sonolisib (PX 866) / Pfizer - LARVOL DELTA

Combined inhibition of class 1-PI3K-alpha and delta isoforms causes senolysis by inducing p21WAF1/CIP1 proteasomal degradation in senescent cells. (PubMed, Cell Death Dis) - "The Pan-PI3K-inhibitor wortmannin and its clinical derivative, PX-866, were identified to act as senolytics...Other Pan-PI3K inhibitors, such as the FDA-approved drug BAY80-6946 (Copanlisib, Aliqopa®), also efficiently and specifically eliminated senescent cells. Interestingly, only the simultaneous inhibition of both PI3K class I alpha (with BYL-719 (Alpelisib, Piqray®)) and delta (with CAL-101 (Idelalisib, Zydelig®)) isoforms was sufficient to induce senolysis, whereas single application of these inhibitors had no effect...This led to a timely induction of apoptosis in senescent tumor cells. Taken together, the senolytic properties of PI3K-inhibitors reveal a novel dimension of these promising compounds, which holds particular potential when employed alongside DNA damaging agents in combination tumor therapies."

Journal • Breast Cancer • Colon Cancer • Colorectal Cancer • Fibrosis • Immunology • Lung Cancer • Oncology • Solid Tumor • CDKN1A • PIK3CA

Suppression of Autophagy Can Augment PIK3 Inhibitor Induced Apoptosis in T Lymphoblastic Leukemia Cell Lines. (PubMed, Ann Clin Lab Sci) - "The results demonstrated that 3-MA could suppress PI3K inhibitor-mediated activation of autophagy to promote the apoptosis of tumor cells. This discovery provided experimental support for constituting a promising strategy for T-cell acute lymphoblastic leukemia (T-ALL) therapy."

Journal • Preclinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • T Acute Lymphoblastic Leukemia • ATG12 • ATG5 • BECN1

Comparison of Second-Line Treatments for Patients with Platinum-Resistant Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: A Systematic Review and Bayesian Network Meta-Analysis. (PubMed, Cancers (Basel)) - "These studies compared 20 different treatments, including the standard of care (SOC: docetaxel, methotrexate, or cetuximab), PD-1 inhibitors (nivolumab or pembrolizumab), durvalumab, tremelimumab, durvalumab + tremelimumab, palbociclib + SOC, tivantinib + SOC, sorafenib + SOC, EMD1201081 + SOC, vandetanib + SOC, PX-866 + SOC, 5-fluorouracil + SOC, cixutumumab + SOC, gefitinib + SOC, cabazitaxel, nolatrexed, duligotuzumab, zalutumumab, gefitinib, and afatinib. Afatinib presented a better PFS and ORR than the SOC. Compared with afatinib, the PD-1 inhibitor had a better OS but a worse PFS."

Journal • Retrospective data • Review • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Abrogation of Cellular Senescence Induced by Temozolomide in Glioblastoma Cells: Search for Senolytics. (PubMed, Cells) - "Here, we tested Bcl-2 targeting drugs including ABT-737, ABT-263 (navitoclax), several natural substances such as artesunate, fisetin and curcumin as well as lomustine (CCNU) and ionizing radiation (IR) for their senolytic capacity in GBM cells...To identify senolytics, we treated the senescent population with the compounds of interest and found that ABT-737, navitoclax, chloroquine, ATMi, ATRi, BV-6, PX-866 and the natural compounds fisetin and artesunate exhibit senolytic activity, inducing death in senescent cells more efficiently than in proliferating cells...We conclude that these factors neither play a critical role in maintaining TMZ-induced CSEN nor can their inhibitors be considered as senolytics. Since IR and CCNU did not exhibit senolytic activity, radio- and chemotherapy with alkylating drugs is not designed to eliminate TMZ-induced senescent cancer cells."

