Levels Matter

Why Levels Matter

Decades of experience show a clinical correlation with Factor VIII (FVIII) activity levels and bleed outcomes^4,7

• FVIII activity levels have played an integral role in hemophilia A management for decades⁷
• For every 1% increase in baseline factor activity levels, there is a decrease in bleeding frequency^4,8
• Clinical guidelines emphasize FVIII activity as an important metric for setting treatment thresholds, assessing surgical readiness, and managing bleeds⁴
   

What are normal & near-normal levels?

Higher Factor VIII levels = less risk of bleeds^4,11

FVIII levels are used to determine the severity of a person's hemophilia, and also correlate with bleed risk. The higher their FVIII levels, the lower their risk for bleeds^2,10,12:

A Phase 3 trial of 134 patients with severe hemophilia A demonstrated that*:

Maintaining FVIII levels in the non-hemophilia range helped achieve zero bleeds.¹³

* GENEr8-1 was a multicenter, open-label, single-arm, Phase 3 trial evaluating the efficacy and safety of a single intravenous infusion of valoctocogene  roxaparvovec in 134 adult men with severe hemophilia A previously receiving FVIII prophylaxis.

The Impact of Lower Factor VIII Levels

Lower Factor VIII (FVIII) levels leave patients vulnerable to more than just bleeds^4,9,14

^{Risk of joint bleeds}

^†According to the WFH Guidelines, more than 80% of acute bleeds occur in joints (hemarthroses), underscoring the critical role of joint protection and early prophylaxis in preventing long-term musculoskeletal damage.⁴

^‡Of the 4771 male patients with mild to moderate hemophilia studied in a retrospective analysis of Universal Data Collection surveillance data, those with factor levels of 15% to 40% experienced a mean number of 0.33 joint bleeds. Patients with factor levels of 6% to 9% experienced a mean number of 0.68 joint bleeds.¹⁵

^§Findings are derived from a published commentary (Valentino, 2024) and a narrative review (Gollard, 2025) describing the clinical impact of joint bleeding and associated outcomes in hemophilia A.^6,16

Bleeding impacts quality of life

^||In a narrative review of chronic pain in people with hemophilia, more than 50% of patients were reported to experience chronic pain severe enough to cause functional incapacity and interfere with activities of daily living.¹⁷

^¶ In an ethnographic study of 51 people with hemophilia across 5 European countries, 78% reported limiting their activity levels due to their condition, reflecting both physical and psychological restrictions related to fear of bleeding.¹⁸

^# In a real-world cross-sectional survey of 244 people with moderate or severe hemophilia A receiving prophylactic treatment in the United States, 80% of patients reported being worried about experiencing breakthrough bleeds despite ongoing prophylaxis.¹⁹

"We need treatments that can help change with us."

- Mark Skinner, JD

A closer look at traditional treatments for hemophilia A

*One stage and chromogenic assays.
^†In vitro TGA and in vivo mouse clip.

Direct comparisons between factor replacement and nonfactor therapies on safety and efficacy data cannot be made.

Higher Factor VIII levels mean greater protection⁴

Raising the bar for hemophilia A management to improve bleed control through higher FVIII levels⁴

• The standard of care for hemophilia A has progressed from episodic rescue to proactive, individualized prophylaxis designed to meet personalized goals⁸
• Treatment for hemophilia A has moved well beyond historical trough levels, and it is now recognized that higher factor levels can help deliver better outcomes²⁸

Evolution of Factor Activity Levels^2,4,6,12,15

Study Limitations:

1. Predictive PK values are not solely representative of observed factor trough levels and are not predictive of clinical outcomes.
2. PK modeling does not fully capture interindividual variability, as it relies on factor activity as a surrogate and does not account for product-specific differences, has limited inclusion of pharmacodynamics, and assumes steady-state conditions and consistent adherence.
3. These PK analyses are retrospective post hoc analyses and are limited by recall bias of patient reported bleeds and incomplete or limited input data.
4. These PK analyses are not adequately powered to predict the relationship between trough levels and bleed protection.

Hear from Mark Skinner, Former President of WFH, on Why FVIII Levels Matter

In a multinational poll of 950 patients with hemophilia, 1080 caregivers, and 679 hematologists²⁹

• 54% of patients report having fair or poor health, though many (71%) tell their HCP they are fine²⁹

• 87% of patients are concerned about both current and long-term health problems²⁹

Targeting high factor levels may^2,4,6,9:

• Prevent bleeds by providing factor activity consistently above the threshold needed to avoid spontaneous bleeding^2,6
• Protect joints by reducing or eliminating hemarthroses, thereby preserving long-term musculoskeletal health and function^2,6
• Reduce chronic pain to allow patients to work more physically active jobs and participate in family life and other daily activities^6,9
• Enable physical activity by sustaining FVIII levels closer to normal that may allow patients to participate safely in sports, work, travel, and other physical pursuits⁶
• Improve confidence in bleed protection through measurable reductions in bleeding rates and meaningful gains in the quality of life and independence^2,5