Polku Therapeutics is a biotechnology company developing first-in-class, disease-modifying small molecules for neurodegenerative diseases, targeting the root causes of tau aggregation and neuroinflammation. Its lead program modulates the PREP–PP2A axis to restore the brain's natural protein-clearing mechanisms, with lead compound POLK-38 showing positive oral efficacy in a PS19 tauopathy mouse model. The company's pipeline spans orphan tauopathies such as frontotemporal dementia and progressive supranuclear palsy, as well as Alzheimer's and Parkinson's diseases.
Funding
Funding not disclosed
Founders
Product
Problem
Neurodegenerative diseases such as Alzheimer's, frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and Parkinson's disease are driven by the accumulation of toxic tau and α-synuclein protein aggregates, along with chronic neuroinflammation. Existing treatments only manage symptoms and do not modify the underlying disease process. Most tauopathies lack any disease-modifying treatments, leaving patients with a progressive loss of neurons that erodes cognition and identity.
Solution
Polku Therapeutics develops first-in-class, small-molecule therapies that target the PREP–PP2A axis, a master regulator of tau homeostasis in the brain. Rather than inhibiting PREP's enzymatic activity, the company's compounds allosterically modulate protein-protein interactions to restore PP2A activity, which promotes tau dephosphorylation and induces autophagy to clear existing toxic aggregates. This dual mechanism addresses both the accumulation of pathological proteins and the inflammation that sustains the neurodegenerative cycle. Lead compound POLK-38 has demonstrated significant treatment effects on brain tau pathology and spatial learning in the PS19 tauopathy mouse model following oral administration. The pipeline is advancing toward first-in-human studies, starting with orphan tauopathies where the need for disease-modifying options is most urgent.
Target Audience
Primary customers are life science investors active in seed rounds and biopharma firms pursuing preclinical R&D collaborations in CNS. The ultimate patient population includes people with orphan tauopathies (FTD, PSP) and common neurodegenerative conditions such as Alzheimer's and Parkinson's disease.
Features
- Modulates PREP via allosteric protein-protein interaction modulation rather than enzyme inhibition, offering a differentiated mechanism from other tau-targeting approaches
- Restores PP2A holoenzyme activity to dephosphorylate hyperphosphorylated tau and prevent new aggregate formation
- Induces autophagy to clear pre-existing tau and α-synuclein aggregates through the cell's own waste-clearance pathways
- Reduces glial cell activation and oxidative stress by harmonizing PP2A holoenzyme composition, breaking the neuroinflammation cycle
- Produces positive oral efficacy data for lead compound POLK-38 in the PS19 tauopathy mouse model, with additional neuropathological analyses ongoing
- Pipeline includes multiple indications—FTD (MAPT), PSP, AD, and PD—all derived from the same PREP/PP2A modulator platform