Gay Men's Health Crisis "Treatment Issues", Vol. 8, No. 5 - July 1994
Rick Loftus

Saquinavir Phase II Trial

On May 31, the Hoffmann-LaRoche company announced the results of ACTG 229, the largest human trial of a protease inhibitor thus far. The 300-person trial tested the safety and activity of three different combinations: saquinavir plus AZT, ddC plus AZT, and the three drugs together. Participants had baseline CD4 T-cell counts of between 50 and 300 per cubic millimeter of blood and an average of over two years' previous treatment with AZT.

Roche found the data so encouraging that it is moving forward on two fronts. First of all, the company will expand its large, Phase III international trial of saquinavir. Originally, this trial was designed to test saquinavir alone and combined with AZT in 1,800 HIV-infected people worldwide. The company now plans to increase the trial to 3,000 people and to add the three-drug combination from ACTG 229. The U.S. Food and Drug Administration (FDA) and international authorities will decide whether these changes are acceptable in late June.

Roche furthermore is considering whether to approach the FDA with an application for accelerated approval of saquinavir. The application's grounds would be that the compound fills a key gap in current anti-HIV treatment strategy. At the June meeting, the FDA also will advise Roche as to whether it can pursue this course. Many observers have commented that the ACTG 229 data is at least comparable to the data being used to justify marketing approval for the HIV drug d4T [see page 3 in this issue]. But as in the case of d4T, the saquinavir data leaves many lingering doubts concerning the drug's effectiveness.

ACTG 229 measured the different treatments' effects on HIV by comparing the levels of HIV present in white blood cells taken from the trial participants and cultured in test tubes (the technical name for the measurement is PBMC co-culture viral titer). After four weeks of treatment, the three-drug combination (AZT, ddC and saquinavir) reduced HIV levels to fifteen percent of the pre- treatment values. After 24 weeks, levels were back up to 35 percent of pre-treatment levels. For the two-drug combination (saquinavir plus AZT), HIV levels actually rose. They averaged 105 percent of initial levels after four weeks and 145 percent of initial levels after 24 weeks. The people receiving AZT plus ddC and no saquinavir did better than this, experiencing some drop in HIV levels on average, but not as much as those receiving the triple combination. Although a growing body of evidence indicates that CD4 T-cell rises do not consistently indicate clinical benefit, at least for nucleoside analogs like AZT, CD4 T-cells are still the most widely used surrogate marker in clinical practice, and the trial used this marker as an indication of immune system improvement. Again, the three- drug regimen resulted in the fastest and the greatest increase in CD4 T-cells. At week twelve, participants on this regimen had a 25 percent increase in CD4 T-cells, after which average cell counts gradually fell off. When measuring CD4 T-cell counts, the saquinavir-AZT combination was the intermediate one, out-performing AZT plus ddC.

These results are very puzzling: Why did saquinavir plus AZT have no discernible effect on HIV levels yet yield a slightly greater rise in CD4 T-cells than AZT plus ddC? Do the data indicate that saquinavir performs little better than ddC? Still, European studies using the more direct PCR test found peak reductions in HIV of 98 percent when administering saquinavir alone or combined with AZT.

Side effects were comparable for the three regimens. Overall, 36 percent of participants had severe or life-threatening metabolic abnormalities or clinical symptoms that seemed related to the treatment received. Among the major adverse reactions were muscle or liver damage, diarrhea, fatigue, nausea and headache.

The number of toxicities and the fact that there was no significant difference between regimens is again confusing. Since protease inhibitors so far have shown few side effects, it would be logical to expect more adverse reactions in the triple drug and ddC plus AZT regimens than in the saquinavir-AZT arm.

High dose saquinavir: An ongoing, 32-person trial of higher doses of saquinavir--3,600 mg or 7,200 mg daily--is being conducted by Thomas Merigan, M.D., of Stanford University. These doses may have the potential to achieve more potent anti-HIV effects than the lower doses, possibly lessening the need to combine saquinavir with the more toxic AZT and ddC.

Controversy in the community recently erupted, though, when Dr. Merigan began excluding from the trial all patients who tested positive for a mutation in HIV that is believed to confer resistance to AZT (the so-called codon 215 mutation). Dr. Merigan invented the codon 215 test, and part of the controversy concerned his alleged conflict of interest in promoting this test - the researcher's employer, Stanford University, has filed for patent rights for the test. Financial gains arising from commercial sales could ultimately filter down to Dr. Merigan's laboratory.

