CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: March 23, 2023
Expiration: March 22, 2024
Allison Wheeler, MD, MSCI:
In patients with severe hemophilia A, spontaneous bleeds in joints or muscle tissue caused by a deficiency (absent or decreased) in the coagulation clotting protein known as factor VIII often occur from general everyday activities involving weight bearing, trauma bleeds related to injuries, surgical procedures, or other invasive procedures. Of importance, chronic pain caused by joint bleeds and degeneration have negative consequences on patients’ health-related QoL, even with conventional standard prophylaxis for severe hemophilia A.39
Patients with severe hemophilia A have always had to receive factor VIII replacement intravenously. The products previously on the market have all had very short half lives─around 8 to 12 hours depending on age. The new generation of extended half life products were able to extend the half life up to about 16 to 18 hours.40 Thus patients with hemophilia A continue to have intravenous infusions 2 to 4 times per week, depending on the product and how quickly it is metabolized.
A previous report from the phase III XTEND-1 study of efanesoctocog alfa—a new extended half-life factor VIII Fc-von Willebrand factor-XTEN fusion protein with a significantly longer half life of approximately 42 hours—showed that it had met its primary endpoint of improving annualized bleeds compared with prior factor VIII prophylaxis in patients with severe hemophilia A (P <.0001).41
Allison Wheeler, MD, MSCI:
At ASH 2022, Wilson and colleagues42 presented a report for the phase III XTEND-1 study of efanesoctocog alfa prophylaxis assessing changes in pain scores in patients with severe hemophilia A who were previously receiving standard of care factor VIII prophylaxis. Patients enrolled were 12 years of age or older and had previously received another factor VIII replacement product for ≥150 exposure days. The study had 2 arms: Patients in arm A received efanesoctocog alfa once weekly for up to 52 weeks, and patients in arm B initially received on-demand efanesoctocog alfa for 26 weeks, then switched to once-weekly prophylaxis for another 26 weeks. As previously mentioned, the primary endpoint of reducing annualized bleeds in arm A was previously reported.41 The key secondary endpoints included pain and QoL.
Investigators in this study looked at pain in several ways, including the Patient-Reported Outcomes Measurement Information System-Short Form (PROMIS SF) v1.0 Pain Intensity 3a score, another 5-level EuroQol 5-Dimension Scale (EQ-5D-5L) pain and discomfort domain, and study exit interviews.
These additional measures may not have been quite as objective and clear in terms of data points for statistical comparison but potentially gave a real world human assessment of changes in the experience of pain from one type of treatment to another.
I think it is commendable that they looked at both objective and subjective measures in this study, but we do have to evaluate PRO measurements knowing that they have some limitations.
Allison Wheeler, MD, MSCI:
Of 133 patients, 56.9% reported that they had at least moderate pain at baseline. After 52 weeks of efanesoctocog alfa prophylaxis, there was a statistically significant improvement in PROMIS-SF v1.0 Pain Intensity 3a scores (n = 119; least squares mean change -0.21; P = .0276), which was considered to be clinically meaningful and supported by psychometric analyses.
Allison Wheeler, MD, MSCI:
The investigators explored pain in a few different ways: with the statistical change already mentioned and by showing that approximately 82% of patients (97 of 119) had numerical improvement or maintained the change in pain intensity. In other words, their pain intensity had decreased, and that improvement was maintained throughout Week 52 of the study. In addition, investigators categorically analyzed patients according to their level of pain and found that more patients had reported no pain in the previous 7 days at the Week 52 assessment compared with those reporting pain at baseline (37% to 29%).
Allison Wheeler, MD, MSCI:
In addition to the PROMIS SF Pain Intensity 3a score, another measure of pain, PROMIS-SF 6a Interference T-score, and EQ 5D 5L were reported. Both of these additional measures reinforced the finding of numerical improvement in pain scores throughout this clinical trial. Change from baseline for PROMIS-SF 6a Interference T-score to Week 52 was -1.16 (P = .0793), and approximately 21% of patients reported improvement in the EQ-5D-5L pain/discomfort domain while receiving once-weekly prophylaxis with efanesoctocog alfa compared with baseline.
