Pipeline Overview

ALD-R491 in Crohn’s disease

• Blocks the 5 main disease features created by vimentin over-stimulation
• Achieves highest statistical significance in multiple colitis models
• Provides clear evidence that eliminating vimentin-linked over-stimulations normalized immune, repair, fibrosis, biome
• Is peer-reviewed, validated (Wu et al. 2021)
• Most differentiated from all peers: use of an IL-10 KO model extended for a longer duration (16 weeks, versus typical 6-9) creating a significantly higher disease challenge.
• When disease reached highest severity, showed most dramatic benefits. Why? Resolving all the parts is more precise, complete and successful relative to only resolving inflammation (see Wynn 2010).
• ALD-R491 actions may apply to other indications within IBD

References

1. Wu J et al. Therapeutic targeting of vimentin by ALD-R491 impacts multiple pathogenic processes to attenuate acute and chronic colitis in mice. Biomed Pharmacother (Dec 2023).
2. Henderson, P. et al. A Role for Vimentin in Crohn’s Disease. Autophagy. (2012).
3. Mor-Vaknin, N. et al. Murine Colitis is Mediated by Vimentin. Sci Rep. (2013).

ALD-R491 in other immune diseases with potential Fibrotic complications

1. ALD-R491 has a broad package showing statistically significant data in lung fibrosis, proving it matches multiple third party papers identifying specific roles of vimentin in over-active fibrotic processes:
   • Lung fibrosis cannot form in a Bleomycin mouse if vimentin is degraded or ablated
   • Autophagic clearance of excess collagen is dysregulated in disease
   • Collagen mRNA requires use of vimentin as a scaffold
   • Fibroblast invasiveness is regulated by vimentin, and can only reach excessive pathological levels if vimentin is present
   • Vimentin is required for the NLRP3 inflammasome to activate
   • Inflammation that does not respond to existing anti-inflammatory pathway target has been shown to have a dysregulation of vimentin partition in T regulatory cells first published by Michael Dustin, Director at Oxford Kennedy Center for Immunology
2. ALD-R491 also has evidence that dampening vimentin's role in creating overactive processes and pathologies in the above list offers a novel approach to Liver Fibrosis, Multiple Sclerosis, Graft versus Host Disease, Type 1 Diabetes, and Lupus

Sepsis and severe infections with immune complications

• Sepsis causes more deaths than the 6 deadliest cancers combined, leads to high long-term disability, and is the largest expense for hospital and public health systems worldwide
• Infection triggers sepsis, but when antibiotics don’t resolve it, a chaotic dysregulation of immune and other systems drives death and also long-term disability
• Recently, leading academics presented a new understanding of the therapeutic challenge in sepsis that led to a history of failures and offers a new and clear requirement for success in drug development:
  • Analyzed 20 years of data and observed it has many processes in overactive state, with unpredictable timing, and oppositional goals (i.e. simultaneous inflammation and immune suppression)
  • Conclusion “drugs with single-action target biology” had to fail and success will require “drugs with wider actions [more parts at once]”
  • Vimentin operates as an amplifier for all key steps, and is key to all critical over-active processes in sepsis and offers a new solution
  • ALD-R491 data shows removing the pathological amplification by vimentin, dampens overactive immune processes on both ‘sides’, restores organ function, promotes tissue healing, clears residual pathogens in tissues (not circulating, so not accessible by antibiotics)
• The above ‘system wide’ rebalancing action is beneficial to any setting of highly dysregulated immune disease. This includes H. pylori and E. coli in gut dysbiosis in Crohn’s as well as cases where anti-inflammatory drugs produce oversuppression and rising rate of infection from existing pathogens known to sequester (HSV, HPV, HIV, Flu, EBV, HBV, Adeno, CoV2 all have steps that rely on vimentin).
• A list of emerging pathogens is suspected to use vimentin (H9N2, Chandipura, Foot and Mouth, Cowpea mosaic virus, Bluetongue, African swine, Monkey pox, CoV3) and published data suggests ALD-R491 could reduce pace and intensity of infection and reduce mortality.