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P133 Computational discovery and preclinical validation of therapeutic leads with novel MOAs for systemic lupus erythematosus (SLE)
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  1. Isaac Hakim,
  2. Sana Mujahid,
  3. Aaron C Daugherty and
  4. Timothy S Heuer
  1. twXAR Inc, Mountain View, CA, USA

Abstract

Background Lupus is a heterogeneous, systemic disease that affects millions of patients globally with a high unmet medical need. We present results from our powerful and efficient computational drug discovery platform that identifies hits with first-in-class mechanisms of action that can advance rapidly and successfully through preclinical validation studies. The twoXAR discovery platform uses an artificial-intelligence framework to integrate diverse patient-derived biomedical data sets to build holistic and unbiased models of human disease biology. The utilization of diverse, proprietary algorithms and deep learning principles provides a highly sensitive platform to elucidate complex disease-specific associations between biology and biomedical data that are integrated with a library of existing drug molecules. This enables the identification of novel, high-value drug discovery hits with known pharmacological properties. The twoXAR platform also preserves interpretable data-driven links to disease biology to facilitate efficient validation and optimization studies.

Methods Using clinical SLE patient data, we employed the twoXAR platform to build an in-silico SLE disease model. Nine molecules with novel mechanisms of action (not previously tested as candidate clinical therapies for lupus) were identified as drug discovery hits and then characterized in preclinical efficacy studies using the MRL mouse model of lupus.

Results In preclinical validation studies with the MRL mouse model, 2 compounds were differentiated by significant efficacy and excellent tolerability. TXR-711 and TXR-712 increased renal function, decreased renal inflammation and decreased inflammation compared to vehicle-treated control mice. In particular, TXR-711 and TXR-712 significantly decreased serum blood urea nitrogen (BUN) levels, decreased proteinuria levels, and significantly improved kidney histology readouts such as glomerulonephritis and tubule basophilia. Additionally, TXR-711 and TXR-712 treatment resulted in significantly decreased inguinal lymph node weight.

Conclusions TXR-711 and TXR-712 were identified as SLE drug discovery leads with novel MOAs for further preclinical development. Ongoing studies with TXR-711 and TXR-712 includes pharmacokinetic, pharmacodynamic, and additional MRL mouse efficacy characterization.

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