A look at new drugs in development
Positively Aware Tim Horn
By Tim Horn @TAGTeam_Tweets

Nearly 20 years after combination antiretroviral therapy became the standard of care throughout the world for the long-term management of HIV, it’s safe to say there’s no shortage of highly effective options for people living with the virus, particularly those starting HIV treatment for the first time. However, there is still a need for new agents, particularly those that further improve tolerability, simplify dosing, and are active against drug-resistant strains of the virus.

There are a number of intriguing compounds making their way down the HIV drug development pipeline. Here we provide a snapshot of experimental agents, in Phase 2 or 3 stages of evaluation, to keep an eye on.

Tenofovir alafenamide fumarate (TAF)
Class: Nucleotide Reverse Transcriptase Inhibitor
Company: Gilead Sciences
Status: Phase 3

Because TAF is converted to tenofovir differently from its long-standing predecessor tenofovir disoproxil fumarate (TDF)—the active ingredient in Viread and a key component of Atripla, Stribild, Complera, and Truvada—there are higher concentrations where the drug is needed (CD4 cells) and much lower circulating in the bloodstream. This likely means improved bone and kidney safety and possible efficacy against strains of HIV at least partially resistant to TDF. It will first be approved as a component of a revamped version of Stribild. It will also be a feature of a cobicistat-boosted darunavir (Prezista) single-tablet regimen (STR) and will replace TDF in newer versions of Complera and Truvada.

Doravirine
Class: Non-Nucleoside Reverse Transcriptase Inhibitor
Company: Merck
Status: Phase 3

Doravirine is a once-daily non-nuke primarily being studied in first-time treatment takers, but with suggested activity against HIV with mutations that confer resistance to current options in this drug class. A Phase 3 clinical trial comparing 100 mg doravirine to ritonavir-boosted darunavir, combined with either Truvada or Epzicom, was started in late 2014. Merck is also developing a single-tablet regimen that combines doravirine with generic tenofovir DF and lamivudine.

BMS-663068
Class: Attachment Inhibitor
Company: Bristol-Myers Squibb
Status: Phase 3

Unlike the cumbersome injectable attachment inhibitor Fuzeon (enfuvirtide), BMS-068 can be taken orally. Because attachment inhibitors are a very useful class of drugs for HIV-positive individuals with a lot of antiretroviral therapy experience under their belts, community activists are pleased with BMS’s decision to focus on getting this drug approved for those in need of novel therapies. A Phase 3 trial is starting soon.

Cenicriviroc
Class: CCR5 Antagonist
Company: Tobira
Status: Phase 2/3

Like ViiV’s Selzentry (maraviroc), cenicriviroc blocks HIV targeting the CCR5 co-receptor on CD4 cells, but not HIV targeting the CXCR4 co-receptor (which tends to emerge some years after HIV first establishes infection). Unlike Selzentry, it also targets CCR2, a co-receptor believed to be associated with inflammation. Whether this translates into health benefits, such as a reduced risk of cardiovascular disease or cancer, has yet to be determined. Development of this drug has been slow, but plans for Phase 3 clinical trials have been discussed. Cenicriviroc will also be studied in a fixed-dose combination with generic lamivudine and, possibly, an STR that includes a third drug.

Once-daily raltegravir
Class: Integrase Inhibitor
Company: Merck
Status: Phase 2/3

Raltegravir (Isentress) was the first approved integrase inhibitor. Though it’s very effective and well tolerated, it needs to be taken twice a day—a deterrent for some people. Merck is currently developing a once-daily formulation to help broaden its acceptability and appeal.

Long-acting cabotegravir
Class: Integrase Inhibitor
Company: ViiV Healthcare
Status: Phase 2

In tablet form, cabotegravir is very similar to its predecessor Tivicay (dolutegravir). It’s the injectable form that is garnering a lot of attention. This long-acting formulation of the drug is being studied in combination with an injectable version of the non-nuke rilpivirine (see below) for once-monthly administration as maintenance therapy, to be initiated after a standard combination of oral drugs suppresses viral load to undetectable. It’s an excitingly novel approach to long-term treatment, though there’s much more to be learned about its safety, efficacy, and acceptability. Because the injections are intramuscular and will require a high volume of drug that likely needs to be administered by a health care provider every month, it’s unclear for whom this will be preferable, compared with oral daily dosing. It’s also being studied as pre-exposure prophylaxis (PrEP), with injections likely to be administered once every two or three months.

Long-acting rilpivirine
Class: Non-Nucleoside Reverse Transcriptase Inhibitor
Company: Janssen Pharmaceuticals
Status: Phase 2

Approved for once-daily oral dosing as Edurant and as a component of the single-tablet regimen Complera, rilpivirine is back in the drug development pipeline in the form of a long-acting injectable formulation. In clinical trials, it’s being paired with long-acting cabotegravir (see above) as a component of two-drug maintenance therapy. It’s also being studied as long-acting PrEP.

BMS-955176
Class: Maturation Inhibitor
Company: Bristol-Myers Squibb
Status: Phase 2

Maturation inhibitors act during the final stages of HIV’s life cycle; they bind to a protein called gag, which helps prevent the formation of virus capable of infecting other cells. Another company’s previous candidate, bevirimat, didn’t get very far—
it didn’t work well against HIV resistant to protease inhibitors—but there are high hopes for BMS’s lead contender. It is set to be evaluated in studies involving first-time treatment takers and treatment-experienced folks. Fixed-dose combinations and single-tablet regimens are also
in the works.

Apricitabine
Class: Nucleoside Reverse Transcriptase Inhibitor
Company: Avexa Ltd.
Status: Phase 2

This Epivir (lamivudine)-like molecule has been stalled since a Phase 3 study was halted in 2009. The drug may have a potential role for those with multiclass-resistant HIV—data supporting this hypothesis are limited—and another Phase 3 study is planned to confirm this. The company has also announced that apricitabine is available through an early access program for people in need of additional options.

Ibalizumab

Class: CD4 Antagonist

Company: TaiMed Biologics

Status: Phase 2

Ibalizumab, a monoclonal antibody that blocks HIV attachment to the CD4 receptor on T-cells, has been slow to develop and has passed through various companies over the years. Its potential for subcutaneous injections administered every few weeks is still being explored. Though no Phase 3 studies have been announced, ibalizumab is to be rapidly reviewed as an “orphan drug” by the FDA—the first HIV medication to do so—given its limited potential (people with multi-class-resistant HIV). The older intravenous formulation of the agent is available on a case-by-case basis through an FDA treatment IND (investigational new drug) approval process.

PRO 140
Class: CCR5 Antagonist
Company: Progenics
Status: Phase 2

Like the monoclonal antibody ibalizumab, PRO 140 has been slow going in the HIV drug development pipeline. A dose optimization study is now underway, as is a small clinical trial evaluating once-weekly injections of the drug as maintenance therapy following viral load suppression with a standard oral combination of drugs. A third trial, evaluating the added benefit of PRO 140 when combined with approved antiretrovirals in injection drug users experiencing viral load rebounds or adherence difficulties, is planned.