There's a simple way to describe leukemia - it's a blood cancer that starts in the bone marrow and is recognized by the proliferation of leukocytes, or white blood cells - but sifting through the subtypes, available treatments and would-be therapies is hardly an easy task.
Even more of a challenge is figuring out which prospective drugs have the best chance of success in the clinic and on the market.
First, the breakdown of types. About a dozen have been found, but the main ones are named according to the cell type involved, i.e., myeloid or lymphoid, and the rate at which the disease advances, which determines whether the illness is acute (moving quickly and affecting the function even of immature cells) or chronic (moving slowly, and not disrupting the growth of already established cells).
If abnormal cells have made their way as far as the body's T cells or B cells before turning into cancer, the type of leukemia may be characterized accordingly.
The four major leukemias, then, are lymphocytic and myelogenous, in their acute and chronic forms. About 144,000 people in the U.S. have leukemia now, with another 30,000 cases expected by the end of 2002.
In adults (who are 10 times more likely than children to get leukemia), acute myelogenous and chronic lymphocytic are the most common forms; in children under 15 years old, acute lymphocytic is the most common.
Five-year survival rates depend on the form, but they can be grim. For acute lymphocytic, the rate is 63.5 percent. For acute myelogenous, 19 percent. For chronic lymphocytic, 73 percent. For chronic myelogenous, 34.5 percent.
The current treatment is chemotherapy, with more than 40 drugs in use, costing about $15,000 annually.
"That's a low-ball estimate," said Chrystyna Bedrij, chief investment officer with Griffin Securities, which has compiled an ambitious overview of the leukemia treatment field in a report that, she noted, has gained an approving nod from the M.D. Anderson Cancer Center.
"More severe cases [cost] more than that," she said, and some drugs may be more expensive, such as Gleevec (imatinib mesylate), the much-ballyhooed therapy from Novartis SA that was approved in May 2001 and sold $255 million in the first half of 2002. Gleevec targets platelet-derived growth factor receptor and inhibits the Bcr-Abl kinase.
"It's the gold standard, and everyone else falls around that," Bedrij told BioWorld Financial Watch. "But is it the gold standard or the marketing standard? I don't know. They were selling the next day [after approval], which is almost unheard of."
With a marketing application reviewed by the FDA in less than three months, Gleevec also is approved in gastric cancer and has garnered attention in the mainstream press as well as medical journals. (See BioWorld Financial Watch, April 15, 2002.)
"It's definitely the strongest in its category [of drugs]," Bedrij said, adding that it's being used off-label for other leukemias as well.
Pablo Vegas, senior analyst with Griffin, cited some side-effect problems with Gleevec and pointed to a separate drug advancing in the chemotherapy space: the second-generation nucleoside analogue Clofarex (clofarabine), being developed by Bioenvision Inc. and Ilex Oncology Inc., which began its first combination trial in October.
Clofarex is being tested in the Phase I/II study with ara-C (cytarabine) in adults with a spectrum of hematologic malignancies, but it was already in Phase II trials in the U.S., which are being conducted by Ilex in both pediatric and adult populations with acute refractory leukemia, and in Europe by Bioenvision. Some Phase II results are expected to be disclosed next month at the American Society of Hematology meeting in Philadelphia.
"We like Bioenvision's because it's a molecule similar to [other nucleoside analogues] but it works better, and it has a more favorable side-effect profile, which is especially important for the pediatric population," Vegas told BioWorld Financial Watch.
The drug seems to damage the DNA of leukemia cells more effectively than Fludara (fludarabine), a nucleoside analogue from Schering AG, and has the favored properties of another, similar drug, Johnson & Johnson's Leustatin (cladribine).
Bedrij noted that "leukemia, in itself, is not a huge market, but Bioenvision is going to be really effective in that market. I expect some big announcements [at the ASH meeting]."
A more lucrative market is non-Hodgkin's lymphoma, she added.
"There are 50,000-plus patients in [NHL], bigger than the total leukemia market, and I see Bioenvision going after them," she said.
"I don't think Gleevec is targeting that area, and it's where the patients are," she said.
Susan O'Brien, professor of medicine at M.D. Anderson, noted that Clofarex was developed by scientists there before it was bought by Ilex, "so we're very big on the drug."
"We've used it to treat relapsed or refractory acute myelogenous leukemia with good results," as well as in some pediatric patients. "We think it could also potentially be used in the chronic leukemias," she said.
Ilex also has the anticancer monoclonal antibody Campath (alemtuzumab), which was developed with Millennium Pharmaceuticals Inc. and sold $10.2 million in the third quarter, up 6 percent, with sales totaling $46.9 million since the product was approved in May 2001 for chronic lymphocytic leukemia in patients who failed Fludara therapy.
