b long study phase 3 2013
TRANSCRIPT
PRESENTED BY MAYLING NG
A Review of “Phase 3 Study of Recombinant Factor IX Fc Fusion Protein in Hemophilia B”
• Historically, Recombinant factor IX has been produced by insertion of human factor IX gene into Chinese hamster ovary cells, selecting the cell line that produces the most factor IX and growing those cells in a bioreactor w.o blood or plasma products, purified via chromatography and filtration and dried into powder
• In Recombinant factor IX-Fc fusion protein, Fc is attached to Factor IX, grown in bioreactor, filtered/separated via centrifuge, goes through nano-purification, then dried into powder 8,9,10
BACKGROUND
• Fc of IgG is believed to prolong the t ½ of recombinant factor IX when fused because the fusion protein delays the IgG degradation and it redirects the recombinant factor IX back into the bloodstream allowing it to be recirculated in the blood
• Recombinant Factor IX t ½ =~16-17 hours• Recombinant Factor IX Fc Fusion Protein t ½ =~82 hours 17
Mechanism of Action
• In a normal cell, the Fc region of the antibody binds to the Fc receptor and alerts the immune system of an invading pathogen which will lead to destruction of the pathogen5
Fc REGION
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http://www.alprolixpro.com/technology/fc-fusion.html
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• Phase 3 Multicenter, international(17 countries), non-randomized, open-label study• Enrollment: 123 patients, 115 pts(93.5%) completed study(per protocol)• Assignment into 4 treatment groups
-Group 1: 50 IU/kg rFIXFc weekly(to start) dose adjusted prophylaxis-Group 2: 100 IU/kg rFIXFc every 10 days(to start) interval adjusted prophylaxis-Group 3: On demand dosing(20-100 IU/kg)-Group 4: Treatment in perioperative period
• Primary Efficacy Endpoint: annualized bleeding rate• Primary Safety Endpoint: development of inhibitors and adverse events• Funding: Biogen• Study Period: January 22, 2010-July 19, 2012• Termination of study when 53 pts had reached 50+ rFIXFc exposure days Powell JS, Pasi KJ, Ragni MV, et al. N Engl J Med.2013; 369(24):2313-23.
STUDY DESIGN
• Group 1 subgroup(22 pts): BeneFIX 50 IU/kg, PK assessment 96 hours post with 120 hour washout period
VS• rFIXFc 50 IU/kg, PK assessment for 240 hours, PK
reassessment at week 26
Powell JS, Pasi KJ, Ragni MV, et al. N Engl J Med.2013; 369(24):2313-23.
Product Comparison Analysis
• Male • Ages: 12 years +• Severe Hemophilia B(</= 2 IU/dL endogenous factor IX)• Receiving prophylaxis or history of 8+ bleeds in year prior to
study• Previous treatment of at least 100+ factor IX(100+ exposure
days)
Powell JS, Pasi KJ, Ragni MV, et al. N Engl J Med.2013; 369(24):2313-23.
INCLUSION CRITERIA
• History of development of inhibitors• Anaphylaxis associated with factor IX or IVIG• Coagulation disorders• Uncontrolled infection with HIV• Renal dysfunction• Active Hepatic Disease
Powell JS, Pasi KJ, Ragni MV, et al. N Engl J Med.2013; 369(24):2313-23.
EXCLUSION CRITERIA
• Primary Efficacy Endpoint: annualized bleeding rate: 83% vs 87% reduction(Group 1 vs Group 2)-3.12(Group 1)vs 2.40(Group 2) vs 18.67(Group 3) P<0.001
• Primary Safety Endpoint: -no development of inhibitors: none in all treatment groups -73.9% pts had at least 1 adverse event in groups 1-3 and 10.9% of pts had serious adverse events• Adverse Events: >/= 5%: nasopharyngitis, influenza,
arthralgia, URI, HA, HTN
Powell JS, Pasi KJ, Ragni MV, et al. N Engl J Med.2013; 369(24):2313-23.
OUTCOMES
• Efficacy analyses conducted w pts with 1+ doses of rFIXFc during efficacy period
• Safety analyses for pts w 1+ rFIXFc or recombinant factor IX
• Comparisons of prophylaxis w episodic tx based on annualized est of bleeding rates
• Descriptive statistics: medians and interquartile ranges for groups 1,2 & 3
• -2 sided alpha tests for all analyses, 5% = statistical significance
Powell JS, Pasi KJ, Ragni MV, et al. N Engl J Med.2013; 369(24):2313-23.
STATISTICAL ANALYSIS15
• Efficacy: Annualized reduction in rate of bleeding in group 1(83%) vs group 2(87%)[prophylactic tx] in comparison to group 3[episodic tx] was significant
• Annualized bleeding rate Group 1 vs 2 vs 3(3.12vs 2.40vs 18.67) P<0.001
• Group 3’s reduction in bleeding was insignificant (17.7 vs 18)• 636 bleeding episodes occurred, 90.4% resolved w 1 injection,
97.3% resolved w 1 or 2 injections• Median weekly rFIXFc dose(Group 1): 45 IU/kg• Median dosing interval(Group 2): 12.5 days, 53.8% in study
6mths+ had dosing interval >/= 14 days in last 3 months of study
Powell JS, Pasi KJ, Ragni MV, et al. N Engl J Med.2013; 369(24):2313-23.
