Review: Clinical Trial Outcomes For reprint orders, please contact: [email protected] 5 Review: Clinical Trial Outcomes 2015/08/28 Turoctocog alfa in the treatment of individuals with hemophilia A: review of quality of life data collected in Phase III trials Clin. Invest. (Lond.) Hemophilia A is an X-linked recessive hereditary bleeding disorder resulting Stephanie Seremetis*,1, Roshni from a deficiency in coagulation factor VIII. Difficulties due to hemophilia and its Kulkarni2, Antoine Regnault3 management present challenges for patient’s quality of life. Turoctocog alfa, a & Elena Santagostino4 1 recombinant, B-domain truncated factor VIII, is a recent US FDA- and EMA-approved Hemophilia R&D Portfolio, Novo Nordisk Inc., Plainsboro, NJ 08536, USA replacement therapy shown to be an effective and safe option for the treatment of 2Department of Pediatrics & Human individuals with hemophilia A. Data collected throughout two Phase 3, multinational, Development, Michigan State University, open-label, non-randomized, non-comparative trials demonstrated that individuals MI, USA with hemophilia A, particularly young adults experienced improvements in health- 3Mapi, Patient-Centered Outcomes, Lyon, related quality of life when switched from an on-demand to a prophylactic regimen France 4Angelo Bianchi Bonomi Hemophilia & of turoctocog alfa. Thrombosis Center, IRCCS Cà Granda Foundation, Maggiore, Hospital Keywords: EQ-5D • factor VIII • health-related quality of life • hemophilia • HAEMO-QOL • Policlinico, Milan, Italy questionnaires • turoctocog alfa *Author for correspondence: Tel.: +1 609 786 8390 [email protected] Hemophilia A is an X-linked recessive hered- a reduced number of bleeds, a greater quality itary bleeding disorder resulting from a defi- of life (QOL) and may potentially reduce the ciency in coagulation factor VIII (FVIII). risk of developing long-term musculoskeletal The annual incidence of hemophilia A is complications. This has been observed both estimated at 1/5000 male births in the USA in adults and younger individuals with severe and in Europe [1,2]. The level of circulating hemophilia [6–8]. Using the Standard Gamble coagulation factor determines the severity of method, Naraine et al. showed that scenarios hemophilia and this may be mild (5–40% with prophylaxis treatment regimens were of normal), moderate (1–5% of normal) or preferred to scenarios with on-demand treat- severe (<1% of normal) [3]. Hemophilia is ment regimens not only by individuals with 9 characterized by bleeding episodes which hemophilia and their parents, but also by may occur spontaneously or following an members of the general public [9]. injury, trauma or surgical procedure. Recur- The US FDA defines patient’s health- rent bleeding episodes can lead to long-term related quality of life (HRQoL) as ‘a multi- 2015 musculoskeletal complications including domain concept that represents the patient’s synovitis, degenerative arthropathy and artic- general perception of the effect of illness and ular deformities [4]. Bleeding episodes are pri- treatment on physical, psychological and marily treated by coagulation factor replace- social aspects of life’ [10] . Individuals liv- ment as a bleed occurs (on-demand) or in a ing with hemophilia may experience several preventive manner (prophylaxis regimen). QOL issues, which may affect their physi- Current standards of care in severe hemo- cal, psychological, social and economic well philia support regular prophylaxis, charac- being on a daily basis. Some individuals need terized by self-infusion of either recombinant to limit their activities due to the potential or plasma-derived FVIII concentrate several risk of a bleeding incident, whereas others are times a week [5]. Prophylaxis, when compared limited in mobility and functional status due part of with on-demand treatment, is associated with to permanent and painful joint damage [11] . 10.4155/cli.15.43 © 2015 Future Science Ltd Clin. Invest. (Lond.) (Epub ahead of print) ISSN 2041-6792 Review: Clinical Trial Outcomes Seremetis, Kulkarni, Regnault & Santagostino For reprint orders, please contact: [email protected] Using standard generic HRQoL questionnaires, the In both trials, HRQoL was a secondary endpoint. Short Form 36 health survey (SF-36) and EuroQol Patients completed two patient-reported question- (EQ-5D), Miners et al. showed that individuals with naires at baseline prior to treatment initiation and severe hemophilia who were not receiving primary at the end-of-treatment visit: the EQ-5D and the prophylaxis with coagulation factor, reported poorer hemophilia quality of life (HAEMO-QOL/HAEM- HRQoL scores compared with individuals with mild- A-QOL) questionnaires. to-moderate hemophilia and members of the UK gen- The EQ-5D is a 5-dimensional generic standard eral population [12] . utility instrument for measurement of health out- Since the introduction of factor replacement ther- come [23]. The EQ-5D includes the following domains: apy, life expectancy and reported HRQoL of indi- Mobility; Self-Care; Usual Activity; Pain/Discomfort viduals with hemophilia