The percentage of patients not taking hemophilia-related pain medication within 14 days preceding their visit increased from 73.6% at baseline to 81.9% at Week 52 while receiving once-weekly prophylaxis with efanesoctocog alfa or on-demand efanesoctocog alfa.
The final qualitative assessment reported in this pain analysis from XTEND-1 was the exit interviews. Overall, 25 of 29 patients participating in exit interviews reported improvement in pain while receiving once-weekly efanesoctocog alfa.
Allison Wheeler, MD, MSCI:
The pain analysis from the phase III XTEND-1 trial showed that once weekly prophylaxis with efanesoctocog alfa resulted in meaningful improvement in pain across multiple timepoints for patients previously receiving standard of care prophylaxis with factor VIII replacement therapy.
The authors also concluded that pain is an important burden in patients with hemophilia A and that exit interviews and psychometric analysis reinforce improvement in pain when switching from standard of care prophylaxis to efanesoctocog alfa—and I absolutely agree with that. Patients who have received prophylaxis to prevent bleeds from a young age have an exceedingly different lifestyle than those who are older and who have daily pain because of their previous bleeds due to severe hemophilia A.
Overall, the primary trial data on efanesoctocog alfa have been very promising and exciting, and this pain analysis is an additional piece of supportive evidence that can help us provide an additional option for our patients with hemophilia A.
We have to remember that real life and clinical trials are a bit different, so I hope that—either through registry studies such as the American Thrombosis and Hemostasis Network or industry sponsors—pain as an endpoint will continue to be studied after market, if this drug does come to market.
I talk about pain with all of my patients at all of their clinic visits. It is one of the questions that I definitely ask. I am primarily a pediatrician, so most of my patients do not have a lot of pain because they have been receiving factor VIII prophylaxis from a young age, but I do have some pediatric patients with pain—most of them not daily, but definitely weekly or monthly depending on their activities. When it comes out in pediatric patients, they say things like, “I played basketball with some of my friends, and then I was in pain the next day, but I didn’t feel like it was an overt bleed.” My adult patients, however, do talk about having pain every day, such that the intensity of that pain and its effects on their daily lives and activities are more clinically meaningful. In addition, I do have patients to whom I reach out or who reach out to me between clinic visits because of increasing pain, either with activity or for arthropathy with weather changes. Pain management is something that most hemophilia providers focus on a little bit at every clinic visit, but the amount of focus varies with the age of the patient and their clinical history.
I am unsure whether efanesoctocog alfa would be an effective treatment for women with hemophilia who have menstrual related pain, but I think that’s a good question to study, along with whether efanesoctocog alfa can provide hemostatic benefit to women who have menstrual pain. Currently, when I talk to women about menstrual pain—which I do quite a bit—I initially gear the conversation toward trying to improve their bleeding symptoms, which for many patients does associate with a decrease in cramping. For those who do not experience relief from cramping, I use celecoxib intermittently during their periods, because this nonsteroidal anti-inflammatory drug can be used without worsening their bleeding phenotype. Pain in association with menstrual bleeding would be a very important endpoint to study with efanesoctocog alfa treatment.
Allison Wheeler, MD, MSCI:
Hemophilia A and B are both bleeding disorders caused by the absence of or a decrease in factor VIII for hemophilia A and factor IX for hemophilia B.43
Patients with hemophilia A or B often produce antibodies against the factor replacement therapy they receive, resulting in the destruction of that factor replacement by their immune system.44,45 These antibodies make it significantly difficult to treat hemophilia and lead to worsened bleeding symptoms and disability for the vast majority of patients who produce inhibitors.43
The novel agent fitusiran is a small interfering RNA (siRNA) therapeutic with SC administration currently under investigation as prophylaxis in hemophilia A or B with or without inhibitors.46 Fitusiran works by inducing the body to produce less of the protein antithrombin, a natural anticoagulant. By decreasing the natural anticoagulants in a patient with hemophilia A or B, we can balance the decrease in procoagulant—either factor VIII or factor IX—that a patient naturally has due to their hemophilia.
