Biotechnology: Mapping out the competitive landscape in sickle cell disease

Research evidence excerpt

Biotechnology: Mapping out the competitive landscape in sickle cell disease

ew, the relative

success of Oxbryta despite not showing clinical benefit is indicative of the unmet need

and the potential opportunity for a safe therapy which can significantly reduce pain

crises.

Competitive landscape

Sickle cell disease is an area of active development across a variety of mechanistic

approaches given its large, rare disease patient base (~100K US patients) and significant

under-met need. Below, we explain each of the different mechanisms of action, prior

clinical data, and key catalyst timings for investigational and approved SCD therapies

(Exhibit 1).

Fetal hemoglobin (HbF) inducers

Therapeutic activation of fetal hemoglobin production is an active field of investigation,

believed to be a true disease-modifying mechanism rather than working downstream of

defective hemoglobin. More mature programs involve broad-based epigenetic

reprogramming to induce γ-globin expression, leading to potential long-term safety

concerns with altering the expression of many genes. More nascent approaches (WIZ

degraders) may mitigate this risk with a narrower mechanism of action, but substantial

mechanistic validation on potential safety is needed.

It has been our view that the fundamental biology of systemically altering a patient’s

genome expression to re-activate γ-globin expression inherently introduces safety risks,

especially in indications where treatment will be chronic/life-long. Disruption of DNA

methylation, DNA acetylation, transcription factors/co-factors, likely need to be localized

to hematopoietic stem cells or erythroid progenitor cells to mitigate malignancy risk.

However, achieving a safe and effective drug profile may be challenging as seen by