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Iron Overload (Hemachromatosis)

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December 13, 2004

BioCryst Pharmaceuticals announced additional data from both phase I and phase I/II clinical trials of forodesine hydrochloride, their investigational Purine Nucleoside Phosphorylase (PNP) Inhibitor for the treatment of several types of leukemia and lymphoma. Results from the phase I study demonstrated pharmacokinetic activity, with a near-total inhibition of PNP at a dose of 40 mg/m2. Evidence of efficacy in treating subjects with cutaneous T-cell lymphoma was also observed, with 9 out of 13 patients showing improvement in skin and/or a pharmacodynamic response (including 3 complete responses and 1 partial response). Furthermore, two patients who received forodesine continued to show evidence of clinical activity through 9 -11. Results from the phase I/II study indicated that the drug was well-tolerated in all patients at all dose levels. 7 of the 15 patients treated demonstrated a decrease in tumor burden, and 2 patients also showed normalization of bone marrow precursor elements. Both studies were multi-center dose-escalating trials; the phase I study enrolled 13 subjects with cutaneous T-cell lymphoma, and the phase I/II study enrolled 15 subjects with mixed hematological malignancies. Based on these results, BioCryst recently initiated a phase I trial in CTCL patients using an oral formulation of forodesine.

Bristol-Myers Squibb reported results of a phase I trial of BMS-354825, for the treatment of chronic myelogenous leukemia (CML). Results from the study demonstrated significant efficacy in treating chronic, accelerated and blast-phase CML: 86% of the chronic phase patients demonstrated complete hematologic response, and 75% and 79% of the accelerated and blast phase patient groups demonstrated some degree of hematologic response. Cytogenetic responses were observed in 28%, 0%, and 53% of patients, respectively. This ongoing, open-label study has enrolled a total of 65 subjects with imatinib-resistant or –intolerant Philadelphia chromosome positive CML at a single US site. The company has announced the intention to initiate phase II development as soon as possible, following successful completion of this trial.

Celgene announced final results from a phase III trial investigating their approved drug Thalomid (thalidomide) for the treatment of multiple myeloma. Results from the study indicate that the addition of Thalomid to standard dexamethasone therapy produced a statistically significant increase in response rate at 4 months, vs. dexamethasone alone (63% vs. 41%; p=0.002). Median time to response was similar for both regimens, at 1.1 months. Subjects receiving Thalomid did experience a significant increase in adverse events, consistent with the drug’s well-established tolerability profile. Deep vein thrombosis was the most frequent of these events. This double blind, controlled trial randomized 207 patients with previously untreated symptomatic multiple myeloma to receive Thalomid (n=103) or placebo (n=104) in addition to standard therapy with dexamethasone. The study was designed to investigate both response and toxicity. Based upon these results, Celgene announced plans to submit a request during Q1, 2005 for accelerated approval of their sNDA for Thalomid for the treatment of multiple myeloma.

Cell Genesys reported positive follow-up data from a phase II trial of their GVAX leukemia vaccine, for the treatment of acute myelogenous leukemia (AML). Data from the ongoing extension study have indicated that the drug is well tolerated, and may reduce residual leukemic cells that persist after chemotherapy. Specifically, post-vaccination declines in levels of WT-1 (a genetic marker of leukemia), were observed in blood samples of 69% of patients (11 of 16) and in 60% (12 of 20) of patients’ bone marrow samples. Furthermore, relapse-free survival was greater in the patients who showed a decrease in WT-1 levels following vaccination, compared to those who did not (80% vs. 0%, p=0.02 for blood, 90% vs. 20%, p=0.002 for bone marrow). This open-label study enrolled 54 AML patients across 4 US leukemia bone marrow transplant centers, who received autologous bone marrow stem cell transplantation and GVAX leukemia vaccine treatment following successful response to chemotherapy.