In the phase III ATLAS-PPX switch trial in patients with hemophilia A or B with or without inhibitors, fitusiran prophylaxis was shown to significantly reduce the annualized bleeding rate by 61% (P = .0008) when compared with factor/bypassing agent (BPA) prophylaxis (primary endpoint).2
Allison Wheeler, MD, MSCI:
At ASH 2022, investigators reported the health-related QoL analyses from the ATLAS-PPX trial.47 As you may remember, patients in the trial were 12 years of age or older and had originally received either factor or BPA for 6 months if they had inhibitors. Patients were “switched” to fitusiran 80 mg for 6 months. The secondary endpoints explored health-related QoL during the fitusiran treatment period vs factor/BPA using various QoL measures: health-related QoL, EQ-5D-5L, Hemophilia Activity List (HAL), Hemophilia Quality of Life Questionnaire (Haem-A-QoL), and Treatment Satisfaction Questionnaire for Medication (TSQM-9), which assesses PROs repeatedly to make comparisons showing changes for each patient.
Allison Wheeler, MD, MSCI:
This graphic on the right shows the baseline data and various parts of the Haem A-QoL score for 65 of 80 patients enrolled on the study. In the first 2 sections of the graphic, the negative is on the left side and the positive is on the right, and the bottom one is reversed. These data show that in terms of QoL, patients who did not have inhibitors at baseline had better QoL scores than patients who had inhibitors. This is not surprising, because it is harder to prevent and treat bleeds in the presence of inhibitors, and therefore those patients would be expected to have more bleeding, more disability, and more pain. Overall, this is an anticipated baseline measurement for this patient population.
Allison Wheeler, MD, MSCI:
This slide provides information about the Haem A-QoL score, which demonstrated lower/improved total (-7.62 vs -3.07) and physical health (-9.60 vs -6.0) scores in favor of fitusiran vs previous factor/BPA prophylaxis.
Allison Wheeler, MD, MSCI:
In addition to the Haem A-QoL score, the investigators employed other patient reported assessment outcomes, including the TSQM-9 questionnaire, which includes measures of convenience, efficacy, and satisfaction. All of the aforementioned metrics were rated better in patients receiving fitusiran prophylaxis vs previous factor/BPA. This demonstrates that not only are QoL, physical changes, and bleeds improving, but the patients also preferred this new treatment.
Allison Wheeler, MD, MSCI:
Patients receiving fitusiran vs factor/BPA prophylaxis also reported good functional ability to perform activities of daily living as measured by HAL functionality status scores and numerical improvement in QoL as measured by the EQ-5D-5L score index.
Allison Wheeler, MD, MSCI:
The investigators concluded that fitusiran prophylaxis improved QoL endpoints in adult and adolescent patients with hemophilia A or B with or without inhibitors, as well as decreased bleeding, and that the patient experience also favored fitusiran vs factor/BPA prophylaxis. I think the latter point is not unexpected, especially for patients who previously received inhibitors.
Transitioning from prophylaxis with factor/BPA to an effective nonfactor therapy or rebalancing agent such as fitusiran, we definitely would expect improvements in QoL. I think this is an important endpoint to study, and it is going to be exciting to see what happens as fitusiran moves into the clinic.
Because of other therapies that are already on the market, fitusiran may be more enticing for our patients with hemophilia B, particularly those with inhibitors who have only BPA as a modality to prevent and treat their bleeds. I think most HCPs are very excited about the rebalancing agents coming through the clinical trial pipeline, fitusiran included.
Patients with hemophilia A have the alternative nonfactor product emicizumab, which is a monoclonal antibody with SC administration that mimics the effects of factor VIII, although not as robustly, and can be given to patients with or without inhibitors. However, patients with hemophilia B do not have this option. So, I think patients with hemophilia B without inhibitors, particularly younger patients, will be very excited about SC rebalancing agents, especially younger children or those who have difficult venous access.
Patients with hemophilia B with inhibitors have very few options right now. Treatment of inhibitors in patients with hemophilia B with immune tolerance induction therapy is less successful than in hemophilia A and often can be associated with kidney damage or allergic reactions.44,45
The BPAs, although effective, are harder to take and not as effective as factor replacement therapies. I believe these rebalancing agents will become the hallmark of prophylaxis for patients with hemophilia B with inhibitors, and it is exciting to see the possibility of products like fitusiran coming to the clinic for that patient population.
Back
