Farmeconomia. Health economics and therapeutic pathways 2017; 18(1): 55-60

https://doi.org/10.7175/fe.v18i1.1321

Letter to the Editor

Recently approved recombinant factor VIII (rFVIII) for the replacement treatment in patients with hemophilia A in Italy

Daniela Paola Roggeri 1, Ezio Zanon 2, Alessandro Roggeri 1

1 ProCure Solutions, Nembro (BG), Italy

2 Regional Center for prevention, prophylaxis and advanced treatment of hemophilic arthropathy. Hemophilia Center, University Hospital of Padua, Italy

Keywords

Hemophilia A, Recombinant factor VIII, Dosage, Number of administration

Corresponding author

Alessandro Roggeri

alessandro.roggeri@procuresolutions.it

Disclosure

This paper was financially supported by Bayer S.p.a.

Hemophilia A

Inherited or acquired genetic mutation resulting in dysfunction or deficiency of factor VIII (FVIII) or acquired inhibitor that binds FVIII are causes of Hemophilia A, a rare bleeding disorder. Among patients with genetic Hemophilia A, up to one third of cases are the results of new mutations (not present in the mother’s X chromosome) [1].

Dysfunction or deficiency of FVIII leads to an insufficient generation of thrombin by the FIXa and FVIIIa complex by means of the intrinsic pathway of the coagulation cascade. This mechanism, in combination with the effect of the tissue-factor pathway inhibitor, generates, depending on the level of FVIII activity, a relevant trend towards easy bruising or inadequate clotting of traumatic or even mild injury or, particularly in subjects with severe hemophilia, with spontaneous hemorrhage [1].

Hemophilia A is classified as mild, moderate, or severe depending on the amount of the clotting FVIII in blood. In severe hemophilia A, the FVIII levels are practically undetectable (<1%) causing chronic debilitating joint disease results from repeated hemarthrosis, synovial membrane inflammation, hypertrophy and, in some cases, destructive arthritis. In order to prevent functional disability, early replacement of coagulation factors through infusion is necessary. In most developed countries, the standard of care is the prophylactic therapy starting in young patients [1].

In Italy, from the epidemiological point of view, the National Register of Congenital Coagulation Disorders [2] reported in 2014 a prevalence of the disease of 6.4 per 100,000 inhabitants, it substantially confirms the findings of the “World Federation of Hemophilia”; of the 3,906 registered subjects with hemophilia A, 1,800 had the severe form.

Hemophilia A has a significant impact on patients’ quality of life (school, work, private life) and [3,4] to date has no cure. Moreover, increased disability and quality of life impairment increase with increased age, higher reported bleed frequency and lower employment [4].

Management of patients with hemophilia A

As stated in both the international guidelines (World Federation of Hemophilia) and the Italian guidelines (Associazione Italiana Centri Emofilia), the treatment for patients with hemophilia A consists in the intravenous administration of the deficient or absent factor (FVIII) [5,6]. At the moment two strategies are availabe: on demand treatment, consisting in the treatment of an ongoing hemorrhage by infusing FVIII (which allows a temporary correction of the FVIII deficiency) or prophylaxis (long-term, regular infusion of FVIII), which reduce the bleeding tendency, and, consequently, the negative consequences of the hemorrhages on the joints, maintaining the factor levels in circulation and avoiding spontaneous bleeds [5,6]. The administration of FVIII, which in the past was carried out in hospital setting, is currently carried out (after adequate training of the patient or caregivers) at home also thanks to the availability of biotechnologic drugs, leading to an improvement in the quality of life of the patients themselves and their families [7].

The approach currently recognised as the most suitable treatment for the prevention of joint complications is the prophylaxis, to be started early in children with severe hemophilia A; the benefits of such a treatment regime have also been demonstrated in adolescent and adult patients. Prophylaxis usually requires the administration of factor three times a week, or on alternate days, although the frequency of administration can vary, depending on the type of drug used and the response of the individual patient to that drug (pharmacokinetics) the bleeding phenotype and the patient’s daily activities and life style.

