Estimating the Cost Savings and Cost Effectiveness of Low Dose Immune Tolerance Induction (ITI) Therapy with Bypassing Agent Prophylaxis Compared to High Dose ITI and Low Dose ITI

Introduction: The International Immune Tolerance Study (I-ITI) demonstrated comparable success rates between low (FVIII 50 IU/kg/TIW) and high dose (FVIII 200 IU/kg/day) ITI regimens for hemophilia A patients with high-titer inhibitors. While costlier, the high dose ITI regimen was associated with shorter time-to-treatment success and with fewer bleeding episodes compared to the low dose ITI regimen. Kenet (2017) estimated that adding aPCC prophylaxis to a low dose ITI regimen may be cost saving to achieve negative titer compared to high dose ITI, while achieving comparable bleeding outcomes. Low dose ITI is certainly the least costly treatment option; however, due to increased bleeds in this arm, many treaters are now using low dose ITI with bypassing-agent prophylaxis (BAP). The choice of which ITI regimen to use is enhanced by a cost effectiveness analysis (CEA) comparing the cost and clinical outcomes of low dose ITI with and without BAP.

Methods: An economic model was developed to compare all three regimens: high dose ITI, low dose ITI and low dose ITI with BAP. All model inputs were derived from clinical trials. In the I-ITI study, patients on the high and low dose regimens were treated for a median of 4.6/6.9/10.6 versus 9.2/13.6/15.5 months, respectively, until achieving negative inhibitor titer/first normal recovery/tolerance, and experienced an average of 0.28/0.09/0.03 versus 0.62/0.13/0.15 bleeds/month, respectively, in each phase. Based on the BAP trials, the addition of aPCC (85 U/kg/TIW) and rFVIIa (90 μg/kg/day) achieved a 62% and 45% reduction in bleeding frequency, respectively. The CEA is based on a Markov model structure and simulates costs and outcomes for each treatment regimen over three years to allow for the average patient to complete ITI and achieve tolerance on either regimen. The analysis uses US third party payer perspective, applies a 3% discount rate, and regimen costs are limited to drug costs. One-way and probabilistic sensitivity analyses were performed.

Results: The estimated treatment costs over three years were $216,024, $57,366, and $30,506 per kilogram body weight for high dose ITI, low dose ITI with aPCC prophylaxis, and low dose ITI alone, respectively. The estimated number of bleeds that occur with each regimen over three years were 3.9, 6.1, and 10.9, respectively.Adding aPCC prophylaxis to a low dose ITI regimen was estimated to prevent 4.8 bleeds and cost $5,642 per kg per bleed avoided relative to low dose ITI alone in the base case. The addition of rFVIIa prophylaxis to low dose ITI also improved bleeding with a higher cost; however, compared to aPCC prophylaxis, low dose ITI with rFVIIa prophylaxis was associated with higher cost, and less improvement in outcomes. Model results were robust in the majority of sensitivity analyses performed. Given the addition of aPCC prophylaxis is expected to reduce the risk of bleeding during ITI, this may improve the time to negative titer, and thus further lower the cost per bleed, i.e. a 50% reduction in time to negative titer results in a 52.8% reduction in cost per bleed avoided due to aPCC prophylaxis.

Conclusion: A low dose ITI regimen with aPCC prophylaxis may be cost saving compared to a high dose ITI regimen, with a comparable risk for breakthrough bleeds. While more costly than low dose ITI alone, adding aPCC prophylaxis to a low dose ITI regimen may be a cost-effective option to control bleeding during ITI, especially if the addition of aPCC prophylaxis leads to a subsequent reduction in the length of time until a negative titer is achieved.