Myelodysplastic Syndromes (MDS)

August 1, 2016

Janssen-Cilag International announced results from an international phase III, randomized, double-blind, placebo-controlled, multicenter study of EPREX (epoetin alfa) for anemia in adult patients with low or intermediate-1 risk myelodysplastic syndromes (MDS). Results demonstrated that 31.8% of patients treated with epoetin alfa achieved the primary endpoint of erythroid response versus 4.4% of placebo patients (p<0.001). An ad hoc analysis, accounting for the dose adjustments as per the protocol, confirmed a statistically significant erythroid response for epoetin alfa, with 45.9% of epoetin alfa patients, versus 4.4% of placebo patients achieving an erythroid response (p<0.001). Median erythroid response duration for epoetin alfa patients was 197 days. The number of patients needing transfusion in the epoetin alfa arm steadily decreased from 51.8% in the eight weeks prior to baseline, to 24.7% by week 24. Transfusion need remained unchanged in the placebo patients (48.9% to 54.1%) over the same interval. Time to first transfusion was longer in the epoetin alfa group (p=0.046). Epoetin alfa demonstrated a statistically significant improvement of quality of life in responding patients. These data, along with three registry studies from across Europe, have been submitted to the French health authority Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM).

February 29, 2016

Amgen reported results of a randomized, double-blind, placebo-controlled, phase III trial of Aranesp (darbepoetin alfa) to reduce the incidence of red blood cell transfusions in for anemic patients with low and intermediate-1 risk myelodysplastic syndrome (MDS). The study enrolled 146 patients with low or intermediate-1 risk MDS who had not previously taken ESAs or biologic response modifiers. During a 24-week period, patients received either Aranesp 500g (n=97) or placebo (n=49) every three weeks. At week 25, when the primary and key secondary endpoints were assessed, patients underwent an end-of-treatment period (EOTP) visit and could subsequently enter a 48-week active treatment period where all participants crossed over to receive Aranesp, with dose escalation allowed beginning on week 31. Aranesp significantly improved erythroid response. Safety data was consistent with the known safety profile of Aranesp. Adverse events were generally balanced between treatment arms. The adverse events reported in the Aranesp arm at least 5% more frequently than in the placebo group were fatigue, pyrexia, headache and myalgia.

December 17, 2012

Celgene International released results from a phase I trial of CC-486 (oral azacitidine) for the treatment of myelodysplastic syndromes (MDS). This multi-arm study enrolled 53 patients with lower-risk MDS who were red blood cell transfusion-dependent and/or thrombocytopenic. Subjects received 300mg of CC-486 once daily for either 14 or 21 days of each 28-day cycle. After a median of seven treatment cycles for the 14-day treatment arm and five for the 21-day treatment arm, the overall response rate was 42.3% (11/26) and 37.0% (10/27), respectively. Additionally, the percentage of patients showing any hematologic improvement was 26.9% in the 14-day arm and 29.6% in the 21-day arm. The percentage of patients who sustained RBC transfusion independence for 56 days was 53.5% in the 14-day arm and 40.0% in the 21-day arm. The percentage of patients who sustained RBC transfusion independence for 84 days was 20% in the 14-day arm and 33.3% in the 21-day arm. CC-486 was well tolerated. The most frequent adverse events were anemia, thrombocytopenia, neutropenia and febrile neutropenia. Based on these and other early-stage data evaluating CC-486, Celgene plans to initiate two phase III studies (QUAZAR program) evaluating this oral agent in lower-risk MDS and acute myeloid leukemia by the end of 2012.

October 22, 2012

Cyclacel Pharmaceuticals released results from an ongoing phase II trial of sapacitabine for the treatment of myelodysplastic syndromes (MDS). This randomized, open-label, multi-center study enrolled 63 patients aged 60 years or older with MDS of intermediate-2 (n=52) or high-risk (n=11) classification by the International Prognostic Scoring System (IPSS). Subjects were divided into three arms and received one of the following doses once every four weeks: sapacitabine 200mg twice daily for seven days (Arm G), 300mg once daily for seven days (Arm H), or 100mg once daily for five days per week for 2 weeks (Arm I). Results showed the median overall survival to date for all 63 patients is 252 days, or approximately eight months. Individual survival rates were 291 days for Arm G, 274 days for Arm H and 227 days for Arm I. Median overall survival for 41 out of 63 patients with 10% or more blasts in their bone marrow is 274 days, or approximately nine months. The drug was well tolerated. Cyclacel reported 22% of patients are still alive and longer follow-up is needed to assess one-year survival and overall survival of each arm.

