People who are identified with a GRN haploinsufficient genetic profile fall into the group
FTD(GRN) and invariably go on to develop the devastating symptoms of FTD.
Asymptomatic carriers and symptomatic carriers share a reduced (by 50%) circulating
concentration of the trophic factor progranulin. Progranulin has multiple functions
including acting as a brake on neuroinflammation. Neuroinflammation is understood to
be a precursor of conversion to symptomatic FTD(GRN) and is a key driver of disease
progression.
VES001 restores circulating progranulin levels to that of healthy comparators by
blocking an uptake mechanism into cells. The uptake mechanism targeted is the
protein sortilin which acts as one of several mechanisms for elimination of progranulin
from the extracellular space. Notably, eliminating sortilin by genetic knock out, blocking
with an antibody or in our case, inhibiting with VES001 elevates extracellular progranulin
levels without affecting the activity of progranulin inside the cell because alternative
pathways remain unaffected.
VES001 is a convenient, oral, home dosage form that is safe and efficacious in healthy
volunteers and will be tested in FTD(GRN) asymptomatic carriers to further
demonstrate safety, efficacy, PK/PD and biomarker readout.
We know from Alector's pioneering work with latozinemab that there is a strong
biological rationale for this approach. We consider that the VES001 approach to home
dosing will be amenable to a wider population of symptomatic and asymptomatic
carriers of the FTD(GRN) genetic profile. Further, there is substantial evidence to
propose that this approach will be useful in broader FTD populations because of the
anti-neuroinflammatory properties of progranulin elevation.
The direct link between VES001 dosing and changes in circulating levels of progranulin
means that we can potentially 'dial a dose' to reflect an individual patient's needs and
therefore optimize and maximize the possible therapeutic effect of this compound.
Moving VES001 into phase Ib forms the next essential step to demonstrate target
engagement in a relevant population and allowing dose selection for patient study. This
phase in FTD(GRN) carriers will also provide additional safety and pharmacodynamic
data including possible amelioration of biomarker changes that may develop prior to
symptom onset.