By Mary Welch
A drug bought in bankruptcy court has demonstrated positive results in the fight against AIDS in a Phase III trial in Barbados.
The drug, Reticulose, is a non-toxic peptide nucleic acid that stimulates the cytocidal arm of the immune system and activates the production of cell signaling proteins, or cytokines.
Reticulose's owner, Advanced Viral Research Corp., of Yonkers, N.Y., expects to file an investigational new drug application with the FDA by the end of the year so Phase III trials can start in the U.S.
Conducted at the Queen Elizabeth Hospital, in Barbados, the clinical trial involved 43 HIV patients who had never received any treatments or therapy for the disease and were given Reticulose as a single agent. The patients showed an early and sustained increase in their CD4 and CD8 cell counts and in body weight. In addition, they displayed decreased viral loads in comparison to the placebo group.
None of the Reticulose-treated patients developed severe or life-threatening opportunistic infections. Plus there were no toxic reactions. CD4 is the cell infected with the HIV; CD8 is crucial to treatment responses.
"And on top of all that wonderful data, these patients had a sense of well being. They are doing and feeling well," said Shalom Hirschman, president and CEO of Advanced Viral Research. "It's a dawn of a new age where we fight disease by stimulating recovery of the immune system. The ability to stimulate immune system repair through internal cellular production of cytokines may be an important way to treat diseases."
The 43 patients received either Reticulose or a placebo for two months. The Reticulose patients averaged a 37 percent increase in their CD4 cell counts, while the patients in the placebo group showed a 7 percent decline. There was a 17 percent increase in the CD8 cell counts in Reticulose patients compared with a 2 percent increase in the control group.
Body weight increased in 71 percent of the treated group while 60 percent of the placebo patients lost weight. HIV viral loads decreased by at least 0.5 logs in four Reticulose treated patients but none in the other group.
Studies Target A Broad Range Of Disorders
Advanced Viral Research intends to continue studies of Reticulose for broad antiviral activities, autoimmune diseases, such as rheumatoid arthritis, and cancer.
In March Reticulose received approval from ANMAT, Argentina's equivalent of the FDA, for final testing in patients infected with HIV and human papilloma virus — "a two-for-one study," Hirschman calls it.
HPV is a sexually transmitted disease that causes genital warts and may be a cause of cervical cancer in women.
"The things you have to look at are: Is the drug safe? Does it have efficacy? This drug has had no reported side effects in three decades." Hirschman said. "The efficacy is there. This drug is an accident. Trying to find a therapeutic active peptide nucleic acid is like finding a needle in a haystack. It's a most unusual drug."
Not only is it unusual, it has a most peculiar history. Reticulose was marketed in the U.S. from 1940 through the early 1960s and was viewed effective in treating a number of interferon-related viruses such as Asian influenza, viral pneumonia, infectious hepatitis, mumps, encephalitis, herpes simplex and herpes zoster. No clinical data existed on the drug and its results only anecdotal.
The concept of an antiviral agent comprised of peptones, peptides, lipoproteins and nucleic acid was developed by Vincent LaPenta, a family physician who produced Reticulose. But he did not have it tested in any controlled studies. In the early 1940s, LaPenta's son formed Chemico Laboratories Inc. in Florida to manufacture the drug. Chemico distributed it in the U.S. until 1962.
In that year, the FDA issued new regulations that caused Reticulose to be designated a "new drug," requiring FDA approval. This action forced the drug to be withdrawn from the market and the rights were sold to Key Pharmaceuticals Inc., of Kenilworth, N.J., a division of Madison, N.J.-based Schering-Plough Corp., which produced and sold the pharmaceutical from Freeport, Bahamas, to countries outside the U.S.
First NDA Filed 30 Years Ago
Key filed a new drug application (NDA) in 1967, but the FDA told the company it would not approve the drug. Key withdrew the NDA and submitted an IND application the next year to conduct clinical trials. After four years with no action taken, the application was withdrawn in 1972 and Key sold the drug to a company based in Hong Kong. That company went bankrupt and Reticulose and the Bahamas manufacturing plant were sold to Bernard Friedland, who was a pharmacist at Key, and William Bregman, an engineer at American Electric Power Co. Friedland and Bregman then formed Advanced Viral Research in 1985. Friedland is chairman and Bregman is vice president.
"They bought it in bankruptcy court in 1984, but they couldn't tell the FDA how it works. They couldn't say what the active ingredients were, and until you establish that, you can't file for an IND," said Hirschman. "That's where I came in."
Not surprisingly, Hirschman got involved with the company in a roundabout way. His wife, a geneticist, was searching for anything to help a friend with HIV. She found the anecdotal research on Reticulose, tracked down Advanced Viral Research, and nudged her husband, then a professor of medicine and director of infectious diseases at Mount Sinai Hospital, in New York, to examine Reticulose.
"It was all hearsay evidence but I believed it could be useful in a way a to fight AIDS." He joined Advanced Viral Research as president and CEO in late 1996.
Since then, Reticulose has attracted some attention. Hirschman refused to comment on whether the company has received any overtures about collaborations.
In March 1997, the company entered a Cooperative Research and Development Agreement with the National Cancer Institute. The deal calls for a study on the molecular mechanism by which Reticulose affects the transcription of the gamma interferon gene.
"This whole thing was an accident," Hirschman said, "But the National Cancer Institute is interested. We have very promising data and we're hopeful to enter trials in this country as soon as possible." *