BARCELONA – June 9, 2020 - The biopharmaceutical company Ability Pharmaceuticals SL announced today that the full description of the mechanism of action of ABTL0812 has been published in the prestigious Autophagy journal (impact +11). The findings confirm a new strategy to tackle cancer based on the Reticular Stress (ER stress) that ABTL0812 induces in tumors, causing cell destruction by cytotoxic autophagy.

ABTL0812 is currently being tested in phase 2 open-label clinical trial in Spain and France in patients with endometrial cancer or squamous cell lung cancer, as a first-line treatment in combination with chemotherapy and as a maintenance treatment after the chemotherapy cycles. In fact, in the publication, the authors also describe for the first time the detection of mRNAs of two ER stress - related proteins (CHOP and TRIB3) in blood samples from patients undergoing this clinical trial, supporting their use as pharmacodynamic biomarkers. 

This work will be also presented by AbilityPharma at the American Association for Cancer Research (AACR) 2020 Congress. “The description of this mechanism of action is a very important step for AbilityPharma, and shows the excellent collaboration engaged by our company and the INc-UAB. Besides, it supports a broader use of ABTL0812 in other cancer paradigms, apart from endometrial and squamous lung carcinoma” explains Carles Domènech, AbilityPharma’s executive chairman. 

The research team was coordinated by Jose Miguel Lizcano from the INc-UAB and the UAB Biochemistry and Molecular Biology Department. For the past years, this team has investigated how ABTL0812 exerts its antitumor action. “Cancer cell death comes from a severe stress of the endoplasmic reticulum, a cellular organelle in charge of protein synthesis, resulting in the accumulation of defective proteins. As a consequence, cells activate a compensatory response, called Unfolded Protein Response (UPR). This response, when sustained in time, can induce autophagy that results in cancer cell death”, says Jose Miguel Lizcano. 

The study also explains why ABTL0812 does not affect non-cancer cells: “The main advantage of this molecule lies in its specificity for tumor cells. To survive the hostile environment, cancer cells overtake it by having elevated levels of ER stress and UPR activity. Our drug provokes cancer cells to overpass the stress level in which this response has protective effects, causing their death, while healthy cells still have a wider margin”, says Pau Muñoz, researcher at the INc-UAB and first author of the article.

The study was performed in strong collaboration with the Bioactive Molecules Research Unit at the Institute for Advanced Chemistry of Catalonia (IQAC-CSIC). Several researchers from the following institutions also collaborated in this work: the Complutense University of Madrid (UCM), the Catalan Institute of Oncology (ICO), the Vall d’Hebron Research Institute (VHIR), the Vall d’Hebron Institute of Oncology (VHIO) and the Bellvitge Biomedical Research Institute (IDIBELL). 

The research was funded by grants from the Spanish Ministry for the Economy and Competitiveness (MINECO) and the European Regional Development Fund (ERDF), the  agency for business competitiveness ACCIÓ (Government of Catalonia), the Centre for the Development of Industrial Technology (CDTI) and the Empresa Nacional de Innovación, Sociedad Anónima (ENISA).

Original article
Muñoz-Guardiola P, Casas J, Megías-Roda E, Solé S, Perez-Montoyo H, Yeste-Velasco M, Erazo T, Diéguez-Martínez  N, Espinosa-Gil  S, Muñoz-Pinedo C, Yoldi  G, Abad  JL, Segura MF, Moran  T, Romeo M, Bosch-Barrera J, Oaknin A, Alfón J, Domènech C, Fabriàs G, Velasco G, Lizcano JM. The Anti-Cancer Drug ABTL0812 Induces ER Stress-Mediated Cytotoxic Autophagy by Increasing Dihydroceramide Levels in Cancer Cells. Autophagy 2020 May 13. doi: 10.1080/15548627.2020.1761651. 

About ABTL0812 

ABTL0812 is a first-in-class fully differentiated oral targeted anticancer compound causing cell death by autophagy (self-digestion).

ABTL0812 is currently in phase 2a open-label clinical trials in Europe in patients with endometrial cancer or squamous cell lung cancer, as a first-line treatment in combination with chemotherapy and as a maintenance treatment after the chemotherapy cycles. The study is being conducted in leading cancer hospitals in Spain and France.
This same phase 2 study was also approved by the US FDA in December 2017. In addition, the FDA approved the protocol for a phase 2 study in pancreatic cancer in January 2018.

ABTL0812 has also received Orphan Drug Designations (ODD) for pancreatic cancer, biliary cancer and the pediatric cancer neuroblastoma by the FDA in the USA and by the EMA in Europe.

A phase 1/1b clinical trial was previously conducted (29 patients with advanced solid tumors), in which ABTL0812 showed great safety and tolerability and no dose-limiting toxicities were identified. There were signs of efficacy, and notably two patients had long-term disease stabilizations, for more than one year (14 and 18 months). In addition, ABTL0812 showed activity on biomarkers with dose-response.

The mechanism of action of ABTL0812 is unique and novel. ABTL0812 is a targeted therapy drug that kills cancer cells through the induction of robust cytotoxic autophagy. ABTL0812 binds and activates the transcriptional activity of the nuclear receptors PPARα and PPARγ, leading to the induction of endoplasmic reticular stress (ER-Stress), and to the blockade of Akt activation, the central kinase of the PI3K/Akt/mTOR pathway. This dual action of ER-Stress activation and Akt/mTOR axis blockade converge to strongly induce autophagy, which results in cancer cell death. The mechanism of action was published partially in Clinical Cancer Research in May 2016, and fully described in Autophagy journal in May 2020.

In preclinical cancer models, ABTL0812 is effective as a single agent with an excellent safety profile in a broad spectrum of cancer types, including lung, endometrial and pancreatic cancer, neuroblastoma and glioma. Likewise, it also enhances chemotherapy (taxanes, platinum compounds and gemcitabine) with a synergistic effect without increasing its toxicity.
 
About Ability Pharmaceuticals

Ability Pharmaceuticals (www.abilitypharma.com) is a biopharmaceutical company with a product, ABTL0812 in phase 2 clinical trials, focused on improving the future of oncology by developing innovative therapies that address unmet medical needs. In April 2016, AbilityPharma signed a territorial license agreement for ABTL0812 with SciClone Pharmaceuticals (Hong Kong) Development Co. Limited to develop and market the product in China.
 
Ability Pharmaceuticals is headquartered in Parc Tecnològic del Vallès and Parc de Recerca UAB (Cerdanyola del Vallès, Barcelona, Catalonia, Spain). Current shareholders include the biotech venture firms Inveready, Fitalent and SODENA, its founders and private investors, and has the financial support from ACCIO (Government of Catalonia), and CDTI, ENISA and MINECO (Government of Spain).