Background, Development and Clinical Use of rfviia. Slovenian Hematology Society April 17, 2015

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1 Background, Development and Clinical Use of rfviia. Slovenian Hematology Society April 17, 2015 Ulla Hedner MD PhD Prof. em. University of Lund, Sweden.

2 Key Issues in Hemophilia Treatment All bleedings should be treated optimally - immediate and quick hemostasis to minimize complications Make major surgery possible Prevent bleedings to occur / develop (prophylaxis) Avoid transfer of blood-borne pathogens

3 Haemophilia patients with inhibitors against FVIII/FIX ~20% of haemophilia patients develop inhibitors against the factor they are missing Treatment options: - high doses of FVIII/FIX combined with extracorp. (absorp. of inhibitors) - plasma-derived activated prothrombin complex concentrate (pd-apcc) Recombinant FVIIa was developed for these patients (approved EU 1996, US 1999)

4 pd-pcc/pd-apcc 50-65% efficacy (Lusher et al. 1983; Sjamsoedin et al. 1981, Young et al 2008) Thromboembolic complications reported (Lusher 1991; Ohga et al. 1993; Ehrlich et al 2002) Booster effect of inhibitors against FVIII (Négrier et al 1997; Hilgartner et al 1990)

5 Characteristics pd-apcc: must be kept refrigerated storage vial and diluent must be at room temp before reconstitution; once diluent added, must be swirled gently until completely dissolved (high viscosity, takes up to 30 min for dissolving); volume of infusion up to a few hundred ml dependent on b.w. long infusion time (high viscosity; at most 2U/kg/min)

6 Summarizing: Treatment of hemophilia patients with inhibitors suboptimal. Joint bleedings were NOT properly treated, which led to - hospitalization - development of athropathy A clear need for improved treatm. of inhib patients identified in the 1970s.

7 Development of FVIIa for use in hemophilia: Proof of concept : successful use of pd-fviia in two hem pat with inh in Proof of principle: successful use of rfviia in orthoped surg in Approved in EU 1996, in US 1999 for use in cong and acquired hemophilia

8 Characteristics of rfviia Stable at room temp 3 yrs; reconstituted solution may also be stored at room temp (6 h) or refrigerated for up to 24 hrs Rapid reconstitution, clear, colorless solution (contains only pure rfviia protein and buffer) Up to 8.2 ml (8 mg) dependent on dose; injection time 2-5 min as a bolus i.v. Resolves joint bleeds in 5 hrs

9 NOVOSEVEN (rfviia) pure recombinant protein (NO RISK OF TRANSMITTING BLOOD BORNE VIRUS; NO BOOSTER EFFECT) small volume (inj. time 5-10 min) quick response (pain; resolution of bleed) known mech of action (localized effect on preactivated platelets) FEIBA (APCC): contains a host of plasma proteins incl. trace amounts of FVIII (booster effect on inhib; potential risk of transmittance of blood borne virus) large volume (inj. time min) longer time for effect unclear mech of action no PK-studies perforemed (active factor unknown)

10 Goals for Treatment of Hemophilia Patients with Inhibitors Achieve hemostasis in serious bleedings incl. major surgery independent of FVIII/FIX Make home-treatment feasible in order to prevent the development of full-blown bleeds Make treatment of hemophilia patients with inhibitors similar to that of uncomplicated hemophilia

11 Recombinant FVIIa in hemophilia % efficacy in major surgery ( µg/kg q2 for at least 24 h) (Shapiro et al. 1998; Ingerslev et al. 1997) 83-95% efficacy in serious bleedings (Lusher et al. 1998; Hedner & Ingerslev 1998) 92% efficacy in joint bleeds (home treatment). Some pat req. more than one dose for hemostasis in mild to mod bleeds (home treatm. setting) (Key et al 1998)

12 Reasons for a Suboptimal Response to rfviia Treatment in Some Patients Suboptimal dosing (more than one single dose for effect) due to: Low recovery (recovery known to vary between 40-80%) High clearance rate (normal adults: 30U/kg/hr; children <15 yrs old: U/kg/hr) Thrombin generation capacity may vary

13 Key issues to minimize hemophilia athropathy: Optimal dose to stop bleeding episode immediately on one injection (new concept of treatm; no assay available to determinge thrombin gen on cell surface) Immediate initiation of treatment at first signs of a bleeding (patient knows best!) Minimize number of joint bleeds (prophylaxis, regular adm of coag conc without ongoing bleed).

