Merck‘s MK-8591 has considerable potential to become the first HIV drug that could be taken as an oral pill weekly, either as treatment or PrEP, according to two studies.
MK-8591 or EFdA is a novel and exceptionally long-lasting and potent HIV drug, being developed by Merck. It is a nucleoside reverse transcriptase translocation inhibitor (NRTTI). Its potency and longevity are due to the fact that it acts at two stages of the HIV lifecycle: as well as blocking HIV from making a DNA copy of its genes that can be inserted into a human cell, it also blocks integrated HIV DNA inside cells from being turned back into viruses.
It also does not get degraded easily by the bodily enzymes that digest molecules: this means its half-life in humans (the time taken for half the drug to leave the body) is 50-60 hours and 120 hours (five days) inside cells. This means it is suitable for weekly dosing.
At last year’s Conference on Retroviruses and Opportunistic Infections (CROI), studies showed that a single dose of MK-8591 of as little as 0.5mg produced HIV viral load drops of at least tenfold in HIV-positive human volunteers (For comparison the daily dose of rilpivirine, one of the most potent current HIV drugs, is 25mg.) In another study, when used as pre-exposure prophyalxis (PrEP), a weekly dose of 4.3 milligrams per kilogram (mg/kg) fully protected a group of eight rhesus macaque monkeys from infection. However, it now looks as if the effective dose of MK-8591 could be even lower than this, especially for PrEP.
Martin Markowitz of New York’s Aaron Diamond AIDS Research Centre told CROI 2018 that the protection against HIV seen when the original dose was used last year was equivalent to a 41-fold reduction in HIV, in other words about a 97.6% efficacy in reducing SHIV (monkey HIV) infection. In that study, no infections were seen after the monkeys were given 14 oral doses of MK-8591 and challenged with 12 rectal doses of virus. After 24 weeks no monkeys given MK-8591 PrEP were infected while all the animals given placebo were infected within five weeks.
The drug levels seen in the monkeys in last year’s study were sufficiently high for the researchers to wonder if a lower dose would also work. The eight rhesus macaques that had received MK-8591 in that study were therefore given six weekly doses of one-third the original amount of drug (1.3 mg/kg) and challenged four times with SHIV. None were infected.
The experiment was again repeated with 0.43 mg/kg (one-ninth the original dose) and again none were infected.
The dose was reduced still further, to 0.1mg/kg or one-fortieth the original dose. At this dose, two out of the eight monkeys became infected with SHIV, one after three challenges and one after four. The other six remained uninfected. Compared with placebo, this represents an efficacy in reducing HIV infections of 86%.
Finally, the experiment was repeated on the remaining uninfected six monkeys using just 0.025mg/kg and four of them became infected, a result statistically no different from zero efficacy.
If these doses are scaled up to humans they are extraordinarily small. In humans, MK-8591 accumulates in tissues more efficiently than monkeys, and its half-life is longer. Markowitz, therefore, predicted that MK-8591 levels protective against HIV could be achieved in humans at weekly doses of less than 250 micrograms weekly or 10 micrograms daily, suggesting that MK-8591 has considerable potential to be used as extended-dose PrEP against HIV infection.
In another presentation, Merck’s Randolph Matthews said that drug levels measured in human volunteers given daily doses of MK-8591 showed that half the dose used in the initial single-dose safety study presented last year would be more than adequate to suppress HIV as part of a combination antiretroviral therapy.
In a study in which three groups of 12 HIV-negative volunteers were given three different doses of the drug, the lowest drug concentration seen in a volunteer given the lowest dose, 0.25mg, 24 hours after the drug was taken, was well above the lowest dose likely to be therapeutic against HIV, and levels seen in cells after three weeks of steady dosing were eight times that level. Furthermore, when the drug was stopped, its level in cells remained above the therapeutic level for 30 days after the last dose.
Levels of the drug seen in rectal tissue biopsies were similar to, or above, the protective level of tenofovir seen in patients given PrEP at the 0.25mg (250 micrograms) dose and although no vaginal biopsies were done in female volunteers taking that dose, they were above protective concentrations in women give the second-lowest 0.5mg dose.
In short, MK-8591 has considerable potential to become the first HIV drug that could be taken as an oral pill weekly, either as treatment or PrEP.
Matthews said that Merck is currently investigating MK-8591 in combination with another new drug, the non-nucleoside reverse transcriptase inhibitor (NNRTI) doravirine, in dose-finding studies in people with HIV.
