West Coast Editor

TopoTarget A/S drew more attention to a steadily growing class of drugs by licensing the preclinical histone deacetylase (HDAC) inhibitor PX118490 to dermatology-focused LEO Pharma A/S in a deal worth as much as €34 million (US$43.4 million), with €2 million up front and the rest in potential milestone payments.

LEO, of Ballerup, Denmark, gets all worldwide rights to the compound for psoriasis and skin disorders. The arrangement, including tiered royalties on any future product sales, puts CuraGen Corp. in line for half of the payments from LEO, thanks to CuraGen's pact with Copenhagen, Denmark-based TopoTarget. (See BioWorld Today, June 7, 2004.)

PX118490, which so far has been tested only in animal models of psoriasis, emerged from a research collaboration between TopoTarget, CuraGen and LEO.

"This is definitely a class of compounds making its debut," said Reni Benjamin, analyst with Rodman & Renshaw in New York. The first HDAC inhibitor to be approved in the U.S. is Merck & Co. Inc.'s Zolinza (suberoylanilide hydroxamic acid, once known as SAHA), cleared in mid-October for cutaneous T-cell lymphoma.

CTCL, though a rare form of non-Hodgkin's lymphoma, is "not such a small indication," Benjamin noted - about 1,500 new cases are diagnosed yearly in the U.S. - and HDAC-targeted drugs for other cancers could be next. Merck, of Whitehouse Station, N.J., acquired Zolinza in its 2004 buyout of Aton Pharma Inc., of Tarrytown, N.Y.

CuraGen has its own hydroxamate-type HDAC inhibitor in the clinic under the TopoTarget deal. Late last month, the firms reported encouraging preliminary results from three of 13 ongoing Phase Ib/II trials.

Scientists believe HDAC inhibitors, which work by altering levels of gene transcription, could be useful against various diseases. Cancer has been the main focus so far, but research last year at Denver-based Myogen Inc. that pointed to a link between HDAC and heart disease led Novartis AG, of Basel, Switzerland, to expand their 2003 deal. (See BioWorld Today, May 27, 2005.)

Others to make news recently in the HDAC inhibitor space include MethylGene Inc., of Montreal, and Pharmion Corp., of Boulder, Colo., which late last month began a Phase I/II trial testing MGCD0103 in combination with Gemzar (gemcitabine) from Eli Lilly and Co., in patients with solid tumors, including pancreatic cancer.

"I think Methylgene probably has more than just the cancer focus in mind," Benjamin said. EntreMed Inc., of Rockville, Md., also has an HDAC inhibitor in preclinical study.

In March, Gloucester Pharmaceuticals Inc., of Cambridge, Mass., said interim data from its Phase II study of the HDAC inhibitor depsipeptide (also known as FK228) in patients with metastatic hormone-refractory prostate cancer proved encouraging. The firm also has depsipeptide in pivotal trials for cutaneous T-cell lymphoma.

HDAC inhibitors are believed to hold value against inflammatory diseases, too, and could even help in bone formation. (See BioWorld Today, Nov. 18, 2004.)

Benjamin compared HDAC inhibitors to epidermal growth factor receptor inhibitors such as the non-small-cell lung cancer therapies Iressa (gefitinib), from AstraZeneca plc, and Tarceva (erlotinib), from Genentech Inc. and OSI Pharmaceuticals.

"They all have a particular class effect; they all the work the same way," he said.

In the first stages, researchers worried about possible toxicity with HDAC inhibitors, just as they did with proteasome inhibitors such as Millennium Pharmaceuticals Inc.'s Velcade (bortezomib) for multiple myeloma.

"The main indication where toxicity is a tolerable concern is in cancer," Benjamin said, which is probably why early efforts tested HDAC inhibitors mainly there. But as with the proteasome blockers, drugs targeting HDAC proved safer than expected.

"They're going to gain in stature," he said. "Clearly, there's been a validation of the space with the approval of [Zolinza]."

No Comments