Journal • Brain Cancer • Glioblastoma • Glioma • Immunology • Inflammation • Oncology • Solid Tumor • BCL2 • CDKN1A • CHEK1 • CHEK2 • RAD51

Longevity Effects of DMSO-Solubilized Rapamycin and Other Compounds in y w Male Drosophila melanogaster. (PubMed, FASEB J) - "The following supplements were delivered continuously throughout adult life, beginning 2 d posteclosion: rapamycin (0.1, 0.5, 1, 10, 100, 200 and 400 µM), spermidine (10 µM - 10 mM), LY294002 (100 nM - 10 µM), wortmannin, KU0063794 and PX-866-17OH (all 1 nM - 10 µM), AZD8055, PI-103 HCl and Torin 2 (all 100 pM - 10 µM), WYE-28 and WYE-132 (both 10 pM - 1 µM) and DMSO solvent (0.02-0.2%). Experiments are in progress to test the effects of high dose rapamycin in male and female flies of several strains, comparing ethanol and DMSO solvents, different food recipes, lighting and storage conditions. A current conclusion is that rapamycin is not universally beneficial in Drosophila and that inhibitors of various kinases at the doses studied have limited or no effect on longevity."

Journal

β-Arrestin-2 attenuates hepatic ischemia-reperfusion injury by activating PI3K/Akt signaling. (PubMed, Aging (Albany NY)) - "In addition, ARRB2 deficiency inhibited PI3K/Akt pathway activation, while the administration of the PI3K/Akt inhibitor PX866 resulted in severe IR injury in mice. Furthermore, the liver-protecting effect of ARRB2 was shown to depend on PI3K/Akt pathway activation. In summary, our results suggest that β-Arrestin-2 protects against hepatic IRI by activating PI3K/Akt signaling, which may provide a novel therapeutic strategy for treating liver ischemia-reperfusion injury."

Journal • Hematological Disorders • Hepatology • Liver Failure • Reperfusion Injury • Transplantation

The extract of Gnaphalium affine D. Don protects against HO-induced apoptosis by targeting PI3K/AKT/GSK-3β signaling pathway in cardiomyocytes. (PubMed, J Ethnopharmacol) - "Our data suggested that GAE showed strong anti-oxidant effect to ameliorate oxidative stress and attenuate apoptosis induced by HO in H9c2 cells by targeting PI3K/AKT/GSK-3β signaling pathway."

IO Biomarker • Journal • Asthma • Cardiovascular • Immunology • Lymphoma • Oncology • Respiratory Diseases • Rheumatoid Arthritis • Rheumatology

A Randomized, Phase II Trial of Cetuximab With or Without PX-866, an Irreversible Oral Phosphatidylinositol 3-Kinase Inhibitor, in Patients With Metastatic Colorectal Carcinoma. (PubMed) - "The addition of PX-866 to cetuximab did not improve PFS, objective response rate, or OS in patients with metastatic CRC. The combination arm had greater toxicity and may have been harmful in this study."

Biomarker • Journal • Biosimilar • Colorectal Cancer

Clinical achievements reached by interfering with the IGF1R-PI3K-PTEN-AKT-mTOR axis (AACR-NCI- EORTC 2011) - The development of inhibitors of the PI3K-AKT-mTOR & IGF1R axis

Review • Breast Cancer • Hematological Malignancies • Hepatocellular Cancer • Melanoma • Multiple Myeloma • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Renal Cell Carcinoma

Inhibition of phosphatidylinositol 3-kinase by PX-866 suppresses temozolomide-induced autophagy and promotes apoptosis in glioblastoma cells. (PubMed, Mol Med) - "The understanding of how TMZ induces survival pathways, such as autophagy, may offer new therapeutic vulnerabilities and opportunities to use sequential inhibition of alternate pro-survival pathways that regulate autophagy. As such, identification of additional ways to inhibit TMZ-induced autophagy could enhance the efficacy of TMZ."

