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Emerging Gene Therapies for Hemophilia in the United States—Value Drivers in a Crystal Ball

By Xcenda


Emerging Gene Therapies for Hemophilia in the United States—Value Drivers in a Crystal Ball

By: Isabell Kang, PharmD; Vishwas R. Agashe, MSc, PhD | Updated April 24, 2020

Hemophilia is currently an incurable rare inherited bleeding disorder caused by genetic defects that lead to the partial or complete absence of one or more protein components (“factors”) required for blood coagulation (clotting). Multiple gene therapies in development promise a potential cure for hemophilia by reversing the underlying genetic defect and removing the need for lifelong intravenous infusions of blood clotting factors. Given the high level of expectations, manufacturers need to carefully tailor the generation of appropriate evidence to demonstrate the value of their products to key stakeholders in the early adopting United States (US) market.

There are two major types of hemophilia: Hemophilia A (also known as classic hemophilia or factor VIII deficiency) and Hemophilia B (also known as Christmas disease or factor IX deficiency). Although very similar in signs and symptoms, they are caused by mutations in different genes located on the X-chromosome. The severity of Hemophilia A is determined by the levels of factor VIII activity: mild disease (5%–40% of normal activity), moderate disease (1%–5%), and severe disease (<1%). Clinical characteristics of the disease include increased likelihood of bleeding and this mirrors disease severity; patients with severe disease may experience spontaneous bleeding into their joints or muscles. In the US, it is estimated that 20,000 people currently have Hemophilia A and it affects approximately 1 in every 5,000 male live births, which is equivalent to 400 babies born with Hemophilia A annually. Hemophilia A is four times more common than Hemophilia B.

In the absence of a cure, management principles of both conditions are similar and the primary aims of care are to prevent and treat bleeding, usually via clotting factor supplementation (Figure 1) or other methods, and to manage bleeding events as quickly as possible. Factor replacement can either be episodic (ie, given at the time of the bleeding episode) or prophylactic (ie, given at a predetermined frequency to prevent the onset or recurrence of spontaneous bleeding). Prophylactic treatment is recommended in clinical guidelines. However, there is no current consensus on the most appropriate regimen. Additionally, up to 30% of patients with severe Hemophilia A may develop inhibitory antibodies against the infused factor, usually early on in their treatment. Development of inhibitory antibodies complicates management because replacement factors may not be as effective or the best choice; worsening outcomes for patients. Notably, even when patients are perfectly compliant with prophylactic therapy, life-threatening, spontaneous, or traumatic bleeding may still occur. The high burden of disease and invasiveness of treatment underline the unmet need for better approaches to treatment.

Figure 1. The Blood Coagulation Cascade and Factor Replacement Therapy 

The Blood Coagulation Cascade and Factor Replacement Therapy


Hemophilia has a high economic and humanistic burden. In US patients with Hemophilia A, the mean annual direct costs (in 2011 US dollars) per patient were reported to range from $53,907 for patients with mild disease to $292,525 for patients with severe disease receiving episodic treatment. Approximately, 25%–30% of patients with Hemophilia A develop inhibitors to factor VIII and the treatment costs for patients with inhibitors is even higher, with annual costs exceeding $400,000 (in 2000 USD). However, these estimates do not account for the human cost borne by patients due to the profound impact of the disease and its treatment on their quality of life. Among patients with hemophilia, 61% reported mobility problems and 76% of patients reported pain or discomfort. Additionally, 43% of patients reported anxiety and depression and 93%, 86%, and 55% of patients reported feeling tired, worn out, and downhearted and depressed, respectively.

Potentially Curative Therapies in Development

In this context, a cure for hemophilia will have the opportunity to address a huge unmet clinical need while simultaneously delivering substantial savings in direct medical and societal costs. Table 1 provides an overview of four gene therapies in later stages of development that may be approved in the US in the near future as prospective cures for hemophilia. Gene therapies aim to cure Hemophilia A either by inserting a functional copy of the defective gene or a gene encoding a protein that can suppress inhibitors of factor VIII. If successful, either approach could restore the deficient clotting factor and reestablish a functional coagulation cascade. 

