CROI 2017: several new drugs in the pipeline of HIV drugs
This year's conference on Retroviruses and Opportunistic Infections (CROI) last month in Seattle included presentations on several new HIV drugs under development, reflecting a stronger test line than we have seen in recent years.
Although modern antiretroviral therapy (ART) is highly effective and well tolerated by most people living with HIV, having more available drugs that work in different ways offers more options for joining optimal regimens.
Some of the experimental agents discussed in CROI represent new classes of drugs that function differently than existing antiretrovirals, including capsid inhibitors in early studies and monoclonal antibodies now in human end-stage assays.
Other presentations focused on next generation candidates for familiar HIV drugs. Given that widely used approved drugs are very effective in HIV treatment, researchers are looking for incremental benefits in the areas of improved tolerance and convenience - such as long-acting drugs - as well as new options for prophylaxis of pre-exposure to HIV or PREP.
Nucleotide / nucleotide reverse transcriptase inhibitors (NRTIs) work by adding a faulty building block that terminates the DNA strand when the HIV reverse transcriptase enzyme attempts to copy viral genetic material.
Kirsten White of Gilead Sciences presented results on GS-9131, a NRTI that works against HIV with resistance to other drugs in this class.
GS-9131 is a prodrug of the GS-9148 adenosine nucleotide analogue. Tenofovir disoproxil fumarate of Gilead and tenofovir alaphenamide are also adenosine nucleotide analogues; All other NRTIs approved are nucleotide analogs, which require an additional processing step to become active.
GS-9131 is converted to the active GS-9148 diphosphate in lymphocytes. It appears to have a low potential for mitochondrial toxicity and minimal accumulation in the kidneys, which is a disadvantage of tenofovir.
In laboratory cell cultures, GS-9131 showed potent activity against all major HIV-1 subtypes (A, B, C, D, E, F, group O and N) and also against HIV-2. The potency was not affected by NRTI resistance mutations including K65R, M184V, mutations in multiple thymidine analyzes or the insertion of T69. It had a great resistance barrier, with multiple mutations needed to confer reduced susceptibility. It has been shown to be additive to synergistic activity, and so far without drug interactions, with several other antiretrovirals.
"GS-9131 is an attractive candidate for a single daily dose in combination with other antiretroviral drugs in patients with NRTI resistance and limited treatment options," the researchers concluded.
A couple of studies looked at Merck's MK-8591, also known as EFdA, a long-acting nucleotide reverse transcriptase translocation inhibitor that binds to the active site of the HIV reverse transcriptase polymerase.
Research presented at CROI last year Showed that MK-8591 was highly potent in animal and human studies. A single oral dose has produced desired concentrations of intracellular drug for more than one week, and a long-acting injectable formulation can maintain effective drug levels for up to 6 months.
Jay Grobler of Merck reported that MK-8591 has reached high concentrations in lymphatic tissue in rats, suggesting the potential to combat continuous replication of HIV in the lymph nodes. The drug also showed good distribution to rectal and vaginal tissues in monkeys, shedding light on its potential suitability for PrEP.
"The levels of MK-8591- [triphosphate] achieved in rectal and vaginal tissue are comparable to the levels of tenofovir diphosphate observed in the rectal tissue of human subjects treated with tenofovir disoproxil fumarate," the researchers concluded. "Given the significantly higher potency of MK-8591 (IC50 = 0.2 nM) compared to TDF (IC50 = 73 nM), these data suggest the utility of MK-8591 for prophylaxis in men and women."
In a separate study, Merck researchers showed that MK-8591 is also a highly potent inhibitor of HIV-2. The drug is about 5 times more active against HIV-2 than against HIV-1, and the virus with certain antiretroviral resistance mutations was "hypersensitive" to MK-8591.
Robert Murphy of Northwestern University and colleagues presented findings on a new non-nucleotide reverse transcriptase inhibitor (NNRTI), elsulfavirine or VM1500A, developed by Viriom, based in San Diego.
Following promising initial studies, an oral once-daily dose of 20 mg of the prophylactic drug Elpida elsulfavirin was selected for further study. This medicine seems to have a long acting potential, with a half-life of about 8 days.
The researchers conducted a Phase 2b clinical trial that compared once-daily Elpida versus efavirenz (Sustiva), both with tenofovir DF / emtricitabine (the drugs in Truvada) in 120 people previously not treated with HIV.
At week 48 of therapy, 81% of the Elpida receptors and 74% of the efavirenz receptors showed HIV RNA <50 copies / mL. Among participants with initial viral load above 100.000 copies / mL, response rates were 78% and 68, respectively. No patient experienced a virologic failure, defined as 2 consecutive viral loads above 400 copies / mL.
Drug-related adverse events were about half of the frequency in the Elpida group compared to the efavirenz group (37% vs 78%, respectively), and only Xpnp receptor from Elpida discontinued early due to adverse events compared to 1 in the efavirenz group . The same happened with the side effects of the central nervous system (7% vs 27%, respectively).
"This study of 48 weeks demonstrated equivalent virological and immunological efficacy of ART regimens, including Elpida or efavirenz in patients infected with native HIV-1," the researchers concluded. "Elpida was significantly safer than efavirenz-based therapy, offering a better tolerated alternative to efavirenz-based ARV."
Based on these findings, Viriom is now testing formulations once a week by oral and longer-acting injected elsulfavirine as well as co-formulations, according to one company Press .
With respect to HIV protease inhibitors, Gilead's John Link presented findings on GS-PI1, a novel protease inhibitor with potential for uncharged oral administration once a day.
Although Gilead dominates the market for HIV drugs in general, it does not yet have an approved protease inhibitor. Existing protease inhibitors should be used with a drug-potentiator or booster, which increases the likelihood of interactions with other medicinal products.
GS-PI1 showed potent anti-HIV activity in laboratory cell cultures. It has greater activity against the virus resistant to atazanavir (Reyataz) or darunavir (Prezista). It had a great barrier to in vitro resistance. GS-PI1 had good oral bioavailability and half-life of 13-14 hours in rats and dogs.
GS-PI1 "represents a new generation of HIV protease inhibitor with potential for combination in a non-compressed single-tablet regime," the researchers concluded.
Finally, by looking at integrase inhibitors, the researchers presented data on a new, longer-acting cabotegravir formulation using nanoparticles.
As previously reported , Long-acting cabotegravir injectel plus rilpivirine given once every 4 or 8 weeks maintained viral suppression at week 48 in people who switched from standard ART regimens with undetectable viral load. Cabotegravir injectable alone is also being studied for PrEP, but the researchers found that The drug was absorbed faster than expected , Which means PrEP would probably have to be given every 2 months instead of every 3.
The new cabotegravir formulation, called NMCAB, administers the drug in small nanoparticles designed to release it more slowly. In laboratory cell cultures, NMCAB was absorbed efficiently by macrophages, with sustained slow release over 30 days. It showed sustained antiretroviral activity for up to 30 days - better than the older injectable cabotegravir formulation. NMCAB was eliminated more slowly in mice, resulting in drug levels up to 300 times higher at 6-8 weeks post-injection than those observed with the older formulation.
The researchers indicated that they are also working on a long-acting nanoparticle formulation of the integrase inhibitor widely approved dolutegravir (Tivicay).
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Translated by Original Claudio Souza in CROI 2017: Several New Candidates in HIV Drug Pipeline Discussed at Conference Written by Liz Highleyman and reviewed by Mara Macedo