MK-8591 (4′-ethynyl-2-fluoro-deoxyadenosine; EFdA), a nucleoside reverse transcriptase translocation inhibitor (NRTTI), was previously shown to completely protect rhesus macaques (RM) against SHIV infection following intrarectal (IR) challenge when dosed at 3.9 mg/kg weekly. At this dose, the mean intracellular MK-8591-triphosphate (TP) concentration of 805 fmol/10Λ6 PBMCs at time of challenge exceeds the lowest MK-8591-TP C168hr that demonstrated potent antiviral activity in HIV infected patients. To determine the lowest drug levels that confer protection, RMs were challenged at progressively lower doses until protection was no longer observed.
The eight male RM that had been successfully treated with 3.9 mg/kg MK-8591 after 20 weeks (w) were dosed with 1.3 mg/kg MK-8591 orally on day 0 and qw for 6 doses. All animals were again challenged IR with 1 mL of 50TCID50 of SHIVC109P3 on day 6 and weekly thereafter for up to 4 challenges or until infection was confirmed. Prior to challenge, blood was drawn for virology and PK. Infection was confirmed by real-time RT PCR in plasma. Proviral DNA was measured qw by PCR and virus-specific antibody responses were assessed. Intracellular levels of MK-8591- TP were measured by LC/MS/MS. After a 4 w washout, the treatment sequence was repeated on uninfected RM, (0.43 mg/kg weekly for 6 doses) with challenge on day 6 and weekly for up to 4 challenges or until infection was confirmed. After 10 w, this was repeated on the remaining uninfected RM at a dose of 0.1 mg/kg.
All 8 animals remained uninfected after challenges at the 1.3 & 0.43 mg/kg dosing levels. At 0.1 mg/kg, 2/8 animals became infected, with one animal infected after 3 challenges and the other after 4 challenges. Mean levels of intracellular MK-8591-TP at the time of challenge were 282 and 102 fmol/10Λ6 PBMCs at the 1.3 and 0.43 mg/kg dosing levels, respectively. At the 0.1 mg/kg dose MK-8591-TP levels are estimated to be ~24 fmol/10Λ6 PBMCs.
In rhesus macaques MK-8591 completely protects against SHIV infection at weekly doses of 1.3 and 0.43 mg/kg and is partially protective at 0.1 mg/kg (HR 7.2, p=0.0004). MK-8591-TP levels that are protective in this model are achievable in humans at weekly doses of less than 250 μg weekly or 10 μg daily, suggesting MK-8591 utility in extended duration prophylaxis against HIV infection.
Martin Markowitz, Agegnehu Gettie, Leslie St. Bernard, Hiroshi Mohri, Brooke Grasperge, James Blanchard2, Li Sun, Kerry Fillgrove, Daria Hazuda, Jay Grobler
MK-8591 is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) in clinical development for the treatment of HIV-1 infection. MK-8591-triphosphate (MK-8591-TP), the active phosphorylated anabolite of MK-8591, exhibits a half-life of ~78-128 hours in human peripheral blood mononuclear cell (PBMCs). MK-8591 has been assessed in a monotherapy pharmacodynamic (PD) trial in treatment-naïve HIV-1-infected subjects, where single oral doses of MK-8591 from 0.5 mg – 30 mg demonstrated robust viral load lowering after 7-10 days. Here we present pharmacokinetic (PK) data from a clinical trial examining daily administration of MK-8591 in healthy subjects, and the relationship of these data with data from the antiviral efficacy trial in HIV-1 infected subjects.
In a double-blind, placebo-controlled, three-panel trial, healthy subjects were administered daily placebo or MK-8591 at 5 mg for six weeks, 0.25 mg for four weeks, or 0.75 mg for four weeks (12 active and 4 placebo in each panel). Blood samples were collected for MK-8591 and PBMC MK-8591-TP PK at prespecified times. Vaginal (5 mg, 0.75 mg) or rectal (all three dose levels) biopsies were performed in a subset of subjects to obtain tissue for PK analysis.
All doses were generally well tolerated, with a limited number of mild/moderate adverse experiences reported. Intracellular concentrations of MK-8591-TP that exceeded the EC50 were noted following the first dose of 0.25 mg MK-8591. After 2-3 weeks of dosing, steady-state levels of intracellular MK-8591-TP exceeded 1.0 pmol/million cells on average, comparable to levels seen after dosing 10 mg weekly. In the limited assessment of tissue PK, steady-state levels of active MK-8591-TP at all examined dose levels were comparable to reported levels of tenofovir diphosphate observed in rectal tissue following single doses of emtricitabine/tenofovir.
MK-8591 would be expected to lead to HIV suppression after multiple daily doses as low as 0.25 mg.
Randolph P Matthews, Deanne J Rudd, Vanessa Levine, Sandra Zhang, Laura Sterling, Jay Grobler, Ryan Vargo, S Aubrey Stoch, Marian Iwamoto