1 of 34

Current and future treatments for �inherited bleeding disorders

​

Mike Makris

Sheffield, UK

2 of 34

Declaration of Interests

  • Research funding: None

​

  • Consultancy: NovoNordisk, Grifols, Sanofi, Freeline

​

  • Project lead for EUHASS which is funded by Bayer, Biomarin, BPL, CSL Behring, Grifols, Kedrion, NovoNordisk, Octapharma, Roche, Sanofi, Sobi, Takeda

​

3 of 34

Current

Future

2022

Standard half-life

    • FVIII/FIX – Plasma/recombinant

Extended half-life

    • FVIII- Fc, PEG
    • FIX- Fc, Albumin, PEG

Bypassing agents

    • rFVIIa
    • Activated PCC

Bispecific antibody

Extended half-life

    • Intravenous: FVIII-Fc+XTEN
    • Subcutaneous: FVIII, FIX, FVIIa

Bispecific antibodies

    • FIX/X mimetics
    • Vs other molecules

Rebalancing therapies

    • Antithrombin siRNA
    • Anti-TFPI
    • Anti-APC

Gene therapy

    • AAV
    • Lentivirus
    • Lipid nanoparticles

HEMOPHILIA TREATMENTS

4 of 34

1950 1960 1970 1980 1990 2000 2010 2020

Cryoprecipitate

Plasma derived

FVIII/FIX

Viral inactivation

rFVIII

​

rFIX

EHL: FVIII/FIX

Emicizumab

(Hemlibra)

5 of 34

Efficacy

Safety

Convenience

Price

Choosing a treatment

Essential: Efficacy & Safety

Balance: Price vs Convenience

6 of 34

Haemophilia A

Licensed and available

Standard half life FVIII

Plasma derived (>30)

Recombinant (7)

Extended half life FVIII

All recombinant (5)

Emicizumab (Hemlibra)

DDAVP

In clinical trials

Ultra-extended FVIII (BIVV001)

Rebalancing agents

Bispecific antibodies

Gene Therapy

Others

BT200

(Subcutaneous FVIII)

(Implantable spheres)

​

7 of 34

Haemophilia B

Licensed and available

Standard half life FVIII

Plasma derived (18)

Recombinant (3)

Extended half life FVIII

All recombinant (3)

In clinical trials

Rebalancing agents

Gene Therapy

Others

Subcutaneous FVIX

(Spheres)

​

8 of 34

Haemophilia A with inhibitors

Licensed and available

  • FEIBA
  • Recombinant VIIa
    • Novoseven
    • Sevenfact
  • Emicizumab (Hemlibra)

​

In clinical trials

Rebalancing agents

Bispecific antibodies

Gene Therapy

9 of 34

Bleeding disorder

Licensed and available

In clinical trials

von Willebrand Disease

DDAVP

Plasma VWF +/-FVIII

Recombinant VWF

Emicizumab (Hemlibra),

BT200

Fibrinogen deficiency

Fibrinogen concentrate

​

Factor V deficiency

FFP

Factor V concentrate

Factor VII deficiency

Plasma and recombinant FVII

Rebalancing therapies

Factor X deficiency

Plasma and recombinant FX

Rebalancing therapies

FXIII deficiency

Plasma and recombinant FXIII

​

Glanzmann Thrombasthenia

Platelet transfusions, NovoSeven

Bispecific antibodies

10 of 34

FVIII and FIX usage in the UK 1995-2019

Plasma (orange), recombinant (blue), EHL (green)

FVIII

FIX

UKHCDO annual report 2021

11 of 34

​

Half-life (hours)

Prophylaxis injections

per week

Standard half-life products

​

​

FVIII

12

3

FIX

18

2

​

​

​

Extended half-life products

​

​

FVIII

18

2

FIX

90

1

12 of 34

Standard vs Extended half-life

Efficacy Safety Price

13 of 34

Emicizumab (Hemlibra): Bispecific antibody

Makris M. Blood 2016; 127:1623-4

14 of 34

Callaghan et al. Blood 2021

Annual bleed rate on emicizumab (Hemlibra)

15 of 34

Emicizumab (Hemlibra)

  • Haemophilia A with or without inhibitors
  • Subcutaneous
  • Once a week or once every 2 weeks or once a month
  • Increasing use in less than 1 year olds
  • 75% are bleed free
  • Standard clotting screening tests are normal
  • Converts severe/moderate haemophilia A to mild (not to normal)
    • May need concentrate for injuries or surgery
  • Other bispecific antibodies are in clinical trials