December 26, 2011

Telik issued results from a phase I trial of Telintra for the treatment of myelodysplastic syndrome. This open label, dose escalation study enrolled 19 subjects who received Telintra 2000 mg orally in combination with standard dose Revlimid (10 mg) on days 1-21 of a 28-day cycle. Four of 10 subjects (40%) met the hematologic improvement in red blood cell levels (HI-E) response criterion. Seven subjects were transfusion dependent, and 3 (43%) achieved transfusion independence, including one who did not respond to prior Revlimid monotherapy. The median duration of red blood cell transfusion independence and HI-E response was not reached. Bilineage responses included: HI-E and hematologic improvement in platelet levels (HI-P) responses in 3 of 5 subjects, HI-E and hematologic improvement in white blood cell levels (HI-N) responses in 1 of 3 subjects and HI-N and HI-P responses in 1 of 3 subjects. One of 3 subjects with trilineage low blood cell levels had a complete response of all 3 blood cell lineages.

August 6, 2007

Genzyme reported positive results from a phase III trial of Mozobil for the treatment of multiple myeloma. This randomized, double-blind, placebo-controlled trial enrolled 302 subjects who were undergoing a hematopoietic stem cell transplant (HSCT) for multiple myeloma. Subjects were treated with Mozobil following granulocyte-colony stimulating factor (G- CSF) or placebo following G-CSF. In the primary efficacy endpoint, 72% of subjects treated with Mozobil and G-CSF achieved the target threshold for collection of at least 6 million CD34+cells/kg from the peripheral blood with two days or fewer of apheresis sessions, compared with 34% of subjects in the G-CSF/placebo group (p<0.0001). Secondary endpoint were achieved as well; the median number of days to achieve the target of 6 million cells was one day for the Mozobil/G-CSF group and four days for the G-CSF/placebo group. Genzyme plans to file for US and European regulatory approval in the first half of 2008.

Oncogenics and Isis released positive preliminary results from a phase II trial of OGX-011 for the treatment of metastatic hormone refractory prostate cancer. This trial enrolled 42 subjects who were randomized to receive 640 mg/week OGX-011 plus prednisone plus either mitoxantrone or docetaxel. The results are from a median follow-up of 7.4 months. In the cohort receiving OGX-011 plus docetaxel: death occurred in 10% of the population, 30% experienced disease progression, 35% had a 50 percent decrease in prostate specific antigen (PSA), and 55% had a 30 percent decrease in PSA. In the cohort receiving OGX-011 plus mitoxantrone: death occurred in 32% of the population, 59% experienced disease progression, 23% had a 50 percent decrease in PSA and 32% had a 30 percent decrease in PSA. Treatment in both arms was generally well tolerated. Based on the results, Oncogenics is planning phase III trials of OGX- 011 in combination with docetaxel.

Pharmion announced positive results from a phase III trial of Vidaza for the treatment of myelodysplastic syndromes. This trial was designed to compare Vidaza to conventional care regimens (CCR), including best supportive care (BSC) alone, low-dose cytarabine plus BSC or standard chemotherapy plus BSC) utilized in the control arm. In the primary endpoint analysis, Vidaza was associated with a median survival of 24.4 months versus 15 months for those receiving CCR treatment, an improvement of 9.4 months with a stratified log-rank p-value of 0.0001. Two-year survival rates were 50.8% versus 26.2% for subjects receiving Vidaza versus CCR (p<0.0001). Based on the results, Pharmion plans to file a MAA in Europe and a sNDA in the US by the end of 2007.

December 4, 2006

Cyclacel released positive interim results from a phase I trial of sapacitabine for the treatment of advanced leukemia or myelodysplastic syndromes (MDS). The preliminary data is from 22 subjects. The primary endpoint of this trial was to determine the maximum tolerated dose (MTD) of sapacitabine administered twice daily by mouth for seven consecutive days, every 21 days. One subject receiving a dose level of 275 mg b.i.d. experienced a dose limiting toxicity, which was resolved after treatment ceased. Dose escalation was ongoing at this time with dose limiting toxicities not yet reached at the dose level of 325 mg b.i.d. Cyclacel planned to use these results in the design of a phase II trial expected to commence in 2007.

