Blood-Brain Barrier Hitchhikers: The Future of CNS Therapeutics
Owing to the blood-brain barrier’s (BBB) relative impermeability, biologics and oligonucleotide-based drugs have restricted CNS penetration, relying either on passive uptake or on local CNS delivery through invasive intrathecal injections. To solve this challenge, active transport pathways are being exploited to improve CNS delivery from systemic routes, with both established pharmas and new biotechs racing to pinpoint BBB receptors that can be co-opted as potent macromolecule “shuttles”.
Here we present our report “Blood-Brain Barrier Hitchhikers: The Future of CNS Therapeutics” that highlights clinically validated mechanisms shown to improve delivery into the CNS, analyses established and emerging companies competing in this space, and discusses what lies ahead.
Report highlights:
- TfR1 has emerged as a mechanism for achieving robust CNS delivery, as evidenced by recent clinical data from Denali (Tividenofusp Alfa).
- Roche’s Trontinemab, a TfR1-shuttled mAb for Alzheimer’s disease, significantly surpasses results achieved with first-generation drugs.
- RNA represents the second wave of shuttled drugs after biologics. In 4Q24/1Q25, Lilly hit the clinic with a shuttled siRNAs against two of the hottest targets in neurodegeneration.
- With AbbVie moving to acquire Aliada for $1.4B after early data in healthy volunteers and Novartis dishing out $200M upfront ($2B total) to Arrowhead for a preclinical-stage TfR1-siRNA against SNCA, big pharma is clearly taking notice.
- Patent filings from big pharma and emerging biotechs outline clear trends in innovation towards shuttles with improved brain PK, ability to target discrete cell populations, and ability to achieve dual RNAi.
- While the field is largely focused on TfR1, novel BBB targets are emerging and reporting promising data. But the question is, can they display TfR1’s apparent dominance?
- With COGS still a consideration for large indications like Alzheimer’s and Parkinson’s, the field is turning to simple scaffolds, such as small molecules and peptides, for BBB delivery.
- Like in many other areas of biotech, China’s prominence is growing. We have identified several promising biotechs with NHP-validated shuttles against established targets as well as new BBB targets.
Link to the full report: https://docsend.com/view/r34vydhy8u3ska2y
