Gay Men's Health Crisis: Treatment Issues, Volume 8 no. 4 - June 1994
Dave Gilden and Jay Levin

A number of immune modulators have been tested in conjunction with anti-HIV drugs in an attempt to improve the immune response. Yet, results have been inconclusive and the side effects often severe. Recently, a small, unblinded Italian study reported that a substance known as alpha-thymosin (thymosin), when used in combination with alpha-interferon and AZT, provided more sustained increases in CD4 cells than AZT alone.

Just announced results from another, larger study of thymosin suggest that the drug is not effective as a treatment for chronic hepatitis B, however. The question now is whether Alpha 1 Biomedicals, the small, underfunded biotech firm developing thymosin, has the resources to mount new, redesigned trials.

Natural Thymic Hormones

The thymus gland has been identified as a key immune system organ. It is thought to be responsible for the development and regulation of the immune system cells that mature in that organ (such "T-cells" as CD4 helper cells and CD8 cytotoxic cells). The thymus seems to exert its regulatory functions through the secretion of various hormone-like products called thymic peptides. Although the importance of thymic peptides remains in dispute, several investigators have reported that thymic peptide products can assist development of immature, precursor cells into fully competent T-cells. They also regulate the functioning of T-cells once they have matured.

Alpha-thymosin is a thymic peptide that adjusts an individual's immune responsiveness when aberrations occur. Thymosin boosts the number of receptors on T-cells, especially for alpha-interferon and IL-2. It also increases the efficiency of T-cells' response to signaling agents and causes cells to produce more of them.[1]

Intercellular signaling molecules ("cytokines") like alpha- interferon and IL-2 commonly have severe adverse effects. These agents are released during disease to help bolster the inflammatory response, which causes a variety of flu-like symptoms. Thymosin, in contrast, circulates in the blood at comparatively constant levels. In a series of clinical trials involving a total of nearly 1,000 people, no serious side effects have been noted.[1] Since thymosin promotes the action of alpha-interferon and IL-2, combining it with these products could allow lower dosages to be used, resulting in both greater safety and more efficacy.

Thymosin in HIV

This year, an Italian research group led by Enrico Garaci published encouraging results from a small trial comparing various combinations of thymosin, alpha-interferon and AZT in people with HIV.[2] The trial enrolled 40 HIV-positive men and women with CD4 cell counts of 200 to 500 per cubic milliliter of blood and without previous treatment for HIV infection. (The trial was randomized, but unblinded - everybody involved knew who was receiving which treatment.) Unfortunately, the dropout rate in this already small trial was high: by the end of twelve months, only 28 patients were available for evaluation, and by eighteen months only 23 remained.

Trial volunteers were assigned to one of four groups. The first received 500mg of AZT twice daily. The second group received AZT plus two million units of natural human alpha- interferon twice weekly, and the third group received AZT plus 1mg thymosin subcutaneously twice weekly. The fourth group had the complete combination - AZT, thymosin and alpha-interferon.

Over the first ten months, CD4 counts rose by an equivalent amount in the AZT plus interferon group and in the triple combination group. In the AZT only group and the AZT plus thymosin group, CD4 counts fell or were stable, respectively. But then CD4 counts in the AZT plus interferon group on average dropped back to baseline whereas the triple-drug people saw their CD4 counts continue to rise. At twelve months, the average increase amounted to 187 CD4 cells per cubic millimeter of blood. At eighteen months, the average increase was 237 CD4 cells while the counts for the other three treatment groups were close to the original, baseline averages.

The small size and high drop-out rate of this trial make it difficult to have confidence in these results. Those who discontinued were not followed, and without this data, it is difficult to draw even tentative conclusions. Be that as it may, the Italian government subsequently funded a much larger, more definitive trial of the thymosin-interferon-AZT regimen. This 100-person study is now two-thirds enrolled. Investigators will present an update on this trial at the "Fourth International Conference on Combined Therapies," to take place next month in Sardinia, Italy. No confirmed data is available at present from this trial.

The investigators hope to release preliminary data on the first six months of treatment by the end of the year. Measurements will include assays of CD4 and CD8 counts, HIV p24 antigen, beta2 microglobulin (an index of immune activation), HIV levels in the blood, and a lab test for immune cell proliferation response. Crucial clinical data on the rate of opportunistic infections also will be available. (A reduced rate of opportunistic infections would confirm that the improvements seen in laboratory tests, if any, actually have functional value in improving people's health.)

A Disappointing U.S. Trial for HIV

Thomas Merigan, M.D., the director of the Center for AIDS Research at Stanford University, has been conducting an initial study of thymosin combined with PEG IL-2 (IL-2 joined to polyethylene glycol for increased stability) and AZT. Dr. Merigan, who has studied IL-2 for some years with disappointing results, says, "Thymosin has had some interesting results in Italy and with hepatitis [see below].

The point of this trial is to see how thymosin boosts the effect of IL-2 in patients with 50 to 200 CD4 counts, where IL-2 just starts to have an effect." Merigan is following changes in trial participants' CD4 counts and HIV levels.

