Islatravir (Merck) is the latest HIV drug to be added to the ever-growing list of antiretrovirals. The drug formerly known as MK-8591 was the subject of one of the most keenly-awaited studies to be presented at the conference. Results showed that an implant containing it, which is inserted under the skin of the upper arm, should provide sustained levels of drug sufficient to prevent HIV infection for over a year.
The drug is being tested for both prevention (PrEP) and for treatment. The status of the long-acting PrEP implant is discussed here.
THE IMPLANT:
Islatravir, formerly called MK-8591, is a new type of reverse transcriptase inhibitor, a nucleoside reverse transcriptase translocation inhibitor (NRTTI). This drug does not just block the transcription of HIV viral RNA into DNA as the older NRTIs, but also locks HIV’s reverse transcriptase enzyme into a conformation where it is more easily degraded by cellular processes. It has major affinity for reverse transcriptase and effectively stops viral replication at blood and intracellular levels 100 times lower than other HIV drugs. With a half-life of as long as seven days, Islatravir could be dosed monthly.
In previous studies of an oral formulation of the drug, a dose of as little as 0.5mg was sufficient to block HIV replication for a week, and oral islatravir is under investigation as an HIV treatment in combination with another daily drug, the recently approved, doravirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI).
A NOVEL DELIVERY SYSTEM
Islatravir has been formulated as an implant, a small plastic insert placed under the skin of the upper arm. The same technology is used for contraceptives, and has been used previously in other antiretrovirals including tenofovir. The implant measures 4cm by 2mm (the size of a spaghetti strand) and is not visible to others when implanted – a benefit for people who may fear being seen taking antiretrovirals. It has the added advantage over long-acting injectable formulations of being removable, so that it can be removed in the event of side-effects. Also, that there is less chance of resistance arising or being transmitted due to drug levels slowly tailing off in the body. According to the research team, once removed, drug decay is similar to the oral dose.
The PrEP implant study announced on July 23, 2019 only evaluated levels of the drug (versus placebo) in two different doses (54mg versus 62mg per implant) given to 16 individuals for a three-month period.
The purpose of the study was to assess the safety and tolerability of the implant, and to estimate the time at which the concentration of intracellular islatravir would fall below 0.05 picomols per million cells, the level previously determined to be the minimum effective level to stop HIV replication.
The higher dose (62mg) produced levels above this threshold in all trial volunteers for the three months the implant was in place, whereas levels fell below this for part of the time in a few people given the lower dose.
Although this was only a three-month study, projections based on the levels of drug seen show that the intracellular concentration of the drug produced by the implant should stay well above the prevention threshold for at least a year, and probably considerably longer.
Nearly all participants said that the implant insertion initially produced some localized internal bleeding and discomfort, and a few complained of inflammation or itching in the implant area, but these side-effects were seen as tolerable by the participants.
This presentation has received a lot of attention. Not because the drug is ready for market, but because it demonstrates, once again, that science will get us to the finish line.
The investigators told the attendees that these initial safety results supported the development potential of the implant as a once-yearly PrEP option. Realistically, this drug is several years down the road; maybe as long as 5 years. The implant needs to be tested in larger numbers of people for a longer time and compared, most likely, to the once a day version of PrEP.
National Institute for Allergy and Infectious Disease Director, Dr. Anthony Fauci, who wasn't involved in the trial, was cautiously optimistic. "If - and I'm emphasizing if - if it pans out in a larger trial that it delivers a level of drug that's protective for a year, that would be a game-changer," he told The New York Times.
Reference:
Matthews RP et al. First-in-human trial of MK-8591-eluting implants demonstrates concentrations suitable for HIV prophylaxis for at least one year. Tenth International AIDS Society Conference on HIV Science, Mexico City, abstract TUAC0401LB, 2019. http://programme.ias2019.org/Abstract/Abstract/4843
7/23/2019 9:32 PM
IAS Mexico City Late-breaker: Once-a-year PrEP Implant in Development
Source: Reporting from Mexico City for PRN News: Bill Valenti, MD