A look at drugs in development for HIV treatment and prevention

Several HIV drugs in development have clinical data showing efficacy when taken only once a month.

One of them has the potential to be taken only once every six months. Another, when used as an implant, has the promise of being taken only once a year for use as HIV prevention (PrEP).

The move towards long-acting medications “underscores the point that with the drugs in development, the approach that less than once-daily dosing, which was once radical, has become the norm among HIV drugs that are currently in development,” said Ethel D. Weld, MD, PhD, Assistant Professor of Medicine at Johns Hopkins University School of Medicine.

Dr. Weld provided an overview of long-acting drugs for HIV treatment and prevention as part of a session on the topic.

“The injectable long-acting combination of cabotegravir long-acting and rilpivirine long-acting has blazed a trail and has established firm proof of concept that long-acting injectable monthly regimens can sustain virologic suppression among people living with HIV with a high degree of acceptability. The results from the ATLAS-2M trial presented at this conference show that a dosing frequency of every two months was non-inferior in efficacy to once monthly,” said Dr. Weld.

“I know from hiking that when you’re blazing a trail and you’re first in line on that trail, you tend to get all the spiderwebs in your face,” she said.

She pointed to an FDA response on December 21, 2019 to ViiV Healthcare and Janssen Pharmaceuticals regarding their long-acting cabotegravir and rilpivirine combination, holding up approval of the dual injectable.

Dr. Weld said the response “is a slight stumbling block that hopefully can be parlayed into a collective step up and boost for the overall long-acting field in terms of anticipating regulatory and manufacturing consistency challenges, which may not be unique in these two compounds.

“GS-6207, the highly potent capsid inhibitor presented here by Eric Daar, has an EC50 in the 50 picomolar range [indicating high potency]. This year clinical data including the first in human studies of a single-dose subcutaneous injection showed efficacy and that concentrations were measurable at out to six months after this injection.

“Islatravir, also a very potent NRTI with translocation inhibition as well as part of its mechanism, has a proposed dosing frequency of once monthly as an oral formulation,” said Dr. Weld. “It is also being explored as an implant primarily for a PrEP option that is once yearly and also as a dual-use implant that combines [with] contraception.”

She listed other compounds as well, in earlier stages of development.

Dr. Weld talked about some of what she called “BIG” ideas in the move towards long-acting HIV therapy.

“I have to say that the first big idea is that non-adherence to daily medication is placed centrally and is accommodated without blame,” she said.

“I hope it’s safe to characterize the big ideas in HIV pharmacology as representing a shift rather than drift. Overall, the development of antiretrovirals, which has been such a win from the discovery of AZT to the evolution of highly potent safer and tolerable oral ART, has been a story of variations on a theme. And the theme has been daily lifelong oral medications. It depends on daily adherence and a provider-focused system of care delivery that people must access, and when people cannot, either temporarily or consistently, a whole different movement rather than variations on the same theme is needed.

“So, I see long-acting approaches, which historically directly improved adherence and therefore efficacy, as forgiving approaches to accommodate unfavorable psychosocial conditions for periods in our lives, logistical and access barriers, and stigma, as well as cover many of the gaps in our care continuum and our cascade with HIV.

“Another big idea is that formulation and delivery innovation can optimize PK [pharmacokinetics], often without requiring a device that needs a separate regulatory pathway of its own. [A specific type of hydrogels] are not particularly inflammatory when injected under the skin and slowly degrade within the body. It can improve the PK of not only small molecules but BNabs [which are large molecules]. Microneedle technology, or microneedle patches, are cones of nanoformulated drug that are solid, poured into a mold, adhere to an occlusive backing, and are self-applied by patients, and results in sustained concentrations of drug even when the patch is removed. [She later explains that this delivery system, as well as others, can be removed in case of adverse reaction or pregnancy.] It requires an every-week re-application and can demonstrate routine levels of antiretrovirals above the therapeutic targets for at least a week on end. Finally, formulation device approaches with regulatory track record can and should be leveraged,” Dr. Weld said. Among such medications currently on the market, she said, are Eligard, ATRIGEL, and Nexplanon (etonogestrel implant).

As the field develops, several questions remain, said Dr. Weld.

“The question of long-acting drugs we have in development—what are their partners? What can we pair them with? Can we pair two highly potent drugs such as islatravir and GS-6207 with each other? How well do the PK profiles need to match? How can we study DDIs [drug-drug interactions] when we’re developing these drugs? Do we need an oral formulation for every single long-acting formulation we develop? For cabotegravir and rilpivirine long-acting, the trailblazing combination, can we re-formulate to reduce volume and reduce injection frequency? Does a long PK tail actually necessarily confer antiretroviral resistance?

“For TAF implants there’s been a local tissue necrosis issue observed in some animal models. So, establishment of first-principles thinking in modeling to predict which molecules and formulations cause local toxicity is needed.

“Implementation is a huge gap,” Dr. Weld noted. Then there’s predicting in whom long-acting ART will be best used and the combination of other preventative and treatment technologies such as contraceptives and antipsychotics and opiate substitution therapy.

In all of the science, lies the excitement of hope.

In her conclusion, Dr. Weld said that, “I see long-acting technologies as technologies for empowerment, and to fully realize that empowerment and the freedom that these technologies can enable, we need to optimize them and maximize their impact by seeking out whom best to use them for.”

Go to croiconference.org to view the presentations. Look for the webcast “Themed Discussion, The Long and Short of It: What’s Next for Long-acting Drugs,” on Wednesday, March 11, 2020.

Long-acting compound in development:

•     cabotegravir long-acting (CAB-LA) with rilpivirine long-acting (RPV-LA), closest to actually being on the market

•     GS-6207 capsid inhibitor

•     dapivirine (DPV) vaginal ring

•     islatravir (NRTTI, first in class), is a nucleoside analogue reverse transcriptase translocation inhibitor NRTTI (first-in-class). Used as an implant for prevention, islatravir has the potential of being taken once a year. Taken orally for prevention or treatment (in combination), there’s the possibility of once-a-week dosing or once-a-month dosing.

Pre-clinical data (not yet tested in human bodies) for:

•     Broadly neutralizing antibodies (bNAbs)

•     dolutegravir ultra-long-acting (DTG ISFI, ULA)

•     tenofovir alafenamide (TAF) implant