PEPTIDE T

Peptide T first gained notoriety in late 1986 and early 1987 when researchers at the Karolinska Institute in Stockholm reported in the Lancet improvements in lymphocyte counts, psoriasis and neuropsychiatric functions in four patients who had been given the drug on a compassionate basis (Wetterberg and others, 1987). Since that time the drug has undergone further tests in Sweden and the United States with scientists reporting some positive results.

Although there was considerable evidence from the earliest laboratory tests that peptide T is nontoxic, the drug has been bogged down for nearly two years in a small phase I toxicity trial in the U. S. Indeed, phase II efficacy studies have been delayed in part because of the drug's lack of toxicity. The questionable logic behind this policy dictates that phase II studies can not begin until a maximum tolerated dose is discovered in phase I. Researchers had ample warning this might be the case, because they could not find an LD50 dose (a dose potent enough to kill half the animals to which it is administered) in studies conducted before human trials began.

An application by the drug's sponsors for phase II studies of peptide T in the National Institutes of Health extensive testing system was denied in late July, 1989. And Bristol-Myers Co. in May, 1989 withdrew from a federal license to market and manufacture the drug.

Peptide T was discovered by Candace Pert, Ph.D., who was chief of the brain biochemistry section at the National Institute of Mental Health. The mechanism of action of the drug is different from most antivirals in that it does not act directly on HIV or infected cells. Rather it is intended to block the virus from entering cells (Pert and others, 1986).

Eight amino acids which constitute part of the viral envelope called gp120 are thought by some scientists to be the key by which HIV gains entry through the CD4 receptor. Indeed, a common metaphor by which the drug's action is explained is the lock and key.

Pert theorized that if HIV could enter the CD4 receptor, it must mimic a chemical produced by the body that used the same receptor (Pert, 1987). She found a sequence of eight amino acids in a hormone called vasointestinal peptide (VIP) that duplicated a section of gp120 and designed peptide T as a way of plugging all the body's CD4 "locks" with artificial "keys". The drug's lack of toxicity is thought to derive from its similarity to a chemical produced by the body.

But the controversy swirling around the drug centers on its efficacy, not its toxicity. And the fact that the drug is plodding through a slow-moving toxicity study has done little to help resolve the issue in a timely fashion.

Six months after Pert and others asserted in the Lancet that peptide T helped Swedish AIDS patients, William Haseltine, Ph.D., of the Dana-Farber Cancer Institute in Boston reported that he and several other researchers found peptide T did not inhibit the virus in test tube experiments. Furthermore, the viral envelope was constantly changing, thus the sequence of amino acids in peptide T could not possibly duplicate a section of the viral envelope (Sodroski and others, 1987).

Two years later, Joseph Sodroski, M. D., one of the drug's critics, asserts, "There is no scientific basis for concluding that peptide T will perform the (blocking) function. The first work that said the peptide T region is not the region on gp120 that interacts with the receptor was from our lab (Kowalski and others, 1987) and Larry Lasky's (Lasky and others, 1987) group at Genentech, which pointed more to the carboxyl terminus on gp120. Subsequently, Hans Wigsell (Nygren and others, 1988) at the Karolinska Institute has cleaved gp120 and they have a fragment that has cleaved off peptide T-related sequences completely and that still binds to CD4."

The drug's sponsors replied that Haseltine, Sodroski and others had used high concentrations of virus in their experiments (Ruff and others, 1987), and that no one knew what concentrations were actually present in the bodies of AIDS patients.

Frederick Goodwin, M. D., then director of NIMH, called a meeting where the opposing researchers could arrive at a consensus about the drug's mechanism of action. However, no agreement was reached (Barnes, 1987). evertheless the Food and Drug Administration, which had a representative at the meeting, granted permission to begin testing the drug in people, half a year after the application was filed.

At about this time, a researcher at Oncogen, a small Seattle- based company later acquired by Bristol-Myers Co. devised her own in vitro tests of peptide T and found the drug worked against low and moderate viral concentrations, but not against high concentrations (Barnes, 1987). This work helped influence the pharmaceutical giant's decision to seek a license for peptide T from NIMH, which has a patent pending on the compound.

Douglas Brenneman, M. D., of the Laboratory of Developmental Neurobiology at the National Institute of Child Health and Human Development has asserted in articles in Nature (Brenneman and others, 1988) and Drug Development Research (Brenneman and others, 1988) that gp120 is associated with neuronal cell death and that VIP and peptide T blocked the action of gp120 in the test tube.

