In treating AIDS, three drug regimens may be better than oneor two. That's the major premise of a Phase III trial of thesynthetic hormone Thymosin alpha 1 that is now at midpoint inItaly.
Sponsored by the Italian Ministry of Health, the year-long,double-blinded study has already enrolled 65 of 108 HIV-infected but asymptomatic patients it will test. All have CD4+cell counts of 200 to 500 per mm3. Microbiologist CartesioFavelli, co-organizer of the study at the University of Rome,told BioWorld in a telephone interview that enrollees are beingrandomized to one of three treatment groups:
-- AZT (zidovudine), the first-line drug of choice for AIDSpatients;
-- AZT plus alpha-interferon, the anti-viral cytokine;
-- both of the above plus Thymosin alpha 1, which is added torestore declining immune responses.
Chemically synthesized Thymosin alpha 1 is a 28-amino-acidpeptide with a molecular weight of 3108 "similar to the naturalhormone made by the thymus gland," said Martin Rose, seniorvice president for clinical and regulatory affairs at Apha 1Biomedicals Inc. (A1B). The Bethesda, Md., company is the solemanufacturer of Thymosin alpha 1, which was developed bythe company's founder, Allan Goldstein, in the early 1970s.
The hormone works by promoting T cell differentiation andmaturation, releasing interferon-alpha and interleukin-2, andaugmenting the expression of IL-2 receptors, Rose toldBioWorld. "Thymosin alpha 1 also boosts NK (natural killer) and(LAK) lymphokine-activated killer cells," he said.
A1B sells its synthetic hormone in bulk to Sclavo SpA of Siena,Italy, a multinational manufacturer of pharmaceuticals. Sclavois supplying the material free to Favelli and the trial's principalorganizer, Enrico Garaci, but funding for the trial is comingfrom the Ministry of Health.
Garaci heads the National Research Council of Italy, acounterpart to the U.S. National Institutes of Health. He andGoldstein co-edited a book called Combination Therapies(Plenum Press,1992). "Garaci has been working in the area ofthymic hormones for years and years," said Rose.
"We began to treat patients last June and hope to completeenrollment in two or three months," said Favelli. By the end ofthis year, he anticipates releasing data on the first six monthsof the study. It will measure immune response recovery byassaying CD4 and CD8 counts, the HIV g24 antigen, beta-2microglobulin, and an HIV viremia test for proliferation oftetanus toxoid and Candida extract.
This pivotal Phase III trial of Thymosin alpha 1 for AIDStherapy was prompted by a smaller, similar study by Garaciand Favelli, the results of which were published last week inthe International Journal of Clinical & Laboratory Research. Thepaper is titled "Combination treatment with zidovudine,thymosin alpha 1 and interferon-alpha in humanimmunodeficiency virus infection."
This four-regimen, randomized, unblinded experiment showeda striking contribution of the synthetic thymosin hormone torestoring CD4 -- a measure of restoring immune responseamong the 28 HIV-seropositive subjects who completed oneyear's worth of treatment. AZT alone resulted in an averageloss of 51 CD4+ cells; AZT and Thymosin alpha1 in an averagegain of 35 CD4+ cells; AZT plus alpha interferon in an averageloss of four CD4+ cells; and AZT plus Thymosin alpha 1 andalpha interferon in an average increase of 187 CD4+ cells peryear.
When Garaci reported these results at the International AIDSConference in Amsterdam in 1992, infectious disease specialistThomas Merigan, who heads the Center for AIDS Research atStanford University, took notice. "Hearing Garaci's data inspiredme to do a small pilot study of Thymosin alpha 1 together withPEGylated interleukin-2," Merigan told BioWorld. "I was lookingat the CD4-enhancing property of the latter molecule andwanted to see if thymosin alpha 1 would give it a greaterboost."
Merigan's unblinded, ongoing study now involves eight HIV-positive patients of the 14 he plans to enroll. They will haveCD4 counts either below 100 or between 100 and 200, andmust be free of symptoms. All are taking AZT. His trial issponsored by the AIDS Clinical Trial Group of the NationalInstitute of Allergy and Infectious Diseases (NIAID). He expectsdata to be available in approximately six months.
Merigan looks at the CD4 endpoint in a trial as "a marker ofimmune capacity. Below 200 is when patients begin to havecomplications, so what we're doing in this pilot study is see ifwe can't lift them above that number." If he succeeds, Merigansaid, "it would be worth a controlled trial to see if that puts offcomplications."
A1B is not about to sponsor such a trial in the U.S. at themoment, Rose told BioWorld. At this point, he explained, thecompany is using its limited financial resources to pursue aPhase II trial of the hormone to treat hepatitis B; it will becompleted next month.
If the current Italian AIDS study finds Thymosin alpha 1 safe(there are reportedly no adverse side effects so far) andefficacious, it will be up to Sclavo to seek permission from thehealth ministry to market the product for therapy, Favelli said."We are merely university researchers, studying the possibilitythat the triple chemotherapy works better thanmonochemotherapy," he said. "But we don't know exactly whatwill happen with this drug."
A year ago, A1B and Sclavo concluded an agreement for theItalian company to build a Thymosin alpha 1 manufacturingfacility using technology supplied by the U.S. parent company.
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.