Are Long-Acting Injectables the Future of TB Treatment?

Caleb Rans, PharmD

March 10, 2021

Long-acting injectable (LAI) drug formulations represent a promising new strategy for the prevention and treatment of tuberculosis in women and children, according to an online presentation at the Conference on Retroviruses & Opportunistic Infections, held virtually.

"As a delivery strategy, LAIs hold the potential to unlock a vast chemical space of lipophilic compounds with very potent anti-TB activity that would otherwise not be developed due to poor predicted oral bioavailability," explained presenter Eric Nuermberger, MD.

He summarized current preventive treatment options for TB and reviewed the potential impact of LAI formulations on TB therapy. In addition, he identified key challenges for future LAI development and proposed a new development path for clinical implementation.

Current TB Preventive Therapies

Despite widespread availability, the uptake of TB preventive therapy is poor and currently lags behind global targets. One key barrier to widespread uptake is the long duration of treatment, which may hinder patient adherence to therapy.

While shorter preventive regimens, such as 1 month of daily isoniazid plus rifapentine, show similar efficacy and higher completion rates, further shortening of therapy and reducing clinic visits are the most direct methods to increase adherence and treatment completion rates, Nuermberger said.

LAI Drugs

LAI drug formulations allow for slow release of suitable drugs from a depot injected subcutaneously or intramuscularly.

The goal of LAI formulations is to free patients from the daily burden of oral administration. Other potential benefits include better adherence and efficacy, drug exposure, and the potential to overcome intrinsic poor oral bioavailability by bypassing the GI tract entirely.

Potential indications for LAIs include treatment of latent tuberculosis infection (LTBI), and as continuous therapy in people living with HIV in high-burden settings. There is also potential for treating younger children, such as household contacts, who have difficulty taking oral medications.

"We've already seen LAIs revolutionize other areas, such as psychiatry and contraception, and we appear to have another revolution in HIV prevention and treatment," Nuermberger explained.

Not all existing TB drugs are suitable for LAI formulations, but drugs such as rifapentine, rifabutin, delamanid, and bedaquiline, show more promise than isoniazid or rifampin because of their physiochemical composition. Of all, bedaquiline may offer the best profile for LAI formulation, Nuermberger said.

Early proof-of-concept in vivo studies have shown potential use of LAI bedaquiline for TB prevention in both drug-sensitive and drug-resistant TB contacts. Translational PK modeling and simulation predicted that a 1-g intramuscular injection of LAI bedaquiline could maintain therapeutic plasma concentrations in humans for greater than 1 month.

Nuermberger noted that novel diarylquinoline-based therapies, currently in phase 1 studies, may be even better candidates for LAI-based TB preventive therapy. Early data suggests these compounds may be 10-20 times more potent and have a lower CV risk profile than that of bedaquiline.

Considerations for Development and Implementation

"Despite the promising potential of long-acting injectables for TB, we are still in the very early stages," said Nuermberger.

Ensuring and optimizing acceptance of LAI formulations, especially in at-risk populations, will be very important, he explained. Early involvement of children and pregnant women in studies of who may benefit most from LAI drugs will also be essential.

Other important considerations include cost-effectiveness, particularly in at-risk and vulnerable populations. Furthermore, new dedicated research and development programs are needed to continue to develop more drug candidates suitable for LAI.

"Long-acting formulations hold enormous promise to be transformative for combating TB, through simplification of delivery and overcoming issues of adherence that can compromise success of current interventions," said Andrew Owen, PhD, of the University of Liverpool (England).

"The ability to deliver an entire course of drug in a single visit promises to ensure missed doses don't compromise outcomes or place unnecessary selective pressure in favor of drug resistance," Owen said.

"Recent studies showing the value of one-month oral treatment regimens for LTBI make long-acting formulations seem more realistic and drugs such as long-acting bedaquiline put a one-shot regimen within reach," Charles W. Flexner, MD, of Johns Hopkins University, Baltimore, said in an interview.

While no LAIs have been approved for TB, Nuermberger was optimistic that the recent success of LAI formulations for HIV treatment and prevention will catalyze further efforts in the TB landscape.

Nuermberger disclosed research support from Janssen Pharmaceuticals, TB Alliance, and the Gates Medical Research Institute. The presentation was sponsored by Janssen Pharmaceuticals, Johns Hopkins CFAR, NIH, Unitaid, and the TB Alliance.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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