16 of 34

BIVV001 (Efanesoctocog): FVIII independent of VWF half life

17 of 34

BIVV-001: the next generation of intravenous FVIII�

Dose

25u/kg

65u/kg

Half life

37.6h

44h

FVIII level at 5 days

12.2%

39.6%

FVIII level at 7 days

5.3%

18.5%

Konkle et al. NEJM 2020

18 of 34

Callaghan M et al. Blood 2018; 132:23-30

19 of 34

Rebalancing therapies

​

Fitusiran

Concizumab

Marstacimab

SerpinPC

​

Antithrombin inhibition

Anti-TFPI

APC inhibition

Target population

HA/HB

HA/HB

HA/HB

Administration route

Subcutaneous

Subcutaneous

Subcutaneous

Bleed prevention

Yes

Yes

Yes

Bleed treatment

No

No

No

20 of 34

Thrombosis in haemophilia

Product

Thrombotic risk

FVIII

1 per 1000 patients per year

Emicizumab (Hemlibra)

30 cases reported

Fitusiran

5 cases in clinical trials

Anti-TFPI

1 trial stopped and 1 temporarily suspended due to thrombotic risk

SerpinPC

Too few patients treated

Gene therapy

2 cases in clinical trials

21 of 34

Gene Therapy in 2022

What it is:

It is gene addition. An extra FVIII or FIX gene is delivered to the liver cells by a virus

​

​

What it is not:

It does not change the abnormal FVIII or FIX gene. A person who has had current gene therapy can still transmit the haemophilia to his daughters

22 of 34

Gene addition therapy

FVIII or FIX gene

23 of 34

The Journey of Gene Therapy for a Patient with Haemophilia

-1 0 +1 +2 +3 +4

+15?

Years

Clinical trial

Or

Approved product

Discussion

And

Informed

consent

Infusion

Day

Very frequent

Hospital visits

And

?steroids

Less frequent

Monitoring

visits

Six monthly monitoring visits

24 of 34

Haemophilia A Biomarin 2 year results

(EAHAD February 2022)

​

Johnny Mahlangu: Biomarin AAV5 Gene Therapy Haemophilia A Phase 3. GENER8-1 two-year analysis

25 of 34

Pipe S, et al. ASH 2020

UniQure: Haemophilia B post-gene therapy FIX levels

26 of 34

Durability – How long will it last?

  • Haemophilia A
  • Biomarin
  • Estimated 8 years
  • Haemophilia B
  • UniQure
  • 10-20+ years

​

27 of 34

Long term issues

  • How long will it last?

​

  • Safety unknown unknowns

​

  • Is it associated with increased risk of cancer?

28 of 34

What is the competition?

Haemophilia A

  • Emicizumab (Hemlibra)
  • Subcutaneous injections every 1-4 weeks
  • 70% bleed free

Haemophilia B

  • Extended half life FIX
  • Intravenous 1x per week
  • 70% bleed free

29 of 34

Gene therapy for other haemophilia groups

  • Children
    • Lentivirus trials starting in India

​

  • Persons with anti-AAV antibodies
    • Trials ongoing both in haemophilia A & B

​

  • Persons with FVIII inhibitors
    • Trial ongoing

​

  • Patients with bleeding disorders other than haemophilia

30 of 34

Gene Therapy for bleeding disorders other than haemophilia

  • Severe factor X, VII, V, II deficiency or Glanzmann Thrombasthenia
  • Very rare so not profitable for companies
  • The technology is available, even today

​

  • Platform technology will get approval eg AAV5 gene therapy platform
  • Multiple gene cassettes can be inserted eg FVII gene inserted into AAV5
  • Possibly by University research labs or publicly funded labs

FX

FVII

FV

FII

31 of 34

Efficacy

Safety

Convenience

Price

Choosing a treatment

32 of 34

Current

Future

2022

Standard half-life

    • FVIII/FIX – Plasma/recombinant

Extended half-life

    • FVIII- Fc, PEG
    • FIX- Fc, Albumin, PEG

Bypassing agents

    • rFVIIa
    • Activated PCC

Bispecific antibody

Extended half-life

    • Intravenous: FVIII-Fc+XTEN
    • Subcutaneous: FVIII, FIX, FVIIa

Bispecific antibodies

    • FIX/X mimetics
    • Vs other molecules

Rebalancing therapies

    • Antithrombin siRNA
    • Anti-TFPI
    • Anti-APC

Gene therapy

    • AAV
    • Lentivirus
    • Lipid nanoparticles

HEMOPHILIA TREATMENTS

33 of 34

Summary

  • We currently have many safe and effective treatments for haemophilia
  • Multiple new therapies are in development
  • Gene therapy is likely to be licensed in 2022
  • Deciding which treatment to choose can be difficult
  • Non-haemophilic bleeding disorder patients have fewer choices both currently and in development

34 of 34

Twitter handle: @ProfMakris