Emerging and future therapies for hemophilia

Figures & data

Table 1 New factor EHL-FVIII agents

Manufacturer	Class	Name	MOA	Phase	References
Baxter	EHL-rFVIII	BAX 855 (PEGAdvate)	PEGylated rFVIII	Phase III	^Citation22, ^Citation23
Baxter	EHL-rFVIII	PSA Factor VIII	PSA added to rFVIII	Preclinical
Bayer	EHL-rFVIII	BAY 94-9027 (EHL rFVIII)	PEGylated rFVIII	Phase III	^Citation25, ^Citation26
Novo Nordisk	EHL-rFVIII	NN-7088-3776, N8-GP	GlycoPEGylation of rFVIII	Phase III	^Citation27^–^Citation30
Pro Bono Bio and PolyTherics	EHL-rFVIII	Subcutaneous long-acting FVIII	PEGylation to allow SC administration – TheraPEG™	Preclinical	^Citation24

Abbreviations: EHL, extended half-life; FVIII, Factor VIII; MOA, mode of action; rFVIII, recombinant FVIII; SC, subcutaneous; PEG, polyethylene glycol; PSA, Polysialic Acid.

Table 2 Predicted proportion of patients with FIX trough levels above 1 IU/dL and 3 IU/dL (steady state after six doses) with weekly dosing

FIX trough level (IU/dL)	Predicted percentage of patients achieving trough FIX level with weekly dosing
	Nonacog alfa	FIX:Fc
	100 IU/kg	50 IU/kg	100 IU/kg
>1	67.0	95.4	99.6
>3	8.9	39.6	85.8

Note: Data from: Powell et al.²⁹

Abbreviations: FIX, Factor IX; IU, international units; Fc, fragment crystallizable.

Table 3 Annualized bleeding rates by treatment regimen, rFIX:Fc

Endpoint	Weekly prophylaxis (N=61)	Adjusted prophylaxis (N=26)	Episodic (on-demand) treatment (N=27)
Mean ABR (95% CI)	3.12 (2.46–3.95)	2.40 (1.67–3.47)	18.67 (14.01–24.89)
Median ABR
Overall	3.0 (1.0–4.4)	1.4 (0.0–3.4)	17.7 (10.8–23.2)
Spontaneous	1.0 (0.0–2.2)	0.9 (0.0–2.3)	11.8 (2.6–19.8)
Traumatic	1.0 (0.0–21)	0.0 (0.0–0.8)	2.2 (0.0–6.8)
Joint
Overall	1.1 (0.0–4.0)	0.4 (0.0–3.2)	13.6 (6.1–21.6)
Spontaneous	1.0 (0.0–2.1)	0.0 (0.0–1.7)	5.1 (2.6–17.3)
Traumatic	0.0 (0.0–1.0)	0	1.3 (0.0–3.6)
Muscle
Overall	0.0 (0.0–1.0)	0	4.0 (1.0–6.8)
Spontaneous	0	0	1.0 (0.0–3.6)
Traumatic	0	0	1.1 (0.0–2.7)

Note: Data from: Powell et al.²⁸

Abbreviations: ABR, annualized bleeding rate; CI, confidence interval; Fc, fragment crystallizable; rFIX, recombinant activated Factor IX.

Table 4 Annualized bleeding rates by treatment regimen, rFIX:PEG

Characteristic	Weekly prophylaxis		On demand (N=15)
	10 IU/kg (N=30)	40 IU/kg (N=29)
Estimated mean ABR (95% CI)*	4.56 (3.01–6.90)	2.51 (1.42–4.43)
Median ABR (IQR)	2.93 (0.96–6.02)	1.04 (0.00–4.00)	15.58 (9.56–26.47)
Spontaneous bleeds
Estimated mean ABR (95% CI)*	3.14 (1.78–5.56)	1.22 (0.48–3.10)
Median (IQR)	0.97 (0.00–4.01)	0.00 (0.00–0.98)	11.1 (7.16–15.8)
Traumatic bleeds
Estimated mean ABR (95% CI)*	1.35 (0.81–2.24)	1.29 (0.76–2.19)
Median (IQR)	0.98 (0.00–1.93)	0.00 (0.00–2.04)	1.73 (0.00–8.95)

Notes: Data from: Collins et al.³⁶

* Estimated rates for prophylaxis patients are based on a Poisson regression model with dose as a factor, allowing for overdispersion and using treatment duration as an offset.

