ATLANTA - Gemin X Biotechnologies reported results from a Phase I study showing that chronic lymphocytic leukemia patients showed some partial and stable responses when treated with it Bcl-2 inhibitor, GX15-070. The results were presented here at the 47th annual meeting of the American Society of Hematology.

An estimated 20,000 attendees converged on the Georgia World Congress Center in downtown Atlanta, which became this year's host after organizers were forced to relocate the conference from New Orleans due to damage from Hurricane Katrina. The four-day meeting wraps up today.

In the Sidney J. Marcus Auditorium, investigators from a number of different studies briefly presented abstracts detailing clinical results. One of those presentations featured Gemin X's GX15-070 (obatoclax), which is being evaluated in a Phase I program in different cancer types. Susan O'Brien, a leukemia specialist with the University of Texas M.D. Anderson Cancer Center, presented data from one of those trials in an abstract titled "A Phase I Trial of the Small Molecule Pan-Bcl Family Inhibitor GX15-070 Administered Intravenously Every Three Weeks to Patients with Previously Treated Chronic Lymphocytic Leukemia (CLL)."

Of the 25 patients enrolled with refractory disease who had failed a median of four prior types of treatment, 12 received the small-molecule drug at doses of 3.5 mg/m² to 14 mg/m² administered as a one-hour infusion, and the remaining 13 received 20 mg/m² to 40 mg/m² given as a three-hour infusion. In addition to determining a safety profile and finding the maximum tolerated dose of 28 mg/m², the study showed significant pharmacodynamic activity.

Data so far indicate that one patient experienced a partial response, and nine patients had stable disease at greater than six weeks. Four of 14 patients with low platelet counts (baseline<150,000/mm3) demonstrated sustained increases of more than 50 percent after treatment, and three of the 11 anemic patients in the study showed sustained hemoglobin elevations, with two of those achieving transfusion independence.

"When there are hints of efficacy in a Phase I trial, that's always a positive sign," Jean Viallet, Gemin X's vice president of clinical development, told BioWorld Today. Since Phase I trials typically recruit pretreated and refractory patients for the purpose of determining dose-limiting toxicities and early pharmacologic profiles, seeing "that kind of efficacy in Phase I is very significant," he added.

The company began clinical testing of GX15-070 about five months ago, starting with CLL partly because, in that disease, the "expression of Bcl-2 is ubiquitous," Viallet said. GX15-070 is designed to target Bcl-2, a family of proteins that prevent apoptosis. The drug is designed to work by inhibiting all the Bcl-2 proteins to induce apoptosis in cancer cells without damaging normal cells. It is the first pan-Bcl-2 inhibitor tested in clinical trials.

There are several drugs in the works targeting one Bcl-2 protein, such as Berkeley Heights, N.J.-based Genta Inc.'s Genasense, an antisense drug that has struggled in the clinic - in 2004, the drug missed its safety endpoints in a Phase III trial of CLL patients and failed to hit the efficacy endpoint in a Phase III trial in multiple myeloma - before reporting positive data earlier this year in a study against relapsed or refractory CLL in combination with chemotherapy. (See BioWorld Today, Nov. 30, 2004, and Sept. 20, 2005.)

"There are other drugs, like Genasense, that have a similar mechanism" to GX15-070, Viallet said, "but, unlike Genasense, our drug is a small molecule that is not specific to a particular member of the Bcl-2 family. We believe that not focusing on any specific family member" will induce apoptosis most effectively.

One exciting part of the trial did not directly involve GX15-070, but a new biomarker that Gemin X integrated to determine short-term biological activity of the drug. Researchers used oligonucleosomal fragments, or circulating DNA fragments, which are released when apoptosis occurs, to measure effect of different exposure rates and doses. The use of the biomarker also indicated that the dose response seen in mouse models was similar to the response later seen in humans.

"What you often see is that a compound will perform well in mouse models, but when you test it in man, it doesn't have the same response," Viallet said. That frequently is due to toxicities that prevent a drug from being administered at a high enough dose to be efficacious.

