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IAP Inhibition

Apoptosis Enhancers

IAP Inhibition

Inhibitor of apoptosis proteins (IAPs) are frequently overexpressed in tumors1-6 including squamous cell carcinoma of the head and neck (SCCHN), and have been shown to increase the ability of cancer cells to evade apoptosis and to resist the effects of anticancer treatments.7-10

IAPs inhibit caspases, blocking apoptotic signaling and suppressing immune cell activation and antitumor immunity.11-15 Inhibition of IAPs is thought to release this blockade and thereby restore cancer cell sensitivity to apoptosis.11,12,14 Therefore, targeting IAPs is being investigated as a potential approach, especially in combination with cell-death-inducing therapies, such as chemotherapy (CT) or radiotherapy (RT).

Xevinapant – IAP inhibitor

Xevinapant (formerly known as Debio 1143) is a potentially first-in-class, investigational, oral, small-molecule IAP inhibitor, designed to restore cancer cell sensitivity to apoptosis and thereby enhance the effects of CT and RT.4,5,16-20

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TrilynXTM22 (NCT04459715)

This is a Phase 3 randomized, double-blind, placebo-controlled study of xevinapant + chemoradiotherapy (CRT) vs placebo + CRT in patients with histologically confirmed, unresected locally advanced SCCHN. The study will assess event-free survival, as well as progression-free survival, overall survival, locoregional control, and safety.

XRay VisionTM23 (NCT05386550)

This is a Phase 3 randomized, double-blind, placebo-controlled study of xevinapant + RT vs placebo + RT in patients with histologically confirmed, resected locally advanced SCCHN who are at high risk for relapse and are ineligible to receive cisplatin-based CRT postoperatively. The study will assess disease-free survival, as well as overall survival, time to subsequent cancer treatment, safety, and quality of life.

HyperlynXTM24 (NCT06056310)

This is a single-arm, open-label, Phase 1b study of xevinapant in combination with weekly cisplatin and intensity-modulated RT to assess safety and tolerability in participants with LA SCCHN, suitable for definitive CRT. The study will assess dose-limiting toxicity, safety, objective response, progression-free survival, locoregional control, and time to subsequent systemic cancer treatment.

This investigational compound has not been approved by any health authority. Safety and efficacy have not been established.

cIAP, cellular inhibitor of apoptosis protein; CRT, chemoradiotherapy; CT, chemotherapy; FADD, Fas-associated protein with death domain; IAP, inhibitor of apoptosis protein; LA SCCHN, locally advanced squamous cell carcinoma of the head and neck; RIP1, receptor-interacting serine/threonine-protein kinase 1; RT, radiotherapy; SMAC, second mitochondria-derived activator of caspases; TNF, tumor necrosis factor; XIAP, X-linked inhibitor of apoptosis proteins.

