What value did the manufacturer place on bleed prevention with Hemlibra (emicizumab-kxwh) versus on-demand treatment with current bypassing agents?
On November 16, 2017, the FDA announced the approval of Hemlibra (emicizumab-kxwh), a first-in-class monoclonal antibody for the prevention or reduction in the frequency of bleeding episodes in patients with hemophilia A who have factor VIII (FVIII) inhibitors. The indication included both children and adults. Drugs developed for use in patients with hemophilia are granted orphan designation by the FDA and emicizumab was granted priority review as well as breakthrough therapy designation. After viewing one emicizumab treatment cost estimate of $500,000 annually, we wanted to ascertain the accuracy of that estimate in addition to estimating if savings from reduced bypassing agent requirement would exceed the cost of emicizumab. Click here to view a similar evaluation on Vyxeos (liposomal Daunorubicin and Cytarabine).
Hemophilia is an inherited bleeding disorder affecting mostly males in which the blood does not clot properly. This can lead to spontaneous bleeding as well as bleeding following injuries or surgery. Classification into mild, moderate and severe forms is based on FVIII activity, expressed in international units (IU), and primary symptoms. In the moderate and severe forms, trauma related or spontaneous bleeds in the joints can cause severe pain and increase the risk of developing joint diseases. While the exact number of people living with hemophilia in the United States is unknown, current estimates are 20,000 with approximately 80% of whom have hemophilia A.
Treatment is based on increasing the blood activity of the deficient factor to inhibit or prevent bleeding. Options include human plasma derived lyophilized factor VIII concentrates, recombinant factors produced by genetic engineering, the antidiuretic hormone derivate desmopressin (DDAVP) as well as antifibrinolytic and local hemostatic agents. Factor VIII is a protein that is either deficient or defective in patients with Hemophilia A. Factor VIII along with activated factor IX (FIXa) is essential for optimal activation of factor X (FX) in the clotting cascade. The first lyophilized factor VIII concentrates appeared on the market in the late 1960s and since that time factor replacement has been the basis of hemophilia A treatment.
It is estimated that approximately 25% to 30% of hemophilia A patients will develop neutralizing antibodies to FVIII or an inhibitor, which make them unresponsive to standard FVIII concentrates. As a result, not only do patients with inhibitors have an increased risk of joint disease and other complications, the presence of an inhibitor makes treatment of bleeding episodes more difficult and expensive. In addition, males with severe hemophilia A who have an inhibitor are at increased risk of hospitalization and death due to complications of hemophilia. Since the development of an inhibitor can occur with no symptoms, a patient may have developed an antibody without realizing it. The CDC recommends annual testing for an inhibitor in patients with hemophilia. Some treatment options for patients with inhibitors include high-dose factor concentrates, bypassing agents (i.e. activated recombinant factor VII or activated prothrombin complex concentrate (APCC)) and immune tolerance induction (ITI) therapy, which are more costly than standard factor VIII therapy.
Emicizumab offers a treatment alternative to patients with an inhibitor. This monoclonal antibody bridges FIXa and FX, thereby replacing the missing factor VIII activation of FX in the clotting cascade. Per the package insert, it is not structurally related to factor VIII and therefore does not induce or enhance the development of inhibitors to factor VIII. Emicizumab is self-administered once weekly via subcutaneous (SC) injection, while factor VIII replacement and bypassing agents are administered via the intravenous (IV) route. The incidence of the most frequently reported side effects of emicizumab include injection site reaction (19%), headache (15%), arthralgia (10%), pyrexia (7%), diarrhea (6%) and myalgia (5%). A black box warning is included in the product labeling which reports of thrombotic microangiopathy (TMA) and thrombotic events when used with activated prothrombin complex concentrate (aPCC) under specific dosing conditions.
Dosing for emicizumab is weight based at 3mg/kg SC per week for the first 4 weeks, then 1.5mg/kg SC every week thereafter. It is available in two concentrations (30mg/ml and 150mg/ml) in four single dose vial sizes including 30mg/ml, 60mg/0.4ml, 105mg/0.7ml, and 150mg/ml. The labeling information recommends against mixing the two different concentrations in the same syringe. Using the 95% U.S. average adult weight of 134kg to calculate a maximum dosing threshold would result in a 402mg weekly starting dose. Administration of this dose using the highest concentration available would require two x 150mg/ml vials and one x 105mg/ml vial. Following this logic and using the currently reported CDC weight for the average male over 20 in the U.S. as 195.7 pounds and a WAC price of $99.20 per mg, the cost of the annual starting and maintenance doses was calculated as shown in table 1.
Table 1: Annual cost estimate of emicizumab.
|Dosing weight: 195.7 lb (89kg)||150mg/ml Vial||First Year||Maintenance|
|Type||Label Dose||Calculated Dose||Number of vials||WAC||WAC+5%||Doses per year||WAC+5%||Doses per year||WAC+5%|
Data from 2 trials are reported in the product labeling for emicizumab, HAVEN 1 and HAVEN 2. HAVEN 1 was a phase III randomized, open-label trial including 109 males aged 12 and up with Hemophilia A with inhibitors who previously received bypassing agents either on demand or prophylactically. Efficacy was measured based on annualized bleeding rate (ABR). Individuals in the treatment arm experienced 2.9 treated bleeding episodes per year while the arm without emicizumab had 23.3 treated bleeding episodes a year. Quality of life end results included improvement in hemophilia-related symptoms (painful swellings and joint pain) and physical functioning (pain with movement and difficulty walking). The HAVEN 2 study was a phase III single arm, open-label study including 55 children under the age of 12 plus 2 infants with hemophilia A with inhibitors. Interim results of 23 participants under the age of 12 included 87% of the patients not experiencing a bleeding episode that required treatment.
