ORLANDO, Fla. - For the city's transportation services, the arrival late last week of nearly 20,000 conventioneers for the annual meeting of the American Society of Hematology was part gold mine, part work force shortage emergency.

The words "19,800 docs in town," scrolled across the combination fare display/intercom system of the MEARS shuttle as it made its way from the airport to hotels on Friday, followed by a pitch to drivers: "Work extra 2nite - cover the Rosen cover the Peabody" - the two official conference hotels.

All those docs surely know of Novartis Inc.'s Gleevec (imatinib), a ground-breaking drug for chronic myelogenous leukemia.

"Before Gleevec, everybody in the industry said that you could never develop a specific kinase inhibitor, and if you did, the toxicity would be way too high," said Entremed's director of research Mark Bray, speaking to BioWorld Today. And when Novartis succeeded, "it spawned a whole industry," in part because of Gleevec's massive success - it brought Novartis $2.2 billion in 2005.

Gleevec has been followed by two second-generation kinase inhibitors: Sprycel (dasatinib) from Bristol-Myers Squibb Co., of Princeton, N.J., approved in June, and Novartis' own AMN107 (nilotinib) currently in clinical trials.

Now, work on third-generation inhibitors of bcr-abl - the kinase that Gleevec targets - is coming down the pike. Many patients develop resistance to both Gleevec and the second-line drugs eventually, and the new generation of compounds wants to overcome that resistance, some by targeting the mutants directly and some by targeting other kinases to circumvent the effects of mutations.

Entremed presented preclinical data on one such inhibitor: ENMD-981693, which, although it targets kinases, also affects angiogenesis. The compound, which will enter the clinic in 2007, preferentially inhibits Aurora A, one of the three known aurora kinases. All three aurora kinases are important for orderly cell-cycle progression, so blocking them will lead to cell-cycle arrest and apoptosis.

Bray said that ENMD-981693's specificity for Aurora A is a plus; because of its precise mechanism of action, inhibiting Aurora B conceivably could trigger genomic instability, though Bray said that has not been experimentally demonstrated and there is "disagreement" in the industry about which aurora kinase would be the best to target.

Indeed, those with an inhibitor that target both kinases do disagree. Cells with disrupted Aurora A and B "all end up dead," Matthew Harding of Vertex Pharmaceuticals told BioWorld Today. "They just take a different path to get there." Harding was presenting data on VX-680, which Vertex partnered with Whitehouse Station, N.J.'s Merck & Co Inc. in 2004. (See BioWorld Today, June 23, 2006.)

Vertex, of Cambridge, Mass., and Merck also presented Phase I data on Monday, along with the announcement that the partners plan to move the compound to Phase II.

In the trial, which began in June 2005, involved 15 patients that already had failed Gleevec plus either Sprycel or AMN107.

The presenter - an understudy for lead investigator Frank Giles, who was giving another presentation somewhere in the vast bowels of the Orange County Conference Center - said that the drug showed particular promise for patients with the so-called T315I mutation, which has so far been the one bcr-abl mutation unresponsive to anything thrown at it in the clinic to date.

The investigators reported that six out of nine patients with the T315I mutation had "some degree of hematological response" to VX-680.

They concluded that VX-680 is "the first reported T315I inhibitor with clinical activity," but it surely will not be the last, since interest in developing an inhibitor that targets that mutation appears to be enormous. In a single session, Sunday's posters sported no fewer than four biotech-academia collaborations in a row reporting preclinical results for novel compounds active against the T315I bcr-abl mutation. Mechanistically speaking, the compounds were an ATP competitor, two kinase inhibitors and a heat-shock protein 90 inhibitor, presented by Innovive, of New York; Ariad Pharmaceuticals, of Cambridge, Mass.; San Diego's TargeGen; and Cambridge, Mass.-based Infinity Pharmaceuticals, respectively.

That frenzy might seem surprising given that patients with mutations in the T315I mutation are only one subset (albeit the most needy one) of patients with refractory CML, which are themselves only a subset of patients. And that subset appears to be relatively small. Investigators from the IRIS study group, which had compared Gleevec to interferon plus cytarabine (formerly the standard of care) presented Monday five-year follow-up data on patients receiving Gleevec. The data, which also were published in the Dec. 7, 2006, issue of New England Journal of Medicine, indicated that the overall five-year relapse rate was 17 percent.

But Stephen Burley, chief scientific officer of SGX Pharmaceuticals Inc., of San Diego, explained that "the story for the CML patients is excellent, but I do believe that resistance is ultimately inevitable in every patient," because Gleevec does not eradicate the leukemic stem cells. Burley said that "ultimately, all newly diagnosed patients will immediately go on combination therapy," as is the case with HIV. SGX presented a poster on its own T315I-fighter, SGX-70393, Saturday.

Other notable news from ASH:

Amgen Inc., of Thousand Oaks, Calif., presented a number of studies on its erythropoiesis-stimulating protein Aranesp (darbepoetin alfa). In a Phase II, single-arm, open-label, 52-week study of treatment with Aranesp administered every three weeks, 74 percent of anemic patients with low- or intermediate-risk myelodysplastic syndromes who had not previously received an erythropoiesis-stimulating agent (ESA) had an erythroid response, with 59 percent classified as major response. A 17-week randomized, double-blind, placebo-controlled, Phase II study evaluating Aranesp administered every four weeks for anemia in cancer patients not undergoing chemotherapy and/or myelosuppressive radiotherapy showed that patients receiving Aranesp were nearly three times more likely to achieve a hematopoietic response than patients receiving a placebo. Data from another study showed that extended dosing of Aranesp is effective in increasing hemoglobin levels to the target level and reducing the need for red blood cell transfusions in patients with chemotherapy-induced anemia.

