National Editor

Hoping to make good on the promise of personalized medicine in cancer therapy, Xanthus Life Sciences Inc. raised $30.8 million in a Series B financing that will be used to pay for clinical trials next year.

"We're looking for this to fund Amonafide [XLS-001, the company's lead drug] through Phase II," said Michael Boss, chief operating officer for Cambridge, Mass.-based Xanthus.

Amonafide, a site-specific DNA intercalating agent and topoisomerase II poison, already has been studied in Phase II trials by the National Cancer Institute, which tested its hydrochloride salt form of the drug against metastatic breast cancer.

Xanthus' Phase II program in breast cancer will begin shortly.

"We plan to begin with an intravenous formulation, but the new salt that we've developed has the potential to move into an oral formulation in due course," Boss told BioWorld Today, adding that the drug also might work well against hormone-refractory prostate cancer.

Using phenotyping technology for the liver enzyme N-acetyltransferase-2 (NAT2), Xanthus aims to individualize treatment by determining each patient's ability to metabolize the drug and then prescribing a dose to induce a response against the tumor with minimal myelosuppressive effect - based on the preliminary finding that such an approach serves fast-metabolizer patients especially well.

"We give patients a probe compound and then determine a few hours later the rate of the metabolism," Boss said. The compound likely will be caffeine, either in a cup of coffee or via a pill, in testing done as part of the entry procedure for trial participants.

"What's different about our approach vs. the traditional pharmacogenomics approach is that here, the aim is not to exclude people, it's to find out if we can get the right dose for the right patient," Boss said.

Population studies have found the NAT2 phenotype is variably distributed, with 60 percent of Caucasians discovered to be slow metabolizers and 80 percent of Japanese/Asians fast metabolizers.

The NCI showed XLS-001 to be "marginally active" in treating advanced breast cancer, with response rates that ranged from 18 percent to 50 percent in patients with Grade 3 or 4 thrombocytopenia (low blood platelets).

But that was before researchers knew XLS-001 is metabolized to an active metabolite, and a population study in women with breast cancer in the mid-1990s established that the wide differences in myelosuppression - lessening of bone marrow activity, which leads to fewer red blood cells, white blood cells, or platelets - was related to patient disparities in N-acetylating activity.

Specifically, at identical doses, slow NAT2 acetylators achieved a minimal response rate (suggesting they were under-dosed), while rapid acetylators had greater hematologic toxicity and slower clearance of XLS-001.

"That's an unusual circumstance, and it's very specific to this particular drug," Boss said, noting that with many drugs, faster metabolism means clearing the drug quicker.

"In this case, a fast metabolizer would be given a lower dose," he said.

"We're born with a set of genes and those don't change during our lives, but our lifestyle - diet, exercise, smoking - all affect us, and these are not genetic phenomena," Boss said. "In terms of treating disease, it would be very nice to have an isolated example where people are taking one drug, but people have been taking a variety of drugs for multiple conditions. You've got a very complex effect."

The smartest approach, he said, "is to determine in each person, at that time, what would be the right dose of the oncology drug."

In preclinical studies, Boss said, Xanthus has C-1311 (XLS-002), a member of the imidazoacridinone anticancer drug family, with a structure said to be "closely aligned" to mitoxantrone (Novantrone, OSI Pharmaceuticals Inc., of Melville, N.Y.) and losoxantrone.

Orally active XLS-002 readily sequesters tumor-cell nuclei and lysosomes and seems particularly effective in animal models of slow-growing tumors, such as colorectal cancer and brain tumors that are normally difficult to treat, Xanthus said.

"We aim to get that into the clinic next year in a Phase I trial," Boss said.

Xanthus also said it appointed as CEO Richard Dean, who will assume duties in mid-January. Most recently, Dean was the head of strategic business development in diagnostics and radiopharmaceuticals at Schering AG, of Berlin.

The financing was led by new investor Oxford Bioscience Partners, of Boston, which was joined by CDP Capital-Technology Ventures, of Montreal; Hambrecht & Quist Capital Management, of San Francisco; GIMV, of Antwerp, Belgium; Genechem, of Montreal; China Development Industrial Bank, of Taipei, Taiwan; CDIB BioScience Ventures, also of Taipei; and Yasuda, of Beijing.