14 Number of rfviia inj. and total amount of rfviia used (Salaj et al 2009 No inj. No episodes 1st inj Tot dose ug/kg ug/kg (mean) (mean) />

15 SINGLE 270 UG/KG-DOSE rfviia vs. STANDARD 90 UG/KG-DOSE rfviia and APCC FOR HOME TREATMENT of JOINT BLEEDS in HAEMOPHILIA PATIENTS WITH INHIBITORS: a randomised comparison. (Young et al 2008) Efficacy (pat not needing rescue medication at 9 hr): % (22/24) 270 ug/kg rfviia % (20/22) 3 x 90 ug/kg rfviia % (14/22) 75 u/kg APCC (FEIBA) Single dose of 270 ug/kg rfviia as safe as 3 x 90 ug/kg rfviia; rfviia potentially more effective than APCC.

16 Not only the SIZE OF DOSE BUT also TIME TO INITIATION OF TREATMENT

17 Time (hours) Cost (YTL) Time to treatment Time to resolution Total costs 70.0 (Kavakli et al 2010) Home/ Outpatient Hospital Home/ Outpatient Hospital Home/ Outpatient Hospital 0

18 Key issues to minimize hemophilia athropathy: Optimal dose to stop bleeding episode immediately on one injection (new concept of treatm; no assay available to determinge thrombin gen on cell surface) Immediate initiation of treatment at first signs of a bleeding (patient knows best!) Minimize number of joint bleeds (prophylaxis, regular adm of coag conc without ongoing bleed).

19 (Konkle et al WFH Vacouver 2006)

20 Further research on rfviia to elucidate its mech of action: A low immediate recovery (10 min after i.v. inj) suggests a large extravascular distribution volume for rfviia; Around 50% recovery found by Lindley et al 1994) Distribution of rfviia in mice shows -95% of tot rfviia in plasma 30 min after inj - no rfviia in plasma, BUT % in tissues after 24 hr (Gopalakrishnan et al 2010) Conclusion: rfviia entered into extravasc compartm is retained much longer than rfviia in circulation.l

21 Hemophilia X II VIII/vWF VIIIa VIIa TF VIIa TF TF-bearing cell Xa Va IIa V XI Va XIa X II platelet VIIa Xa Va IIa activated platelet

22 Confocal microscopy image of fibrin gel in plasma deficient of factor VIII rviia: 0 µg/ml 4.9 µg/ml 9.8 µg/ml He et al. 2003

23 What does rfviia do? rfviia enhances thrombin generation on thrombin-activated platelets (Kjalke et al 1999) rfviia induces a tighter fibrin structure of fibrin clots formed from FVIII and FIXdeficient plasma (He et al 2003, Wolberg et al 2005)

24 Normal Hemostasis X II VIII/vWF VIIIa FVII Iab IX TF VIIa TF VIIa TF-bearing cell Xa Va IIa V XI Va XIa IXa X FVIII ab II platelet XIa IX VIIIa IXa Xa Va activated platelet IIa

25 Use of rfviia in Acq. Hemophilia. Arkin et al /23 pat with acq.hem. 97% efficacy. Hay et al /74 bleeds first line: 100% efficacy; 60/74 bleeds rescue treatm: 75%. Case reports: - Siegbahn et al 1995; severe hematuria; - Shafi et al 1997; immediate stop of bleed; - Maliekel et al 1997; pseudotumour extirp. - Papadaki et al 1998; severe muscle bleeds.

26 FENOC STUDY (Astermark et al. 2007; Blood 109: ) was designed to test equivalence of the products, rfviia and FEIBA parameters: the percentage of patients who reported efficacy in response to FEIBA and the percentage that reported efficacy in response to NovSeven

27 THE FENOC STUDY WEAKNESSES: Study design: prospective, open-label, randomized, crossover study comparing 2 doses of rfviia (~100 ug/kg x 2; mean dose) with one dose of FEIBA (~85 U/kg; only 50% of pat controlled by 1 dose) Self-assessment potentially biased by previous experience (only 50% had exposure to both FEIBA and rfviia) More knee bleeds in the rfviia group (26 vs 15 pat); more elbow bleeds in the FEIBA group (21 vs 10) Astermark et al. 2007; Blood 109:

