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Science

The science behind KP405

KP405 is a dual GLP-1/GIP receptor agonist designed by Kariya co-founder Christian Hölscher to treat neurodegenerative disease.

Why incretins

GLP-1 and GIP are gut hormones whose receptors are also found in the brain. Activating them protects neurons in models of Parkinson's disease.

Getting into the brain

Most GLP-1 medicines are modified to last longer in the blood, usually by attaching a fatty-acid chain. That modification also makes it harder for the drug to cross the blood-brain barrier.

An independent laboratory at the University of Washington measured brain uptake of 13 incretin receptor agonists (Rhea et al., Tissue Barriers 2024). The compounds carrying a fatty-acid chain, including liraglutide, semaglutide and tirzepatide, showed no measurable entry. The authors listed KP405 among the compounds with fast transport that should be considered for testing in Alzheimer's and Parkinson's disease.

KP405 has no fatty-acid chain. Its 40-amino-acid GLP-1/GIP backbone carries a short cell-penetrating sequence at one end, which helps it cross cell membranes.

Head to head in Parkinson's models

Each study compared KP405 with a marketed incretin drug at the same or a lower dose.

Comparator
Model
Result
Source
Exenatide (exendin-4)
MPTP mouse
Improved motor performance at a tenth of the dose exenatide needed, and preserved more dopamine neurons at the same dose
Zhang et al., J Parkinsons Dis 2020
Liraglutide
A53T alpha-synuclein mouse
More effective at half the dose
Zhang et al., Parkinsons Dis 2023
Semaglutide
6-OHDA rat
Restored striatal dopamine to normal levels; semaglutide did not
Zhang et al., Parkinson's Dis 2022
Tirzepatide
6-OHDA rat
Protected dopamine neurons and motor function; tirzepatide showed no effect at the same dose
Lingyu et al., Front Endocrinol 2026
In people

Phase I

The Phase I trial enrolled 88 participants in single and multiple ascending dose cohorts, including healthy older adults and people with Parkinson's. It was run by MAC Clinical Research in Manchester, UK. KP405 was safe and well tolerated, with no serious adverse events. Dose-dependent reductions in appetite and food intake, familiar from other GLP-1 medicines, confirmed its pharmacological activity.

Brain biomarkers

An exploratory study with NeuroDex measured neuron-derived vesicles isolated from blood, a way of sampling brain-cell biology without a spinal tap. After dosing, markers of insulin signalling rose and markers of inflammation fell in healthy older adults and people with Parkinson's. The results were presented at AD/PD 2026 in Copenhagen.

Selected publications

  • Athauda D et al. Lancet 2017;390(10103):1664-75. Exenatide once weekly versus placebo in Parkinson's disease. Journal link
  • Meissner WG et al. N Engl J Med 2024;390(13):1176-85. Trial of lixisenatide in early Parkinson's disease. Journal link
  • Rhea EM et al. Tissue Barriers 2024;12(4):e2292461. Brain uptake of incretin receptor agonists.
  • Zhang L et al. J Parkinsons Dis 2020. KP405 compared with exendin-4 in the MPTP mouse.
  • Zhang L et al. Parkinsons Dis 2023;2023:7427136. KP405 compared with liraglutide in the A53T mouse.
  • Lingyu et al. Front Endocrinol 2026. KP405 superior to tirzepatide in the 6-OHDA rat. Journal link
  • Hölscher C. CNS Drugs 2025;39(12):1201-20. Incretin hormones GLP-1 and GIP normalize energy utilization and reduce inflammation in the brain in Alzheimer's disease and Parkinson's disease. Journal link