The Conference on Retroviruses and Opportunistic Infections this year (CROI 2017) held last month in Seattle, included presentations on several new antiretroviral drugs in development, reflecting a more robust pipeline than we have seen in recent years.
Although modern antiretroviral therapy (ART) is highly effective and well tolerated by most people living with HIV have more available drugs that work in different ways, it offers more options for the development of optimal schemes.
Some of the experimental agents discussed at CROI represent new classes of drugs that work differently from existing antiretroviral drugs, including capsid inhibitors (opens in another tab, in another site, in Portuguese) in initial studies and Monoclonal antibodies (Opens in wikipedia) now in human trials late phase.
Other presentations focused on next-generation candidates in family antiretroviral classes. Since the widely used medicines are very effective for the treatment of HIV, researchers are seeking incremental benefits in the areas of greater tolerability and convenience - as long-acting drugs - as well as new options for pre-exposure prophylaxis or PrEP HIV.
reverse transcriptase inhibitors nucleoside / nucleotide inhibitors (NRTIs) adding a defective function building block, ending the DNA strand when the reverse transcriptase enzyme of HIV attempts to copy viral genetic material.
Kirsten White, Gilead Sciences, presented results of GS-9131, an NRTI that works against HIV with resistance to other drugs in this class.
GS-9131 is a prodrug analogue GS-9148 adenosine nucleotides. Tenofovir disoproxil fumarate Gilead alafenamida and tenofovir are also analogues of adenosine nucleotides; All other approved NRTIs are nucleoside analogs, which require an additional processing step to become active.
The GS-9131 is converted to the GS-9148 active diphosphate in lymphocytes. It seems to have a low potential for mitochondrial toxicity and minimal accumulation in kidneys, which is a disadvantage of tenofovir.
In laboratory cultures of cells, the GS-9131 showed a potent activity against all major subtypes of HIV-1 (A, B, C, D, E, F, group O and N) and against HIV-2. The power was not affected by NRTI resistance mutations including K65R, M184V, multiple analog mutations of thymidine or will insert T69. I had a high barrier resistance with multiple mutations required to impart reduced susceptibility. It has been demonstrated additive to synergistic activity, and so far no drug interactions with several other antiretrovirals.
"The GS-9131 is an attractive candidate for a daily dosage in combination with other antiretroviral drugs in patients with resistance to NRTIs and limited treatment options," the researchers concluded.
A pair of studies examined the MK-8591 Merck EFDA also known as a reverse transcriptase inhibitor translocation long-acting nucleoside which binds to the active site of the polymerase HIV reverse transcriptase.
The research presented at CROI last year showed that MK-8591 was highly potent in animal studies and humans. A single oral dose produced intracellular drug concentrations desired for more than a week and an injectable formulation of prolonged action can maintain effective drug levels over six months.
Jay Grobler Merck reported that MK-8591 reached high concentrations in lymphoid tissue in mice, suggesting the potential to combat HIV replication in lymph nodes. The drug also showed good distribution for rectal and vaginal tissues in monkeys, shedding light on their potential suitability for PrEP.
"The levels of MK-8591- [triphosphate] achieved in the rectal and vaginal tissue are comparable to the levels of tenofovir diphosphate observed in the rectal tissue of humans treated with tenofovir disoproxil fumarate [TDF]," the researchers concluded. "Given the significantly greater power MK-8591 (IC50 = 0,2 nM) compared to TDF (IC50 = 73 nM), these data suggest MK-8591 useful for prophylaxis in men and women."
In a separate study, researchers showed that Merck MK-8591 is also a highly potent inhibitor of HIV-2. The drug is about five times more active against HIV-2 than against HIV-1 and the virus with certain antiretroviral resistance mutations was considered "hypersensitive" to MK-8591.
Robert Murphy of Northwestern University and colleagues presented findings on a new non-nucleoside reverse transcriptase inhibitor (NNRTI), Elsulfavirine or VM1500A, being developed by San Diego-based Viriom.
After the initial promising studies, an oral dose of 20 mg once a day Elsulfavirine Elpida prodrug was selected for further study. The drug appears to have a potential of prolonged action, with a half-life of approximately eight days.
The researchers conducted a clinical trial phase 2b comparing once daily Elpida versus efavirenz (Sustiva), both with tenofovir DF / emtricitabine (the drugs in Truvada) in 120 people with HIV, previously untreated.
At week of therapy 48, 81% of Elpida receptors and 74% of efavirenz recipients had HIV RNA <50 copies / ml. Among participants with baseline viral load above 100.000 copies / ml, response rates were 78 68% and, respectively. No receiver suffered virologic failure, defined as two consecutive viral loads above 400 copies / ml.
Adverse events related to the drug were about more frequent half the Elpida group compared to the group with efavirenz (37% vs 78%, respectively), and only one Elpida receiver discontinued early due to adverse events compared to seven in group with efavirenz. The same is observed for side effects of the central nervous system (27 50% vs%, respectively).
"This 48 week study showed virological and immunological efficacy equivalent of ART regimens including Elpida or efavirenz in patients infected with HIV-uninfected 1 with HAART," the researchers concluded. "Elpida was significantly safer than efavirenz-based therapy, offering a better tolerated alternative to treatment with efavirenz."
Based on these findings, the Viriom is now testing formulations of Elsulfavirine injected once a week orally and longer-acting, and coformulações, according to a press release from the company.
Turning to HIV protease inhibitors, John link Gilead findings presented on GS-PI1, a new protease inhibitor with potential for oral dosing once a day unreinforced.
Although Gilead dominate the market of anti-HIV drugs in general, does not have an approved protease inhibitor. Existing protease inhibitors should be used with a drug-enhancer or booster, which increases the likelihood of interactions with other drugs.
GS-PI1 shown potent activity against HIV in laboratory cell cultures. He had greater activity against resistant virus than atazanavir (Reyataz) or darunavir (Prezista). We had a high resistance barrier in vitro. GS-PI1 showed good oral bioavailability and half-life 13-14 hours in rats and dogs.
GS-PI1 "represents a new generation of HIV protease inhibitors with potential for combination in a single pill," the researchers concluded.
Finally, looking to the integrase inhibitors, researchers presented data on a new formulation of long-lasting cabotegravir using nanoparticles.
As previously reported, the injectable long-acting cabotegravir more rilpivirine given once every four to eight weeks maintained viral suppression at week 48 in people who switched ART standard schemes with an undetectable viral load. Injectable Cabotegravir 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 two months instead of every three.
The new formulation of cabotegravir called NMCAB, administers the drug into tiny particles designed to release it more slowly. In laboratory cell cultures, NMCAB was efficiently absorbed by the macrophages, with slow release sustained over 30 days. Showed antiretroviral activity sustained for up to 30 days - better than the older formulation of injectable cabotegravir. The NMCAB was eliminated more slowly in mice, resulting in drug levels to 300 times higher than six to eight weeks after injection than that observed with earlier formulation.
The researchers indicated that they are also working on a formulation of long-acting nanoparticles widely used integrase inhibitor approved dolutegravir (Tivicay).
Published: 15 March 2017