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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 funds for research support from Genentech/Roche; fees for non-CME/CE services from Bioverativ, Genentech/Roche, and Sanofi; and consulting fees from CSL-Behring, Genentech/Roche, Grifols, Kedrion, Novo Nordisk, Sanofi, Spark, Takeda, and UniQure.
For decades, factor VIII replacement therapy has dominated our management approach to patients with hemophilia A. We have witnessed an evolution from plasma-derived to recombinant concentrates including those with longer treatment half-life, which affords patients a reduced dosing frequency of every 3-5 days instead of every other day. Imagine an approximate shift from 185 to 90 IV infusions per year—that’s substantial! Lowering this treatment burden naturally enhances adherence, which leads to fewer missed doses and fewer bleeding events. With standard half-life factor VIII replacement therapy, we see a sawtooth pattern comprising classic postdose peaks and subsequent troughs as factor VIII levels wane. This sawtooth pattern is less extensive with extended half-life factor replacement therapies. Furthermore, in terms of versatility, the same patient may use a single factor VIII product for everyday prophylaxis, treatment during breakthrough bleeds, and prevention of bleeding with surgery.
Most patients in the United States receive standard half-life recombinant factor VIII concentrates, which have firmly established safety and efficacy profiles. Newer, extended half-life products seem to mirror these long-standing profiles. The most serious adverse event associated with factor VIII replacement therapy is the development of inhibitors, which can occur in previously untreated patients. Based on the SIPPET study, plasma-derived products may lead to fewer high-titer inhibitors compared with standard half-life recombinant options. We lack long-term data on inhibitor prevalence with extended half-life factor VIII therapies, but I suspect the rate will be similar to standard half-life agents.
Mimicking the Function of Factor VIII in Lieu of Direct Replacement
Emicizumab, initially approved by the FDA in 2017, fulfills the role of factor VIII by linking factors IXa and X without the concomitant risk of inducing anti–factor VIII inhibitors. Three major characteristics underpin the appeal of this humanized bispecific monoclonal antibody: first, that it is dosed subcutaneously instead of intravenously; second, that it retains activity in patients with inhibitors because of its conformational uniqueness from factor VIII; and third, that it boasts a half-life of 30 days. This latter fact eliminates the sawtooth pattern described for factor VIII concentrates as well as the accompanying “trough periods of vulnerability.” In the phase III HAVEN study, patients without inhibitors switching from factor VIII replacement therapy to emicizumab reduced their annualized bleeding rate by 96-97% (P < .001). With only slight undulations between doses, a near steady-state level of emicizumab is maintained in the blood. After an initial series of 4 loading doses, emicizumab may be dosed every 1-4 weeks. Consider this reduction in treatment burden—down to as few as 16 injections annually!
We do not yet know to what extent emicizumab prevents joint damage, but its recognized prevention of joint bleeds offers indirect evidence that functional deficits would be mitigated as well. In general, injection-site reactions are fairly mild and do not cause drug discontinuation, and there seems to be a very low risk of developing an antibody against emicizumab. Of note, among trial patients with anti–factor VIII inhibitors who received prophylactic emicizumab alongside bypassing agent aPCC for breakthrough bleeds, 5 thrombotic events occurred. For this reason, prescribing information for emicizumab contains a black box warning regarding the potential for thrombotic microangiopathy or thromboembolism with this combination.
Factors to Consider When Selecting Therapy
Deciding whether a patient should receive factor VIII replacement therapy or emicizumab hinges on a case-by-case discussion between the prescriber and either the patient or the pediatric patient’s parents. The first issue to consider in any patient is venous access. If any obstruction exists, for instance in children who experience recurrent infection with ports or in overweight, less dexterous adults with deep veins, subcutaneous emicizumab may be preferred.
I often see adults older than 30 years of age who experience severe hemophilia with cyclic bleeding but have no interest in constant IV infusions for prophylaxis. Approaching this type of patient with a convenient, alternative option could convince someone to adopt full-time prophylaxis with emicizumab. Emicizumab is a valuable option for teenagers and young adults where adherence is notoriously difficult. Sometimes, it is as simple as a patient forgetting, but in the best hands, IV infusion takes at least 10-15 minutes. When the requirement for this kind of consistent time and effort impedes adherence, shifting focus to an easily deliverable modality could increase adherence and positively affect prognosis.
Of course, if a patient is not doing well on factor VIII replacement therapy—meaning they experience intermittent bleeding despite consistent adherence—switching to nonfactor therapy would be an appropriate strategy. Even in patients without any of the aforementioned issues, convenience may overshadow their lack of tangible reasons to switch. Someone may be adherent with no venous access issues or reported bleeding events, but they desire the simplicity of weekly vs near daily dosing.
On the Horizon: Emerging Treatment Options for Unmet Needs
Despite the steady-state prophylaxis offered by emicizumab, thus far, nonfactor therapy has been unable to bring the bleeding rate to zero in every individual. Because patients are gaining more confidence to be active, I see trauma-related bleeds where contact happened for someone playing a sport or exercising at the gym. The question we then have to ask is: Can we make a second-generation bispecific monoclonal antibody that does not convert patients to mild hemophilia, but instead restores essentially normal coagulation function? Clinical trials assessing agents such as Mim8 are working to address this unmet need.
Late-phase trial data are emerging for enhanced factor VIII therapies (BIVV001), anti‑antithrombin molecules (fitusiran), and drugs that block tissue factor pathway inhibitor (concizumab, marstacimab).
Every therapeutic I have discussed leaves patients still having to think about hemophilia and having to treat hemophilia. Being able to get a one‑time treatment that normalizes factor VIII levels and obviates the need for further infusion or injection is the ultimate goal. Gene therapy approaches aim to provide this functional cure. As an example, phase I/II data for valoctocogene roxaparvovec show a correction of factor VIII level that persists through the first year but then slowly declines over ensuing years, with data out to 4 years. Whether this downward trend translates to the eventual need for reintroduction of injectable therapy remains to be seen.
To summarize, in 2-5 years, we will have at our disposal a plethora of treatment options for patients with hemophilia A including better factor VIII products, next-generation nonfactor therapies, and molecules with brand new mechanisms of action. Just beyond that, more in the 3-year to 5-year window, we should also have gene therapy. This will enhance our ability as clinicians to tailor therapeutic trajectories based on both patient need and desire.
How is your practice changing? I invite you to join the conversation by sharing your experience managing hemophilia A in the comments box or by answering the poll question.
Do you want to learn more about optimizing the care of patients with hemophilia? Sign up here to attend a live Webinar “Contemporary Management of Hemophilia A: Expert Guidance to Improve Patient Outcomes” on Friday, December 4, 2020, at 3:00 PM Pacific time with Miguel A. Escobar, MD; Michael Callaghan, MD; and Rebecca Kruse-Jarres, MD, MPH, where they will discuss the available evidence, key ongoing clinical issues, and new data.