Table 1. Select Key Gene Therapies Seeking US Approval for Treatment of Hemophilia A

Select Key Gene Therapies Seeking US Approval for Treatment of Hemophilia A
Sources: BioMarin 2019; Pfizer 2020; Spark Therapeutics 2020.


US Market Considerations

Understanding the key value drivers for emerging cell and gene therapies across the fragmented multi-payer healthcare system in the US presents a significant challenge. As these therapies are lauded as potentially curative for conditions that have historically managed with supportive care and requiring fewer doses, there may need to be a shift in thinking with regards to their evaluation. Additionally, since these therapies are entering the market at a much higher price tag than previously approved therapies, payers are trying to mitigate their immediate budget impact, working with manufacturers to develop outcomes-based payment models that promote risk sharing. For example, Spark Therapeutics and Harvard Pilgrim established a model where Spark would pay rebates for Luxturna (voretigene neparvovec), if a pre-specified threshold for certain patient outcomes are not met. Moreover, a thoughtful evidence generation strategy is needed, as US healthcare decision makers may be more restrictive than the label on their coverage criteria, particularly for high cost therapies; an analysis of 30 payers showed that although Zolgensma (onasemnogene abeparvovec) was covered by payers, the actual coverage criteria were more restrictive than the official FDA approved label. Lastly, the long-term impact of these new therapies on patient-relevant outcomes is still uncertain, which further complicates their evaluation.

However, some useful insights can be obtained by studying the results of recent cost-effectiveness value assessments conducted by the Institute for Clinical and Economic Review (ICER) and its emerging position on how the value of potentially curative cell and gene therapies should be established. Unlike the statutory Health Technology Assessment (HTA) bodies in other markets, Although ICER is not the decision maker for patient access or reimbursement in the US, their assessments are playing an ever-increasing market-shaping role by influencing payer opinions or value expectations from innovative therapies. This is particularly relevant for hemophilia because ICER has published an updated version of the background and scope of their evaluation of valoctocogene roxaparvovec (a gene therapy) and emicizumab (a bispecific antibody therapy) for Hemophilia A on February 25, 2020. In 2018, ICER had reviewed emicizumab and determined that a prophylactic regimen utilizing emicizumab was cost saving for patients with Hemophilia and had inhibitors. In the upcoming review, however, valoctocogene roxaparvovec and emicizumab will be compared to each other, as well as to other Factor VIII preparations being used prophylactically; the evaluation will include clinical, economic, and humanistic outcomes. At the time of writing this article, ICER was anticipating discussing and evaluating hemophilia treatments during the latter half of 2020. Thus, ICER’s previous assessments of two other gene therapies and a position paper on assessing value and determining the price for potential curative therapies approved in the US may offer insights that benefit manufacturers considering a value strategy in Hemophilia A for their products.

Luxturna (voretigene neparvovec)

Luxturna was the first gene therapy to enter the US market and did so at a list price of $850,000 ($450,000 per eye). It is indicated for treatment of biallelic RPE65 mutation-associated retinal dystrophy, a rare inherited condition associated with poor vision at birth and near-complete loss of vision in early adulthood resulting in a serious negative impact on the quality of life of patients, their families, and caregivers.