"The use of this biomarker indicated a correlation" between dose and response that has been consistent in human trials, he added.

Additional data from the trial showed that pharmacodynamic activity was frequently noted, with apoptosis shown by an increase in histone-oligonucleosomal DNA levels one to six hours after infusion, peaking 24 hours to 168 hours post-infusion. Analysis suggested that those peak levels correlated with dose and AUC.

Trial investigators also measured the drug's activity by looking at the reduction of peripheral lymphocyte counts. Of the 25 patients evaluated, 18 of them showed an average reduction of 29 percent.

In preclinical studies of GX15-070, presented in four separate posters at the ASH meeting, data have shown its ability to induce apoptosis in several types of blood cancers, as both a single agent and in combination with cancer drugs, such as proteasome inhibitors and chemotherapy products.

"The potential for [GX15-070] is huge," Viallet said. "Thanks to our collaborations with academic and research institutions, we plan to conduct other trials of [GX15-070] in combination with drugs such as [Velcade], and for other indications."

Velcade is made by Millennium Pharmaceuticals Inc., of Cambridge, Mass.

Montreal-based Gemin X anticipates completing Phase I testing of GX15-070 within the next three or four months, then starting on single-agent Phase II studies. In addition to the trial in CLL, the company also has Phase I trials ongoing in patients with advanced, refractory solid tumors. Results from that trial are expected in 2006.

Preclinical work is ongoing to test the effects of prolonging the infusion time to 24 hours to increase exposure to the drug.

Viallet said the company might look at adding a partner following the completion of Phase II development, but for now Gemin X is relying on its most recent financing to fund continued work on its lead compound. In May, the company completed its largest financing to date, bringing in $65.2 million, comprised of a $50 million private equity investment and up to $15.2 million in a loan facility. (See BioWorld Today, May 20, 2005.

In other news from the meeting:

Affymax Inc., of Palo Alto, Calif., said a Phase II trial of Hematide demonstrated potent and sustained erythropoietic activity in patients with anemia due to chronic kidney disease who are not on dialysis and have not previously been treated with erythropoietin.

Alexion Pharmaceuticals Inc., of Cheshire, Conn., said patients with paroxysmal nocturnal hemoglobinuria given eculizumab showed sustained and significant reductions in red blood cell destruction and in need of blood transfusions, according to three-year results of an open-label extension study.

Allos Therapeutics Inc., of Westminster, Colo., said Phase I/II data of PDX (pralatrexate) in patients with non-Hodgkin's lymphoma showed a high complete response rate, suggesting that PDX might offer advantages over current treatments.

Amgen Inc., of Thousand Oaks, Calif., said updated interim data from a Phase II study evaluating the use of 500 mcg of Aranesp (darbepoetin alfa) administered every three weeks to treat anemia in patients with myelodysplastic syndrome showed an overall response rate of 70 percent, increased hemoglobin levels and improvements in patient-reported fatigue. Phase III data of Aranesp in cancer patients with chemotherapy-induced anemia revealed that the drug increased and maintained patient hemoglobin levels, and reduced the need for red blood cell transfusions by almost half compared to placebo.

AnorMed Inc., of Vancouver, British Columbia, said re-mobilization with Mozobil (AMD3100) and G-CSF allowed cancer patients requiring a stem cell transplant to collect enough stem cells for transplant, after failing to do so with standard mobilization regimens.

Ascenta Therapeutics Inc., of San Diego, said AT0101 binds to proteins Bcl-2, Bcl-XL, Mcl-1 and other proteins in the Bcl-2 family, and induces apoptosis in chronic lymphocytic leukemia cells in vitro.

BioCryst Pharmaceuticals Inc., of Birmingham, Ala., said Phase IIa data of intravenous Fodosine demonstrated an overall response rate of 35 percent in 23 refractory T-cell leukemia patients and indicated it may offer a less toxic therapy.

