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).

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

• All disease of Th1/Th17 imbalance feature the key deficit linked to vimentin in T regulatory cells proven by Oxford
• Aluda proof of principle data: Psoriasis, Multiple Sclerosis, Graft versus Host Disease, Type 1 diabetes, Lupus
• Transplant and Graft versus Host. and more, as well as providing important utility in transplantation and cancer.

Topical ALD-R491 for dermatological and healing diseases

• Dermatitis is not fully resolved — up to 50% patients have remaining itching and inflammation.
• Aluda has proof of principle data showing these dermatological pathologies result from vimentin over-stimulations (link to diagram)
• Multiple models, all highest statistical significance Aluda paper Wu et al. 2021)
• Eliminating vimentin-linked over-stimulations repair, fibrosis, biome that is now peer-reviewed, validated
• IL-10 KO model exceptional for a longer duration (16 weeks, versus typical 6-9) presenting higher disease challenge. Here, with most complex disease, data showed highest significance with histopathology composites and disease activity scores matching healthy normal untreated.

Sepsis and severe infections with immune complications

ALD-R491 has combination of its dual immunomodulatory and antiviral actions.

In combination, these important and novel anti-inflammatory actions are extremely well matched to disease biology., an extremely important and additive effect to tools in the fight against severe disease.

Also relevant to COVID is the literature showing viruses have a critical dependence on vimentin to get in and out of the host cell. This is a fundamental biology so cannot be evaded or escaped, and has been demonstrated across many viruses in the literature so is a pan-viral mechanism applicable to new pandemics, including a next COVID. For SARS-CoV specifically, literature has already established that

• Viral entry through ACE2 receptor-mediated endocytosis requires vimentin 3

References

• Ramos, I. et al. Vimentin as a Multifaceted Player and Potential Therapeutic Target in Viral Infections. Int J Mol Sci. 21:4675 (2020)
• Li, Z. et al. Vimentin as a Target for the Treatment of COVID-19. BMJ Open Respir Res. 7(1):e000623 (2020).
• Yu. Surface vimentin is critical for the cell entry of SARS-CoV. J Biomed Sci. 2016.
• Wang,H. SARS entry into host cells through a novel clathrin- and caveolae-indep endocytic pathway. Cell Res. 2008.
• Wu W. Vimentin plays a role in the release of the influenza A viral genome from endosomes. Virology 2016.
• Zanin-Zhorov. Protein kinase C-theta mediates negative feedback on regulatory T cell function. Science 2010.
• McDonald-Hyman. Vimentin network restrains Treg cell suppression of graft-versus-host disease. J Clin Invest. 2018.
• de Santos. Vimentin regulates activation of the NLRP3 inflammasome. Nature Communications. 2015.
• Zhou. A Pneumonia Outbreak Assoc. w a New Coronavirus of Probable Bat Origin. Nature. Mar. 2020.
• Korber et al. Spike mutation pipeline reveals the emergence of a more transmissible form of SARS-CoV-2. Cell, June 2020; Update from Hu et al. medRxiv preprint. May 8, 2020