Keros Therapeutics, Inc. · NASDAQ:KROS
Keros Therapeutics — Technical Presentation (June 2020)
12 slides from Keros Therapeutics's technical presentation, June 2020
Slide 1: Selective Inhibition of ALK-2 Signaling Ameliorates Disease in a Novel Model of IRIDA
Selective Inhibition of ALK‐2 Signaling Ameliorates Disease in a Novel Model of Iron Refractory Iron Deficiency Anemia (IRIDA) Thomas Backus, Natalia Medeiros, Evan Lema, ffolliott Fisher, Jasbir Seehra, Jennifer Lachey Keros Therapeutics, Lexington MA, USA June 2020 Iron in Focus
Slide 2: Disclosure
Disclosure All listed authors are employees of and shareholders in Keros Therapeutics, Inc. June 2020 Iron in Focus
Slide 3: Hepcidin is a Key Regulator of Iron Metabolism
Hepcidin is a Key Regulator of Iron Metabolism ‒ Encoded by the HAMP gene ‒ Hepcidin acts to regulate serum iron by sequestering iron in storage tissues and preventing uptake of dietary iron ‒ Expressed, in part, in response to signaling through activin receptor‐like kinase 2 (ALK2) ‒ ALK2 is activa
Slide 4: MT-2 Regulates ALK2 Signaling and Downstream Hepcidin Levels
MT‐2 Regulates ALK2 Signaling and Downstream Hepcidin Levels ‒ ALK2 signaling and subsequent hepcidin expression is downregulated by the transmembrane type II serine protease MT‐2 ‒ MT‐2 acts by cleaving HJV from the cell surface, preventing ALK2 signaling ‒ MT‐2 is encoded by the gene TMPRSS6 ‒ ALK
Slide 5: Loss of functional MT-2 Results in Iron Refractory Iron Deficiency Anemia (IRIDA)
Loss of functional MT‐2 Results in NORMAL IRIDA Iron Refractory Iron Deficiency Anemia (IRIDA) ‒ Lack of functional MT‐2 results in continuous ALK2 activation, high hepcidin, low serum iron and anemia. ‒ Inhibition of BMP signaling and downstream SMAD phosphorylation may suppress hepcidin in IRIDA,
Slide 6: IRIDA Can Be Modeled in Mice by Knocking Down TMPRSS6
IRIDA Can Be Modeled in Mice by Knocking Down TMPRSS6 ‒ siRNA was utilized to knock down TMPRSS6 expression in WT mice ‒ TMPRSS6 expression was reduced by > 80% within 24 hours of administration ‒ Knockdown was confirmed to persist through 10 days following injection TMPRSS6 Expression 10 days post
Slide 7: Changes in mice treated with TMPRSS6 siRNA phenocopy changes observed in IRIDA patients
Changes in mice treated with TMPRSS6 siRNA phenocopy changes ** ** observed in patients with IRIDA ‒ Eight‐week‐old male C57BL/6 mice were treated intravenously with lipid RBC Levels 8d post-siRNA encapsulated siRNA targeted against 12 103 cells per microliter ** either Luciferase (control) or 11 -
Slide 8: KTI-2338 is a selective small molecule ALK2 inhibitor
KTI‐2338 is a selective small IRIDA IRIDA + 2338 molecule ALK2 inhibitor 3.596 275.036 1342.567
Slide 9: Therapeutic intervention in the siRNA model of IRIDA with the ALK2 inhibitor KTI-2338
Therapeutic intervention in the siRNA model of IRIDA with the ALK2 inhibitor KTI‐2338 ‒ Following confirmation of disease, once‐daily treatment dosing commenced at day 8 post initial siRNA administration with a second siRNA administration on day 10. ‒ Studies were terminated 18d post initial siRNA a
Slide 10: Therapeutic Dosing with KTI-2338 Improved Hematologic Parameters, Serum Iron, and Hepcidin
Therapeutic Dosing with KTI‐2338 Resulted in Improvement of Hematologic Parameters, Serum Iron, and Serum Hepcidin * P < 0.05, ** P < 0.01, **** P < 0.0001 via two‐way ANOVA
Slide 11: Summary/Discussion
Summary/Discussion ‒ A novel siRNA‐based murine model of IRIDA recapitulates the biology observed in patients with IRIDA ‒ The kinase inhibitor, KTI‐2338, potently and selectively targeted the ALK2 receptor in preclinical studies ‒ Selective ALK2 inhibition with KTI‐2338 resulted in improvement of h
Slide 12: Acknowledgements
Acknowledgements Poster Presentations by Keros Research Colleagues: Thanks to all of team Keros and collaborators!
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