Editor

Non-small-cell lung cancer gets most of the press, but the less common, small-cell tumors strike in about 25 percent of cases - and could provide an entry to the market followed by handsome revenues for the likes of Poniard Pharmaceuticals Inc. and would-be competitor Pharmion Corp.

At the start of the month, Poniard kicked off a pivotal Phase III trial testing picoplatin in SCLC called SPEAR (Study of Picoplatin Efficacy After Relapse), conducted under a special protocol assessment agreement with the FDA. The randomized, controlled study is enrolling about 400 patients who are refractory to - or who have progressed within six months of completing - treatment with first-line, platinum-containing chemotherapy of cisplatin or carboplatin.

Poniard's primary efficacy endpoint is overall survival, though investigators also are tracking overall response rates, progression-free survival and disease control. The trial is set up to detect at least a 33 percent increase in survival over best supportive care.

"It's a miserable disease, where there's a lot of opportunity to do combination therapies," noted Jerry McMahon, chairman and CEO of Poniard. Chemo patients whose SCLC recurs only live 16 weeks to 20 weeks. "We'd love to move it into a first-line setting [eventually]," he said.

Coming up behind picoplatin is Pharmion's third-generation anthracycline amrubicin, which aims to launch a Phase III trial by the end of this year in SCLC. Picoplatin (which has already shown a 27-week overall survival benefit) might be a hard act to follow.

Amrubicin trials can boast an 8.8-month median survival result, but it came from Japan. They were done by Nippon Kayaku Co. Ltd., which markets amrubicin under the trade name Calsed in Japan, where the drug (developed by Dainippon Sumitomo Pharmaceuticals Co. Ltd.) won approval in 2002 for SCLC and NSCLC.

A confirmatory Phase II study is under way in the U.S. and Europe, and investors expect to hear more about the Japanese data at the American Society of Clinical Oncology meeting in Chicago in early June.

So far, all that's available as standard therapy for patients whose SCLC has progressed despite chemo is GlaxoSmithKline plc's Hycamtin (topotecan), which carries troubling hematological side effects and has a 5 percent treatment-related mortality rate when the full course is used, McMahon noted. Oncologists have been looking for a better way, and picoplatin might be just the ticket. Data from the Phase III trial are expected in the fourth quarter of 2008 or the first quarter of the following year.

Poniard has picoplatin in Phase I/II trials for metastatic colorectal cancer, and Phase I data are due at the ASCO meeting. Another early stage trial is testing the compound against prostate cancer, but the colorectal bid seems particularly promising, with the 185-patient study in Europe testing the drug in combination with 5-flurouracil and leucovorin, as part of a modified FOLFOX regimen (which typically consists of fluorouracil, leucovorin and oxaliplatin, given separately in a single cycle).

Sanofi-Aventis Group has the colorectal-cancer market cornered with Eloxatin (oxiplatin), against which picoplatin eventually will go head to head in trials. The Phase I part of the study will include about 45 patients to determine safety and settle on a maximum tolerated dose. Then, in Phase II, picoplatin will be tried as a replacement for oxaliplatin in FOLFOX vs. the regular FOLFOX, a trial 80 percent powered to show a difference in neuropathy between the two arms at p<0.15. The primary endpoint of the trial is progression-free survival, and survival data likely will not become available until 2008.

Though SCLC likely is the easiest route to approval for picoplatin, the bigger money waits in colorectal cancer, especially if the FOLFOX-plus-picoplatin, or FOL-P regimen, turns out to work just as well but with less peripheral sensory neuropathy (PSN, a side effect common with oxaliplatin) when used as part of FOLFOX. Bristol-Meyers Squibb Co.'s Paraplatin (carboplatin) also brings high rates of neuropathy, nephropathy and ototoxicity, but picoplatin's results so far show only mild to moderate effects in those areas. A physician survey by Lazard Capital Markets found that 60 percent of doctors believe neuropathy-sparing remedies are only "moderately effective" or "not effective" at treating PSN - and 70 percent said they would switch to FOL-P if results merited.

Picoplatin brings only a "very manageable myelosuppression that oncologists can deal with and treat," McMahon told BioWorld Financial Watch. "The time is now to find a platinum that has a more manageable safety profile, and that we can link to Avastin or Erbitux, whatever is going to be moved into a first-line setting."

CIBC World Markets pegged worldwide peak sales of picoplatin for second-line SCLC at about $360 million, with about $200 million in off-label sales in front-line disease and for other cancers, but CIBC noted the numbers "could be conservative" if picoplatin's side-effect profile continues to improve, or if it works better, or both.

"If picoplatin is approved for first-line [colorectal cancer], we would expect an additional $320 million in worldwide sales of the drug in 2013, conservatively," wrote CIBC analyst Bret Holley in a research report.

Picoplatin's history is tangled. The compound came originally from Johnson Matthey plc and the Cancer Research Campaign (a research group in the UK). Johnson Matthey spun out AnorMED Inc. in 1996, and two years later AnorMED granted AstraZeneca plc an exclusive worldwide license to picoplatin. In 2001, after trying picoplatin against solid tumors in Phase I and Phase II trials, AstraZeneca returned all rights to AnorMED.

But this probably was no reflection on the drug. At the time, positive late-stage results with AstraZeneca's Iressa (gefitinib) for NSCLC were popping, and the pharma giant most likely wanted to focus on Iressa and the larger market. (AstraZeneca had tried picoplatin in second-line SCLC, with strongly positive results, but still opted not to go ahead.)

Poniard - then known as NeoRx Corp. - licensed picoplatin in 2002, and later negotiated worldwide rights. Genzyme Corp. (which bought AnorMED for $580 million in 2006) stands to get royalties of 5 percent to 9 percent on picoplatin's net sales.

Analysts tend to echo McMahon's optimism about the Phase III pivotal study in SCLC. "It's a clean registrational trial," he said. "When you go up against no-chemo, it reduces your risk substantially."

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