By Randall Osborne

On the verge of filing a new drug application (NDA) for Panretin gel, its topical formulation of 9-cis retinoic acid against AIDS-related Kaposi's sarcoma, Ligand Pharmaceuticals Inc. said Phase II trials with an oral version of the compound have shown encouraging results.

Patient response rates in the two multicenter, open-label trials with Panretin capsules reached 38 percent and 37 percent, and Ligand, of San Diego, said it will devote more of its resources to pushing the oral formulation of the drug to market.

Panretin capsules are also being studied for acute promyelocytic leukemia (APL). One of the ongoing Phase III trials in that program will be terminated, with a goal of filing an NDA next year for oral Panretin against Kaposi's sarcoma.

At the same time, Ligand is putting together the NDA for Panretin's gel formulation, said spokeswoman Susan Atkins.

"All hands are on deck working toward this NDA," Atkins said. "We expect to file it around March."

In the oral Phase II studies, Panretin capsules were given once daily at increasing doses to patients with biopsy-proven disease who had at least five skin lesions. The lesions were assessed every two weeks for response, over an evaluation period of 16 weeks.

One study, conducted by a group of oncologists called the AIDS Malignancy Consortium (AMC) and sponsored by the National Cancer Institute (NCI), enrolled 66 patients at eight sites and showed an overall response rate, for patients who met the evaluation criteria, of 38 percent (19 out of 50), including one complete responder, as measured by standard AIDS Clinical Trial Group criteria.

Side effects were manageable and included headache, dry skin, rash, alopecia, peeling and flaking, and hyperlipidemia.

The second study, conducted directly by Ligand, enrolled 57 men at five centers. Overall response rate for patients who met the evaluation criteria was 57 percent (21 of 37), and the response rate for all patients was 37 percent (21 of 57). Side effects were similar.

No response rate for all patients was available from the AMC trial, Atkins said.

"Everybody doesn't calculate exactly the same," she said, adding that Ligand provided the response rate of all patients — including those who did not meet evaluation criteria — because it had been calculated.

"We're trying to be Caesar's wife here," Atkins said. "We're trying to give all the information we have."

Almost all patients in both trials were on highly active antiretroviral therapy, including at least one protease inhibitor, before they started treatment with Panretin capsules.

Final results of both studies will be reported in scientific forums this spring.

Numerous Other Trials Ongoing

In addition to the two single-agent Phase II trials, Panretin capsules are being studied in a Phase I trial combined with interferon. That trial is expected to conclude in May 1999.

Phase II trials also are ongoing in breast, ovarian and pediatric cancers, as well as bronchial metaplasia.

"We've got it in a variety of trials that we're conducting and the NCI is conducting," Atkins said. "We want to get the NDA [for Panretin gel] filed, and after that we'll start being more concerned about reporting other trials."

Already completed are trials in myelodysplastic syndrome and severe plaque psoriasis. Results from those studies will be made public later this year, and the company expects to determine new indications for NDA filings. The studies in APL will continue.

Two pivotal Phase III trials showed 42 and 35 percent response rates at 16-week assessments, and the response rate rose as high as 48 percent when treatment continued.

The trial showing the 42 percent response rate, held in Europe, was so encouraging it was concluded early. (See BioWorld Today, Aug. 28, 1997, p. 1.)

Panretin was the lead product of a joint venture between Ligand and Allergan Inc., of Irvine, Calif., called Allergan Ligand Retinoid Therapeutics, to develop retinoid therapies for various cancers, as well as skin and eye diseases. Last November, Ligand bought ALRT from Allergan for $71.2 million. (See BioWorld Today, Nov. 25, 1997, p. 1.)

As a treatment for breast cancer, Ligand is developing the retinoid Targretin (LGD 1069). The drug showed regression in 72 percent of established tumors in one of the more commonly used rat models of the disease.

Ligand's stock (NASDAQ:LGND) closed Wednesday at $13.375, up $0.25. *