George Hanna, MD: Islatravir Presentations at CROI 2020

This year the annual Conference on Retroviruses and Opportunistic Infections (CROI 2020) was held in a virtual format due to the developing coronavirus situation. Contagion® spoke to George Hanna, MD, vice president and therapeutic head of infectious diseases at Merck Laboratories to learn more about data being presented on islatravir.

Hanna: One issue, particularly from a pharmaceutical company perspective, is that we feel that HIV continues to be a worldwide threat. This is because the market doesn't have all of the necessary tools to address the unmet medical needs that are out there. At this point, we are poised to develop a molecule called islatravir, or it has been called also MK-8591.

This is a novel and potentially first in class NRTTI or nucleoside reverse transcriptase translocation inhibitor. It has a different mechanism of action against the HIV reverse transcriptase enzyme compared to other drugs that have targeted that enzyme.

We think that with this molecule, and this new mechanism of action that islatravir may serve as the foundation for multiple HIV treatment and prevention strategies in the future. We're happy to present 3 research presentations at CROI on different aspects about HIV.

Islatravir has some pretty unique attributes that we believe are aligned with some of the changing needs of people living with HIV and people at risk of HIV infection. So the novel mechanism of action suggests that could that it has a very potent effect against the virus. In fact, it has about 10 times the potency of other antiretrovirals that are on the market.

It also has a very high barrier to the system. It has a very wide to issue distribution. And it also has a very long half life, which allows us to think about it either as a once a day therapy like other therapies that are available now, but also eventually, as a less frequently given therapy.

It allows us to think about using it in long acting formulations such as an implant that can be inserted and changed perhaps once a year for either prevention of HIV or for treatment.

The first intended islatravir regimen that we're making progress on is a 2 drug, oral antiretroviral regimen, that combined islatravir with our recently introduced NNRTI doravirine. We have a comprehensive phase 3 clinical program that's going to be looking at treatment in treatment naïve, but also in heavily treatment experienced population.

So the first study is an analysis of our phase 2 study of doravirine + islatravir. This study looked at different doses and compared it to doravirine 3TC TDF which was approved in the US about a year and a half ago. In this study, we presented the efficacy data and the safety data during the last IAS meeting.

What's new here is that we looked at some of the metabolic outcomes. During our phase 2 study, when we look at levels of glucose and lipids, those were the changes were modest, and very little compared to baseline in the 1-year study that we're reporting. When we look at bone mineral density, we see that islatravir + doravirine had the lower impact on the hip bone mineral density, then the comparator while the changes in the spine were similar. But most importantly, the change in the weight and the BMI, the body mass index was actually quite similar in the islatravir + doravirine group compared to the control. This was consistent with the average weight getting that we see among the general adult population. So overall, the results from the metabolic analysis were very gratifying and do support moving forward into phase 3.

The second study that we are presenting is looking at how we determine the dose of islatravir to combined with doravirine in the phase 3 program. We have selected the middle dose from that phase 2 study which is a.75 milligram dose to combine with doravirine. The reason we selected it is to make sure that we not only are able to cover wild type virus in people who are initiating therapy, but also that we have a dose that will be able to cover viruses that already have resistance to nucleoside reverse transcriptase inhibitors in patients who are treatment experienced and have previously failed therapy.

[The dose] gives us considerable confidence that we will be able to cover both wild type virus as well as virus with resistance to other antiretrovirals. The next step is to confirm that and 1 of the phase 3 studies looking at heavily treatment experienced patient populations, is designed to really interrogate this.

Finally, the third islatravir-related study looked at the idea of whether islatravir can be given for post-exposure prophylaxis. In the past, we have presented data on animal models that suggests that giving islatravir once a week in rhesus macaque animals prevents them from acquiring HIV. They were then given an infectious dose of simian immunodeficiency virus. We showed what happens if you inject HIV in these animals on day 1, and then subsequently give islatravir for a certain number of weekly doses, does that prevent WIV infection in these animals?

And in fact, the data do suggest that giving islatravir post exposure may allow the prevention of SIV infection. All animals that received at least 2 of the weekly doses after exposure were protected. And in fact, a majority of those who got a single dose after infections were protected. This does suggest that it's a possibility to look at post exposure prophylaxis in human populations in the future.