Zeltia : Aplidin®, Yondelis®, PM01183 and PM060184 highlighted at the 2014 Annual Meeting of the American Association for Cancer Research (AACR)

Aplidin®, Yondelis®, PM01183 and PM060184 highlighted at the 2014 Annual Meeting of the American Association for Cancer Research (AACR)

Aplidin® confirmed as a first-in-class drug, with the mechanism of action highlighted for the first time, showing it targets the eEF1a protein in tumour cells

A new study supports the clinical use of PM01183 in Ewing's sarcoma as directed treatment, either alone or in combination with irinotecan

PM060184 evidences notable antitumour activity in vivo in a range of xenografted tumour types

Additional Yondelis® data to be presented showing a synergistic combination with Olaparib in breast cancer tumour cell lines

San Diego, 7 April 2014.- PharmaMar, a biotechnology subsidiary of Grupo Zeltia

- MC:ZEL) will have an extensive presence at the 105th Annual Meeting of the
American Association for Cancer Research (AACR), which takes place April 5-9,
2014 in San Diego, CA. The oncology conference will highlight multiple studies for several drugs developed internally by PharmaMar.
Abstracts:
Role of the eukaryotic elongation factor eEF1A in the mechanism of action of Aplidin. Alejandro Losada, Juan F. Martínez-Leal, Federico Gago, Carmen Cuevas, Luis F. García-Fernández and Carlos M. Galmarini
PM01183 shows an improved therapeutic index relative to trabectedin and suppresses EWS-FLI1 activity at clinically achievable concentrations. Matt Harlow, Nichole Maloney, Maria Jose Guillen Navarro, Maurizio D'Incalci, Carlos Galmarini, Pablo Manuel Aviles Marin, Patrick J. Grohar
Synergistic combination of Trabectedin and Olaparib in breast cancer tumor cell lines. Sonia Avila, Marta Martínez, Victoria Moneo, Juan F. Martínez- Leal, Carmen Cuevas, Luis F. García-Fernández and Carlos M. Galmarini

1

Studies with Aplidin®
The results from a preclinical study with Aplidin®, a cyclodepsipeptide derived from the marine tunicate Aplidium albicans, shed new light on its mechanism of action, highlighting the target and confirming its status as a first in class drug.
A study by Alejandro Losada et al. highlights the important role of the proto- oncogene eukaryotic elongation factor 1A (eEF1A) in the drug's biological activity in tumour cells. The study showed that tumour cells resistant to Aplidin® express low levels of eEF1A when compared with tumour cells that are sensitive to the drug. Reintroduction of the protein into resistant cells renders them sensitive to treatment. A molecular model that demonstrates the interaction between Aplidin® and eEF1A will be presented. Overall, the results indicate that eEF1A is Aplidin®'s target in the cell.
Results with PM01183
PM01183, a 2nd generation drug to Yondelis®, is a novel synthetic marine-derived compound that covalently binds to the minor groove of the DNA and will be the subject of several studies to be presented.
Matt Harlow et al. reported that "PM01183 shows an improved therapeutic index relative to trabectedin and suppresses EWS/FLI1 activity at clinically achievable concentrations". EWS/FLI1 is an oncogenic protein that plays a crucial role in Ewing's sarcoma (EWS), an orphan disease with only a few treatment options.
Ewing's sarcoma is a paediatric tumour characterized by a genetic abnormality - translocation - mechanical breakage and subsequent reconnection of two different chromosomes. The translocation takes place between chromosomes 11 and 22, referred to as t(11;22) or EWS/FLI1. It is currently known that cells of Ewing's sarcoma depend on the transcriptional program of EWS/FL11 for survival, and the therapeutic objective is to suppress it in tumor cells. PM01183 has been found to have this effect, and is synergistic with irinotecan in suppressing tumour growth in experimental models of this disease. In addition, the study confirms that PM01183 has an excellent pharmacological profile, suggesting that its effects are bio- achievable in humans. According to the authors of the trial, this suggests clinical development of PM01183 as a EWS/FLI1 targeted therapy both alone and in
combination with irinotecan is warranted.

