Gene Therapy and Hemophilia: Where Do We Go from Here?

Figures & data

Table 1 Clinical Trial Results for AAV-Mediated Gene Therapy for Factor IX Deficiency

Vector Product	NCT	Trial Phase	Vector Dose	Number Treated	FIX (%) at Year: 0.5–1y	1.5–2y	2.5–3y	4y	5y	6y	Transaminitis Rate	Reference
CHOP/Avigen
rAAV2-FIX (intramuscular)		1	0.2 to 1.8 ×10^12	8	0							[11,12]
CHOP/Avigen
rAAV2-FIX-WT (intra-hepatic artery)	NCT00515710	1/2	0.08 to 2×10^12	7	0							[13]
St. Jude/UCL
rAAV8-FIX-WT	NCT00979238	1/2	2×10^12	6	1.4–7.2	5.1±1.7				5.1	4/6 (67%)	[15–17]
Uniqure/CSL Behring
AMT060, rAAV5-FIX-WT	NCT02396342	1	2×10^13	5	6.9 (2.6–11.3)	7.1	8.4	7.4	5.2		2/5 (40%)	[19,20]
AMT061, (etranacogene dezaparvovec, rAAV5-FIX-R338L)	NCT03489291	2	2×10^13	3	47 (33–57)		50 (37.1–58.6)				0/0 (0%)	[21]
	NCT03569891	3	2×10^13	54	39±18.7 (8.2–97.1)		36.9±21.4 (4.5–122.9)				0/0 (0%)	[22]
Pfizer/Spark
SPK9001, (fidanacogene elaparvovec, SPK100-FIX-R388L)	NCT02484092	2	5×10^11	15		22.9±9.9					3/15 (20%)	[23,24]
	NCT03861273	3	n/a	n/a
UCL/Freeline
FLT180a, (AAVS3-FIX-R388L)	NCT03369444	1	8.3×10^11	4	50–180						n/a	[25]
	NCT05164471	1/2	7.7×10^11	1							n/a
IHBDH/SBDB
BBM-H901, AAV843-FIX-WT	NCT04135300	1/2	5×10^12	10							n/a
HBDH/FIX Variant
VGB-R0-4	NCT05152732	2	n/a	n/a							n/a
Dimension/Ultragenics
DTX101, AAVrh10-FIX-WT	NCT02718915	1	5×10^12	3	0						n/a	[27]
Baxalta/Takeda
BAX335, rAAV8-FIX-R388L	NCT01687608	1	3×10^12	2	45.3 (32–59)	20 (n=1)					n/a	[26]
Takeda/Baxalta/Shire
SHP648, rAAV8-FIX-R388L	NCT04394286	1	n/a

Table 2 Clinical Trial Results for AAV-Mediated Gene Therapy for Factor VIII Deficiency

Vector Product	NCT	Trial Phase	Dose	Number Treated	FVIII (%) at Year: 0.5y	1y	2y	3y	4y	5y	Transaminitis Rate	Reference
Biomarin
BMN270, Roctavion	NCT02576795	1/2	6×10^13	7	-	93±48	36	33	–	11.6±12.2	7/7 (100%)	[30–32]
			4×10^13	6	-	21	15	–	5.6		4/6 (66%)	[30–32]
	NCT03370913	3	6×10^13	134	-	42.9±45.5	24.4±29.2				106/134 (79%)	[29]
	NCT03392974	3	4×10^13	1	-
Spark
SPK8011, AAV-LK03-coBDD-F8	NCT03003533	1/2	5×10^11	2	-							[35]
			1×10^12	3	-							[35]
			1.5×10^12	4	-	All four doses:						[35]
			2×10^12	9	-	6.9±3.8 (3.0–14.3)*					13/18 (72%)	[35]
SPK8016, AAV-coBDD-F8	NCT03734588	1/2	5×10^11	4	-	10.4 (6.2–21.8)					3/4 (75%)	[36]
UCL/St. Jude
GO8, scAAV2/8 HLP-FVIII-V3	NCT03001830	1	6×10^11	1	-	7					0/1	[39]
			2×10^12	n/a	-
			4×10^12	n/a	-
			6×10^12	n/a	-
Pfizer/Sangamo
SB525, PF07055480, giroctocogene fitelparvovec	NCT03061201	1/2	3×10^13	5	-	42.6	25.4				4/5 (80%)	[37]
	NCT04370054	3	3×10^13	n/a	-
Bayer/Ultragenix
Bay2599023, DTX201, AAVhu37-BDD-F9	NCT03588299	1/2	0.5×10^13	2	-	≥5						[38]
			1.0×10^13	2	-	2–10					1/2	[38]
			2.0×10^13	4	10–45						2/2	[38]
			4.0×10^13	n/a	-
Takeda/Shire/Baxalta
TAK754, SHP654, BAX888, AAV8-BDD-F8	NCT03370172	1/2	2×10^12	n/a	-
			6×10^12	n/a	-
			1.2×10^13	n/a	-

Note: *Two participants lost expression and their FVIII values are not included here.