In an interview, Dr. Sodroski said, "That work is of dubious significance. It's not clear what neuronal cell death in that
system really means....The neuronal cells in that system are mouse cells. The problem is that gp120 does not bind to mouse CD4."

Although FDA allowed phase I testing to begin, the National Institutes of Health refused the sponsors' application for a phase I study of the drug in the agency's drug trials network. The agency wanted more documentation of the drug's mechanism of action as well as more studies in animals. NIMH (which is part of the Alcohol, Drug Abuse and Mental Health Administration, not the NIH) searched for months for a medical center in which to conduct its studies, finally contracting with the Los Angeles County/University of Southern California Medical Center. Peter Heseltine, M. D., was selected as principal investigator.

Intravenous administration of peptide T to the first group of six patients in this trial began in November, 1987. NIMH expanded this study in July, 1988 to include 24 patients. They were given the drug by intravenous injection for twelve weeks, followed by a four week "washout" period, during which no antivirals (including peptide T) could be taken. The patients were then given the option of continuing to take the drug intranasally. This study focused on searching for toxic side effects and determining a suitable dose for later trials of the drug's effectiveness.

The first results of human trials came from the Karolinska Institute, where seven patients were given the drug by intravenous injection. Dr. Lennart Wetterberg and others reported, "There was no evidence of clinical improvement in any of the patients except in one case where a remarkable improvement in the patient's psoriasis was observed. From all patients HIV was isolated from peripheral blood mononuclear cells or plasma before and after treatment. However, in three of the seven patients there was a decline of HIV p24 antigen levels in serum.

"During treatment a transient rise in the CD4 (T4) cell count was recorded in two patients. In four of the six treated patients, which could be evaluated, the area of pathologically altered brain white matter, as estimated by magnetic resonance imaging, was reduced.

"These findings suggest that peptide T may have biological effects in HIV-infected individuals. The results from this small series of patients should be followed by further trials to evaluate the possible therapeutic usefulness of peptide T" (Wetterberg and others, 1988).

Dr. Wetterberg did not respond to requests to reconcile the statement of "no evidence of clinical improvement" with the assertions made in his next two paragraphs.

The Swedish researchers suspended a double-blind, placebo controlled study in 36 patients when Bristol-Myers was granted the federal license in August, 1988. The Karolinska team sought financial assistance as well as clarification of their access to the drug. The study was not resumed.

When Bristol-Myers acquired the license for peptide T some people anticipated the pharmaceutical giant would speed up testing of the drug and resolve the lingering questions about its efficacy. However, the trial's pace was not increased. The company withdrew from the license in May, 1989. Susan Yarin, manager of public affairs for pharmaceuticals at Bristol-Myers, said, "We determined that peptide T's antiviral activity against the HIV-1 virus is limited."

Some of the drug's supporters said the firm's decision had a strong financial component, namely to concentrate the millions of dollars necessary for large phase II trials on DDI. Integra Institute, which had shared the license with Bristol-Myers, recently notified the government it wishes to be the sole licensee, according to Pert, one of Integra's founders. Pert responded to Bristol-Myers' announcement saying, "I think it's an unwise decision. Integra is ready, willing and able to meet all responsibilities of the license to the drug." Bristol-Myers will continue to fund the Los Angeles trial and supply the drug to a phase I trial at the Fenway Community Health Center in Boston (see "Boston, Los Angeles: Peptide T Trials Recruiting," AIDS TREATMENT NEWS # 78, May 5, 1989).

Reports from the Los Angeles study presented at the Fifth International Conference on AIDS in Montreal concentrated on the drug's ability to improve neuropsychiatric and neuromotor functioning in HIV-impaired individuals. Peter Bridge, M. D., from NIMH reported that peptide T reversed neuropsychiatric problems in AIDS and ARC patients with HIV-related brain and central nervous system impairment.

Dr. Heseltine asserted there were significant improvements in brain function measured by tests of memory, motor speed, attention and cognitive processing. The patients' test scores declined when the drug was withdrawn after 12 weeks of treatment. He said comparisons with other clinical trials that measured the ability of AZT to improve brain function showed peptide T to be twice as effective. Heseltine was associated with early studies of AZT.

Responding to these assertions, Dr. Sodroski said, "It may very well make people feel better or give them better appetites, or do other things because it does have this homology (similarity) with VIP, but in terms of stopping HIV infection in patients, I think peptide T will do absolutely nothing."