Bioenvision Inc., of New York, said an interim analysis of data from the Phase II regulatory trial of clofarabine in elderly patients with acute myeloid leukemia who were unsuitable for intensive chemotherapy showed a response rate of 36 percent in the first 44 patients.

Celgene Corp., of Summit, N.J., said Phase III data of Revlimid (lenalidomide) plus dexamethasone in previously treated multiple myeloma patients showed that the combination of the two therapies led to a statistically significant improvement in median time to disease progression (p=0.001) and in overall survival. As of June, median overall survival of Revlimid plus dexamethasone had not been reached, as compared to 104 weeks with dexamethasone plus placebo. A separate study in chronic lymphocytic leukemia patients showed that 16 out of 19 evaluable patients achieved stable disease or better after treatment with Revlimid and experienced a median decrease of 61 percent in absolute lymphocyte count, a measure of tumor burden.

Cell Genesys Inc., of South San Francisco, said Phase II data of GVAX vaccine for chronic myelogenous leukemia demonstrated a reduction in persistent leukemia disease in nine out of 19 patients when added to Gleevec.

Cephalon Inc., of Frazer, Pa., said CEP-701 inhibits a specific genetic mutation targeted by the compound in patients' blood samples, which is predictive of a positive clinical response in a Phase II trial of patients with acute myelogenous leukemia. The company also said that in a Phase II study of patients with advanced indolent non-Hodgkin's lymphoma who were previously exposed to multiple courses of therapy, 74 percent responded to Treanda (bendamustine HCl), including 35 percent with a complete response.

ChemGenex Pharmaceuticals Ltd., of Melbourne, Australia, said two abstracts related to the clinical development of Ceflatonin were published in the Nov. 16 issue of Blood. In a Phase II study, all five evaluable patients achieved a complete hematologic response and the therapy was well tolerated.

Cougar Biotechnology Inc., of Los Angeles, said Phase I data of CB3304 (noscapine) in patients with relapsed or refractory non-Hodgkin's lymphoma showed that one out of 10 evaluable patients had a partial response. Noscapine has been well tolerated, with no grade three or four hematologic toxicities.

Cytogen Corp., of Princeton, N.J., said preclinical data of Quadramet in combination with bortezomib (Velcade, Millennium Pharmaceuticals Inc.) demonstrated broad anticancer activity in a murine myeloma model, including greatly prolonged median survival, rapidly reduced clonogenicity of bone-marrow resident 5TGM1 cells, slowed elevation of serum myeloma-associated paraprotein levels and longer-term preservation of bone mineral density.

Gemin X Biotechnologies Inc., of Montreal, said Phase I/II data of GX15-070 (obatoclax) in patients with chronic lymphocytic leukemia showed the drug was generally well tolerated, was biologically active and generated clinical improvements. Also, preclinical studies showed that GX15-070 has potential in treating several types of cancer and in combination with various existing cancer treatments.

Genentech Inc., of South San Francisco, said it will donate $500,000 to the American Society of Hematology to help fund the Society's Minority Medical Study Award Program.

Genitope Corp., of Redwood City, Calif., said long-term follow-up results from a Phase II trial of MyVax Personalized Immunotherapy to treat follicular non-Hodgkin's lymphoma after chemotherapy showed a significant increase in time to progression of f-NHL compared to chemotherapy alone. Measured from the end of chemotherapy, the median time to disease progression was 37.7 months.

Genta Inc., of Berkeley Heights, N.J., said Genasense (oblimersen sodium) injection, in combination with fludarabine plus rituximab (Rituxan), in patients with chronic lymphocytic leukemia demonstrated a major response in five previously untreated patients during a Phase I/II study.

Human Genome Sciences Inc., of Rockville, Md., said Phase II data demonstrate that HGS-ETR1 (mapatumumab) was well tolerated and capable of producing clinical responses when administered as monotherapy in patients with advanced non-Hodgkin's lymphoma.

Immunomedics Inc., of Morris Plains, N.J., said a Phase I/II trial of its humanized anti-CD20 monoclonal antibody in patients with non-Hodgkin's lymphoma demonstrated an overall objective response rate of 61 percent in the 23 evaluable patients.