2

A retrospective study by Manuel Hidalgo et al. ("Potential use of pharmacogenomic modelling for patient stratification in the Phase II study of PM01183 in pancreatic cancer") highlights the usefulness of genomic tests to improve stratification of pancreatic cancer patients who are candidates for treatment with PM01183. Specifically, these tests were used to evaluate chemosensitivity profiles in order to predict which patients are eligible for inclusion in a Phase II trial with PM01183 and even to predict the response rate. In this retrospective trial with 32 patients, the authors concluded that three had a chemosensitivity profile that was positive to PM01183, two of whom might display a clinical response to the drug (one of them eventually did). This confirms the assumption that these techniques to evaluate chemosensitivity can be useful in the future to better select patients for clinical trials with this drug.
Results with PM060184
PM060184 belongs to a new family of tubulin-binding agents originally isolated from the marine sponge Lithoplocamia lithistoides and currently produced by total synthesis. PM060184 demonstrated a very strong antitumour activity in preclinical models as well as an acceptable toxicology profile in preclinical evaluation. It is currently assessed in phase I clinical studies.
At the AACR Meeting, Manuel Hidalgo et al. will present a study entitled "In vivo antitumour activity of PM060184 in patient-derived xenografted tumour (Avatar)". Mice bearing patient-derived tumors (NSCLC, stomach, pancreas and colon), were treated with PM060184. The treatment demonstrated a very relevant in vivo antitumor activity including complete tumor remissions in some representative tumors pf NSCLC and gastric.
Tiziana Pernice et al. will present a study entitled "Plasma, tissue and tumour pharmacokinetics of PM060184 in NSCLC xenograft mouse model". In this study, mice bearing H460 tumors (NSCLC) were treated with PM060184 and then, plasma and tissue pharmacokinetics determined. Results demonstrated a better distribution of PM060184 in tumors than in other tissues, such as brain, spleen, lung, muscle or
heart.

3

Other studies of interest
Sonia Ávila et al. will present a study entitled "Synergistic combination of trabectedin and olaparib in breast cancer tumour cell lines", which revealed a strong apoptotic effect in cancer cells when administered in combination (olaparib at 5µM and varying concentrations of trabectedin between 0.05 and 2.5 nM). The synergistic combination appears to be the result of a high accumulation of DNA double-strand breaks, causing cell death.
A new resource for the early identification of marine-based compounds with potential for treating multiple myeloma will also be featured. The research is being backed by the European Union's Seventh Framework Programme.
Jayanthi Ganesan et al. will present an "Analysis of the impact of compounds derived from marine organisms on 3D co-spheroids generated from multiple myeloma cells and stroma cell types", based on the idea that stromal components (e.g. endothelial cells and mesenchymal stromal cells) play a crucial role in resistance to therapy in multiple myeloma.

About PharmaMar

PharmaMar is a biopharmaceutical subsidiary of Grupo Zeltia; it is a world leader in discovering, developing and marketing marine-based drugs to treat cancer. Yondelis® is Spain's first antitumour drug. Yondelis® is currently approved for soft tissue sarcoma (STS) in 42 countries outside the EEA, and for platinum-sensitive relapsed ovarian cancer (ROC) in 31 of those countries plus Brazil. Yondelis® is approved for STS and platinum-sensitive ROC in all 30 countries of the EEA. Yondelis® is also undergoing Phase II trials on breast and paediatric cancers. PharmaMar has four other compounds in clinical development: Aplidin®, Zalypsis®, PM01183 and PM060184. PharmaMar also has a rich pipeline of pre-clinical candidates and a major R&D programme.

About Zeltia

Zeltia S.A. is a world-leading biopharmaceutical company specialised in the development of marine- based drugs for use in oncology. Grupo Zeltia consists mainly of the following companies: PharmaMar, the world-leading biotechnology company in advancing cancer care through the discovery and development of innovative marine-derived medicines; GENOMICA, Spain's leading molecular diagnostics company; Sylentis, dedicated to researching therapeutic applications of gene silencing (RNAi); and a chemical division comprising Zelnova and Xylazel, two profitable companies that are leaders in their

respective market segments.

4

Important note

PharmaMar, which is headquartered in Madrid (Spain), is a subsidiary of Grupo Zeltia (Spanish stock exchange: ZEL), which has been listed on the Spanish Stock Exchange since 1963 and on Spain's Electronic Market since 1998. This document is a press release, not a prospectus. This document does not constitute or form part of an offering or invitation to sell or a solicitation to purchase, offer or subscribe shares of the company. Moreover, no reliance should be placed upon this document for any investment decision or contract and it does not constitute a recommendation of any type with regard to the shares of the company.

For more information +34 91 444 4500

This note is also available on the PharmaMar web site: www.pharmamar.comand at Zeltia's website:

www.zeltia.com

5

distributed by