Michael Ruff, Ph.D., Pert's associate, reported at Montreal that cerebrospinal fluid "from 9 out of 18 HIV-infected individuals (in the Los Angeles trial) showed significant (>20% of control) in vitro neuronal killing activity which was always blocked by peptide T. "

A draft of a letter submitted to The Lancet and expected to be published in July, 1989 reports on results of administering peptide T to six patients: "No toxicity was observed. Where HIV-associated deficits (2 Standard Deviations below population norm) had been present at baseline, cognitive neuromotor function returned to normal during drug testing. Similarly, where HIV constitutional symptoms had been present at baseline (weight loss, watery diarrhea, fatigue, anergy, HIV- associated dermatitis), improvement or resolution was observed. Two patients were p24 antigen positive at baseline, becoming negative at follow-up. T4 counts remained stable while T8 counts increased 50% on average (400 to 600). No changes were observed in natural killer cell activity or in delayed hypersensitivity skin testing....Constitutional/neuropsychiatric benefit, absent toxicity, and reduced p24 antigenemia in these patients is encouraging" (Bridge and others, 1989).

A serious snafu at the Los Angeles study occurred this summer. Two volunteers who had gone off AZT for one month in compliance with the protocol were told nine hours after they had entered the hospital that there was no drug for them. They were asked to return a month later. One volunteer came down with PCP and the other was told one month later there still wasn't enough drug. The volunteer said he had great difficulty getting information from officials connected with the study and has decided not to participate in the trial. He says his T4 count decreased significantly while he was off AZT. "I feel helpless and victimized, in addition to fearing for my life more than ever before," said Gordon McMahon, Ph.D., the volunteer.

The third study of the drug began in May, 1989 at the Fenway Community Health Center in Boston. Sixty volunteers will receive the drug intranasally for six months. Seventeen people have enrolled in the trial so far, according to Kenneth Mayer, M. D., the study's research director and an assistant professor at Brown University. "The jury is still out (on the drug's efficacy) and these studies need to be done....We don't have enough data to know the drug's efficacy," Dr. Mayer said.

[David Smith is a free-lance reporter based in San Francisco, who has participated in the Peptide T study in Los Angeles. He has reported on AIDS treatments for the Bay Area Reporter, The San Francisco Sentinel, Bay Windows, Frontiers, Health Week and other publications.]

References

Barnes, D. Debate over potential AIDS drug. Science, 237(4811), pages 128-130, July 10, 1987.

Brenneman, D. and others. Neuronal cell killing by the envelope protein of HIV and its prevention by vasoactive intestinal peptide. Nature, 335(6191), pages 639-642, October 13, 1988.

Brenneman, D. and others. Peptide T prevents gp120 induced neuronal cell death in vitro: relevance to AIDS dementia. Drug Development Research, volume 15, pages 361-369, 1988.

Bridge, P. and others. Peptide T: Improvements in phase I trial of AIDS patients. Draft of letter submitted to Lancet, July 1989.

Kowalski, M. and others. Functional regions of the envelope glycoprotein of human immunodeficiency virus type 1. Science, 237 (4820), pages 1351-1355, 1987.

Lasky and others. Delineation of a region of the human immunodeficiency virus type 1 gp120 glycoprotein critical for interaction with the CD4 receptor. Cell, volume 50 number 6, pages 975-985, 1987.

Nygren and others. 95- and 25-kDa fragments of the human immunodeficiency virus envelope glycoprotein gp120 bind to the CD4 receptor. Proceedings of the National Academy of Sciences U. S. A., volume 85 number 17, pages 6543-6546, 1988.

Pert, C., and others. Octapeptides deduced from the neuropeptide receptor-like pattern of antigen T4 in brain potently inhibit human immunodeficiency virus receptor binding and T-cell infectivity. Proceedings of the National Academy of Sciences U. S. A., volume 83, pages 9254-9258, December 1986.

Pert interview, Science Impact, pp. 6-7, June 1987.

Ruff, M., and others. Peptide T[4-8] is core HIV envelope sequence required for CD4 receptor attachment.Lancet, 2(8561), page 751, Sept. 26, 1987.

Sodroski, J., and others. HIV envelope-CD4 interaction not inhibited by synthetic octapeptides. Lancet, 1(8547), pages 1428- 1429, June 20, 1987.

Wetterberg, L., and others. Treatment with peptide T in seven immunodepressed HIV infected patients. Draft of paper submitted to AIDS, Gower Academy Journal, London, June, 1988.

Wetterberg, L., and others. Peptide T in treatment of AIDS. The Lancet, 1(8525), page 159, Jan. 17, 1987.