July 19, 2004

SuperGen has published positive combined results of three phase II studies of Dacogen (decitabine), a DNA-hypomethylating agent, for the treatment of several subtypes of myelodysplastic syndromes (MDS). The trials found that the drug was significantly efficacious in improving symptoms of MDS, with 63% of subjects demonstrating an increase in platelet count following administration (the studies’ primary endpoint). The trials also found the drug to be efficacious in producing platelet response after one dose (53% of subjects), and in the ability of platelet response to predict overall survival (p<0.0001); these measures were the studies’ secondary endpoints. The three trials enrolled a total of 170 subjects with high risk MDS, of whom 126 were thrombocytopenic at trial outset. SuperGen announced that this data would be submitted as part of its rolling NDA later this quarter.

April 5, 2004

Hybridon reported positive results from a phase I trial investigating HYB2055, an immunomodulating TLR9 agonist for the treatment of cancer. Results showed the treatment was safe and biologically active. The randomized, placebo-controlled study enrolled 28 healthy subjects sorted into groups of four. One subject per group received placebo and three per group received HYB2055. Each subject received three weekly doses and was followed for a period of 42 days from the first dose. Results were reported at the 95th Annual Meeting of the American Association for Cancer Research in Orlando, FL. Subject assessments included ELISA measurement of plasma cytokines and detailed flow cytometry analysis of circulating leukocyte populations.

SuperGen reported positive results from a phase III trial investigating Dacogen (decitabine), an injectable chemotherapeutic agent for the treatment of myelodysplastic syndromes (MDS). Results showed that 92 subjects reached the primary endpoint of either delayed progression to acute myelogenous leukemia (AML) or death. Subjects taking Dacogen had a median time of progression to AML or death of 338 days compared to 263 days in subjects taking supportive care only. In addition, subjects on Dacogen reported an overall response rate of 22% compared to 0% for subjects on supportive care only. The randomized study enrolled 170 subjects with MDS and was conducted at 22 sites in North America. Subjects were administered Dacogen plus supportive care (antibiotics, growth factors and/or transfusions) or supportive care only. SuperGen plans to submit an NDA to the FDA based on the results on this trial.

November 24, 2003

Celgene reported positive preliminary results from a phase II trial investigating Revimid (CC-5013), an immunomodulator for the treatment of myelodysplastic syndromes. Results showed 21 subjects (64%) demonstrated a erythroid response to treatment with Revimid that was defined by at least a 50% decrease in transfusions or an increase in hemoglobin of 2 g/dl. Data showed that 19 of those subjects (90%) no longer required transfusions. Preliminary data suggests a complete response and durable response had been sustained for a an average of 38 weeks. The trial enrolled 45 subjects with refractory anemia who also had 5q- syndrome, of which 33 were evaluable for response after completing 8 weeks or more. Results were reported in November 2003 at the annual Chemotherapy Foundation Symposium XXI in New York.

April 21, 2003

Telik reported positive interim results from a phase I/IIa trial investigating TLK199, a glutathione S-transferase inhibitor for the treatment of myelodysplastic syndrome (MDS). Result showed that all subjects achieved clinically significant increases in at least two of the three major blood elements. Data also showed that 50% of the subjects demonstrated evidence of clinical activity. One subject with advanced MDS demonstrated a decrease in pre-leukemic cell levels. TLK199 has been generally well tolerated and the maximum tolerated dose has not been reached. The open label, multicenter, dose escalation trial enrolled twelve subjects with MDS and was designed to evaluate the safety, pharmacokinetics and efficacy of TLK199.

January 14, 2002

Phase II trial results indicate that rubitecan, an oral anticancer drug, is active in both chronic myelomonocytic leukemia (CMML) and myelodysplastic syndromes (MDS). The trial included 35 evaluable subjects who had received a minimum of one prior therapy and who were diagnosed with either CMML (23 subjects) or MDS (12 subjects). Results showed an objective response rate of 28%, with four complete responses and six partial responses. An overall response rate of 42% was reported, taking into account hematological improvement in 14% of subjects. Rubitecan is being developed by SuperGen.

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