Since 90’s, the available treatments have improved in safety, with the use of plasma concentrations produced through increasingly sophisticated purification techniques, which undergo viral inactivation, to factors obtained with recombinant DNA technology, which have no protein of human or animal origin.

As recently in Italy three new drugs have been made available for the treatment and prophylaxis of bleeding in patients with hemophilia A, our aim is to compare drugs consumption for all the recombinant FVIII actually reimbursed by the Italian National Health Service (NHS).

Kovaltry®

Kovaltry® (octocog alfa, Bayer SpA) a full length recombinant human coagulation factor VIII (rDNA), is a purified protein that has 2332 amino acids; it is produced by recombinant DNA technology in baby hamster kidney cells (BHK) into which the human factor VIII gene has been introduced [8]. The new manufacturing advances allow the co-expression of the human chaperone protein heat shock protein 70 (HSP70); HSP70 is a chaperone protein that may increase FVIII expression by facilitating proper protein folding and improves cell survival by inhibiting apoptosis (i.e., programmed cell death). Kovaltry® is prepared without the addition of any human or animal derived protein in the cell culture process, purification or final formulation and has undergone nanofiltration with a 20 nm filter. The addition of this method to the production process represents a further guarantee of safety, since it is able to remove even potential non-capsulated viruses, previously unknown pathogens and protein aggregates, thus reducing the risk of pathogen transmission.

The efficacy and safety of Kovaltry® were assessed in the LEOPOLD broad clinical development programme [9-11] that consisted of three international trials conducted on over 200 children, adolescents and adults with hemophilia A.

The use of Kovaltry® in prophylaxis demonstrated a decrease in the annualised bleeding rate (ABR) of about 97%, compared to the on-demand treatment (2 vs. 60 bleeds/patient/year; p < 0.0001) allowing the progression of the hemophilic arthropathy to be reduced [9].

The LEOPOLD I and LEOPOLD II trials also demonstrated that Kovaltry® allows effective prevention of bleeds both with 3 infusions per week (3x) and with 2 infusions per week (2x). In LEOPOLD I trial, 29% of patients received the prophylaxis regime with administration twice a week, while in LEOPOLD II trial 47% was randomized to receive this reduced prophylaxis regime. Moreover, about 30% of the patients in prophylaxis with Kovaltry® reported no bleeds during the observation period. In the LEOPOLD Kids Part A trial, 45,1% patients had no bleeds during the six months treatment period [11].

Regarding the immunogenicity, in Kovaltry® clinical trials conducted on more than 200 patients (children and adults) with severe hemophilia A (FVIII < 1%) and previously treated with FVIII ≥ 50 ED, no inhibitors were detected.

Elocta®

Elocta® (efmoroctocog alfa, Swedish Orphan Biovitrum srl) a recombinant human coagulation factor VIII, Fc fusion protein (rFVIIIFc), has 1890 amino acids. It is produced by recombinant DNA technology in a human embryonic kidney cell line (HEK) without the addition of any exogenous human or animal-derived protein in the cell culture process, purification or final formulation [12].

The safety, efficacy, and pharmacokinetics of Elocta® was evaluated in 2 multinational, open-label, pivotal studies [13,14]; median annualized bleeding rates estimates from a negative binomial regression model were 2.91 (the ABR was estimated using the negative binomial model) for subjects in the individualized prophylaxis arm, 8.92 for subjects in the weekly prophylaxis arm and 37.25 for subjects in the on demand treatment arm. No bleeding episodes were experienced in 45.3% of subjects while on individualized prophylaxis and in 17.4% of subjects while on weekly prophylaxis.

