New life for an old drug

Israeli researchers hope to gain approval for clinical trials soon.New hope for AIDS and cancer patients lies in the resurrection of a drug slated for testing soon in clinical trials in Israel – a drug that dates back to World …

Israeli researchers hope to gain approval for clinical trials soon.New hope for AIDS and cancer patients lies in the resurrection of a drug slated for testing soon in clinical trials in Israel – a drug that dates back to World War II, when it was regarded as a “miraculous drug” that boosted the immune systems of U.S. soldiers suffering from the flu.

Reticulose, also known as Product R, is claimed not only to suppress the immune system, but in other circumstances to promote it. The hoped-for applications for this “immunomodulator” drug could run the gamut, from treating autoimmune diseases such as rheumatoid arthritis and immune-suppressing diseases such as AIDS to reducing complications from toxic chemotherapy.

Product R is likely to be tested soon in clinical trials in Israel. An application has been presented by New York-based Advanced Viral Research Corp. to Health Ministry officials for treating seriously ill patients with AIDS and cancer at Hadassah-University in Jerusalem’s Ein Kerem and Kaplan Hospital in Rehovot.

Efforts to design animal models for the study of Product R are about to be launched by professor Irun Cohen, a world-renowned immunologist and physician and director of the Robert Koch-Minerva Center for Research into Autoimmune Diseases at the Weizmann Institute of Science.

The original drug has a long, meandering history. It was developed in 1933 by Vincent LaPenta, who wanted to treat his patients in the United States with medication that mimicked the human immune system. From 1940 to 1960, it was listed in the widely used Physician’s Desk Reference.

Produced by Phillips Roxanne Pharmaceuticals, the injectible drug was described as a lipo-protein nucleic acid complex and prescribed against viral diseases, including encephalitis, hepatitis, mumps, influenza and herpes.

The company was forced by 1962 U.S. Food and Drug Administration regulations to substitute bovine (cow) serum for horse serum as a stabilizer (blood from horses being linked to a condition called serum sickness). The rights were then sold to Key Pharmaceuticals, whose scientists did not know how the drug worked.

Owing to a small change that had been made in the drug, the FDA regarded it as an entirely new one that had to start the approval process from scratch. Unable to decipher the chemistry, Key Pharmaceuticals dropped the drug and sold it to a company in Singapore that eventually filed for bankruptcy.

But, instead of disappearing, the drug continued to fascinate Bernard Friedland, a Key chemist who bought the drug rights in 1985, along with a disused factory in the Bahamas.

“I felt the drug was too important to lose,” said Friedland, now 75.

In 1995 he asked professor. Shalom Z. Hirschman to investigate the drug. For 28 years Hirschman had been a leading clinician and researcher at New York’s prestigious Mount Sinai Hospital, where he founded one of New York’s first AIDS treatment centers. He had conducted research on nucleic acids at the U.S. National Institutes of Health in the 1960s.

Hirschman was struck by the importance of Reticulose.

“I was looking at a peptide nucleic acid, a relatively new class of substances that have powerful effects on the inflammatory process,” said Hirschman, who granted a two-hour interview to The Jerusalem Post – the first Israeli media exposure of Product R.

Quickly realizing the tremendous potential for interacting with the human immune system, he discussed it with his wife, Fran Neumann-Hirschman, a geneticist and AIDS crisis worker. Given samples of the drug to test and knowing a terminal AIDS patient, she asked that Reticulose be used in a last-ditch effort to save him.

“It was too late for him,” she said. But the couple were so impressed by Reticulose that Hirschman left his tenured position at Mount Sinai and set up Advanced Viral Research Corp., establishing himself as its president and CEO.

ADVR is a publicly owned biopharmaceutical firm committed to researching, developing and bringing to market new, effective therapies for viral and other diseases. Its flagship drug, Product R, is a more effective variant of the original drug serendipitously developed by LaPenta, he said.

During the past three years Product R has been tested in the Bahamas on AIDS patients already receiving three or more anti-AIDS (nucleoside analogs and protease inhibitor) drugs. Controlled trials showed that patients’ toxic reactions to the anti-AIDS drugs were “significantly mitigated” by the addition of Product R, which served to modulate their immune systems.

“Eight seriously ill AIDS patients who had never received any treatment before are still getting Product R and doing very well in their fifth year of getting the drug,” Hirschman said. Two hundred AIDS patients in the United States also have been treated with the drug and have shown “great progress.”

Indeed, Hirschman said, patients already suffering toxic reactions to the nucleoside analogs markedly improved after getting Product R injections. This apparent beneficial effect of Product R has allowed patients to be treated with effective doses of the traditional AIDS drugs for prolonged periods of time. Moreover, the absence of the toxicity of the anti-AIDS therapeutic regimen allows patients to live normal, productive lives.

Aware of the fact that many chemotherapy drugs interfere with nucleic acid synthesis, Hirschman proposed using Product R to reduce the toxic effects of these anti-cancer drugs. “If, indeed, Product R mitigates the toxicity of anti-tumor chemotherapeutic agents, as it appears to mitigate the toxic effects of antiviral drugs used to treat HIV infection, then the possibility of treating cancer patients with more effective doses of chemotherapeutic agents for longer periods of time holds the promise of significantly increasing the effectiveness of cancer chemotherapy.”

Hirschman said that so far, Product R has shown “absolutely no side effects” in patients. Hirschman, an Orthodox Jew and graduate of Yeshiva University’s Albert Einstein College of Medicine in New York, was the personal physician of the Lubavitcher rebbe for four years. He has strong ties to Israel and visits regularly, as do his children.

He contacted Alf Fischbein, director of the Selikoff Center for Environmental Health and Human Development in Ra’anana, and asked him and his team to lay the groundwork for clinical trials of Product R in patients with advanced-stage cancer and AIDS.

Hirschman is hopeful that approval for trials in Israel is forthcoming from the Health Ministry and expects that if convincing results can be documented, FDA approval of Product R will follow.

The FDA has already approved ADVR’s application for Phase I trials in the United States on Product R as an investigational new drug, a topical therapy for genital warts caused by HPV. Infection with this virus is a worldwide problem because of victims’ high risk of developing cervical cancer. There are estimates of 24 million to 40 million people being infected with the virus in the United States alone, and so new, effective and nontoxic therapies are greatly needed.

“A lot more research and clinical trials are needed to see long-term effects and discover which other diseases Product R could be effective against,” Hirschman said. “But if it continues to show beneficial effects it could help people suffering from chronic illnesses to lead a normal life.

“We think it opens a whole new field of chemistry, one that could lead to the development of more drugs We have already started to work on this.”