The fourteen volunteers for this study started out on AZT alone (500mg per day) for eight weeks. Then they went on AZT plus IL-2 (one million units per square meter of body surface every other week) for another eight weeks. In the final twelve weeks, an escalating dose of thymosin was added. Merigan will not yet comment on the results of this trial, which enrolled its first volunteer a year ago. (The final analysis of the data will not be available until late summer, he says.)

Several informed sources have told Treatment Issues, though, that the trial has not found any benefits from the triple combination regimen. Some suggest that the participants were not receiving thymosin long enough to make a difference or that, alternatively, since patients in the U.S. trial, who had more advanced disease than those in the Italian trial, may have been too sick for thymosin to have an effect. A final possibility is that thymosin plus IL-2 is just the wrong combination for fighting HIV.

Discouraging Results with Hepatitis B

In the United States, Alpha 1 Biomedicals has concentrated on developing the product for chronic hepatitis B, which affects at least 300 million people worldwide. Chronic hepatitis C is also under study.

Of course, a safe treatment for chronic hepatitis would be of great interest to people with HIV, many of whom are co- infected with hepatitis B or hepatitis C. Progression of hepatitis disease may trigger progression of HIV or vice versa. Alpha-interferon, the only approved treatment for chronic hepatitis B, induces sustained disease remission in only 25 to 30 percent of those treated, and side effects often dictate stopping treatment.

Data from a phase II study of chronic hepatitis B suggested that thymosin might be a significant advance.[3] Nine of the twelve of the "thymosin treated" volunteers responded favorably to treatment, and seven (58 percent) had a sustained remission with normal liver tests and negative hepatitis B antigen status after four years.

However, recently announced results of a phase III, placebo controlled study indicate that thymosin was no better than placebo as a treatment for chronic hepatitis B. The 99 patients in the study received either thymosin or placebo for six months, with another six months of follow-up. After one year, eleven of the 49 people in the thymosin arm tested negative for hepatitis B virus DNA, compared to twelve of 50 people in the placebo arm.

Unraveling the Contradictions

The hepatitis B trial is extremely disappointing. The Italian group, meanwhile, is conducting a combined alpha-interferon plus thymosin study for hepatitis B and C in 30 people. Researchers are reporting high rates of remission, even in people who previously had not responded to interferon alone. Thymosin's main hope is now likely to be new trials using interferon and thymosin together.

But Alpha 1 may not be financially able to mount more trials, let alone large, definitive ones. The day the recent hepatitis B results were announced, Alpha 1 Biomedicals' stock fell by two-thirds.

The company has been further weakened by a dispute with the company's marketing licensee for outside North America and Europe, which is now before an arbitrator. That licensee, SciClone Pharmaceuticals, is demanding and may well get damages and greater rights to alpha-thymosin because Alpha 1 has not been able to provide the drug due to a breakdown in the manufacturing agreement with a Belgian company. The damage award alone could bankrupt cash-starved Alpha 1.

SciClone is moving aggressively to sell thymosin in Asia, which has an enormous population of hepatitis B carriers. (Thymosin is already approved in Singapore.) The day Alpha 1's stock price fell, SciClone bought 15 percent of the shares, making it Alpha 1's largest shareholder. This only adds to the uncertainty concerning alpha-thymosin's future development.

Meanwhile, Alpha 1's Italian licensee, Sclavo, has been caught up in Italy's general financial scandal, and progress in bringing thymosin to market in Italy (where it is approved as a vaccine additive) has been retarded.

Because of these difficulties, thymosin is not available outside of clinical trials anywhere in the world, although Italian supplies are expected to exist eventually. Thymosin may soon appear in the U.S. underground market, too, but wide availability awaits future positive trial data. Lacking quick, convincing results from the Italian HIV trials, funding will be a serious problem.

Despite the problematic aspects of past thymosin trials, some believe that the drug merits further scientific attention. The Los Angeles-based Search Alliance wants to conduct a rigorous study combining AZT, alpha-interferon and alpha- thymosin in HIV-positive individuals.

Chuck Chesson, Search Alliance's clinical trial coordinator, says, "Thymosin results have been interesting. The question has to be answered - people need to know whether thymosin works or not."

Although Search Alliance is a community organization, the total cost of this medium-size trial still will amount to $200,000, not counting the cost of the medicine. Encouraging findings from this economical option (or the current Italian government funded HIV study) may offer thymosin its only chance for garnering the grassroots and financial support. Without that support, its continued development is questionable, regardless of the compound's value.

References:

1. Goldstein, A. personal communication, April 24, 1994.

2. Garaci E, et al. International Journal of Clinical and Laboratory Research, 1994; 24(1):23-8.

3. Mutchnick MG, et al. In: Graci E and Goldstein AL. Combined Therapy: Biological Response Modifiers in the Treatment of Cancer and Infectious Diseases, 1992; Plenum Press.

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