Afstyla®

Afstyla® (lonoctocog alfa, CSL Behring SpA), a single chain recombinant human factor VIII produced in Chinese hamster ovary (CHO) cells, is a single polypeptide chain with a truncated B-domain that allows for a covalent bridge to link the factor VIII heavy and light chains [15]. Registrative study in adults and adolescent patients determined the efficacy and safety in the prevention of bleeding events in prophylaxis of Afstyla® [16,17]. The study enrolled 175 previously treated patients (age: 12 to 65 years) with severe hemophilia A who accumulated a total of 14,306 ED with rVIII-SingleChain. A total of 146 subjects were assigned to a prophylaxis regimen and had a median ABR of 1.14. In the study conducted in pediatric population on prophylaxis (81 patients, age < 12 years), median ABR was 3.69 in both studies no patient developed an inhibitor or experienced an anaphylactic reaction.

Other recombinant products

The other recombinant products for the treatment of hemophilia A currently available in Italy, which represent the standard of care, are Advate® (octocog alfa from CHO protein free, Shire Inc.), Helixate NexGen® e Kogenate Bayer® (octocog alfa from BHK, Bayer SpA) Recombinate® (octocog alfa from CHO, with human albumin as stabilizer, Shire Inc.), Refacto AF® (moroctocog alfa from CHO protein free, Pfizer S.r.l.), NovoEight® (turoctocog alfa from CHO protein free, Novo Nordisk S.p.A.) and Nuwiq® (simoctocog alfa from HEK protein free, Octapharma Italy S.p.A.). For each of these drugs, the summary of product characteristics recommends a dosage of 20-40 IU/kg every 2/3 days [12,15,18-24] except for NovoEight® (turoctocog), which is recommended at a dosage of 20-40 IU/kg every two days or 20-50IU/kg 3 times a week [25].

Comparison between available treatments

Table I reports the annual average consumption per patient (dosage X number of administrations) of the available treatments based on European SPCs [12,15,18-25].

Data from clinical trials reported that for Kovaltry® the 30% of patients were treated with two administrations per week and for Elocta® this percentage account at 33%.

Even though the average number of administrations per years appears to be lower with Elocta®, if we consider the total consumption of drug per patient/year, in terms of IU, the results for an hypothetical patient with a weight of 70 kg are summarized in Figure 1.

As shown above , the use of Kovaltry® as indicated in the SPC (20-40 IU/kg 2-3 times a week) [24], allows to reduce the number of administrations/year without increasing the unitary dosage per administration. Considering average dosages per year of Kovaltry® and competitors (reported in SPCs [12,15,18-25]), all therapies are associated with higher drug consumption versus Kovaltry:

• Standard therapy (Advate®, Helixate NexGen®, Recombinate®, Kogenate®, Refacto AF®, Nuwiq®) = +17%;
• Novoeight® = +31%, +32%;
• Elocta® = +17%;
• Afstyla® = +19%.

The potential benefit in terms of drug consumption reduction will be further evaluated in real life condition according to current clinical practice. As in Italy the rFVIII are acquired by NHS facilities through tenders, the annual cost was estimated considering the average selling prices to NHS structures [26-38]. As Afstyla® has been very recently reimbursed and no data on real selling price (i.e. Regional determinations or NHS structures tenders) are available, even if approved price per IU is higher than the average selling prices of other rFVIII, we have conservatively estimated the average annual cost per patient considering the same price per IU (0.65 €) of the other rFVIII (excluding Recombinate® which has a net selling price of 0.60 €/IU).

As highlighted by the Figure 2, at average dosages reported in SPCs [12,15,18-25], all the competitors result to be more expensive than Kovaltry® on a yearly bases with incremental costs ranging from about +15,000 €/year (+8% for Recombinate®) to +60,000 €/year (+32% for NovoEight®). Elocta®, at average dosage (45 IU/kg) leads to an incremental cost of about € 32,000 (+17%) versus Kovaltry®. The last marketed rFVIII, Afstyla® at average dosage (35 IU/kg) leads to an incremental cost of about 35,500 € (+19%) versus Kovaltry®

The estimates of average consumptions and related costs of the different rFVIII reported in the present analysis, are based on dosages/frequence of administration reported in the European Summary of Product Characteristics and clinical trials and should be confirmed through real world observations.

