The study was designed to test HIV-patients' ability to stay off anti-retroviral therapy (ART) after having been immunized with Vacc-4x. Although the study did not meet its primary endpoints, as announced October 1, the findings from the additional analysis discovered that treatment difference with regard to viral load was statistically significant both within the study period and when compared to the viral load prior to ever starting ART. In patients who received immunization, viral load never returned to its pre-ART level, which normally happens when being taken off ART.
Due to the new findings, the Company has reversed its decision to stop development of Vacc-4x. Along with upcoming immunological data, these findings are expected to become the basis for the future positioning of Vacc-4x as a viable therapeutic HIV-vaccine.
As announced October 1, the Vacc-4x phase IIB study did not meet its two primary endpoints; i.e. no difference between the two groups with regard to the number of patients that needed resumption of ART nor any difference in immune cell (CD4) counts at the end of the ART-free period.
Still, the effect on viral load is by health authorities and most clinical experts seen as more important clinically for the treatment of HIV-patients than the effect on CD4-counts. Change in viral load between Vacc-4x and placebo during the study period was among the secondary endpoints in the phase IIB study. A statistically significant treatment difference with regard to viral load was found for the whole patient population (p=0.028), and a statistically significant effect was reproduced also in the sub-set of patients that did not resume ART (P=0.0012).
Additional support for the effect of Vacc-4x on viral load has come from a pooled post-hoc analysis including pre-ART viral loads. Pre-ART level is an important set-point since viral load normally migrates back to this level after ART interruption. Company researchers discovered on further review that patients blinded and randomly assigned to Vacc-4x treatment group had a pre-ART viral load three times higher than that of patients assigned to the placebo group. The study showed that viral load in patients who received immunization never returned to its pre-ART level. A statistically significant reduction in viral load from the pre-ART level (0.55 log, p=0.0003) was found in patients treated with Vacc-4x compared to a non-statistically significant reduction in viral load (0.08 log, p=0.89) in patients in the placebo group.
"These follow up findings on viral load reduction in the Vacc-4x arm compared to placebo are positive and very encouraging," says Professor Dr. med. Jürgen Rockstroh, Oberarzt an der Medizinischen Universitätsklinik, Innere-Rheuma-Tropen Ambulanz, Bonn, Germany. "It is therefore important in follow on studies to investigate whether Vacc-4x in combination with ART could reduce the viral set-point and allow extended periods without HIV medicine."
"Patients starting on anti-retrovirals see the viral load effectively reduced, but this is dependent on daily treatment, and we know that HIV remains in the reservoirs," says Richard Pollard, MD, Division Chief of Infectious Disease, University of California Davis Center for AIDS Research, Education, and Services and the principle investigator in the trial. "A therapeutic HIV vaccine like Vacc-4x reducing the viral load set-point, could have significant implications for future HIV management used in combination with ART. More research is needed to confirm this hypothesis."
"I am pleased to see that immunization with Vacc-4x, a candidate therapeutic vaccine under clinical development, has shown the ability to reduce virus levels in blood of chronically HIV infected patients," says Professor Giuseppe Pantaleo, Professor of Medicine, Chief Division of Immunology and Allergy and Head of the Laboratory of AIDS Pathogenesis, Department of Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland. "These results are important since they indicate that better virus control may be achieved through immunological intervention. Vacc-4x through a different antiviral mechanism may represent a novel intervention to complement antiviral therapy."
"The new analysis gives indications that Vacc-4x has an important effect on viral load despite the failure to reach our primary endpoints in the phase IIb study," says CEO of Bionor Pharma Henrik Lund. "While post-hoc analyses are subject to statistical limitations, they are commonly used in vaccine trials due to the complex nature of data interpretation. The full immunological analysis and long term data will give us a better basis for evaluating the outcome and implications for the positioning of Vacc-4x as a therapeutic product for HIV-patients. A possible application of Vacc-4x is a combination therapy with repeated ART-Vacc-4x together with analytical treatment interruptions in order to establish a functional cure."