Small Molecule Long-Acting Injectables (LAIs) Leading to a Paradigm Shift in HIV Treatment and Prophylaxis

In this highlight, Dr. Dennis C. Koester reviews treatment options for HIV and explains how small molecule long-acting injectables (LAIs) are offering significant promise in both HIV treatment and prophylaxis.

A Coming Paradigm Shift for HIV Treatment and Prophylaxis

By Dennis C. Koester

The surge of the coronavirus pandemic has made our society increasingly aware of the threats posed by viral diseases. One of the most terrifying viral infections is HIV leading to AIDS. While the HIV epidemic can be considered under control thanks to small molecules (combined anti-retroviral therapy or cART), a definitive cure for the disease remains elusive. The WHO estimates that 37.7 million people live with HIV, with 1.5 million new infections per year and 680,000 annual deaths due to HIV.

In this highlight we explain why emerging small molecule LAIs may bring about a paradigm shift in HIV treatment, discussing:

  • The current standard of care for HIV treatment
  • The problem of drug resistance
  • Why emerging small molecule LAIs such as cabotegravir and lenacapavir are promising

Standard of Care for Treating HIV

The current standard of care for HIV treatment is daily, oral antiretroviral combination therapy, consisting of two nucleoside reverse transcriptase inhibitors (NRTI) (e.g. emtricitabine/tenofovir (Truvada) or lamivudine or abacavir) combined with either a non-nucleoside reverse transcriptase inhibitor (NNRTI) (e.g. efavirenz or rilpivirine), a protease inhibitor (PI) (e.g. ritonavir, lopinavir or darunavir), or an integrase strand transfer inhibitor (INSTI) (e.g. dolutegravir, bictegravir, cabotegravir).

While reverse transcriptase and protease inhibitors have been around for decades, HIV integrase was only clinically validated in 2007 with the first INSTI raltegravir. HIV integrase was found to be an attractive target because it has no mammalian counterpart. The US FDA has since approved four next generation INSTIs:

HIV Integrase strand Transfer Inhibitors (INSTIs)
raltegavir (2007)
elvitegravir (2012)
dolutegravir (2013)
bictegravir (BIC) (2018)
cabotegravir (2021)

HIV Drug Resistance is a Significant Problem

The risk of drug resistance is one of the reasons that there are more than 40 treatment options for HIV patients today. HIV has an extremely high mutation rate of 4.7 * 10-3 per base per cell. This is the highest reported mutation rate of any biological entity, making it easier for HIV to become drug resistant. For this reason, HIV therapy is performed with drug combinations leveraging multiple independent antiviral mechanisms.

Because it is not currently possible to eradicate the HIV virus with drugs, HIV remains a chronic disease, with patients needing to take medication daily for their entire lives. This frequent dosing puts a heavy burden on the patient and leads to adherence challenges. Low adherence exacerbates the problem of drug resistance by allowing the virus to adapt to certain medications.

In the absence of a cure, the drug discovery community has thought about how to address the challenge of drug resistance and low adherence. An emerging solution is treatment with small-molecule long acting injectables (LAIs). They allow for less frequent dosing through sustained release and activity of enough drug to suppress the virus. Durable efficacy of antivirals typically requires drugs to maintain exposures covering the protein-binding adjusted EC95 concentration.

The principle is depicted in the following concentration-time curve. For a therapy with daily oral dosing, forgotten doses and variability in PK lead to the risk of reaching concentrations below the efficacious concentration of the medication. This in turn leads to a higher risk for drug resistance as well as an ineffective therapeutic effect.

Daily Oral vs. Monthly Injectable Dosing for HIV

An injectable with lower dosing frequency and a sustained release over a long period of time leads to a fully effective therapy and a lower risk to generate viral resistance against the medication. Slow release and prolonged activity of compounds at the efficacious concentration for a long time, though technically difficult to achieve, would present an ideal mechanism for the management and prevention of HIV.

Treatment and Prophylaxis with Small Molecule LAIs

There have been several recent breakthroughs in making long-acting injectable HIV treatments a reality. The INSTI cabotegravir, which was FDA-approved in Jan. 2021, is a landmark in this area. The approval covered an oral combination (Vocabria) consisting of cabotegravir with rilpivirine, a NNRTI, and the same combination as a once monthly injectable under the brand name Cabenuva.

The oral regimen (30 mg of cabotegravir and 25 mg of rilpivirine once daily for one month) is used as a lead-in for the injectable to ensure drug tolerability prior to prolonged treatment. If the treatment is successful in keeping HIV in check and is well tolerated, the lead-in period is followed by an injection of cabotegravir in combination with rilpivirine (600 mg and 900 mg, respectively, on the last day of oral lead-in, followed by 400 mg and 600 mg, respectively, every month thereafter). So far the treatment has been well tolerated and very well received. In fact, it was so successful that the FDA approved dosing Cabenuva every two months as recently as Feb. 2022.

Not only have LAIs been successfully used for the treatment of HIV patients, but they have also made an enormous impact on HIV prevention for people at high risk of contracting HIV, such as partners of HIV positive individuals. In Dec. 2021, the FDA approved Apretude, a single drug injectable form of cabotegravir, for pre-exposure prophylaxis (PrEP). Considering the substantial amount of new infections every year, prophylaxis is an effective way of preventing HIV infections in the absence of a vaccine.

Cabotegravir containing LAIs are just the beginning of this revolution in the HIV field.

Small Molecule of the Year

Lenacapavir, Drug Hunter’s 2020 Molecule of the Year, has the potential to re-write HIV history. This compound introduces an unprecedented MoA, HIV capsid inhibition, to the field. In Feb. 2022, a positive read-out on the Phase II/III CAPELLA trial for a once every six-month subcutaneous injection for patients suffering from multi-drug resistant HIV made waves through the HIV community. Considering the fact that HIV therapy typically consists of a combination of at least two different MoAs, monotherapy with an LAI twice per year marks a real revolution on how multi-drug resistant HIV is treated. The multi-stage activity of lenacapavir as well as the lack of cross resistance to existing treatment options set lenacapavir apart from other HIV drugs. Lenacapavir is currently primarily used in individuals that experienced treatment failures with established drugs and has not yet obtained FDA approval at the time of this writing.

It is really good to see the progress that we have made on keeping HIV/AIDS in check over the past couple of years. Three cases of HIV cure have been reported by stem cell transplant. This is certainly not an option for all HIV patient and remains a risky and invasive medical procedure. I am hopeful that we will witness a more sustainable cure of this terrifying disease by the end of this decade. Let’s discover it together!

About Dennis C. Koester

Dennis is a drug hunter at the Novartis Institutes for Biomedical Research (NIBR) in Emeryville, CA. His experience as a medicinal chemist spans across property-driven as well as target-based drug discovery programs in infectious and tropical diseases. Recently, Dennis helped advance programs on Chagas disease and Malaria as a project team leader. He is driven by contributing to disease areas with extremely high unmet medical need. Dennis obtained his PhD in Organic Chemistry from the University of Göttingen in 2013 specializing in carbohydrate chemistry and transition-metal catalysis. He worked at the University of Kyoto in 2011 and at the University of Münster in 2013. Before starting his career in Global Drug Discovery at Novartis in 2015, he conducted postdoctoral research at Stanford. Dennis had outstanding mentors throughout his career and was fortunate to be a Kekule fellow, a fellow of the Alexander von Humboldt foundation, the Japanese Society for the Promotion of Science (JSPS), and the Studienstiftung des deutschen Volkes.  

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