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Gay Men's Health Crisis
Peptide T Fails in Phase II Test
Jim Brudner
March 1, 1994
GMHC Treatment Issues 1994 Mar 1; 8(1): 3

Results from the first controlled, phase II trial of Peptide T show that the widely used underground drug is not effective in controlling pain associated with HIV-related peripheral neuropathy.

Background of Peptide T Peptide T, created in 1986 at the National Institute of Mental Health (NIMH), was one of the first drugs to be designed specifically as an AIDS therapy. The basic concept of the drug - the small molecule occupies cellular receptor sites in the brain and the immune system that might otherwise be used by gp120 - the outer (envelope) protein of HIV, is both simple and elegant. The drug's developers suggest that Peptide T can slow or reverse neurological (nerve system) and cognitive (mental or thinking abilities) effects of HIV, including AIDS dementia, fatigue and pain.

Peptide T has been the subject of many anecdotal accounts from underground users regarding its effects on cognition, constitutional symptoms and neuropathy. However, the Phase II peripheral neuropathy trial is the first peptide T study to provide rigorous evidence of either the drug's efficacy or lack of it.

What is Peptide T? Peptides, the general class of compounds to which Peptide T belongs, are small strings of amino acids. Because some peptides function as the active portion of many hormones, growth factors, and neurotransmitters, they play important roles in digestion, immunity and emotion.[1] These peptide components interact with key cells in the responsive organs by means of receptor molecules located on the cells' surfaces. The same receptors may exist in more than one organ system. At least 30 are common to the brain and immune system.

One common receptor site is "CD4." This is the molecule that the HIV envelope protein gp120 attaches to as the first step in infecting several different types of immune cells. CD4 receptor sites also exist on glial cells, which excrete various substances necessary for maintaining the metabolism of nerve cells (neurons). One theory is that the neurocognitive effects of HIV, such as dementia, are due to the linkage of gp120 to CD4 molecules on glial cells. Some scientists believe that this improper "connection" impedes glial cell performance and damages neurons. Peptide T is designed to mimic the attachment sequence in gp120. According to Candice Pert, a former NIMH researcher who is Peptide T's inventor and chief promoter, introducing Peptide T into the brain allows the drug to compete with HIV and free-floating gp120. By occupying CD4 receptor sites, it prevents HIV from interfering with brain function.

Other experts point out, though, that the process leading to HIV-associated nerve tissue damage is extremely varied from one individual to another. The inflammatory process that arises in response to the presence of HIV in the brain can disrupt the operation of neurons and their support cells, which form a complex and delicate interactive network. Another important factor is the opening up of the calcium channels on neuron membranes. Too much calcium can poison cells. In addition, other HIV proteins, besides gp120, seem to be toxic to cells in neural tissue.

Pert makes a number of other claims for Peptide T, which she calls a "selective antidote" to gp120. In the first place, Peptide T may also compete with HIV and free gp120 in binding to the CD4 on immune cells. A growing number of researchers suspect that when gp120 links up with the CD4 sites on the immune system's T-helper cells it leads to a cascade of events fatal to these cells (a process known as "apoptosis"). However, at this time, there is no evidence to substantiate Peptide T's benefits in this area.

Peptide T has been found to reduce levels of tumor necrosis factor-alpha (TNF-alpha).[2] Release of this cytokine has been associated with HIV disease progression. Excess TNF-alpha is widely alleged to contribute to wasting syndrome, increased replication of HIV, immune cell dysfunction and death, and nerve cell damage as well.

Finally, Peptide T is very similar to the active section of vasoactive intestinal peptide (VIP), a naturally occurring regulator of digestion that may have "growth promoting functions" in the central nervous system.[3] VIP seems to interact with the CD4 on immune system cells, too. This has led some researchers to suggest that Peptide T can supplement VIP in promoting general mental and physical health.

What is Peripheral Neuropathy? Peripheral Neuropathy is usually characterized by a sensation of pins and needles, burning, stiffness, or numbness in the feet or toes. It is a common, sometimes painful, condition in HIV-positive patients, affecting up to 30 percent of people with AIDS.[4] It is perhaps most common in people with a history of multiple opportunistic infections and low CD4 counts.[5] Peripheral neuropathy in people with AIDS can range from a minor nuisance to a disabling weakness.

