Emicizumab in infants: not just cost-effective but mandatory Open Access

In this issue of Blood Advances, Glaeser-Khan et al¹ in their publication titled “Emicizumab for prevention of intracranial hemorrhage in infants with severe hemophilia A: a cost-effectiveness analysis” provide a detailed analysis assessing the cost-effectiveness of emicizumab for the prevention of intracranial hemorrhage (ICH) in infants. The authors explore the available data and make their analyses in an extraordinarily scientific manner (much to their credit) and present it in this article giving us “the cold hard facts.” Although I must say that as a pediatric hematologist for over 25 years (and as a parent), I, personally, find it difficult to discuss such a devastating complication, which I have witnessed in my career far too often without at least some, if not a lot of, emotion. I have been around long enough to see young adults with hemophilia, who had ICH as infants, attempt to navigate the challenges of adult life (which is challenging enough with perfect health) with a variety of neurological impairments. Without a doubt, this part of my patient care fills me with the most sympathy and compassion.

First, let us review the science of this article. The authors built a Markov cohort model using the previously published epidemiology of ICH in infants, and they included not only the incidence but also the outcomes. For the infants that survive ICH (which happens to be most of them), the neurologic outcomes are paramount when assessing cost-effectiveness. Next, the authors evaluated the recently published data from the Haven 7 trial that enrolled infants from birth to the age of 12 months on emicizumab prophylaxis.² This cohort includes a large proportion (nearly half) who started emicizumab before the age of 3 months. This is particularly important as the rate of ICH rises in infancy from almost immediately after birth before leveling off at the age of ∼9 months.³ The model assumptions are all entirely reasonable, lending strength to the model similar to the cost assumptions. Finally, the authors used incremental cost-effectiveness ratios (ICERs) in US dollars per quality-adjusted life-years (QALYs) as their main outcome measure. ICER is a highly utilized outcome measure in cost-effectiveness research, providing the reader with an understanding of what the actual cost is to improve the patient’s quantity as well as quality of life. This is not the first time that ICERs were used in assessing the benefits of emicizumab.⁴ Ultimately, the authors found that the cost of emicizumab is in the range of $100 000 per QALY, which is even less and acceptable in all willingness to pay thresholds in the US if the dose of emicizumab was reduced by 50%. However, an important caveat here is that although data exist regarding the potential effectiveness of emicizumab at lower doses,^5-7 these data do not apply to the prevention of ICH in infants.

As emphasized earlier, the science here is extremely strong in my view, and it certainly supports the practice of starting emicizumab as early in life as possible, which is the practice that we adhere to in my center. However, as stated above, it is difficult to leave this discussion only to dollars and cents and somewhat abstract concepts such as QALYs. The harsh reality is that ∼6% of infants with severe hemophilia A³ will have an ICH, and sadly, some will die; although perhaps paradoxically, the hardship of the survivors and their parents may be much worse. For those of you who have cared for such children and watched them grow into adults, you will understand this well, whereas for those of you who have not, it is one of the more devastating situations that you will have to face. With that said, can we really put a monetary value on the prevention of ICH in infants with hemophilia? This study indeed accomplishes that and on a macro level, this is important because it is such data that can motivate the entire hemophilia community to ensure that we provide this option (even insist on it) for parents of newborns with severe hemophilia A. It certainly can help with access because these “cold hard facts” as mentioned above are what the payers are looking for.

Let me conclude with an anecdote. Emicizumab was licensed for patients with severe hemophilia A without inhibitors in October 2018. In early 2019, I diagnosed my first infant with severe hemophilia A after that approval. The infant’s family had no history of hemophilia; however, they had spent many hours educating themselves online and on social media, and coincidentally (or perhaps not), they met the parents of another patient of mine who had an ICH at the age of 3 months and who had mild neurologic sequelae. When we first met, he was aged 5 weeks, and the parents told me about that interaction and stated to me in words that I will never forget: “Dr. Young, please do everything you can to ensure our son does not bleed in his brain.” In my mind, I thought to myself, “challenge accepted.” At this time, the youngest patient in any publication who received emicizumab was from the Haven 2 trial, and he was aged 11 months and had a factor VIII inhibitor, making it an entirely different situation.⁸ To make a long story short, I reviewed what we knew and did not know about emicizumab at that time, and based on that discussion, I prescribed him emicizumab, which he started a few days later. What I did not realize at that moment was that I had changed our center’s practice forever. Clearly, after that scenario, every subsequent infant with severe hemophilia A was offered the same treatment.

In conclusion, as a data-driven person, I will concede that although no patients on the Haven 7 trial had an ICH, statistical proof is still lacking (even though it is unlikely to be ever achieved). During the 6 years of my practice since we have instituted starting emicizumab as early in life as possible, we have had 0 cases of ICH out of ∼40 infants. This is really all the proof I need, but the Glaeser-Khan study data certainly help.

Conflict-of-interest disclosure: G.Y. has received consulting fees from Alnylam, ASC Biotherapeutics, Bayer, BioMarin, CSL Behring, Genentech/Roche, Hema Biologics, Hemab, Novo Nordisk, Octapharma, Pfizer, Sanofi Genzyme, Spark, and Takeda and funds for research support from Sanofi.