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Wolfgang Miesbach: New FVIII‑QQ Gene Therapy Aims for “Less is More” – Durable Expression with Enhanced Potency
Wolfgang Miesbach/LinkedIn
Dec 13, 2025, 07:44

Wolfgang Miesbach: New FVIII‑QQ Gene Therapy Aims for “Less is More” – Durable Expression with Enhanced Potency

Wolfgang Miesbach, Professor of Medicine at Frankfurt University Hospital, shared on LinkedIn:

“Less is more: How enhanced‑function FVIII‑QQ can optimize a low‑dose gene therapy approach for haemophilia A. Great ASH presentation by Nina Frey. SPK‑8011QQ leverages the established SPK‑8011 capsid (dirloctocogene samoparvovec), which in Phase 1/2 trials demonstrated:

  • Up to 6.5 years of durable FVIII expression within the mild HA range
  • No wide expression variability across time points
  • No sustained or late ALT elevations
    Shortened corticosteroid exposure with IVMP; return to prophylaxis in only 5 of 25 participants

Now combining this proven durability and safety profile with the enhanced functional potency of FVIII‑QQ.

Wolfgang Miesbach: New FVIII‑QQ Gene Therapy Aims for "Less is More" – Durable Expression with Enhanced Potency

Introducing SPK‑8011QQ: This novel construct incorporates FVIII‑QQ – an enhanced‑function FVIII variant with just two amino‑acid substitutions (R336Q and R562Q) that:

  • Confer resistance to activated protein C (aPC) cleavage
  • Preserve physiological A2‑domain dissociation (maintaining natural control mechanisms).

Enhanced potency in the presence of aPC:

– FVIII‑QQ retained ~65% residual activity in chromogenic assays (vs. ~43% for FVIII‑WT) at 10 nM aPC
– Significantly higher residual peak thrombin across aPC concentrations in thrombin generation assays (p=0.0018 at 4 nM)
– 80–100% FVIII activity equivalent in mouse ex vivo plasma, with markedly enhanced thrombin generation vs. FVIII‑WT

Superior haemostatic control at lower FVIII activity levels:

Tail‑clip bleed model: FVIII‑QQ achieved enhanced bleed control at markedly lower FVIII levels than FVIII‑WT, with significantly reduced blood loss (p=0.0089 and p=0.0079)
Encouraging preliminary safety profile:
Ferric chloride thrombosis model: FVIII‑QQ showed a lower incidence of animals reaching the near‑occlusive zone (>85% blood flow reduction) vs. positive control

A Phase 2b study by Roche is now underway to translate these preclinical insights into meaningful clinical benefit.”

Read more from Wolfgang Miesbach on Hemostasis Today.

American Society of Hematology (ASH) ASH2025 ASH25 FVIII‑QQ Gene therapy Health Hematology Hemostasis Hemostasis Today Medicine Nina Frey Wolfgang Miesbach
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