Trial Results The purpose of the Phase II study was to determine if Peptide T was effective in reducing pain associated with peripheral neuropathy in HIV-infected individuals. According to officials of Advanced Peptides, Inc., a Pennysylvania-based company which sponsored the Phase II study, there were "no statistically significant differences between Peptide T at 6mg per day and placebo in the treatment of painful peripheral neuropathy in AIDS patients." The study, conducted in Miami, New York and San Francisco, enrolled 108 patients, of whom 81 were considered evaluable for analysis. Advanced Peptides, with which Dr. Pert is associated, is one of two companies licensed to develop the U.S. government-owned drug.

In a secondary analysis of the study, company sources reported that Peptide T also failed to show significant benefits related to cognition. This was based on a battery of eight neuropsychological tests which participants received at the beginning of the trial (baseline) and at week twelve. Study participants received either Peptide T or placebo for twelve weeks. The drug was given by spray through the nose (intranasally) in doses of 2mg, three times per day. All participants had initial scores of at least 8 on the 15 point Gracely Scale, a self reported measure of pain. During the study, participants kept pain diaries in which they recorded a Gracely pain score three times per day. The goal of the study was to see if the Gracely Scores of participants receiving active drug improved more than those receiving placebo. Improvement was defined as a decline on the scale of at least 2.5 points. At twelve weeks, approximately 35 percent of the patients in each group showed such improvement, demonstrating no advantage of Peptide T over placebo. The result was the same for patients irrespective of CD4 count or use of AZT.

Despite the negative study results, seventeen study participants have elected to continue taking the drug which is being supplied by Advanced Peptides without charge. In addition, several hundred persons with HIV infection and AIDS continue to purchase Peptide T on the underground, according to Sally Cooper, Executive Director of the PWA Health Group, a New York-based buyer's club which sells the drug.

Cooper speculates that one factor in the study's failure to find a statistical benefit might have been the health of the trial participants. Over 60 percent of the enrollees, she says, had fewer than 50 CD4 cells. Another factor, according to New York-based activist Anna Blume, might have been what she describes as the "high pain level" required of study participants. Blume says she has heard anecdotal reports of people with lower pain levels who have had success in using Peptide T to control it.

In addition, Candice Pert claims that blood tests showed that up to a third of the people in the study's placebo arm actually were taking peptide T, presumably obtained from the underground suppliers. This alleged violation of the trial protocol, which could not be independently confirmed by Treatment Issues, would account for some of the apparent improvement in the placebo arm - up to 11.5 percent out of the 35 percent to be exact.[6] The peripheral neuropathy study, nevertheless, is the only double-blinded phase II (efficacy) study of Peptide T that has been completed. The failure of the trial to show any benefit is sobering news - particularly to advocates and users of the drug.

Advanced Peptides told GMHC Treatment Issues that it will not abandon the drug's development, but is exploring the possibility of a phase II trial aimed at determining whether the drug prevents the onset of opportunistic infections and increases survival. A company proposal to examine the peptide's effects on quality of life variables was recently turned down by the Food and Drug Adminstration (FDA), which cited the lack of an adequate quality of life scale on which participants might be measured.

Peptide T Still Available on the Underground Testing difficulties have not prevented the drug from becoming one of the top sellers of the AIDS underground - despite a pricetag of $260 a month. The drug's top-selling status has been fueled by widely repeated anecdotal accounts of relief from AIDS dementia and cognitive impairment, of increases in quality of life variables, and indeed, of relief from the pain of peripheral neuropathy. (Of course, as with all anecdotal evidence, extreme caution must be exercised in attributing improvements to a particular therapy.) Additional Phase II Studies Underway Because it has been suggested that Peptide T might be able to reverse HIV-related neurological impairment, a phase II multicenter study of the drug's neuropsychological effects is nearing completion. This study, sponsored by the NIMH, was expanded to two new sites (U.C. San Diego and the University of Miami) after participant recruitment at the University of Southern California failed to meet expectations. Enrollment was closed in December 1993, and results are expected in the Fall 1994. A negative result, says Anna Blume, would probably sink any remaining interest in developing Peptide T as an AIDS drug.

A smaller, phase II dose comparison study is being conducted at Sibley Hospital in Washington, D.C. Twenty four patients completed the initial open label phase of that study, which is now being analyzed. In a continuation phase, ten patients are receiving one of three doses of Peptide T.

