, we should focus on more than just the factor troughs. Factor peaks, as well as the area under the curve, are both important in providing hemostatic support. There is some evidence that in sports, a larger area under the curve is important for avoidance of injury.


We likely are missing out on the peaks with HEMLIBRA; however, for individual patients, perhaps associated with their activity level, this will have more or less effect. The very high peaks of BIVV001 may prove to be beneficial (in sports and other activities), but that remains to be seen as its lack of interaction with the body鈥檚 VWF may also be an issue.

Why is it so difficult to get factor VIII subcutaneous (SQ)? And why do companies keep trying to do so if it is 鈥渘ot a good idea,鈥 just like the doctor said? Factor VIII SQ has resulted in increased inhibitor development. Multiple companies have attempted factor VIII via the SQ route, and it has only led to inhibitors in patients with no history of inhibitors. Likely, the exposure under the skin to the lymph or white cells leads to this. It will take a significant advance before we see SQ factor VIII.


Companies continue trying, and they are trying different methods, which we think is important.

Is there value in using an extended half-life product to treat breakthrough bleeds while on HEMLIBRA, compared to regular recombinant factor? If a patient generally requires multiple factor doses to treat a bleed, then extended half-life products may be beneficial for them. This should be a discussion with your HTC provider about your specific needs and response to factor. For most persons with hemophilia, standard half-life products work well.
What about using DDAVP for breakthrough bleeds with HEMLIBRA? Most people who respond adequately to DDAVP do not need HEMLIBRAprophylaxis, thus this is rarely done. However, it could definitely be considered. In the end, antifibrinolytics would be easier to give and useful in most of the situations where DDAVP would be used since it does not work in most moderate hemophiliacs and many mild hemophiliacs.
Any side effects for using HEMLIBRAbesides the possible allergy reactions? Injection site reactions.

Burning with injection.

Rarely one can develop antibodies against HEMLIBRA (enough to lead to lower levels and bleeding), which occur in 1% of patients.

Is the XTEN polymer PEG? It is similar in concept, however the molecule itself is cleared more easily. They are not the same but provide a similar benefit. It is biodegradable and potentially less likely to lead to a hypersensitivity reaction, but this has not been proven yet.

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