28 FENOC STUDY. Study design : - 1 dose of FEIBA ( U/kg; target dose: 85 U/kg - 2 doses of NovoSeven ( ug/kg; target dose:105 ug/kg x 2. Effect evaluated at 2, 6, 12, 24, 36, 48 h Knee joint bleeds: FEIBA 15 NovoSeven 26

29 FENOC STUDY. No statistically significant differences of outcomes; Neither product was shown to be superior at any time points Does NOT mean that similarity shown. The criteria for declaring the two products equivalent at 6 h was not met (Astermark et al 2007)

30 Questions related to the FENOC study: Time from onset of bleeding and initiation of treatment: median 2 hrs in both groups. However, range was hrs. Distribution in the groups NOT given. The dose of FEIBA used (84.6 IU/kg; IU/kg) in previous controlled studies efficacy rate 55-65%. In this study %. 3/24 pat in the FEIBA group, doses <recommended; 7/27 pat in the NovoSeven group, doses <recomm. Only 50% of pat exposure to both agents Age distribution in the two groups (range: 8-55 yrs)

31 Efficacy of rfviia and pd-apcc in a unified Bayesian metaregression model (Treur et al 2009) 17 studies identified reporting on >2000 joint bleeds - rfviia dose: 90 ug/kg repeated every 3 hrs if needed - pd-apcc dose: 75 IU/kg repeated every 12 hrs if needed. Cumulative joint bleed resolution (efficacy): rfviia pd-apcc - at 12h 66% 39% - at 24h 88% 62% - at 36h 95% 76%

32 Total medical costs (2005 US$) The rfviia health economics evidence Worldwide published evidence 40,000 35,000 30,000 25,000 20,000 15,000 10,000 5,000 14,703 12,567 14,137 12,54210,958 13,500 8,977 8,794 9,113 7,590 28,076 25,201 22,274 32,150 20,295 35,220 0 Slovakia Turkey Iran Brazil Russia UK HT US UK CC rfviia apc C The total medical costs associated with the resolution of one bleed are lower or equivalent when rfviia is given in first-line therapy

33 COST EVALUATION OF TREATMENT ALTERNATIVES IN MILD-MOD BLEEDINGS IN HAEMOPH. PAT. WITH INH IN TURKEY. (Dundar et al) Mean number of doses/episode: -rfviia: 3.6 -apcc: 4.8 Mean time to resolution of bleed: -rfviia: 17.3 hrs -apcc: 43.6 hrs Effectiveness: -rfviia: 89.3% -apcc: 66.7%

34 OVERALL COST (for both over 97% was attributable to the drug) rfviia: US$ 9,113 apcc: US$ 12,542 High-dose FVIII: US$ 15,075 CONCLUSION: rfviia is safe and has a higher efficacy relative to other treatment options.

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36 CLINICAL EXPERIENCE OF rfviia in GLANZMANN S THROMBASTHENIA. (Poon 2007) 90 patients with Glz thrombasthenia bleeding episodes - 57 surgical procedures 71/154 episodes epistaxis (46/70 successful) 34/154 oropharyngeal bleeds (27/34 s-ful) 18/154 gastrointestinal bleeds (10/18 s- ful) 20/57 dental procedures (19/19 s-ful) 37/57 others (96% s-ful all over in surg)

37 Glz PPP + rfviia + rfviia + plts N PPP + rfviia PPP VIII-def + rfviia + rfviia +plts + rfviia +plts He et al J Haemost Thromb.

38 SAFETY Total number of TE events reported corresponds to approx. 2 events per 10,000 standard doses NovoSeven sold (standard dose: 90 ug/kg x 70 kg) In more than 800,000 doses given TE events reported to be around 1%

39 Thromboembolic (TE) events reported (O Connell et al. JAMA, 2006) Med Watch includes reports of AE from: product manufacturers health care professionals public 11,000 patients treated with rfviia /11,000 reported AE; 185 TE events in 168/431 pat. No confirmation of diagnosis required

40 Conclusion: This case series does not provide incidence rates for TE AEs after use of rfviia. Case series usually cannot establish whether the relationship between a product and an event is causal or coincidental, because spontaneous reports have no controls, are subject to numerous potential reporting biases, and have other limitations. O Connell et al 2006; JAMA:295:249

41 SAFETY (cont.) No inhibitors against FVII reported, neither in hemophiliacs nor in patients on off-label use Two patients with FVII-DEFICIENCY (no FVII protein) developed transient inhibitors against FVII. Both these patients had previously been treated with plasma or plasma-derived FVII-conc.