By Lisa Seachrist
Allergan Ligand Retinoid Therapeutics Inc. (ALRT) appears to be on track to file a new drug application in the fourth quarter of 1997 for its topical retinoid designed to treat Kaposi’s sarcoma (KS) based on positive clinical results from a Phase I/II trial and promising interim results from a pivotal Phase III trial.
Panretin — a topical gel formulation of 9-cis retinoic acid — shrank or eliminated as many as 30 percent of the treated KS skin lesions in AIDS patients in the Phase I/II trial.
“This is an exciting, statistically-significant result,“ said Susan Atkins, vice president of corporate communications with the San Diego-based company.
Retinoids are naturally occurring hormones chemically related to vitamin A and are known to regulate a number of cellular activities including cell growth. They work through six receptors that can be classified into two groups, RAR and RXR. Among other activities, retinoids can stimulate programmed cell death or apoptosis by activating different versions of the retinoid receptor. Panretin binds and activates all of the receptors.
ALRT is a joint venture undertaken by Allergan, of Irvine, Calif., and Ligand Pharmaceuticals Inc., in San Diego, to develop retinoid therapies for various cancers, skin and eye disease. Panretin is this venture’s lead product.
In the completed Phase I/II clinical trial, Panretin shrank or eliminated 27 percent of the treated KS lesions compared to 16 percent of the untreated lesions. Interim results from this study presented in Vancouver this summer at the XIth International AIDS Conference were slightly better showing that 30 percent of the treated lesions shrank or were eliminated by the drug whereas only 9 percent of the control lesions improved. However, this was an open-label study where patients served as their own controls. Some of the patient’s KS lesions were designated treatment lesions and others were index or untreated lesions. At the end of the trial some of the index lesions showed signs of being treated with Panretin.
“If you read between the lines, you can see that some of the patients were treating all of their lesions with Panretin,“ Atkins said. “That is why the double-blind, placebo-controlled pivotal trial is so important.“
The Phase III pivotal trial has the patients applying Panretin or placebo gel to their KS lesions for 12 weeks when all patients can switch to active drug if they so choose. The company announced at the Hambrecht & Quist Healthcare Conference in San Francisco, that looking at the interim results of the control group, only 9 percent have shown improvement in their lesions. In addition, the company intends to add 35 additional patients to the study to make sure that they can produce statistically significant data for an end of the year filing.
“These patients are being added so that the statisticians can work their magic,“ Atkins said.
Atkins also pointed out that the company is beginning a Phase II trial of systemic therapy for KS using Panretin Oral Capsules. In addition to KS, Panretin Oral Capsules are also being evaluated in clinical trials for renal cell carcinoma, non-Hodgkin’s lymphoma, multiple myeloma, prostate, breast and ovarian cancer.
The company also presented preclinical results of three new retinoid drugs in San Francisco. These drugs specifically stimulate the various retinoid receptors rather than turning them all on like Panretin. ALRT268, decreased the blood glucose and triglyceride levels of diabetic mice over a 14 day treatment period. The company is considering pursuing the molecule as a human treatment for non-insulin dependent diabetes.
The company also is considering a retinoid that specifically blocks activation of the RAR beta and gamma receptors which appear to be associated with retinoid side effects such as bone toxicity. And another product which selectively activates the RAR alpha receptor is being considered as a treatment for leukemia and breast cancer.
The company has yet to decide which of these three compounds it intends to take to clinical trials but fully expects to have two of them in clinical trials by 1998.
“I am very excited by retinoids,“ Atkins said. “They have broad cellular activities and now we are beginning to specifically target those activities.“