Abbreviations: IU, international units; ABR, annualized bleeding rate; CI, confidence interval; IQR, interquartile range; PEG, polyethylene glycol; rFIX, recombinant activated Factor IX.

Table 5 New agents for hemophilia patients with inhibitors

Manufacturer	Class	Name	MOA	Phase	References
Baxter	Bypass agent avoidance of antibody	OBIZUR BAX801(OBI-1)	Porcine FVIII not reactive with some inhibitor molecules	BLA filed for acquired inhibitor patients	^Citation31
CSL	EHL bypass agent	CSL-689 rFVIIa-FP (long-acting)	Prolonged FVIIa activity by fusion to albumin	Phase II	^Citation32^–^Citation34
OPKO/Prolor Biotech	EHL bypass agent	MOD-5014, EHL-rFVIIa-CTP (long-acting FVIIa)	CTP technology peptide extension to prolong half-life	Phase I
Pro Bono Bio and PolyTherics	EHL bypass agent	SC long-acting FVIIa	PEGylation to allow SC administration – TheraPEG™	Preclinical	^Citation24
Biogen Idec	EHL bypass agent		rFVIIa fusion to Fc	Preclinical

Abbreviations: MOA, mode of action; FVIII, Factor VIII; BLA, basic licensing application; EHL, enhanced half-life; FVIIa, activated Factor VII; CTP, carboxyl terminal peptide; SC, subcutaneous; rFVIIa, recombinant FVIIa; Fc, fragment crystallizable.

Table 6 Nonfactor replacement therapies

Manufacturer	Class	Name	MOA	Phase	References
Novo Nordisk	Anti-TFPI	NN-7415	Anti-TFPI antibody to ↓ TFPI	Phase I	^Citation48, ^Citation49
Alnylam	Anti-AT3	ALN-AT3	RNAi therapeutic targeting antithrombin	Phase I	^Citation50, ^Citation51
	Reduces production of antithrombin protein
Chugai	Nonclotting factor replacement for FVIII	ACE-910	Bivalent antibody (absent Fc) binds FIXa and FX to “replace” FVIII cofactor activity	Phase I complete	^Citation52^–^Citation56
				Phase II 2015

Abbreviations: MOA, mode of action; TFPI, tissue factor pathway inhibitor; AT3, antithrombin 3; FVIII, Factor VIII; Fc, fragment crystallizable; FIXa, activated Factor IX; FX, Factor X.

Figure 1 Gene therapy using an adenovirus vector.

Note: Reproduced from US National Library of Medicine.⁶⁷

Table 7 Gene therapy programs for hemophilia

Manufacturer	Indication	Vector	Construct	Phase
Baxter/Asklepios Bio	Hem B	AAV8	FIX Padua	Phase I (2014)
Pfizer/Spark	Hem B	Modified AAV8 (AAV8-hFIX19)	FIX Padua	Phase I (2015)
UniQure BV/Chiesi	Hem B	AMT-060 (AAV5-hFIX)	wt FIX	Phase I
St Jude	Hem B	scAAV 2/8-LP1-hFIXco	wt FIX	Phase II
Bayer/Dimension	Hem A		FVIII	Discovery
BioMarin/St Jude/UCL	Hem A	BMN270 (hFVIII)	BDD FVIII	Preclinical
Baxter/Chatham/ReGenX	Hem A	BAX 888 (BNP-FVIII)	BDD FVIII	Discovery
St Jude/Royal Free Hos	Hem A	AAV-HLP-codop-hFVIIIV3	BDD FVIII and glycos linker (HLP)	Preclinical
Emory Univ/Lentigen Ther	Hem A	Lentiviral HSC	FVIII-expressing stem cells	Preclinical
Biogen Idec/Fonda Tele/	Hem A and B	Lentiviral		Discovery
Ospe San Raffaele

Abbreviations: Hem, hemophilia; FVIII, Factor VIII; FIX, Factor IX; HLP, hybrid liver-specific promoter.

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