DURHAM, N.C.—More than 30 years after the once-mysterious, devastating disease we now know as AIDS cut a treacherous, deadly path through gay communities and intravenous drug use populations, biopharmaceutical company Argos Therapeutics Inc. has unveiled compelling clinical studies showing that HIV patients’ own immune systems can fight the disease.
The entire AGS-004-006 study is fully funded by a National Institute of Health (NIH) government contract valued at $39.3 million, and the key to this latest therapeutic insight lies in Argos’ Arcelis technology platform.
Argos brought its latest findings to light with presentation data from clinical studies of AGS-004, the company’s patient-specific immunotherapy currently in development for the treatment of HIV infection. These latest results were presented in two poster presentations at the Conference on Retroviruses and Opportunistic Infections (CROI) meeting in Boston, March 4.
The first poster, titled “Immune Function and Viral Load Post-AGS-004 Administration to Chronic HIV Subjects Undergoing STI,” presents new findings from a Phase 2a clinical trial to assess safety and efficacy of AGS-004 during a 12-week antiretroviral therapy (ART) structured treatment interruption (STI) in chronic HIV-1 infected patients. Results showed that AGS-004 induced anti-HIV T memory stem cell-like immune responses (TSCM) that were associated with a longer time to viral rebound after ART treatment interruption. In addition, the longer time to viral rebound was also associated with lower expression of the checkpoint inhibitor PD-1 on activated CD8+ T cells.
“This is the first demonstration that AGS-004 can induce antiviral TSCM-like immune responses in chronic HIV patients and that these responses are associated with viral load control in the absence of ART drugs,” according to Charles Nicolette, chief scientific officer and vice president of research and development for Argos. “Establishing long-lasting immune memory is a critical component of durable viral load control, and bodes well for our planned eradication and functional cure studies.”
Nicolette, an expert in cellular immunology with extensive experience with dendritic cells, tells DDNews that each patient’s own T cells work toward the patient’s own immune-memory, thus giving patients immunity to the virus.
“This is important because it has historically been difficult for researchers to correlate immune responses with clinical outcomes,” Nicolette says. “The type of antiviral ‘memory’ T cell response we identified is known to be long-lasting and, therefore, may provide a long-term clinical benefit. We plan to extend this analysis to include more patients going forward, including the patients treated in our Phase 2b study.”
The second poster, “Immunogenicity of AGS-004 Dendritic Cell Therapy in Patients Treated During Acute HIV Infection,” highlights results from an open-label, single-arm study in which treatment with AGS-004 was administered to patients who initiated ART within 45 days of primary HIV infection.
The study was led by Dr. David Margolis, at the University of North Carolina School of Medicine, other faulty members and Dr. Charles B. Hicks, professor of medicine at Duke University Medical Center. Results showed that new anti-HIV memory T cell immune responses were induced in all six patients treated.
One patient was able to maintain sufficient viral control while off ART drugs for approximately five months and another patient continued ART treatment interruption after nearly nine months, Nicolette said. Additionally, three of six patients had decreases in circulating CD4+ T cells containing HIV DNA of 25 percent, 47 percent and 63 percent, respectively, when measured after three doses of AGS-004 while on ART.
Margolis said the study “demonstrates that AGS-004 can induce anti-viral memory T cell responses in acute patients and may result in depletion of persistent HIV infection in ART-suppressed patients in combination with anti-latency therapy” and he noted that data “showed that in a small cohort of acute patients (i.e., patients that initiated ART therapy within 45 days of becoming infected), who are expected to be more immunologically healthy, AGS-004 was able to induce anti-viral memory T cell responses.”
“Importantly, we also demonstrated that some patients experienced a reduction in persistently infected CD4+ T cells containing HIV DNA in the blood after just three monthly doses of AGS-004 while on ART,” Nicolette says.
“This is important because the depletion of persistently infected cells is a necessary step towards eradicating the virus entirely,” he adds. “This study is supportive of our strategy to combine AGS-004 with a latency-reversing therapy in an effort to achieve viral clearance.”
And if this Argos discovery survives upcoming clinical trials (Nicolette says they plan to initiate two additional studies this year) resulting in a new treatment allowing the patient’s immune system to fight against the disease, the daily cocktails of drugs could be a thing of the past.
“The first trial will attempt to eradicate the virus from patients by combining AGS-004 with a histone deacetylase inhibitor drug which has been shown to activate latently infected cells which should make them ‘visible’ to the immune system,” he explains.
“The second planned trial will be in pediatric patients that have very minimal viral reservoirs, but lack antiviral immunity,” Nicolette continues. “If we can successfully induce antiviral immunity in these children with AGS-004, we hypothesize that they may no longer need continuous ART drug therapy. The goal of this trial is to induce sustained remission without the need for ART drugs.”
“The study that we just completed does not have a name, but is designated AGS-004-003,” Nicolette notes. “This is a Phase 2b randomized double blind placebo controlled study that enrolled 53 chronically infected patients that were successfully treated with anti-retroviral drugs. Patients stopped taking their drugs after four monthly doses of AGS-004, and then continued to receive AGS-004 doses on a monthly basis.”
The goal of the study “is to demonstrate lower viral load set points after three months without ART drugs in the AGS-004-treated patients compared to placebo-treated patient,” according to Nicolette. “This study was completed in March, and we are in the process of un-blinding and analyzing the data.
“If we can complete the analysis in time for the April late-breaker abstract deadline for the International AIDS Society, we will present data at that meeting in July in Melbourne, Australia,” he added. “If the analysis cannot be completed in time, we will select a different venue later in the year.”
Argos plans to focus development of AGS-004 in combination with other therapies for the eradication of HIV, the company states. The current standard of care, antiretroviral drug therapy, can reduce levels of HIV in a patient´s blood, increase the patient’s life expectancy and improve the patient´s quality of life.
“However, antiretroviral drug therapy cannot eliminate the virus, which persists in latently infected cells, remains undetectable by the immune system and can recur,” Argos points out. “In addition, antiretroviral therapy requires daily, lifelong treatment and can have significant side effects.”
The Centers for Disease Control and Prevention (CDC) estimated that less than 30 percent of the 1.2 million HIV-positive Americans have been diagnosed and treated successfully to the point where their viral loads are undetectable. The main challenge to achieving this clinical result is patient adherence to taking the medication daily as prescribed.