have seen noticeable improve- and Anxiety/Depression. In addition, a 10 cm visual ments [13] . In addition, the promise of further potential analog scale (VAS) also enables recording of individ- benefits arises from a number of new drugs that are ual’s rating for their current HRQoL; the VAS ranges currently in development. Coagulation factor concen- from 0-worst to 100-best imaginable health state. The trates with prolonged bioavailability require less fre- single index score is derived from application of coun- quent injections and can therefore minimize venous try-specific value sets (the UK value set in the case of access problems and infusion-related pain [14] . Patients the guardian trials) to responses from each domain. An may also benefit in the future from drugs that can index score of 0.0 represents a state approximately as overcome the barrier of immunogenicity, since the desirable as ‘death’ while an index score of 1.0 repre- development of inhibitory antibodies to factor concen- sents ‘perfect health.’ trates (inhibitors) continues to be a major complication The HAEMO-QOL is a disease-specific HRQoL in hemophilia treatment [15] . family of questionnaires that consists of four age- There is recognition that perceived benefits for specific instruments (4–7 years, 8–12 years, 13–16 patients, in particular the balance between therapeutic years and the HAEM-A-QOL for 17 years and efficacy, treatment risks (such as experience of adverse above) specifically designed to assess HRQoL in events) and treatment constraints are of key concern individuals with hemophilia [24,25]. HAEMO-QOL for patients, physicians and health authorities, as they questionnaires cover various domains of HRQoL may impact adherence to treatment [16–18]. including: psychological, physical and social factors. Turoctocog alfa (NovoEight®) is an FDA- and EMA- For all HAEMO-QOL questionnaires, a score for approved replacement therapy option for the treatment each domain as well as a total score summarizing the of individuals with hemophilia A. Turoctocog alfa is global HRQoL of individuals with hemophilia can be a human, recombinant, B-domain truncated FVIII, calculated. Scores range from 0 to 100; lower scores produced in Chinese hamster ovary cells without addi- indicate better HRQoL (and thus a negative change tion of any human- or animal-derived materials [19,20]. in this score should be interpreted as improvement). As part of its development, two Phase 3, multinational, The present review compiles existing available open-label, non-randomized, non-comparative trials data complemented with as yet unpublished patient- demonstrated that turoctocog alfa administered as a reported outcome data collected throughout the turoc- prophylaxis treatment was both effective and safe to tocog alfa development program (guardian trials) to treat bleeding episodes in 24 adolescents and 126 adults provide a comprehensive picture of the impact of pro- with hemophilia A (guardian™ 1) and in 63 children phylactic turoctocog alfa in the treatment of individu- with hemophilia A (guardian 3) [21,22]. In these trials, als with hemophilia A. most children received prophylaxis in the 12 months preceding the trial (68% in the 4–7 years; 67% in the Individuals with hemophilia A treated with 8–12 years groups). Among adolescents, 44% received prophylactic turoctocog alfa maintained on-demand regimen, 22% received prophylaxis and their level of HRQoL 33% received a mixed regimen. Among adults, 39% Overall, the mean HAEMO-QOL/HAEM-A-QOL received on-demand regimen, 36% received prophy- total score did not change between baseline and end- laxis and 26% received a mixed regimen. The observed of-treatment assessments [26,27]. This indicated that in success rate defined as ‘excellent’ or ‘good’ hamostatic the overall population, individuals who were prophy- response was 81% in guardian 1 and 92% in guard- lactically administered turoctocog alfa maintained ian 3. The estimated median annualized bleeding rates their level of HRQoL. As shown in Table 1, only were 3.7 bleeds/patient/year in adolescents and adults, children aged 4–7 years reported a small worsening and 3.0 in children. None of the patients enrolled (1.4, SD = 13.4) in the HEMO-QOL total score in developed FVIII inhibitors during the trials. the version completed by their parents between base- 10.4155/cli.15.43 Clin. Invest. (Lond.) (Epub ahead of print) future science group Turoctocog alfa in the treatment of individuals with hemophilia A Review: Clinical Trial Outcomes For reprint orders, please contact: [email protected] line and the end-of-trial visit; all other age groups were observed, suggesting that the transition to this reported an improvement, -2.6 (SD = 10.7) for the recombinant FVIII compound is not detrimental 8–12 years, -5.8 (SD = 10.0) for the 13–16 years and for patient HRQoL from the patients’ perspective. -1.6 (SD = 8.9) for the adults. Only minor changes Despite the absence of evidence of statistical signifi- in HRQoL of patients treated with turoctocog alfa cance of the change in scores from baseline to end-of- Table 1.