Chiron halts major IL-2 study, for business reasons
Graham McKerrow, HIV i-Base
The Chiron Corporation, which manufactures interleukin-2 (IL-2), has halted a major study of the drug that has been monitoring nearly 2,000 people to compare highly active antiretroviral therapy (HAART) alone to HAART with IL-2. The study was expected to continue until 2007.
The company has also halted development of a new treatment for cystic fibrosis and an immunotherapy for people with chronic hepatitis B infection.
Bruce Scharschmidt, vice president, clinical development, for Chiron, said in a letter to investigators: “This is primarily a business decision.” The company said the study would take longer and be more expensive than expected.
The SILCAAT study is a randomised, controlled, open-label trial of subcutaneous IL-2 that has been following people with advanced HIV infection at 137 clinical sites in 11 countries. So far Chiron has completed two scheduled interim analyses of data from the trial, including data from 1,000 patients followed for a year. Participation was expected to last four to six years.
The SILCAAT Scientific Committee wrote to investigators saying: “Chiron has recently announced their closure of the SILCAAT study as part of a unilateral business decision. We understand the need for such difficult decisions on the part of a company. In this instance the decision seems particularly tragic to us insofar as it terminates a study that is fully enrolled and at the last DSMB [Data Safety Monitoring Board] meeting was noted to be proceeding as planned with intact assumptions regarding sample size.”
The Scientific Committee said in the letter that it was trying to salvage “this important” Phase III trial by discussing with the company the possibility of transferring it to “an academic based platform”. The committee asked investigators to continue with the study until these discussions were complete.
Scharschmidt told investigators that Chiron’s decision reflected the extended timelines of an open-label clinical endpoint study in the era of HAART. He said that improving treatments resulted in decreased incidence of clinical events and reduced the overall rate of disease progression.
“Since the primary endpoint for SILCAAT is time to first AIDS defining event or death, the extended timelines make the duration and magnitude of this investment unfeasible for Chiron.”
The California-based company said data from the second interim analysis of SILCAAT were consistent with results preciously obtained in Phase II studies, which had shown substantial CD4 count increases and no negative effect of IL-2 on viral load.
“The safety of IL-2 is not a factor in Chiron’s decision to discontinue SILCAAAT,” said the company is a statement. “Data from two interim analyses of SILCAAT demonstrated that the safety of IL-2 was consistent with that seen in previous studies.”
Scharschmidt said in his letter to investigators that Chiron has initiated discussions with regulatory agencies about the possibility of a regulatory submission which, if approved, could make IL-2 available to people with persistently low CD4 counts despite virologic control — “HAART discordant responders” — a patient group which, he said, had important unmet needs.
Chiron is continuing its cooperation with the ESPRIT study, a randomised, international, 5-year, 4000-person study of IL-2. Whereas SILCAAT was looking at IL-2 in people with CD4 counts between 50 and 299/mm3, ESPRIT is studying people with CD4 counts of at least 300.
The goal of ESPRIT is to evaluate and compare the effectiveness of IL-2 plus anti-HIV therapy versus anti-HIV therapy alone on numbers and severity of AIDS-related illnesses and deaths over a five year period. ESPRIT is being conducted at clinical sites in North America, South America, Australia, Asia and Europe, including clinics in 11 British cities. It is nearing its enrolment goal but there are still some places for participants. ESPRIT has announced that its sponsor, the US National Institutes of Health remains committed to seeing this study through to its planned completion.
Dr James D Neaton of the ESPRIT Executive Committee told ESPRIT researchers: “We believe it is essential that the efficacy of IL-2, with respect to clinical endpoints, be established. The timely completion of ESPRIT is now even more important.”
SILCAAT is the acronym that loosely stands for a study of IL-2 in people with low CD4+ T cell counts on active anti-HIV therapy.
ESPRIT stands for evaluation of subcutaneous proleukin in a randomised international trial.
IL-2 is a cytokine. Interleukins signal the immune system to act when it is under attack. Interleukin-2 in particular causes more CD4+ T cells to be produced. During HIV infection, natural IL-2 production gradually declines. Treatment with supplemental IL-2 therapy is being studied as a way to increase CD4+ T cell counts and possibly improve immune function. Proleukin® is a manufactured version of IL-2.