In addition, Yale University researchers are continuing their work on administering Peptide T to HIV-positive injection drug users (IVDUs). They are presently seeking additional subjects for an ongoing study.

Earlier Peptide T Studies To date, the Phase II peripheral neuropathy study is the only placebo-controlled, double blinded (efficacy) study of Peptide T to have been completed. Such studies are, of course, the only studies considered by scientists to provide conclusive evidence of whether a drug is useful. However, a series of small phase I safety studies have been reported. Several of them, according to advocates of Peptide T, suggest a possible lessening of HIV-related symptoms in the areas of neuropsychology and general well being.

A very early phase I study was conducted at Sweden's Karolinska Institute in 1987. Four near-terminal men with AIDS were treated with intravenous Peptide T (1mg twice daily) for one week, followed by 2mg twice daily for three weeks. Significant decreases in serum levels of p24 antigen, decreased levels of beta-2 microglobulin and significant improvement in abnormal MRI (magnetic resonance imaging) scans and lymphocyte counts were reported.[7] One patient's psoriasis was reported to have improved. No toxicities were reported.

No toxicity was again observed in a second uncontrolled phase I study conducted by Bridge and Heseltine et. al. at the University of Southern California (USC). Six AIDS patients with moderate neuropsychiatric impairment and a mean CD4 cell count of 42 received intravenous Peptide T for 30 days followed by intranasal administration (sprayed into the nostrils) for three to seven days. According to a letter published in The Lancet, "where HIV-associated [neurocognitive] deficits were present, 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 p24 antigen positive subjects became negative; CD4 cell counts remained stable and CD8 counts increased 50 percent.[8] In a separate USC study, fourteen volunteers with HIV-related cognitive impairment were given intravenous Peptide T (.1mg to 3.2mg/kg/day) for twelve weeks. After a four-week washout period, six of the participants were given 25mg intranasal Peptide T daily for another eight weeks. According to the investigators, toxicity was minimal. They reported a reduction in neurological symptoms and improvements on a repeated battery of neuropsychological tests compared to a group of 18 HIV-negative gay male controls who took the same tests but were given neither drug nor placebo. There were no significant immunologic or antiviral changes.[9] At Boston's Fenway Community Health Center, 32 patients not using antiretrovirals were randomized to receive one of three dose levels of intranansal Peptide T (1.2mg per day, 6mg per day, 30mg per day) in a 24 week on-off-on trial (12 weeks on drug, four weeks on placebo, eight weeks on drug).

Researchers noted a stabilization of CD4 cells, reduction in p24 antigenemia, and significant improvements in memory loss and malaise.[10] On a battery of five neuropsychological tests, statistically significant clinical benefits were suggested by the researchers. In their abstract for the Seventh International AIDS Conference in Florence in 1991, the researchers noted that the lowest dosage group (1.2mg per day) showed the greatest improvement.[11] Another phase I study was conducted at Yale University, where five HIV-positive cognitively-impaired intravenous drug users (IVDUs) with HIV were treated intranasally with Peptide T (5mg, three times a day for four weeks, followed by four weeks of placebo). Subjects, who were maintained on methadone, showed an improvement on neuropsychological tests on which they had previously been impaired, compared to those given placebo.[12] The most recent clinical work has come from a trio of researchers in Toronto who presented several papers at the Ninth International AIDS Conference in Berlin and at an HIV neuroscience conference held in Vienna. One study of fifteen patients was designed to assess whether or not Peptide T was immunosuppressive. According to the authors' paper, the subjects' immune capacity was "enhanced" and not decreased following two weeks of Peptide T treatment thereby "confirm[ing] that Peptide T is not immunosuppressive."[13] In addition, the researchers found that levels of TNF were decreased in five of eight patients.

