zeltia ( Seite 2)

Aplidin

Background

Initial in vitro studies showed that cell lines derived from human leukaemia and lymphoma were particularly sensitive to Aplidin(R), including in vivo lymphoma models. Further experiments in normal blood and malignant blood cells derived from children with leukaemia also showed that Aplidin(R) was selectively toxic to malignant leukemic cells, while sparing normal blood cells. This is consistent with the observation during Phase I clinical studies in solid tumours in adults that Aplidin(R) is rarely myelotoxic (rarely toxic to normal white blood cells).

Aplidin(R) appears to be equally cytotoxic against cell lines from initial and relapsed leukaemia and does not show cross-resistance with commonly used antileukaemic agents. This indicates the possibility of combining Aplidin(R) with other agents to treat relapsed or resistant leukaemia. Indeed, the combination of Aplidin(R) with the standard agents used to treat malignant haematological diseases increases their cytotoxic effect against these cell lines in vitro and in vivo.

Aplidin(R) also demonstrated activity against a panel of 35 human multiple myeloma (MM) cell lines. Activity was not only observed in sensitive MM cell lines but also in primary MM tumour cells freshly isolated from patients resistant to conventional and also to novel anti-MM agents.

Phase II Trials

Details of the four trials are as follows:

Multiple Myeloma

The MM trial is a European-United States multicentre study to evaluate the efficacy of Aplidin(R) in patients with relapsed or refractory MM. The primary end-point of the trial is Objective Response Rate (sum of Complete, Partial and Minor responses) following treatment with Aplidin(R).

Non-Hodgkin Lymphoma (Aggressive and Indolent)

The NHL trials are European multicentre studies to evaluate the efficacy of Aplidin(R) in patients with relapsed or refractory Indolent and Aggressive Non-Hodgkin``s Lymphoid neoplasms. The primary end-point of the trials is Objective Response Rate following treatment with Aplidin(R).

Acute Lymphoblastic Leukaemia

The ALL trial is a German multicentre study to evaluate the efficacy of Aplidin(R) in adult patients with relapsed or refractory ALL. The primary end-point of the trial is Objective Response Rate (sum of Complete, Partial and Minor responses) following treatment with Aplidin(R).

Notes to Editors

About Aplidin(R)

Aplidin(R) is a cyclic peptide, originally isolated from the marine tunicate Aplidium albicans, currently obtained by total synthesis. It induces apoptosis rapidly and persistently, inhibits VEGF secretion and blocks cell-cycle.

It is currently in therapeutic exploratory clinical evaluation (Phase II) in solid and haematological malignancies, including paediatrics. The clinical program involves hospitals in Europe, Canada and the US. Approximately 400 patients have been treated up to date. In pre-clinical development, human leukaemia, myeloma and lymphoma tumour cell lines were particularly sensitive to Aplidin(R). There is no evidence of cross-resistance with commonly used therapeutic agents for haematological malignancies.

There is no clinical evidence of relevant bone marrow toxicity. Its side effects are reversible and manageable (including muscular and liver biochemical alterations). Hair loss and oral ulcers are not a common side effect.

Aplidin(R) was granted Orphan Drug Designations for the treatment of Acute Lymphoblastic Leukaemia in the European Union in 2003 and in the US in 2004. The US FDA and the E.C. also granted ODD for the treatment of Multiple Myeloma in 2004.

(x) Aplidin(R) is a PharmaMar registered trademark.

Multiple Myeloma (MM)

MM is the second most common haematological malignancy after Non-Hodgkin Lymphoma, accounting for about 10% of haematological malignancies and for about 1% of all cancers, according to the Multiple Myeloma Research Foundation. It is a malignant proliferation of the plasma cells within the bone marrow. Plasma cells are mature B-lymphocytes, an important component of the immune system responsible for the production of immunoglobulins. These cells can destroy normal bone marrow and bone tissue leading to a haematopoietic imbalance caused by an overcrowding of the bone marrow.

MM remains a fatal disease: median overall survival does not exceed 4 years with conventional chemotherapy approaches. For advanced stages, median survival time is about 2 years. In 2004, an estimated 15,270 new cases of MM and 11,000 deaths attributable to MM are expected in the US. At present, there are approximately 50,000 people in the United States living with MM. In the EU, it is estimated that about 27,500 new patients will develop the disease each year and 19,000 people die of it. The disease affects slightly more men than women and peak incidence is among the elderly with a median age of diagnosis of 71 years. Only 1% of cases are diagnosed in people younger than 40 years old.

Non-Hodgkin Lymphoma (NHL)

NHL is classified in two types: Aggressive NHL, characterised by rapid division of cancer cells; and Indolent NHL, which grows slowly and is more difficult to diagnose. NHL are tumours of the lymphatic tissue which are found in the body in lymph nodes, thymus gland, spleen, tonsils and bone marrow.

An estimated 54,370 patients will be diagnosed with NHL in the US in 2004 and more than 19,000 will die of the disease. In the EU about 64,000 new cases of NHL occur every year and an estimated 32,000 people die of it.

Despite the availability of initial chemotherapy regimens for patients with Aggressive NHL, the majority of patients will die within a five year period due to the disease. Approximately 40 to 50% of patients will die of their disease.

Acute Lymphoblastic Leukaemia (ALL)

ALL is a malignant disease of the bone marrow. It affects the lymphocyte-progenitor cells called lymphoblasts. Malignantly transformed lymphoblasts proliferate and accumulate in the bone marrow and prevent the production of healthy red cells, platelets and white cells.

Nearly 75% of all children with leukemia have the ALL type. About 3,830 cases of ALL are expected to be diagnosed in the US in 2004, about 2,400 of them in children and young people under 20.

This type of leukaemia is the leading cause of death by cancer under the age of 35 years. It is estimated that more than 40,000 people are living with ALL in US. Approximately 3,830 new cases will be diagnosed in 2004 and that about 1,500 deaths will occur due to the disease each year. In the EU there are 6,434 new cases and 4,327 deaths per year. Despite the availability of effective first line chemotherapy regimens for patients with ALL, up to 60% of patients die due to their disease. Expected median survival is 10 months following a conventional chemotherapy regimen. Allogeneic haematopoietic stem cell transplantation might cure a higher percentage of patients but is limited in availability due to a lack of suitable donors.

About PharmaMar

PharmaMar is a biopharmaceutical company, advancing cancer care through the discovery and development of innovative marine-derived medicines. PharmaMar``s clinical portfolio currently includes YondelisTM in Phase II clinical trials (co-developed with Johnson & Johnson Pharmaceutical Research & Development), designated Orphan Drug for STS by the European Commission (E.C.) in 2001 and by the FDA in 2004, and Orphan Drug for ovarian cancer by the E.C. in 2003; Aplidin(R), in Phase II, designated Orphan Drug for acute lymphoblastic leukaemia by the E.C. in 2003 and by the FDA in 2004, and for multiple myeloma by the FDA and the E.C. in 2004; Kahalalide F in Phase II and ES-285 in Phase I clinical trials.

PharmaMar, based in Madrid, Spain, is a subsidiary of the Zeltia Group (Spanish stock exchange: ZEL.MC; Bloomberg: ZEL SM; Reuters: ZEL.MC). PharmaMar can be found on the Web at www.pharmamar.com).

PharmaMar