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Professor of Pediatrics
Director, Hemostasis and Thrombosis Center
Children's Hospital Los Angeles
University of Southern California Keck School of Medicine
Los Angeles, California
Guy A. Young, MD, has disclosed that he has received consulting fees from Apcintex, BioMarin, Genentech/Roche, Grifols, Novo Nordisk, Pfizer, Rani, Sanofi Genzyme, Spark, Takeda, and UniQure and funds for research support from Genentech/Roche, Grifols, and Takeda.
Patients with severe hemophilia A or those with moderate hemophilia A with approximately 1% residual clotting factor activity in their blood tend to bleed often. If left untreated, these patients may end up with severe joint damage. For these patients, prophylaxis therapy is the only appropriate therapy. Historically, for prophylaxis, patients infused blood-clotting factors intravenously 2-3 times per week. Now, we’ve seen the FDA approval of the bispecific antibody, emicizumab, for prophylaxis for adult and pediatric patients. This agent could improve patient outcomes by increasing adherence as it is given subcutaneously, which is much easier than intravenous infusion. Additionally, emicizumab can be given less often with a once a week, every 2 weeks, or every 4 weeks dosing schedule.
Adherence Challenges With Prophylaxis Therapy in Teenagers and Young Adults
Adherence with prophylaxis therapy can be a major problem especially for teenagers and young adults. Some patients who should be on prophylactic therapy have chosen to stop therapy because of the burden of infusing factor VIII replacement therapy intravenously multiple times per week. Teenagers and young adults often say that they either don’t have the time or they don’t feel like making the effort to keep up with their treatments. They may also not be comfortable with others seeing them take their medicine intravenously, especially if they are in college and/or living with roommates.
There are 2 types of nonadherent patients that I see in my clinic. The first type is prescribed prophylaxis and tell their doctors they are taking their treatment when they are not. These patients are difficult to manage because we are unsure why they are still having joint damage or muscle bleeds despite presumably being on the best available treatment regimen. The second type of nonadherent patients are open with their doctors that they are unable to keep up with their prophylaxis therapy, often when they make a major life change like going to college. I understand that it can be difficult to continue on prophylaxis therapy, and I try to support my patients who struggle with adherence while also stressing the importance of getting any bleeds treated right away. Managing bleeds when they occur instead of remaining on prophylaxis therapy is not an ideal situation, but I can understand their perspective.
As mentioned above, the landscape for prophylactic therapy for patients with hemophilia has changed with the FDA approval of the bispecific antibody emicizumab based on the phase III HAVEN 1-4 trials. Emicizumab targets factor IXa and factor X and is approved for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients ages newborn and older with hemophilia A (congenital factor VIII deficiency) with or without factor VIII inhibitors. Across the HAVEN trials, approximately 98% of patients had fewer than 3 treated bleeds after Week 24 of the trials. Emicizumab also offers the convenience of being administered subcutaneously once weekly (1.5 mg/kg), every 2 weeks (3 mg/kg), or every 4 weeks (6 mg/kg).
Now that emicizumab is available, I would strongly urge nonadherent patients to make the switch because it is administered less frequently than other prophylactic therapies and given subcutaneously. The treatment burden is, thus, much lower, even though there is still a needle involved and there is still a need for disclosure to roommates or others involved.
Cost Considerations With Emicizumab
For patients with severe hemophilia or moderate hemophilia who are on prophylaxis or were previously on prophylaxis, cost is not a major consideration when prescribing emicizumab. The cost of emicizumab is similar to the cost of factor VIII replacement therapy on a year-to-year basis. I have not had issues with payers approving emicizumab because I think they understand that it is effective, safe, and a good option for many patients. I have had very rare instances with a denial of authorization in a patient who should be on prophylaxis therapy, and in those cases, we can overcome the denial through an appeal process. For patients with mild hemophilia A, payers may deny approval for emicizumab. This may be because there isn’t a need for prophylaxis in that situation, as episodic therapy may be more appropriate given the relative infrequency of bleeding in the vast majority of patients with mild hemophilia.
Adverse Events With Emicizumab
The most common adverse events with emicizumab are injection-site reactions, such as pain, swelling and redness. In the HAVEN trials, approximately 15% to 31% of patients experienced an injection-site reaction. Typically, these are mild to moderate reactions that resolve without treatment.
Thromboembolic events, including venous thromboembolisms and thrombotic microangiopathy, may be a concern with emicizumab. For patients who do not have factor VIII inhibitors, there is much less concern for blood clots with emicizumab as none were reported in clinical trials and the occurrence is very rare in the real-world setting. However, there is clearly a risk for thrombosis and thrombotic microangiopathy for those who do have factor VIII inhibitors, depending on how they treat their bleeds. Patients are advised not to combine emicizumab with activated prothrombin complex concentrates (for doses >100 IU/kg for more than 1 day) to treat bleeds.
Anti-drug neutralizing or clearance antibodies to emicizumab may occur, and to the best of my knowledge, there have been 3 reported cases (2 neutralizing and 1 clearance) of such antibodies out of approximately 10,000 patients who have received emicizumab. These anti-drug antibodies are rare, but when they occur, they will render emicizumab ineffective or less effective such that patients on emicizumab who continue to have bleeds should be checked for anti-drug antibodies. While there are no specific assays for the identification of these antibodies, neutralizing antibodies should be suspected in any patient on emicizumab with a prolonged partial thromboplastin time. A human chromogenic factor VIII assay or a modified one stage clotting assay with an emicizumab-specific calibrator and controls can be used to determine approximate or actual emicizumab levels, respectively. Clearance antibodies will be more difficult to ascertain but can be suspected if the half-life of emicizumab is shorter than expected when performing pharmacokinetic studies.
Patient Counseling for Adherence
It is essential to discuss the importance of adherence with teenage and young adult patients with hemophilia. Adherence should be improved with the easier and less frequent administration of emicizumab, but it is not guaranteed. I have lengthy discussions with my patients about how they are going to make sure that they do not miss their doses. For example, if their dosing schedule is every 2 or every 4 weeks, it can be easy to forget to dose. We discuss what measures they are going to put in place to make sure they do not miss the doses, like adding reminders on their cell phones or setting up a treatment calendar.
Lifestyle Consideration for Patients With Hemophilia
We encourage our patients to be physically active and participate in sports, but we advise them not to participate in collision sports like tackle football, ice hockey, or lacrosse. We tell them it is okay if they want to go to the gym or play other sports like tennis or soccer because emicizumab should offer sufficient protection to prevent bleeds with these activities, though this has not been proven and is currently under study. Patients should be aware that bleeds can still occur while on emicizumab especially in association with physical activity or trauma. Emicizumab does not prevent every bleed in every patient who is active, and bleeds should be treated immediately if they do occur.
With more convenient prophylaxis therapeutic options and improved patient education, we are hoping to curtail adherence challenges seen in adolescent and young adult patients with hemophilia A.
What questions do you have about improving adherence in young adult patients with hemophilia A in your clinical practice? Please answer the polling question and post your thoughts and questions in the discussion box below.