Ixazomib reduces HIV1 reservoir size in a Casp

Ixazomib reduces HIV-1 reservoir size in a Casp 8 p 41 dependent manner Nathan W Cummins, MD Assistant Professor of Medicine, Consultant in Infectious Diseases, Chair of Infectious Diseases Research, Mayo Clinic College of Medicine and Science Rochester, MN USA cummins. nathan@mayo. edu #AIDS 2018 | @AIDS_conference | www. aids 2018. org

Disclosures • Research funding from Takeda Pharmaceuticals • Off-label usage – Ixazomib – FDA IND 130299 #AIDS 2018 | @AIDS_conference | www. aids 2018. org

• HIV-1 protease cleaves procaspase 8 Casp 8 p 41, which is expressed exclusively in infected cells, and is bound and inactivated by Bcl 2 • Casp 8 p 41/Bcl 2 complex is • Proteasome inhibitors, including ixazomib, increase Casp 8 p 41 expression. • Proteasome inhibitors independently induce HIV 1 reactivation in an NFk. B dependent manner • Proteasome inhibitors induce preferential apoptosis in HIV-1 infected cells versus uninfected cells. • Treatment of ex vivo CD 4 T cells from ART-suppressed patients with ixazomib significantly reduces total and integrated HIV-1 DNA. polyubiquinated for proteasomal degradation. #AIDS 2018 | @AIDS_conference | www. aids 2018. org

#AIDS 2018 | @AIDS_conference | www. aids 2018. org

• • Phase 1 b/2 a, single center, dose escalation cohort clinical trial of ixazomib in ARTsuppressed patients – NCT 02946047 – IND 130299 11 of 17 participants enrolled No serious AEs in 1 mg, 2 mg (completed) or 3 mg (ongoing) cohorts to date HIV-1 reservoir measurements in peripheral CD 4 T cells will be reported at a later date #AIDS 2018 | @AIDS_conference | www. aids 2018. org

Acknowledgments • Andrew D. Badley • – – – • Sekar Natesampillai Zilin Nie Rahul Sampath Gary Bren Amy Sainski Mayo Clinic Collaborators • Scott Kaufmann David J. Katzmann Eric Polley External Collaborators – – Clinical Trial Team – – – – Badley HIV Immunology Lab, Mayo Clinic – – – • • Jason V. Baker Keith Henry Marilia Pinzone Una O’Doherty #AIDS 2018 | @AIDS_conference | www. aids 2018. org Stacey A. Rizza Aaron J. Tande Maryam Mahmood Shaji Kumar John Zeuli Christina Rivera James Allen DSMB – – – Jennifer Whitaker Zelalem Temesgen Vincent Rajkumar