Main ICER findings:

  • Acknowledgment of clinical efficacy demonstrated using a novel endpoint in the clinical trial; product improves vision and prevents the condition from getting worse
  • Highlighted limitations resulting from the small patient population in trials and uncertainty about long-term efficacy outcomes
  • High price tag coupled with uncertain long-term clinical efficacy resulted in an unacceptable cost-effectiveness ratio, which would require significant discounts to meet the acceptable threshold of $100,000 to $150,000 per quality-adjusted life-year (QALY)

Key learnings:

  • Novel trial endpoints for gene therapies may demonstrate value if the efficacy outcomes are significant and convincing from a patient perspective; even without a complete restoration of normal physiological function
  • High price tags will understandably be scrutinized rigorously and should reflect the quality and level of certainty in long-term efficacy outcomes (eg, a one-time treatment with acceptable lifetime efficacy [“cure scenario”] vs uncertain long-term efficacy requiring repeat treatment in a lifetime [“less than/not a cure scenario”])

Zolgensma (onasemnogene abeparvovec)

Zolgensma is a one-time gene therapy launched in the US in 2019 that was assessed by ICER prior to its FDA approval. It is indicated for the treatment of pediatric patients (aged <2 years) with spinal muscular atrophy (SMA) with biallelic mutations in the survival motor neuron 1 (SMN1) gene. SMA causes substantial disability and may lead to increased mortality and reduced life expectancy. The most severe types of SMA typically cause death before the age of 2 years. In their analysis, ICER individually compared Zolgensma and Spinraza (nusinersen), a previously approved therapy for SMA, to best supportive care. Nusinersen is not a one-time gene therapy but an antisense oligonucleotide given as an intrathecal injection every 4 months after 4 initial loading doses.

Main ICER findings:

  • Expressed concerns about the clinical trial design, generalizability of results, and the certainty of long term benefits
  • Undiscounted price of $2 million did not meet the traditional cost-effectiveness thresholds ($100,000 to $150,000 per QALY) but a discounted price of $900,000 could meet this threshold
  • Alternative evaluation by cost per life-year gained (LYG) suggested a price around $1.5 million to achieve a cost-effectiveness ratio of $150,000 per LYG
  • ICER expressed a willingness to reconsider its evaluation in the future with the availability of additional long-term outcomes data

Key Learnings:

  • Although the undiscounted price was found to be not cost-effective, ICER does recognize that there is uncertainty around the long-term efficacy outcomes
  • ICER's willingness to reconsider the value evidence at a later date reflects its emphasis on provision of long-term data by manufacturers to establish the durability of their product’s treatment benefits, especially if they have a curative intent

Outlook for Manufacturers

Of note, ICER’s position paper on methods for assessing value and determining the price for potential cures considered Hemophilia A gene therapies as a case study. ICER estimated that a one-time gene therapy for Hemophilia A could offset $90–$114 million in lifetime costs for patients who have developed inhibitors to standard factor replacement therapies. Even without considering additional indirect costs (eg, loss of employment or home care), ICER’s analysis revealed that a price of $80 million would still be cost-effective in this population. While such price estimates will understandably be attractive for manufacturers, the real-world price will have to factor in the strength of the evidence supporting the duration of response and demonstrable cost offsets. This situation would qualitatively differ from conditions such as blindness and SMA, where value demonstration may be predominantly focused on improvements in quality of life. Therefore, manufacturers have a unique opportunity to plan rigorous studies to demonstrate the short and long-term clinical, humanistic, and economic value of their products.

Given that ICER intends to assess gene therapies in Hemophilia A, manufacturers developing therapies in this space should take ICER evaluations into account in their market access strategies to ensure the best possible outcome. This could be done through a reactive or proactive approach. Ahead of an ICER review, manufacturers can gain insights from previous ICER decisions to determine future directions. Following an evaluation, manufacturers can utilize ICER critiques to invest in new evidence generation that would strengthen a product’s value proposition ahead of payer negotiations.

Finally, given the cost and financing precedents set by Luxturna and Zolgensma for patient access, innovative financing mechanisms may be required. Especially, if a manufacturer sets a price that exceeds those seen with preceding products, in spite of obvious disease-specific nuances, they can expect to have tough negotiations with payers around the definition of a cure for the target population and their ability to provide certainty of the cost savings that will likely be at the heart of their value proposition.



The article should be referenced as follows: 

Kang I, Agashe V. Emerging gene therapies for hemophilia in the United States—value drivers in a crystal ball. HTA Quarterly. Summer 2020. 


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