On May 18, Roche informed activists that eight people with the 215 mutation will be added to the study. The duration of the study will be lengthened from sixteen to 24 weeks, with patients then receiving whatever saquinavir regimen "is considered most effective at that time." In total, twenty slots remain to be filled in the study, which should finish this year. (For further information on this trial, call Jane Norris at 415/723-2805.)

New Merck Trials

Researchers working with Merck's experimental protease inhibitor (known as L-524) have confirmed intriguing rumors about effects seen in the ongoing Phase II trial. A handful of patients with CD4 T-cell counts of less than 50 have experienced rises to about 200 while on L-524 monotherapy. This is highly surprising, given that increases of this magnitude are rarely seen at such low counts. But it must be cautioned that just how many patients had this effect will not be known until the study results are announced. Moreover, it is not known how well these "new" CD4 T-cells are functioning, although the ostensible increases in antibodies against HIV's p24 core protein that accompany the CD4 T-cell rises is a positive sign of returning immune competence.

Another concern is that some patients who have been on the Merck drug for several months seem to show signs of emerging HIV resistance to the drug. Monotherapy with the Merck drug appears to result in a 99.9 percent reduction in viral load as measured by PCR tests of HIV in blood plasma. In six patients for whom data is available, though, this effect began to wane after about sixteen weeks of treatment. At 24 weeks, HIV levels were back to 90 percent of pre-treatment levels. Nonetheless, improvements in CD4 T-cell counts and the anti-p24 activity gained during the drug's period of effect were sustained beyond this sixteen week period.

Due to the resistance question, Merck has decided to conduct three new studies of its protease inhibitor, one combining it with AZT and the other combining it with AZT and ddI. There are also plans to conduct a dose-ranging study to establish the maximum safe dose. These trials will test whether combination therapies or higher doses suppress HIV further and delay the emergence of treatment- resistant virus strains.

The first study, of L-524 plus AZT, has already begun screening potential participants. It is open to people with 500 or fewer CD4 T-cells. Participants must have had little or no treatment with AZT (two weeks or less), although exposure to other nucleosides (ddI, ddC, and d4T) will not exclude patients from the study. The trial has three arms (L-524 alone at 600 mg four times daily versus AZT alone at 200 mg three times daily versus L-524 and AZT in combination). It will last 24 weeks. After the trial period ends, patients will be put on whatever treatment showed the greatest benefit.

The second trial has similar features to the first, but adds ddI to arm one and arm three. The last study, the dose-ranging one, reportedly will not exclude people who have used AZT for significant lengths of time. Everyone in this study will receive L-524, at doses varying from 600 mg four times a day up to at least 1000 mg four times a day.

At press time, confirmed sites for the first trial (AZT plus L-524) are: University of Pennsylvania, Philadelphia (Dr. Ian Frank at 215/662-2473); Thomas Jefferson Hospital, Philadelphia (Janet Tientka at 215/955-8575); Hershey Medical Center, Hershey, Pennsylvania (Fran Damianos at 717/531-7488); Pacific Oaks medical practice in Sherman Oaks, California (Jackie Bennette at 818/906-6279); and the Research and Education Group of Portland, Oregon (Brian Fodell at 503/229-8428). Other planned sites include: Henry Ford Hospital, Detroit; the University of North Carolina, Chapel Hill; San Francisco General Hospital; and Leahi Hospital, Honolulu. Although there are no planned trial sites in New York City, the two Philadelphia institutions are actively recruiting patients from the New York area.

The apparently limited time-span of L-524's effect is disappointing, but the potency of its effect is very encouraging. It may be possible to combine this compound with saquinavir or other protease inhibitors and create anti-HIV combinations that avoid the significant toxicities of AZT and the like while combating HIV's tendency to become resistant to treatment. Studies to date indicate that HIV resistance to each protease inhibitor is possible, but a virus strain resistant to one protease inhibitor does not appear to be cross-resistant to another. Although more information is needed on the safety and activity of some of these compounds, especially the Abbott and the two Searle drugs, there is no reason why plans could not begin for combination studies.

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