The sales amount was slightly lower than some analysts expected, but the drug is believed to be moving toward more acceptance as a front-line therapy for CLL. Campath is used mainly now as third-line salvage therapy for that indication - although not by many physicians, probably because of concerns over toxicity. The drug is in two Phase II trials as a front-line treatment, where alkylating agents have been the choice, sometimes with corticosteroids.
Ilex's market research among 200 physicians found they preferred to use it in combination with Fludara or Rituxan (rituximab), the non-Hodgkin's lymphoma drug from Genentech Inc., though more than half said they would increase their use of Campath and more than three-fourths said they would start using it.
Still strong are the first-generation nucleoside analogues such as Fludara. Fludara and Leustatin are the two most often used nucleoside analogues. Another choice in that treatment area is Gemzar (gemcitabine), from Eli Lilly and Co.
Rituxan, partnered with IDEC Pharmaceuticals Corp., can hardly be discounted. Also being studied as a rheumatoid arthritis drug, Rituxan has grabbed about 24 percent of the market for CLL - although the third-quarter jump of 38 percent in Rituxan sales was due mainly to physicians' favoring the drug for NHL.
Other players in the leukemia space are Cell Therapeutics Inc.'s Trisenox (arsenic trioxide), for acute myelogenous patients whose disease has recurred after initial therapy, and Enzon Inc.'s Oncaspar, a pegylated version of the enzyme L-asparaginase, for acute lymphocytic leukemia.
Among the leukemia drugs in Phase III are Genta Inc.'s Genasense, a targeted inhibitor of Bcl-2, for chronic lymphocytic leukemia, and Maxim Pharmaceuticals Inc.'s Ceplene, a free radical blocker based on naturally occurring histamine, for acute myelogenous leukemia.
Undergoing Phase II trials are Tragen Pharmaceuticals Inc.'s ISF154; Novogen Ltd.'s phenoxodiol; SuperGen Inc.'s Nipent, an already approved small-molecule purine analogue for hairy-cell leukemia (an uncommon type of adult chronic lymphocytic leukemia); and the GVAX vaccine from Cell Genesys Inc., in various Phase II trials.
Although research is marching steadily forward, there have been setbacks in the hunt for new leukemia approaches. Making headlines recently was Protein Design Labs Inc., which in May dropped development of Zamyl in acute myelogenous leukemia patients after a Phase III trial failed to show statistical significance. The drug is a humanized antibody that binds to the CD33 antigen on myeloid leukemia cells.
And the leukemia field generally is starved for fresh ways to fight.
"There's a lot in early stage [research] in CLL, and some small developments in B-cell CLL, but nothing much has gone on," Bedrij said.
Hence what seems to be the growing success of Gleevec and Rituxan, which could overshadow - at least for the moment - the promise of drugs such as Clorafex.
O'Brien pointed out that although Gleevec is approved for later-stage chronic myelogenous leukemia, the drug targets patients whose DNA has changed to form the Philadelphia chromosome (named after the city where it was discovered), and about 20 percent of acute lymphocytic patients also have the chromosome.
"So [Gleevec] does cross the boundary, in terms of chronic and acute leukemia," she said, and Rituxan's versatility looks promising as well.
"Each of these drugs is very exciting, but their niches are smaller," she said.
Regarding the latter drug, she said, the "real breakthrough" is its use with chemotherapy as "co-potentiators."
O'Brien said "there is some specificity to where drugs may be the most active, but it's not complete," and used the example of low-grade lymphoma and CLL.
"They're both indolent diseases and they tend to be chemo-sensitive," she said. "Patients relapse and can be treated and go into remission three our four different times. As a single agent, Rituxan works better in low-grade lymphoma than CLL" - but combined with chemotherapy, that picture can change.
"More and more people are using it all the time," O'Brien said. "The data are very encouraging but very limited. Different drugs kill cells differently. If you look at some of the prototypical cancers that are cured with chemotherapy - people often use Hodgkin's disease as an example - we took active single agents and combined them."
A similar approach was used in tuberculosis, she added.
Bedrij said that, in terms of companies making money on existing drugs, market research such as that conducted by Ilex is important, along with getting the word out to physicians.
"That's nine-tenths of the battle, unfortunately," Bedrij said. "I mean, look at the ads for Paxel [paroxetine]," GlaxoSmithKline plc's popular antidepressant, which continues to sell well despite news reports of withdrawal problems.
Added Vegas: "We all know how this works. [Success is largely] pure marketing, and word of mouth."
O'Brien called the topic "hazy," since treatments such as Clofarex may not have been approved but could benefit from attention, so that patients will know about therapies when they reach the market.
"Clearly, in that setting, the way to do it is through data," she said, and getting papers published in significant medical journals. "Nowadays, patients are so savvy in terms of the Internet that they can also access these things," she said. "If the data's out there, that's what generates interest."