  1. Vucic D. Targeting IAP (inhibitor of apoptosis) proteins for therapeutic intervention in tumors. Curr Cancer Drug Targets. 2008;8(2):110-117.  
  2. Fulda S, Vucic D. Targeting IAP proteins for therapeutic intervention in cancer. Nat Rev Drug Discov. 2012;11(2):109-124. 
  3. Michie J, Kearney CJ, Hawkins ED, Silke J, Oliaro J. The immuno-modulatory effects of inhibitor of apoptosis protein antagonists in cancer immunotherapy. Cells. 2020;9(1):207.  
  4. Brunckhorst MK, Lerner D, Wang S, Yu Q. AT-406, an orally active antagonist of multiple inhibitor of apoptosis proteins, inhibits progression of human ovarian cancer. Cancer Biol Ther. 2012;13(9):804-811.  
  5. Serova M, Tijeras-Raballand A, Albert S, et al. Effects of Debio 1143, a novel oral IAP inhibitor, in monotherapy and in combination with platinum drugs in human SCCHN tumor specimens. Cancer Res. 2014;74(suppl 19). Abstract 2752. 
  6. Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536):576-582.  
  7. Rathore R, McCallum JE, Varghese E, Florea AM, Büsselberg D. Overcoming chemotherapy drug resistance by targeting inhibitors of apoptosis proteins (IAPs). Apoptosis. 2017;22(7):898-919.  
  8. Dubrez L, Berthelet J, Glorian V. IAP proteins as targets for drug development in oncology. Onco Targets Ther. 2013;9:1285-1304.  
  9. Vucic D, Fairbrother WJ. The inhibitor of apoptosis proteins as therapeutic targets in cancer. Clin Cancer Res. 2007;13(20):5995-6000.  
  10. Fulda S. Targeting IAP proteins in combination with radiotherapy. Radiat Oncol. 2015;10:105. 
  11. Duckett CS. IAP proteins: sticking it to Smac. Biochem J. 2005;385(Pt 1):e1-e2.  
  12. Abbas R, Larisch S. Targeting XIAP for promoting cancer cell death-the story of ARTS and SMAC. Cells. 2020;9(3):663.  
  13. Obexer P, Ausserlechner MJ. X-linked inhibitor of apoptosis protein - a critical death resistance regulator and therapeutic target for personalized cancer therapy. Front Oncol. 2014;4:197.  
  14. Zhao XY, Wang XY, Wei QY, Xu YM, Lau ATY. Potency and selectivity of SMAC/DIABLO mimetics in solid tumor therapy. Cells. 2020;9(4):1012.
  15.  Sun SC. Non-canonical NF-κB signaling pathway. Cell Res. 2011;21(1):71-85. 
  16. Cai Q, Sun H, Peng Y, et al. A potent and orally active antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in clinical development for cancer treatment. J Med Chem. 2011;54(8):2714-2726. 
  17. Matzinger O, Viertl D, Tsoutsou P, et al. The radiosensitizing activity of the SMAC-mimetic, Debio 1143, is TNFα-mediated in head and neck squamous cell carcinoma. Radiother Oncol. 2015;116(3):495-503. 
  18. Thibault B, Genre L, Le Naour A, et al. DEBIO 1143, an IAP inhibitor, reverses carboplatin resistance in ovarian cancer cells and triggers apoptotic or necroptotic cell death. Sci Rep. 2018;8(1):17862. 
  19. Gomez-Roca C, Evan C, Le Tourneau C, et al. Open-label, non-randomized, exploratory pre-operative window-of-opportunity trial to investigate the pharmacokinetics and pharmacodynamics of the smac mimetic Debio 1143 in patients with resectable squamous cell carcinoma of the head and neck. Cancer Res. 2019;79(suppl 13). Abstract 5001. 
  20. Viertl D, Perillo-Adamer F, Rigotti S, et al. The SMAC-mimetic Debio 1143 efficiently enhanced chemo and radiotherapy in head and neck squamous cell carcinoma models. Cancer Res. 2013;73(suppl 8). Abstract 2055. 
  21. Ferris RI, Harrington K, Schoenfield JD, et al. Inhibiting the inhibitors: development of the IAP inhibitor xevinapant for the treatment of locally advanced squamous cell carcinoma of the head and neck. Cancer Treat Rev. 2023;113:102492.
  22. A study of xevinapant (debio 1143) in combination with platinum-based chemotherapy and standard fractionation intensity-modulated radiotherapy in participants with locally advanced squamous cell carcinoma of the head and neck, suitable for definitive chemoradiotherapy (TrilynX). ClinicalTrials.gov identifier: NCT04459715. Updated October 24, 2023. Accessed December 1, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04459715
  23. Phase III xevinapant (debio 1143) and radiotherapy in resected LA SCCHN, high risk, cisplatin-ineligible participants (XRAY VISION). ClinicalTrials.gov identifier: NCT05386550. Updated November 2, 2023. Accessed December 1, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05386550
  24. Phase 1b safety study of xevinapant, weekly cisplatin, and RT in participants with unresected LA SCCHN (HyperlynX). ClinicalTrials.gov identifier: NCT06056310. Updated November 14, 2023. Accessed January 22, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06056310

GL-MULO-00161 | January 2024

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