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Therapeutics


models in mice have shown that TL32711 leads to tumour-regression as a single agent and that it dis- plays synergy when combined with specific chemotherapies. TL32711 has been shown to restore cancer cell sensitivity to apoptotic stimuli, such as TNF or TRAIL, in a panel of patient- derived human cell lines.


A Phase I first-in-man study of TL32711 in adult patients with advanced solid tumours and lym- phoma showed that intravenous TL32711 was well tolerated with no dose-limiting toxicities (maximum tolerated dose had not been reached) and demonstrated evidence of anti-tumour activi- ty20. Pharmacokinetics were dose proportional with moderate to low inter-patient variability in Cmax and AUC and a long terminal half-life in plasma. Importantly, TL32711 showed high con- centrations and good retention in tumour tissues with suppression of the cIAP1 target for the entire one-week dose interval. TL32711 also induced activation of serum caspase-3 and -7. A Phase Ib/IIa five-arm study of TL32711 in combination with five different chemotherapies is currently under way. Additional Phase I and II clinical stud- ies are planned for both solid tumours and hema- tological malignancies.


Other Smac mimetics in clinical development include:


LCL161(Novartis) – LCL161 is a high affinity, monovalent Smac mimetic that has been tested as both single agent and in combination with other agents showing good anti-tumour activity in solid tumours including triple-negative breast cancer21. LCL-161 has completed a Phase I safety and effi- cacy study and is currently being evaluated in Phase I study in advanced solid tumours in combi- nation with paclitaxel22,23.


GDC-0917 (Genentech) – GDC-0197 is a monova- lent Smac mimetic that is currently in Phase I study evaluating safety, tolerability and pharmacokinet- ics in patients with refractory solid tumours or lymphoma24.


HGS1029 (Human Genome Sciences) – A bivalent Smac mimetic, in preclinical studies HGS1029 showed good anti-tumour activity against a num- ber of tumour types alone and in combination with other agents. HGS1029 is currently in Phase I study evaluating safety and tolerability as monotherapy in patients with advanced solid tumours25. HGSI also plans to study HGS1029 in combination with human monoclonal TRAIL receptor antibodies.


Drug Discovery World Fall 2011


AT-406 (Ascenta) – AT-406 is a monovalent Smac mimetic that has shown good anti-tumour activity against xenographs of a number of tumour types. AT-406 is currently being evaluated in Phase I study as a single agent in patients with advanced solid tumours and lymphomas and in combination with daunorubicin and cytarabine in patients with poor-risk acute myelogenous leukaemia (AML)26,27.


Conclusion


Smac mimetics are a new class of cancer therapeutics with great potential to overcome the limitations of current anticancer therapies. Smac mimetics are gen- erally well tolerated and have demonstrated rapid suppression of their target (the IAPs), activation of apoptosis and anti-tumour activity. Additionally, Smac mimetics may help to overcome the resistance associated with conventional cancer therapies medi- ated by the NF-B and IAP pathways.


DDW


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19 Martinez-Ruiz, G, Maldonado, V, Ceballos- Cancino, G, Grajeda, JP, Melendez-Zajgla, J. Role of Smac/DIABLO in cancer progression. J Exp Clin Cancer Res. 2008 Sep 26;27:48. 20 Amaravadi, RK, Schilder, RJ, Dy, GK, Ma, WW, Fetterly, GJ, Weng, DE, Graham, MA, Burns, JM, Chunduru, SK, Condon, SM, McKinlay, MA, Adjei, AA. Phase 1 study of the Smac mimetic TL32711 in adult subjects with advanced solid tumors & lymphoma to evaluate safety, pharmacokinetics,


Dr Mark A. McKinlay is Co-Founder, Senior Vice- President, Research & Development and Chief Scientific Officer of TetraLogic Pharmaceuticals. Prior to TetraLogic, Dr McKinlay was a co- founder and Vice-President of R&D ViroPharma Corporation. Dr McKinlay was also a Senior Director of Virology and Oncopharmacology at Sterling Winthrop Pharmaceuticals Research Division. He was a post-doctoral fellow at the Johns Hopkins School of Public Health and holds a PhD and MS in biology from Rennselaer Polytechnic Institute.


pharmacodynamics and anti- tumor activity. Poster abstract #2532. 102nd AACR annual meeting. 2011, Orlando, FL. 21 The Pipeline of Novartis Oncology, Novartis website, Novartis, 2011. 22 Safety and Efficacy of LCL161 in Patients With Solid Tumors. Clinicaltrials.gov, 2011. 23 A Study of LCL161 in Combination With Weekly Paclitaxel in Adult Patients With Advanced Solid Tumors. Clinicaltrials.gov, 2011. 24 A Study Evaluating the Safety, Tolerability and Pharmacokinetics of GDC- 0917 Administered to Patients With Refractory Solid Tumors or Lymphoma . Clinicaltrials.gov, 2011. 25 A Study of HGS1029 (AEG40826-2HCl) in Subjects With Advanced Solid Tumors. Clinicaltrials.gov, 2011. 26 Dose Escalation Study of Safety and Tolerability of AT- 406 in Patients With Advanced Solid Tumors and Lymphomas. Clinicaltrials.gov, 2011. 27 Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamic Properties of Oral AT-406 in Combination With


Daunorubicin and Cytarabine in Patients With Poor-risk Acute Myelogenous Leukemia (AML). Clinicaltrials.gov, 2011.


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