Journal • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor

PX-866 and docetaxel in patients with advanced solid tumors (ASCO 2012) - Presentation time: Saturday June 2, 1:15 PM to 5:15 PM; P1, N=43; PX-866-002; Best response in 32 evaluable pts was 2 PR (6%), 22 SD (69%) & 8 PD (25%); The PRs were in NSCLC & ovarian cancer (both PIK3CA/KRAS WT). 8 other pts had ≥15% tumor shrinkage, including NSCLC (n=2); PX-866 with docetaxel was associated with a disease control rate of 75%, with 50% of evaluable pts demonstrating SD or better for ≥ 6 cycles

P1 data • Non Small Cell Lung Cancer • Pancreatic Cancer

Using human Pompe disease-induced pluripotent stem cell-derived neural cells to identify compounds with therapeutic potential. (PubMed, Hum Mol Genet) - "Using the Pom-iPSC-derived neurons as an in vitro drug-testing model, we then identified three compounds, ebselen, wortmannin and PX-866, with therapeutic potential to alleviate Pompe disease-associated pathological phenotypes in the neurons derived from Pom-iPSCs...Moreover, they were able to enhance the GAA activity in several important internal organs of GAA-deficient mice when co-injected with recombinant human GAA, and we found that intraperitoneal injection of ebselen was able to promote the GAA activity of the GAA-heterozygous mouse brain. Our results prove the usefulness of Pom-iPSC-derived neuronal populations for identifying new compounds with therapeutic potential."

Journal • Metabolic Disorders

A multicenter phase 1 study of PX-866 and cetuximab in patients with metastatic colorectal carcinoma or recurrent/metastatic squamous cell carcinoma of the head and neck (Invest New Drugs) - P1, N=11; NCT01252628; Sponsor: Oncothyreon; "No dose limiting toxicities were observed. The RP2D was 8 mg, the same as the single-agent PX-866 MTD. Best responses in 9 evaluable patients were: 4 partial responses (44.4 %), 4 stable disease (44.4 %), and 1 disease progression (11.1 %). The median progression free survival was 106 days (range: 1-271)."

P1 data • Biosimilar • Colorectal Cancer • Head and Neck Cancer • Oncology

Results from the phase 1 portion of a phase 1/2 study of the irreversible PI-3K inhibitor PX-866 and cetuximab (AACR-NCI- EORTC 2011) - P1, N=11; PX-866-003; Four pts had PR, three had SD & one had PD, for a DCR of 88%; In five response-evaluable pts who had previously received an EGFR inhibitor, best response was one pt had PR, three SD & one PD; The median number of cycles received was six, with PD as the most common reason for discontinuation; Treatment & PX-866 and cetuximab was well tolerated, with no increase in toxicity of either drug attributable to the combination; The P2 dose of PX-866 in combination with full dose cetuximab is the same as the single agent MTD; The ORR of 50% is encouraging compared to the historical ORR of 11% for single agent cetuximab

P1 data • Colorectal Cancer • Oncology

Multi-institution phase 1 study of BRAF (vemurafenib) and PI3K inhibition (PX-866) in advanced BRAF mutant solid tumors and melanoma (SMR 2013) - P1, N=17; “Four pts were treated in cohort 1 (720 mg vem, 6 mg PX-866) with no dose limiting toxicities (DLT). Eight pts were treated in cohort 2 (960 mg vem, 6 mg PX-866) with 1 DLT of grade 3 rash. Five pts were treated in cohort 3 (960 mg vem, 8 mg PX-866). There was 1 episode of grade 3 pancreatitis, and asymptomatic Grade 3 lipase elevation in a separate patient. Non DLT Grade 3 AST/ALT elevations were also observed. Therefore, cohort 3 was considered not tolerable; cohort 2 expansion is ongoing….. Updated results will be presented, along with PK and PD data from paired tumor biopsy samples and PTEN status for the subjects enrolled.”

P1 data • Melanoma • Oncology

Conference Call (Oncothyreon) - Anticipated primary endpoint data from P2 (PX-866 and cetuximab combo) trial for metastatic colorectal carcinoma in late Q1 2013/early Q2 2013; Anticipated data from single-arm P2 trial for glioblastoma in mid-2013; Anticipated completion of enrollment in P1/2 (PX-866 and docetaxel combo) trial for head and neck cancer in mid-2013; Anticipated completion of enrollment in P1/2 (PX-866 and cetuximab combo) trial for head and neck cancer in mid-2013; Anticipated data from P1/2 (PX-866 and docetaxel combo) trial for head and neck cancer at the end of 2013; Anticipated data from P1/2 (PX-866 and cetuximab combo) trial for head and neck cancer at the end of 2013; Anticipated data from P2 (PX-866 and vemurafenib) trial for melanoma in 2014