FibroGen reported results from both phase I and IIa trials of FG-2216, their investigational oral treatment for anemia. Results from the phase I study met their primary safety and tolerability endpoints, with no serious adverse events or dose-limiting toxicities. The trial also characterized the drug’s pharmacokinetic profile, noting a dose-dependent increase in serum levels of erythropoietin (EPO), a hormone which stimulates red blood cell production. Repeated doses maintained EPO elevation, which lead to a consistent increase in the number of circulating reticulocytes (young read blood cells) after three weeks of dosing. Preliminary data from the first dosing cohort (n=8) from the ongoing phase IIa study indicated that patients receiving FG-2216 experienced a increases in mean hemoglobin levels from baseline, while subjects who received placebo experienced a mean decrease; the difference between the FG-2216 and placebo groups was statistically significant at both 3 (p = 0.024) and 6 (p=0.025) weeks. The open-label phase I trial enrolled 54 healthy male volunteers, who received dose-escalating single or multiple doses of the drug for up to 3 weeks. The phase IIa trial is one of several ongoing single-blind, placebo controlled studies designed to evaluate the safety and efficacy of FG-2216 in anemic patients suffering from chronic kidney disease, including both EPO naïve and EPO experienced individuals.

Icagen announced positive results of a phase II study of ICA-17043, for the treatment of sickle-cell anemia. Trial data met their primary efficacy endpoints, with a dose-dependent increase in hemoglobin level from baseline; this increase was statistically significant for the high-dose treatment group (p<0.001). Secondary efficacy measures were also achieved, including increases in hematocrit and red blood cell counts, and statistically significant improvements in dense red blood cells, reticulocyte count, LDH, and indirect bilirubin. These improvements suggest that the drug reduces hemolysis and improves anemic symptoms in patients with sickle cell anemia. This randomized, double-blind, placebo-controlled, dose-range-finding study enrolled 90 patients with sickle cell anemia across 19 academic medical centers in the US, who received one of two daily doing regimens (6 or 10 mg) or placebo. It was designed to establish the efficacy of the drug in producing a change in hemoglobin level from baseline.

Novartis issued mixed results of a phase III trial of ICL670, an orally-available once-daily iron chelator, for the treatment of chronic hyperferremia (iron overload). The two high-dose regimens of the drug achieved their primary endpoint of maintaining or reducing absolute liver iron concentration (LIC), producing a highly significant reduction of -5.3 plus or minus 8.0 mg Fe/g dry weight (P<0.001), compared to baseline. This reduction was non-inferior to the reduction produced by standard therapy with deferoxamine. The two lower dose of ICL670, however, did not demonstrate non-inferiority, meaning that the overall endpoint of non-inferiority to deferoxamine for all doses was not met. The international, open-label, randomized, multicenter Phase III study enrolled 586 patients with beta-thalassemia and transfusion-related iron overload, who were randomized to receive once daily ICL670 at one of four doses (5, 10, 20 or 30 mg/kg) or deferoxamine (20-60 mg/kg/day for 5 days/week). Based on these results, Novartis announced that they anticipated filing regulatory submissions with a number of international bodies for ICL670 in the first half of 2005.

Nuvelo issued positive results of a phase II trial of alfimeprase, their recombinant thrombolytic enzyme under investigation for its potential to restore function in patient’s occluded central venous access devices (CVADs). The highest trial dose demonstrated significant efficacy in improving catheter patency, with total patency rates of 50% at 15 minutes after the first dose, 60% at 120 minutes after the first dose, and 80% at 120 minutes after the second dose, compared to rates of 0%, 46%, and 62% among patients receiving approved therapy with Cathflo Activase. This randomized, double-blind, active-controlled, dose-ranging study compared the safety and efficacy of three doses of alfimeprase (0.3 mg; 1.0 mg; and 3.0 mg) against an approved dose of Cathflo Activase (2.0 mg), enrolling 55 patients with occluded CVADs. Catheter patency was assessed at 5, 15, 30, and 120 minutes after each dose, with subsequent doses administered only if patency was not achieved after the first.

December 16, 2002

Novartis reported positive results from a phase II trial investigating ICL670, an oral iron chelator for the treatment of chronic iron overload resulting from blood transfusions. The average liver iron decrease was greater in subjects treated with 20 mg/kg/day of ICL670 (- 2.2 mgFe/g liver) than those treated with Desferal (-1.2 mgFe/g liver) or 10 mg/kg/day of ICL670 (-0.6 mgFe/g liver). The open-label, randomized, multicenter study enrolled 63 subjects with iron overload resulting from a transfusion treatment of beta-thalassemia. The trial was designed to compare the overall safety, tolerability and efficacy of ICL670 relative to Desferal by measuring decreases in liver iron concentrations (LIC). After nine-months, LIC in 63 subjects taking ICL670 (10 or 20 mg/kg) decreased by 5.61% and 26.3%, respectively, compared with 13.9% of 20 subjects in the Desferal group.