For our purposes since all patients underwent treatment in the HAVEN 2 study, only the results of the HAVEN 1 study can be used to evaluate the reduction of bypassing agent requirement with emicizumab prophylaxis. Also since all patients receiving prophylactic bypassing agents were enrolled to receive prophylactic emicizumab only episodic or on-demand dosing of bypassing agents was used to estimate the cost of bypassing agent use reductions demonstrated in the study. According to HAVEN 1 the estimated difference was 20.4 treated bleeds a year.
Treatment of patients with hemophilia A with inhibitors is very individualized and depends on the titer and persistence of the inhibitor. In the case of a low titer (<5 BU), replacement with factors VIII and IX may be sufficient. Patients with high titers are treated with bypassing agents.
NovoSeven RT is a recombinant coagulation Factor VIIa (rFVIIa) indicated for the use of treatment of bleeding episodes in adults and children with hemophilia A with inhibitors in addition to other indications. Standard dosing for the referenced indication is 90 mcg/kg every two hours, adjustable based on severity of bleed until hemostasis is achieved with 90mcg/kg every 6-8 hours after hemostasis is achieved for severe bleeds.
Feiba is an anti-inhibitor coagulant complex indicated for both the control and prevention of bleeding episodes in patients with hemophilia A with inhibitors in addition to other indications. Standard dosing for bleeding control is 50 to 100 units/kg every 6 to 12 hours depending on the type of bleeding episode.
To compare the cost of emicizumab to the reduction in the cost of on-demand treatment dosing of bypassing agents as reported in HAVEN I, on-demand treatment cost was estimated for each bypassing agent. For cost comparison purposes a reimbursement of WAC+5% and dosing weight of 89kg was used. In Table 2, Novoseven RT on demand treatment dosing was estimated based on 90mcg/kg for 2 doses in addition to one 90mcg/kg dose post hemostasis. In Table 3, Feiba on demand treatment dosing was estimated using 75units/kg q12h for 36 hours or 3 doses. Each was then multiplied by the annualized number of reduced on-demand treatment occurrences (20.4) as reported in the HAVEN I study for an estimated annual cost savings. Results are in table 4.
Table 2: Novoseven RT on demand treatment dose cost estimate.
|Dose (mcg/kg)||Dose (mcg)||Dose (mcg) rounded to SDV||Doses per treatment||Total Treatment Dose (mcg)||WAC/mcg||WAC+5%/mcg||Cost Per Treatment
Table 3: Feiba on demand treatment dose cost estimate.
|Dose (U/kg)||Dose (Units)||Doses per day||Daily dose (U)||Days of Treatment||Total Treatment Dose (U)||WAC/Unit||WAC+5%/Unit||Cost Per Treatment
Table 4: Annual estimated savings.
|Drug||Cost Per Treatment||Annualized Treatment Reduction||Annual Estimated Treatment Savings||Estimated Cost Emicizumab Maintenance||Annual Estimated Savings
Based on this very rough estimate, it appears emicizumab pricing is set to generate annual savings opportunities for an average weight adult male with severe hemophilia A with inhibitors currently undergoing on-demand treatment with bypassing agents.
Future Considerations for Emicizumab
Two additional studies are in progress that should shape the future of emicizumab, HAVEN 3 and HAVEN 4. HAVEN 3 is studying emicizumab in patients with hemophilia A without inhibitors and HAVEN 4 is evaluating bi-weekly and monthly dosing schedules.
RJ Health is an authority on pricing issues in the specialty drug market. For more pricing information specific to the specialty drug market, you can click here to view part one of our two part white paper titled, The Optimization of Specialty Drug Costs Under The Medical Benefit.
U.S. Food &Drug Administration. 11/16/2017. FDA approves new treatment to prevent bleeding in certain patients with hemophilia A [Online] Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm585567.htm
EmicizumabTM (emicizumab-kxwh) [package insert]. South San Francisco, CA: Gentech, Inc; 11/2017. Available at: https://www.gene.com/download/pdf/emicizumab_prescribing.pdf
Mazurkiewicz-Pisarek A, Płucienniczak G, Ciach T, Płucienniczak A. The Factor VIII Protein and Its Function Acta Biochimica Pol. 2016;63(1):11-16 Available at: http://www.actabp.pl/pdf/1_2016/2015_1056.pdf
Center for Disease Control. 04/2017. Hemophila [Online] Available at: https://www.cdc.gov/ncbddd/hemophilia/data.html
Center for Disease Control. 05/2017. National Center for Health Statistics [Online] Available at: https://www.cdc.gov/nchs/fastats/body-measurements.htm
Hemophilia Association of America. 2017. Bleeding Disorders [Online] Available at: http://www.hemophiliafed.org/bleeding-disorders/hemophilia/treatment/
NovoSeven RTTM (Coagulation Factor VIIa (Recombinant)) [package insert]. Bagsvaerd, Denmark: Novo Nordisk; 10/2017. Available at: http://www.novo-pi.com/novosevenrt.pdf
FeibaTM (Anti-Inhibitor Coagulant Complex) [package insert]. Westlake Village, CA: Baxalta US Inc.; 4/2017. Available at: http://www.shirecontent.com/PI/PDFs/FEIBA_USA_ENG.pdf
Castellino A, Emicizumab ‘Life-Changing’ for Hemophilia A With Inhibitors Medscape Pharmacists [Online] December 10, 2017 Available at: https://www.medscape.com/viewarticle/889831?src=WNL_confalert_171210_MSCPEDIT&uac=83943BV