Anticipated enrollment status • Anticipated P1/2 data • Anticipated P2 data • Oncology

Oncothyreon: Rodman & Renshaw Healthcare Conference (Oncothyreon) - Anticipated top-line data from P2 trial for squamous cell carcinoma of the head and neck in Q4 2013

Anticipated P2 data • Oncology

BIOCEO Investor Conference (Oncothyreon) - PX-866 / Oncothyreon; Initiation of single agent P2 trials expected in Q2 ’11 & P2 data expected in H2 ’11 & H1 ’12; Anticipated  trials for chemotherapy naive prostrate & glioblastoma in Q2 ’11; Anticipated Health Canada approval in 2011

Anticipated P2 data • Anticipated P2 trial initiation • Oncology

Multifunctional zero- and one-dimensional nanomaterials for imaging, sensing and multidrug delivery (ACS-Fall 2018) - "...Single-walled carbon nanotubes (SWCNTs) are used as one-dimensional carriers for anti-inflammatory siRNA and anti-fibrotic PX-866 drug delivery to liver intended to mitigate the effects of nonalcoholic steatohepatitis and prevent its potential translation into hepatocellular carcinoma...GQDs are specifically designed as biocompatible materials emitting fluorescence both in the visible (with up to 60% quantum yield) and near-infrared that can be potentially used for in-vitro and in-vivo detection respectively. pH-sensitivity of the emission allows for optical detection of cancer environments combining the essential optical diagnostic functions in one simplistic glucose-derived platform."

Biosimilar • Gastrointestinal Cancer • Hepatocellular Cancer • Immunology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Oncology • Ophthalmology • Solid Tumor

Oncothyreon: Annual Report 2013 (Oncothyreon) - Anticipated expiry of patents covering composition of matter and method of use in between 2022-2033

Anticipated patent expiry • Oncology

Oncothyreon awaits key lung cancer vaccine data (Reuters) - Oncothyreon expects results late this year from four P2 cancer trials of its experimental drug PX-866

Anticipated P2 data • Non Small Cell Lung Cancer • Oncology

A randomized, phase 2 trial of docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer (Oral Oncology) - P2, N=80; Sponsor: Oncothyreon Inc; NCT01204099; "There was a non-significant improvement in response rate in the combination arm (14% vs. 5%; P = 0.13). Median PFS was 92 days in Arm A and 82 days in Arm B (P = 0.42). There was no difference in OS between the two arms (263 vs. 195 days; P = 0.62)...The addition of PX-866 to docetaxel did not improve PFS, RR, or OS in patients with advanced, refractory HNSCC without molecular pre-selection."

P2 data • Head and Neck Cancer • Oncology

Wedbush Securities Life Sciences Management Access Conference (Oncothyreon) - PX-866 / Oncothyreon; Anticipated P2 initial data in H2 '11 & final data in H1 '12

Anticipated P2 data • None • Oncology

A multicenter phase 1 trial of PX-866, an oral irreversible phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors (Clin Cancer Res) - P1, N=84; Study ID PX-866-001; MTD was 12mg & 8mg for Arm 1 (days 1-5 and 8-12 of a 28-day cycle) & 2 (days 1-28 of a 28-day cycle), respectively; DLTs were of grade 3 (g3) diarrhea (N=3) & g3 elevated AST (N=1); PK profile was dose proportional & did not show any evidence of drug accumulation

P1 data • Oncology

A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours (Br J Cancer) - P1, N=43; PMID: 23942080; NCT01204099; Sponsor: Oncothyreon; "Co-administration of PX-866 and docetaxel did not affect either drug's PKs. Best responses in 35 evaluable patients were: 2 partial responses (6%), 22 stable disease (63%), and 11 disease progression (31%). Eleven patients remained on study for >180 days, including 8 who maintained disease control on single-agent PX-866. Overall median progression-free survival (PFS) was 73.5 days (range: 1-569)."

P1 data • Oncology