ROCKVILLE, Md.—Taking a giant step toward a potential “one-and-done” cure for HIV/AIDS, American Gene Technologies (AGT) reports the U.S. Food and Drug Administration (FDA) recently cleared the path for a Phase 1, first-in-human clinical trial for AGT’s lead HIV program, AGT103-T. In September, researchers began enrolling people for the trial from the Baltimore/Washington, D.C. area, hotspots for HIV/AIDS, with data expected by the end of 2020.
The purpose of the trial is to investigate the safety of AGT103-T, measure key biomarkers and explore surrogate markers of efficacy. AGT103-T is a single-dose, lentiviral vector-based gene therapy developed to eliminate HIV from the patient. This genetically modified cell product is made from a person's own cells, and focuses on repairing key immune system damage done by HIV and allowing the patient’s natural responses to control the virus. AGT's approach is designed to repair the T helper cell defect and provide durable virus control that is not compromised by HIV strains.
It has been nearly 40 years since the first cases of HIV/AIDS in the United States were discovered. Today, 38 million people globally—including 1.2 million in the United States—are infected with the disease.
“The levels of potency in the AGT103-T cell product that have been repeated and validated by the National Institute of Allergy and Infectious Diseases (NIAID) have given AGT further confidence that antiretroviral therapy-free HIV remission could be achieved soon,” says AGT founder and CEO Jeff Galvin. “I am confident AGT103-T will be an important step towards an eventual cure for HIV.”
As Galvin tells DDN, “Supporting evidence is published in Molecular Therapy, June 2020, in an article co-authored by NIAID, which describes the evolution of the AGT103-T manufacturing process as researchers developed the large-scale production of modified HIV-specific CD4 T cells that resist infection and depletion by HIV.”
“The autologous cell product that is produced by the AGT process is orders of magnitude more effective at controlling viremia than previous CCR5-removal approaches from other companies,” he continues. “The number of target cells (HIV-specific CD4+ T cells) is >1,000 times the previous attempt by Sangamo (Therapeutics Inc.), and the combination of RNAi against CCR5, with RNAis against conserved regions of the HIV genome, provides added protection against HIV T cell infection and depletion.”
The Sangamo study “only worked with people that were half-immune to HIV (already possessing one ‘broken’ CCR5 allele, referred to as a heterozygous delta32 mutation, which is only approximately 3 percent of the human population),” Galvin explains. “AGT’s therapy produces 2,000 times the number of critical helper T cells that are capable of protecting the body from HIV.”
According to Galvin, their therapy is expected to work against “the various clades of HIV.” Furthermore, he adds, AGT’s therapeutic vector modifies up to 90 percent of the HIV-specific CD4+ T cells, removing their CCR5 receptor and producing further RNAi within the cell that binds to conserved regions across the full spectrum of known HIV clades.
“A prerequisite to participating in the AGT103-T study (Phase 1 human trial) is that the individual does not have AIDS-defining conditions,” Galvin tells DDN. “We hope HIV+ individuals treated with this therapy will become ‘functionally cured.’ This would tell me they would no longer be able to progress to AIDS. However, AGT103-T is not designed to restore people directly from AIDS. The Phase 1 study is primarily designed to establish the safety of the treatment.”
“We will attempt to measure secondary markers to determine if there is an ‘efficacy signal’ which may justify further tests to determine the extent of efficacy and whether the treatment is able to achieve ‘functional cure’ (defined as durable suppression of HIV sufficient to prevent AIDS transmission through intimate contact and reinfection, without the need for further antiretroviral treatment),” Galvin says of the Phase 1 trial.
“Although persons with AIDS symptoms will not be admitted to this study, it is possible they will not be restricted from future studies, depending on the results of this study and FDA decisions on further testing,” he adds.
Current treatments for HIV “are effective, but require a lifetime regimen of antiretrovirals that have numerous short- and long-term side effects,” according to Galvin. “This product is designed to be a one-and-done treatment, and AGT hopes that it may be durable for the life of the patient.”
Since the late 1980s, antiretroviral drugs have restored quality of life to people living with HIV and, in some cases, have even been used to prevent new infections. However, no approved treatments can cure HIV.
Gene and cell therapy “are on an incredible technology curve,” Galvin remarks. “Costs seem to be halving every year, while the power of the technology doubles. AGT expects those trends to continue, and that this therapy and many like it will be broadly available in the not-too-distant future.”