Phase II trial demonstrates Elacytarabine may increase survival threefold in patients with late-stage leukaemia
New investigational drug also shown to improve remission rates and reduce short-term mortality compared to previous treatments
Oslo, Norway, June 17, 2009. Clavis Pharma ASA (OSE: CLAVIS) today announces positive final results from a Phase II trial of its novel investigational cancer drug, elacytarabine (CP-4055), in patients with late-stage acute myeloid leukaemia (AML). In the trial, elacytarabine showed statistically significant superior efficacy compared to published clinical data for late-stage AML. Based on these encouraging results an elacytarabine registration study is being planned.
Key results compared to published clinical data
* Median survival three times longer (5.5 months vs. 1.5 months) * Remission rate significantly increased (15% vs 2.5%, p<0.0001) * Well tolerated - short-term mortality substantially lower (13 per cent vs. 25 per cent)
Elacytarabine is a novel cytotoxic agent being developed by Clavis Pharma for the treatment of hematologic cancers and solid tumors, especially those resistant to existing agents. One particularly difficult-to-treat patient group is late-stage acute myeloid leukaemia (AML) patients who have failed two previous therapeutic regimens. There is currently no standard therapy available for these patients and life expectancy is very short. It is in this patient group that Clavis Pharma has evaluated the safety and efficacy of elacytarabine.
Extended survival, improved remissions In the Phase II study, 61 patients with late stage AML who failed to respond or relapsed after two separate rounds of treatments received third-line therapy (also called second salvage) with intravenous elacytarabine. The response to treatment was compared with a detailed historical outcome analysis of 594 similar second salvage AML patients, who were treated at the MD Anderson Cancer Center (Houston, TX, USA) (published by Giles et al, Cancer 2005;104:547-54). Median overall survival in the elacytarabine study was an impressive three times that of the historical control patients (5.5 months vs. 1.5 months). Further follow up on survival is ongoing.
In addition, 9 patients responded to elacytarabine with a complete remission or complete remission without full recovery of platelet counts as assessed by the investigator (of which 6 have been confirmed by an independent review of bone marrow histology), representing an overall remission rate of 15 per cent. By contrast, the expected remission rate for similar group of patients, matched for prognostic factors as described by Giles et al. was only 2.5 per cent. Using a pre-defined statistical analysis method, the improvement in outcome was statistically highly significant (corresponding to p<0.0001). If only patients whose complete remission has been confirmed by histology are included in the analysis, the improvement in remission rate is still statistically highly significant (corresponding to p<0.01).
Elacytarabine was relatively well tolerated and 30 day all cause mortality following treatment was substantially lower than published data for existing therapies (13 per cent vs. 25 per cent). Out of the 61 patients treated with elacytarabine, 10 were referred for stem cell transplantation following treatment, including some patients in complete remission and others with a more modest level of clinical benefit. Stem cell transplantation represents a potential cure for life for these patients.
Professor Francis Giles, the lead author on the 2005 published clinical data and Chief of Haematology and Medical Oncology at The University of Texas Health Science Center, was the Coordinating Investigator for this multicenter trial. Commenting on the outcome of the trial, Professor Giles said: "Patients with refractory / relapsed AML today have no standard therapy as existing therapies are inadequate for most patients. Remarkably, elacytarabine has shown prolonged survival, a significant reduction in early mortality and a substantially and unexpectedly higher complete remission rate for these patients compared to previously published experience. Since elacytarabine also is well tolerated by both younger and elderly patients, it has the potential to become the standard of therapy for refractory / relapsed AML. An elacytarabine pivotal trial in this patient population is highly warranted."
Geir Christian Melen, CEO of Clavis Pharma, also commented: "We are encouraged by the positive results from this elacytarabine Phase II study in AML, particularly as this is a very difficult patient population to treat. The results represent a clinical proof of concept for elacytarabine as an improved treatment for AML and also validate the potential of our Lipid Vector Technology to produce cancer drugs with enhanced performance. We look forward to continuing the development of elacytarabine, and commencing potential registration trials."
Phase III and further development Preliminary data from this phase II study have been previously reported at the American Society of Hematology (ASH) Annual Meeting in December 2008 and at the American Society of Clinical Oncology (ASCO) in May 2009. Based on the final data from all of the patients in the study, Clavis Pharma is now in the process of designing a pivotal registration study.
NOTES FOR EDITORS
About Elacytarabine Elacytarabine is a novel nucleoside drug designed to overcome the shortcomings of cytarabine, an established anti-cancer agent often used in acute myeloid leukaemia. Unlike cytarabine, uptake of elacytarabine by cancer cells is not dependent on the presence of the nucleoside transporter, hENT1. As a result, elacytarabine is taken up by cancer cells that are resistant to cytarabine due to deficient expression of hENT1 on the cells. The enhanced cytotoxic activity of elacytarabine is thought to be mediated through increased cellular uptake, decreased deactivation and prolonged exposure to the active metabolite ara-C triphosphate (ara-CTP) within the cell.
In the Phase II trial, Elacytarabine was given as a single agent to patients with late stage AML who had received two prior treatments with chemotherapy (2nd salvage treatment). A dose of 2000 mg/m2/day was given as continuous infusion for five days. One repeated course was allowed in order to attain remission. Elacytarabine showed a favourable safety profile and clinical responses have been reported throughout the phase I and II parts of the program. Most commonly reported adverse events were as expected related to the drug's effect on the blood cells. Elacytarabine was also well tolerated by elderly patients.
Elacytarabine has previously been granted orphan drug designation by both the FDA and the European Commission for the treatment of AML. Elacytarabine is proposed by the World Health Organization as the international non-proprietary name (pINN) for CP-4055, whilst elacytarabine has already been adopted by the United States Adopted Name Council (USAN).
About Leukaemia Approximately 300,000 new cases of leukaemia are diagnosed globally each year, resulting in around 220,000 deaths. Leukaemia represents a market with high unmet medical needs, which may open for accelerated approval processes to expedite market access for new drugs. It is a segmented market covering a broad variety of disorders. A major clinical concern is the high rate of disease recurrence. The five-year survival for the most common acute leukaemia type, acute myeloid leukaemia (AML), is in the range of 5-10% for treated elderly patients, and approximately 30% for treated younger adults. The AML market is estimated to be a multi-hundred USD market and is expected to grow significantly over the coming years.
About Clavis Pharma Clavis Pharma ASA is an oncology focused pharmaceutical company using its proprietary Lipid Vector Technology (LVT) platform to create New Chemical Entities (NCEs), by significantly improving already established drugs. The improvements are achieved by chemically binding specific unsaturated lipids to existing, and well understood, approved pharmaceuticals. Data generated suggests the resulting patentable NCEs offer improved efficacy and reduced side effects through enhanced pharmacokinetic properties, greater tissue penetration and, in many cases, additional modes of action.
Clavis Pharma's objective is to develop its drug candidates until significant value has been created and proof of principle in man has been shown. For further clinical development and commercialisation of the products, Clavis Pharma will enter into strategic partnerships with established pharmaceutical or biotech companies. The company's product portfolio includes four new cancer drugs: Elacytarabine is in clinical phase II, Intravenous CP-4126 is in clinical phase II, Oral CP-4126 in phase I, and CP-4200 is in early preclinical development. Results indicate that these products have promising potential for several cancer indications within solid tumours and leukaemia. The shares of Clavis Pharma ASA are listed on the Oslo Stock Exchange (ticker: CLAVIS).
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Posted: June 2009