However, an approach that has the potential to reduces the number of administrations per year without any increase in dosage, as is proposed for Kovaltry®, can potentially improve patient quality of life and faciliate compliance to treatment as well as produce potential savings for the Italian NHS thanks to the reduction of rFVIII utilization and a reduction in costs related to a lower risk of breakthrough bleedings and the related complications.

References

1. Hemophilia A. Medscape. Available at http://emedicine.medscape.com/article/779322-overview#a4 (last accessed June 2017)

2. Abbonizio F, Giampaolo A, Arcieri R, Hassan HJ e Associazione Italiana Centri Emofilia (AICE). National Register of Congenital Coagulation Disorders. Report 2014. Roma: Istituto Superiore di Sanità; 2016 (Rapporti ISTISAN 16/20)

3. Forsyth AL, Gregory M, Nugent D, et al. Haemophilia Experiences, Results and Opportunities (HERO) study: survey methodology and population demographics. Haemophilia 2014; 20: 44-51; https://doi.org/10.1111/hae.12239

4. Forsyth AL, Witkop M, Lambing A, et al. Associations of quality of life, pain, and self-reported arthritis with age, employment, bleed rate, and utilization of hemophilia treatment center and health care provider services: results in adults with hemophilia in the HERO study. Patient Prefer Adherence 2015; 9: 1549-60; https://doi.org/10.2147/PPA.S87659

5. European Medicines Agency – EMA. Committee for medicinal products for human use – CHMP. Guideline on the clinical investigation of recombinant and human plasma-derived factor VIII products. EMA/CHMP/BPWP/144533/2009. Available at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/02/WC500201773.pdf (last accessed June 2017)

6. Rocino A, Coppola A, Franchini M, et al. Principles of treatment and update of recommendations for the management of haemophilia and congenital bleeding disorders in Italy. Blood Transfusion 2014; 12: 575-98; https://doi.org/10.2450/2014.0223-14

7. Strawczynski H, Stachewitsch A, Morgenstern G, et al. Delivery of care to hemophilic children: home care versus hospitalization. Pediatrics 1975; 51: 986-91

8. Garger S, Severs J, Regan L, et al. BAY 81-8973, a full-length recombinant factor VIII: manufacturing processes and product characteristics. Haemophilia 2017; 23: e67-e78; https://doi.org/10.1111/hae.13148

9. Kavakli K, Yang R, Rusen L, et al.; LEOPOLD II Study Investigators. Prophylaxis vs. on-demand treatment with BAY 81-8973, a full-length plasma protein-free recombinant factor VIII product: results from a randomized trial (LEOPOLD II). J Thromb Haemost 2015; 13: 360-9

10. Saxena K, Lalezari S, Oldenburg J, et al. Efficacy and safety of BAY 81-8973, a full-length recombinant factor VIII: results from the LEOPOLD I trial. Haemophilia 2016; 22: 706-12; https://doi.org/10.1111/hae.12952

11. Ljung R, Kenet G, Mancuso ME, et al. BAY 81-8973 safety and efficacy for prophylaxis and treatment of bleeds in previously treated children with severe hemophilia A: results of the LEOPOLD Kids Trial. Haemophilia 2016; 22: 354-60; https://doi.org/10.1111/hae.12866

12. Elocta®– Summary of Product characteristics. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003964/WC500198642.pdf (last accessed June 2017)

13. Powell JS, Josephson NC, Quon D, et al. Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients. Blood 2012; 119: 3031-7

14. Mahlangu J, Powell JS, Ragni MV, et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood 2014; 123: 317-25; https://doi.org/10.1182/blood-2013-10-529974

15. Afstyla® – Summary of Product characteristics. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004075/WC500224591.pdf (last accessed June 2017)

16. Stasyshyn O, Djambas Khayat C, Iosava G, et al. Safety, efficacy and pharmacokinetics of rVIII-SingleChain in children with severe hemophilia A: results of a multicenter clinical trial. J Thromb Haemost 2017; 15: 636-44; https://doi.org/10.1111/jth.13647

17. Mahlangu J, Kuliczkowski K, Karim FA, et al. Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A. Blood 2016; 128: 630-7; https://doi.org/10.1182/blood-2016-01-687434