Dynavax Technologies Corp., of Berkeley, Calif., announced preliminary data from an ongoing open-label Phase IIa study of the company's TLR9 agonist used in combination with rituximab for patients with non-Hodgkin's lymphoma. Patients treated with the TLR9 agonist who had clearly increased expression of TLR9 agonist- and interferon-inducible genes showed a prolonged time to progression as compared to patients who were less responsive to the drug and to historical controls. The combination of rituximab and the TLR9 agonist was well tolerated.

Others presenting:

Celgene Corp.'s Revlimid (lenalidomide) was the focus of 49 posters detailing its benefits across a range of indications; Genta Inc. detailed a randomized trial of Genasense (oblimersen) in advanced chronic lymphocytic leukemia showed that a durable clinical benefit correlates with major objective response; Affymax Inc. reported results from an ongoing Phase II trial of Hematide in anemic cancer patients receiving chemotherapy; and Alexion Pharmaceuticals Inc. said an open-label, Phase III study demonstrated eculizumab's ability to significantly improve PNH patients over a year's worth of treatment. Cell Therapeutics Inc. said pixantrone's complete remission rates and survival data in relapsed, indolent non-Hodgkin's lymphoma patients pointed to a new potential registration trial.

In addition, Telik Inc. reported data showing that Telintra enhances the production of granulocyte-colony stimulating factor and granulocyte-macrophage colony-stimulating factor; Avalon Pharmaceuticals Inc.'s AVN944 was shown to inhibit IMPDH and induce apoptosis-related biomarkers in patients with hematological cancers; and data demonstrated that Geron Corp.'s telomerase inhibitor cancer drug is active against cancer stem cells from multiple myeloma patients. OrthoLogic Corp.'s Chrysalin (TP508) showed specific receptor-binding activity and effects in human endothelial cells, and Pharmion Corp. reported new data validating Vidaza response rates in myelodysplastic syndromes.

Vion Pharmaceuticals Inc. reported data on Cloretazine (VNP40101M); Ziopharm Oncology Inc. presented positive ZIO-101 myeloma findings; BioCryst Pharmaceuticals Inc. said clinical results suggested that Fodosine demonstrated activity in certain types of leukemia and lymphoma; and Kosan Biosciences Inc.'s second-generation Hsp90 inhibitor, alvespimycin, showed antitumor activity in refractory leukemia. Also, Phase I/II data supported Biogen Idec Inc.'s continued development of its anti-CD23 antibody for chronic lymphocytic leukemia, Bioenvision Inc. released the latest data on Evoltra in pediatric and adult leukemias, MedImmune Inc. highlighted its advancing cancer pipeline and Hana Biosciences Inc. reported data on Talvesta (talotrexin) and Marqibo (vincristine). Osiris Therapeutics Inc. updated a Phase II trial of Prochymal for acute graft-vs.-host disease, and ChemGenex Pharmaceuticals Ltd. detailed the activity of Ceflatonin and Gleevec combination therapy in CML patients resistant to Gleevec alone.

Among initial clinical data, Genmab A/S reported early results from ongoing studies of HuMax-CD4, preliminary Phase I data from Sunesis Pharmaceuticals Inc. demonstrated SNS-595's promising clinical activity in patients with advanced leukemias, GPC Biotech AG presented preliminary data on its anticancer monoclonal antibody 1D09C3 and Novacea Inc. detailed positive Phase I findings on AQ4N in lymphoma. Neose Technologies Inc. reported positive Phase I data on NE-180, Gemin X Biotechnologies Inc. said Phase I results demonstrated GX15-070's clinical activity in myelodysplastic syndromes and Micromet Inc. released interim Phase I findings on MT103.

More news: Allos Therapeutics Inc. presented interim results from its ongoing Phase I/II trial of PDX (pralatrexate) in patients with relapsed or refractory non-Hodgkin's lymphoma and Hodgkin's disease; Amgen Inc. said interim results from an open-label extension study showed that long-term administration of AMG531 stimulated platelet production and was generally well tolerated in adult patients with immune thrombocytopenic purpura; and Bioenvision Inc. said Phase II data of BIOV-121 demonstrated significantly higher response rates and improved survival compared to the current standard of care, especially in high-risk subgroups.

Also, Genzyme Corp. and Berlex Inc. announced results from CAM307, an international Phase III trial comparing Campath with chlorambucin in previously untreated patients with B-cell chronic lymphocytic leukemia; Kosan Biosciences Inc. presented results from a dose-escalating Phase Ib trial of its lead Hsp90 inhibitor, tanespimycin, in combination with bortezomib, showing a high degree of antitumor activity and tolerability in patients with multiple myeloma who had previously progressed following treatment with multiple conventional therapies; and Millennium Pharmaceuticals Inc. said several trials of Velcade (bortezomib) in relapsed multiple myeloma showed overall response rates as high as 93 percent and complete and near-complete response rates as high as 43 percent.