By Mary Welch

Dark clouds continued to hang over pimagedine, Alteon Inc.¿s advanced glycosylation end-product (AGE) formulation inhibitor, as the company said it will close out a Phase III trial in end-stage renal disease (ESRD), but remains ¿hopeful¿ about the drug¿s prospects.

The news comes less than six months after the company disclosed a preliminary analysis of Phase III trial data that showed pimagedine did not reach statistical significance in its primary endpoint for Type 1 diabetics with overt nephropathy, or progressive kidney disease. (See BioWorld Today, Nov. 11, 1998 p. 1.)

Alteon will meet with the FDA this quarter to discuss data on the Type 1 diabetes trial and the future of pimagedine.

¿Obviously our strategy for the future on many fronts is clearly dictated by the outcome of our meeting with the FDA,¿ said Kenneth Moch, president and CEO. ¿It¿s a very pivotal meeting, and one that we will go into with a lot of detailed data and present it in a straightforward manner. I am hopeful.¿

Originally, the study of pimagedine for ESRD was a Phase II study, and it was expanded into a Phase III in July of 1997, with patients still being enrolled.

Trial Set The Bar Very High¿

¿Patients with ESRD die at a high and predictable rate,¿ Moch said. ¿About 45 percent die within two years. Our Phase II trial was showing a differential in the mortality rate, between the placebo and the drug. We expanded it into a Phase III, and set a mortality differential rate of 50 percent, meaning that only 22.5 percent of the people would die after two years.

¿That was a very high bar to set,¿ Moch said. ¿We could have expanded this trial to a higher number of patients to show statistical significance. However, the expansion to a larger trial would strain the statistical underpinnings in such a way that it wasn¿t considered appropriate. It was a statistical decision, based on the fact that we want to conduct a trial that has a probability of working. It¿s a trial-success issue.¿

On the FDA¿s table will be data from the completed Phase III trial in Type 1 diabetics with overt nephropathy. In that trial, the primary endpoint ¿ reduced risk of doubling serum creatinine ¿ did not reach statistical significance. However, the data achieved a statistically significant reduction in urinary protein, LDL cholesterol and triglycerides, as well as lowered diastolic blood pressure and the progression of retinopathy. In addition, the data indicated favorable outcomes in other measures of renal function, including estimated creatinine clearing and glomerular filtration rate.

¿It¿s a very ill patient population, for whom there are no specific treatments,¿ Moch said. ¿The company received fast-track designation because of the unmet need in this patient population. We have to make sure that we¿ve done everything in our power to see if this drug should go forward.¿

Pimagedine is designed to inhibit formation of AGEs by preventing glucose from binding to proteins. AGEs have been shown to be a causative factor in many of the complications of diabetes and age-related diseases, including kidney disease, nerve damage, atherosclerosis and retinopathy. Everyone develops AGEs, but diabetic patients are prone to high levels as a result of excess glucose in their bloodstreams. Accumulation of AGEs can damage kidneys, blood vessels and nerves.

To date, Alteon has received $37.5 million from its development partner Genentech Inc., of South San Francisco. The collaboration, at the time of its 1997 signing, was estimated to be worth at least $200 million, excluding royalties. Genentech made an initial $15 million investment, and agreed to fund development costs up to $48 million. The pact further provided that Alteon could receive up to $50 million in milestones related to regulatory filings and approvals in the U.S. and Europe. Genentech returned the rights to Alteon following the negative preliminary Phase III report for Type 1 diabetic patients. (See BioWorld Today, Dec. 5, 1997, p. 1, and Feb. 10, 1999 p. 1.)

In March 1998, Alteon ended a Phase III study of the drug in Type II diabetics, following the recommendation of an external advisory panel that found an unfavorable risk-to-benefit ratio. (See BioWorld Today, March 20, 1998, p. 1.)

The company also investigated the use of pimagedine for inflammatory conditions, starting a Phase I/II study with topical pimagedine. The company has not pursued this indication further, Moch said.

Alteon¿s stock (NASDAQ:ALTN) closed Friday at $0.906, up $0.093.