Kosan Biosciences Inc., of Hayward, Calif., said interim results from KOS-953, its formulation of the Hsp90 inhibitor 17-AAG, demonstrated early signs of anticancer activity and tolerability in patients with relapsed-refractory multiple myeloma.

Lorus Therapeutics Inc., of Toronto, said GTI-2040 combined with cytarabine in recurrent or refractory acute myeloid leukemia patients showed in a clinical trial a complete response in 44 percent of patients who were 60 years of age or younger.

MGI Pharma Inc., of Minneapolis, and SuperGen Inc., of Dublin, Calif., said Dacogen (decitabine) injection data in patients with myelodysplastic syndromes and initial data from a Phase II trial of Dacogen in elderly acute myeloid leukemia patients supported the drug's potential as an option for MDS patients. The company is awaiting an FDA decision for the indication, expected in early 2006.

Millennium Pharmaceuticals Inc., of Cambridge, Mass., said data demonstrated a six-month survival advantage for relapsed myeloma patients in the Velcade arm of a Phase III trial. Velcade demonstrated a median overall survival of 30 months, while the dexamethasone arm had a median overall survival of 24 months.

Pharmacyclics Inc., of Sunnyvale, Calif., said Phase I data suggested that Xcytrin (motexafin gadolinium) injection, when given in combination with Zevalin (ibritumomab tiuxetan), is well tolerated and demonstrated synergistic activity in patients with Rituxan (rituximab)-refractory low-grade and transformed non-Hodgkin's lymphoma. In a second Phase II study, Xcytrin demonstrated single-agent activity in refractory low-grade lymphoma and chronic lymphocytic leukemia.

PharmaMar SA, of Madrid, Spain, said Aplidin reached its objective of overall response rate in the first stage of its Phase II trial in patients with advanced multiple myeloma. The second stage is under way.

Pharmion Corp., of Boulder, Colo., said data from the Vidaza pivotal Phase III study in high-risk MDS patients showed a median overall survival of 19.5 months, compared with 14 months for patients in the supportive care arm. Median time to AML transformation with Vidaza was 42 months, compared to 17.7 months on supportive care.

Point Therapeutics Inc., of Boston, said Phase II data of talabostat in combination with rituximab showed an overall response rate of 22.5 percent in patients with advanced chronic lymphocytic leukemia.

Seattle Genetics Inc., of Bothell, Wash., said Phase I data demonstrated that SGN-40 was well tolerated and showed signs of antitumor activity in both non-Hodgkin's lymphoma and multiple myeloma. Phase II trials for systemic anaplastic large-cell lymphoma and cutaneous ALCL showed that SGN-30 was well tolerated and had antitumor activity, including complete and partial responses. And preclinical data supported the advancement of SGN-35, an anti-CD30 antibody-drug conjugate, into clinical development in 2006. Preclinical studies of SGN-40 demonstrated broad application in B-cell malignancies, while other data showed SGN-70's therapeutic potential in hematologic malignancies.

Telik Inc., of Palo Alto, Calif., said Telintra demonstrated positive clinical results in a Phase II trial in patients with myelodysplastic syndrome. Of 34 patients, 65 percent had clinically significant hematologic improvement.

Transgene SA, of Strasbourg, France, said TG1042 demonstrated positive results in a Phase I/II trial in cutaneous lymphoma. To date, 31 patients are evaluable for efficacy and enrollment now is complete.

Vion Pharmaceuticals Inc., of New Haven, Conn., said Cloretazine demonstrated an overall response rate of 32 percent in 107 elderly patients with previously untreated acute myelogenous leukemia or high-risk myelodysplasia.

ZymoGenetics Inc., of Seattle, said preliminary data from a Phase I study of TACI-Ig in patients with multiple myeloma and Waldenstrom's macroglobulinemia showed reduced circulating polyclonal immunoglobulin levels and an acceptable tolerability profile with few treatment-related adverse events.