Aplidin(R) Enters Phase II Trials in Haematological Cancers

Madrid, Spain, November 25 (ots/PRNewswire) -

- Aplidin(R) now in Phase II trials in both solid andhaematological cancers

PharmaMar, the biopharmaceutical company specialising in cancertherapy, today announces that its marine derived anti-tumour agent,Aplidin(R), has commenced Phase II clinical trials in haematologicalmalignancies, including studies in Multiple Myeloma (MM),Non-Hodgkin Lymphoma (NHL) (both aggressive and indolent), and adultAcute Lymphoblastic Leukaemia (ALL). Aplidin(R) is already in PhaseII trials in a number of solid tumour indications, the results ofwhich are expected in 2005.

The commencement of the Phase II haematology trials follows anumber of pre-clinical studies and Phase I trials in which Aplidin(R)demonstrated activity in haematological malignancies as well as afavourable safety profile. Aplidin(R) does not present limiting bonemarrow toxicity, which differentiates it from most anti-canceragents.

Isabel Lozano, CEO of PharmaMar, said: "The commencement of thesePhase II trials in haematological cancers, coupled with the existingPhase II trials in solid tumours, demonstrates the potentially broadscope of Aplidin's(R) therapeutic profile. We remain firmly onschedule with the development plans for this product that wereannounced at our strategic review earlier this year."


Initial in vitro studies showed that cell lines derived from humanleukaemia and lymphoma were particularly sensitive to Aplidin(R),including in vivo lymphoma models. Further experiments in normalblood and malignant blood cells derived from children with leukaemiaalso showed that Aplidin(R) was selectively toxic to malignantleukemic cells, while sparing normal blood cells. This is consistentwith the observation during Phase I clinical studies in solid tumoursin adults that Aplidin(R) is rarely myelotoxic (rarely toxic tonormal white blood cells).

Aplidin(R) appears to be equally cytotoxic against cell lines frominitial and relapsed leukaemia and does not show cross-resistancewith commonly used antileukaemic agents. This indicates thepossibility of combining Aplidin(R) with other agents to treatrelapsed or resistant leukaemia. Indeed, the combination ofAplidin(R) with the standard agents used to treat malignanthaematological diseases increases their cytotoxic effect againstthese cell lines in vitro and in vivo.

Aplidin(R) also demonstrated activity against a panel of 35 humanmultiple myeloma (MM) cell lines. Activity was not only observed insensitive MM cell lines but also in primary MM tumour cells freshlyisolated from patients resistant to conventional and also to novelanti-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 toevaluate the efficacy of Aplidin(R) in patients with relapsed orrefractory MM. The primary end-point of the trial is ObjectiveResponse 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 theefficacy of Aplidin(R) in patients with relapsed or refractoryIndolent and Aggressive Non-Hodgkin's Lymphoid neoplasms. Theprimary end-point of the trials is Objective Response Rate followingtreatment with Aplidin(R).

Acute Lymphoblastic Leukaemia

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

Notes to Editors

About Aplidin(R)

Aplidin(R) is a cyclic peptide, originally isolated from themarine tunicate Aplidium albicans, currently obtained by totalsynthesis. It induces apoptosis rapidly and persistently, inhibitsVEGF secretion and blocks cell-cycle.

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

There is no clinical evidence of relevant bone marrow toxicity.Its side effects are reversible and manageable (including muscularand liver biochemical alterations). Hair loss and oral ulcers are nota common side effect.

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

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

Multiple Myeloma (MM)

MM is the second most common haematological malignancy afterNon-Hodgkin Lymphoma, accounting for about 10% of haematologicalmalignancies and for about 1% of all cancers, according to theMultiple Myeloma Research Foundation. It is a malignant proliferationof the plasma cells within the bone marrow. Plasma cells are matureB-lymphocytes, an important component of the immune systemresponsible for the production of immunoglobulins. These cells candestroy normal bone marrow and bone tissue leading to ahaematopoietic imbalance caused by an overcrowding of the bonemarrow.

MM remains a fatal disease: median overall survival does notexceed 4 years with conventional chemotherapy approaches. Foradvanced stages, median survival time is about 2 years. In 2004, anestimated 15,270 new cases of MM and 11,000 deaths attributable to MMare expected in the US. At present, there are approximately 50,000people in the United States living with MM. In the EU, it isestimated that about 27,500 new patients will develop the diseaseeach year and 19,000 people die of it. The disease affects slightlymore men than women and peak incidence is among the elderly with amedian age of diagnosis of 71 years. Only 1% of cases are diagnosedin people younger than 40 years old.

Non-Hodgkin Lymphoma (NHL)

NHL is classified in two types: Aggressive NHL, characterised byrapid division of cancer cells; and Indolent NHL, which grows slowlyand is more difficult to diagnose. NHL are tumours of the lymphatictissue 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 USin 2004 and more than 19,000 will die of the disease. In the EU about64,000 new cases of NHL occur every year and an estimated 32,000people die of it.

Despite the availability of initial chemotherapy regimens forpatients with Aggressive NHL, the majority of patients will diewithin 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 thelymphocyte-progenitor cells called lymphoblasts. Malignantlytransformed lymphoblasts proliferate and accumulate in the bonemarrow and prevent the production of healthy red cells, platelets andwhite cells.

Nearly 75% of all children with leukemia have the ALL type. About3,830 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 cancerunder the age of 35 years. It is estimated that more than 40,000people are living with ALL in US. Approximately 3,830 new cases willbe diagnosed in 2004 and that about 1,500 deaths will occur due tothe disease each year. In the EU there are 6,434 new cases and 4,327deaths per year. Despite the availability of effective first linechemotherapy regimens for patients with ALL, up to 60% of patientsdie due to their disease. Expected median survival is 10 monthsfollowing a conventional chemotherapy regimen. Allogeneichaematopoietic stem cell transplantation might cure a higherpercentage of patients but is limited in availability due to a lackof suitable donors.

About PharmaMar

PharmaMar is a biopharmaceutical company, advancing cancer carethrough the discovery and development of innovative marine-derivedmedicines. PharmaMar's clinical portfolio currently includesYondelisTM in Phase II clinical trials (co-developed with Johnson &Johnson Pharmaceutical Research & Development), designated OrphanDrug for STS by the European Commission (E.C.) in 2001 and by the FDAin 2004, and Orphan Drug for ovarian cancer by the E.C. in 2003;Aplidin(R), in Phase II, designated Orphan Drug for acutelymphoblastic 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; KahalalideF in Phase II and ES-285 in Phase I clinical trials.

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

ots Originaltext: PharmaMarIm Internet recherchierbar: http://www.presseportal.de

Contact:For more information, please contact: Lola Casals, PharmaMar, Tel: +34-91-846-6000; David Yates & Deborah Scott, Financial Dynamics, Tel: +44(0)20-7831-3113


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Aplidin(R) Enters Phase II Trials in Haematological Cancers