18. Advate® – Summary of Product characteristics. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000520/WC500022467.pdf (last accessed June 2017)

19. Helixate NexGen® – Summary of Product characteristics. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000276/WC500047822.pdf (last accessed June 2017)

20. Refacto AF® – Summary of Product characteristics. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000232/WC500049008.pdf (last accessed June 2017)

21. Kogenate Bayer® – Summary of Product characteristics. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000275/WC500044445.pdf (last accessed June 2017)

22. Recombinate® – Summary of Product characteristics. Available at https://farmaci.agenziafarmaco.gov.it/aifa/servlet/PdfDownloadServlet?pdfFileName=footer_003822_028687_RCP.pdf&retry=0&sys=m0b1l3

23. Nuwiq® – Summary of Product characteristics. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002813/WC500179340.pdf (last accessed June 2017)

24. Kovaltry®– Summary of Product characteristics. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003825/WC500202781.pdf (last accessed June 2017)

25. NovoEight® – Summary of Product characteristics. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002719/WC500157553.pdf (last accessed June 2017)

26. Regione Calabria. Tabelle relative al 28° aggiornamento elenco unico dei farmaci del PHT di cui agli Accordi Quadro stipulati tra la Regione Calabria e le Industrie Farmaceutiche per l’acquisto dei farmaci del PHT di cui alla Determinazione AIFA del 29 ottobre 2004 e s.m.i. Available at http://www.regione.calabria.it/sanita/allegati/novit/28_aggiornamento_dellelenco_dei_farmaci_in_accordo_quadro.pdf (last accessed June 2017)

27. Regione Autonoma della Sardegna. AO “G. Brotzu”, Cagliari. Deliberazione n.562 del 15/03/2017. Available at http://www.aobrotzu.it/documenti/9_204_20170316092953.pdf (last accessed June 2017)

28. Regione Autonoma della Sardegna. AOU di Sassari. Deliberazione n.192 del 12/04/2017. Available at http://www.aousassari.it/documenti/11_175_20170412175041.pdf (last accessed June 2017)

29. Regione Autonoma della Sardegna. AOU di Sassari. Deliberazione n.133 del 08/03/2017. Available at http://www.aousassari.it/documenti/11_175_20170308192010.pdf (last accessed June 2017)

30. Regione Liguria. Asl 3 “Genovese”. Determinazione n.152 del 31/01/2017. Available at http://delibere.asl3.liguria.it/pdf/determinazioni/2017/2017_152_2_77_Pubblico.pdf (last accessed June 2017)

31. Usl Umbria 1. Delibera Del Direttore Generale n. 296 del 08/03/2017

32. Regione del Veneto. AO di Padova. Delibera del Direttore Generale n.410 del 24/03/2017

33. Regione Liguria. Usl 3 “Genovese”. Recepimento gara CRA Liguria 2016 prodotti farmaceutici per un periodo di mesi 24, con opzione di rinnovo per ulteriori mesi 12 lotto 352 A – Refacto Fusengo – Ditta Pfizer

34. Regione Ligura. Usl n.1 Imperiese. Recepimento gara a.li.sa./C.R.A. per la fornitura di “prodotti farmaceutici 2016” per mesi 24 + 12 di rinnovo. Ditta Baxalta Italy – lotto 2285 - Advate 1000 UI

35. AUSL della Romagna. Determinazione n. 1396 del 26/05/2017. Autorizzazione alla fornitura di nuovi farmaci per emofilia non aggiudicate nelle procedure intercent-er - periodo dal 30.05.2017 al 31.01.2018

36. Regione Liguria. Usl 3 “Genovese”. Gara 34977564. Farmaco elocta (efmoroctocog fattore VIII della coagulazione) polvere e solvente per soluzione iniettabile uso endovenoso

37. Regione del Veneto. AO di Padova. Delibera del Direttore Generale n. 472 del 06/04/2017

38. Regione del Veneto. Ulss6 Euganea. Deliberazione del Direttore Generale n.164 del 28/03/2017