RESULTS
• Safety: no inhibitors detected even with 55 pts with 50+ exposure days(95% CI, 0-6.5)
• 3 pts before receiving rFIXFc had low titer/borderline positive titer of non-neutralizing antibodies but such levels did not affect PK of rFIXFc
• 88/119 pts(73.9%) had >/= 1 A/E• 3/119 pts(10.9%) had >/= 1 serious A/E• -no deaths occurred during study
Powell JS, Pasi KJ, Ragni MV, et al. N Engl J Med.2013; 369(24):2313-23.
RESULTS CONT…
• PK Subgroup of Group 1: rFIXFc has much longer ½ than recombinant factor IX
• Time to reach 1% factor IX activity in body 11.2 days(rFIXFc) vs 5.1 days recombinant factor IX
Powell JS, Pasi KJ, Ragni MV, et al. N Engl J Med.2013; 369(24):2313-23.
SUBGROUP COMPARISON15
• rFIXFc safe and effective for tx of hemophilia B bleeds/prophylaxis • Long t ½ of rFIXFc prophy allows for injections every 1-2 weeks-actual
dosing will vary between individuals due to trough levels• Limitations - Small population of pts - No active-comparator control group-ethical issue - non-randomized, open label study• Bias
-uneven distribution of pts in each tx group: more ppl in prophylactic group 1(pts whom had more bleeds/previous episodic tx) -pts chose which group to enter in: self selection bias
Powell JS, Pasi KJ, Ragni MV, et al. N Engl J Med.2013; 369(24):2313-23.
AUTHORS’ CONCLUSIONS
BeneFIX rFIXFc
Dosing 15-30 IU/kg 2X week
50 IU/kg q week or 100 IU/kg q 10 days
Price $1.56/IU $3.42/IU
Advantages Cost Longer t ½Less injections/mth
Disadvantages
Shorter t ½More injections/mth
Cost
• Currently on market: BeneFIX (1997) + Rixubis (2014): 15-30 IU/kg 2 x week
• Prophylaxis enables pts to maintain a normal life and delay associated joint arthropathy 3,4,16
CLINICAL RELEVANCE
• If pt were to switch to rFIXFc at 50 IU/kg 1 x week…
• What is the total units taken per month?
-ANS: 14,000 IU• What is the total cost per
month if 1 IU=$3.42?-ANS: $ 47,880
• Ex. Pt is 70 kg, injects recombinant factor IX 30 IU/kg 2 x week
• What is the total units taken per month?
-ANS: 16,800 IU• What is the total cost per
month if 1 IU= $1.56?-ANS: $26,208
Practical Application
WHAT IS THIS MYSTERY rFIXFc?
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REMEMBER THE PATIENT!
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WHICH WOULD YOU
CHOOSE?
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8. Harrison S, Adamson S, Bonam D, et al. The manufacturing process for recombinant factor IX. Semin Hematol. 1998; 35(2 Suppl 2): 4-10.
9. Hoots WK, Shapiro AD. Treatment of hemophilia. In: UpToDate [database on the Internet]. Waltham (MA): UpToDate; 2014[cited 16 June 2015].
10. How beneFIX is made [Internet]. Pfizer Inc; 2014 [cited 2015 June 16]. Available from: http://www.benefix.com/every-batch-benefix-has-pass-more-150-tests-quality-control/#made.
11. Kozma CM, et al. Economic, clinical and humanistic outcomes: a planning model for pharmacoeconomic research. Clin Ther.1993;15:1121-32.
12. Laws C. Together forever [Internet]. Pinterest; 2015. [cited 2015 June 16]. Available from: https://www.pinterest.com/carolynlaws/together-forever/.
13. NHF’s 67th annual meeting [Internet]. National Hemophilia Foundation. 2015. [cited 2015 June 16]. Available from: http://www.hemophilia.org/Events-Educational-Programs/Annual-Meeting.
14. Pappas A. Graduation: a departing senior’s thoughts [Internet]. IL: Northeastern Illinois University; 2015[cited 2015 June 17]. Available from: http://neiuindependent.org/3971/opinions/graduation-a-departing-seniors-thoughts/.
15. Powell JS, Pasi KJ, Ragni MV, et al. Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia b. N Engl J Med.2013; 369(24):2313-23.
16. Rixubis [package insert]. Westlake Village, CA: Baxter Healthcare Corporation; 2013.
17. The Fc region has been clinically shown to prolong half-life[Internet]. Biogen; 2015 [cited 2015 June 17]. Available from: http://www.alprolixpro.com/technology/fc-fusion.html
18. The science behind alprolix [Internet]. Biogen; 2015 [cited 2015 June 16]. Available from: http://www.alprolix.com/the-science/fc-fusion.html.
REFERENCES
THANK YOU