Table 3 Guide for Physicians for Discussing Gene Therapy with Persons with Hemophilia

Topic	Sub-topics
Fundamentals of gene therapy	What is a vector?
	What is a functional gene?
	How is the vector delivered?
	How does the body react to the vector?
	Anti-vector antibodies
Expectations after gene therapy
Efficacy	Treatment of bleeding events
	Frequency of bleeding events
	Pain management
	Factor expression (level and duration)
Safety (short- term)	Side effects (ie, transaminitis, inhibitor development, thrombosis, anti-vector antibodies)
	Treatment of side effects
Safety (long-term)	Risk of developing cancer or other disorders
	Possibility of unknown side effects
	Long-term monitoring and annual follow-up for many years
Eligibility for gene therapy	Severity of disease (factor level ≤2%)
	Adults or young adults
	Patients without inhibitors
	Patients without neutralizing antibodies to AAV capsid
Current clinical trials	Status of ongoing clinical trials
	Major findings of clinical trials
Other things to consider	Psychological functioning and emotional maturity
	Social support
	Family planning

Table 4 Summary of Cost-Effectiveness Models Comparing Gene Therapy to Alternative Treatments for Hemophilia

	Machin 2018^Citation81	Cook 2020^Citation82	Rind 2020^Citation83 (ICER Report)	Bolous 2021^Citation84	Ten Ham 2021^Citation85
Model Outline
Model type	Markov state-transition model	Microsimulation Markov model	Markov model	Microsimulation Markov model	Markov state-transition model
Disease	Severe hemophilia A	Severe hemophilia A	Severe hemophilia A	Severe hemophilia B	Severe hemophilia A
Intervention	Gene therapy (No brand specified)	Valoctocogene roxaparvovec	Valoctocogene roxaparvovec	Gene therapy (No brand specified)	Valoctocogene roxaparvovec
Comparator	FVIII prophylaxis	FVIII prophylaxis  - SHL (base case)  - EHL (scenario analysis)	FVIII prophylaxis  - SHL  - EHL	1) FIX prophylaxis 2) On-demand treatment  - SHL (for both options)  - EHL (for both options)	1) FVIII prophylaxis 2) Emicizumab
Model Specifications
Time horizon	10 years starting at 30	Lifetime starting at 30	Lifetime starting at 18	Lifetime starting at 18	10 years starting at 31
Perspective	US healthcare perspective (Assumed 2018 USD)	US healthcare perspective (2019 USD)	US healthcare perspective (2019 USD)	US healthcare perspective (2020 USD)	Dutch societal perspective (2019 Euro)
Discounting	3%	3%	3%	3%	Costs 4% QALYs 1.5%
Model Input Parameters
Gene therapy cost	$850,000	$2,000,000	$2,500,000	$2,000,000	€2,125,000 ($1,891,250)
Clotting factor unit cost	$1/IU	$1.63/IU WAC	Advate net: $1.08/IU Eloctate net: $1.82/IU Net price was used in base case Advate WAC: $1.69/IU Eloctate WAC: $2.23/IU	Benefix WAC: $1.41/IU Alprolix WAC: $3.24/IU	FVIII: €0.89/IU ($0.79/IU) (11% discount from WAC for base case) Emi: €2476 per 30 mg/mL vial ($2204)
Mean weight	88.7 kg for 30-year-old	90.2 kg for 30-year-old	81.4 kg for 18-year-old	89.3 kg for 30-year-old	85 kg for 31-year-old
Dosing	Prophy: 33 IU/kg 3 times weekly Bleed: 50 IU/kg/d 2 or 4 days	Prophy: 40 IU/kg 3 times a week Bleed: 50 IU/kg 2 doses	Not stated	Prophy: 40 IU/kg twice weekly Bleed (minor): 50 IU/kg 3 doses per episode	Prophy: 30 IU/kg 3 times a week. Emi: 3 mg/kg biweekly. Bleed: 25 IU/kg then twice daily 15IU/kg for 3.5 days.
Effectiveness of gene therapy	Effective for 10 years. Success rate 90%, complications 1% for first 12 months.	90% mean 12.43 years and median 11.33 years. 10% mean 11.13 years and median 10.73 years. Move back to prophylaxis below 5 IU/dL. No joint bleeds above 15IU/dL	FVIII ≥1% for 12 years (7 and 15 years in conservative and optimistic scenarios)	31 years >3%, switch all patients to prophylaxis at 3% (worst case scenario 4 years)	Mean 11.5 years before dropping below 1% and switching to prophylaxis. 15% limited response (FVIII<5% after 2 years).
Results
Gene therapy cost over entire time horizon	$1,022,249	$16,700,000 (10 years: $3,469,487)	$13,693,000	SHL: $6,293,502 EHL: $7,315,914	€2,839,210 ($2,526,897)
Gene therapy QALYs	8.33 QALYs	18.07 QALY (10 years: 6.88 QALY)	19.091 QALYs	SHL: 23 QALYs EHL: 23.04 QALYs	7.03 QALYs
Comparator cost over entire time horizon	$1,693,630	$23,500,000 (10 years: $8,502,702)	$18,722,000	OD SHL: $11,596,617 OD EHL: $7,917,721 Pro SHL: $15,109,058 Pro EHL: $20,324,299	Prophy: €3,284,690 ($2,923,374) Emi: €4,252,167 ($3,784,428)
Comparator QALYs	6.62 QALYs	17.32 QALYs (10 years: 6.37 QALYs)	19.087 QALYs	OD SHL: 11.81 QALYs OD EHL: 12.20 QALYS Prophy SHL: 20.95 QALYs Prophy EHL: 21.57 QALYs	Prophy: 6.38 QALYs Emi: 6.90 QALYs
ICER	Dominant	Dominant	Dominant	Dominant	Dominant

Note: ICER is calculated by the following formula: Costs ^{New Intervention} – Costs ^{Standard Intervention}/QALYs ^{New Intervention} – QALYs ^{Standard Intervention}.

Abbreviations: ICER Report, Institute for Clinical and Economic Review Report; SHL, standard half-life; EHL, extended half-life; USD, United States dollar; QALYs, quality-adjusted life years; WAC, wholesale acquisition cost; Emi, emicizumab; OD, on-demand treatment; Prophy, prophylaxis; ICER, incremental cost-effectiveness ratio of the intervention being investigated versus the alternative, in costs per added QALY.

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