Potential New Clinical Biomarker for Measurement of Myelin Synthesis Identified
Data Presented During the Society for Neuroscience Annual Meeting 2021
SAN DIEGO – Nov. 3, 2021 – Autobahn Therapeutics, a biotechnology company focused on restoring hope for people affected by CNS disorders, today announced new preclinical data highlighting the company’s thyroid hormone-targeted approach to precisely deliver tailored therapeutics to the brain for the treatment of a range of CNS disorders. The data will be presented during two poster sessions at the Society for Neuroscience Annual Meeting, being held virtually from November 8-11, 2021. Posters will be made available to registered attendees online beginning on November 3, 2021.
“We are excited to present new preclinical data that highlight the potential of our unique drug development approach for the treatment of CNS disorders,” said Brian Stearns, Ph.D., chief scientific officer of Autobahn. “These findings support our hypothesis that we can leverage our brain-targeting platform to specifically tailor our molecules based on the target indication, enhancing their therapeutic potential. Importantly, findings from our preclinical studies in demyelination models support the use of 24S-hydroxycholesterol as a biomarker to measure remyelination in certain CNS disorders, such as multiple sclerosis and adrenomyeloneuropathy, and could help inform the design of future clinical trials.”
Poster Title: Thyroid receptor beta-selective agonist enhances functional brain delivery and accelerates remyelination in in vitro and in vivo rodent demyelination models
Data Summary: Leveraging its brain-targeting platform, Autobahn is advancing brain-directed thyromimetics, which are designed to induce oligodendrocyte differentiation and enhance remyelination in neurodegenerative diseases, such as multiple sclerosis (MS). The data presented are from preclinical studies of LL-341070, a novel thyromimetic prodrug activated by fatty acid amide hydrolase (FAAH)-mediated conversion to LL-341070a, a potent and selective small molecule agonist of thyroid hormone receptor beta. The FAAH-activated delivery allows for enhanced brain penetration of the active molecule. Key findings are as follows:
- LL-341070 demonstrated robust brain penetration and target engagement at both 30 mg/kg and 100 mg/kg doses in vivo.
- LL-341070a enhanced oligodendrocyte precursor cell differentiation, which can lead to increases in remyelination in vitro.
- LL-341070 administration led to a dose-dependent response across mean maximum clinical score and histological endpoints of inflammation and demyelination in an experimental autoimmune encephalitis model, a commonly used MS model.
- Administration of LL-341070 led to increased fractional synthesis rate of brain 24S-hydroxycholesterol (24OHC) during active remyelination. Brain cholesterol is primarily incorporated into myelin with 24OHC reflecting a brain specific isoform of cholesterol that can also be measured in plasma. The 24OHC synthesis rate in plasma closely reflected the 24OHC synthesis in multiple regions of the brain, supporting the potential of plasma 24OHC synthesis as a useful biomarker of brain cholesterol, and thus myelin, synthesis.
Poster Title: Feedback control on the pituitary-thyroid hormone axis by thyroid hormone agonists correlates with peripheral exposure as opposed to central exposure and on-target activity
Data Summary: Thyromimetic delivery to the brain has significant therapeutic potential for the treatment of neurodegenerative diseases, but historically, dosing and delivery to the CNS have been limited by poor delivery. Autobahn is leveraging its proprietary technology to enhance brain delivery of thyromimetic prodrugs using FAAH-inhibitors, which can be used to control how the molecule is delivered to the brain. FAAH is highly expressed in the CNS and prodrugs enhance delivery by approximately 30-fold, however it was unclear if enhanced delivery to the CNS could enhance feedback control on the thyroid hormone axis (THA), which has been observed clinically for other non-brain-directed thyromimetics. The company conducted a series of preclinical studies to determine whether feedback control on thyroid hormone axis derives from central (hypothalamic) or peripheral (pituitary) mechanisms. Key findings are as follows:
- Adding a peripheral FAAH inhibitor with FAAH-mediated delivery of a potent thyromimetic enhanced delivery to the brain compared to those without prodrugs and resulted in a greater than 1500-fold improvement in brain versus liver activity.
- Increasing delivery of the thyromimetic to the brain did not enhance inhibition of the THA, while reducing peripheral exposure provided greater protection from the limiting effects.
- Taken together, this suggests that feedback control of the THA is dominated by peripheral rather than central mechanisms. Further, the data suggest that the therapeutic index of thyromimetics can be tuned and optimized by adding peripheral FAAH inhibitors based on the specific CNS disorder.
About Autobahn Therapeutics
Autobahn Therapeutics is focused on restoring hope for people affected by CNS disorders. Autobahn is leveraging its brain-targeting chemistry platform to unlock new therapeutic opportunities through precision tuning of the central exposure of its molecules. The company’s pipeline is led by ABX-002, a thyroid hormone receptor beta agonist prodrug for the treatment of multiple sclerosis and adrenomyeloneuropathy (AMN), a rare genetic disorder. Autobahn Therapeutics is based in San Diego. For more information, visit www.autobahntx.com.
Alicia Davis, THRUST Strategic Communications