Positive results from a clinical study conducted with acadesine (Acadra)?) in Chronic Lymphocytic Leukemia (CLL) patients resistant to current therapies were presented earlier today by Advancell , a Spanish biopharmaceutical company based in Barcelona.

Acadesine (5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside, AICA-riboside) is an AMP-activated protein kinase activator which is used for the treatment of acute lymphoblastic leukemia and may have applications in treating other disorders such as diabetes. It is an investigational, intravenous, small molecule that is transformed to its monophosphate active form (ZMP) once present within cells. The drug candidate works by selectively inducing cell death (apoptosis) to B-cell leukemic cells with a mechanism of action independent of p53 status.

This mechanism of action differentiates acadesine from other drugs currently used in CLL, whose mechanism is generaly highly dependent on p53 status. Acadesine eliminates B-cells without affecting T-cells, thus preserving the patient’s immunity.

Terminated trial in cardiovascular diseases
The drug was studied as recently as 2010 by Merck & Co in a Phase III study for prevention of reperfusion injury in coronary-artery bypass graft surgery (CABG) and was safe and well tolerated when administered by an intravenous infusion in a single dose. However, an independent data safety monitoring board recommended Merck, who inherited the drug with its acquisition of Schering-Plough, to stop enrolling patients in a late-stage trial, which was intended to enroll 7,500 patients and run through 2012, because an analysis showed it had a low probability of meeting the primary efficacy goal.

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Promissing results
Advancell also announced promising non-clinical results in Multiple Myeloma (MM), Mantle Cell Lymphoma (MCL) and other lymphoproliferative disorders. Synergism of acadesine in combination with current treatment in these indications has been demonstrated. “We are very pleased with these strong results that make Acadra a promising first-in-class candidate for further development in CLL and other indications,” said Dr. Kenneth Weissmahr, CEO of Advancell.

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“The efficacy observed with Acadra is of particular interest because there is a clear unmet clinical need in patients who become resistant to standard therapies and particularly in those who have alterations in the p53 gene,” said Dr. Clara Campas, who is responsible for the clinical development programs and co-author of the Acadra patent. “The drug has important synergic effects with other chemotherapy agents including bortezomib in multiple myeloma and anti-CD20 monoclonal antibodies in mantle cell lymphoma. The advantage of Acadra and anti-CD20 antibodies as combination agents is that both are B-cell directed and independent of p53.”

The results of the Phase I/II study (NCT00559624)) demonstrated that acadesine has an acceptable safety and tolerability profile in doses which induce reduction in the leukemic tumor burden. The study patient population included 24 patients with relapsed or refractory CLL who had received a minimum of one prior line of treatment including either a fludarabine or an alkylator-based regimen.

Seven out of the nine patients treated with acadesine at the Optimal Biological Dose presented a decrease in absolute B cell count, a reduction of clinically palpable lymphadenopathies or both. Two patients presented with symptomatic CLL-related neuropathic pain and skin infiltration that resolved after acadesine treatment.

Reversible asymptomatic hyperuricaemia was observed in some patients in part I and was significantly reduced in incidence with the introduction of mandatory prophylactic allopurinol in subsequent cohorts. The study results showed that acadesine did not induce myelosuppression at any of the doses tested. No Grade 3 or 4 adverse events occurred at the OBD or below and no Grade 5 events occurred in the study.

The study was closely followed by a Data Monitoring Board formed by four independent CLL international experts which concluded that, “Although the study was not designed to analyze peripheral blood response and lymph node response, clear evidence of efficacy has been obtained to move forward. The good safety profile of Acadra observed makes it an attractive combination partner with other CLL therapies.”

Other lymphoproliferative disorders
The company has also conducted in vivo non-clinical studies in other lymphoproliferative disorders. These studies showed that acadesine has anticancer activity in Multiple Myeloma and Mantle Cell Lymphoma at doses which are safe and well tolerated in humans. Interestingly, the drug has demonstrated synergic effects in combination with bortezomib in a Multiple Myeloma animal model and in combination with rituximab in a p53-mutated Mantle Cell Lymphoma animal model. These results suggest the potential use of acadesine as part of combination therapy in such indications. Dr. Kenneth Weissmahr comments,”The very encouraging non-clinical data is showing the potential of acadesine in Multiple Myeloma and Mantle Cell Lymphoma which increases substantially the market potential of this drug. These results validate our business model and now we look forward to partner the program with a company that guarantees its development to market.”

Acadesine was in-licensed by Advancell from the University of Barcelona and co-developed with Protherics (BTG) until November 2009, when the Spanish biotech licensed-back its rights from BTG.

For more information
Public summary of positive opinion for orphan designation of acadesine for the treatment B-cell chronic lymphocytic leukemia

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