There are currently 28 drugs for the treatment of HIV approved by the U.S. Food and Drug Administration (FDA). But there's always room for improvement and more choices. At ICAAC/ICC 2015, Roy Gulick, M.D., provided a look into the antiretroviral therapy pipeline. Many new drugs are in development, both in existing classes and in new classes, but here are the five that are farthest along in clinical development.
The biggest need for a new nucleoside reverse transcriptase inhibitor (NRTI) is less long-term toxicity, Gulick explained. Currently, the drug that is farthest along in development is tenofovir alafenamide (TAF). We've heard a lot of buzz about TAF as studies have continued to show that TAF is non-inferior to tenofovir disoproxil fumarate (TDF, Viread) and has fewer toxicities in the kidneys and bones. The FDA will decide on a new coformulation of elvitegravir/cobicistat/emtricitabine/tenofovir (Stribild) using TAF by early November 2015. The FDA will also decide on a new coformulation of tenofovir/emtricitabine (Truvada) using TAF by early April 2016.
Non-Nucleoside Reverse Transcriptase Inhibitor: Doravirine
The biggest need for a new non-nucleoside reverse transcriptase inhibitor (NNRTI) is less toxicity, better tolerability, activity against viral resistant strains and fewer drug interactions, according to Gulick. Doravirine (DOR) is an investigational NNRTI that has been shown to be potent at low doses, with fewer side effects when compared to efavirenz (Sustiva, Stocrin).
Integrase Inhibitor: Cabotegravir
We're currently in the new era of the integrase inhibitor, but even integrase inhibitors could benefit from having fewer dosing frequencies. Cabotegravir (CAB) is an integrase inhibitor that has a structure similar to dolutegravir; it has a similar resistance profile and is potent at low oral dosages. However, cabotegravir really stands out because of its nanotechnology formulation, which gives it a half-life of 21 to 50 days. This supports monthly or quarterly dosing when cabotegravir is delivered in subcutaneous or intramuscular injections. Studies found that injection site reactions were mild, and this formulation is being studied for both treatment and prevention.
Additionally, oral cabotegravir, when taken with a long-acting form of rilpivirine (Edurant), works as maintenance therapy -- as shown in the LATTE study. This two-drug maintenance regimen could be an option for patients who have achieved undetectable viral loads on other regimens. What's more, the LATTE-2 study is looking into long-acting cabotegravir and long-acting rilpivirine as an injectable two-drug maintenance therapy.
CD4 Attachment Inhibitor: BMS-663068
A CD4+ attachment inhibitor is a new drug class that provides a new mechanism of action against HIV -- which is especially important for patients with multi-drug resistance, Gulick said. HIV's entry into a CD4+ cell is a three-step process: first CD4+ binding (in which the virus recognizes the target CD4+ cell), followed by coreceptor binding (either attaching to CCR5 or CXCR4) and ending with virus-cell fusion. We currently have maraviroc (Selzentry, Celsentri) as a CCR5 antagonist and enfuvirtide (T-20, Fuzeon) as a fusion inhibitor, but we lack a CD4+ attachment inhibitor.
BMS-663068 is being studied as the first CD4+ attachment inhibitor. BMS-663068 is a prodrug of BMS-626529 that inhibits CD4+ binding by itself binding to the gp120 protein on HIV. Early pharmacokinetic data suggests once or twice daily dosing; however, there is a baseline susceptibility in about 12% of patients because of envelope polymorphisms, according to Gulick.
A recent study compared regimens with BMS-663068 to regimens with atazanavir (Reyataz) boosted with ritonavir (Norvir) in treatment-experienced patients. At week 48, 61% to 82% of those taking BMS-663068 achieved an undetectable viral load versus 71% of those in the atazanavir group. Studies are ongoing.
A maturation inhibitor is another new drug class that would provide a new mechanism of action against HIV. After infecting a host cell, HIV creates copies of itself, with the final step being maturation of the new copies. A maturation inhibitor would stop this step.
Years ago, the maturation inhibitor bevirimat was studied as HIV treatment, but up to 50% of patients had baseline polymorphisms, rendering the drug ineffective, Gulick said. A successful maturation inhibitor would have no baseline polymorphisms that confer resistance.
BMS-955176 is a "second-generation" maturation inhibitor that has shown a much better resistance profile than bevirimat. Early study data in humans showed good antiviral activity for BMS-955176 at four different dosage levels. Studies for this drug are also ongoing.
What Else Will Be in the Pipeline?
Just a few years ago, there was some concern that the pipeline may have dried up, but according to Gulick, the pipeline is fuller than ever. Still, new treatment with better potency, fewer toxicities and less-frequent dosing are welcome as we look toward a cure. Moreover, there’s still a great need to reduce inflammation and enhance immune responses; therefore, we look forward to continued progress in drug development.