The Canadian investigators also presented results of an ongoing open label study that they have been conducting for over three years, in which 50 symptomatic HIV-positive patients with CD4 cell counts below 200 (median 15) have self-administered 8.5mg of Peptide T daily by subcutaneous injection. In a subgroup of this study that began with 24 patients and ended after sixteen weeks with fourteen patients still participating, statistically significant improvements were observed in the "areas of energy-fatigue, physical function, and overall health status." In addition, there was statistically significant improvement on several neuropsychological exams, and a reduction of nighttime awakenings. Said the researchers: "preliminary results support previous findings of neurocognitive improvement in patients given Peptide T and our findings that Peptide T can have a beneficial impact on health related quality of life by improving constitutional symptoms, particularly HIV-related fatigue."[14] Reported Side Effects of Peptide T Reported side effects related to Peptide T administration have been relatively minor. One patient in the Swedish phase I study had a transitory blood pressure drop when his infusion rate was increased. One patient in the USC phase I had a rash that recurred upon rechallenge with Peptide T. Participants in intranasal trials report occasional nasal congestion and related symptoms, and these have, on occasion, required either decongestants or antibiotics. According to a letter in AIDS Patient Care, participants in a study of Peptide T sponsored by the AIDS Clinical Research Center of Washington, D.C. experienced symptoms of a "second puberty," including increased hirsutism (excessive hair growth), acne, increased libido, wet dreams and an increase in serum testosterone levels.[15] The author of the letter concluded that "Peptide T may cause masculination and a rise in low or low normal serum testosterone levels in some HIV-positive patients. Further investigation into hormonal changes induced by Peptide T is warranted." Another potentially troubling side effect has emerged in anecdotal accounts of underground users and in the NIMH phase II study. Several Peptide T users reported bouts of extreme anger, which they attribute to the effect of the drug. Some of these individuals have discontinued use of Peptide T.

How to Get Peptide T Peptide T can be accessed in one of two ways: either participation in a clinical trial, or by purchase through the underground (buyers clubs). A vial of intranasal Peptide T costs $65, according to Sally Cooper of the PWA Health Group (212/255-0520). The vial, lasts a week when taken at a dose of 2mg three times a day. Pending completion of quality control tests, drug from a new supplier should reduce the price by approximately one third of its present cost. HIV- positive IVDUs are eligible to enroll in the Yale New Haven trial. Call Dr. Kosten at 203/781-4770. A pediatric trial will also soon be enrolling 40 children. Call Anna Blume at 718/363-1194.

Conclusion Data from the Phase II study suggest that Peptide T is probably not of significant benefit in the treatment of peripheral neuropathy in HIV-positive individuals. These results conflict with a number of earlier phase I studies and anecdotal reports of benefits from the use of Peptide T in some HIV-positive individuals. Reported side effects associated with Peptide T appear limited. A Phase II trial of the drug in the treatment of HIV-related neuropsychological conditions is near completion. It is likely that the results of this trial will determine the future development of Peptide T as a treatment for HIV-related conditions. In the meantime, while positive anecdotal reports can never be completely discarded, those who are currently considering the use of Peptide T are advised: caveat emptor (let the buyer beware).

References: 1 Candice B. Pert, Modern Medicine. January 1989. 57:44.

2 D.J. Phipps, et. al. Abstract PO A13 0232. Eighth International Conference on AIDS, Berlin, Germany. June 1993.

3 Pert, et. al. AIDS as a neuropeptide disorder: Peptide T, VIP and the HIV receptor. Psychopharmacology Bulletin.

4 Parry GJ. Ann Neurol.1988; 23 (suppl):S49-S53.

5 Cornblath ER, et al. Neurology. 1988; 38:794-796.

6 Personal Communication. Candice Pert. February 8, 1994.

7 Wetterburg L, et. al. The Lancet. 1987; 329:8525:159.

8 Bridge, TP, et al. The Lancet, 1989; 334:8656:226-227.

9 Bridge TP, Heseltine et. al. Psychopharmacology Bulletin. 1991; 27:3:237-245.

10 K. Mayer et. al. Phase I study of intranasal Peptide T: clinical and lab results, Fenway Community Health Center 4th Annual Public Forum, July 10, 1990.

11 Bridge et. al., Neuropsychologic Results of Control HIV-1 Trial of Peptide T, Abstract for the 7th International Conference on AIDS, Florence, Italy, June 16-21, 1991.

12 Rosen et. al. American Journal of Addiction, 1992; 1:332-338.

13 MacFadden, Phipps and Doob. Abstract PO-B28-2164. Ninth International Conference on AIDS, Berlin, Germany, June 1993.

14 Doob, Phipps and MacFadden, Paper presented at Neuroscience of HIV Infection: Basic and Clinical Frontiers Conference, Vienna, Austria, June 1993. Abstract published in Clinical Neuropathology 1993; 12(Sup. 1): S30.

15 Harris PJ. AIDS Patient Care. February 1992. 6:1.

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