Results of the first trial of new immunomodulatory drugs presented in Mexico City
Long-acting antibodies and TLR7 agonist in first safety and dose-finding trials in people with HIV
Gus Cairns July 26, 2019
Grace Chen of NIAID. From Archive: Gus Cairns
Several studies of new types of HIV drugs that had previously only been conducted in preclinical studies (laboratory or animal studies), or in drug-level studies in HIV-negative people, were presented at the 10th International AIDS Society Conference on HIV Science (NIC 2019) in Mexico City.
Dr. Grace Chen, from the Vaccine Research Center of the U.S. National Institute of Allergy and Infectious Diseases (NIAID), reported on the safety and virological effects of two broadly neutralizing antibodies, VRC01 and VRC07-523.
Although the virological effects of these antibodies have been tested before, this was the first study of the safety and virological activity of the 'LS' version of the antibodies. This adds a sequence to the antibody protein that makes them bind more tenaciously to cells, meaning they have a much longer half-life in the body.
Seven HIV-positive participants aged 18 to 70 years received a single dose of VRC01-LS, and nine participants received a single dose of VRC07-523-LS. They were followed for three days to check for immediate immune system reactions to the antibodies and for up to 56 days to detect slower-developing side effects.
Antibodies are immunologically active proteins, meaning they can have unexpected effects on the immune system, both adverse and beneficial. In addition to acting as inhibitors of HIV entry, they can mark cells for destruction by other parts of the immune system and can form 'immune complexes' consisting of bound antibodies and viral particles, which can have a vaccine-like effect.
VRC07-523-LS appeared to be more virologically effective than VRC01-LS, but it also produced a somewhat higher rate of transient immunological side effects, such as local inflammation and mild fever. No clinically significant adverse events were attributed to VRC01-LS, but two were attributed to VRC07-523-LS: numbness at the injection site, which resolved after one day, and a temporary decrease in immune cells called neutrophils, which resolved after eight days.
Seven days after an infusion of the antibodies, less than half of the people who received VRC01-LS had a reduction in viral load of more than 0.5 logs (a three-fold reduction); but eight of the nine recipients of VRC07-523-LS had a reduction in viral load of more than 1.2 logs (a 16-fold reduction).
At a press conference, lead researcher Dr. Pablo Tebas said that an upcoming study would analyze the effects of VRC07-523-LS infusions in combination with injectable cabotegravir, both administered every two months.
They were also designing a study that would offer people combination therapy with several broadly neutralizing antibodies and then discontinue their antiretroviral therapy (ART), hoping to improve upon a study published last year that allowed most of a group of eleven patients to take five or more antibodies for months without their viral load returning.
In the longer term, there are high-tech possibilities, such as developing immune complexes to act as therapeutic vaccines or delivering antibodies to cells as messenger RNA (mRNA) molecules, which could enable cells to generate their own antibodies. But, Tebas cautioned, “it could be three to five years before we have a candidate therapy ready to move into proof-of-concept trials.”
Vesatolimod, the first TLR-7 agonist in human trials, passes safety test
An example of the type of drug that could be combined with broadly neutralizing antibodies is vesatolimod, formerly known as GS-9620. This drug acts on a cell receptor called TLR7, which alerts the innate immune system—the oldest and fastest-acting part of the immune system—to the presence of foreign molecules. It is fair to say that it is currently a drug with potential, rather than one with a clear role. Originally, its immune-stimulating properties led to its investigation as a latency-reversing agent in so-called "kick and kill" strategies, but it could also be used to alert the immune system to the presence of other drugs, such as therapeutic vaccines, and strengthen the immune response to them.
In studies with monkeys, it has been used successfully to induce viral control of ART. Given to monkeys in combination with broadly neutralizing antibodies, it was able to induce five out of eleven to become viral controllers of ART, and three out of nine when administered in combination with a therapeutic vaccine. Interestingly, viral control did not occur immediately, but rather several months after antiretroviral treatment was withdrawn, as if the drug were "teaching" the immune system to recognize HIV.
The first human safety study of this agent in HIV-positive people taking ART was reported in Mexico.
In this dose-escalation study, six different doses of vesatolimod were administered as individual oral pills two weeks apart (it is anticipated that, as an immunomodulatory agent rather than an antiretroviral, it can be dosed approximately once every two weeks).
These were administered to six groups of six patients each, for a total of 36 people receiving the drug, while two in each group received a placebo, so twelve participants received the placebo. The six doses were 1, 2, and 4 mg tablets administered six times, 6 and 8 mg doses administered ten times, and a 10 mg dose that increased to 12 mg after the third dose, also administered ten times. Thus, 18 patients received lower doses of vesatolimod for a period of eleven weeks, while another 18 received higher doses for a period of 19 weeks. All patients were followed up for 22 weeks.
The participants were mostly men (five out of 48, or about 10%, were women), had an average age of 48, had been diagnosed with HIV six to 15 years ago, and had been on antiretroviral treatment for four to 14 years.
There were no serious drug-related adverse events or laboratory abnormalities; one participant experienced very high creatinine, often a sign of kidney damage, but this was related to "vigorous exercise".
Doses of 1, 2, 4, and 6 mg of the drug were biologically inactive, but doses of 8, 10, and 12 mg produced transient increases in the proportion of activated natural killer (NK) cells, from a baseline of approximately 20% to 50–80%, a sign that the innate immune system was responding. However, similar increases in T cells were also observed, so vesatolimod also appears to activate the adaptive immune system. Doses of at least 6 mg induced significant production of the immune-modulating interferon that kills the virus.
Vesatolimod produced immune activation without causing transient increases in viral load, which may be a strength. The highest viral load observed in a participant receiving vesatolimod was 69 copies/ml in a person who received the 4 mg dose, and this was the only instance of a viral load above 50 copies/ml, except, ironically, in a participant who received a placebo, who experienced a viral 'blip' to approximately 2500 copies/ml.
This safety and dose-finding study of vesatolimod shows that there may be beneficial effects on the immune system at doses above 8 mg, and that doses up to 12 mg produce few side effects.
At a press conference, Dr. Romas Geleziunas of Gilead said the drug had produced a dramatic decrease in the number of HIV-containing reserve cells in monkey studies. Trials evaluating the efficacy of vesatolimod were underway to see if the success seen in monkeys could be replicated in humans, he added.
An audience member asked if there would be more studies in women, as more and more data was presented showing gender differences in how women responded to HIV medications, especially reverse transcriptase inhibitors. This could be particularly important for TLR7 agonists, since the TLR7 gene is located on the X chromosome.
References
Chen G et al. Safety and virological effect of HIV-1 neutralizing antibodies, VRC01LS or VRC07-523LS, administered to HIV-infected adults in a phase 1 clinical trial. IAS2019 Conference, Mexico City. Abstract WEAA0305LB. 2019.
Riddler SA et al. Vesatolimod (GS-9620) is safe and pharmacodynamically active in HIV-infected individuals. IAS2019 Conference, Mexico City. Abstract WEAA0304. 2019.
In: https://www.aidsmap.com/news/jul-2019/first-trial-results-new-immune-modulating-drugs-presented-mexico-city